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Resistance Hypertension: Renal Artery Intervention using Stenting

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED 2/4/2014

Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis

Christopher J. Cooper, M.D., Timothy P. Murphy, M.D., Donald E. Cutlip, M.D., Kenneth Jamerson, M.D., William Henrich, M.D., Diane M. Reid, M.D., David J. Cohen, M.D., Alan H. Matsumoto, M.D., Michael Steffes, M.D., Michael R. Jaff, D.O., Martin R. Prince, M.D., Ph.D., Eldrin F. Lewis, M.D., Katherine R. Tuttle, M.D., Joseph I. Shapiro, M.D., M.P.H., John H. Rundback, M.D., Joseph M. Massaro, Ph.D., Ralph B. D’Agostino, Sr., Ph.D., and Lance D. Dworkin, M.D. for the CORAL Investigators

N Engl J Med 2014; 370:13-22 January 2, 2014DOI: 10.1056/NEJMoa1310753

BACKGROUND

Atherosclerotic renal-artery stenosis is a common problem in the elderly. Despite two randomized trials that did not show a benefit of renal-artery stenting with respect to kidney function, the usefulness of stenting for the prevention of major adverse renal and cardiovascular events is uncertain.

METHODS

We randomly assigned 947 participants who had atherosclerotic renal-artery stenosis and either systolic hypertension while taking two or more antihypertensive drugs or chronic kidney disease to medical therapy plus renal-artery stenting or medical therapy alone. Participants were followed for the occurrence of adverse cardiovascular and renal events (a composite end point of death from cardiovascular or renal causes, myocardial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy).

RESULTS

Over a median follow-up period of 43 months (interquartile range, 31 to 55), the rate of the primary composite end point did not differ significantly between participants who underwent stenting in addition to receiving medical therapy and those who received medical therapy alone (35.1% and 35.8%, respectively; hazard ratio with stenting, 0.94; 95% confidence interval [CI], 0.76 to 1.17; P=0.58). There were also no significant differences between the treatment groups in the rates of the individual components of the primary end point or in all-cause mortality. During follow-up, there was a consistent modest difference in systolic blood pressure favoring the stent group (−2.3 mm Hg; 95% CI, −4.4 to −0.2; P=0.03).

CONCLUSIONS

Renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease. (Funded by the National Heart, Lung and Blood Institute and others; ClinicalTrials.gov number, NCT00081731.)

SOURCE

http://www.nejm.org/doi/full/10.1056/NEJMoa1310753

based on

What Do CORAL and ERASE Mean for Peripheral Intervention?

Seth Bilazarian, MD, Mark A. Creager, MD

November 27, 2013

Seth Bilazarian, MD: Hi. I’m Seth Bilazarian from the heart.org on Medscape. I’m here at the American Heart Association Scientific Sessions in Dallas with Dr. Mark Creager, Director of Vascular Medicine at Brigham and Women’s Hospital in Boston. Dr. Creager was the moderator of a session enriched with peripheral vascular disease topics yesterday. And I’m fortunate to be with him to unpack 2 of those studies: the ERASE study,[1] a study of peripheral artery disease in the lower extremities and exercise; and the CORAL study,[2] a study of renal artery intervention using stenting.

As a practicing endovascular medicine physician, I’m excited to get Dr. Creager’s take on this. The CORAL study, to start with, was a study that was sponsored by the NHLBI (National Heart, Lung, and Blood Institute), -looking at patients who had greater than 60% stenosis who had resistant hypertension or renal insufficiency and were optimally treated with medical therapy. The patients were given free antihypertensive therapies and statin therapy. And that alone was compared with medical therapy plus renal artery intervention with stenting.

Dr. Creager, can you summarize the take-home message and the results for our audience?

Mark A. Creager, MD: Thank you, Seth. This was an important study. The CORAL study compared these 2 groups, and the primary endpoints were cardiovascular and renal death, hospitalization for congestive heart failure, stroke, myocardial infarction, progressive renal insufficiency, and renal replacement therapy. The trial found that there was no significant difference in this primary composite endpoint between the 2 groups.

That’s an important message: that if we treat our patients with hypertension and renal insufficiency who have concomitant renal artery stenosis with appropriate medical therapy, they will do as well — in terms of cardiovascular and renal endpoints — as those who undergo renal artery stenting.

Dr. Bilazarian: A very strong message that stenting adds nothing, if we take home the short answer that renal stenting adds nothing on top of optimal medical therapy. Previously, enthusiasts for renal stenting criticized studies such as ASTRAL[3] and STAR[4] that the patients may not have been optimally chosen and may not have had significant enough renal artery stenosis.

In the CORAL study, we saw yesterday that in a subgroup analysis looking at patients who had greater or less than 80% stenosis, the average was 72% in the whole trial. But those at greater than 80% did not seem to fare any better from this study. They were the same as those at less than 80%. So does this largely close the door to renal stenting for atherosclerotic disease?

Dr. Creager: As implied by your question, one might have anticipated that those individuals with the most severe renal artery stenosis would have been those most likely to benefit. But as you stated, there was no difference between the patients who had a greater than 80% stenosis and those who did not. That really continues to raise questions about the efficacy of renal artery stenting in this population in general.

But it doesn’t entirely close the door. I think it still is very important for all physicians to deal with their patients individually and inform their decisions by the evidence that’s available. But there will be patients who have hypertension and remain refractory despite aggressive and appropriate medical therapy. And in those individuals, one might consider looking for the presence of renal artery stenosis, and if found, treat them.

But keep in mind that in this trial, the group randomized to medical therapy did demonstrate benefit. In fact, they demonstrated a 15-mm Hg (on average) decrease in systolic blood pressure, indicating that before enrollment in the trial they probably were being treated as aggressively as they should be.

My take-home message is: If you have a patient with significant hypertension, make sure you’re implementing guideline-based therapies to bring their blood pressure into appropriate control. And if one is not successful in that case, then consider other options.

Dr. Bilazarian: One of the findings in the study was that at the end of the trial, there was a 2.5-mm Hg blood pressure difference between those with renal stenting and those without renal stenting (both on optimal medical therapy). Did that result surprise you?

Dr. Creager: It did surprise me for the very reason I just alluded to. I think that prior to enrollment in the trial, many of these patients who were treated with 2 or more antihypertensive drugs still might not have been treated aggressively enough with the right doses of these drugs or the right number of drugs to bring their blood pressure down.

In fact, I was pleased to see that an intensive medical regimen could be effective in these patients. And it sends another important message to our medical community that we can do more for these patients.

Dr. Bilazarian: You mentioned in this last answer that there may still be a role for identifying patients with renal artery stenosis. Can you help clarify that for me as a director of the vascular lab at Brigham and Women’s Hospital? As a teacher of postgraduate physicians, help me understand in what situation patients should be evaluated.

Currently, patients who may not have frank resistant hypertension get referrals to duplex ultrasound for assessment. Should that bar be moved up? Or is it only the most refractory patients who should be investigated? Or is it still valuable to know whether a patient has renal artery stenosis with noninvasive testing?

Dr. Creager: The bar does need to be moved without question. But there are several situations. I’ll give you 2 examples. One I mentioned: The patient who continues to have resistant hypertension despite aggressive medical therapy will be one such patient where I’ll be looking for secondary causes. And one of those secondary causes could be renal artery stenosis. So in that individual, duplex ultrasound would be appropriate, and if renal artery stenosis is found, continue the evaluation and treat that patient as the renal artery stenosis is confirmed.

Another example might be an individual who has recurrent acute pulmonary edema that cannot be explained by coronary artery disease or severe left ventricular dysfunction. That’s a patient I would consider working up for bilateral renal artery stenosis. And if found, I would treat. That patient population was really not the type that was included in the CORAL trial. So those are 2 examples.

Dr. Bilazarian: Our current guidelines say that there is a role for renal artery intervention for resistant hypertension, acute pulmonary edema, and declining renal function. It seems like the first of those has been taken off the table. Is there a role in the patient with declining renal function?

Dr. Creager: Well, that’s an important subset of patients, indeed. And I would be evaluating them for the potential causes of declining renal function. If they have renal artery stenosis, I would then initiate aggressive risk factor modification, antiplatelet therapy, and if they’re hypertensive, treat that as well.

But if in spite of that there still is evidence of declining renal function, then there’s a situation of someone who has failed medical therapy, and I would consider evaluating them for a renal artery stenosis. If one were to find, for example, bilateral renal artery stenosis in that patient or a severe stenosis to a single functioning kidney, then, yes, I would consider renal artery stenting in that individual.

Dr. Bilazarian: Great. Thank you for that summary on the trial called CORAL. Let’s move on to the second trial that you moderated. That trial is called ERASE, a study looking at supervised exercise therapy — an abbreviation I wasn’t familiar with: SET — supervised exercise therapy alone or supervised exercise therapy plus intervention of lower-extremity peripheral arterial disease. And that study was called ERASE. It built on an earlier study called CLEVER.[5] Please summarize the take-home message for the audience in that trial.

Dr. Creager: These were patients with peripheral artery disease and intermittent claudication, and the peripheral artery disease could have affected the aortoiliac system or the femoropopliteal system. The bottom line is that those patients who were randomized to both endovascular intervention and supervised exercise training had a much greater improvement in their walking time as assessed by treadmill testing, and also in quality of life as assessed by a number of instruments, compared with those patients who were just treated with supervised exercise training.

It adds incrementally to what we’ve previously understood. We know that supervised exercise training is extremely effective in improving walking time in patients with intermittent claudication. And as was shown with CLEVER, compared with medical therapy, endovascular intervention — at least in the aortoiliac area — is also associated with improvement in walking time.

So perhaps it’s no surprise that if you put the two together, they’re going to do better. And that’s what the ERASE trial showed.

Dr. Bilazarian: I agree with you. Many times, studies compare one or the other. And, of course, both is better than one or the other. I was happy to see that this trial looked at both.

There is one part of the trial that I had difficulty getting a take-home message from, and I’d love your input. As endovascular medicine physicians, we think in terms of the 3 zones of lower-extremity vascular disease: above the inguinal ligament, the fem-pop system, and then below the knee. Each becomes increasingly difficult, both for acute result as well as for durability. In this trial, half the patients had aortoiliac disease and half had fem-pop disease. Am I right to say that that might make it somewhat difficult to interpret whether the effects of supervised exercise therapy might be different for fem-pop disease or, say, aortoiliac disease, and that the bar for intervention might be lower for aortoiliac disease?

Dr. Creager: That’s a very important question. We don’t know yet what the subset analysis will be between those patients who had aortoiliac disease and underwent randomization and those who had femoropopliteal artery disease. And I’m sure we all await that analysis when it’s available.

Having said that, however, the studies show several things. It underscores the fact that no matter where the lesion is, patients still do better when exercise training is included in their therapeutic interventions. I think those of us who practice vascular medicine recognize the fact that endovascular intervention in the iliac arteries has been extremely successful and durable. And those patients really do benefit. d Our practice pattern and standard of care is to do endovascular intervention in patients with disabling claudication who have aortoiliac disease.

Superficial femoral artery disease, as you implied, is a little bit of a different situation. Those lesions are sometimes more difficult to treat and the durability is not as great. Within the context of this study, durability was pretty good in terms of restenosis. But I still think we need to see the subset analysis to make sure that those patients benefited as much as the entire group.

Dr. Bilazarian: Help us with a take-home message for US-based physicians. This was supervised exercise therapy in-home. We don’t have that available in the United States. Other than adding to our knowledge base, which is, of course, valuable, and being able to impart this knowledge to our patients and show them that this is of value, what other things can we do as a change in our practice to integrate this?

Dr. Creager: Currently we do need changes in healthcare policy, at least as it applies to supervised exercise training. We need reimbursement from CMS (Centers for Medicare & Medicaid Services). We need reimbursement from other third-party payers to provide additional incentive for physicians to recommend supervised exercise training for their patients. Unfortunately, that’s not available. And that’s one reason why patients in this country are not being referred for supervised exercise training. It’s an extremely effective intervention in patients with intermittent claudication.

Dr. Bilazarian: Great. Mark, thanks for joining me and for helping unpack these 2 trials for our audience: the ERASE trial of lower-extremity exercise in PAD patients, and the CORAL trial of renal artery stenting. I think they will add to our knowledge base and hopefully make practice changes in both areas. Thank you again for joining. And thank you for joining us for this program.

SOURCE

http://www.medscape.com/viewarticle/815029?src=emailthis#1

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Comment by Cardiologists posted on LinkedIn’s

European Cardiovascular Medical Devices Group, a subgroup of Cardiovascular Medical Devices Group

on Stenting for Proximal LAD Lesions: In Reference to the Invasive Procedure performed on former President George W. Bush

UPDATED on 8/7/2018

Long-Term Outcomes of Stenting the Proximal LAD

Study Questions:

What are the outcomes of patients undergoing drug-eluting stent (DES) implantation according to lesion location within or outside the proximal left anterior descending (LAD) artery?

Methods:

Among the 8,709 patients enrolled in PROTECT (Patient Related Outcomes With Endeavor Versus Cypher Stenting Trial), a multicenter percutaneous coronary intervention (PCI) trial, the investigators compared the outcomes of 2,534 patients (29.1%; 3,871 lesions [31.5%]) with stents implanted in the proximal LAD with 6,172 patients (70.9%; 8,419 lesions [68.5%]) with stents implanted outside the proximal LAD. For each event, a multivariate model was constructed that examined the effect of several individual baseline clinical and angiographic characteristics, including proximal LAD target lesion, on outcomes (i.e., MACE [major adverse cardiac events], target vessel failure [TVF], and myocardial infarction [MI]).

Results:

At 4-year follow-up, death rates were the same (5.8% vs. 5.8%; p > 0.999), but more MIs occurred in the proximal LAD group (6.2% vs. 4.9%; p = 0.015). The rates of clinically driven TVF (14.8% vs. 13.5%; p = 0.109), MACE (15.0% vs. 13.7%; hazard ratio, 1.1; 95% CI, 0.97-1.31; p = 0.139), and stent thrombosis (2.1% vs. 2.0%; p = 0.800) were similar. DES type had no interaction with MACE or TVF. In multivariate analysis, the proximal LAD was a predictor for MI (p = 0.038), but not for TVF (p = 0.149) or MACE (p = 0.069).

Conclusions:

The authors concluded that proximal LAD location was associated with higher rates of MI during the long-term follow-up, but there were no differences in stent thrombosis, death, TVF, or overall MACE.

Perspective:

This post hoc analysis of a prospective, multicenter study reports no difference in the rates of death, MACE, or TVF at 4 years according to intervention at a proximal LAD or nonproximal LAD lesion. The occurrence of the predefined primary endpoint of stent thrombosis was also not dependent on whether a proximal LAD or nonproximal LAD site was treated. However, of note, stenting of proximal LAD lesions was associated with significantly higher rates of MI compared with stenting of nonproximal LAD lesions. Overall, these findings appear to suggest that proximal LAD lesions may not have additional risk in the contemporary DES era, but the higher risk of MI needs to be studied further. Future studies should compare longer-term clinical outcomes between proximal LAD PCI with DES and minimally invasive left internal mammary artery to LAD.

SOURCE

https://www.acc.org/latest-in-cardiology/journal-scans/2017/03/22/15/11/long-term-outcomes-of-stenting-the-proximal-lad

 

Stenting for Proximal LAD Lesions

Curator: Aviva Lev-Ari, PhD, RN

Michael Reinhardt • First, the media really should not be calling this “stent surgery” its a stent procedure just ask any post-CABG patient… Anyway it really is not possible to determine whether or not is was “unnecessary” without all the relevant patient data; which coronary vessel(s) involved, percent stenosis, etc. Actually I find it interesting that they apparently decided to stent the former president on the basis of a CT Angiogram which is not the standard of care for coronary imaging. I have to assume they performed an additional testing like a CT perfusion analysis and saw a clinically relevant defect and this support the decision to stent. Regarding the post-stent drugs cloplidigrel is not a benign drug but benefits far outweigh the downside of a sub-acute thrombosis which might result in a more serious future event = acute MI.

Rafael Beyar • This was absolutely an indicated procedure and almost all rational physician will treat a young patient with proximal LAD lesions with either a stent or bypass surgery

Dov V Shimon MD • No doubt! Proximal (‘close to origin’) LAD lesions are the leading “Widow makers”. Reestablishing of flow in the artery is saving from cardiac damage and death. Drug eluting stent have 2nd and 3rd generations with very low and acceptable reclosure rates and almost no abrupt closure (thrombosis). True, CTA is a screening test, but it astablishes the need for diagnostic and therapeutic angiogram. We, heart surgeons can provide long-term patency to the LAD using LIMA arterial bypass. The current advantage of stent is the incovenience and pain of surgery. Any responsible physician would opt the procedure even for himself, his relatives , his patients and for definitely for GW Bush.

http://www.linkedin.com/groupItem?view=&gid=3358310&type=member&item=265974376&commentID=157366758&goback=%2Egmr_3358310&report%2Esuccess=8ULbKyXO6NDvmoK7o030UNOYGZKrvdhBhypZ_w8EpQrrQI-BBjkmxwkEOwBjLE28YyDIxcyEO7_TA_giuRN#commentID_157366758

Coronary anatomy and anomalies

On the left an overview of the coronary arteries in the anterior projection.

Coronary anatomy and anomalies

RCA, LAD and Cx in the anterior projection

On the left an overview of the coronary arteries in the lateral projection.

  • Left Main or left coronary artery (LCA)
    • Left anterior descending (LAD)
      • diagonal branches (D1, D2)
      • septal branches
    • Circumflex (Cx)
      • Marginal branches (M1,M2)
  • Right coronary artery
    • Acute marginal branch (AM)
    • AV node branch
    • Posterior descending artery (PDA)

Eur J Cardiothorac Surg. 2004 Apr;25(4):567-71.

Isolated high-grade lesion of the proximal LAD: a stent or off-pump LIMA?

Source

Thoraxcentre, Groningen University Hospital, Groningen, The Netherlands.

Abstract

OBJECTIVES:

The objective of this study was to compare the long-term outcome of patients with an isolated high-grade stenosis of the left anterior descending (LAD) coronary artery randomized to percutaneous transluminal coronary angioplasty with stenting (PCI, stenting) or to off-pump coronary artery bypass grafting (surgery).

METHODS:

Patients with an isolated high-grade stenosis (American College of Cardiology/American Heart Association classification type B2/C) of the proximal LAD were randomly assigned to stenting (n=51) or to surgery (n=51) and were followed for 3-5 years (mean 4 years). Primary composite endpoint was freedom from major adverse cardiac and cerebrovascular events (MACCEs), including cardiac death, myocardial infarction, stroke and repeat target vessel revascularization. Secondary endpoints were angina pectoris status and need for anti-anginal medication at follow-up. Analysis was by intention to treat.

RESULTS:

MACCEs occurred in 27.5% after stenting and 9.8% after surgery (P=0.02; absolute risk reduction 17.7%). Freedom from angina pectoris was 67% after stenting and 85% after surgery (P=0.036). Need for anti-anginal medication was significantly lower after surgery compared to stenting (P=0.002).

CONCLUSION:

Patients with an isolated high-grade lesion of the proximal LAD have a significantly better 4-year clinical outcome after off-pump coronary bypass grafting than after PCI.

Daily Dose

08/12/2013 | 5:48 PM

Was George Bush’s stent surgery really unnecessary?

By Deborah Kotz / Globe Staff

VIEW VIDEO

Ever since President George W. Bush had stent surgery last Tuesday to open a blocked artery, leading physicians who weren’t involved in his care have wondered publically why he had this “unnecessary” procedure. Large clinical trials have demonstrated that stent placement doesn’t extend lives or prevent a future heart attack or stroke in those with stable heart disease.

What’s more, Bush could wind up with complications like a reblockage where the stent was placed or excessive bruising or internal bleeding from the blood thinners that he must take likely for the next year.

Dr Richard Besser, the chief medical correspondent for ABC News, questioned why Bush had an exercise stress test as part of his routine physical exam given that he had no symptoms like chest pain or shortness of breath. The stress test indicated signs of an artery blockage.

“In people who are not having symptoms, the American Heart Association says you should not do a stress test,” Besser said, “since the value of opening that artery is to relieve the symptoms.”

Cleveland Clinic cardiologist Dr. Steve Nissen agreed in his interview with USA Today. Bush, he said, likely “got the classical thing that happens to VIP patients, when they get so-called executive physicals and they get a lot of tests that aren’t indicated. This is American medicine at its worst.”

Two physicians wrote in an Washington Post op-ed column titled “President Bush’s unnecessary surgery” that they worry that the media coverage of Bush’s stent will lead “patients to pressure their own doctors for unwarranted and excessive care.”

But none of these doctors actually treated Bush or examined his medical records, so I’m a little surprised they’re making such firm calls.

Bush, an avid biker who recently completed a 100-kilometer ride, probably shouldn’t have had the exercise stress test if he wasn’t having any heart symptoms. “Routine stress testing used to be done 20 years ago, but isn’t recommended any longer since it doesn’t have any benefit,” said Brigham and Women’s cardiologist Dr. Christopher Cannon.

But Bush’s spokesman insisted the stent was necessary after followup heart imaging via a CT angiogram “confirmed a blockage that required opening.”

Cannon said Bush’s doctors may have seen signs that blood flow wasn’t getting to a significant part of the heart muscle, a condition known as ischemia. Researchers have found that those with moderate to severe ischemia appear to experience a reduction in fatal heart attacks when they have a stent placement along with medical therapy, rather than just taking medications alone. (Larger studies, though, are needed to confirm this finding.)

“If a blockage occurs at the very start of the artery and it’s extensive—95 percent blocked—then chances are it will cause significant ischemia,” Cannon said. While severe ischemia usually causes light-headedness or dizziness during exercise, Bush may have had more moderate ischemia that didn’t cause such symptoms.

It’s impossible to know for certain, he added, without seeing his medical records firsthand.

http://www.boston.com/lifestyle/health/blogs/daily-dose/2013/08/12/was-george-bush-stent-surgery-really-unnecessary/DzklhNCGVlgriNxgpKZtuO/blog.html

President Bush’s unnecessary heart surgery

  • By Vinay Prasad and Adam Cifu, Published: August 9

Vinay Prasad is chief fellow of medical oncology at the National Cancer Institute and the National Institutes of Health. Adam Cifu is a professor of medicine at the University of Chicago.

Former president George W. Bush, widely regarded as a model of physical fitness, received a coronary artery stent on Tuesday. Few facts are known about the case, but what is known suggests the procedure was unnecessary.

Before he underwent his annual physical, Mr. Bush reportedly had no symptoms. Quite the opposite: His exercise tolerance was astonishing for his age, 67. He rode more than 30 miles in the heat on a bike ride for veterans injured in the wars in Iraq and Afghanistan.

If Mr. Bush had visited a general internist practicing sound, evidence-based care, he would not have had cardiac testing. Instead, the doctor would have had conducted age-appropriate cancer screening. For the former president, this would include only colon cancer screening. It no longer would include even prostate-specific antigen testing for cancer. The doctor would have screened for cholesterol, checked for hypertension and made sure the patient was up to date on age-appropriate vaccinations, including those for pneumococcal pneumonia and shingles. Presumably Mr. Bush got these things, and he got the cardiac test as well.What value does a stress test add for an otherwise healthy 67-year-old?No study has shown that this examination improves outcomes. The trials that have been done for so-called routine stress testing examined higher-risk patients. They found that performing stress tests on people at high risk of cardiovascular disease may detect blockages but does not improve symptoms or survival. Routine stress testing does, however, increase the use of procedures such as coronary stenting.Unfortunately, Mr. Bush, like many VIPs, may be paying the price of these in-depth investigations. His stress test revealed an abnormality, prompting another test: a CT angiogram. This study showed a blockage, which was stented open during an invasive procedure. It is worth noting that at least two large randomized trials show that stenting these sorts of lesions does not improve survival. Because Mr. Bush had no symptoms, it is impossible that he felt better after these procedures.

Instead, George W. Bush will have to take two blood thinners, aspirin and Plavix, for at least a month and probably a year. (The amount of time a blood thinner is needed depends on the type of stent placed). While he takes these medications, he will have a higher risk of bleeding complications with no real benefit.

Although this may seem like an issue important only to the former president, consider the following: Although the price of excessive screening of so-called VIPs is usually paid for privately, follow-up tests, only “necessary” because of the initial unnecessary screening test, are usually paid for by Medicare, further stressing our health-care system. The media coverage of interventions like Mr. Bush’s also leads patients to pressure their own doctors for unwarranted and excessive care.

http://www.washingtonpost.com/opinions/president-bushs-unnecessary-heart-surgery/2013/08/09/c91c439c-0041-11e3-9a3e-916de805f65d_story.html

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Stent Design and Thrombosis:  Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents

Curator: Aviva Lev-Ari, PhD, RN

UPDATED 2/8/2014

Reva Completes Drug-Eluting Bioresorbable Stent Trial Enrollment

January 24, 2014
Reva Medical Clinical Trial ReZolve2 Bioresorbable Stent
January 24, 2014 — Reva Medical Inc. has completed enrollment in the clinical trial of the ReZolve2 drug-eluting bioresorbable scaffold. A total of 112 patients from three continents have been enrolled in the trial to provide the data needed to apply for CE marking.

The company anticipates filing a CE mark application before the end of 2014. It plans to report an update on trial data at the Paris Course on Revascularization (EuroPCR) in Paris, France, May 2014.

For more information: http://www.teamreva.com

This article has the following SIX Parts:

Part I: Bifurcation Intervention – Stent Design and Thrombosis

Part II: Biodegradable Polymer DES Reduce Stent Thrombosis Rates vs. Durable Polymer DES

Part III: Stent Flexibility versus Stent Concertina Longitudinal Deformation Effect on Outcomes

Part IV: Stent Thrombosis Through the Generations of Stent Design

Part V: Stent Thrombosis in Randomized Trials of Drug-Eluting Stents: Reappraisal of the Synthesis of Evidence!

Part VI. Duration of Dual Antiplatelet Therapy following Zotarolimus-Eluting Stents and A New Strategy for Discontinuation of Dual Antiplatelet Therapy

Conclusions by Larry H Bernstein, MD, FCAP

 

Part I

Bifurcation Intervention – Stent Design and Thrombosis

 

The 5 Ts of Bifurcation Intervention: Type, Technique, Two Stents, T-Stenting, Trials

Ron Waksman, MD, FACC; Laurent Bonello, MD

Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.

J Am Coll Cardiol Intv. 2008;1(4):366-368. doi:10.1016/j.jcin.2008.06.006

http://interventions.onlinejacc.org/article.aspx?articleid=1110233

Bifurcation, the division of an artery into 2 branches, is a common anatomy feature of the human coronary tree and is recognized as a common site for atherosclerotic plaque buildup due to the differences in coronary flow, turbulence, and shear stress at the site of the bifurcation. The prevalence of bifurcation stenosis in the human coronary tree is reported to be between 15% to 20% of all interventions and is considered complex and challenging for percutaneous intervention.

Numerous techniques and devices have been proposed to address the treatment of bifurcation lesions: balloon angioplasty, metallic stents, drug-eluting stents (DES), newly designed stents with dedicated access to the side branch, and full bifurcated stents. Clearly, the interest in the treatment of bifurcation stenting has increased with the availability to significantly reduce the recurrence rate, but this was associated with the increasing fear of stent thrombosis. Despite this extensive body of work and the latest innovations of 2008, there is not a “one size fits all” solution to the bifurcation puzzle, while the optimal percutaneous coronary intervention technique remains undetermined.

In this issue of JACC: Cardiovascular Interventions, Routledge et al. (1) present 2-year outcome data of 477 patients treated for bifurcation coronary disease with provisional side branch T-stenting using DES, and claim a systematic approach feasible for 90% of the patients, with acceptable efficacy and safety profiles. This editorial is written in response to this provocative study and will cover the 5 Ts of bifurcation stenting: Type of bifurcation, Techniques, Two stents versus one, T-stenting, and Trial design.

Types Of Bifurcation

Part of the complexity in treating bifurcation lesions and applying technique standardization is in regard to the numerous anatomic patterns of bifurcation stenosis and the lack of consistent, reliable methodology. Further, the variations in anatomy, angulations, and location of the disease within the bifurcation have led to the development of numerous classifications of bifurcation lesions, with differentiation between “true” bifurcation (both the main and the branch are diseased) and “false” bifurcation (either the main or the branch is disease) based on angiography. The most popular and intuitive classification is that of Medina et al. (2), which identifies at least 7 types of bifurcation involving the proximal main branch, the distal main branch, and the side branch, with different variations. If we add this to the classification of the various potential angulations between the main and the side branches, the sizes of the parent vessel and the side branch, and the different potential morphologies of the diseased segment (calcification, fibrosis, and so on), we can identify nearly endless anatomic and morphologic configurations of bifurcations types (3).

Technique

2 stents versus 1

Numerous techniques have been proposed for the treatment of bifurcation lesions. The first decision that the operator must make is whether the procedure will involve 1 or 2 stents. The most important information relates to the size of the side branch and the degree of the disease in this branch. Or do we really care about the side branch? Initially, the thought of using 2 stents for all bifurcated lesions was appealing because this approach usually resulted in an optimal angiographic success rate. Among the most popular techniques that employed the use of 2 stents are the culotte, crush, V-stenting, T-stenting, and simultaneous kissing stents (4). However, after numerous reports of high rates of late complications, including an increase in stent thrombosis and restenosis frequency, systematical use of 2 stents did not live up to expectations (58). These poor outcomes were observed regardless of the technique used and thus discouraged the liberal use of 2 stents. Therefore, the provisional strategy gained ground: try 1 stent first, and, if the result is not acceptable (dissection, impaired lumen, or flow of the other branch), use a second stent for the side branch. The superiority of such a provisional approach over a 2-stent technique was confirmed by the Nordic Bifurcation study (9). The results of this study had operators favoring the provisional rather than the 2-stent approach. However, many questions still remain regarding this approach: can we predict which bifurcation will require 2, rather than 1 stent? In how many patients is the provisional approach feasible? If a second stent is required, what then is the optimal technique for implantation of the second stent? Is provisional stenting still superior to the 2-stent approach with the new generation of stents available? And lastly, are the latest technique modifications, including pre- and post-kissing, clinically beneficial?

The present study demonstrated that provisional stenting is feasible in 90% of all patients, and those who received a second stent in the side branch, 28%, had similar long-term outcomes as those treated with 1 stent. The outcome of this study is similar to that of the Nordic Bifurcation study, which observed no difference in outcomes at 6 months’ follow-up between 1 and 2 stents (9). Finally, the latest Nordic Bifurcation Stent Technique study, comparing the culotte and crush techniques, reported low rates of angiographic restenosis and major adverse cardiac events for both techniques (10), with similar angiographic and clinical outcomes as the provisional approach with T-stenting reported in the Routledge et al. study (1). This leaves us with the question of whether, in 2008, provisional stenting is still superior to 2 stents when an improved technique is applied and new-generation stents are used?

T-stenting

Use of the provisional T-stenting technique is gaining interest because of its simplicity and subsequent reports of good mid-term outcomes (1113). As illustrated in the present report by Routledge et al. (1), it is feasible in a large majority of patients and is associated with low rates of recurrent events during long-term follow-up. In the past, the technique was described to resolve dissections of a side branch (8) or as a new technique for the use of 2 stents for the treatment of bifurcation lesions (11). In the present study, the authors used provisional T-stenting as the default technique. From a technical point of view, provisional T-stenting offers several advantages compared with other bifurcation techniques: it is simple to perform in most cases, and it limits the need for a second stent, as illustrated by the low rate of stenting in the side branch in the present study. One technical aspect of the procedure remains in question: is kissing post-procedure mandatory in the provisional T-stenting approach with 1 or 2 stents? Bench testing observed that the final kissing balloon may have several interesting advantages: it opens the stent cells to the side branch, it allows the side branch ostium to be at least partially covered by stent struts, and it prevents the main branch stent from becoming deformed by side branch dilation. Further, in previous studies involving crush stenting, kissing balloon was shown to be critical in preventing restenosis (14). Nevertheless, the clinical impact of a final kissing balloon in provisional T-stenting must be established in future trials. Several limitations should be considered with T-stenting: it is not applicable for all lesions, it is dependent on the bifurcation angle and cannot be applied to angles <40°; the second stent, if needed, may not be able to fully cover the ostium, which will result in switching to a mini-crush technique, and like other techniques, there is a learning curve. Nevertheless, among today’s available options, the provisional T-stenting technique seems to be the simplest and is associated with favorable long-term outcomes.

Table 1 Comparison of Bifurcation Studies in the DES Era

Bifurcation stenting continues to challenge the interventional cardiologist. Despite the recent literature, including the present manuscript, there is a lack of consensus on an array of important issues, such as: Which branches deserve protection? Should provisional stenting be the default strategy of bifurcation stenting? Should we always pre-dilate the side branch? And if 2 stents are required, which technique would be the best? Is kissing always mandatory for both branches? Are DES more thrombogenic? And finally, how will the special dedicated bifurcated stents be integrated into current practice? With further trials and perhaps the sixth T in bifurcation stenting (Time), the answers to these important questions will be answered.

References

1 Routledge  H.C., Morice  M.-C., Lefèvre  T.; 2-year outcome of patients treated for bifurcation coronary disease with provisional side branch T-stenting using drug-eluting stents. J Am Coll Cardiol Intv. 1 2008:358-365.

2 Medina  A., Suárez de Lezo  J., Pan  M.; A new classification of coronary bifurcation lesions. Rev Esp Cardiol. 59 2006:183

3 Thomas  M., Hildick-Smith  D., Louvard  Y.; Percutaneous coronary intervention for bifurcation disease. A consensus view from the first meeting of the European bifurcation club. Euro Intervention. 2 2006:149-153.

4 Louvard  I., Lefevre  T., Morice  M.C.; Percutaneous coronary intervention for bifurcation coronary disease. Heart. 90 2004:713-722.

5 Iakovou  I., Schmidt  T., Bonizzoni  E.; Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 293 2005:2126-2130.

6 Finn  A.V., Kolodgie  F.D., Harnek  J.; Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation. 112 2005:270-278.

7 Daemen  J., Wenaweser  P., Tsuchida  K.; Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 369 2007:667-678.

8 Carrie  D., Karouny  E., Chouairi  S., Puel  J.; “T” shaped stent placement: a technique for the treatment of dissected bifurcation lesions. Cathet Cardiovasc Diagn. 37 1996:311-313.

9 Steigen  T.K., Maeng  M., Wiseth  R.; Randomized study on simple versus complex stenting of coronary artery bifurcation lesions: the Nordic Bifurcation study. Circulation. 114 2006:1955-1961.

10 Gunnes P, Niemela M, Kervinen K, et al, for the Nordic-Baltic PCI Study Group. Eight months angiographic follow-up in patients randomized to crush or culotte stenting of coronary artery bifurcation lesions. The Nordic Bifurcation Stent Technique study. Paper presented at: ACC 2008 Late Breaking Trials; April 1, 2008; Chicago, IL.

11 Palvakis  G., de Man  F., Hamer  B., Doevendas  P., Stella  P.R.; Registry of new technique on coronary bifurcation lesions: the Utrech-“T” experience. Euro Intervention. 3 2007:262-268.

12 Pan  M., Suárez de Lezo  J., Medina  A.; Drug-eluting stents for the treatment of bifurcation lesions: a randomized comparison between paclitaxel and sirolimus stents. Am Heart J. 153 2007:15-17.

13 Ormiston  J.A., Webster  M.W., El Jack  S.; Drug-eluting stents for coronary bifurcations: bench testing of provisional side-branch strategies. Catheter Cardiovasc Interv. 67 2006:49-55.

14 Ge  L., Airoldi  F., Iakovou  I.; Clinical and angiographic outcome after implantation of drug-eluting stents in bifurcation lesions with the crush stent technique: importance of final kissing balloon post-dilation. J Am Coll Cardiol. 46 2005:613-620.

15 Hoye  A., Iakovou  I., Ge  L.; Long-term outcomes after stenting of bifurcation lesions with the “crush” technique: predictors of an adverse outcome. J Am Coll Cardiol. 47 2006:1949-1958.

16 Sharma  S.K.; Simultaneous kissing drug-eluting stent technique for percutaneous treatment of bifurcation lesions in large-size vessels. Catheter Cardiovasc Interv. 65 2005:10-16.

17 Moussa  I., Costa  R.A., Leon  M.B.; A prospective registry to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions using the “crush technique”. Am J Cardiol. 97 2006:1317-1321.

18 Yanagi  D., Shirai  K., Takamiya  Y.; Results of provisional stenting with a sirolimus-eluting stent for bifurcation lesion: multicenter study in Japan. J Cardiol. 51 2008:89-94.

19 Di Mario  C., Morici  N., Godino  C.; Predictors of restenosis after treatment of bifurcational lesions with paclitaxel eluting stents: a multicenter prospective registry of 150 consecutive patients. Catheter Cardiovasc Interv. 69 2007:416-424.

20 Tsuchida  K., Colombo  A., Lefèvre  T.; The clinical outcome of percutaneous treatment of bifurcation lesions in multivessel coronary artery disease with the sirolimus-eluting stent: insights from the Arterial Revascularization Therapies Study part II (ARTS II). Eur Heart J. 28 2007:433-442.

SOURCE

J Am Coll Cardiol Intv. 2008;1(4):366-368. doi:10.1016/j.jcin.2008.06.006

http://interventions.onlinejacc.org/article.aspx?articleid=1110233

 

Bifurcation Stenting

David Hildick-Smith, MD

Consultant Cardiologist and Director of Cardiac Research

Brighton-Sussex University Hospital NHS Trust

Brighton, UK

Slide 1

Bifurcation stenting and its various ramifications in the modern cardiology world. The objectives of this presentation are to talk about some of the difficulties of bifurcation stenting, to summarize the recent study data, and to talk a little bit about dedicated stent systems, as well.

Dedicated Bifurcation Stent Systems – Main types:

Side branch facilitation

Side branch stenting incorporated

Main branch stenting with enhanced access

True dedicated systems

Slide 32

So we then have the issue of dedicated stent systems. Are they the answer to some of these questions? Are they going to bail us out of these difficult geometric issues of bifurcations? There are a number of dedicated stent systems in development and available at the moment, and they fall into a few different groups. There are systems which simply facilitate side branch access. There are systems which actually incorporate side branch stenting as the primary philosophy. There are those which are essentially a main branch stent with enhanced access. And then there are the truly dedicated systems.

Bifurcation Stenting: Should You Keep it Simple

You Keep it Simple

Facilitation

Increasing success of provisional T

Slide 33

If we look at the facilitation group, there are stent systems available where there’s a wire that is integral to the balloon system, and will perhaps then facilitate getting into the side branch, and may certainly facilitate making sure that you are,

Side Branch Ostial Coverage Stents:

Scaffold side branch ostium

Allow subsequent main vessel stenting

The side branch ostial coverage stents are intended to scaffold the side branch and retain main vessel stenting capabilities. There are a couple of stents of this nature on the market at the moment which are undergoing clinical trials to see their general applicability.

Main Vessel Enhanced Access Stents

Pop-up/expand into side vessel

Improve subsequent or immediate access to side branch

Slide 35

The next group is the main vessel enhanced access stents, which, either through a pop-up mechanism with mechanical scaffolding of the side branch ostium, or with a proximal stent which is self-expanding, enhance the access to the side branch, so that you have both immediate access and subsequent access. Which is one of the things that people worry about in this situation, which is, what happens if you have to come back to that side branch vessel a few months later? Will you be able to gain access to it? So these tools may have a role there.

True Dedicated Bifurcation Stent

Stenting of both branches

Slide 36

The fourth group is the true dedicated bifurcation stent. These are clearly the most useful, but of course, mechanically and from an engineering point of view, the most difficult to create and make work. They will certainly have a potential role in bifurcation stenting, but there’s a little  way to go before they could be used in a wide manner.

Slide 37

The dedicated systems, while most are quite ingenious, unfortunately most will not survive in their current format. But the true dedicated bifurcation stent will certainly have a role in the left main. And, as we come back increasingly from these bifurcations to the left main and get a mandate to be able to treat that, this is an area where there will be a significant place for dedicated bifurcation stent systems.

Conclusions

• Bifurcations remain troublesome

• Provisional T stenting is the gold standard

• Subsets of bifurcations require complex strategies

• Large side branches

• Longer ostial disease

• Current complex strategies fail us

• Crush fails more than culotte

• Dedicated devices will have a role

• Large bifurcations in main coronary tree

• Left main

Slide 38

In conclusion, bifurcation stenting is still a troublesome area. Provisional T stenting is the gold standard approach across the board, but we mustn’t forget that there may well be, and I believe there are, subsets of bifurcations which do require a complex strategy. These are the ones with large side branches and significant length of disease at the ostium of that side branch. The current complex strategies do fail from a mechanical point of view, and in that respect crush fails more than culotte. Although it’s a difficult time for dedicated devices at the moment, I think they will have a role, particularly in large bifurcations in the main coronary tree and, most particularly of all, in the left main stem.

SOURCE

http://www.theheart.org/documents/satellite_programs/intervsurgery/913801/BifurcationStenting_REVISED_FINAL.pdf

Part II

Biodegradable Polymer DES Reduce Stent Thrombosis Rates vs. Durable Polymer DES

March 27, 2012 — Biodegradable polymer drug-eluting stents (DES) provide better long-term safety and efficacy than durable polymer DES, according to findings from an analysis of three major clinical trials

  • ISAR-TEST 3,
  • ISAR-TEST 4 and
  • LEADERS.

The data were presented at at the American College of Cardiology’s 61st Annual Scientific Session. The findings provide the first combined long-term data on the comparison between biodegradable polymer DES and durable polymer DES. Designed to improve long-term clinical outcomes while also shortening healing time, biodegradable polymer DES are a new generation of DES that have undergone little research and thus have yet to substantiate its claims. The three analyzed studies showed that after four years, use of biodegradable polymer DES resulted in

  • lower rates of target lesion revascularization,
  • definite stent thrombosis and
  • cardiac death and
  • heart attack than durable polymer DES.

“Because it is often difficult to design individual trials to test for differences in rarely occurring adverse events [like stent clotting], we pooled the data from the three largest trials to see if any differences between the two stent types could be seen,” said co-lead investigator Robert A. Byrne, M.B., B.Ch., Ph.D., a cardiologist at Deutsches Herzzentrum in Munich, Germany. “In addition, by including surveillance out to four years, this helped us better capture the differences between the two stents, as benefit was expected to first emerge with long-term follow-up.”

Among all three analyzed trials, 2,358 patients were randomly assigned to angioplasty with a biodegradable polymer DES (sirolimus-eluting = 1,501; biolimus-eluting = 857), while 1,704 patients were treated with a durable polymer SES (all sirolimus-eluting).

At the four-year follow-up point, the researchers found that the risk of target lesion revascularization (the study’s primary efficacy endpoint) was significantly lower among those patients treated with a biodegradable polymer DES than for those treated with a durable polymer DES (hazard ratio [HR] 0.82, 95 percent confidence interval [CI] 0.68-0.98, P=0.029). In addition, the risk of having a blood clot, called stent thrombosis (the study’s primary safety endpoint), was also significantly lower for those patients treated with a biodegradable polymer DES compared to those treated with a durable polymer DES (HR 0.56, 95 percent CI 0.35-0.90, P=0.015). This was driven by a lower risk of very late stent thrombosis (clots occurring more than one year after angioplasty) for the biodegradable polymer group (HR 0.22, 95 percent CI 0.08-0.61, P=0.004).

Furthermore, the incidence of heart attack late after stenting was lower for patients treated with biodegradable polymer versus durable polymer stents (HR 0.59, 95 percent CI 0.73-0.95, P=0.031).

While the arrival of DES has allowed interventionalists to provide treatment for more complex patients, concerns have arisen about the stents’ long-term safety, particularly concerning stent thrombosis. As a result, the polymer coating on the first-generation stents was targeted as an area for improvement. Specifically, the durable polymer remains in the coronary artery wall beyond the time when its useful function is served. This may cause delayed healing and a hypersensitivity reaction, leading to inflammation and stent thrombosis.

As a potential solution to these problems, new-generation stents with a bioabsorbable polymer were created. This polymer, which fully degrades and leaves a bare-metal stent in place, has been suggested to shorten healing time and cause less inflammation and subsequent stent thrombosis.

“These findings show that biodegradable polymer DES can provide better long-term safety and efficacy,” said Byrne. “This advantage, coupled with a shortened healing time compared with durable polymer DES, means that biodegradable polymer stents look to become an important tool for the interventional cardiologist in everyday practice.”

The current analysis was industry independent, supported in part by a grant from the Swiss National Science Foundation, and conducted at the ISAR Research Center in Munich, Germany, and the Clinical Trials Unit in Bern, Switzerland.

This study was simultaneously published in the European Heart Journal and was released online at the time of presentation.

The results offer a promising outlook for Boston Scientific’s Synergy DES, now in development. It uses the same platform stent as the Ion and Promus, but instead of a duable polymer it uses abluminal biodegradable polymer containing everolimus. The company presented its first-in-man study at TCT 2011 and hopes to begin its EVOLVE II U.S. Food and Drug Administration (FDA) investigational decive exemption trial later this year.

For more information: www.acc.org

Biosensensors BioMatrix Flex was among the stents included in this study. It uses an abluminal, biodegradable polymer as a carrier for its BA9 drug.

http://www.dicardiology.com/article/biodegradable-polymer-des-reduce-stent-thrombosis-rates

First Patient Enrolled in Dissolving Drug-Polymer Coronary Stent Trial

February 21, 2011 – The first patient has been enrolled the DESSOLVE II study to support CE mark for a coronary stent that uses a bioresorbable drug polymer. The MiStent drug-eluting coronary stent system (MiStent DES), by Micell Technologies.

The trial involves treatment of patients with de novo lesions in the native coronary arteries. Stefan Verheye, M.D., Ph.D. at Middelheim Hospital, Antwerp, Belgium enrolled the first patient in the study.

The MiStent DES employs supercritical fluid technology, which applies a precisely controlled absorbable polymer – active drug (sirolimus) matrix onto a cobalt-chromium stent. The polymer dissolves and releases the drug into the surrounding tissue in a controlled manner, designed to optimize dosing of the drug throughout the affected artery. In preclinical trials, the drug completely elutes and the polymer is eliminated from the stent within 45 to 60 days in-vivo, resulting in a bare-metal stent.

DESSOLVE II is a prospective, controlled, 2:1 unbalanced randomized, multicenter study of approximately 270 patients. Patients will be enrolled at 26 clinical sites in Europe, New Zealand and Australia. Candidates for the trial are patients with documented stable or unstable angina pectoris or ischemia. The primary endpoint is superiority of MiStent DES in minimizing in-stent late lumen loss at nine months, compared to Medtronic’s Endeavor DES, as measured with angiography in treated de-novo lesions ranging in diameter from 2.5 to 3.5 mm and amenable to treatment with a maximum 23 mm long stent.

Along with secondary clinical endpoints such as major adverse cardiac events and revascularization rates, the extent of stent coverage and re-endothelialization, via optical coherence tomography (OCT), and endothelial function (vasomotor response) will be evaluated in a subgroup of patients at nine months.

“Drug-eluting stents have significantly improved and expanded our ability to treat coronary atherosclerotic lesions compared to bare-metal stents,” said William Wijns, M.D., Cardiovascular Center, Aalst, Belgium, and principal investigator of the study. “However, cardiologists are still looking for options to improve safety and outcomes. The MiStent DES may address some of these issues directly. Based on recent GLP animal data, the polymer and drug are gone from the stent within 45 to 60 days. This may reduce the risk of late-stent thrombosis related to long-term exposure to DES nonerodible polymers. Given the relatively short residence time of polymer on the stent, MiStent DES may allow for a shorter duration of dual antiplatelet therapy and be a safer choice for noncompliant patients. These performance-enhancing properties are what interventional cardiologists are looking for in a new drug-eluting stent.”

For more information: www.micell.com

http://www.dicardiology.com/article/first-patient-enrolled-dissolving-drug-polymer-coronary-stent-trial

 

Part III

Stent Flexibility versus Stent Concertina Effect

 

Stent flexibility versus concertina effect: mechanism of an unpleasant trade-off in stent design and its implications for stent selection in the cath-lab.

Foin N, Di Mario C, Francis DP, Davies JE.

Abstract

The “concertina effect”, longitudinal deformation of the proximal segments of a deployed stent when force is applied from a guide catheter or other equipment, is a recently recognised problem which seems to particularly affect more recent stent designs. Until now, flexibility and deliverability have been paramount aims in stent design. Developments have focused on optimizing these features which are commonly evaluated by clinicians and demanded by regulatory bodies. Contemporary stent designs now provide high flexibility by reducing the number of connecting links between stent segments and by allowing the connecting links to easily change their length. These design evolutions may, however, simultaneously reduce longitudinal strength and have the unintended effect of inducing some risk of longitudinal compression of the stent (the “concertina effect”) during difficult clinical cases. Progress in stent design and elimination of restenosis by drug coating has improved PCI outcome and enabled new applications. Here we discuss design trade-offs that shaped evolution and improvement in stent design, from early bare metal designs to the latest generation of drug eluting stent (DES) platforms. Longitudinal strength was not recognised as a critical parameter by clinicians or regulators until recently. Measurements, only now becoming publically available, seem to confirm vulnerability of some modern designs to longitudinal deformation. Clinicians could be more guarded in their assumption that changes in technology are beneficial in all clinical situations. Sometimes a silent trade-off may have taken place, adopting choices that are favourable for the vast majority of patients but exposing a few patients to unintended hazard.

Int J Cardiol. 2013 Apr 15;164(3):259-61. doi: 10.1016/j.ijcard.2012.09.143. Epub 2012 Oct 22.

http://www.ncbi.nlm.nih.gov/pubmed/23084111

 

Stent “Concertina:” Stent Design Does Matter

On-Hing Kwok, MBBS

From the Cardiac Catheterization & Intervention Center, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong.

ABSTRACT: The development of modern coronary stent platforms has transformed the landscape of interventional cardiology. Contemporary coronary stents are much more deliverable than older-generation stents. However, longitudinal deformation has emerged as a “new” complication in modern coronary stent platforms. Although most reported cases of longitudinal stent deformation involve mechanical or technical mishaps, it appears that it is more frequently associated with a particular stent design: the “offset peak-to-peak” stent design. This review summarizes the latest data around stent performance. Within this context, two clinical cases where longitudinal deformation was observed in the absence of any mechanical mishaps are also presented. Collectively, this evidence suggests that stent design may be a major determinant of stent performance.

SOURCE

Journal Cardiology, Volume 25 – Issue 6 – June 2013

Key words: longitudinal deformation, stent design, stent concertina, drug-eluting stent

Over the past decades, stent design and material has undergone significant evolution. The introduction of the drug-eluting stent (DES) has also made “drug delivery” another major determinant in modern stent design.1

Coronary stent design. The majority of early coronary stents were made of stainless steel. These designs were associated with variable basic manufacture, cell geometry, and strut thickness.2 Use of alloys such as cobalt chromium and platinum chromium has enabled stents to have thinner struts, while maintaining strength and radioopacity.3 Thin-strut stents improve deliverability and conformability. However, there is limited evidence suggesting that thinner struts may result in less vessel wall damage and hence less risk of restenosis.4-6 Although thin-strut DESs have never been shown to have lower restenosis rates than thick-strut DESs, the trend of thinner strut platforms has triggered innovative designs to maintain stent radial strength. The development of longer, thinner, more flexible, and easier-to-deliver stent platforms made percutaneous coronary intervention (PCI) possible even in the most tortuous anatomy and calcified vessels.7 However, longitudinal stent strength may be compromised with these modern designs.3 Stent design requires careful consideration of several performance characteristics, including crimped and expanded stent flexibility, shortening upon expansion, trackability, scaffolding, radioopacity, longitudinal strength, radial strength, and recoil.8

Stent longitudinal flexibility and deliverability prior to deployment, and vessel conformability after deployment, are widely dependent on the number, orientation, shape, thickness, and material of the crests and links.9 These parameters also determine the longitudinal strength of the stent, defined as maintenance of intact stent architecture upon exposure to compressing or elongating forces.9 Alteration of any one feature of a stent platform will undoubtedly impact other aspects of stent performance and may result in clinical complications. For instance, thinner struts improve deliverability, but reduce radio-opacity of the cobalt chromium stents. In addition, reduction of the number of fixed links between cells or alteration of their geometry may enhance flexibility and conformability, but as a consequence may compromise longitudinal strength.7

Although stent flexibility may be influenced by a variety of factors, it has been shown that stent longitudinal integrity, defined by the number of links between hoops, correlates with stent stiffness. In addition, the alignment of the links with the long axis of the stent may also be an important factor for longitudinal integrity.9

Architectural design differences are major factors affecting resistance against longitudinal compression. The peak-to-peak or peak-to-valley strut architectures of platforms result in variation between the longitudinal stiffness and strength of stents. It is highly likely that the occurrence of longitudinal deformation is dependent on a particular stent design.10

Longitudinal stent deformation. Until recently, the longitudinal strength of coronary stents has never been considered a standard parameter of stent performance. However, recent evidence identified longitudinal compression, or postdeployment stent shortening, as a newly observed complication. Longitudinal stent deformation is defined as the distortion or shortening of a stent in the longitudinal axis following successful stent deployment.3 This phenomenon describes the effect of a longitudinal compression force on the stent rings, causing them to nest or concertinate.

PCI procedures involve multiple and complex techniques that may increase the risk for longitudinal stent compression. These include the use of extra-support guide catheters, aggressive guide catheter manipulation (deep-seat), mother and child catheter systems, multiple balloon postdilations, bifurcation stent techniques, and adjunctive devices such as intravascular ultrasound (IVUS), distal protection devices, etc.7 In a clinical setting, longitudinal compression may occur in various situations (Table 1),8 and it may simply represent an angiographic detection of an exceptional PCI complication. Protrusion of struts into the lumen and extensive malapposition of struts due to longitudinal deformation may result in disruption of flow and increasing the risk of stent thrombosis. Moreover, longitudinal deformation of a DES may result in uneven drug delivery and increase the risk for in-stent restenosis (ISR).9

Clinical reports of longitudinal deformation. Hanratty and Walsh recently described 3 cases where longitudinal compression of a previously deployed stent resulted in stent deformation. Two cases were detected angiographically, while 1 was detected on adjunctive imaging. The complication was first reported with the Promus Element (Boston Scientific) platform. However, Hanratty and Walsh noted that this phenomenon has since been observed with all modern DES platforms. They concluded that such deformation could potentially result in a suboptimal technical result for the medium- to long-term and increase the risk for stent thrombosis and ISR if left undetected.7

References

1. Htay T, Liu MW. Drug-eluting stent: a review and update. Vasc Health Risk Manag. 2005;1(4):263-276.

2. Colombo A, Stankovic G, Moses JW. Selection of coronary stents. J Am Coll Cardiol. 2002;40(6):1021-1033.

3. Williams PD, Mamas MM, Morgan K, et al. Longitudinal stent deformation — a retrospective analysis of frequency and mechanisms. EuroIntervention. 2012;8(2):267-274. Epub AOP 2011.

4. Pache J, Kastrati A, Mehilli J, et al. Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO-2) trial. J Am Coll Cardiol. 2003;41(8):1283-1288.

5. Moreno R, Jimenez-Valero S, Sanchez-Recalde A. Periprocedural (30-day) risk of myocardial infarction after drug-eluting coronary stent implantation: a meta-analysis comparing cobalt-chromium and stainless steel drug-eluting coronary stents. EuroIntervention. 2011;6(8):1003-1010.

6. Kastrati A, Mehilli J, Dirschinger J, et al. Strut thickness effect on restenosis outcome (ISAR-STEREO) trial. Circulation. 2001;103(23):2816-2821.

7. Hanratty CG, Walsh SJ. Longitudinal compression: a “new” complication with model coronary stent platforms — a time to think beyond deliverability. EuroIntervention. 2011;7(7):872-877. Epub AOP 2011.

8. Prabhu S, Schikorr T, Mahmoud T, Jacobs J, Potgieter A, Simonton C. Engineering assessment of the longitudinal compression behavior of contemporary coronary stents. EuroIntervention. 2012;8(2):275-281.

9. Ormiston JA, Webber B, Webster MWI. Stent longitudinal integrity — bench insights into a clinical problem. JACC Cardiovasc Interv. 2011;4(12):1310-1317.

10. Mortier P, De Beule M. Stent design back in the picture: an engineering perspective on longitudinal stent compression. EuroIntervention. 2011;7(7):773-776.

11. Stone GW, Teirstein PS, Meredith IT, et al; PLATINUM Trial Investigators. A prospective randomised evaluation of a novel everolimus-eluting coronary stent: the PLATINUM trial. J Am Coll Cardiol. 2011;57(16):1700-1708.

12. Pitney M, Pitney K, Jepson N, et al. Major stent deformation/pseudofracture of 7 Crown Endeavor/Micro Driver stent platform: incidence and causative factors. EuroIntervention. 2011;7(2):256-262.

13. Finet G, Rioufol G. Coronary stent longitudinal deformation by compression: is this a new global stent failure, a specific failure of a particular stent design, or simply an angiographic detection of an exceptional complication. Eurointervention. 2012;8(2):177-181. Epub AOP 2011.

Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The author reports no conflicts of interest regarding the content herein.

Manuscript submitted September 12, 2012, provisional acceptance given October 31, 2012, final version accepted January 14, 2013.

Address for correspondence: On-Hing Kwok, MBBS, FRCP, FACC, FSCAI, Cardiology Center, 6/F Li Shu Fan Building, Hong Kong Sanatorium & Hospital, 2 Village Road, Happy Valley, Hong Kong. Email:vohkwok@hksh.com

SOURCE

J INVASIVE CARDIOL 2013;25(6):E114-E119

 

Part IV

Stent Thrombosis Through the Generations of Stent Design

A recent retrospective analysis provided further valuable information on the frequency and mechanisms of longitudinal stent deformation. The study involved 4455 interventional cases performed during a 4-year period. Stent deformation occurred in a total of 9 cases (0.2%) and affected 0.097% of stents deployed. In 6 cases, the Promus Element stent was involved, and there was 1 case each involving Endeavor (Medtronic), Biomatrix (Biosensors Interventional Technologies), and Taxus Liberté (Boston Scientific) stents. Stent deformation varied from 0% in several stent types to 0.86% in the case of Promus Element.3 It was virtually unseen in the Cypher and Xience (Abbott Vascular) platforms. Longitudinal stent deformation is probably not a “class effect,” but highly dependent on a particular stent design.

http://www.invasivecardiology.com/articles/stent-“concertina”-stent-design-does-matter

Author(s): 

Lawrence Rajan, MD and David J. Moliterno, MD

From the Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky.

Stent thrombosis (ST), while infrequent, remains a dreaded complication of percutaneous coronary revascularization because of the associated rates of

  • major myocardial infarction (60%-70%) and
  • early mortality (20%-25%).1

As coronary stents became more widely used in clinical practice during the late 1990s to treat acute vessel closure and to reduce restenosis, the emergence of ST redirected the efforts of the cardiology community to mitigate or eliminate this potentially catastrophic event. Advances in

  • stent design and strut thinness,
  • the advent of drug-eluting stent (DES) options, and
  • more potent antithrombotic therapy

have been substantial influences on ST.

  • DESs have been associated with higher ST rates as compared to their bare-metal counterparts, particularly when utilized among high-risk groups and high-risk lesions.

More recently, early meta-analyses of smaller studies have suggested

  • reduced ST rates with newer-generation DESs versus prior versions.2 Similarly, observations from a randomized trial suggested
  • lower ST rates with the newer-generation everolimus-eluting stent (<1%) compared to rates for the older-generation paclitaxel-eluting stent (3%).3

So while this uncommon but catastrophic complication persists in contemporary practice, its low frequency has made it difficult to study, particularly in the real-world setting.

In the current issue of the Journal of Invasive Cardiology, Dores et al have analyzed the outcome data from a large-volume, single-center prospective registry evaluating the incidence of definite ST.4 The study consisted of 3806 patients who underwent percutaneous coronary intervention between January 2003 and December 2010. In the registry, a total of 2388 patients (62.7%) were treated with first-generation DESs (sirolimus-eluting and paclitaxel-eluting stents), while 1418 patients (37.3%) were treated with second-generation DESs (everolimus-eluting and zotarolimus-eluting stents). The overall occurrence of Academic Research Consortium (ARC)-defined definite ST at 12 months was 1.2% (46 events). After correction for baseline differences between study groups and other variables deemed to influence the occurrence of ST, Dores et al concluded that the

  • use of first-generation DESs was associated with a 2.4-fold increase in the risk of definite ST. Among the cases receiving a first-generation DES,
  • the risk of ST was higher for paclitaxel-eluting versus sirolimus-eluting stents.

The observations from Dores et al are consistent with prior reports, in that the rates of definite ST are low and decreasing in recent years. As can be seen in Dores’s Figure 3 considering annual frequency of definite ST, the numerically highest years were 2003 and 2004, and over the most recent years, rates have averaged closer to 1%. Questions will remain in the field of ST, some of which will require large-scale registry data to help consider their relevance and possible answers.

The underlying challenge remains how to afford to study such low-frequency events with multifactorial and variable etiologies. Beyond the events during the interventional procedure and device utilized (ie, type of DES), many other factors that affect the rate of ST (eg, patient genotype and phenotype) are still being unraveled. Considerable research has gone into finding predictive subsets for those at increased risk for ST.5 Among identified factors are the timing and acuity of presentation. Patients presenting with an ACS are known to be more vulnerable to early ST than patients with chronic stable disease. The initial plaque rupture of ACS triggers a prothrombotic avalanche of events, from platelet activation to local thrombus formation and occlusion, spasm, and distal embolization of microcirculatory debris.6 It is interesting to note in the Dores et al. registry that patients receiving second-generation DESs more often presented with an ACS, making their observations reassuring that ST rates can be kept low with evolving care strategies.

In an analysis of the ACUITY trial, which particularly enrolled patients with ACS,7 early ST occurred with similar frequency after anticoagulation with either heparin plus glycoprotein IIb/IIIa inhibitors or bivalirudin (with or without IIb/IIIa inhibitors), and not surprisingly was predicted by diffuse atherosclerosis, suboptimal angiographic results, and inadequate pharmacotherapy. Such patients also had a higher incidence of renal insufficiency and insulin-dependent diabetes mellitus. The ACUITY subanalysis found that the rate of ST within 30 days was 1.4%, significantly higher than the 0.3%-0.5% ST rates reported among patients with stable coronary artery disease.

Among the most critical factors in mitigating the risk of ST are adequate and consistent dual-antiplatelet therapy (DAPT). A remarkable interpatient variability in the antiplatelet response to clopidogrel has been well documented. The frequency of

  • clopidogrel hyporesponsiveness has been reported among as many as 30% of patients undergoing PCI, yet the clinical relevance of antiplatelet responsivity is modest,8 again since the factors related to ST are many.
  • Loss-of-function alleles have been identified for clopidogrel metabolism, and these have been associated with an increased risk of adverse cardiovascular events, including ST.
  • Among patients with ACS, the need for more rapid and potent pharmacological suppression of platelet reactivity in the prevention of early ST is highlighted in clinical trials testing newer antiplatelet therapies.

In a landmark trial,

  • prasugrel, a more potent, consistent, and faster-acting third-generation thienopyridine has shown a significant reduction in overall ST rates compared to clopidogrel (1.1% vs 2.4%).9 Similarly,
  • ticagrelor, an oral, reversible, direct-acting inhibitor of the ADP receptor P2Y12 that has a more rapid onset and greater potency of platelet inhibition than clopidogrel was recently studied in a large clinical trial.
  • In the Platelet Inhibition and Patient Outcomes (PLATO) study, there was a significant reduction in ST in the ticagrelor group vs the clopidogrel group, with definite ST rates of 1.3% and 1.9%, respectively.10

It is becoming clear that there has been a generational improvement in DESs that has reduced the risk of ST. This has been paralleled by advances in DAPT regimens and interventional techniques that have collectively reduced the risk of ST. While the field will continue to search for answers to the

  • optimum duration of DAPT, and whether this is dependent on
  • stent type and
  • acuity of patient presentation,

DES polymers, design characteristics, and the antiproliferative drugs will also continue to evolve. Understanding incremental improvements in techniques, devices, and drugs will remain quite challenging as the rate of ST slowly moves closer to zero.

References

1. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation. 2001;103(15):1967-1971.

2. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet. 2012;379(9824):1393-1402.

3. Kedhi E, Joesoef KS, McFadden E, et al. Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial. Lancet. 2010;375(9710):201-209.

4. Dores H, Raposo L, Teles RC, et al. Stent thrombosis with second versus first generation drug eluting stents in real world coronary percutaneous intervention. J Invasive Cardiol. 2013;25(7):330-336.

5. Holmes DR Jr, Kereiakes DJ, Garg S, et al. Stent thrombosis. J Am Coll Cardiol. 2010;56(17):1357-1365.

6. Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol. 2010;30(7):1282-1292.

7. Aoki J, Lansky AJ, Mehran R, et al. Early stent thrombosis in patients with acute coronary syndromes treated with drug-eluting and bare metal stents: the Acute Catheterization and Urgent Intervention Triage Strategy trial. Circulation. 2009;119(5):687-698.

8. Holmes DR Jr, Dehmer GJ, Kaul S, Leifer D, O’Gara PT, Stein CM. ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning.” A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart Association. J Am Coll Cardiol. 2010;56(4):321-341.

9. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet. 2008;371(9621):1353-1363.

10. Wallentin L, Becker RC, Budaj A, et al; the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndrome. N Engl J Med. 2009;361(11):1045-1057.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Address for correspondence: David J. Moliterno, MD, Department of Internal Medicine, The University of Kentucky, 900 S. Limestone Avenue, 329 Wethington Building, Lexington, KY 40536-0200. Email: moliterno@uky.edu

Journal of invasive Cardiology, Volume 25 – Issue 7 – July 2013

http://www.invasivecardiology.com/articles/stent-thrombosis-through-generations

Stent Thrombosis With Second- Versus First-Generation Drug-Eluting Stents in Real-World Percutaneous Coronary Intervention: Analysis of 3806 Consecutive Procedures From a Large-Volume Single-Center Prospective Registry

Stent thrombosis (ST) is a serious and often fatal event limiting the efficacy of percutaneous coronary intervention (PCI). The pathophysiology of ST is multifactorial, and underlying causes including stent-, procedure-, lesion-, and patient-related factors seem to play different roles at different time points after the index procedure.1,2 When compared to first-generation (1stGEN) drug-eluting stents (DESs), newer DESs have been associated with a lower rate of ST in several randomized clinical trials, subsequent meta-analyses, and also in some registries, such as the recently published Swedish Coronary Angiography and Angioplasty Registry (SCAAR).3-7 New, second-generation (2ndGEN) DESs have been developed with improved design and materials, both of which may contribute to overcome some of the limitations of the older DESs. Decreased strut thickness — resulting in higher flexibility, conformability, and deliverability — and optimized polymer biocompatibility and drug delivery kinetics have been shown to contribute to a low late-loss rate and to a lower thrombotic risk.1 Despite the evidence pointing in this direction, most of the data comes from post hoc analysis and meta-analysis, mainly because studies defining ST as a primary endpoint are scarce.

We aimed to assess whether or not the systematic use of a 2ndGEN DES, relative to the 1stGEN DES, translates into a higher safety rate in a real-world population where DES implantation was indicated. For that purpose, we conducted an analysis of a single-center prospective registry, evaluating the incidence of definite ST, as defined by the Academic Research Consortium (ARC), at 12 months of follow-up as the primary outcome measure.

Author(s): 

Helder Dores, MD, Luís Raposo, MD, Rui Campante Teles, MD, Carina Machado, MD, Sílvio Leal, MD, Pedro Araújo Gonçalves, MD, Henrique Mesquita Gabriel, MD, Manuel Sousa Almeida, MD, Miguel Mendes, MD

Abstract

Background and Aims. When compared to their first-generation (1stGEN) counterparts, second-generation (2ndGEN) drug-eluting stents (DESs) have been associated with better clinical outcomes in randomized clinical trials, namely by reducing the rates of stent thrombosis (ST). Our goal was to investigate whether or not the broad use of newer devices would translate into higher safety in a real-world population. For that purpose, we compared the occurrence of definite ST at 12 months between two patient subsets from a large-volume single-center registry, according to the type of DES used. Total mortality was a secondary endpoint.

Methods and Results. Between January 2003 and December 2010, a total of 3806 patients were submitted to percutaneous coronary intervention (PCI) with only 1stGEN or 2ndGEN DES: 2388 patients (62.7%) were treated with 1stGEN DES only (sirolimus-eluting stent [SES] = 1295 [34.0%]; paclitaxel-eluting stent [PES] = 943 [24.8%]; both stent types were used in 150 patients) and 1418 patients (37.3%) were treated with 2ndGEN DESs only. The total incidence of definite ST (as defined by the Academic Research Consortium) at 12 months was 1.2% (n = 46). After correction for baseline differences between study groups and other variables deemed to influence the occurrence of ST, the use of 1stGEN DES was associated with a significant 2.4-fold increase in the risk of definite ST (95% confidence interval [CI], 1.05-5.42; P=.039) at 12 months; adjusted risk was higher with PES (hazard ratio [HR], 3.6; 95% CI, 1.48-8.70; P=.005) than with SES (HR, 2.3; 95% CI, 0.92-5.65; P=.074). Total mortality (3.7% vs 3.5%) did not differ significantly between groups (adjusted HR, 1.2; 95% CI, 0.81-1.84, P=.348).

Conclusions. Our data suggest that in the real-world setting of contemporary PCI, the unrestricted use of newer 2ndGEN DESs translates into an improvement in PCI safety (relative to 1stGEN DESs), with a significantly lower risk of definite ST at 12 months.

Journal of Invasive Cardiology                    Volume 25 – Issue 7 – July 2013

J INVASIVE CARDIOL 2013;25(7):330-336

Key words: stent thrombosis, drug-eluting stent

http://www.invasivecardiology.com/articles/stent-thrombosis-second-versus-first-generation-drug-eluting-stents-real-world-percutaneous

 

Part V

Stent Thrombosis in Randomized Trials of Drug-Eluting Stents:

Reappraisal of the Synthesis of Evidence!

Stent Thrombosis in Randomized Clinical Trials of Drug-Eluting Stents

Laura Mauri, M.D., Wen-hua Hsieh, Ph.D., Joseph M. Massaro, Ph.D., Kalon K.L. Ho, M.D., Ralph D’Agostino, Ph.D., and Donald E. Cutlip, M.D.

N Engl J Med 2007; 356:1020-1029February 12, 2007DOI: 10.1056/NEJMoa067731

http://www.nejm.org/doi/full/10.1056/NEJMoa067731?goback=%2Egde_675087_member_263490750

 

EDITORIAL on  bare-metal stents (BMS) vs sirolimus-eluting stents (SES)

With full interest, we read the article “Stent thrombosis in randomized clinical trials (RCT) of drug-eluting stents (DES)” by Mauri L et al, previously published in the New England Journal of Medicine in 2007 [1]. The authors concluded that “The incidence of stent thrombosis (ST) did not differ significantly between patients with DES and those with bare-metal stents (BMS) in RCT, although the power to detect small differences in rates was limited” [1]. 
I have the following concerns. First and foremost, ST in the BMS groups occurred more frequently among patients who underwent intervening target lesion revascularization (TLR) versus those who did not [1]. And since brachytherapy was the standard of care for treatment of restenosis at that time, it was used more frequently in patients with restenosis following BMS (9 out of 11 patients with BMS who underwent intervening TLR and subsequently developed definite/probable ST), in whom restenosis occurred more frequently and more diffusely, compared with DES [1]. In an observational study, brachytherapy was associated with a high risk of late (thrombotic) total occlusion of the index vessel at 6-month angiographic follow-up [2]. In that study, the mean time from brachytherapy to late total occlusion was 5.4 ± 3.2 months [2]. Therefore, brachytherapy may constitute selection bias for devices with higher rates of restenosis, by increasing the risk of late ST following intervening procedures for these devices. This might explain the much higher rate of late (beyond 30 days to 1 year) definite/probable ST following BMS compared with sirolimus-eluting stents (SES) (1% versus 0.1%, respectively), which was obviously responsible for the higher overall rate of definite/probable ST following BMS compared with SES at 4-year follow-up (1.7% versus 1.5%, respectively, p=0.7) [1]. It is worth mentioning that

  • BMS was associated with a lower rate of very late (beyond 1 year) definite/probable ST compared with SES (0.4% versus 0.9%, respectively) [1]. Second,
  • the study included 4 RCT of SES published from 2002 to 2004, and 4 RCT of paclitaxel-eluting stents (PES) published from 2003 to 2005, all of which were published before the Academic Research Consortium (ARC) report that put forward the current standard definitions of ST [3].

Thus, the ARC definitions were applied to all of these trials retrospectively, and therefore, might have missed some of the ST events.

  • Third, the study enrolled 878 patients with SES versus 870 treated with the corresponding BMS, 1400 patients with PES versus 1397 treated with the corresponding BMS; thus, it was clearly underpowered for detection of a difference in rare-by-nature events such as ST.  Forth, the
  • RCT included in the study were the earliest RCT of SES and PES; hence, they enrolled relatively low-risk patient, lesion, and clinical subsets, that do not reflect real-world practice.
  • Finally, the individual databases of RCT of PES were managed by Boston Scientific, which might introduce another source of bias!

References

1. Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007;356:1020-9.

2. Waksman R, Bhargava B, Mintz GS, et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol. 2000;36:65-8.

3. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51.

Part VI

Duration of Dual Antiplatelet Therapy following Zotarolimus-Eluting Stents and A New Strategy for Discontinuation of Dual Antiplatelet Therapy

Dr. Pearlman: Drug eluting stents decrease in stent stenosis from endothelial exuberant growth at the cost of increased propensity to thrombosis, offset by prolonged use of dual anti platelet medication. The net effect depends on compliance which if good results in net decrease. The risk has increased due to drug eluting stent prevalence, but that is offset by management with dual anti platelet agents, so the net incidence is reduced. There have been a number of presentations based on angioscopy showing thrombus inside bare metal and drug eluting stents that supported the general concensus also supported by TIMI trials that stent thrombosis is promoted by metal stents until they endothelialize, and that drug-eluting stents impede the endothelialization “too well” prolonging that issue, so minimal dual platelet agent duration in practice is 3 months for BMS, 6-12 months for DES, but benefit fades to 2% at 1 year, 1% at 2 years at which point risk-benefit is unconvincing and many stop plavix, while some insist it is a lifetime medication.

With full interest, we read the article “Dual antiplatelet therapy duration and clinical outcomes following treatment with zotarolimus-eluting stents (ZES)” by Kandzari DE, et al [1]. The authors concluded that “Among patients treated with ZES, late-term events of death, myocardial infarction (MI), stroke, and stent thrombosis (ST) do not significantly differ between patients taking 6 months dual antiplatelet therapy (DAPT) compared with continuation beyond 1 year” [1].
I have the following concerns. First, although the authors claimed that their study was based on a pooled analysis of patients who received ZES in 5 ‘clinical trials’; actually, 2 out of 5 were not ‘trials’. One was a registry of direct stenting with ZES [2], and the other was a study of pharmacokinetics of ABT 578 in a subset of the ENDEAVOR II trial, that was not published in a medical journal [3]! Second, patients were classified by “DAPT adherence according to the most recent report of compliance with aspirin and thienopyridine”. Evidence supports that premature discontinuation clopidogrel is the most powerful independent predictor of late ST [4].

There is no evidence, however, that stopping aspirin predisposes to ST following drug-eluting stent implantation. Third, follow-up of DAPT adherence was done at 30 days, 6 months, then annually for 3 years. Reporting DAPT adherence based on “the last reported follow-up interval of compliance with both aspirin and clopidogrel” does not reflect the actual duration of clopidogrel received in any of the comparison groups. Forth, in the second comparison of “6 months on/24 months off” (on DAPT at 6 but not at 24 months) versus “≥24 months” (on DAPT at 6 and 24 months)”, the first group included, by definition, patients who were also on DAPT at 12 months (but not at 24 months). Thus, it cannot be taken to reflect a comparison between 6-month DAPT and 24-month DAPT!  Fifth, the ENDEAVOR II and ENDEAVOR III trials were published in 2006, before the publication of ARC report [5,6]. Therefore, the ARC definitions of ST were applied retrospectively in many patients, which might explain the absence of ‘probable’ ST in all comparison groups, in all time points. Sixth, major bleeding was defined exclusively as “any hemorrhagic event that required blood product transfusion”. This might explain why such rates were 0% in all groups, in all time points. Finally, the study involved low-risk patient and lesion subsets, and was statistically underpowered for rare events such as ST, cardiac death, or MI.

References

1. Kandzari DE, Barker CS, Leon MB, et al. Dual antiplatelet therapy duration and clinical outcomes following treatment with zotarolimus-eluting stents. JACC Cardiovasc Interv 2011;4:1119-28.
2. Schultheiss HP, Grube E, Kuck KH, et al. Endeavor II Continued Access Investigators. Safety of direct stenting with the Endeavor stent: results of the Endeavor II continued access registry. EuroIntervention 2007;3:76–81.
3. Pharmacokinetics of ABT-578 in patients from Endeavor stent: results from a subset of a double-blind, randomized, multicenter (ENDEAVOR-II) trial. In: The ENDEAVOR II Study 30-Day Pharmacokinetic Report. Abbot Park, IL: Abbott Laboratories, 2004.
4. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-30.
5. Fajadet J, Wijns W, Laarman GJ, et al. ENDEAVOR II Investigators. Randomized, double-blind, multicenter study of the Endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent for treatment of native coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial. Circulation 2006;114:798–806.
6. Kandzari DE, Leon MB, Popma JJ, et al. ENDEAVOR III Investigators. Comparison of zotarolimus-eluting and sirolimus-eluting stents in patients with native coronary artery disease: a randomized controlled trial. J Am Coll Cardiol 2006;48:2440–7.
SOURCE
interventions.onlinejacc.org <http://interventions.onlinejacc.org> interventions.onlinejacc.org <http://interventions.onlinejacc.org>

A New Strategy for Discontinuation of Dual Antiplatelet Therapy

With interest, we read the article “A New Strategy for Discontinuation of Dual Antiplatelet Therapy: REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation (RESET) Trial” by Kim B-K, et al [1]. The authors concluded that Endeavor zotarolimus-eluting stent (E-ZES) with 3-month dual antiplatelet therapy (DAPT) was noninferior to other drug-eluting stents (DES) with 12-month DAPT (standard therapy) with respect to the occurrence of the primary endpoint (a composite of cardiovascular death, myocardial infarction (MI), stent thrombosis (ST), target vessel revascularization (TVR), or bleeding at 1 year) [1]. 
I have the following concerns. First, the study design was defective since the comparator group should have been composed of patients who received the same stent (E-ZES) and took DAPT for 12 months. Moreover, the comparator group was not homogeneous, since it was composed of patients who received sirolimus-eluting stents (SES, Cypher, 28.5%), everolimus-eluting stents (EES, Xience, 30%), and ZES with a biocompatible polymer (R-ZES, Resolute, 41.5%). This would further complicate the comparison since it dilutes the results of the comparator group by mixing first- (Cypher) with second-generation (Xience and Resolute) DES. Further confusion was added with the unjustified stratified randomization of the comparator group: patients with Diabetes mellitus (DM) and those with acute coronary syndrome (ACS) were assigned to R-ZES; those with short lesions to SES; those with long lesions to EES. Second, whereas the trial compared two regimens (short versus long) of DAPT following DES, the primary endpoint adopted by the authors included ischemia-driven TVR; an event completely unrelated to the safety or efficacy of a DAPT regimen. Third, the authors could not explain why the event rates were very low (cardiovascular death 0.2%, MI 0.2%, ARC definite/probable ST 0.2%) compared with previous reports of the E-ZES at a similar time point: ENDEAVOR II trial (total death 1.2%, MI 2.7%, ST 0.5% at 9 months); ENDEAVOR IV trial (cardiac death 0.5%, MI 1.6%, ARC definite/probable ST 0.9% at 12 months) [2,3]. Forth, unexpectedly, both TVR and ST rates in patients with DM who received E-ZES were lower than the rates for the whole E-ZES group! And in the ACS subgroup, patients who received the standard therapy (R-ZES) had rates of cardiovascular death 0%, MI 0%, and ST 0%, at 12 months! And surprisingly, in the subset of short lesions, despite the shorter duration of DAPT, bleeding rates were higher with E-ZES + 3-month DAPT versus standard therapy (0.6% versus 0%)! Fifth, based on the current low 12-month rates of primary composite endpoint (4.7%) compared with the figure used for statistical power calculation (10-11%), the trial was underpowered for the primary endpoint. Additionally, the non-inferiority margin of 4% was very wide for the 12-month rates of primary endpoint (4.7%). Finally, enrollment of 2117 patients in 26 centers over 20 months speaks of a low enrollment rate of 4.1 patients/center/month, that reflects an overt selection bias.

References 


1. Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012;60:1340-8.

2. Fajadet J, Wijns W, Laarman GJ, et al. Randomized, double-blind, multicenter study of the Endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent for treatment of native coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial. Circulation 2006;114:798-806.

3. Leon MB, Mauri L, Popma JJ, et al. A randomized comparison of the ENDEAVOR zotarolimus-eluting stent versus the TAXUS paclitaxel-eluting stent in de novo native coronary lesions 12-month outcomes from the ENDEAVOR IV trial.

SOURCE

J Am Coll Cardiol 2010;55:543-54.

content.onlinejacc.org content.onlinejacc.org

http://digitalreprints.elsevier.com/i/85787/6

Conclusions

by Larry H Bernstein, MD, FCAP

This has been a six part discussion on the progress of stent design, and the decreasing problem of stent thrombosis, which evades elimination with a tradeoff in greater utility and somewhat greater risk.  However, the risk of thrombotic events has become low enough that accurate comparisons of stent technologies, method of placement, and antithrombotic techniques to avoid thrombotic complications is burdened by statistical power limitations.  In addition to the issue of sample size, there is an issue of patient characteristics that probably confer increased risk.

In the first part we found that stent placement is done in 15-20% of cases at a bifurcation site, where it is most favorable for plaque buildup from turbulent flow and shear stress.  Recall that Routledge et al. (1) presented 2-year outcome data of 477 patients treated for bifurcation coronary disease with provisional side branch T-stenting using drug-eluting stents (DES), and they concluded that a systematic approach is feasible for 90% of the patients, with acceptable efficacy and safety profiles.  There are several inherent problems that encumbered any analysis.  These were: numerous anatomic configurations of bifurcation types, with the concern for late complications, restenosis, and its frequency, leading to the dilemma of placing two stents versus one stent, and then another as a side branch, if needed.  The study (1) did indicate that provisional stenting is feasible in 90% of all patients, and those who received a second stent in the side branch, 28%, had similar long-term outcomes as those treated with 1 stent. The outcome of this study is similar to that of the Nordic Bifurcation study, which observed no difference in outcomes at 6 months’ follow-up between 1 and 2 stents (9).  As for technique, the latest Nordic Bifurcation Stent Technique study, comparing the culotte and crush techniques, reported low rates of angiographic restenosis and major adverse cardiac events for both techniques (10). However, kissing balloon was shown to be critical in preventing restenosis. Provisional T-stenting offers several advantages compared with other bifurcation techniques. It seems to be the simplest and is associated with favorable long-term outcomes.  It has also been shown that side branches and osteal disease are most problematic and that dedicated devices will have a role in left main disease.

The next issue for consideration is the use of biodegradable drug-eluting stents versus durable polymer DES. Biodegradable polymer DES resulted in lower rates than durable polymer DES of

  • target lesion revascularization (hazard ratio [HR] 0.82, 95 percent confidence interval [CI] 0.68-0.98, P=0.029).
  • definite stent thrombosis (the study’s primary safety endpoint), (HR 0.56, 95 percent CI 0.35-0.90, P=0.015).
  • very late stent thrombosis (clots occurring more than one year after angioplasty) for the biodegradable polymer group (HR 0.22, 95 percent CI 0.08-0.61, P=0.004).
  • cardiac death and heart attack (HR 0.59, 95 percent CI 0.73-0.95, P=0.031).

The third topic for consideration is the tradeoff between stent flexibility versus the concertina effect. Longitudinal strength was not recognized as a critical parameter by clinicians or regulators until recently. Measurements, only now becoming publically available, seem to confirm vulnerability of some modern designs to longitudinal deformation. Stent designs now provide high flexibility by reducing the number of connecting links between stent segments and by allowing the connecting links to easily change their length.  However, this design results in reduced longitudinal strength with the unintended effect of inducing some risk of longitudinal compression of the stent (the “concertina effect”).  While contemporary coronary stents are much more deliverable than older-generation stents, longitudinal deformation has emerged as a “new” complication in modern coronary stent platforms. This is more frequently associated with a particular stent design: the “offset peak-to-peak” stent design.  Thin-strut stents improve deliverability and conformability. There is only limited evidence that thinner struts may result in less vessel wall damage reducing risk of restenosis. The trend of thinner strut platforms has triggered innovative designs to maintain stent radial strength. The development of longer, thinner, more flexible, and easier-to-deliver stent platforms made percutaneous coronary intervention (PCI) possible even in the most tortuous anatomy and calcified vessels.  Longitudinal stent deformation, the distortion or shortening of a stent in the longitudinal axis is the effect of a longitudinal compression force on the stent rings, causing them to nest or concertinate.

The fourth question is the effect of stent design on stent thrombosis.  A recent retrospective analysis provided further valuable information on the frequency and mechanisms of longitudinal stent deformation. The study involved 4455 interventional cases performed during a 4-year period. Stent deformation occurred in a total of 9 cases (0.2%) and affected 0.097% of stents deployed.   Longitudinal stent deformation is probably not a “class effect,” but highly dependent on a particular stent design.

Stent thrombosis (ST), while infrequent, remains a dreaded complication of percutaneous coronary revascularization because of the associated rates of

  • major myocardial infarction (60%-70%) and
  • early mortality (20%-25%).1

the emergence of ST redirected the efforts of the cardiology community to mitigate or eliminate this potentially catastrophic event by

  • stent design and strut thinness,
  • the advent of drug-eluting stent (DES) options, and
  • more potent antithrombotic therapy

DESs have been associated with higher ST rates as compared to their bare-metal counterparts, particularly when utilized among high-risk groups and high-risk lesions.

The overall occurrence of Academic Research Consortium (ARC)-defined definite ST at 12 months was 1.2% (46 events). After correction for baseline differences between study groups and other variables deemed to influence the occurrence of ST, Dores et al concluded that the

  • use of first-generation DESs was associated with a 2.4-fold increase in the risk of definite ST. Among the cases receiving a first-generation DES,
  • the risk of ST was higher for paclitaxel-eluting versus sirolimus-eluting stents.

It should not be a surprise that patients presenting with an ACS are known to be more vulnerable to early ST than patients with chronic stable disease. The initial plaque rupture of ACS triggers a prothrombotic avalanche of events, from platelet activation to local thrombus formation and occlusion, spasm, and distal embolization of microcirculatory debris.6 It is interesting to note in the Dores et al. registry that patients receiving second-generation DESs more often presented with an ACS, making their observations reassuring that ST rates can be kept low.   Patients who had early ST were characterized by diffuse atherosclerosis, angiography, inadequate pharmacotherapy, and had a higher incidence of renal insufficiency and insulin-dependent diabetes mellitus.  The ACUITY subanalysis found that the rate of ST within 30 days was 1.4%, significantly higher than the 0.3%-0.5% ST rates reported among patients with stable coronary artery disease.

Among the most critical factors in mitigating the risk of ST are adequate and consistent dual-antiplatelet therapy (DAPT).  Among patients with ACS, the need for more rapid and potent pharmacological suppression of platelet reactivity in the prevention of early ST is highlighted in clinical trials testing newer antiplatelet therapies.  In the Platelet Inhibition and Patient Outcomes (PLATO) study, there was a significant reduction in ST in the ticagrelor group vs the clopidogrel group, with definite ST rates of 1.3% and 1.9%, respectively.

This brings us to ST in randomized trials of DES.  There was a much higher rate of late (beyond 30 days to 1 year) definite/probable ST following BMS compared with sirolimus-eluting stents (SES) (1% versus 0.1%, respectively).  BMS was associated with a lower rate of very late (beyond 1 year) definite/probable ST compared with SES (0.4% versus 0.9%, respectively) [1].  The different overall rate of definite/ probable ST following BMS compared with SES is nearly equal at 4-year follow-up (1.7% versus 1.5%, respectively), is indeterminate (p=0.7) [1]. The study was underpowered for detection of a difference in rare-by-nature events such as ST.

Finally, Dr. Pearlman analyzes the published studies concerning whether there should be a reduction in the length of dual antiplatelet therapy to six months.  Drug eluting stents decrease in stent stenosis from endothelial exuberant growth at the cost of increased propensity to thrombosis, offset by prolonged use of dual anti-platelet medication.  The risk has increased due to drug eluting stent prevalence, but that is offset by management with dual anti platelet agents, so the net incidence is reduced. Stent thrombosis is promoted by metal stents until they endothelialize, but drug-eluting stents impede the endothelialization, so minimal dual platelet agent duration in practice is 3 months for BMS, 6-12 months for DES, but benefit fades to 2% at 1 year, 1% at 2 years at which point risk-benefit is unconvincing.  Evidence supports that premature discontinuation clopidogrel is the most powerful independent predictor of late ST.

So here we have the status in a nutshell.

  • ST has driven the design of stents to be simpler to insert effectively, with a clear goal to minimize ST
  • The stent designs have resulted in thinner, and multi-segmented longer insertions as needed.
  • The result of improved stent design has been an effect of local vessel distortion.
  • The standard of practice is provisional T-branch DES
  • The use of dual antiplatelet therapy for not less than 1 year is determined by the time required for endothelialization of the artery.
  • There is a risk difference incurred by ACS versus stable disease, and by adequacy of antithrombotic therapy prior to an acute event.

Other related articles published on this Open Access Online Scientific Journal, include the following:

AHA, ACC Change in requirement for surgical support:  Class IIb -> Class IIa Level of Evidence A: Supports Nonemergent PCI without Surgical Backup (Change of class IIb, level of Evidence B).

Larry H Bernstein, MD, FCAP and Justin D Pearlman, MD, PhD, FACC

Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Coronary Reperfusion Therapies: CABG vs PCI – Mayo Clinic preprocedure Risk Score (MCRS) for Prediction of5. in-Hospital Mortality after CABG or PCI

Larry H. Bernstein, MD, FCAP  and Aviva Lev-Ari, PhD, RN

Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents

Aviva Lev-Ari, PhD, RN

Absorb™ Bioresorbable Vascular Scaffold: An International Launch by Abbott Laboratories

Aviva Lev-Ari, PhD, RN

CABG or PCI: Patients with Diabetes – CABG Rein Supreme

Aviva Lev-Ari, PhD, RN

To Stent or Not? A Critical Decision

Aviva Lev-Ari, PhD, RN

New Drug-Eluting Stent Works Well in STEMI

Aviva Lev-Ari, PhD, RN

Revascularization: PCI, Prior History of PCI vs CABG

Aviva Lev-Ari, PhD, RN

Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

Larry H Bernstein, MD, FCAP and  Aviva Lev-Ari, PhD, RN

Outcomes in High Cardiovascular Risk Patients: Prasugrel (Effient) vs. Clopidogrel (Plavix); Aliskiren (Tekturna) added to ACE or added to ARB

Aviva Lev-Ari, PhD, RN

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After Cardiac Transplantation: Sirolimus acts as immunosuppressant Attenuates Allograft Vasculopathy

Writer and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN 

 

Sirolimus as primary immunosuppression attenuates allograft vasculopathy with improved late survival and decreased cardiac events after cardiac transplantation

Topilsky Y, Hasin T, Raichlin E, Boilson BA, Schirger JA, et al.
Circulation. 2012 Feb 7;125(5):708-20.    http://dx.doi.org/10.1161/CIRCULATIONAHA.111.040360. Epub 2011 Dec 29

BACKGROUND: We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant

  1. in the long-term attenuation of cardiac allograft vasculopathy progression and
  2. the effects on cardiac-related morbidity and mortality.
METHODS:  Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors.
  • Age,
  • sex,
  • ejection fraction, and
  • time from transplantation to baseline intravascular ultrasound study were not different (P>0.2 for all) between the groups;
  • neither were secondary immunosuppressants and
  • use of steroids.

Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later.

RESULTS:  Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P=0.0003) owing to
  1. reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation (P=0.05) and
  2. improved positive vascular remodeling (P=0.01) in patients analyzed late (>2 years) after transplantation.
Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations.
  1. Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P=0.006),
  2. There was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P=0.002).
CONCLUSIONS:  Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant
  1. attenuates long-term cardiac allograft vasculopathy progression and
  2. may improve long-term allograft survival owing to favorable coronary remodeling.
Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.

Related articles

Other related articles published on this Open Access Online Scientific Journal include the following:

Svelte Drug-Eluting Stent Utilizing New Class of Bioabsorbable Drug Coating Attains 0% Clinically-Driven Events Through 12-Months in First-In-Man Study
Aviva Lev-Ari, PhD, RN
Biomaterials Technology: Models of Tissue Engineering for Reperfusion and Implantable Devices for Revascularization
Larry h Benstein, MD, FCAP
Vascular Repair: Stents and Biologically Active Implants
Larry h Benstein, MD, FCAP
New Drug-Eluting Stent Works Well in STEMI
Aviva Lev-Ari, PhD, RN
Coronary Artery DiseaseMedical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents
Aviva Lev-Ari, PhD, RN
Table 1 Illustration

Table 1 Illustration (Photo credit: Libertas Academica)

Photograph of the Taxus drug-eluting stent, fr...

Photograph of the Taxus drug-eluting stent, from the web site of the U.S. Food and Drug Administration. (Photo credit: Wikipedia)

Read Full Post »


Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty

Larry H. Bernstein, MD, Writer
And
Aviva Lev-Ari, PhD, RN, Curator

 

This is a summary of several studies, mostly reviewing one decade of work at Texas Heart Institute, Houston, TX.

Seminal treatments of the evolving methods, leading to a recent review of options for

  • Survival comparison of CABD vs PCI
  • Mitral valve repair or mitral valve replacement for the treatment of ischemic mitral regurgitation. This might further consolidate a series of articles in these chapters.

SOURCES

1. Bypass, Angioplasty Similar in Survival 10 Years After Heart Procedures, Survival Rates Differ Little. K Doheny. WebMD Health News   Oct. 15, 2007
3. Will Stent Revascularization Replace Coronary Artery Bypass Grafting? JM Wilson Tex Heart Inst J. 2012; 39(6): 856–859
4. Coronary Artery Bypass Surgery versus Coronary Stenting. Risk-Adjusted Survival Rates in 5,619 Patients. RP Villlareal,V-V Lee, MA Elayda, JM Wilson.  Tex Heart Inst J. 2002; 29(1): 3–9.
5. Should all ischemic mitral regurgitation be repaired? When should we replace?  DJ LaPar, IL Kron. Curr Opin Cardiol. 2011 March; 26(2): 113–117
6. Hybrid Cath Lab Combines Nonsurgical, Surgical Treatments

Bypass, Angioplasty Similar in Survival 10 Years After Heart Procedures

The survival rates 10 years after coronary artery bypass surgery and angioplasty are similar, according to a new analysis of nearly 10,000 heart patients. Five years after the procedures, 90.7% of the bypass patients and 89.7% of the angioplasty patients were still alive, says  Mark A. Hlatky, MD, senior author of the analysis and a professor of health research and policy and professor of medicine at Stanford University School of Medicine in Palo Alto.

Hlatky and colleagues stress that their analysis only applies to a select group of heart patients: those for whom either procedure would be considered a reasonable choice. For patients who are eligible for either heart intervention, “either is feasible,” Hlatky tells WebMD. The report is released early online and will be published in the Nov. 20 issue of the Annals of Internal Medicine.

CABG vs. Angioplasty

The researchers evaluated the results of 23 clinical trials in which 5,019 patients (average age 61 years; 73% men) were randomly assigned to get angioplasty with or without stents (PCI), and 4,944 were assigned to get coronary artery bypass graft surgery (CABG) In angioplasty, interventional cardiologists push a balloon-like device into the coronary arteries and inflate the balloon to widen the vessel. An expandable wire mesh tube called a stent may be inserted to keep the vessel open. Some stents are coated with drugs meant to help prevent the artery from clogging up. In 2005, about 645,000 angioplasty procedures were done in the U.S. In bypass surgery, cardiac surgeons harvest a segment of a healthy blood vessel from another part of the body and use it to bypass the clogged artery or arteries, rerouting the blood to improve blood flow to the heart. About 261,000 bypass procedures were done in the U.S. in 2005.

Findings

Besides similar survival rates overall, the researchers found no significant survival differences between the two procedures for patients with diabetes, although earlier research had seemed to favor bypass surgery. Similar numbers of patients suffered heart attacks within five years of the procedures. While 11.9 of those who got angioplasty had a heart attack within five years, 10.9% of those who got bypass did. Repeat procedures were more common in angioplasty patients. While 46.1% of angioplasty patients who didn’t get a stent needed repeat procedures, 40.1% of those who got a stent did. But just 9.8% of surgery patients needed another procedure.  The study didn’t include information on drug-coated stents.

Second Opinions

The new analysis is “very complete,” says Kim A. Eagle, MD, director of the Cardiovascular Center and Albion Walter Hewlett Professor of Internal Medicine at the University of Michigan, Ann Arbor. The study shows, he says, that if either procedure is considered appropriate for an individual patient, the decision can rest on patient attitudes and preferences. Patients preferences might be based on lower need to repeat in favor of surgery, or on avoidance of surgery in favor of angioplasty. But it is important to note, acoording to Curtis Hunter at Santa-Monica-UCLA, that the studies cover the least sick with heart disease, so the two procedures are shown to be equal in a very small subset of the patients.

Coronary Artery Bypass Surgery versus Coronary Stenting – Risk-Adjusted Survival Rates in 5,619 Patients  THIJ. 2002

We used the Texas Heart Institute Cardiovascular Research Database to retrospectively identify patients who had undergone their 1st revascularization procedure with coronary artery bypass surgery (CABG; n=2,826) or coronary stenting (n=2,793) between January 1995 and December 1999. Patients were classified into 8 anatomic groups according to the number of diseased vessels and presence or absence of proximal left anterior descending coronary artery disease. Mortality rates were adjusted with proportional hazards methods to correct for baseline differences in severity of disease and comorbidity.
We found that in-hospital mortality was significantly greater in patients undergoing CABG than in those undergoing stenting (3.6% vs 0.75%; adjusted OR 8.4; P <0.0001). At a mean 2.5-year follow-up, risk-adjusted survival was equivalent (CABG 91%, stenting 95%; adjusted OR 1.26; P = 0.06). When subgroups matched for severity of disease were compared, no differences in risk-adjusted survival were seen. A survival advantage of stenting was noted in 3 categories of patients: those >65 years of age (OR 1.33, P = 0.049), those with non-insulin-requiring diabetes (OR 2.06, P = 0.002), and those with any noncoronary vascular disease (OR 1.59, P = 0.009).
In this nonrandomized observational study, CABG had a higher periprocedural mortality rate than did percutaneous stenting. At 2.5 years, however, the survival advantage of stenting was no longer evident. These data suggest that there is no intermediate-term survival advantage of CABG over stenting in patients who have multivessel disease with lesions that can be treated percutaneously. (Tex Heart Inst J 2002;29:3–9)

Fig. 1 Adjusted and unadjusted survival rates in all patients treated with CABG or PCI-stenting
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC101260/table/t3-2/?report=previmg

survival rates  of CABG or PCI-stenting

TABLE III. Multivariate Correlates of Intermediate-Term (2.5-Year) Mortality
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC101260/table/t3-2/?report=previmg

Fig. 2 Adjusted odds ratios comparing the results of CABG and PCI-stenting in the 8 anatomic subgroups.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC101260/bin/2FF2.jpg

Adjusted odds ratios comparing the results of CABG and PCI-stenting in the 8 anatomic subgroups

TABLE IV. Intermediate-Term (2.5-Year) Survival According to Treatment in Each of the 8 Anatomic Groups
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC101260/bin/2TT4.jpg

Intermediate-Term (2.5-Year) Survival According to Treatment in Each of the 8 Anatomic Groups

Fig. 3 Adjusted odds ratios comparing the results of CABG and PCI-stenting in the various prespecified subsets.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC101260/bin/2FF3.gif

Adjusted odds ratios comparing the results of CABG and PCI-stenting in the various prespecified subsets.

Will Drug-Eluting Stents Replace Coronary Artery Bypass Surgery?

Abstract

Introduction
The growth of the PCI industry and the consequent decline in the number of patients referred for CABG has produced much speculation about the future role of each type of intervention. Because the new drug-eluting stents allow PCI to be performed with lower rates of early restenosis than do bare-metal stents or percutaneous transluminal coronary angioplasty (PTCA) alone, 2–8 some have predicted that surgical revascularization will soon be obsolete.

CABG vs Pharmaco-Therapy

Randomized clinical trials performed during the 1970s and early 1980s clearly established the advantages of CABG over medical therapy in patients with triple-vessel CAD, left main coronary artery stenosis, double-vessel CAD with proximal left anterior descending (LAD) coronary artery stenosis, or left ventricular dysfunction. Problems arose subsequently because of the limitations built into the trial so that the results were biased in favor of medical therapy.  These were:
  • stringent exclusion criteria that eliminated a large percentage of potential participants
  • left main CAD and an ejection fraction of less than 0.40, eliminated patients for whom CABG would have been beneficial
  • the high rate of crossover from the medical to the surgical groups

The numerous technical and technological advances made since these trials were completed limit the degree to which their results resemble those of the CAD treatments used today. The maximal medical therapy used during the trials did not routinely include lipid-lowering agents, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, clopidogrel, or some of the other drugs currently used for CAD. Nor did the CABG groups benefit from advances that were subsequently made in preoperative imaging, perfusion and myocardial protection, anesthesia, and perioperative and intensive care practices. CABG did not then include the use of left internal mammary artery (LIMA) grafts, much less other arterial conduits. Finally, PCIs, including balloon angioplasty and stenting, were not included in these trials.

CABG vs PTCA

Randomized trials comparing PTCA with CABG revealed dramatically higher re-intervention rates in the PTCA groups and better angina relief in the CABG groups, although there were no significant differences in death or myocardial infarction rates. The Duke database study. 9 showed better survival rates with PTCA than with CABG in patients with single-vessel CAD, whereas CABG produced better survival than did PTCA in patients with severe, triple-vessel CAD.
These results are not necessarily representative of the results obtainable today with PTCA and CABG, for several reasons.
1.  stents were not used in the PTCA patients in these trials
2.  operative mortality rates for the CABG groups were higher than the rates currently found in the Society of Thoracic Surgeons (STS) database
3.  the inclusion/exclusion criteria of these studies eliminated a high percentage of those patients who might have benefited more from CABG than from PTCA

CABG vs Stents

The introduction of coronary artery stenting resulted in better outcomes than those produced by balloon angioplasty or by other adjuncts, including rotational atherectomy, brachytherapy, and laser angioplasty.  Since then, stent designs and delivery techniques have advanced considerably. The use of coronary stents has greatly decreased the necessity of emergent CABG for technical failure of PCI and for dissection or rupture of coronary arteries during PCI. Another major advance in the application of PCI is the use of the antiplatelet agent clopidogrel in addition to aspirin after PCI, as well as the use of glycoprotein (GP) IIb/IIIa receptor inhibitors during the procedure. These adjuncts have significantly reduced the incidence of acute and subacute thrombosis after PTCA with stenting.
Randomized trials comparing PTCA plus stenting with PTCA alone have shown that stenting significantly reduces rates of restenosis and re-intervention, as well as the frequency of emergent CABG.  On the other hand, randomized trials of stenting versus surgery have produced less conclusive results regarding the mid-term survival and freedom from adverse events.  For example, the Stent or Surgery (SOS) trial reported a greater need for repeat revascularization in the stent group (21%) than in the CABG group (6%) and a survival advantage in the CABG group (hazard ratio, 2.91; 95% CI, 1.29–6.53; P = 0.01) during the 3-year follow-up period. Additionally, angina and the use of anti-angina medications were less common in the CABG group at 1-year follow-up.
The ARTS and ERACI trials also reported an increased need for revascularization in the stent groups but did not show a survival advantage in the CABG groups. This was due in part to a higher operative mortality rate in the CABG group than reported in the STS database. Like the PCI versus CABG trials mentioned previously, these randomized trials involved a select group of patients with relatively low expected mortality rates and relatively high expected technical success with PCI.
Observational data in retrospective analyses of large patient databases comparing CABG with PCI plus stenting does indicate that, because of the greater invasiveness of surgical revascularization, CABG produces greater operative mortality than does PCI. However, in patients with multivessel CAD, the risk-adjusted survival rates at 2.5 years of follow-up are no better for PCI than for CABG, and 3 recent risk-adjusted observational studies showed that the CABG patients had a significant survival advantage at 3- to 8-year follow-up.   The CABG patients had significantly more preoperative risk factors than did the PCI patients in each study, so that unadjusted, the CABG groups in each study included significantly more patients with triple-vessel disease and fewer patients with double-vessel disease than did the PCI groups. Again, we have a moving target with recent advances in both surgery and PCI technology.

Disadvantages of Stenting

The Achilles’ heel of PCI is restenosis and the need for repeat revascularization. Stents have decreased the rate of acute and subacute  periprocedural thrombosis. The newer, drug-eluting stents (DESs) have improved in-stent restenosis rates, especially in the carefully selected patient populations studied in the early DES trials. In the RAVEL trial, the early reports of zero in-stent restenosis compared favorably with the 27% in-stent restenosis rates in the bare-metal stent control group at 6-month follow-up. However, the RAVEL trial excluded patients with lesions longer than 18 mm, ostial targets, calcified or thrombosed targets, or target arteries less than 2.5 mm in diameter.
The media frenzy that followed the release of these findings created a public demand for these new “miracle” stents that apparently did not re-occlude. Stories of CAD patients refusing conventional PCI and CABG —instead, adding their names to the list of patients waiting for U.S. Food and Drug Administration (FDA) approval of DESs—appeared to change the practice patterns of cardiologists and cardiac surgeons overnight.  And then there were the calls for class-action lawsuits and recall of various DES models. After the FDA approved the Cordis Cypher™ DES (Cordis Corporation, a Johnson & Johnson company; Miami Lakes, Fla), a few reports of subacute thrombosis and hypersensitivity reactions prompted the FDA to release a public health notification on 29 October 2003.
The SIRIUS trial had slightly less strict exclusion criteria than did the RAVEL trial, admitting patients with target lesions 2.5 to 3.5 mm in diameter and 15 to 30 mm long, as well as patients with diabetes mellitus (who constituted 26% of the total group).  The SIRIUS trial also differed from the RAVEL trial in that the reported end-point was in-segment restenosis, rather than in-stent restenosis. The results showed a significant advantage of DESs over bare-metal stents for preventing in-segment restenosis (9.2% vs 32.3%) and target failures (10.5% vs 19.5%), but major adverse cardiac events were more frequent in the DES group than in the bare-metal stent group (3.7% vs 1.0%). Interestingly, the 6-month restenosis rates of the bare-metal stents in the RAVEL and SIRIUS control groups were much higher than the 19% 12-month restenosis rate associated with bare-metal stents in an earlier study comparing bare-metal stents with PTCA. In fact, the restenosis rates in the RAVEL and SIRIUS control groups more closely resembled the 40% restenosis rate reported for the PTCA control group in the earlier study.
The practical advantages of DESs over bare-metal stents are evident; nonetheless, we still do not have sufficient mid-term or long-term clinical data to argue that PTCA with DESs is preferable to CABG in “real-world” patients who require revascularization. Although DESs will likely provide better outcomes than bare-metal stents for many patients for whom stenting is indicated, a general extrapolation of existing data to justify the use of DESs in patients for whom CABG is currently indicated is unknown, perhaps undeterminable because the lesion and patient characteristics that lead to the failure of PCI are multifactorial, and the size of the population with lesions having unfavorable characteristics , such as,
  • longer
  • total occlusion
  • branch
  • small-diameter
  • calcified
  • multiple
  • left main
  • ostial, and
  • diffuse lesions
are being treated with PCI more often, as well as diabetics, multiple lesions, and patients with multiple comorbidities.

Advantages of CABG

Over the last 4 decades, surgical coronary artery revascularization techniques and technology have advanced significantly. As a result, despite an increasingly older and sicker patient population, CABG outcomes continue to improve. Observed operative mortality rates have decreased because advances in preoperative evaluation, including more precise coronary artery and myocardial imaging and diagnostic techniques, have allowed more appropriate patient selection and surgical planning. In addition, preoperative, intraoperative, and postoperative monitoring and therapeutic interventions have made CABG safer, even for critically ill and high-risk patients. Improvements in cardiopulmonary perfusion and careful myocardial protection, as well as the use of off-pump and on-pump beating- heart techniques in selected patients, have also decreased perioperative morbidity and mortality rates.

LIMA-to-LAD Long-Term Patency

The long-term benefits of CABG with regard to survival and quality of life are dependent on prolonged graft patency. The LIMA-to-LAD bypass, which is now performed in more than 90% of CABG procedures, shows excellent patency in 10- to 20-year angiographic follow-up studies, setting the gold standard with which other revascularization strategies should be compared. Tatoulis et al. reported that LIMA-to-LAD grafts had a 97.1% patency rate in patients who underwent angiography for cardiac symptoms. Those authors also found high patency rates at 5-year (98%), 10-year (95%), and 15-year (88%) follow-up. However, there are not yet long-term data on bare-metal stents or DESs, and by the time 10- or 20-year data are available, DESs probably will have been replaced by a newer, more advanced technology.
Because of the reported success of the LIMA-to-LAD bypass, other types of arterial conduits are also being used much more frequently. Conduit selection has become an area of great interest to cardiac surgeons, and conduit studies are expanding our understanding of the mechanisms of graft failure and ways to improve bypass graft patency. For example, studies have shown that patients who undergo CABG with both LIMA and right internal mammary artery (RIMA) conduits have better results than those who undergo CABG with one IMA and one or more saphenous vein grafts.

Techniques to Improve Conduit Patency

To maximize the odds of long-term graft patency, surgeons carefully harvest the graft as a pedicled or skeletonized conduit using “no touch” techniques. Using careful anastomotic technique to avoid excessive turbulence at the anastomosis site will prolong graft patency, and the quality of the conduit is crucial. Long-term graft patency depends not only on the conduit chosen but also on the target artery and the degree of stenosis proximal to the anastomosis. Maintaining flow patterns in the native artery, including residual flow (that is, competitive flow) and outflow, is important to avoid stasis in the graft, turbulence at the anastomosis, and vasospasm, especially in arterial conduits. Studies have shown an inverse relationship between the degree of proximal stenosis and graft patency. Targeting the LAD produces the highest patency rates. The characteristics of the target artery also determine graft patency, including –
1. the diameter of the target artery,
2. the presence or absence of diffuse disease within the artery,
3. whether or not the artery requires endarterectomy
Surgeons can avoid atheroembolic events by handling the aorta carefully or not at all. They can also improve safety by
1. using aggressive myocardial protection techniques;
2. avoiding the induction of inflammatory mediators; and
3. carefully controlling
  • blood pressure,
  • body temperature, and
  • electrolyte and glucose levels.
Although there have been major innovations that have enabled surgeons to perform cardiac surgery (including CABG) less invasively, minimally invasive surgical procedures are useful only if they are at least as efficacious as conventional surgery. New technology is being developed to enhance the evolving field of minimally invasive coronary bypass surgery.

Hybrid Coronary Revascularization

As PCI technology improves and techniques of LIMA-to-LAD grafting become less invasive, hybrid coronary revascularization is becoming a distinct possibility. For example, a minimally invasive, off-pump, direct LIMA-to-LAD anastomosis can be combined with DES placement in a focal mid-right-coronary-artery lesion in a patient with complex proximal LAD lesions. Hybrid coronary revascularization procedures are currently being performed, with promising early results. A few centers now have hybrid operating rooms with cardiac surgical and coronary angiographic capabilities that make it possible to perform simultaneous hybrid coronary revascularizations.

Although coronary artery bypass grafting (CABG) remains the treatment of choice for certain types of coronary artery disease (CAD), percutaneous coronary intervention (PCI)—particularly coronary angioplasty with stenting—has become the most popular nonmedical treatment approach to CAD. Some have speculated that, with the advent of drug-eluting stents (DESs), PCI will replace CABG entirely. However, the complete disappearance of CABG is both unlikely and unwarranted, for several reasons. Published randomized trials of CABG, PCI, and medical approaches to CAD compared only highly selected subgroups of patients because of strict exclusion criteria that often favored the PCI cohorts. Therefore, their results do not constitute sufficient evidence for the superiority of PCI over CABG in all CAD patients requiring revascularization. As PCI indications broaden to include more complex lesions and more high-risk patients, outcomes will not remain as favorable. In addition, although PCI is less invasive than surgery, CABG offers more complete revascularization and better freedom from repeat revascularization. Furthermore, no long-term patency data on DESs yet exist, whereas excellent 10- and 20-year patency rates have been reported for the left internal mammary artery-to-left anterior descending artery graft used in most CABG procedures. While PCI has been changing, CABG has not been stagnant; recently, advances in many aspects of the CABG procedure have improved short- and long-term outcomes in CABG patients. Both CABG and PCI technologies will continue to advance, not necessarily exclusive of one another, but no data yet exist to suggest that DESs will render CABG obsolete any time soon. 

Will Stent Revascularization Replace Coronary Artery Bypass Grafting?

When we discuss revascularization outcomes, we are talking about 3 major endpoints: death, myocardial infarction, and symptom control. With respect to death, we know that revascularization benefits patients who have severe multivessel disease and left ventricular dysfunction or other physiologic indicators of high risk. 2-vessel disease with proximal left anterior descending coronary artery (LAD) stenosis has been accepted as an indication for revascularization, even though the supporting data come from a small subgroup in a single trial. There has been no success in proving that endovascular treatment has a positive impact on stable CAD, but it is relevant because we leave the native arteries relatively intact. Attempts to improve graft performance beyond the relatively spectacular performance of the pedicled internal mammary artery (IMA) graft to the LAD have been disappointing.

Fig. 1 Graph of graft patency shows deterioration rates over 10 years and the comparative superiority of using the internal mammary artery (IMA) instead of the saphenous vein (SVG).http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528239/bin/25FF1.gif

graft patency of IMA vs SVG

Percutaneous Transluminal Coronary Angioplasty

When angioplasty was introduced, the hope was for a method of revascularization that would rival coronary artery bypass grafting. However, the results were mixed. Angioplasty worked well in patients with no major risk factors, such as diabetes mellitus, but failed miserably in diabetic patients. In fact, the Bypass Angioplasty Revascularization Investigation (BARI)  taught us this: if revascularization is needed, regardless of physiologic markers of high risk, the use of percutaneous coronary intervention (PCI) is potentially harmful in comparison with an IMA bypass for the LAD.

Stents and Short-Term Outcomes

The use of stents drastically reduced the probability of emergent surgery after attempted; however, the probability of new lesion formation or restenosis after intervention did not decrease.

Fig. 2 Diagrams  show the calculated success (after percutaneous revascularization) of A) percutaneous transluminal coronary angioplasty (PTCA), and B) bare-metal and C) drug-eluting stenting in patients with 3-vessel coronary artery disease (CAD).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528239/bin/25FF2.gif

At the same time, surgeons got better. Myocardial preservation techniques improved, and the use of the pedicled IMA graft changed the game. As a result, successful revascularization, meaning long-term success, became the domain of the surgeon. We at the Texas Heart Institute/St. Luke’s Episcopal Hospital (THI/SLEH) examined our long-term outcomes after stenting or surgery, and we initially reported that stenting was just as beneficial as surgery. This was in accord with the results of several trials: whenever placing a stent was feasible, stent therapy and surgery had the same outcome.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528239/bin/25TT1.jpg

success after PTCA vs bare-metal and drug-eluting stents

Stents and Long-Term Outcomes

Later, when we looked at longer-term follow-up data and the effects of multiple procedures, this picture began to change. Stented patients underwent more procedures. When the risk of one surgical procedure was compared with that of multiple endovascular procedures, the outcomes became more similar, especially in patients with bifurcation lesions or lesions with severe calcification. Drug-eluting stents, with their promise of no restenosis, substantially increased interventional cardiologists’ reach, but not their grasp. In patients with multivessel disease and high-risk lesions, DES placement was almost as risky as surgery and did not yield the same long-term benefit.

Nevertheless, we found locally that the introduction of the DES, with its lower risk of restenosis, was treated as a blessing to proceed with stenting (Table I). This did not follow the data, but cardiologists continued anyway, given the promise of less restenosis. Early risk was discounted, glycoprotein IIb/IIIa inhibitor use declined overnight, and the rate of endovascular procedural complications rose to meet that of surgery without the promise of an IMA graft in our future.

Table I. Independent Predictors of 30-Day Major Adverse Cardiac Events and 3-Year Survival after Drug-Eluting Stent Placement
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528239/bin/25TT1.jpg

Comparing Stenting and Surgery

For decades, methods have been sought to quantify lesion complexity in order to compare the early and late risks associated with stenting versus surgery. Although no perfect system has been devised, the SYNTAX was an important step forward. The SYNTAX score is a simple, computer-based tool for evaluating the risk of complications or failure after PCI. And there are other tools for estimating the same complications after surgery. These estimates enable cardiologists to give patients objective advice regarding the revascularization method that has the best short- and long-term probability of success.
In the patient with non-life-threatening disease (that is, not left main or severe multivessel CAD with left ventricular dysfunction or severely impaired function), stent revascularization has become a reasonable, although not ideal, alternative to surgical revascularization. However, this is true only if stenting is confined to patients whose anatomy and physiology are suited to it—considerations that are well quantified in the SYNTAX score. Whenever questions arise as to the most appropriate therapy, the SYNTAX score should be weighed against clinical characteristics that affect surgical risk. This will guide discussions between the cardiologist, cardiovascular surgeon, patient, and treating physician.
I think that our THI risk is more useful than the other available scores. It uses simple clinical data and can be easily calibrated to the geographic location of its use. Other scores require data that might not be available at the time of clinical decision-making or at all—making such predictions hazardous, at best.

Conclusion

With regard to the chosen mode of revascularization, it is perhaps safe to say that the decision goes beyond the individual physician and must become collective. When a patient has multivessel disease, a reasoned approach must be taken, using these predictive tools and considering the patient’s wishes. Treatment decisions should include all interested parties: the patient, cardiologist, cardiovascular surgeon, and anesthesiologist. The time of ad hoc angioplasty for the patient with multivessel CAD has passed.

Should all ischemic mitral regurgitation be repaired? When should we replace?   Curr Opin Cardiol. 2011

Abstract

Purpose of review

Ischemic mitral regurgitation (IMR) is a major source of morbidity and mortality. Although mitral valve repair has become recently popularized for the treatment of IMR, select patients may derive benefits from replacement. The purpose of this review is to describe current surgical options for IMR and to discuss when mitral valve replacement (MVR) may be favored over mitral valve repair.

Recent findings

Current surgical options for the treatment of IMR include surgical revascularization alone, mitral valve repair, or MVR. Although surgical revascularization alone may benefit patients with mild–moderate IMR, most surgeons advocate the performance of revascularization in combination with either mitral valve repair or replacement. In the current era, mitral valve repair has proven to offer improved short-term and long-term survival, decreased valve-related morbidity, and improved left ventricular function compared with MVR. However, MVR should be considered for high-risk patients and those with specific underlying mechanisms of IMR.

Summary

In the absence of level one evidence, mitral valve repair offers an effective and durable surgical approach to the treatment of mitral insufficiency and remains the operation of choice for IMR. MVR, however, is preferred for select patients. Future randomized, prospective clinical trials are needed to directly compare these surgical techniques.

Introduction

Ischemic mitral regurgitation (IMR) describes insufficiency of the mitral valve in the setting of myocardial ischemia, resulting from coronary artery disease. Although IMR may present in the acute setting, usually as a papillary rupture (Carpentier type II), it is usually a consequence of chronic myocardial ischemia that typically presents weeks following a complete infarction. IMR describes mitral insufficiency in the absence of degenerative (structural) mitral valve disease. The underlying pathophysiologic mechanisms of IMR are often complex, resulting from several different structural changes involving left ventricular geometry, the mitral annulus, and the valvular/subvalvular apparatus. Although changes to any one component may result in detectable mitral valve insufficiency, moderate-to-severe IMR requiring surgical correction often involves the complex interplay of several co-existent anatomic changes. These underlying mechanisms result in clinically significant valve incompetence due to the combined effects of decreased ventricular function and restricted motion of the valve itself due to tethering.
IMR is a major source of patient morbidity and mortality. Although the frequency of IMR differs based upon imaging modality, estimates have suggested that nearly 20–30% of patients experience mitral insufficiency following myocardial infarction. Furthermore, its intimate association with heart failure and poor outcomes for suboptimal medical management further complicates the management of clinically significant IMR. Recent evidence suggests that moderate or severe mitral regurgitation may be associated with a three-fold increase in the adjusted risk of heart failure and a 1.6-fold increase in risk-adjusted mortality at 5-year follow-up. In addition, unfavorable patient profiles and co-existing comorbid disease, including renal failure, chronic obstructive pulmonary disease, diabetes, and impaired left ventricular function, further complicate the clinical picture for those with IMR. Consequently, surgical correction of this condition is often required.
The purpose of this review is to analyze published results for the surgical correction of IMR and to provide current opinion regarding the selection of mitral valve procedure in the setting of myocardial ischemia. Herein, we review current surgical options for IMR and discuss when MVR may be favored over mitral valve repair.

Surgical options for ischemic mitral regurgitation: surgical revascularization alone

Surgical revascularization alone with CABG may be beneficial for some patients. Although CABG alone may be performed in cases of mild-to-moderate IMR, for the treatment of severe IMR, evidence supports performance of CABG with a mitral valve. In fact, a lack of evidence exists to support the performance of CABG alone for severe IMR. In one retrospective review of propensity-matched cohorts, Diodato et al. suggested that addition of a mitral valve procedure to patients undergoing CABG for moderately severe to severe IMR did not increase mortality or improve survival over the performance of CABG alone. This study, however, was limited by small sample sizes (51 CABG + mitral valve repair vs. 51 CABG alone) and 3-year follow-up. To the contrary, substantial evidence exists to support the performance of surgical revascularization alone in cases of mild-to-moderate IMR.
A study by Aklog et al. investigated the role of CABG alone in the correction of moderate IMR. In their series of 136 patients with moderate IMR, they demonstrated that performance of revascularization alone conferred improvement of mitral regurgitation in 51% of patients with complete resolution in an additional 9%. Despite these results, 40% of patients remained with 3–4+ mitral regurgitation, leading the authors to conclude that CABG alone may not be the optimal therapy for most patients and suggest that concomitant mitral annuloplasty may improve results. Other series similarly suggest that complete resolution of functional IMR is uncommon following revascularization alone. Despite the presence of residual mitral regurgitation following revascularization, the impact of performance of CABG without a valve procedure on long-term survival remains ill defined. Currently, on-going prospective evaluation may help to define the potential role of revascularization alone for patients with moderate IMR. Until the completion of these trials, however, evidence supports the performance of surgical revascularization combined with a mitral valve procedure for moderate-to-severe mitral regurgitation.

Surgical revascularization with a mitral valve procedure

The majority of patients with moderate-to-severe IMR require surgical revascularization with a concomitant mitral valve procedure (MVR or mitral valve repair). Historically, these procedures have been associated with high morbidity and mortality as well as poor long-term. However, improved surgical techniques and postoperative management have improved contemporary outcomes. Those favoring mitral valve repair promote its beneficial effects on survival, preserved ventricular function, and the avoidance of long-term anticoagulation, whereas those favoring MVR argue that it ensures long-term freedom from recurrent mitral insufficiency.

Mitral valve replacement vs. mitral valve repair

The use of MVR for IMR eliminates the possibility of recurrent IMR. In addition, previous literature suggests improvements in surgical technique for MVR 29–32. For patients with IMR, MVR with preservation of the subvalvular apparatus using a chordal sparing technique has been shown to be beneficial 33. David and Ho 33 demonstrated a significant survival benefit for patients undergoing MVR with preservation of chordae tendineae (89%) compared with complete excision of the mitral valves (59%) in a cohort of 51 patients with IMR. In addition, Cohn et al. suggested disproportionate survival benefits favoring MVR in a cohort of 150 patients with both functional and structural IMR, concluding that survival following performance of mitral valve procedures for IMR was more dependent on underlying pathophysiology rather than surgical technique. More recently, series have suggested equivalent results for the MVR and mitral valve repair. Mantovani et al. report that prosthetic MVR and mitral valve repair offer very similar results for chronic IMR, demonstrating similar operative mortality and 5-year actuarial survival for both techniques. In a similar report, Magne et al.•• compared short-term and long-term outcomes for 370 patients undergoing mitral valve repair (n = 186) and MVR (n = 184) for IMR. Although operative mortality was lower for mitral valve repair compared with MVR (9.7 vs. 17.4%, P = 0.03), 6-year survival was similar for both operations (73 ± 4 vs. 67 ± 4%, P = 0.17). Type of procedure was also not an independent predictor of mortality following risk adjustment. As a result, the authors suggest that mitral valve repair is not superior to MVR for patients with IMR.
In contrast, other series favor the performance of mitral valve repair for functional IMR. Although several repair techniques exist, restrictive annuloplasty remains the most commonly performed operation 37• and has been shown to be beneficial in both functional and chronic IMR 38•. The purported benefits of improved survival, decreased valve-related morbidity, and improved left ventricular function have been previously established, and several series have reported lower hospital mortality with mitral valve repair compared with MVR.
The Cleveland Clinic published a landmark review of 482 patients undergoing mitral valve procedures for IMR to study the influence of mitral valve procedure type on survival 1. In this series, propensity-matched cohorts were compared: mitral valve repair (n = 397) vs. MVR (n = 85). Concomitant CABG was performed in 95% of operations, and annuloplasty for repair occurred in 98% of cases. After matching, patients were risk stratified into five quintiles. Group 1 represented the highest-risk patients with higher degrees of heart failure and emergent operations, and group 5 represented the lowest-risk patients. Subsequent survival analysis revealed that overall 5-year survival was poor for patients with IMR (58% mitral valve repair vs. 36% MVR, P = 0.08). Moreover, within matched quintiles, the highest-risk patients (quintile 1) had the worst survival, but survival was similar (P = 0.4) despite mitral valve procedure type. In contrast, survival favored mitral valve repair over replacement for quintiles III–V (P = 0.003).
In the absence of published randomized trials, two recently published meta-analyses provide more robust comparisons of the influence of surgical mitral valve repair or replacement. Shuhaiber and Anderson  compared outcomes of 29 studies, including over 10 000 patients. Study groups were stratified based upon mitral valve etiology into ischemic, degenerative/myxomatous, rheumatic, and mixed groups. Summary analyses indicated worse overall survival for MVR (early mortality odds ratio = 2.24 and total survival hazard ratio = 1.58) compared with repair. Mitral valve repair was also associated with lower rates of thromboembolism. Moreover, a nonsignificant trend toward lower 30-day mortality favored mitral valve repair for those with IMR. The most recent meta-analysis to date compared short-term and long-term survival of mitral valve repair vs. replacement specifically for IMR ••. In this analysis, nine studies were included based upon stringent exclusion criteria to ensure direct comparisons of survival for mitral valve procedures exclusively performed for IMR. Interestingly, in this series, although patients undergoing MVR were older, those undergoing repair often had higher rates of hypertension and diabetes with lower ejection fractions. Further, the proportion of patients with severe ventricular dysfunction was similar between procedure groups. These findings conflict with a common assumption that an inherent selection bias exists within published studies for the performance of mitral valve repair in healthier patients. Nevertheless, MVR was associated with worse short-term mortality (odds ratio = 2.667) and long-term mortality (hazard ratio = 1.35) compared with mitral valve repair, and the authors advocate that choice in mitral procedure should be based upon individual patient profile.

When not to repair ischemic mitral regurgitation?

Within the context of published literature and current dogma among practicing surgeons, the fundamental question of when not to repair an ischemic mitral valve remains. For several years, accumulated evidence supports the performance of mitral valve repair over replacement for the surgical treatment of functional IMR. The aforementioned benefits of repair include improved long-term survival, durability and efficacy, improved ventricular function, and avoidance of chronic anticoagulation therapy. Nevertheless, MVR still plays a select role in the treatment of IMR.
With respect to the performance of MVR, the use of bioprosthetic valves and the avoidance of mechanical valve replacement are preferred. This choice is largely driven by the avoidance of complications due to long-term anticoagulation use as well as by the belief that it is unlikely that the majority of patients requiring MVR are likely to encounter bioprosthetic deterioration in their lifetime. In addition, MVR with techniques to preserve the subvalvular apparatus should be performed when possible.

Summary

Undoubtedly, the debate regarding when to perform repair or replacement for IMR remains unsettled. In the recent era, mitral valve repair has proven efficacious and remains the preferred surgical strategy for most cases of IMR. MVR should be considered for severe tethering, complex or uncertain mechanisms of mitral insufficiency, regurgitation due to papillary muscle rupture, and perhaps for the sickest and highest-risk patients.
The present review was supported by Award Number 2T32HL007849-11A1 (D.J.L.) from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors.
Hybrid Cath Lab Combines Nonsurgical, Surgical Treatments  2008
A new cardiac treatment facility that couples the benefits of interventional cardiology with cardiothoracic surgery for critically ill newborns, children and adults has opened at Rush University Medical Center, Chicago.  Toshiba’s new biplane hybrid cardiac suite, which is one of only three facilities of its kind in the U.S., is equipped with the latest in continuous, real-time imaging technology and radio frequency identification (RFID) technology which allows “all-in-one-room” care. The suite allows collaboration between the surgeon and interventional cardiologist on complex heart problems. For example, fixing a very large hole in the heart can be done by inserting a catheter through a small incision in the chest rather than relying on major surgery to open the chest to reach the heart. “Now, interventional cardiologists and cardiothoracic surgeons working together in this suite will reduce the amount of time required to correct complex heart problems and reduce the emotional and physical stress placed on a patient and their family – which translates into less pain, less scarring and a faster recovery time,” Ziyad Hijazi, M.D., director of the new Rush Center for Congenital and Structural Heart Disease. The hybrid suite is equipped with the latest technology for minimally invasive interventional cardiology that involves the use of a catheter and an image-guidance system to thread tiny instruments through blood vessels to repair the heart. Through these special catheters, physicians at Rush can implant stents, artificial heart valves and insert patches for holes in the heart. In many complex cardiac cases, patients who would otherwise have no other option but to undergo open-heart bypass surgery can now have minimally invasive procedures that would otherwise not be available to them. “We can now communicate with colleagues and obtain their expertise in real time for very complex situations,” said Dr. Hijazi. “If physicians decide another procedure is needed, even surgery, the suite can be converted into an operating room and the surgical team can be assembled in the new suite ”Patients at Rush will stay in one place in the new hybrid cardiac suite where all the imaging technology and implantable devices that might be needed are stored and located. The additional ability it gives us to provide surgical treatments allows us to provide the most comprehensive care in the most sensitive manner for patients with often extremely fragile conditions.”  The new hybrid cardiac catheterization suite has the most advanced imaging technologies and can still get a precise, optimal image of any region of the heart regardless of the size or complexity of congenital heart disease. The imaging system also features eight-inch cardiac flat panel detectors designed to deliver distortion-free images. The suite also includes intravascular ultrasound machines, which takes real-time images to allow physicians to see the progress of the procedure taking place inside the patient’s body. A high-tech, automated clinical resource management system located in the suite stores and tracks the medication, surgical tools, medical devices, and implantable devices and supplies using the latest RFID enabled technology.

Hybrid Cath Lab/ORs Are the Way of the Future

Recent developments in cardiac surgery and interventional cardiology with new percutaneous alternatives for aneurysm repair, valve replacements, shunt closure devices and aortic arch reconstruction have led to the creation of integrated, hybrid cath lab/operating rooms (OR) that allow both surgical and intravascular procedures. These rooms offer both surgical equipment and high-end angiographic equipment. Creating such rooms requires special planning and design from both surgical and interventional cardiologists working closely together. Cath labs have high-quality fluoroscopy equipment, but generally are smaller rooms and lack the sterile requirements and equipment needed for surgical procedures. ORs tend to use lower quality mobile C-arms, which are not ideal for interventional procedures. The hybrids aim to provide the best of both worlds. The trend toward hybrid labs has been reinforced by digital angiography manufacturers partnering with surgical equipment companies to create easy-to-integrate hybrid room solutions with coordinated installation. Philips partners with both Skytron and Steris. Toshiba partners with MAQUET. GE Healthcare, Siemens and Toshiba also offer hybrid installations. Philips said while some hospitals want to combine interventional procedures with minimally invasive surgeries, they also want a properly equipped room in case emergency surgery is needed.
Philips said hybrids also allow hospitals with lower PCI numbers to get a bigger bang for their buck by allowing the same room to serve the needs of surgeons. Penn Presbyterian Medical Center in Philadelphia, PA, created a hybrid lab with help from Siemens, which opened in November. Wilson Szeto, M.D., cardio-thoracic surgeon, and William Matthai, M.D., interventionalist, both from Penn Presbyterian said hybrid labs are ideally suited for procedures that require both percutaneous and surgical interventions, percutaneous valve replacements, deploying percutaneous septal occluders or installing aortic stent grafts. Interventionalists can also be called in after cardiac surgery to perform a completion angiography.

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36. Beauford RB, Saunders CR, Lunceford TA, Niemeier LA, Shah S, Karanam R, et al. Multivessel off-pump revascularization in patients with significant left main coronary artery stenosis: early and midterm outcome analysis. J Card Surg 2005;20:112–8. [PubMed]
37. Banning AP, Westaby S, Morice MC, Kappetein AP, Mohr FW, Berti S, et al. Diabetic and nondiabetic patients with left main and/or 3-vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel-eluting stents. J Am Coll Cardiol 2010;55(11):1067–75. [PubMed]
38. Laham RJ, Carrozza JP, Berger C, Cohen DJ, Kuntz RE, Baim DS. Long-term (4- to 6-year) outcome of Palmaz-Schatz stenting: paucity of late clinical stent-related problems. J Am Coll Cardiol 1996;28(4):820–6. [PubMed]
39. Rodriguez A, Bernardi V, Navia J, Baldi J, Grinfeld L, Martinez J, et al. Argentine Randomized Study: Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in patients with Multiple-Vessel Disease (ERACI II): 30-day and one-year follow-up results. ERACI II Investigators [published erratum appears in J Am Coll Cardiol 2001;37(3):973–4]. J Am Coll Cardiol 2001;37(1):51–8. [PubMed]
40. Serruys PW, Unger F, Sousa JE, Jatene A, Bonnier HJ, Schonberger JP, et al. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 2001;344(15):1117–24. [PubMed]
41. Goy JJ, Kaufmann U, Goy-Eggenberger D, Garachemani A, Hurni M, Carrel T, et al. A prospective randomized trial comparing stenting to internal mammary artery grafting for proximal, isolated de novo left anterior coronary artery stenosis: the SIMA trial. Stenting vs Internal Mammary Artery. Mayo Clin Proc 2000;75(11):1116–23. [PubMed]
42. SoS Investigators. Coronary artery bypass surgery versus percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a randomised controlled trial. Lancet 2002;360 (9338):965–70. [PubMed]
43. Reul RM. Will drug-eluting stents replace coronary artery bypass surgery? Tex Heart Inst J 2005;32(3):323–30. [PMC free article] [PubMed]
44. Sianos G, Morel MA, Kappetein AP, Morice MC, Colombo A, Dawkins K, et al. The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease. EuroIntervention 2005;1(2):219–27. [PubMed]
45. Madan P, Elayda MA, Lee VV, Wilson JM. Predicting major adverse cardiac events after percutaneous coronary intervention: the Texas Heart Institute risk score. Am Heart J 2008; 155(6):1068–74. [PubMed]
46. Gillinov AM, Wierup PN, Blackstone EH, et al. Is repair preferable to replacement for ischemic mitral regurgitation? J Thorac Cardiovasc Surg. 2001;122:1125–1141. [PubMed]
47. Grigioni F, Enriquez-Sarano M, Zehr KJ, et al. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation. 2001;103:1759–1764. [PubMed]
48. Lamas GA, Mitchell GF, Flaker GC, et al. Clinical significance of mitral regurgitation after acute myocardial infarction. Survival and Ventricular Enlargement Investigators. Circulation. 1997;96:827–833. [PubMed]
49. Bursi F, Enriquez-Sarano M, Nkomo VT, et al. Heart failure and death after myocardial infarction in the community: the emerging role of mitral regurgitation. Circulation. 2005;111:295–301. [PubMed]
50. Adams DH, Filsoufi F, Aklog L. Surgical treatment of the ischemic mitral valve. J Heart Valve Dis. 2002;11 (Suppl 1):S21–S25. [PubMed]
51. Filsoufi F, Salzberg SP, Adams DH. Current management of ischemic mitral regurgitation. Mt Sinai J Med. 2005;72:105–115. [PubMed]
52. Micovic S, Milacic P, Otasevic P, et al. Comparison of valve annuloplasty and replacement for ischemic mitral valve incompetence. Heart Surg Forum. 2008;11:E340–E345. [PubMed]
53. Aklog L, Filsoufi F, Flores KQ, et al. Does coronary artery bypass grafting alone correct moderate ischemic mitral regurgitation? Circulation. 2001;104 (12 Suppl 1):I68–I75. [PubMed]
54. Lam BK, Gillinov AM, Blackstone EH, et al. Importance of moderate ischemic mitral regurgitation. Ann Thorac Surg. 2005;79:462–470. discussion 462–470. [PubMed]
55. Ryden T, Bech-Hanssen O, Brandrup-Wognsen G, et al. The importance of grade 2 ischemic mitral regurgitation in coronary artery bypass grafting. Eur J Cardiothorac Surg. 2001;20:276–281. [PubMed]
56•. Goland S, Czer LS, Siegel RJ, et al. Coronary revascularization alone or with mitral valve repair: outcomes in patients with moderate ischemic mitral regurgitation. Tex Heart Inst J. 2009;36:416–424. This series documents current outcomes for the performance of CABG alone with/without concomitant mitral valve repair for ischemic mitral regurgitation. The authors report similar 5-year survival rates for both techniques; however, revascularization with repair resulted in significantly reduced mitral regurgitation grade, improved left ventricular function, and functional class compared with revascularization alone. This study provides an important comparison of these two techniques in the current surgical era. [PMC free article] [PubMed]
57••. Magne J, Girerd N, Senechal M, et al. Mitral repair versus replacement for ischemic mitral regurgitation: comparison of short-term and long-term survival. Circulation. 2009;120(11 Suppl):S104–S111. In this study, the authors compare postoperative outcomes for mitral valve repair and replacement for ischemic mitral regurgitation. Despite lower operative mortality following mitral valve repair, long-term survival was equivalent between surgical groups. This study adds important long-term comparisons of mitral valve procedures to accumulating data examining surgical treatments for ischemic mitral regurgitation. [PubMed]
58. Silberman S, Klutstein MW, Sabag T, et al. Repair of ischemic mitral regurgitation: comparison between flexible and rigid annuloplasty rings. Ann Thorac Surg. 2009;87:1721–1726. discussion 1726–1727. This study provides a contemporary comparison between the use of flexible and rigid annuloplasty rings for the surgical treatment of IMR. The authors report significantly improved clinical and hemodynamic results for rigid mitral annuloplasty rings compared with flexible rings. [PubMed]
59•. Tekumit H, Cenal AR, Uzun K, et al. Ring annuloplasty in chronic ischemic mitral regurgitation: encouraging early and midterm results. Tex Heart Inst J. 2009;36:287–292. This study reports early and midterm results for the use of flexible annuloplasty rings for the surgical treatment of chronic IMR. The authors demonstrate that use of flexible mitral valve annuloplasty conferred a reduction in left ventricular diameter with improved New York Heart Association functional class. This study reports current, encouraging results and provides a context for future investigations comparing flexible and rigid annuloplasty rings for chronic IMR. [PMC free article] [PubMed]
60. Shuhaiber J, Anderson RJ. Meta-analysis of clinical outcomes following surgical mitral valve repair or replacement. Eur J Cardiothorac Surg. 2007;31:267–275. [PubMed]
61••. Vassileva CM, Boley T, Markwell S, Hazelrigg S. Meta-analysis of short-term and long-term survival following repair versus replacement for ischemic mitral regurgitation. Eur J Cardiothorac Surg. 2010 [Epub ahead of print] This meta-analysis provides a comparison of nine published series specifically addressing the performance of mitral valve repair vs. replacement for IMR. The authors demonstrate worse short-term and long-term mortality for MVR. Their analysis offers an up-to-date and robust comparison of these two surgical techniques. [PubMed]

Other Related articles  published on this Open Access Online Scientific Journal, include the following:

Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”    https://pharmaceuticalintelligence.com/2013/01/08/cardiac-surgery-theatre-in-china-vs-in-the-us-cardiac-repair-procedures-medical-devices-in-use-technology-in-hospitals-surgeons-training-and-cardiac-disease-severity/

Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony                                                                                     https://pharmaceuticalintelligence.com/2012/07/23/heart-remodeling-by-design-implantable-synchronized-cardiac-assist-device-abiomeds-symphony/
Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI    https://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/
Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)
Clinical Trials on transcatheter aortic valve replacement (TAVR) to be conducted by American College of Cardiology and the Society of Thoracic Surgeons
FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology
PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity
The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX
Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles
Ablation Devices Market to 2016 – Global Market Forecast and Trends Analysis by Technology, Devices & Applications
Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered
Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.
To Stent or Not? A Critical Decision
Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation
Transcatheter Aortic-Valve Replacement for Inoperable Severe Aortic Stenosis
Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics
New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia
Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report
New Drug-Eluting Stent Works Well in STEMI
Expected New Trends in Cardiology and Cardiovascular Medical Devices
Minimally Invasive Structural CVD Repairs: FDA grants 510(k) Clearance to Philips’ EchoNavigator – X-ray and 3-D Ultrasound Image Fused.
Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES
https://pharmaceuticalintelligence.com/2013/04/25/contributions-to-vascular-biology/

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Denton A. Cooley, MD

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First-of-Its-Kind FDA Approval for ‘AUI’ Device with Endurant II AAA Stent Graft: Medtronic Expands in Endovascular Aortic Repair in the United States

Reporter: Aviva Lev-Ari, PhD, RN

 

Medtronic, Inc. (MDT) Expands Endovascular Aortic Portfolio With Two New Devices

5/30/2013 8:39:47 AM

Medtronic Garners First-Of-Its-Kind FDA Approval for ‘AUI’ Device with Endurant II AAA Stent Graft 

MINNEAPOLIS — May 30, 2013 — Medtronic, Inc. (NYSE: MDT) is expanding its market-leading portfolio of products for endovascular aortic repair in the United States with two new medical devices: the company recently received approval from the U.S. Food and Drug Administration (FDA) for the Endurant II Aorto-Uni-Iliac (AUI) Stent Graft System and the FDA’s 510(k) clearance for the Sentrant Introducer Sheath; both devices will be on exhibit at the Medtronic booth during the Society for Vascular Surgery‘s “Vascular Annual Meeting,” which runs May 30-June 2 in San Francisco.

Endurant II AUI Stent Graft System

The Endurant II AUI Stent Graft System is the only FDA-approved AUI device in the United States indicated for the primary endovascular treatment of infrarenal abdominal aortic or aorto-iliac aneurysms in patients whose anatomy does not allow for the use of a bifurcated device. Both the bifurcated and AUI configurations of the Endurant Stent Graft System provide a new pathway for blood flow through the iliac arteries in abdominal aortic aneurysms, thereby reducing risk of aneurysm rupture.

Whereas use of the bifurcated device requires access to both iliac arteries, the AUI device requires access to only one iliac artery (Endurant II Aorto-Uni-Iliac (AUI)). In published studies of endovascular abdominal aortic aneurysm (AAA) repair.

Current global usage of AUI stent graft configurations averages

  • 5 percent (range 0-26%) for intact AAA and
  • 39 percent (range 0-91%) for ruptured AAA.[i],[ii]

“The new Endurant II Aorto-Uni-Iliac Stent Graft extends the proven performance of the Endurant System to patients with difficult access,” said Dr. Michel Makaroun, chief of vascular surgery at the University of Pittsburgh Medical Center and co-director of the UPMC Heart and Vascular Institute. “By maintaining the deliverability, conformability and deployment accuracy of the bifurcated Endurant device, the AUI configuration offers aneurysm patients with challenging outflow anatomies a better option for a successful endovascular aortic repair.”

As with the bifurcated Endurant II Stent Graft, distinguishing features of the Endurant II AUI Stent Graft include a low delivery profile, tip capture for easy and accurate deployment and compatibility with contralateral iliac limbs and aortic extensions for ultimate patient applicability.

Sentrant Introducer Sheath

The Sentrant Introducer Sheath complements Medtronic’s market-leading portfolio of stent grafts for endovascular aortic repair. It is specially designed for use with the Endurant II AAA and Valiant Captivia Stent Graft Systems and is also compatible with competitive systems. The Sentrant Introducer Sheath is inserted at the access site

in the patient’s femoral artery and advanced upwards into the iliac arteries to facilitate the implant procedure and enable smooth passage of the stent graft delivery system en route to the treatment site in the aorta.

The Sentrant Introducer Sheath can accommodate a wide range of anatomies, with diameters of 12-26 French and shaft lengths of 28cm. Other distinguishing features of the accessory device include:

  • optimal seal for superior hemostasis,
  • reinforced coil for kink resistance,
  • hydrophilic coating and
  • flexibility for easy tracking through tortuous and calcified iliacs and a
  • dilator locking mechanism for secure positioning.

The Sentrant Introducer Sheath received the CE (Conformité Européenne) mark in April 2013. Its FDA clearance expands the accessory device’s availability to endovascular specialists in the United States.

In collaboration with leading clinicians, researchers and scientists, Medtronic offers the broadest range of innovative medical technology for the interventional and surgical treatment of cardiovascular disease and cardiac arrhythmias. The company strives to offer products and services that deliver clinical and economic value to healthcare consumers and providers worldwide.

ABOUT MEDTRONIC

Medtronic, Inc. (www.medtronic.com), headquartered in Minneapolis, is the global leader in medical technology-alleviating pain, restoring health and extending life for millions of people around the world.

Any forward-looking statements are subject to risks and uncertainties such as those described in Medtronic’s periodic reports on file with the Securities and Exchange Commission. Actual results may differ materially from anticipated results.

http://www.devicespace.com/news_story.aspx?NewsEntityId=298363&type=email&source=DS_053013

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Reporter: Aviva Lev-Ari, PhD, RN

 

2013 GREAT DEBATE: THE BURNING ISSUES – BIORESORBABLE SCAFFOLDS AND DUAL ANTIPLATELET THERAPY

With an unrestricted educational grant from MEDTRONIC

Watch the videoWatch the video

WATCH VIDEO

BIORESORBABLE SCAFFOLDS AND DUAL ANTIPLATELET THERAPY

SOURCE:

http://www.pcronline.com/EuroPCR/EuroPCR-2013/2013-Great-Debate-The-burning-issues-Bioresorbable-scaffolds-and-dual-antiplatelet-therapy

 

Full Program for May 21 to May 24, 2013 is presented, below

EUROPCR 2013, Paris 5/21-5/24, 2013 Conference for Cardiolovascular Intervention and Interventional Medicine

https://pharmaceuticalintelligence.com/2013/05/29/europcr-2013-paris-521-524-2013-conference-for-cardiolovascular-intervention-and-interventional-medicine/

 

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Svelte Medical Systems’ Drug-Eluting Stent: 0% Clinically-Driven Events Through 12-Months in First-In-Man Study

Reporter: Aviva Lev-Ari, PhD, RN

 

Svelte Drug-Eluting Stent Utilizing New Class of Bioabsorbable Drug Coating Attains 0% Clinically-Driven Events Through 12-Months in First-In-Man Study

NEW PROVIDENCE, N.J.–(May 23, 2013)–Final 6 and 12-month results of the DIRECT first-in-man clinical study were presented by study principal investigator Dr. Mark Webster at the late-breaking clinical trials session of the EuroPCR meeting yesterday in Paris, France. No patients experienced clinically-driven TLR, TVR or MACE at 6 months, with results sustained through 12 months. It is believed the Svelte drug-eluting stent is the first ever to achieve 0% clinically-driven MACE through 12 months in a independent core-lab and DSMB adjudicated clinical study.

The Svelte drug-eluting stent utilizes a new class of drug coating composed of a fully bioabsorbable, amino acid-based drug carrier mixed with the well-known anti-proliferative compound sirolimus. Amino acids occur naturally in the human body, providing a non-inflammatory and inherently bio-friendly drug-eluting platform. Unlike current-generation bioabsorbable coatings relying on hydrolysis for absorption, amino acids undergo gradual enzyme-based surface erosion with no bulk degradation or pH change activating an inflammatory response.

Invasive imaging at 6 months in the DIRECT study corroborates these clinical outcomes, revealing stent volume obstruction of 2.7%, approximately one-half that observed in current-generation, market-leading drug-eluting stent first-in-man studies. Optical coherence tomography revealed 98% of stent struts were fully covered, indicative of low inflammation and consistent vessel healing.

The DIRECT (Direct Implantation of Rapamycin-eluting stent with bio-Eroding Carrier Technology) study evaluated the Svelte drug-eluting stent mounted on a fixed-wire Integrated Delivery System (IDS) in 30 patients at 4 sites in New Zealand. Providing the lowest crimped stent profile on the market, the Svelte system facilitates use of the transradial approach and general downsizing of the access site, while allowing access to more difficult to cross and distal lesions. The IDS also incorporates proprietary Balloon Control Band (BCB) technology providing uniform and controlled balloon growth, even at high pressures, to safely perform direct stenting as well as high-pressure post-dilatation, thereby minimizing procedure time and cost. This balloon technology will also be available with a rapid-exchange delivery system at commercial launch.

Approximately one-fifth of patients in the study were diabetic, while one-half presented with Type B2 or C lesions. Procedural success was 100% and device success was 97%. Study results are published in the current issue of EuroIntervention, the official journal of EuroPCR and the European Association of Percutaneous Cardiovascular Interventions (EAPCI).

The Svelte drug-eluting stent is currently under evaluation in the DIRECT II study. DIRECT II is a prospective, randomized, multi-center clinical study comparing the safety and efficacy of the Svelte drug-eluting coronary stent mounted on the IDS to Medtronic’s Resolute Integrity™ drug-eluting stent. The DIRECT II study will enroll 159 patients at up to 20 clinical sites in Europe and Brazil to assess the

  • primary endpoints of target vessel failure (TVF) and
  • in-stent late loss (LL).

All patients are scheduled to receive 6-month clinical and angiographic follow-up, with clinical follow-up through 5 years. A subset of patients will receive optical coherence tomography (OCT) imaging at 6 months.

Headquartered in New Providence, New Jersey, Svelte Medical Systems (www.sveltemedical.com) is a privately-held company engaged in the development of highly deliverable balloon expandable stents.

http://www.cathlabdigest.com/Svelte-Drug-Eluting-Stent-Utilizing-New-Class-Bioabsorbable-Drug-Coating-Attains-0-Clinically-Driven

RELATED SOURCES:

Bioabsorbable Drug Coating Scaffolds, Stents and Dual Antiplatelet Therapy

https://pharmaceuticalintelligence.wordpress.com/wp-admin/post.php?post=13686&action=edit&message=6&postpost=v2

Full Program for May 21 to May 24, 2013 is presented, below

EUROPCR 2013, Paris 5/21-5/24, 2013 Conference for Cardiolovascular Intervention and Interventional Medicine

https://pharmaceuticalintelligence.com/2013/05/29/europcr-2013-paris-521-524-2013-conference-for-cardiolovascular-intervention-and-interventional-medicine/

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Biomaterials Technology: Models of Tissue Engineering for Reperfusion and Implantable Devices for Revascularization

Author and Curator: Larry H Bernstein, MD, FACP

and

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/5_04_2013/bernstein_lev-ari/Bioengineering_of_Vascular_and_Tissue_Models

This is the THIRD of a three part series on the evolution of vascular biology and the studies of the effects of biomaterials
in vascular reconstruction and on drug delivery, which has embraced a collaboration of cardiologists at Harvard Medical School , Affiliated Hospitals, and MIT,
requiring cardiovascular scientists at the PhD and MD level, physicists, and computational biologists working in concert, and
an exploration of the depth of the contributions by a distinguished physician, scientist, and thinker.

The FIRST part – Vascular Biology and Disease – covered the advances in the research on

Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

  • vascular biology,
  • signaling pathways,
  • drug diffusion across the endothelium and
  • the interactions with the underlying muscularis (media),
  • with additional considerations for type 2 diabetes mellitus.

The SECOND part – Stents and Drug Delivery – covered the

Vascular Repair: Stents and Biologically Active Implants

  • purposes,
  • properties and
  • evolution of stent technology with
  • the acquired knowledge of the pharmacodynamics of drug interactions and drug distribution.

In this THIRD part, on Problems and Promise of Biomaterials Technology, we cover the biomaterials used and the design of the cardiovascular devices, extension of uses, and opportunities for improvement

Biomaterials Technology: Tissue Engineering and Vascular Models –

Problems and Promise

We have thus far elaborated on developments in the last 15 years that have led to significant improvements in cardiovascular health.

First, there has been development of smaller sized catheters that can be introduced into

  • not only coronary arteries, but into the carotid and peripheral vasculature;

Second, there has been specific design of coated-stents that can be placed into an artery

  • for delivery of a therapeutic drug.

This began with a focus on restenosis, a serious problem after vascular repair, beginning
with the difficult problem of  control of heparin activity given intravenously, and was
extended to modifying the heparan-sulfate molecular structure

  • to diminish vascular endothelial hyperplasia,
  • concurrent with restriction of the anticoagulant activity.

Third, the ability to place stents with medicated biomaterials locally has extended to

  • the realm of chemotherapy, and we shall see where this progresses.

The Engineered Arterial Blood Flow Models

Biomedical engineers, in collaboration with physicians, biologists, chemists, physicists, and
mathematicians, have developed models to predict vascular repair by knowledge of

  • the impact of interventions on blood flow.

These models have become increasingly sophisticated and precise, and they propel us
toward optimization of cardiovascular therapeutics in general and personalizing treatments
for patients with cardiovascular disease. (1)
The science of vascular biology has been primarily stimulated by the clinical imperative to

  • combat complications that ensue from vascular interventions.

Thus, when a novel vascular biological finding or cardiovascular medical/surgical technique
is presented, we are required to ask the 2-fold question:

  • what have we learned about the biology of the blood vessel?
  • how might this knowledge be used to enhance clinical perspective and treatment?

The innovative method of engineering arterial conduits presented by Campbell et al. in
Circulation Research presents us with just such a challenge, and we deal with it’s biological and clinical ramifications.

Each of four pivotal studies in vascular tissue engineering has been an important advance
in the progression to a tissue-engineered blood vessel that can serve as a

  • living graft, responsive to the biological environment as
  • a self-renewing tissue with an inherent healing potential.
  • Weinberg and Bell taught us that a tissue-engineered graft could be constructed
  • and could be composed of human cells.

L’heureux et al demonstrated that the mechanical strength of such a material

  • derived in major part from the extracellular matrix and
  • production of matrix and integrity of cellular sheets
  • could be enhanced by alterations in culture conditions.

Niklason et al. noted that grafts are optimally formed

  • when incubated within environmental conditions that they will confront in vivo
  • or would have experienced if formed naturally.

Campbell et al. now demonstrate that it is possible to remove

  • the immune reaction and acute rejection that may follow cell-based grafting
  • by culturing tissues in the anticipated host and
  • address a fundamental issue of whether cell source or site of cell placement
  • dictates function after cell implantation.

It appears that the vascular matrix can be remodeled by the body according to the needs of the environment. It may
very well be that the ultimate configuration of autologous cell-based vascular graft need not be determined at
outset by the cells that comprise the device, but rather

  • by a dynamics that is established by environmental needs, wherein the body molds
  • tissue-engineered constructs to meet
    • local flow,
    • metabolic, and
    • inflammatory requirements.

In other words, cell source for tissue reconstruction may be secondary to
cell pliability to environmental influence.

Endothelial and smooth muscle cells from many, perhaps any,

  • vascular bed can be used to create new grafts and will then
  • achieve secondary function once in place in the artery.

The environmental remodeling observed after implantation

  • may modify limitations of grafts that are composed of nonvascular peritoneal cells whose initial structure
    is not either venous or arterial. (2)
  • The trilaminate vascular architecture provides biochemical regulation and mechanical integrity.
  • Yet regulatory control can be regained after injury without recapitulating tertiary structure.

Tissue-engineered (TE) endothelium controls repair even when

  • placed in the perivascular space of injured vessels.

It remains unclear from vascular repair studies whether endothelial implants recapitulate the vascular
epithelial lining
or expose injured tissues to endothelial cells (ECs) with unique healing potential because

  • ECs line the vascular epithelium and the vasa vasorum.

Authors examined this issue in a nonvascular tubular system, asking whether airway repair is controlled by

  • bronchial epithelial cells (EPs) or by
  • Endothelial Cells (ECs) of the perfusing bronchial vasculature.

Localized bronchial denuding injury

  • damaged epithelium, narrowed bronchial lumen, and led to
  • mesenchymal cell hyperplasia, hypervascularity, and inflammatory
  • cell infiltration. Peribronchial TE constructs embedded with

EPs or ECs limited airway injury, although optimum repair was obtained

  • when both cells were present in TE matrices.

EC and EP expression of

  • PGE2, TGF1, TGF2, GM-CSF, IL-8, MCP-1, and soluble VCAM-1
  • and ICAM-1 was altered by matrix embedding,

but expression was altered most significantly when both,

  • EC and EP,  cells were present simultaneously.

EPs may provide for functional control of organ injury and fibrous response, and

ECs may provide for preservation of tissue perfusion and the epithelium in particular.

Together the two cells

  • optimize functional restoration and healing, suggesting that
  • multiple cells of a tissue contribute to the differentiated biochemical function and repair
    of a tissue, but 
    need not assume
  • a fixed, ordered architectural relationship, as in intact tissues, to achieve these effects. (3)

Matrix-embedded Endothelial Cells (MEECs) Implants

The implantation of matrix-embedded endothelial cells (MEECs)

  • is considered to have therapeutic potential in controlling the vascular response to injury and
  • maintaining patency in arteriovenous anastomoses.

Authors considered the 3-dimensional microarchitecture of the tissue engineering scaffold to be
a key regulator of endothelial behavior in MEEC constructs.

Notably, Authors found that

  • ECs in porous collagen scaffold had a markedly altered cytoskeletal structure with oriented actin
    fibers
    and rearranged focal adhesion proteins, in comparison to cells grown on 2D surfaces.

Examining the immunomodulatory capabilities of MEECs revealed, MEECs were able to reduce the recruitment
of monocytes
to an inflamed endothelial monolayer by 5-fold compared to EC on 2D surfaces.

An analysis of secreted factors from the cells revealed

  • an 8-fold lower release of Monocyte Chemotactic Protein-1 (MCP-1) from MEECs.

Differences between 3D and 2D cultured cells were abolished in the presence of

  • inhibitors to the focal adhesion associated signaling molecule Src, suggesting that
  • adhesion-mediated signaling is essential in controlling the potent immunomodulatory
    effects of MEEC. (4)

Cardiogenesis is regulated by a complex interplay between transcription factors. How do these interactions
regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs)?

Yin Yang 1 (YY1), a member of the GLI-Kruppel

  • family of DNA-binding zinc finger transcription factor (TF), can
  • activate or inhibit transcription in a context-dependent manner.

Bioinformatic-based Transcription Factor Genome-wide Sequencing Analysis

These investigators performed a bioinformatic-based transcription factor genome-wide sequencing analysis

  • binding  site analysis on upstream promoter regions of genes that are enriched in embryonic stem cell–derived CPCs
  • to identify novel regulators of mesodermal cardiac lineage

From 32 candidate transcription factors screened, they found that

  • Yin Yang 1 (YY1), a repressor of sarcomeric gene expression, is present in CPCs.

They uncovered the ability of YY1 to transcriptionally activate Nkx2.5,

  • Nkx2.5 as a key marker of early cardiogenic commitment.
  • YY1 regulates Nkx2.5 expression via a 2.1-kb cardiac-specific enhancer as demonstrated by in vitro
  1. luciferase-based assays,
  2. in vivo chromatin immunoprecipitation,
  3. and genome-wide sequencing analysis.

Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with Gata4.

Cardiac mesoderm–specific loss-of-function of YY1 resulted in early embryonic lethality.

This was corroborated in vitro by embryonic stem cell–based assays which showed the

  • overexpression of YY1 enhanced the cardiogenic differentiation of embryonic stem cells into CPCs.

The results indicate an essential and unexpected role for YY1

  • to promote cardiogenesis as a transcriptional activator of Nkx2.5
  • and other CPC-enriched genes. (5)

Proportional Hazards Models to Analyze First-onset of Major
Cardiovascular Disease Events

Various measures of arterial stiffness and wave reflection are considered to be cardiovascular risk markers.

Prior studies have not assessed relations of a comprehensive panel of stiffness measures to prognosis

Authors used Proportional Hazards Models to analyze first-onset of major cardiovascular disease events 

  • myocardial infarction,
  • unstable angina,
  • heart failure, or
  • stroke

In relation to arterial stiffness measured by

  • pulse wave velocity [PWV]
  • wave reflection
  • augmentation index [AI]
  • carotid-brachial pressure amplification [PPA]
  • and central pulse pressure [CPP]

in 2232 participants (mean age, 63 years; 58% women) in the Framingham Heart Study.

During median follow-up of 7.8 (range, 0.2 to 8.9) years,

  • 151 of 2232 participants (6.8%) experienced an event.

In multivariable models adjusted for

  • age,
  • sex,
  • systolic blood pressure,
  • use of antihypertensive therapy,
  • total and high-density lipoprotein cholesterol concentrations,
  • smoking, and
  • presence of diabetes mellitus,

Higher aortic PWV was associated with a 48% increase in

  • cardiovascular disease risk
    (95% confidence interval, 1.16 to 1.91 per SD; P0.002).

After PWV was added to a standard risk factor model,

  • integrated discrimination improvement was 0.7%
    (95% confidence interval, 0.05% to 1.3%; P < 0.05).

In contrast, AI, CPP, and PPA were not related to

  • cardiovascular disease outcomes in multivariable models.

(1) Higher aortic stiffness assessed by PWV is associated with

  • increased risk for a first cardiovascular event.

(2) Aortic PWV improves risk prediction when added to standard risk factors

  • and may represent a valuable biomarker of CVD risk in the community. (6)

1. Engineered arterial models to correlate blood flow to tissue biological response. J Martorell, P Santoma, JJ Molins,
AA Garcıa-Granada, JA Bea, et al.  Ann NY Acad Sci 2012: 1254:51–56. (Issue: Evolving Challenges in Promoting
Cardiovascular Health)    http://dx.doi.org/10.1111/j.1749-6632.2012.06518.x

2.  Vascular Tissue Engineering. Designer Arteries. Elazer R. Edelman. Circ Res. 1999; 85:1115-1117
http://www.circresaha.org  http://dx.doi.org/10.1161/01.RES.85.12

3.  Tissue-engineered endothelial and epithelial implants differentially and synergistically regulate airway repair.
BG Zani, K Kojima, CA Vacanti, and ER Edelman.   PNAS 13, 2008; 105(19):7046–7051.
http://www.pnas.org/cgi/doi/10.1073/pnas.0802463105

4.  The role of scaffold microarchitecture in engineering endothelial cell immunomodulation.
L Indolfi, AB Baker, ER Edelman. Biomaterials 2012; http://dx.doi.org/10.1016/j.biomaterials.2012.06.052

5.  Essential and Unexpected Role of Yin Yang 1 to Promote Mesodermal Cardiac Differentiation. S Gregoire, R Karra,
D Passer, Marcus-André Deutsch, et al.  Circ Res. 2013;112:900-910. http://dx.doi.org/10.1161/CIRCRESAHA.113.259259
http://circres.ahajournals.org/doi:10.1161/CIRCRESAHA.113.259259

6.  Arterial Stiffness and Cardiovascular Events. The Framingham Heart Study.
GF Mitchell, Shih-Jen Hwang, RS Vasan, MG Larson, et al.  Circulation. 2010;121:505-511.
http://circ.ahajournals.org/doi/10.1161/CIRCULATIONAHA.109.886655

Cardiology Diagnosis of ACS and Stents – 2012

The Year in Cardiology 2012: Acute Coronary Syndromes.

Nick E.J. West      http://www.medscape.com/viewarticle/779039

The European Society of Cardiology (ESC) produced updated guidance on management of STEMI in 2012.
It also produced a third version of the Universal Definition of Myocardial Infarction.
The importance of early diagnosis is stressed, with first ECG in patients

  • with suspected STEMI recommended within 10 min of first medical contact (FMC)
  • and primary percutaneous coronary intervention (PPCI) for STEMI
  • ideally within 90 min (rated ‘acceptable’ out to a maximum of 120 min).

The guidance highlights the importance of collaborative networks

  • to facilitate achievement of such targets.
  • the importance of prompt assessment
  • management of atypical presentations not always considered under the umbrella of STEMI, including
    • left bundle branch block (LBBB),
    • paced rhythms, and
    • isolated ST-segment elevation in lead aVR,

especially when accompanied by symptoms consistent with myocardial ischaemia.

Therapeutic hypothermia is now recommended for

  • all resuscitated patients with STEMI complicated by cardiac arrest
  •  immediate coronary angiography with a view to follow-on PPCI
  • when the ECG demonstrates persistent ST-segment elevation.

In the light of recently published studies and meta-analyses,

  • including that of Kalesan et al., drug-eluting stents (DES) are
  • now routinely preferred to bare metal stents (BMS) in view of
  • the reduced need for repeat revascularization and the lack of
  • previously perceived hazard for stent thrombosis.

The more potent antiplatelet agents prasugrel and ticagrelor are also preferred

  • to clopidogrel for all STEMI cases, with duration of dual antiplatelet therapy (DAPT)
  • ideally for 1 year, but reduced to a strict
  • minimum of 6 months for patients receiving DES.

The Third Universal Definition of Myocardial Infarction was published
simultaneously with the STEMI guidance. This guideline endorses

  • cardiac troponin as the biomarker of choice to detect myocardial necrosis
  • with spontaneously occurring myocardial infarction (MI) defined as an
  • elevation above the 99th percentile upper reference value for the assay.

There is further development and clarification of MI in different settings

  • to allow standardization across trials and registries

in particular after revascularization procedures: after CABG with normal baseline troponin

  • MI is defined as a rise to a value 10 times greater than baseline in the first 48 h, and
  • a rise to 5 times greater than 99th percentile upper reference after PCI

in patients with a normal baseline level (or a 20% rise when troponin is elevated and stable or falling pre-procedure).

ACCF/AHA  updated guidance on the management of unstable angina/non-STEMI:

angiography with a view to revascularization

  • is now recommended within 12–24 h of presentation, with
  • DAPT pre-loading prior to PCI procedures also now advocated.

Ticagrelor and prasugrel are cited as acceptable alternatives to clopidogrel.
The maintenance dose of aspirin recommended for the majority of cases is 81 mg daily.
This guideline brings about transatlantic agreement in most areas.

Risk Stratification

Identification and appropriate triage of patients presenting to emergency departments
with acute chest pain remains a difficult dilemma:

  • many are low-risk and have a non-cardiac origin
  • a significant minority with coronary artery disease may not be picked up
    on clinical grounds even when accompanied by appropriate tests,

    • including ECG and biomarker estimation used in conjunction
    • with a clinical risk score (e.g. GRACE, TIMI).

As endorsed in ESC guidance, there has been increasing interest in

  • non-typical ECG patterns for the diagnosis of STEMI; although LBBB is
  • an accepted surrogate

Widimsky et al.  retrospectively analysed 6742 patients admitted to hospital with acute MI

  • in patients presenting with right bundle branch block, a blocked epicardial vessel was
  • more common (51.7 vs. 39.4%; P < 0.001) and incidence of both shock and mortality
  • comparable with LBBB (14.3 vs. 13.1%; P = NS; and 15.8 vs. 15.4%; P = NS, respectively).

Wong et al. demonstrated the importance of ST-elevation in lead aVR,

  • often viewed as indicative of left main stem occlusion, having increased mortality
  • in patients presenting with both inferior and anterior infarction.

Perhaps the most important data regarding the ECG in 2012 were also the most simple:

  • Antoni et al. highlighted a powerful and very simple method of risk stratification;
  •  heart rate measured on a 12-lead ECG at discharge after Primary PCI (PPCI) is an
  • independent predictor of mortality at 1 and 4 years of follow-up.

Patients with a discharge heart rate of ≥70 b.p.m. had a two-fold higher mortality at both follow-up
time points, with every increase of 5 b.p.m. in heart rate

  • equating to a 29% increase in mortality at 1 year and 24% at 5 years.

These findings have important implications for the optimization of patient therapies after MI (including the use of
rate-limiting agents such as beta-blockers, calcium channel-blockers, and ivabradine), although large randomized
trials are needed to confirm that

  • interventions to reduce heart rate will replicate the benefits observed in this study.

http://img.medscape.com/article/779/039/779039-thumb1.png

Figure 1.  Kaplan–Meier time-to-event plots for heart rate at discharge divided by quartiles and all-cause mortality
(A and C) and cardiovascular mortality (B and D) at 1-year (A and B) and 4-year (C and D) follow-up,
demonstrating relationship between discharge heart rate and mortality after PPCI for STEMI.
Modified from Antoni et al.

Coronary Intervention and Cardioprotection in Acute Coronary Syndromes

Microvascular obstruction during PCI for ACS/STEMI is associated with increased infarct size and adverse prognosis;
its pathophysiology is thought to be a combination of

  • mechanical distal embolization of thrombus and plaque constituents during PCI,  coupled with
  • enhanced constriction/hyperreactivity of the distal vascular bed.

The most novel Strategy to Reduce Infarct Size

is the use of a Bare Metal Stent (BMS) covered on its outer surface with a mesh micronet designed to
trap and hold potentially friable material that might embolize distally at the time of PCI.

The MASTER study randomized 433 STEMI patients to PPCI

  • with conventional BMS or DES at the operator’s discretion vs.
  • the novel MGuard stent (InspireMD, Tel Aviv, Israel);

the primary endpoint of complete ST-segment resolution was better

  • in patients receiving MGuard (57.85 vs. 44.7%; P = 0.008), as was
  • the achievement of TIMI grade 3 flow in the treated vessel (91.7 vs. 82.9%; P = 0.006).

Nevertheless, median ST-segment resolution did not differ

  • between treatment groups,
  • myocardial blush grade was no different, and
  • safety outcomes at 30 days (death, adverse events) as well as
  • overall MRI-determined infarct mass.

Higher TVR rates may accrue with a BMS platform when compared with

  • current-generation DES (as now endorsed for PPCI in ESC guidance).

In comparing the four studies in cardioprotection, there remains little to choose between strategies as evidenced by

  • the relatively minor differences between surrogate endpoints employed regardless of
  • therapeutic intervention chosen (Figure 2).

http://img.medscape.com/article/779/039/779039-fig2.jpg

Figure 2.  Comparison of study endpoints for reduction in infarct size in STEMI.
Study endpoints listed on the x-axis. STR, ST-segment resolution; TIMI 3, thrombolysis in
myocardial infarction grade 3 antegrade flow; myocardial blush grade 2/3 (MBG 2/3).

Recent advances in

  • PCI equipment,
  • peri-procedural pharmacology,
  • technique, and safety, as well as
  • convergence of national guidance,

are leading to the point where

  • even in the highest risk patients such as those presenting with ACS, small improvements
  • may be difficult to discern despite large well-designed and -conducted studies.

References

  1. a. The Task Force on the management of ST-segment elevation acute myocardial infarction
    of the European Society of Cardiology. ESC guidelines for the management of acute
    myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J
    2012;33:2569–2619.  b. Management of acute myocardial infarction in patients presenting
    with ST-segment elevation. The Task Force on the Management of Acute Myocardial
    Infarction of the European Society of Cardiology.  Eur Heart J 2003; 24 (1): 28-66.
    http://dx.doi.org/10.1093/eurheartj/ehs215
  2. ESC Guidelines for the management of acute coronary syndromes in patients presenting
    without persistent ST-segment elevation: The Task Force for the management of acute
    coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation
    of the European Society of Cardiology (ESC).  http://dx.doi.org/10.1093/eurheartj/ehr236
  3. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BS, White HD. The Writing Group on
    behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of
    Myocardial Infarction. Third universal definition of myocardial infarction.
    Eur Heart J 2012;33:2551–2567.  http://dx.doi.org/10.1093/eurheartj/ehm355
  4. Kalesan B, Pilgrim T, Heinimann K, Raber L, Stefanini GG, et al. Comparison of drug-eluting
    stents with bare metal stents in patients with ST-segment elevation myocardial infarction.
    Eur Heart 2012;33:977–987.
  5. Jneid H, Anderson JL, Wright RS, Adams CS, et al. 2012 ACCF/AHA Focused Update of the
    Guideline for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial
    Infraction (Updating the 2007 Guideline and Replacing the 2011 Focused Update). A Report
    of the American College of CardiologyFoundation/American Heart Association Task Force
    on Practice Guidelines. J Am Coll Cardiol 2012;60:645–681.
  6. Widimsky P, Rohác F, Stásek J, Kala P, Rokyta R, et al. Primary angioplasty in acute myocardial
    infarction with right bundle branch block: should new onset right bundle branch block be added
    to future guidelines as an indication for reperfusion therapy? Eur HeartJ 2012;33:86–95.
  7. Wong CK, Gao W, Stewart RA, French JK, and the HERO-2 Investigators. The prognostic meaning of
    the full spectrum of aVR ST-segment changes in acute myocardial infarction.
    Eur Heart J 2012;33:384–392.
  8. Antoni L, Boden H, Delgado V, Boersma E, et al. Relationship between discharge heart rate and mortality
    in patients after myocardial infarction treated with primary percutaneous coronary intervention.
    Eur Heart J 2012;33:96–102.
  9. Stone GW, Abizaid A, Silber S, Dizon JM, Merkely B, et al. Prospective, randomised, multicenter evaluation
    of a polyethylene terephthalate micronet mesh-covered stent (MGuard) in ST-segment elevation myocardial
    infarction. The MASTER Trial. J Am Coll Cardiol. doi:pii:S0735-1097(12)04506-8. 10.1016/j.jacc.2012.09.004. 
  10. Zhou C, Yao Y, Zheng Z, Gong J, Wang W, Hu S, Li L. Stenting technique, gender, and age are associated with
    cardioprotection by ischaemic postconditioning in primary coronary intervention: a systematic review of
    10 randomized trials. Eur Heart J 2012;33:3070–3077.

Resistant Hypertension.

Robert M. Carey.
Hypertension. 2013;61:746-750.  http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.00601

Resistant hypertension is defined as failure to achieve goal blood pressure (BP) <140/90 mm Hg
(or <130/80 mm Hg in patients with diabetes mellitus or chronic kidney disease) in patients with

  • hypertension who are compliant with maximum tolerated doses of an appropriate antihypertensive drug regimen consisting of a minimum of 3 agents of different classes, including a diuretic.
  • Patients who meet the criteria for resistant hypertension but whose BP can be controlled on maximum tolerated
    doses of ≥4 antihypertensive agents are classified as having controlled resistant hypertension.

Although the number of failed antihypertensive drugs required for the classification of resistant hypertension is arbitrary,

  • this diagnosis identifies patients at high risk for having a potentially curable form of hypertension, and
  • those who may benefit from specific therapeutic approaches to lower BP.

Summary

The first portion of this document shows the impact that ER Edelman and his peers have had in the development
of interventional cardiology, and in carrying out studies to test, validate, or reject assumptions about the interaction of
biomaterials with

  • vascular and smooth muscle tissue in the repair of injured vessels, by
  1. trauma
  2. inflammatory injury
  3. stent placement.

In the second portion of this discussion, I introduce current views about complications in implanted devices, evolving
standards, and the current definitions of stable, unstable, and previously unclassified ACS risk.

Pushing Drug-Eluting Stents Into Uncharted Territory

Simpler Than You Think—More Complex Than You Imagine

Campbell Rogers, MD; Elazer R. Edelman, MD, PhD.  Circulation 2006; 113: 2262-2265.
http://dx.doi.org/10.1161/​CIRCULATIONAHA.106.623470

Mechanical failure is a characteristic of a material or a device and not necessarily an indication of inadequacy. All devices
will fail under some specific stress. It is only failure at the lowest levels of stress that may represent inadequacy. Stress on
a material, for example, rises with strain until a critical load is exceeded, at which point the material fatigues and loses
mechanical integrity. Failure analysis, the science by which these conditions are rigorously defined, is an important
component of device design, development, and use. Once the transition point to failure is identified, material use can be
restricted to the zone of safety or modified so as to have this zone expanded. Just as the characterization of a material is
incomplete unless pushed to the limits of load bearing, characterization of an implantable device is incomplete unlesspreclinical and clinical environments test the limits of device functionality. It was in this light in 1999 that the Authors noted the impossibility of defining the functional limits of novel bare metal stents in head-to-head trials, which, by necessity, could only include lesions into which the predicate device (the Palmaz-Schatz stent, Cordis, Warren, NJ) could have be placed.

New School Percutaneous Interventions

Over the past 5 years, the number of percutaneous interventions has grown by 40%. This expansion derives from an
increased breadth of cases, as percutaneous interventions are now routinely performed in diabetic, small-vessel, multilesion,diffuse disease, and acute coronary syndrome settings. Contemporaneously, widespread adoption of drug-eluting stents has emboldened clinicians and provided greater security in the use of these devices in lesions or patients previously thought to

Head-to-head randomized trial data have accumulated so that analysis may demonstrate differences among drug-eluting stents. The playing field for prospective randomized trials could enhance the weight of evidence to unanswered questions about what underlying factors determine device failure.

Complexity Simplified

Drug-eluting stent “failure” can be defined operationally in the same way as material failure:

  • inadequate function in the setting of a given load or strain.

The inability to withstand stress may take many forms that can change over time. Failure may be manifest acutely as

  • the inability to deliver a stent to the desired location,
  • subacutely as stent thrombosis or
  • postprocedural myonecrosis, and later as
  • restenosis

“Simple lesions” are those in which few devices should fail;“Complex” lesions have a heightened risk of failure. To be of value, each scale of advancing complexity must provoke higher failure rates.  For any device may fail sooner than another along one such “complexity” scale and later along another. As advanced drug-eluting stent designs have enhanced deliverability and reduced restenosis rates, 7 randomized trials comparing directly the two Food and Drug Administration (FDA)-approved drug-eluting stents, Cypher (Cordis-Johnson and Johnson) and Taxus (Boston Scientific, Boston, Mass), have been reported.  These trials report a broad range of restenotic failure as evidenced by the need for revascularization. Across these trials, driven by a variety of factors, revascularization rates vary quite widely.

The clinical end point of target lesion revascularization (TLR) becomes

  • a single measure of device failure.

When the 7 trials are depicted in order of increasing TLR, the rate of failure increases more slowly with 1 device than
the other.  This gives two regression plots for Taxus vs Cypher with different slopes, as complexity increases, and the

  • separation between the failure rates of the two devices broadens plotted against “degree of complexity” assigned by the  slopes of the lines.

Finally, the correlation between TLR rates for Taxus and Cypher stents indicates that trial-specific events and conditions determined TLR (with a sharp slope of Taxus vs Cypher (r-sq = 0.85).  The ratio of TLR (the slope) wasgreater than 3, suggesting that although both devices are subject to increasing failure as complexity increases,

  • one device becomes ever-more likely than the other to fail when applied in settings with ever-higher TLR risk.

In other words, composite medical devices with a wide range of

  • structural,
  • geometric, and
  • pharmacological differences
    • can be shown to produce different clinical effects
    • as the environments in which they are tested become increasingly complex.

What the Individual Trials Cannot Tell Us

The progressive difference between the performances of the 2 FDA-approved drug-eluting stents as they are pushed into
more complex settings is precisely what one would anticipate from medical devices with different performance signatures.
Most randomized trials, even if they include high complexity, are unable to identify predictors of failure because of the low numbers of patients enrolled, and the problem gets worse as the number of subsets increase. Consequently, device development, and clinical practice, knowing which patient or lesion characteristics confer higher failure rates is critical.
This analysis has centered on restenosis. Other failure modes to be considered are

  • stent thrombosis,
  • postprocedural myonecrosis
  • late plaque rupture
  • vascular disease away from the site
  • heightened inflammatory reaction
    • are no less critical and may be determined by
    • completely different device or patient characteristics.

Well-executed registry or pooled data

It is in this light that the registry report of Kastrati et al. in the current issue of Circulation is of greatest value. There are
two ways in which well-executed registry or pooled data can be most complementary to randomized trials.

First, large numbers of patients provide a higher incidence of rare failure modes as well as allow more granular determination of lesion- or patient-specific predictors of failure (meta-analysis or better, combined data file). A pooled analysis of several head-to-head randomized bare metal stent trials allowed identification of clear risk factors for stent thrombosis that had eluded analysis of the individual (smaller) trials.

Second, registry or pooled data may incorporate a broader range of patient characteristics, allowing greater discrimination between devices. The report of Kastrati et al may fall into this category as well, as it includes “high risk” populations from several randomized trials. They report on more than 2000 lesions in 1845 patients treated with either Taxus or Cypher drug-eluting stents at two hospitals.  The study population is from a series of randomized trials comparing Taxus and Cypher stents.   Using multivariate analysis to identify what lesion and patient characteristics predict failure (restenosis), they identified risk factors that included

  • prior history of coronary bypass surgery
  • calcification
  • smaller vessel size
  • greater degree of prestent and poststent stenosis.

Use of a Cypher rather than Taxus stent was independently associated with lower restenosis risk.

An interesting negative finding was the absence of diabetes as a significant predictor, at odds with strong suggestions from several other analyses. A better understanding from preclinical or clinical studies of the effect of diabetic states on restenosis is critical.

Author’s opinion voiced:

This Author (LHB), considers the study underpowered to answer that question because of further partitioning with several variables. Pooled data with

  • rigorous ascertainment and
  • careful statistical methodology, taken
  • together with randomized trial data, open a door to device choice based on the knowledge that risk of failure (complexity) does vary, and
  • the higher the complexity, the greater the incremental benefit of choosing one device over another.

A decision algorithm is therefore possible, whereby multiple failure modes and risk factors are weighed, and

  • an optimum stent choice made which balances
  • safety and efficacy based on the totality of evidence, rather than anecdote and loose comparisons of disparate subgroups from individual trials.

Evaluating Clinical Trials

The subject of trial(s) is difficult… the aim and meaning of all the trials… is

  • to let people know what they ought to do or what they must believe

It was perhaps naïve to imagine that devices as different one from another as the two current FDA-approved drug-eluting
stents would produce identical clinical results. If so, it ought not to come as a surprise that head-to-head randomized trial
data from many different countries in complex settings are now indicating just how differently the 2 devices may perform.

Future trials should be designed and evaluated to examine why these differences exist. Trials residing
only in previous safety and complexity domains

  • are unlikely to offer deeper insights into
    1. device performance,
    2. patient care decisions, or
    3. discrimination of alternative therapies.

We look forward to more trials that will examine what we currently believe to be the limits of

  • drug-eluting stents and interventional cardiology and to

help define in simple terms differences

  • between complex devices applied to complex problems.

This 2009 article was an excellent demonstration of comparing two commonly used coated-stents, and then extending the argument to the need for more data to further delineated the factors that explain the differences they found. In the previous article, the SECOND in the three article series,  Stents and Drug Delivery

Vascular Repair: Stents and Biologically Active Implants

we concentrated on stents and drug delivery, and not on stent failure.  But the following article in J Control Release,

was published the following year, and is another example of this method of explanatory approach to the problem.

Lesion Complexity Determines Arterial Drug Distribution After Local Drug Delivery

AR Tzafriri,  N Vukmirovic, VB Kolachalama, I Astafieva, ER Edelman. J Control Release. 2010; 142(3): 332–338.
http://:dx. doi:.org/10.1016/j.jconrel.2009.11.007       PMCID: PMC2994187

Local drug delivery from endovascular stents has transformed how we treat coronary artery disease. Yet, few drugs are in fact effective when delivered from endovascular implants and those that possess a narrow therapeutic window. The width of this window is predicated to a great degree upon the extent of drug deposition and distribution through the arterial wall.

  • Drugs that are retained within the blood vessel are far more effective than those that are not.

Thus, for example, heparin regulates virtually every aspect of the vascular response to injury, but it is so soluble and diffusible that it simply cannot stay in the artery for more than minutes after release.

  • Heparin has no effect on intimal hyperplasia when eluted from a stent.
  • Paclitaxel and sirolimus in contradistinction are far smaller compounds with perhaps more narrow and specific effects than heparin.

These drugs bind tenaciously to tissue protein elements and specific intracellular targets and remain beneath stent struts long after release.

The clinical efficacy of paclitaxel and sirolimus at reducing coronary artery restenosis rates following elution from stents appears incontrovertible. Emerging clinical and preclinical data suggest that the benefit of the local release of these drugs is beset by significant complications, that rise with lesion complexity as

  • the native composition and layered ultrastructure of the native artery is more significantly disrupted.

Virmani and others have hypothesized that the attraction of lipophilic drugs like paclitaxel and sirolimus to fat should affect their retention within and effects upon atheromatous lesions.

Though stents are deployed in diseased arteries drug distribution has only been quantified in intact, non-diseased vessels.

Authors @ MIT, correlated steady-state arterial drug distribution with tissue ultrastructure and composition in abdominal aortae from atherosclerotic human autopsy specimens and rabbits

  • with lesions induced by dietary manipulation and controlled injury.

Drug and compositional metrics were quantified and correlated at a compartmental level, in each of the tunica layers, or at an intra-compartmental level. All images were processed to

  • eliminate backgrounds and artifacts, and
  • pixel values between thresholds were extracted for all zones of interest.

Specific algorithms analyzed each of the histo/immuno-stained arterial structures. Intra-compartmental analyses were

  • performed by sub-dividing arterial cross-sections into 2–64 equal sectors and
  • evaluating the pixel-average luminosity for each sector.

Linear regression of drug versus compositional luminosities asymptotically approached steady state after subdivision into 16 sectors. This system controlled delivered dose and removed the significant unpredictability in release that is imposed by variability

  • in stent position relative to the arterial wall,
  • inflation techniques and stent geometry.
As steady state tissue distribution results were obtained under constant source conditions, without washout by flowing blood,
  • they constitute upper bounds for arterial drug distribution
  • following transient modes of in vivo drug delivery wherein
  • only a fraction of the eluted dose is absorbed by the artery

Paclitaxel, everolimus, and sirolimus deposition in human aortae was maximal in the media and scaled inversely with lipid content.

Net tissue paclitaxel and everolimus levels were indistinguishable in mildly injured rabbit arteries independent of diet. Yet, serial sectioning of cryopreserved arterial segments demonstrated

  • a differential transmural deposition pattern that was amplified with disease and
  • correlated with expression of their intracellular targets, tubulin and FKBP-12.

Tubulin distribution and paclitaxel binding increased with

  • vascular injury and macrophage infiltration, and
  • were reduced with (reduced) lipid content.

Sirolimus analogues and their specific binding target FKBP-12 were less sensitive to alterations of diet
in mildly injured arteries, presumably reflecting a faster transient response of FKBP-12 to injury.

The idea that drug deposition after balloon inflation and stent implantation within diseased, atheromatous and sclerotic vessels tracks so precisely with specific tissue elements is

  • an important consideration of drug-eluting technologies and
  • may well require that we consider diseased rather than naïve tissues in preclinical evaluations.

Another publication in the same year reveals the immense analytical power used in understanding the complexities
of drug-eluting stents.

Luminal Flow Amplifies Stent-Based Drug Deposition in Arterial Bifurcations

Kolachalama VB, Levine EG, Edelman ER.    PLoS ONE 2009; 4(12): e8105.
 http://dx.doi.org/10.1371/journal.pone.0008105

Treatment of arterial bifurcation lesions using drug-eluting stents (DES) is now common clinical practice.
Arterial drug distribution patterns become challenging to analyze if the lesion involves more than a vessel
such as in the case of bifurcations.  As use extends to nonstraightforward lesions and complex geometries,
questions abound

  • regarding DES longevity and safety

Indeed, there is no consensus on best stent placement scenario, no understanding as to

  • whether DES will behave in bifurcations as they do in straight segments, and
  • whether drug from a main-branch (MB) stent can be deposited within a side-branch (SB).

It is not evident how to

  • efficiently determine the efficacy of local drug delivery and
  • quantify zones of excessive drug that are
  • harbingers of vascular toxicity and thrombosis,
  • and areas of depletion that are associated
  • with tissue overgrowth and
  • luminal re-narrowing.

Geometry modeling and governing equations

Authors @MIT constructed two-phase computational models of stent-deployed arterial bifurcations

  • simulating blood flow and drug transport to investigate the
  • factors modulating drug distribution when the main-branch (MB) was treated using a DES.

The framework for constructing physiologically realistic three dimensional computational models of single
and bifurcated arterial vessels was SolidWorks (Dassault Systemes) (Figs. 1A–1B, Movie S1). The geometry
generation algorithm allowed for controlled alteration of several parameters including

  • stent location
  • strut dimensions
  • stent-cell shape
  • lumen diameter to arterial tissue thickness ratio
  • lengths of the arterial branches
  • extent of stent apposition and
  • the bifurcation angle.

For the current study, equal lengths (2LS) were assumed for the proximal and distal sections of the MB from the bifurcation. The SB was constructed at an angle of 300. The inlet conditions were based on

  • mean blood flow and
  • diameter measurements

obtained from human left anterior descending coronary artery (LAD).

The diameter of the lumen (DMB) and thickness (TMB) for the MB were defined such that DMB=TMB~10 and

  • this ratio was also maintained for the SB.

Schematics of the computational models used for the study. A stent of length LS is placed at the upstream section of the arterial vessel in the (A) absence and in the (B) presence of a bifurcation, respectively.

  • Insets in (B) denote delta wing stent design (i),
  • strut thickness (d) (ii), and
  • the outlets of the side-branch in (iii) and
  • and the main-branch in (iv).

A delta wing-shaped cell design belonging to the class of slotted-tube stents was used for all simulations.
The length (LS) and diameter (DS) were

  • fixed at 9|10-2 m and 3|10-2 m, respectively, for the MB stent.

All stents were assumed to be perfectly apposed to the lumen of MB and the intrinsic strut shape was modeled as

  • square with length 10-4 m.

The continuity and momentum equations were solved within the arterial lumen, where

vf , rho~1060 kg=m3, P and m are

  • velocity
  • density
  • pressure and the
  • viscosity of blood.

In order to capture boundary layer effects at the lumen-wall (or mural) surface, a Carreau model was employed for

  • all the simulations to account for shear thinning behavior of blood at low shear rates

In the arterial lumen, drug transport followed advection-diffusion process.  Similar to the momentum transport in the arterial lumen, the continuity equation was solved within the arterial wall by assuming it as a porous medium.

A finite volume solver (Fluent, ANSYS Inc.) was utilized to perform the coupled flow and drug transport simulations. The semi-implicit method for pressure-linked equations-consistent (SIMPLEC) algorithm was used with second order spatial accuracy. A second order discretization scheme was used to solve the pressure equation and second order  upwind schemes were used for the momentum and concentration variables.

Simulations for each case were performed

  • for at least 2500 iterations or
  • until there was a 1028 reduction in the mass transport residual.

Drug distribution in non-bifurcating vessels

Constant flow simulations generate local recirculation zones juxtaposed to the stent which in turn act as

  • secondary sources of drug deposition and
  • induce an asymmetric tissue drug distribution profile in the longitudinal flow direction.

Our3D computational model predicts a far more extensive fluid mechanic effect on drug deposition than previously appreciated in two-dimensional (2D) domains.

Within the stented region, drug deposition on the mural interface quantified as

  • the area-weighted average drug concentration (AWAC)
  • in the distal segment of the stent is 12% higher than the proximal segment

Total drug uptake in the arterial wall denote as volume-weighted average concentration (VWAC) is highest in the middle segment of the stent and 5% higher than the proximal stent region

Increased mural drug deposition along the flow direction in a non-bifurcating arterial vessel.

Inset shows a high magnification image of drug pattern in the distal stent segment outlined by black dashed line.
The entire stent is divided into three equal sections denoted as proximal, middle and distal sections, respectively
and the same notation is followed for subsequent analyses.

http://dx.doi.org/10.1371/journal.pone.0008105.g002

These observations indicate that the flow-mediated effect induced by the presence of the stent in the artery

  • is maximal on the mural surface and
  • increases in the longitudinal flow direction.

Further, these results suggest that transmural diffusion-mediated transport sequesters drug from both

  • the proximal and distal portions of the stent
  • into the central segment of the arterial wall beneath the stent.

Predicted levels of average drug concentration varied exponentially

  • with linear increments of inlet flow rate

but maintained similar relationship between the inter-segment concentration levels within the stented region.

Stent position influences drug distribution in bifurcated beds

The location of the stent directly modulates

  • the extent to which drug is deposited on the arterial wall as well as
  • spatial gradients that are established in arterial drug distribution.

Similar to the non-bifurcating vessel case,

  • peaks in drug deposition occur directly beneath the stent struts regardless of the relative location of the SB with respect to the stent. However,
  • drug distribution and corresponding spatial heterogeneity within inter-strut regions depend on the stent location with respect to the flow divider.
  • Mural drug deposition is a function of relative stent position with respect to the side-branch and Reynolds number in arterial bifurcations.

Impact of flow on drug distribution in bifurcations

One can appreciate how blood flow and flow dividers affect arterial drug deposition, and especially on inter-strut drug deposition.

  • Drug deposition within the stented-region of MB  and the entire SB significantly decreases with flow acceleration regardless of stent placement.

Simulations predicted

Local endovascular drug delivery was long assumed to be governed by diffusion alone. The impact of flow was
thought to be restricted to systemic dilution.

  • 2D computational models suggested a complex interplay between the stent and blood flow
  1. Arterial drug deposition is a function of stent location.   http://dx.doi.org/10.1371/journal.pone.0008105.g005
  2. Arterial drug deposition is mediated by flow in bifurcated beds.
    http://dx.doi.org/10.1371/journal.pone.0008105.g006
  • extensive flow-mediated drug delivery in bifurcated vascular beds where the drug distribution patterns are heterogeneous and sensitive to relative stent position and luminal flow.

A single DES in the MB coupled with large retrograde luminal flow on the lateral wall of the side-branch (SB) can provide drug deposition on the SB lumen-wall interface, except

  • when the MB stent is downstream of the SB flow divider.
  • the presence of the SB affects drug distribution in the stented MB.

Fluid mechanic effects play an even greater role than in the SB

  • especially when the DES is across and downstream to the flow divider
  • and in a manner dependent upon

    the Reynolds number.

Summary

We presented the hemodynamic effects on drug distribution patterns using a

  • simplified uniform-cell stent design, though our methodology is adaptable to
    several types of stents with variable design features.

Variability in arterial drug distribution due to other geometric and morphologic aspects such as

  • bifurcation angle, arterial taper as well as presence of a trifurcation can also be understood using our computational framework.

Further, performance of a candidate DES using other commonly used stenting procedures for bifurcation lesions such as culotte and crush techniques can be quantified based on their resulting drug distribution patterns.

Other Related Articles that were published on this Open Access Online Scientific Journal include the following:

Vascular Repair: Stents and Biologically Active Implants

Larry H Bernstein, MD, FACP and Aviva Lev-Ari, RN, PhD, 5/4/2013

Modeling Targeted Therapy

Larry H Bernstein, MD, FACP 3/2/2013

Quantum Biology And Computational Medicine

Larry H Bernstein, MD, FACP 4/3/2013

Virtual Biopsy – is it possible?

Larry H Bernstein, MD, FACP 3/3/2013

Reprogramming cell fate  3/2/2013

Larry H Bernstein, MD, FACP

How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

Larry H Bernstein, MD, FACP 4/4/2013

Amyloidosis with Cardiomyopathy

Larry H Bernstein, MD, FACP 3/31/2013

Nitric Oxide, Platelets, Endothelium and Hemostasis

Larry H Bernstein, MD, FACP 11/8/2012

Mitochondrial Damage and Repair under Oxidative Stress

Larry H Bernstein, MD, FACP 10/28/2012

Endothelial Function and Cardiovascular Disease

Larry H Bernstein, MD, FACP 10/25/2012

Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease –Therapeutic Potential of cEPCs

Aviva Lev-Ari, PhD, RN 8/27/2012

Prostacyclin and Nitric Oxide: Adventures in Vascular Biology – A Tale of Two Mediators

Aviva Lev-Ari, RN, PhD, 4/30/2013

Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Aviva Lev-Ari, PhD, 4/28/2013

https://pharmaceuticalintelligence.com/2013/04/28/genetics-of-conduction-disease-atrioventricular-av-conduction-disease-block-gene-mutations-transcription-excitability-and-energy-homeostasis/

Revascularization: PCI, Prior History of PCI vs CABG

Aviva Lev-Ari, PhD, 4/25/2013

https://pharmaceuticalintelligence.com/2013/04/25/revascularization-pci-prior-history-of-pci-vs-cabg/

Revascularization: PCI, Prior History of PCI vs CABG

Aviva Lev-Ari, PhD, RN 4/25/2013

https://pharmaceuticalintelligence.com/2013/04/25/revascularization-pci-prior-history-of-pci-vs-cabg/

Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD

Aviva Lev-Ari, PhD, RN 4/7/2013

https://pharmaceuticalintelligence.com/2013/04/07/cholesteryl-ester-transfer-protein-cetp-inhibitor-potential-of-anacetrapib-to-treat-atherosclerosis-and-cad/

Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients

Aviva Lev-Ari, PhD, RN 4/4/2013

https://pharmaceuticalintelligence.com/2013/04/04/hypertriglyceridemia-concurrent-hyperlipidemia-vertical-density-gradient-ultracentrifugation-a-better-test-to-prevent-undertreatment-of-high-risk-cardiac-patients/

Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore

Aviva Lev-Ari, PhD, RN 4/3/2013

https://pharmaceuticalintelligence.com/2013/04/03/fight-against-atherosclerotic-cardiovascular-disease-a-biologics-not-a-small-molecule-recombinant-human-lecithin-cholesterol-acyltransferase-rhlcat-attracted-astrazeneca-to-acquire-alphacore/

High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk

Aviva Lev-Ari, PhD, RN 3/31/2013

https://pharmaceuticalintelligence.com/2013/03/31/high-density-lipoprotein-hdl-an-independent-predictor-of-endothelial-function-artherosclerosis-a-modulator-an-agonist-a-biomarker-for-cardiovascular-risk/

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI

Aviva Lev-Ari, PhD, RN 3/10/2013

https://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

Lev-Ari, A. and L H Bernstein 3/7/2013

https://pharmaceuticalintelligence.com/2013/03/07/genomics-genetics-of-cardiovascular-disease-diagnoses-a-literature-survey-of-ahas-circulation-cardiovascular-genetics-32010-32013/

The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN

Aviva Lev-Ari, PhD, RN 2/28/2013

https://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/

Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

Aviva Lev-Ari, PhD, RN 2/27/2013

https://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/

Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles

Aviva Lev-Ari, PhD, RN 12/29/2012

https://pharmaceuticalintelligence.com/2012/12/29/coronary-artery-disease-in-symptomatic-patients-referred-for-coronary-angiography-predicted-by-serum-protein-profiles/

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Bernstein, HL and Lev-Ari, A. 11/28/2012

https://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes

Aviva Lev-Ari, PhD, RN 11/13/2012

https://pharmaceuticalintelligence.com/2012/11/13/peroxisome-proliferator-activated-receptor-ppar-gamma-receptors-activation-pparγ-transrepression-for-angiogenesis-in-cardiovascular-disease-and-pparγ-transactivation-for-treatment-of-dia/

Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

Aviva Lev-Ari, PhD, RN 10/19/2012

https://pharmaceuticalintelligence.com/2012/10/19/clinical-trials-results-for-endothelin-system-pathophysiological-role-in-chronic-heart-failure-acute-coronary-syndromes-and-mi-marker-of-disease-severity-or-genetic-determination/

Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

Aviva Lev-Ari, PhD, RN 10/4/2012

https://pharmaceuticalintelligence.com/2012/10/04/endothelin-receptors-in-cardiovascular-diseases-the-role-of-enos-stimulation/

Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography

Aviva Lev-Ari, PhD, RN 10/4/2012

https://pharmaceuticalintelligence.com/2012/10/04/inhibition-of-et-1-eta-and-eta-etb-induction-of-no-production-and-stimulation-of-enos-and-treatment-regime-with-ppar-gamma-agonists-tzd-cepcs-endogenous-augmentation-for-cardiovascular-risk-reduc/

Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

Aviva Lev-Ari, PhD, RN 8/29/2012

https://pharmaceuticalintelligence.com/2012/08/29/positioning-a-therapeutic-concept-for-endogenous-augmentation-of-cepcs-therapeutic-indications-for-macrovascular-disease-coronary-cerebrovascular-and-peripheral/

Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs

Aviva Lev-Ari, PhD, RN 8/28/2012

https://pharmaceuticalintelligence.com/2012/08/28/cardiovascular-outcomes-function-of-circulating-endothelial-progenitor-cells-cepcs-exploring-pharmaco-therapy-targeted-at-endogenous-augmentation-of-cepcs/

Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs

Aviva Lev-Ari, PhD, R N 8/27/2012

https://pharmaceuticalintelligence.com/2012/08/27/endothelial-dysfunction-diminished-availability-of-cepcs-increasing-cvd-risk-for-macrovascular-disease-therapeutic-potential-of-cepcs/

Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs

Aviva Lev-Ari, PhD, RN 8/24/2012

https://pharmaceuticalintelligence.com/2012/08/24/vascular-medicine-and-biology-classification-of-fast-acting-therapy-for-patients-at-high-risk-for-macrovascular-events-macrovascular-disease-therapeutic-potential-of-cepcs/

Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Aviva Lev-Ari, PhD, RN 7/19/2012

https://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair

Aviva Lev-Ari, PhD, RN 4/30/2012

https://pharmaceuticalintelligence.com/2012/04/30/93/

Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

Aviva Lev-Ari, PhD, RN 5/29/2012

https://pharmaceuticalintelligence.com/2012/05/29/445/

Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk

Aviva Lev-Ari, PhD, RN 7/2/2012

https://pharmaceuticalintelligence.com/2012/07/02/macrovascular-disease-therapeutic-potential-of-cepcs-reduction-methods-for-cv-risk/

Mitochondria Dysfunction and Cardiovascular Disease – Mitochondria: More than just the “powerhouse of the cell”

Aviva Lev-Ari, PhD, RN 7/9/2012

https://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

Bystolic’s generic Nebivolol – positive effect on circulating Endothelial Proginetor Cells endogenous augmentation

Aviva Lev-Ari, PhD, RN 7/16/2012

https://pharmaceuticalintelligence.com/2012/07/16/bystolics-generic-nebivolol-positive-effect-on-circulating-endothilial-progrnetor-cells-endogenous-augmentation/

Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

Aviva Lev-Ari, PhD, RN 2/27/2013

https://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/

Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”

Aviva Lev-Ari, PhD, RN 1/8/2013

https://pharmaceuticalintelligence.com/2013/01/08/cardiac-surgery-theatre-in-china-vs-in-the-us-cardiac-repair-procedures-medical-devices-in-use-technology-in-hospitals-surgeons-training-and-cardiac-disease-severity/

Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony

Aviva Lev-Ari, PhD, RN 7/23/2012

https://pharmaceuticalintelligence.com/2012/07/23/heart-remodeling-by-design-implantable-synchronized-cardiac-assist-device-abiomeds-symphony/

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI

Aviva Lev-Ari, PhD, RN 3/10/2013

https://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)

Aviva Lev-Ari, PhD, RN 3/10/2013
https://pharmaceuticalintelligence.com/2013/03/10/dilated-cardiomyopathy-decisions-on-implantable-cardioverter-defibrillators-icds-using-left-ventricular-ejection-fraction-lvef-and-midwall-fibrosis-decisions-on-replacement-using-late-gadolinium/

The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN

Aviva Lev-Ari, PhD, RN 2/28/2013
https://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/

FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology

Aviva Lev-Ari, PhD, RN 1/28/2013
https://pharmaceuticalintelligence.com/2013/01/28/fda-pending-510k-for-the-latest-cardiovascular-imaging-technology/

PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

Aviva Lev-Ari, PhD, RN 1/10/2013
https://pharmaceuticalintelligence.com/2013/01/10/pci-outcomes-increased-ischemic-risk-associated-with-elevated-plasma-fibrinogen-not-platelet-reactivity/

The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX

Aviva Lev-Ari, PhD, RN 1/3/2013
https://pharmaceuticalintelligence.com/2013/01/03/the-acuity-pci-score-will-it-replace-four-established-risk-scores-timi-grace-syntax-and-clinical-syntax/

Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles

Aviva Lev-Ari, PhD, RN 12/29/2012
https://pharmaceuticalintelligence.com/2012/12/29/coronary-artery-disease-in-symptomatic-patients-referred-for-coronary-angiography-predicted-by-serum-protein-profiles/

Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered

Aviva Lev-Ari, PhD, RN 12/23/2012
https://pharmaceuticalintelligence.com/2012/12/23/heart-renewal-by-pre-existing-cardiomyocytes-source-of-new-heart-cell-growth-discovered/

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

Aviva Lev-Ari, PhD, RN 10/30/2012
https://pharmaceuticalintelligence.com/2012/10/30/cardiovascular-risk-inflammatory-marker-risk-assessment-for-coronary-heart-disease-and-ischemic-stroke-atherosclerosis/

To Stent or Not? A Critical Decision

Aviva Lev-Ari, PhD, RN 10/23/2012
https://pharmaceuticalintelligence.com/2012/10/23/to-stent-or-not-a-critical-decision/

New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia

Aviva Lev-Ari, PhD, RN 8/27/2012
https://pharmaceuticalintelligence.com/2012/08/27/new-definition-of-mi-unveiled-fractional-flow-reserve-ffrct-for-tagging-ischemia/

Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report

Aviva Lev-Ari, PhD, RN 8/23/2012
https://pharmaceuticalintelligence.com/2012/08/23/ethical-considerations-in-studying-drug-safety-the-institute-of-medicine-report/

New Drug-Eluting Stent Works Well in STEMI

Aviva Lev-Ari, PhD, RN 8/22/2012
https://pharmaceuticalintelligence.com/2012/08/22/new-drug-eluting-stent-works-well-in-stemi/

Expected New Trends in Cardiology and Cardiovascular Medical Devices

Aviva Lev-Ari, PhD, RN 8/17/2012
https://pharmaceuticalintelligence.com/2012/08/17/expected-new-trends-in-cardiology-and-cardiovascular-medical-devices/

Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents

Aviva Lev-Ari, PhD, RN 8/13/2012

https://pharmaceuticalintelligence.com/2012/08/13/coronary-artery-disease-medical-devices-solutions-from-first-in-man-stent-implantation-via-medical-ethical-dilemmas-to-drug-eluting-stents/

Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia

Aviva Lev-Ari, PhD, RN 7/18/2012

https://pharmaceuticalintelligence.com/2012/07/18/percutaneous-endocardial-ablation-of-scar-related-ventricular-tachycardia/

Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)

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https://pharmaceuticalintelligence.com/2012/06/22/competition-in-the-ecosystem-of-medical-devices-in-cardiac-and-vascular-repair-heart-valves-stents-catheterization-tools-and-kits-for-open-heart-and-minimally-invasive-surgery-mis/

Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders) in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites

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Vascular Repair: Stents and Biologically Active Implants

Author and Curator: Larry H Bernstein, MD, FACP
and
Curator: Aviva Lev-Ari, PhD, RN

This is the second article of a three part series recognizing the immense contribution of Elazer Edelman, MD, PhD, and his laboratory group at MIT to vascular biology, cardiovascular disease studies, and the bioengineering, development, and use of stenting technology for drug delivery, vascular repair, and limitation of vessel damage caused by stent placement.

The first article, published on this Open Access Online Scientific Journal
was concerned with vascular biology, and largely on both the impact of drug delivery design and placement on the endothelium of the vessel wall, and on the kinetics of drug delivery based on the location of stent placement versus intravascular injection as well as the metabolic events taking place in the arterial endothelium, intima, and muscularis.
This second article, is concerned with stents and drug delivery as it has evolved since the last decade of the 20th century based on biomaterials development and vascular biology principles to minimize inherent injury risk over this period.
The third. will be concerned with the lessons from biomaterials and stent mechanics going forward.
Heart care is in the midst of a transformation. Patients who once required heart surgery are treated with a stent, catheters for repair of valves, rhythm abnormalities, and a growing number of heart or vascular distrbances.
The catheters are threaded in through the femoral artery, and sometimes through the radial artery. The American College of Cardiology annual meeting highlights research on these devices.  The procedure allows patients to leave the hospital after a day or two post-implant, but the initial cost of the novel devices is high.  Not everyone qualifies for the treatment, and it will take a few years to compare the long term results with the benefits from surgery. But these procedures have allowed many patients treatment alternatives to surgery, and they offer an option for people who cannot be successfully managed by conservative medical therapy.

The effects of stent placement on vascular injury and the initiation of an inflammatory response

Leukocytes are recruited early and abundantly to experimentally injured vessels,

  • in direct proportion to cell proliferation and intimal growth.
Activated circulating leukocytes and Mac-1 (CD11 by CD18, aMb2) (monocytic) expression are
  • markers of restenosis risk in patients undergoing angioplasty.
Angioplastied vessels lack endothelium but have extensive fibrin(ogen) and platelet deposition.  Consequently, Mac-1-dependent adhesion to fibrin(ogen)  would be expected to
  • signal leukocyte recruitment and function, thereby
  • promote intimal growth
In this study
  • M1/70, an anti-CD11b blocking mAb, was  administered to rabbits before, and every 48 hr for 3, 6, or 14 days after iliac artery balloon denudation.
  • M1/70 was bound to isolated rabbit monocytes.

The result was

  • Mac-1-mediated dose-dependent
  • inhibition of fibrinogen binding in vitro, thereby,
  • reducing by half leukocyte recruitment at 3, 6, and 14 days after injury.
Neointimal growth 14 days after injury was markedly attenuated by treatment with M1/70 –
intimal area after balloon injury, 0.12+0.09 mm2, compared with
  •  0.32+0.08 mm2 in vehicle treated controls, P<0.01, and
  •  0.38+0.08mm2 in IgG-treated controls, P<0.005;
intimal area after stent injury, 0.56+0.16 mm2, compared with
  •  0.84+ 0.13 mm2 in vehicle-treated controls, P <0.05, and
  •  0.90+0.15 mm2 in IgG-treated controls, P <0.02).
Mac-1 blockade reduces experimental neointimal thickening. These findings suggest that
  • leukocyte recruitment to and
  • infiltration of injured arteries

may be a valid target for preventing intimal hyperplasia. (1) Emerging data indicate that the inflammatory response after mechanical arterial injury

  • correlates with the severity of neointimal hyperplasia in animal models
  • and post angioplasty restenosis in humans.
The present study was designed to examine whether a nonspecific
  • stimulation of the innate immune system,
  • induced in close temporal proximity to the vascular injury,
  • would modulate the results of the procedure.
A LPS dose was chosen to be sufficient to induce systemic inflammation but not septic shock. Key markers of inflammation increased after LPS administration were:
  • serum interleukin-1 levels, and
  • monocytic stimulation (CD14 levels on monocytes)
Arterial macrophage infiltration at 7 days after injury was
  • 1.7+1.2% of total cells in controls and
  • 4.2+1.8% in LPS-treated rabbits (n=4, P<0.05).
The injured arteries 4 weeks after injury had significantly increased
  • luminal stenosis:   38+4.2% versus 23+2.6%, mean+SEM; n=8, P<0.05; and
  • neointima-to-media ratio:  1.26+0.21 versus 0.66+0.09, P<0.05 in LPS-treated animals compared with controls.
This effect was abolished by anti-CD14 Ab administration. Serum Il-1 levels and monocyte CD14 expression were significantly increased
  • in correlation with the severity of intimal hyperplasia.
  • LPS treatment increased neointimal area after stenting
    • from 0.57+0.07 to 0.77+0.1 mm2, and
  • stenosis from 9+1% to 13+1.7% (n=5, P<0.05).
Nonspecific systemic stimulation of the innate immune system
  • concurrently with arterial vascular injury
  • facilitates neointimal formation, and conditions associated with
  • increased inflammation may increase restenosis.(2)
Millions of patients worldwide have received drug-eluting stents
  • to reduce their risk for in-stent restenosis.
The efficacy and toxicity of these local therapeutics depend upon
  • arterial drug deposition,
  • distribution, and
  • retention.
To examine how administered dose and drug release kinetics control arterial drug uptake, a model was created using principles of
  • computational fluid dynamics and
  • transient drug diffusion–convection.
The modeling predictions for drug elution were validated using
  • empiric data from stented porcine coronary arteries.
Inefficient, minimal arterial drug deposition was predicted when a bolus of drug was released and depleted within seconds.
Month-long stent-based drug release
  • efficiently delivered nearly continuous drug levels, but
  • the slow rate of drug presentation limited arterial drug uptake.
Uptake was only maximized when
  • the rates of drug release and absorption matched,
  • which occurred for hour-long drug release.
Of the two possible means for increasing the amount of drug on the stent,
  • modulation of drug concentration potently impacts
  • the magnitude of arterial drug deposition,
  • while changes in coating drug mass affect duration of release.
We demonstrate the importance of drug release kinetics and administered drug dose
  • in governing arterial drug uptake and suggest
  • novel drug delivery strategies for controlling spatio-temporal arterial drug distribution.(3)
Arterial drug concentrations determine local toxicity. Therefore, the emergent safety concerns surrounding drug-eluting stents mandate an investigation of the factors contributing to fluctuations in arterial drug uptake.
  • Drug-eluting stents were implanted into porcine coronary arteries, arterial drug uptake was followed and modeled using 2-dimensional computational drug transport.
Arterial drug uptake in vivo occurred faster than predicted by free drug diffusion, thus
  • an alternate, mechanism for rapid transport has been proposed involving carrier-mediated transport.
Though there was minimal variation in vivo in release kinetics from stent to stent,
  • arterial drug deposition varied by up to 114% two weeks after stent implantation.
  • extent of adherent mural thrombus fluctuated by 113% within 3 days.
The computational drug transport model predicted that focal and diffuse thrombi
  • elevate arterial drug deposition in proportion to the thrombus size
  • by reducing drug washout subsequently increasing local drug availability.
Variable peristrut thrombus can explain fluctuations in arterial drug uptake even in the face of a narrow range of drug release from the stent. The mural thrombus effects on arterial drug deposition may be circumvented by forcing slow rate limiting arterial transport, that cannot be further hindered by mural thrombus. (4)
1.  A mAb to the b2-leukocyte integrin Mac-1 (CD11byCD18) Reduces Intimal Thickening after Angioplasty or Stent Implantation in Rabbits. C Rogers, ER Edelman, and DI Simon. PNAS Aug 1998; 95: 10134–10139.
2.  Formation After Balloon and Stent Injury in Rabbits Systemic Inflammation Induced by Lipopolysaccharide increases Neointimal Formation After Balloon and Stent Injury in Rabbits. HD Danenberg, FGP Welt, M Walker, III, P Seifert, et al. Circulation 2002;105;2917-2922; http://dx.doi.org/10.1161/01.CIR.0000018168.15904.BB
3.  Intravascular drug release kinetics dictate arterial drug deposition, retention, and distribution.
B Balakrishnan, JF Dooley, G Kopia, ER Edelman. J Controlled Release  2007;123:100–108.
http://dx. doi.org/10.1016/j.jconrel.2007.06.025.
4.  Thrombus causes fluctuations in arterial drug delivery from intravascular stents. B Balakrishnan, J Dooley, G Kopia, ER Edelman. J Control Release 2008. http://dx.doi.org/10.1016/j.jconrel.2008.07.027

Perivascular Graft Repair

Heparin remains the gold-standard inhibitor of the processes involved in the vascular response to injury. Though this compound has profound and wide-reaching effects on vascular cells, its clinical utility is unclear. It is clear that the mode of heparin delivery is critical to its potential and it may well be that
  • routine forms of administration are insufficient
  • to observe benefit given the heparin’s short half-life and complex pharmacokinetics.
When ingested orally, heparin is degraded to inactive oligomer fragments while systemic administration
  • is complicated by the need for continuous infusion
  • and the potential for uncontrolled hemorrhage.
Thus alternative heparin delivery systems have been proposed to maximize regional effects while limiting systemic toxicity. Yet, as heparin is such a potent antithrombotic compound and since existing local delivery systems lack the ability to
  • precisely regulate release kinetics,
  • even site-specific therapy is prone to bleeding.
Authors now describe the design and development of a novel biodegradable system for the perivascular delivery of heparin to the blood vessel wall with well-defined release kinetics.
This system consists of heparin-encapsulated
  • poly(DL lactide-co-glycolide) (pLGA) microspheres sequestered in an alginate gel.
Controlled release of heparin from this heterogeneous system is obtained for a period of 25 days.
The experimental variables affecting heparin release from these matrices were investigated by
  • gel permeation chromatography (GPC) and scanning electron microscopy (SEM)
  • to monitor the degradation process and correlated well with the release kinetics.
Heparin-releasing gels inhibited growth in tissue culture of
  • bovine vascular smooth muscle cells in a dose-dependent manner.
  • and also controlled vascular injury in denuding and
  • interposition vascular graft animal models of disease even when uncontrolled bleeding was evident with standard matrix-type release.
This system provided an effective means of examining
  • the effects of various compounds in
  • the control of smooth muscle cell proliferation in accelerated arteriopathies and also
  • shed light on the biologic nature of these processes.(1)
Soft tissue adhesives are employed to repair and seal many different organs that range in both
  • tissue surface chemistry and
  • mechanical effects during organ function.
This complexity motivates the development of tunable adhesive materials with
  • high resistance to uniaxial or multiaxial loads
  • dictated by a specific organ environment.
Co-polymeric hydrogels comprising
  • aminated star polyethylene glycol and
  • dextran aldehyde (PEG:dextran)
are materials exhibiting physico-chemical properties that can be modified
Here we report that resistance to failure
  • under specific loading conditions, as well as
  • tissue response at the adhesive material–tissue interface, can be modulated through regulation of
  • the number and density of adhesive aldehyde groups.
Author found that atomic force microscopy (AFM) can
  • characterize the material aldehyde density available for tissue interaction,
  • facilitating rapid, informed material choice.

Further, the correlation between AFM quantification of nanoscale unbinding forces

  • with macroscale measurements of adhesion strength
  • by uniaxial tension or multiaxial burst pressure allows the design of materials with specific cohesion and adhesion strengths.
However, failure strength alone does not predict optimal in vivo reactivity. The development of adhesive materials is significantly enabled when
  • experiments are integrated along length scales to consider
  • organ chemistry and mechanical loading states concurrently
  • with adhesive material properties and tissue response. (2)
Cell culture and animal data support the role of endothelial cells and endothelial-based compounds in regulating vascular repair after injury.
Authors describe a long-term study in pigs in which the biological and immunological
  • responses to endothelial cell implants were investigated 3 months after angioplasty,
  • approximately 2 months after the implants have degraded.
Confluent porcine or bovine endothelial cells grown in polymer matrices were implanted adjacent to 28 injured porcine carotid arteries.
Porcine and bovine endothelial cell implants significantly
  • reduced experimental restenosis compared to control by 56 and 31%, respectively.
Host humoral responses were investigated by detection of an increase in serum antibodies that bind to the bovine or porcine cell strains used for implantation.
A significant increase in titer of circulating antibodies to the bovine cells was observed
  • after 4 days in all animals implanted with xenogeneic cells.
Detected antibodies returned to presurgery levels after Day 40.
No significant increase in titer of antibodies to the porcine cells was observed during the experiment in animals implanted with porcine endothelial cells.
No implanted cells, Gelfoam, or focal inflammatory reaction could be detected
  • histologically at any of the implant sites at 90 days.

Suggesting that tissue engineered endothelial cell implants

  • may provide long term control of vascular repair after injury,
  • rather than simply delaying lesion formation and that
  • allogeneic implants are able to provide a greater benefit than xenogeneic implants. (3)
Vascular access complications are a major problem in hemodialysis patients. Native arteriovenous fistulae, historically the preferred mode of access, have a patency rate of only 60% at 1 year.
The most common mode of failure is due to progressive stenosis at the anastomotic site.
Authors have previously demonstrated that perivascular endothelial cell implants
  • inhibit intimal thickening following acute balloon injury in pigs, and now seek to determine if these
  • implants provide a similar benefit in the chronic and more complex injury model of arteriovenous anastomoses.
Side-to-side femoral artery-femoral vein anastomoses were created in 24 domestic swine.
  • toxicological,
  • biological and
  • immunological responses

were investigated 3 days and 1 and 2 months postoperatively to allogeneic endothelial cell implants . The anastomoses were wrapped with polymer matrices containing

  • confluent porcine aortic endothelial cells (PAE; n = 14) or
  • control matrices without cells (n = 10).
PAE implants significantly reduced intimal hyperplasia at the anastomotic sites
  • compared to controls by 68% (p ! 0.05) at 2 months.
The beneficial effects of the PAE implants were not due to
  • differences in the rates of reendothelialization between the groups.
No significant immunological response to the allogeneic endothelial cells that impacted on efficacy was detected in any of the pigs.
No apparent toxicity was observed in any of the animals treated with endothelial implants.
These data suggest that perivascular endothelial cell implants
  • are safe and reduce early intimal hyperplasia in a porcine model of arteriovenous anastomoses. (4)
1.  Perivascular graft heparin delivery using biodegradable polymer wraps. ER Edelman, A Nathan,
M Katada, J Gates, MJ Karnovsky. Biomaterials 2000; 21:2279 -2286.
onlinelibrary.wiley.com/doi/10.1002/anie.200461360/full
2.  Tuning adhesion failure strength for tissue-specific applications. N Artzi, A Zeiger, F Boehning,
A bon Ramos, K Van Vliet, ER Edelman.  Acta Biomateriala 2010.
http://dx.doi.org/10.1016/j.actbio.2010.07.008.
3. Endothelial Implants Provide Long-Term Control of Vascular Repair in a Porcine Model of Arterial Injury. HM Nugent, ER Edelman. J Surg Res 2001; 99:228–234.  http://dx.doi.org/10.1006/jsre.2001.6198
4.  Perivascular Endothelial Implants Inhibit Intimal Hyperplasia in a Model of Arteriovenous Fistulae: A Safety and Efficacy Study in the Pig. HM Nugent, A Groothuis, P Seifert, et al. J Vasc Res 2002;39:524–533.

Luminal Flow and Arterial Drug Delivery

Endovascular stents reside in a dynamic flow environment and yet the impact of flow
  • on arterial drug deposition after stent-based delivery is only now emerging.
Authors employed computational fluid dynamic modeling tools to investigate
  • the influence of luminal flow patterns on arterial drug deposition and distribution.
Flow imposes recirculation zones distal and proximal to the stent strut that extend
  • the coverage of tissue absorption of eluted drug and
  • induce asymmetry in tissue drug distribution.
Our analysis now explains how the disparity in
  • sizes of the two recirculation zones and
  • the asymmetry in drug distribution are determined by a complex interplay of local flow and strut geometry.
When temporal periodicity was introduced as a model of
  • pulsatile flow,
  • the net luminal flow served as an index of flow-mediated spatiotemporal tissue drug uptake.
Dynamically changing luminal flow patterns are intrinsic to the coronary arterial tree. Coronary drug-eluting stents should be appropriately considered where
  • luminal flow,
  • strut design and
  • pulsatility
have direct effects on tissue drug uptake after local delivery.(1)
The efficacy of drug-eluting stents (DES) requires delivery of potent compounds directly to the underlying arterial tissue.
The commercially available DES drugs rapamycin and paclitaxel bind specifically to
  • their respective therapeutic targets, FKBP12 and polymerized microtubules,
  • while also associating in a more general manner with other tissue elements.
As it is binding that provides biological effect, the question arises as to whether other
  • locally released or systemically circulating drugs can
  • displace DES drugs from their tissue binding domains.
Specific and general binding sites for both drugs are distributed across the media and adventitia with higher specific binding associated with the binding site densities in the media.
The ability of rapamycin and paclitaxel to compete for specific protein binding and general tissue deposition
  • was assessed for both compounds simultaneously and
  • in the presence of other commonly administered cardiac drugs.
Drugs classically used to treat standard cardiovascular diseases, such as hypertension and hypercoaguability,
  • displace rapamycin and paclitaxel from general binding sites, possibly
  • decreasing tissue reserve capacity for locally delivered drugs.
Paclitaxel and rapamycin do not affect the other’s binding
  • to their biologically relevant specific protein targets, but
  • can  displace each other from tissue at three log order molar excess,
  • decreasing arterial loads by greater than 50%.
Local competitive binding therefore should not limit the placement of rapamycin and paclitaxel eluting stents in close proximity.(2)
Stent thrombosis is a lethal complication of endovascular intervention. There is concern about the inherent risk associated with specific stent designs and drug-eluting coatings
Authored examined whether drug-eluting coatings are inherently thrombogenic and whether the response to these materials was determined to any degree
  • by stent design and
  • stent deployment with custom-built stents.
Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold; P 0.011).
Thick-strutted (162 m) stents were 1.5-fold more thrombogenic than otherwise
  • identical thin-strutted (81 m) devices in ex vivo flow loops (P< 0.001),
commensurate with 1.6-fold greater thrombus coverage
  • 3 days after implantation in porcine coronary arteries (P 0.004).
When bare metal stents were deployed in
  • malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold, P < 0.001; and 2.32-fold, P <0.001).
The thrombogenicity of polymer-coated stents with thin struts was
  • lowest in all configurations and remained insensitive to incomplete deployment.
Computational modeling– based
  • predictions of stent-induced flow derangements
  • correlated with spatial distribution of formed clots.
Drug/polymer coatings do not inherently increase acute stent clotting;
  • they reduce thrombosis.
However, strut dimensions and positioning relative to the vessel wall
  • are critical factors in modulating stent thrombogenicity.
Optimal stent geometries and surfaces, as demonstrated with thin stent struts,
  • help reduce the potential for thrombosis
  • despite complex stent configurations and variability in deployment. (Circulation. 2011;123:1400-1409.) (3)
1. Luminal flow patterns dictate arterial drug deposition in stent-based delivery.
VB Kolachalama, AR Tzafriri, DY Arifin, ER Edelman. J Control Release 2009; 133:24–30.
2. Local and systemic drug competition in drug-eluting stent tissue deposition properties.
AD Levin, M Jonas, Chao-Wei Hwang, ER Edelman.  J Control Release 2005; 109:236-243.
3. Stent Thrombogenicity Early in High-Risk Interventional Settings Is Driven by
Stent Design and Deployment and Protected by Polymer-Drug Coatings
Kumaran Kolandaivelu, Rajesh Swaminathan, William J. Gibson,.. ER Edelman

Management of Obstructive Coronary Artery Disease

Multiple studies have shown that diabetes mellitus (DM) can affect the
  • efficacy of revascularization therapies and subsequent clinical outcomes.
Selecting the appropriate myocardial revascularization strategy is critically important
  • in the setting of multivessel coronary disease.
Optimal medical therapy is an appropriate first-line strategy in patients with DM and mild symptoms. When medical therapy does not adequately control symptoms,
  • revascularization with either PCI or CABG may be used.
In patients with treated DM, moderate to severe symptoms and complex multivessel coronary disease,
  • coronary artery bypass graft surgery provides better survival,
  • fewer recurrent infarctions and
  • greater freedom from re-intervention.
Decisions regarding revascularization in patients with DM must take into account multiple factors and as such require a multidisciplinary team approach (‘heart team’). (1)
An incomplete understanding of the transport forces and local tissue structures
  • that modulate drug distribution has hampered
  • local pharmacotherapies in many organ systems.
These issues are especially relevant to arteries, where stent-based delivery allows fine control of locally directed drug release.
Local delivery produces tremendous drug concentration gradients
  • these are in part derived from transport forces,
  • differences in deposition from tissue to tissue

This suggests that tissue ultrastructure also plays an important role.

Authors measured the equilibrium drug uptake and the penetration and diffusivity of
  • dextrans (a model hydrophilic drug similar to heparin) and albumin
  • in orthogonal planes in arteries explanted from different vascular beds.
Authors found significant variations in drug distribution with
  • geometric orientation and
  • arterial connective tissue content.
Drug diffusivities parallel to the connective tissue sheaths were
  • one to two orders of magnitude greater than across these sheaths.
This diffusivity difference remained relatively constant for drugs up to 70 kDa
  • before decreasing for larger drugs.
Drugs also distributed better into elastic arteries, especially at lower molecular weights,
  • with almost 66% greater transfer into the thoracic aorta
  • than into the carotid artery.
Arterial drug transport is thus highly anisotropic and
  • dependent on arterial tissue content.
The role of the local composition and geometric organization of arterial tissue
  • in influencing vascular pharmacokinetics
is likely to become a critical consideration for local vascular drug delivery (2)
Radiolabeled drug-eluting stents have been proposed
  • to potentially reduce restenosis in coronary arteries.
A P-32 labeled oligonucleotide (ODN) loaded on a polymer coated stent
  • is slowly released in the arterial wall to deliver a therapeutic dose to the target tissue.
A relatively low proportion of drugs is transferred to the arterial wall (< 2%– 5% typically). This raises questions about the degree to which radiolabeled drugs eluted from the stent
  • can contribute to the total radiation dose delivered to tissues.
A three-dimensional diffusion-convection transport model is used
  • to model the transport of a hydrophilic drug released
  • from the surface of a stent to the arterial media.
Large drug concentration gradients are observed
  • near the stent struts giving rise to a
  • non-uniform radiation activity distribution for the drug
  • in the tissues as a function of time.
A voxel-based kernel convolution method is used to calculate the radiation dose rate
  • resulting from this activity build-up in the arterial wall
  • based on the medical internal radiation dose formalism.
Measured residence time for the P-32 ODN in the arterial wall and
  • at the stent surface obtained from animal studies
  • are used to normalize the results in terms of absolute dose to tissue.
The results indicate radiation due to drug eluted from the stent
  • contributes only a small fraction of the total radiation delivered to the arterial wall,
  • the main contribution comes from the activity embedded in the stent coating.
For hydrophilic compounds with rapid transit times in arterial tissue and minimal binding interactions,
  • the activity build-up in the arterial wall contributes only a small fraction
  • to the total dose delivered by the P-32 ODN stent.
For these compounds, it is concluded that radiolabeled drug-eluting stent
  • would not improve the performance of radioactive stents in treating restenosis.
Also, variability in the efficacy of drug delivery devices
  • makes accurate dosimetry difficult and
  • the drug washout in the systemic circulatory system
may yield an unnecessary activity build-up and dose to healthy organs. (3)
The first compounds considered for stent-based delivery,
  • such as heparin have failed to stop restenosis clinically.
More recent compounds, such as paclitaxel, are of a different sort.
They are hydrophobic, and their effects after local release seem far more profound.
This dichotomy raises the question of whether drugs that have an effect when released from a stent do so because of
  • differences in biology or differences in physicochemical properties and targeting.
Authored applied continuum pharmacokinetics to examine the effects of
  • transport forces and device geometry on
the distribution of stent-delivered hydrophilic and hydrophobic drugs.
Stent-based delivery leads to large concentration gradients.
Drug concentrations range from nil to several times the
  • mean tissue concentration over a few micrometers.
Concentration variations were a function of the Peclet number (Pe),
  • the ratio of convective to diffusive forces.
Although hydrophobic drugs exhibit greater variability than hydrophilic drugs,
  • they achieve higher mean concentrations and
  • they remain closer to the intima.
Inhomogeneous strut placement influences hydrophilic drugs
  • more negatively than hydrophobic drugs, and notably
  • affect local concentrations without changing mean concentrations.
Local concentrations and gradients are inextricably linked to biological effect. Therefore,
  • these results provide a potential explanation for the variable success of stent-based delivery.
Authors conclude that mere proximity of delivery devices to tissues
  • does not ensure adequate targeting,
  • because physiological transport forces cause
  • local concentrations to deviate significantly from mean concentrations. (4)
1.  Role of CABG in the management of obstructive coronary arterial disease in patients with diabetes mellitus. D Aronson, ER Edelman.  Curr Opin Pharmacol 2012, 12:134–141. Issue on Cardiovascular and renal. [Eds: JY Jeremy, K Zacharowski, N Shukla, S Wan].  http://dx.doi.org/10.1016/j.coph.2012.01.011
2.  Arterial Ultrastructure Influences Transport of Locally Delivered Drugs. Chao-Wei Hwang, ER Edelman. Circ Res. 2002; 90:826-832. http://www.circresaha.org/dx.doi.org/10.1161/01.RES.0000016672.26000.9E
3.  Dose model for stent-based delivery of a radioactive compound for the treatment of restenosis in coronary arteries. C Janickia, Chao-Wei Hwang, ER Edelman.  Med Phys 2003; 30(10), 2622-7.    http://dx.doi.org/10.1118/1.1607506
4.  Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery. Chao-Wei Hwang, D Wu, ER Edelman. Circulation. 2001;104(5) :600-605; e14 – e9010.     http://dx.doi.org/10.1161/hc3101.09221
Stent-Versus-Stent Equivalency Trials. Are Some Stents More Equal Than Others? Elazer R. Edelman, Campbell Rogers Circulation. 1999; 100(9): 896-898; e47 – e47.  http://dx.doi.org/10.1161/01.CIR.100.9.896
New endovascular stent designs are displacing tried and-true devices for use in an ever-broader array of lesions. There is disagreement as to which device is most advantageous and whether design determines outcome. Preclinical research says that this should be the case. Clinical trials have failed to validate design dependence. Can the divergent results be reconciled? More than 50 different stent configurations are available. The processes of industrial development and federal regulatory evaluation support the importance of design.
Stents are made from
  • a spectrum of materials
  • a range of manufacturing techniques, and have
    • variable surfaces,
    • dimensions,
    • surface coverage, and
    • strut configurations.
The number of parameters involved may doom the number of subsets to approach the number of designs. Moreover, each device seems to have a unique optimal mode of placement.  Differences have been reported in
  • flexibility,
  • tracking ability,
  • expansion,
  • radiovisibility,
  • side-branch access, and
  • resistance to compression and recoil for different devices.
Regulatory approval includes standards for safety:
  • toxicity,
  • biocompatibility,
  • structural and material analysis, and
  • fatigue testing
It has been suggested that
  • hoop strength,
  • surface cracking,
  • uniformity of expansion, and
  • other features become standardized as well.
Four different direct comparisons of first-generation Palmaz-Schatz slotted-tube stents and
second-generation stents have been made. In several studies there were no significant differences
in restenosis at follow-up, including
  • minimal luminal diameter (MLD),
  • percent diameter stenosis,
  • late loss, or
  •  binary restenosis rate.
In the fourth study, restenosis was far greater for the Gianturco-Roubin II (GR-II) stent (Cook) than
  • the Palmaz-Schatz stent (Cordis-Johnson & Johnson).
The data for all stents bunch across trials: with the exception of the GR-II stent,
variability between the test stent groups was no greater than
  • the variability between the Palmaz-Schatz stent groups in the different trials.
Three distinct possibilities exist to explain the absence of clinical evidence that different designs behave differently:
(1) no differences in clinical outcomes exist between devices;
(2) differences exist but are so slight as to be clinically meaningless; and
(3) differences exist that may be clinically meaningful, but trials performed to date were not designed to detect them.
Schematic representation of device performance plotting outcome against indication indicates that
  • complication rates rise as lesion complexity increases.
When 2 devices are clinically different, their curves are displaced, and when they are indistinguishable, their curves overlap.
Clinical trials that restrict the test population to lesions low on the complexity scale
  • ensure safety for all patients but are not the ideal venues in which to detect differences between devices.
Thus, although stents 1 and 2 may have different clinical outcomes, in a restricted-criteria equivalency trial with low complexity, they appear identical. It is only when the test device performs worse than the standard, that differences can be appreciated.
In contrast, an open registry will not only show when a test stent is worse than the standard stent but also when it is better.

Equivalency Trials

Stent-versus-stent trials are equivalency trials, designed to show that a test device performs “as well as” a standard, currently acceptable device.  This is a valid regulatory threshold but
  • not the means to evaluate the full potential of a device.
Equivalency trials must by definition commence with a patient population for whom the standard device is safe. Trials with currently approved devices as the standard necessitate that
  • patient entry and lesion selection be determined by
  • limitations of the standard, not the device.
to observe a difference in such a trial
  •  the test device performs worse
For the test device to perform better, both the test and the standard must be challenged.
This was not the case for the trials in which
  • the average reference vessel size was 3.0+0.05 mm and
  • American College of Cardiology type B2 and C lesions accounted for only ~65% of lesions.
These lesions are those for which the Palmaz-Schatz stent is approved and technically suited, but
  • they represent only a minority of those lesions now receiving stents

Complexity, Equivalence, and Better

In truth, it may be most appropriate to think about parameters of device success and safety as a continuum, describing a correlation between events such as
  • thrombosis or restenosis and
  • a continuous measure of indication,
  • vessel dimension, or lesion complexity (Figure).
A given device may be represented by a characteristic response over a range of indications.
When there is a lateral offset to the curves,
  • differences in potential performance are anticipated.
Curves might even cross, rather than run parallel, indicating that devices might be matched
to lesions and indications. Open trials would consider the entire range of the curves.
  • equivalency trials are limited to a small region of the curve.
The first-generation stents were a major innovation in interventional cardiology, and their place in medical history and biotechnology is unassailable.
Demonstration that new stents are better than old will require that evaluations be
  • performed in lesions for which current devices have marginal or limited application.
Complex or acutely unstable lesions, small arteries, and diseased bypass grafts are
  • the next great challenges of interventional cardiology.
Perhaps in these settings, future stent trials will provide firm evidence that
  • the manner in which blood vessels are manipulated dictates biological sequelae.
Proof that stent design can alter clinical outcomes may then unleash the potential
  • to change the way in which we consider design, approval, and use of new devices.
REFERENCES

Menichelli, M. (2006). Sirolimus Stent vs. Bare Stent in Acute Myocardial Infarction Trial. Presented at The European Paris Course on Revascularization (EuroPCR), May 16-19, 2006, Paris, France Paris, France.http://www.medscape.com/viewprogram/5505?rss

Pfisterer, P.E. (2006). Basel Stent Cost-effectiveness Trial-Late Thrombotic events (BASKET LATE) Trial. Presented at American College of Cardiology 55th Annual Scientific Session, March 11 – 14, 2006, Atlanta, Georgia.http://www.medscape.com/viewprogram/5185 

Rogers, C. Edelman E.R. (2006). Pushing drug-eluting stents into uncharted territory, Simpler then you think – more complex than you imagine. Circulation,113, 2262-2265.

Shirota, T., Yasui, H., Shimokawa, H. & Matsuda, T. (2003). Fabrication of endothelial progenitor cell (EPC)-seeded intravascular stent devices and in vitro endothelialization on hybrid vascular tissue. Biomaterials 24(13), 2295–2302.

Simonton, C. (2006). The STENT Registry: A real-world look at Sirolimus- and Pacitaxel-Eluting Stents. Cath Lab Digest, 14 (1), 1-10.

Turco, M. (2006). TAXUS ATLAS Trial – 9-Month results: Evaluation of TAXUS Liberte vs. TAXUS Express. Presented at The European Paris Course on Revascularization (EuroPCR), May 16-19, 2006, Paris, France Paris, France.http://www.medscape.com/viewprogram/5505?rss

Verma, S. and Marsden, P.A. (2005). Nitric Oxide-Eluting Polyurethanes – Vascular Grafts of the Future? New England Journal Medicine, 353 (7), 730-731.

Wood, S. (2006). Guidant suspends release of Xience V everolimus-eluting stent due to manufacturing standards http://www.theheart.org/article/679851.do 

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