Posts Tagged ‘American College of Cardiology’

HOT TOPICS 2014: Heart – The medpage TODAY View

Reporter: Aviva Lev-Ari, PhD, RN

HOT TOPICS 2014: Heart – Medical 1
(Post Date: 1/2/14)



HOT TOPICS 2014: Heart – Medical 1
(Post Date: 1/2/14)
Steven Nissen, MD – Cleveland Clinic
Clyde Yancy, MD – Northwestern University, Feinberg School of Medicine
Robert Califf, MD – Duke Medical Center
Elliott Antman, MD – BWH


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American Association of Clinical Endocrinologists (AACE) can’t support the new cardiovascular risk guidelines issued by the American Heart Association (AHA) and the American College of Cardiology (ACC)

Reporter: Aviva Lev-Ari,PhD, RN

Endocrinology Group Rejects New AHA/ACC CVD Guidelines

Miriam E. Tucker

December 13, 2013

The American Association of Clinical Endocrinologists (AACE) says it can’t support the new cardiovascular risk guidelines issued by the American Heart Association (AHA) and the American College of Cardiology (ACC), saying the set of 4 guideline documents is out of step with its own recommendations.

“AACE was asked to review and endorse the obesity and cholesterol guidelines. After careful consideration by the appropriate scientific committees of our organization, AACE declined to endorse these new cholesterol and obesity guidelines,” the organization said in a statement that was sent to its members in November and forwarded to the media today. “There are multiple reasons for this decision, including, principally, the incompatibility of these new guidelines with our existing guidelines.”

The 4 guidelines are:

All of the guidelines were issued with the support of the National Heart, Lung and Blood Institute, which had last updated its Adult Treatment Panel 3 (ATP3) National Cholesterol Education Panel (NCEP) guidelines for cholesterol and lipid management in 2004. AACE had “generally agreed” with those guidelines.

AACE welcomes the intent of the AHA and ACC in the creation of these new guidelines but cannot endorse them.

The endocrinology group faults the new AHA/ACC guidelines for focusing exclusively on randomized clinical trials and for not including studies published since 2011. “They are highly restrictive regarding the database considered and omit much new information… Taken together, these actions have resulted in a considerable number of at-risk patients being omitted from consideration.”

And, AACE says that the new cardiovascular disease calculator that was published along with the guidelines—and generated the most controversy—is already outdated. “It is based upon outmoded data, does not model the totality of the US population, has not been validated, and therefore has only limited applicability.”

As for new lipid guidelines, AACE disagrees with removal of the LDL targets and the idea that statin therapy alone is sufficient for all at-risk patients, noting that many who have multiple risk factors, including diabetes and established heart disease, will need additional therapies.

Finally, the new obesity guidelines, AACE says, “fail to classify obesity as a disease and continue the paradigm of [body-mass-index] BMI-centric risk stratification, both of which are contrary to recently stated AACE positions.” In addition, newly FDA-approved weight-loss medications are not included.

The statement concludes, “AACE welcomes the intent of the AHA and ACC in the creation of these new guidelines but does not agree with the complete content and therefore cannot endorse them.”




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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


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).


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?


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.


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.


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



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


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.


• 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.



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

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.


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



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.


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.



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.


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


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


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.



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.


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


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.


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


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



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



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!


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.


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.
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.


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.


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

content.onlinejacc.org content.onlinejacc.org



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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AHA, ACC Change in Requirement for Surgical Support for PCI Performance: Class IIb -> Class III, Level of Evidence A: Support Nonemergent PCI without Surgical Backup (Change of class IIb, Level of evidence B).

AHA, ACC Change in Requirement for Surgical Support:  Class IIb -> Class III, Level of Evidence A: Supports Nonemergent PCI without Surgical Backup (Change of class IIb, Level of Evidence B).

Larry H Bernstein, MD, FCAP, Author, Curator, Volumes 1,2,3,4,5,6 Co-Editor and Author, Volume Two & Five, Co-Editor and Justin Pearlman, MD, PhD, FACC, Content Consultant to Six-Volume e-SERIES A: Cardiovascular Diseases


Voice of content consultant: Justin Pearlman, MD, PhD, FACC

The American Heart Association (AHA) and the American College of Cardiology (ACC) have convened teams of experts to summarize evidence and opinion regarding a wide range of decisions relevant to cardiovascular disease. The system accounts for some of the short comings of “evidence based medicine” by allowing for expert opinion in areas where evidence is not sufficient. The main argument for evidence-based medicine is the existence of surprises, where a plausible decision does not actually appear to work as desired when it is tested. A major problem with adhesion to evidence based medicine is that it can impede adaptation to individual needs (we are all genetically and socially/environmentally unique) and impede innovation. Large studies carry statistical weight but do not necessary consider all relevant factors. Commonly, the AFFIRM trial is interpreted as support that rate control suffices for most atrial fibrillation (AFIB), but half of those randomized to rhythm control were taken off anticoagulation without teaching patients to check their pulse daily for recurrence of AFIB. Thus the endorsed “evidence” may have more to do with the benefits of anticoagulation for both persisting and recurring AFIB and rhythm control may yet prove better than rate control. However, with wide acceptance of a particular conclusion, randomizing to another treatment may be deemed unethical, or may simply not get a large trial due to lack of economic incentive, leaving only the large trial products as the endorsed options. A medication without patent protection, such as bismuth salts for H Pylori infection, lacks financial backing for large trials.

The American Heart Association Evidence-Based Scoring System
Classification of Recommendations

● Class I: Conditions for which there is evidence, general

agreement, or both that a given procedure or treatment is

useful and effective.

● Class II: Conditions for which there is conflicting evidence,

a divergence of opinion, or both about the usefulness/

efficacy of a procedure or treatment.

● Class IIa: Weight of evidence/opinion is in favor of


● Class IIb: Usefulness/efficacy is less well established by


● Class III: Conditions for which there is evidence, general

agreement, or both that the procedure/treatment is not useful/

effective and in some cases may be harmful.

Level of Evidence

● Level of Evidence A: Data derived from multiple randomized

clinical trials

● Level of Evidence B: Data derived from a single randomized

trial or nonrandomized studies

● Level of Evidence C: Consensus opinion of experts

Circulation 2006 114: 1761 – 1791.

Assessment of Coronary Artery Disease by Cardiac Computed Tomography

A Scientific Statement From the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology

Reported by Chris Kaiser, Cardiology Editor, MedPage  7/2013  


Action Points

  1. Patients with indications for nonemergency PCI who presented at hospitals without on-site cardiac surgery, were randomly assigned to undergo PCI at a hospital without on-site cardiac surgery or at a hospital with on-site cardiac surgery.
  2. The rates of death, myocardial infarction, repeat revascularization, and stroke did not differ significantly between the groups.
  3. Community hospitals without surgical services can safely perform percutaneous coronary intervention (PCI) in low-risk patients — and not refuse higher-risk patients either, the MASS COMM trial found.


  • The co-primary endpoint of major adverse cardiac events (MACE) at 30 days occurred at a rate of 9.5% in the 10 hospitals without surgical backup versus 9.4% in the seven hospitals with onsite surgery (P<0.001 for noninferiority), Alice K. Jacobs, MD, of Boston University School of Medicine, and colleagues found.
  • The other co-primary endpoint of MACE at 12 months was also significant, occurring in 17.3% of patients in hospitals without backup versus 17.8% in centers with surgical services (P<0.001 for non-inferiority), they reported in the study published online by the New England Journal of Medicine. The findings were also reported at the American College of Cardiology meeting.

Study Characteristics and Results

Primary Endpoints

  1. death
  2. myocardial infarction
  3. repeat revascularization
  4. stroke
no significant differences between the two groups at 30 days and at 12 months.

Rate of stent thrombosis at 30 days

similar in both groups (0.6% versus 0.8%) and at 12 months (1.1% versus 2.1%).
Jacobs and colleagues noted that the 2011 PCI guidelines lacked evidence to fully support nonemergent PCI without surgical backup (class IIb, level of evidence B).

CPORT – E trial

Even though those guidelines came out before the results of the CPORT-E trial were published, CPORT-E trial showed similar non-inferiority at 9 months between centers that perform PCI with or without surgical backup in a cohort of nearly 19,000 non-emergent patients. The CPORT-E results were published in the March 2012 issue of the New England Journal of Medicine, and in May three cardiology organizations published an update to cath lab standards allowing for PCI without surgical.

 MASS COMM study

To further the evidence, Jacobs and colleagues in 2006  had designed and carried out the Randomized Trial to Compare Percutaneous Coronary Intervention between Massachusetts Hospitals with Cardiac Surgery On-Site and Community Hospitals without Cardiac Surgery On-Site (MASS COMM) in collaboration with the Massachusetts Department of Public Health who collaborated to obtain “evidence on which to base regulatory policy decisions about performing non-emergent PCI in hospitals without on-site cardiac surgery.”

  • Hospitals without backup surgery were required to perform at least 300 diagnostic catheterizations per year, and operators were mandated to have performed a minimum of 75 PCI procedures per year.
  • The researchers randomized 3,691 patients to each arm in a 3:1 ratio (without/with backup). The median follow-up was about 1 year.
  • The median age of patients was 64, one-third were women, and 92% were white. Both groups had similar median ejection fractions at baseline (55%).
  • The mean number of vessels treated was 1.17 and most patients (84%) had one vessel treated. The mean number of lesions treated was 1.45 and most patients (67%) had one lesion treated.

The indications for PCI were:

1. ST-segment elevated MI (>72 hours before PCI of infarct-related or non–infarct-related artery — 19% and 17%
2. Unstable angina — 45% and 47%
3. Stable angina — 27% and 28%
4. Silent ischemia — 5% and 6%
5. Other — 2.5% and 2.8%
Regarding secondary endpoints, both groups had similar rates of emergency CABG and urgent or emergent PCI at 30 days. Results at 30 days and 12 months were similar for rates of ischemia-driven target-vessel revascularization and target-lesion revascularization. Other endpoints as well were similar at both time points, including
  • all-cause death
  • repeat revascularization
  • stroke
  • definite or probable stent thrombosis
  • major vascular complications
Researchers adjusted for a 1.3 greater chance of MACE occurring at a randomly selected hospital compared with another randomly selected hospital and found
  • the relative risks at 30 days and 12 months “were consistent with those of the primary results” (RR 1.02 and 0.98, respectively).

However, they cautioned that new sites perhaps should be monitored as they gain experience.

A prespecified angiographic review of 376 patients who were in the PCI-without-backup arm and 87 in the other arm showed no differences in
  1. rates of procedural success,
  2. proportion with complete revascularization, or
  3. the proportion of guideline-indicated appropriate lesions for PCI.
Such results show consistent practice patterns between the groups, they noted.
The study had several limitations including the
  • loss of data for 13% of patients, the
  • exclusion of some patients for certain clinical and anatomical features, and
  • not having the power to detect non-inferiority in the separate components of the primary endpoint, researchers wrote.

Cardio Notes: Score Predicts PCI Readmission

Published: Jul 15, 2013

By Chris Kaiser, Cardiology Editor, MedPage Today

A simple calculation of patient variables before PCI may help stem the tide of readmission within the first month. Also this week, two blood pressure drugs that benefit diabetics and imaging cardiac sympathetic innervation.

Pre-PCI Factors Predict Return Trip

A new 30-day readmission risk prediction model for patients undergoing percutaneous coronary intervention (PCI) showed it’s possible to predict risk using only variables known before PCI, according to a study published online in Circulation: Cardiovascular Quality and Outcomes.

After multivariable adjustment, the 10 pre-PCI variables that predicted 30-day readmission were older age (mean age 68 in this study), female sex, insurance type (Medicare, state, or unknown), GFR category (less than 30 and 30-60 mL/min per 1.73m2), current or history of heart failure, chronic lung disease, peripheral vascular disease, cardiogenic shock at presentation, admit source (acute and non-acute care facility or emergency department), and previous coronary artery bypass graft surgery.

Additional significant variables post-discharge that predicted 30-day readmission were beta-blocker prescribed at discharge, post-PCI vascular or bleeding complications, discharge location, African American race, diabetes status and modality of treatment, any drug-eluting stent during the index procedure, and extended length of stay.

A risk score calculator using the pre-PCI variables will be available online soon, according to Robert W. Yeh, MD, MSc, of Massachusetts General Hospital in Boston, and colleagues.

English: Patient Positioning for a Left Anteri...

English: Patient Positioning for a Left Anterior Thoracotomy (Photo credit: Wikipedia)

A coronary angiogram that shows the LMCA, LAD ...

A coronary angiogram that shows the LMCA, LAD and LCX. (Photo credit: Wikipedia)

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Reporter: Aviva Lev-Ari, PhD, RN

Heart Failure and Dietary Sodium: Do we know as much as we think?

Samar Sheth,1 Alan B. Weder2 and Scott L. Hummel2,3; 1. Department of Internal Medicine, University of Michigan; 2. Division of Cardiovascular Medicine, Department of Medicine, University of Michigan Medical School; 3. Staff Cardiologist, Department of Veterans Affairs Medical Center, Ann Arbor, Michigan

Treatment Strategies Cardiology, Volume 3 Issue 1, 44-48

Depolarisation Reserve: A New Identification Concept of Responders to Biventricular Stimulation.

Philippe Chevalier and Alina Scridon; Centre de Référence des Troubles du Rythme Cardiaque Héréditaires, Hôpital Cardiologique Louis Pradel, Bron Cedex

Treatment Strategies Cardiology, Volume 3 Issue 2, 65-70

Selective Site Pacing During Cardiac Resynchronization Therapy

Leonidas Tzogias and Attila Roka, Hospital of St. Raphael, New Haven, Connecticut

Treatment Strategies Cardiology, Volume 4 Issue 1, 37-40

The Clinical Utility of BNP with Heart Failure in the European Physician Oce Setting

Treatment Strategies Cardiology, Volume 4 Issue 2, 49-52

The Treatment of Virus-associated Inammatory Cardiomyopathy

Uwe Kühl and Heinz-Peter Schultheiss, Department of Cardiology and Pulmonology, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin

Treatment Strategies Cardiology, Volume 4 Issue 2, 63-68


Treatment Strategies – Cardiology is a print (on request) and online eBook publication that provides its readership with a collection of comprehensive and thought-provoking articles from the most respected key opinion leaders, leading doctors and authorities in the cardiology field. The series informs and educates clinicians on the latest therapeutic and technological advances. Published in line with the foremost cardiology congresses, the editorial content includes an unbiased, independent inbound supplement reviewing either the ESC or ACC congress. The review is dedicated to bringing readers the latest cardiology breaking news, exhibition highlights, awards and prizes and research developments from the key-note presentations at the congress.

Treatment Strategies – Cardiology (European and US edition) is available online as a free-to-view eBook providing its readers with an exciting interactive experience. Easily accessible, user friendly and free-to-print, the eBook can provide you with a wide range of dynamic features, including links to external websites, newsletters and email addresses to direct readers to your specialist products and services forming strong links with media partnerships. Importantly, an eBook can be sent out to clients worldwide in an organised and professional layout that allows a far-reaching distribution of your products. The eBook also offers you the opportunity to include, on any page, videos and podcasts of current events such as symposium proceedings that you may wish to highlight for the readership. The latest eBook also permits the advertiser to track statistical data for each page and publication; including the number of unique visits, click though pages, geographical location of the visitor and average time spent viewing.

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 Treatment Strategies – Cardiology is shaped by an advisory panel of world-renowned specialists from the leading associations and societies, including experts from:

American College of Cardiology (ACC)
American Society of Echocardiography (ASE)
European Association of Cardiothoracic Anaesthesiologists (EACTA)
European Association of Echocardiography (EAE)

European Society of Cardiology (ESC)

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Carl J. Pepine, Professor of Medicine, Division of Cardiovascular Medicine, University of Florida; Past-President, American College of Cardiology (ACC)

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For our full Editorial Advisory Panel list please click here.

US Edition

Treatment Strategies – Cardiology Volume 5 Issue 1 will include an unbiased, independent inbound supplement reviewing the ACC Congress, taking place in San Francisco in March. The inbound supplement will present the readers with the latest news, exhibition highlights, awards and prizes and research developments from the key-note presentations from the ACC. The publication will be published in April 2013.

European Edition

Treatment Strategies – Cardiology Volume 5 Issue 2 will include an independently written review of the ESC congress taking place in Amsterdam in August. The review is dedicated to bringing readers the latest cardiology news, exhibition highlights, awards and prizes and research developments from the key-note presentations at the congress. Please click on the image (below) to view the media pack as an eBook. Volume 5 Issue 2 will be published in September 2013.



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Vascular Repair: Stents and Biologically Active Implants

Author and Curator: Larry H Bernstein, MD, FACP
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.
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.
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.

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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Assessing Cardiovascular Disease with Biomarker

Author and Curator: Larry H Bernstein, MD, FCAP


A Changing expectation from cardiac biomarkers.

This article on Assessing Cardiovascular Disease with Biomarkers will demonstrate the unique role in the discipline evolution that each of the following biomarkers has played in our understanding of CVD risk:

The article is introduced with an entire section on the evolution of our knowledge of cardiac biomarkers and how concepts from thermodynamics have transformed
the way we investigate biochemical mechanisms, and how we have gone from a macro- to a micro- landscape of high complexity.  The same concepts from physics
have also transformed the mathematical stage upon which we model data.  BIG Data is not just about business!  We have entered a new domain of knowledge enabling.

(1)  Enzymes and Isoenzymes

  • AST, ALT, LD, alkaline phosphatase
  • Isoenzymes evolution and genomic loci for polypeptides
  • Emergence of pathway divergence and regulation from gene-loci peptide changes
  • A reflection to implications for biomarkers and therapeutic development based on critical links

(2)  Natriuretic Peptides

  •       Cause of Death: silent cardiac target organ damage (cTOD) (no so sign of cardiac disease)
  •       B Type natriuretic peptide in evolution of CHF
  •       2D and Doppler echocardiography and BNP serum level
  •       Amino terminal pro B-type Natriuretic Peptide
  •       Renal Effect on NT-proBNP
  •       pro-atrial natriuretic peptide

(3)     CRP as Biomarker, theory that lowering the C-reactive protein (CRP) level with statin therapy is predictive of cardiovascular outcomes independent of lowering the low-density lipoprotein (LDL) cholesterol level

(4)     CRP as an Inflammatory Agent

Acute phase reaction is a systemic response: physiological condition  in the beginning of an inflammatory process.

(5)     troponins and hs-troponins (I, T)

(6)     New Candidate  Biomarkers for NSTEMI

(7)    Guidelines for Cardiovascular Risk Assessment

(8)     Statistical Issues to be Resolved

Historical perspective

The use of cardiac markers emerged in the late 1950s, when the physician was faced with the problem of a patient with recent onset of squeezing, crushing, or heaviness in the chest, with or without a Q-wave or definitive ST elevation (acute injury), and perhaps a non specific elevation of the neutrophil count.   A medical student at Albert Einstein Medical school at the time, Arthur Karmen identified the first enzymatic test for acute myocardial infarct (MI), serum glutamic oxaloacetic acid transaminase (SGOT), which is renamed Aspartate Aminotransferase (AST) in a seminal study with Wroblewski and LaDue[1].  The enzyme is ubiquitous, and the authors published another observation that the SGPT, now referred to as Alanine Aminotransferase, has a greater specific activity in liver and myocardial infarct can be distinguished from necrotizing liver disease by using AST and ALT.  These two enzymes were among the three enzymes,with lactate dehydrogenase (LD) and alkaline phosphatase that appeared on the original Technicon (later Siemens) SMA-12 profile, prior to the designated panels used today.  At that time it was common for the pathologist to stain the heart lesion at autopsy in identifying the “ischemic necrosis” postmortem.

In 1957 Hunter and Markert described the five isoenzymes of lactate dehydrogenase, the most anodal migrating pattern was associated with heart and the most cathodal isoenzymes with liver, the five bands being combinations of two subunits.  These were described as different variants of the same enzyme having identical functions, but different tissue specific patterns, such that,  enzyme variants have altered gene loci that results in an amino acid change but catalyze the same reaction.  When mutation modifies the enzymatic catalysis, or its pattern of gene expression, then any of two (or more) variants may be favoured by natural selection and become specialized to different cell environments.  His group suggested that a single gene might somehow encode an array of isozymes differing in “structural variations,” a concept that seems to presage our current understanding of alternative mRNA splicing and post-translational protein modification. A former student of George beadle, he transformed the “concept of one gene one enzyme”  to “one gene one polypeptide”. By treating the enzyme with denaturing agents it was learned that LDH is a tetramer of two types of polypeptide chains (Appella and Markert, 1961). Thus the multiple-gene hypothesis was partially correct: Two different LDH subunits, each encoded by a distinct gene, re-sort themselves in various tetrameric combinations to give rise to five different isozymes (Markert, 1963). During the succeeding years Markert and his students and postdocs elucidated how the study of isozymes could contribute to our understanding of the biochemical variation that underlies cell differentiation and evolution, culminating in the new perspective presented in a Science paper (Markert et al., 1975) entitled “Evolution of a Gene.”

In the early 1960’s Nathan Kaplan postulated that the major LD-isoenzyme types were associated with fundamental differences in the metabolism of the tissue of origin, either catabolic (heart) or anabolic (liver), and skeletal muscle would appear to be in the same class as liver (ignore the ratio of fast and slow twitch), which was elaborated on further by studies of the flight wing patterns of birds.   These isoenzymes not only had different migration in an electrophoretic field and could be separated chromatographically, but they also had different kinetic properties. They all have the same Km, but the purified heart LD is inhibited by a ternary complex of the enzyme, the NAD, and pyruvate that forms, slowing the reaction in the forward direction (pyruvate to lactate).

At about the same time, Masahiro Chiga discovered that adenylate kinase, the enzyme that converts ATP to ADP, from skeletal muscle can be inhibited by inorganic S (myokinase), which led Bernstein and Russell to publish on the identification of adenylate kinase from heart in myocardial infarction using sulfhydryl inhibition in J Molec Cellular Cardiology.  Burton Sobel in the early 1970s showed that CK and the MB isoenzyme of CK, which has a more rapid increase and disappearance than the AST or LD ,  could be used to estimate the amount of cardiac damage in MI.   This meant that a test could be done at any time of day or night with a result in less than an hour.  He applied this to determining whether the extent of infarction was an important determinant of prognosis after myocardial infarction and furthermore, whether the extent of infarction could be modified by interventions that reduce myocardial oxygen requirements or increase myocardial oxygen supply. This work has had a major impact on how patients with acute myocardial infarction are treated and led to a reduction of mortality secondary to treatments, such as thrombolysis, that were validated initially with the methods developed. This led to an immunoassay for CK isoenzyme MB that was offered by Roche on the Cobas analyzer, and by Dupont on the ‘aca’. What emerged is a new imperative to reduce infarct size under the rubrick – “Time is Muscle”.


  1. Karmen Arthur, Wróblewski Felix, LaDue John S. TRANSAMINASE ACTIVITY IN HUMAN BLOOD. J Clin Invest. 1955; 34(1):126–133.
  2. LADUE JS, WROBLEWSKI F, KARMEN A. Serum glutamic oxaloacetic transaminase activity in human acute transmural myocardial infarction. Science 1956; 75(11).
  3. Hunter, R. L. and C.L. Merkert. (1957) Histochemical demonstration of enzymes separated by zone electrophoresis in starch gels. Science 125: 1294-1295.
  4. Bernstein L, Kerrigan M, Maisel H. Lactic dehydrogenase isoenzymes in lens and cornea. Exp Eye Res 1965; 5(3):999-1005. ICID: 844979
  5. Nathan O. Kaplan Papers. MSS 0099. UC San Diego::Mandeville Special Collections Library.

Enzyme-coenzyme-substrate complex. of pyridine nucleotide depend. dehydrogenases 1958.  box 39, folder 5.
Enzymatic studies with analogues of diphosphopyridine nucleotide 1959. box 39, folder 12.
Heterogeneity of the lactic dehydrogenases of new-born and adult rat heart as determined with enzyme analogs 1961. box 39, folder 37.
Regulatory effects of enzyme action 1961. box 39, folder 38.
Inhibition of dehydrogenase reactions by a substance formed from reduced dpn 1961. box 39, folder 40.
Lactic dehydrogenases: functions of the two types 1964. box 39, folder 67.
Lactate dehydrogenase – structure and function. 1964. box 40, folder 4.
Role of the two types of lactic dehydrogenases 1964. Box 40, folder 9.
Structural and functional properties of h and m subunits of lactic dehydrogenase 1965. Box 40, folder 12.

  • Bernstein LH, Everse J, Shioura N, Russell PJ. Detection of cardiac damage using a steady state assay for lactate dehydrogenase isoenzymes in serum. J Mol Cell Cardiol 1974; 6(4):297-315. ICID: 825597
  • Bernstein LH, Everse J.  Determination of the isoenzyme levels of lactate dehydrogenase. Methods Enzymol 1975; 41 47-52.
  • Bernstein LH. Automated kinetic determination of lactate dehydrogenase isoenzymes in serum. Clin Chem 1977; 23(10):1928-1930. ICID: 825616
  • Bernstein LH, Scinto P. Two methods compared for measuring LD-1/total LD activity in serum. Clin Chem 1986; 32(5):792-796. ICID: 825581
  1. Shell WE, Kjekshus JK, Sobel BE: Quantitative assessment of the extent of myocardial infarction in the conscious dog by means of analysis of serial changes in serum creatine phosphokinase activity. J Clin Invest 50:2614-2626, 1971.
  2. Bergmann SR, Fox KAA, Ter-Pogossian MM, Sobel BE (Washington University), Collen D (University of Leuven): Clot-selective coronary thrombolysis with tissue-type plasminogen activator. Science 220:1181-1183, 1983.
  3. Van de Werf F, Ludbrook PA, Bergmann SR, Tiefenbrunn AJ, Fox KAA, de Geest H, Verstraete M, Collen D, Sobel BE: Coronary thrombolysis with tissue-type plasminogen activator in patients with evolving myocardial infarction. N Engl J Med 310:609-613, 1984.
  • Adan J, Bernstein LH, Babb J. Can peak CK-MB segregate patients with acute myocardial infarction into different outcome classes?  Clin Chem 1985; 31(2):996-997. ICID: 844986
  • Bernstein LH, Reynoso G.  Creatine kinase B-subunit activity in serum in cases of suspected myocardial infarction: a prediction model based on the slope of MB increase and percentage CK-MB activity. Clin Chem 1983; 29(3):590-592. ICID: 825549
  • Bernstein LH, Horenstein JM, Sybers HB, Russell PJ.  Adenylate kinase in human tissue. II. Serum adenylate kinase and myocardial infarction. J Mol Cell Cardiol 1973; 5(1):71-85. ICID: 825590

A Metabolic Functional Meaning of Existence of Isoenzymes

There are many examples of  isozymes, such as glucokinase, a variant of hexokinase which is not inhibited by glucose 6-phosphate. It has different regulatory features and lower affinity for glucose (compared to other hexokinases). Alkaline and acid phosphatase isoenzymes were used briefly for a time in clinical diagnostics.  These isoenzymes are oligomeric proteins that have distinct subunits that affect their binding with substrate.  A distinctive type of protein that can form two or more different homo-oligomers, comes apart and changes shape to convert between forms is called a morpheein. The alternate shape may reassemble to a different oligomer, and the shape of the subunit dictates which oligomer is formed. Morpheeins can interconvert between forms under physiological conditions and can exist as an equilibrium of different oligomers. Features of morpheeins can be exploited for drug discovery. A small molecule compound can shift the equilibrium either by blocking or favoring formation of one of the oligomers. The equilibrium can be shifted using a small molecule that has a preferential binding affinity for only one of the alternate morpheein forms. This introduces the concept of allostericity.  Most allosteric effects can be explained by a model put forth by Monod, Wyman, and Changeux, and also by a model described by Koshland, Nemethy, and Filmer. Both postulate that enzyme subunits exist in one of two conformations, tensed (T) or relaxed (R), and that relaxed subunits bind substrate more readily than those in the tense state.  This concept provides a foundation for another generation of biomarkers than was the focus of the 20th century, and only has been investigated since the 1980’s, and takes another dimension after the completion of the Human Genome Project, opening a “Pandora’s box”. This moved biomedical science forward into an emerging field of ‘OMICs’, which tied small molecules into regulatory processes, transcription, and the possibility of identifying new biomarkers and developing new biomolecules that could modify disease progression.


  1. Bu Z, Callaway DJ. “Proteins MOVE! Protein dynamics and long-range allostery in cell signaling”. Adv in Protein Chemistry and Structural Biology 2011; 83: 163–221. doi:10.1016/B978-0-12-381262-9.00005-7. PMID 21570668.
  2.  Monod J, Wyman J, Changeux JP. On the nature of allosteric transitions:A plausible model. J Mol Biol, May 1965; 12:88-118.
  3.   Koshland DE, Némethy G, Filmer D. Comparison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry. Jan 1966; 5(1):365-8
  4.  Jaffe EK. “Morpheeins – a new structural paradigm for allosteric regulation”. Trends Biochem Sci 2005; 30(9): 490–497. doi:10.1016/j.tibs.2005.07.003. PMID 16023348.
  5.  Huang Z, Zhu L, Cao Y, Wu G, Liu X, et al.  ASD: a comprehensive database of allosteric proteins and modulators. Nucleic Acids Res 2011; 39: D663-669

Fundamental Transformative Concepts Carried Over from Physics to Biomolecular Processes.

A colleague once noted that we are learning more and more about less and less.  This is the remarkable evolution of our thinking from macrostates to microstates and segmentation of processes, further leading us to exploration of interactions between states.  This has required a breakdown and a repeated remodeling or resynthesis of ideas based on new findings in science.  It has gradually driven medicial science to a greater dependence on chemistry and physics in underlying principle.  We can better envision the mechanism of evolution from the concepts put forth.

In 1824 Sadi Carnot published the concept that heat is lost in the conversion into work, using the term “caloric”, equivalent to entropy in the second law of thermodynamics.  Clausius then develops the concepts of interior work in 1854, i.e. that “which the atoms of the body exert upon each other”, and exterior work, i.e. that “which arise from foreign influences [to] which the body may be exposed”, anticipating the concept of entropy. He enunciated the passage of the quantity of heat Q from the temperature T1 to the temperature T2 has the equivalence-value entropy, symbolized by S :  dS = Q (1/T2 – 1/T1), which led to his 1865 statement on irreversible heat loss: I propose to name the quantity S the entropy of the system, after the Greek word [τροπη trope], the transformation. I have deliberately chosen the word entropy to be as similar as possible to the word energy.”  In 1876, physicist J. Willard Gibbs, building on the work of Clausius, Hermann von Helmholtz and others, proposed that the measurement of “available energy” ΔG in a thermodynamic system could be mathematically accounted for by subtracting the “energy loss” TΔS from total energy change of the system ΔH, and in 1877, Ludwig Boltzmann formulated the alternative definition of entropy S defined as:

S = kBlnΩ


kB is Boltzmann’s constant and

Ω is the number of microstates consistent with the given macrostate.

An analog to thermodynamic entropy is information entropy. Claude Shannon set out to mathematically quantify the statistical nature of “lost information” in phone-line signals  and developed  a concept of information entropy, a fundamental cornerstone of information theory. The close similarity between his new quantity and earlier work in thermodynamics is attributed to a visit and discussion with Jon von Neumann in 1949. Shannon then called the “measure of uncertainty” or attenuation in phone-line signals with reference to his new information theory.  This led to the elucidation of a signal (as opposed to noise, by Solomon Kullback, which became the basis for the measure of an optimum diagnostic decision point of a laboratory test by Bernstein and Rudolph, related to Eugene Rypka’s “Syndromic Clustering”.  The loop was closed by the Japanese mathematician Akaike, who brought Fisher’s statistical formulations and Kullback-Liebler distance into alignment.   This is not a digression because it has been central to underlying principles in resolution in spectroscopy, and to classification of biochemical molecular features.

Although Boltzmann first linked entropy and probability in 1877, it seems the relation was never expressed with a specific constant until Max Planck first introduced k, and gave an accurate value for it (1.346×10−23 J/K, about 2.5% lower than today’s figure), in his derivation of the law of black body radiation in 1900–1901. Before 1900, equations involving Boltzmann factors were not written using the energies per molecule and the Boltzmann constant, but rather using a form of the gas constant R, and macroscopic energies for macroscopic quantities of the substance. The iconic terse form of the equation S = k log W on Boltzmann’s tombstone is in fact due to Planck, not Boltzmann. Planck actually introduced it in the same work as his h. Planck noted in his 1920 Nobel Prize acceptance : “:This constant is often referred to as Boltzmann’s constant, although, to my knowledge, Boltzmann himself never introduced it — a peculiar state of affairs.”  The Kullback–Leibler divergence (also information divergence, information gain, relative entropy, or KLIC) is a non-symmetric measure of the difference between two probability distributions P and Q, was  introduced by Solomon Kullback and Richard Leibler in 1951. KL-divergence of a model from reality may be estimated, to within a constant additive term, by a function (like the squares summed) of the deviations observed between data and the model’s predictions. When trying to fit parametrized models to data there are various estimators which attempt to minimize Kullback–Leibler divergence, such as, the familiar maximum likelihood  estimator.


  1. Planck, Max (2 June 1920), The Genesis and Present State of Development of the Quantum Theory (Nobel Lecture)
  2. Kalinin M, Kononogov S. “Boltzmann’s Constant, the Energy Meaning of Temperature, and Thermodynamic Irreversibility”, Measurement Techniques 2005; 48 (7): 632–36, doi:10.1007/s11018-005-0195-9
  3. Kullback S, Leibler RA “On Information and Sufficiency”. Annals of Mathematical Statistics 1951; 22 (1): 79–86. doi:10.1214/aoms/1177729694. MR 39968.
  4. Kullback S (1959) Information theory and statistics (John Wiley and Sons, NY).
  5. Jaynes ET(1957) Information theory and statistical mechanics, Physical Review 106:620
  6. Jaynes ET(1957) Information theory and statistical mechanics II, Physical Review 108:171
  7. Burnham KP and Anderson DR. (2002) Model Selection and Multimodel Inference: A Practical Information-Theoretic Approach, Second Edition (Springer Science, New York) ISBN 978-0-387-95364-9.
  8. Rudolph RA, Bernstein LH, Babb J.  Information induction for predicting acute myocardial infarction. Clin Chem 1988; 34(10):2031-2038. ICID: 825568

A New Imperative

Cardiovascular Biomarkers


[A] Aids in the Prevention of Cardiac Events by Detecting Silent Ischemic Lesions and Selecting Patients for Imaging

12/17/12 · Emily Humphreys

Physicians use risk factors, such as history, exercise level, diabetes, blood pressure, lipid profiles, and other laboratory measurements to ascertain risk for cardiac events, which are not foolproof in predicting all cardiac events. Nonetheless, 40% to 50% of sudden cardiac deaths (SCD) occur before risk factors are able to predict cardiac events.2,3 Those who die suddenly with no so sign of cardiac disease often have silent cardiac target organ damage (cTOD).  While patients with silent ischemia have a 21-fold increase in risk of a coronary event.4 It has also been shown that cTODs such as left ventricular hypertrophy (LVH), left ventricular systolic dysfunction (LVSD), left ventricular diastolic dysfunction (LVDD), and left atrial enlargement (LAE) each independently predict cardiovascular events5,6,7,8 Nadir et al. hypothesized that identification of silent cTOD would aid in the prevention of cardiovascular events, including SCDs.9 To identify cTOD present, The Nadir group evaluated several known cardiac biomarkers including: B-type natriuretic peptide (BNP), high-sensitivity cardiac troponin T (hs-cTnT), microalbuminuria, the estimated glomerular filtration rate, and uric acid.  The lab results of 300 asymptomatic individuals recruited for the study were compared with primary screening using transthoracic echocardiography, stress echocardiography, and/or myocardial perfusion imaging.
  • 34% of study volunteers had evidence of a cTOD. Out of all biomarkers analyzed, BNP levels were significantly higher in those with cTOD compared with those without. BNP levels were also higher in those who had more than one form of cTOD compared with those who had a single form of cTOD.
  • Hs-cTnT also performed well, but BNP levels had the highest correlation to imaging data. The gold standard diagnostic tool for cardiovascular disease is imaging studies, such as echocardiography.
  • It is not standard practice to investigate healthy individuals for possible cTOD and would be costly and time consuming to perform imaging on these individuals.
  • Biomarkers like BNP could be used as a primary screening tool with follow-up image studies performed, if necessary.

The eventual hope is to reduce the mortality of cardiovascular diseases and prevent silent cTOD from leading to more serious and potentially life-threatening cardiac events.


1. Roger, V.L. (2012) ‘AHA statistical update: Heart disease and stroke statistics-2012 update. A report from the american heart association‘, Circulation, 125 (2012), (pp. e2-e220)

2. Chiuve, S.E., et al., (2006) ‘Healthy lifestyle factors in the primary prevention of coronary heart disease among men: Benefits among users and nonusers of lipid-lowering and antihypertensive medications‘ Circulation, 114 (2006), (pp. 160-167)

3.De Vreede-Swagemakers, J.J., et al. (1997) ‘Out-of-hospital cardiac arrest in the 1990s: A population-based study in the Maastricht area on incidence, characteristics and survival‘, Journal of the American College of Cardiology, 30 (1997), (pp. 1500-1505)

4. Rutter, M.K., et al. (2002) ‘Significance of silent ischemia and microalbuminuria in predicting coronary events in asymptomatic patients with type 2 diabetes‘, Journal of the American College of Cardiology, 40 (2002), (pp. 56-61)

5. Tsang, T.S., et al. (2003) Prediction of risk for first age-related cardiovascular events in an elderly population: The incremental value of echocardiography‘, Journal of the American College of Cardiology, 42 (2003), (pp. 1199-1205)

6. Gosse, P., (2005) ‘Left ventricular hypertrophy—the problem and possible solutions‘,The Journal of International Medical Research, 33 (Suppl 1) (2005), (pp. 3A-11A)

7. Benjamin, E.J., et al. (1995) ‘Left atrial size and the risk of stroke and death‘ The Framingham Heart Study Circulation, 92 (4), (pp. 835-41)

8. Redfield, M.M., et al. (2003) ‘Burden of systolic and diastolic ventricular dysfunction in the community: Appreciating the scope of the heart failure epidemic‘, JAMA, 289 (2003), (pp. 194-202)

9. Nadir, M.A., et al., (2012) ‘Improving the primary prevention of cardiovascular events by using biomarkers to identify individuals with silent heart disease‘, Journal of American College of Cardiology, 60 (11), (pp. 960-968) Tags: 

[B] Evaluating CHF patients in the emergency department

The role of B-type natriuretic peptide in the evaluation of congestive heart failure patients in emergency department

Congestive heart failure (CHF) is a severe cardiovascular disorder seen in the Emergency Department (ED). B-type Natriuretic Peptide (BNP) is usually ordered to evaluate the CHF severity.

However, it is difficult to interpret serum BNP level when different clinical entities existed.

The aim of this study is to illustrate the correlation between serum BNP level and

  • relevant clinical variables and
  • further determine the role of serum BNP in different CHF patients.

High variability of serum BNP levels exists in CHF patients with weak-to-moderate correlation effects particularly on obesity and diastolic/systolic HF.

Physicians should be cautious on interpreting BNP in different CHF populations.

[C]   NT-proBNP compared with ECHO

Comparison of N-Terminal Pro B-Natriuretic Peptide and Echocardiographic Indices in Patients with Mitral Regurgitation.  Shokoufeh Hajsadeghi1, Niloufar Samiei2, Masoud Moradi3, Maleki Majid2, et al. Corresponding author email: masoud_moradi65@yahoo.com


Introduction: Echocardiographic indices can form the basis of the diagnosis of systolic and diastolic left ventricular (LV) dysfunction in patients with Mitral regurgitation (MR). However, using echocardiography alone may bring us to a diagnostic dead-end. The aim of this study was to compare N-Terminal pro B-natriuretic peptide (BNP) and echocardiographic indices in patients with mitral regurgitation.

Methods: 2D and Doppler echocardiography and BNP serum level were obtained from 54 patients with organic mild, moderate and severe MR.

Results: BNP levels were increased with symptoms in patients with mitral regurgitation (NYHAI: 5.7 ± 1.1, NYHAII: 6.9 ± 1.5, NYHAIII: 8.3 ± 2 pg/ml, P , 0.001). BNP plasma level were significantly correlated with MPI (myocardial performance index)(r = 0.399, P = 0.004), and following echocardiographic indices: LVEDV (r = 0.45, P , 0.001), LVESV (r = 0.54, P , 0.001), LVEDD (r = 0.48, P , 0.001), LVESD (r = 0.54, P , 0.001), dp/dt (r = −0.32, P = 0.019) and SPAP (r = 0.4, P = 0.006).

Conclusion: The present study showed that BNP may be useful in patients with MR and may confirm echocardiographic indices.

Keywords: mitral regurgitation, N-Terminal pro-B natriuretic peptide, echocardiographic indices.

The hypothesis assumes that there is a linear sequence of most effective screening that comes out of this study, from a b-type natriuretic peptide to the imaging.  It’s not clear that that is the case, and moreover, silent myocardial infarct is taken and lumped with other serious conditions affecting the myocardium, presumably through compromise of the end-artery circulation to the heart (R, L, and circumflex coronaries).  There is no mention of whether the patients were screened out for peripheral, carotid, or other associated artery disease (superior mesenteric).

I’ll assume that that is the case.  I see a problem with a linear, monothetic, “gold standard” approach, when the disease and the diagnosis of it is multivariate and requires a method that uses a classificatory approach.  We’ll return to that.

English: A Wiggers diagram, showing the cardia...

English: A Wiggers diagram, showing the cardiac cycle events occuring in the left ventricle. (Photo credit: Wikipedia)

[D]  reference normal for NT-proBNP


Background: The natriuretic peptides, B-type natriuretic peptide (BNP) and NT-proBNP that have emerged as tools for diagnosing congestive heart failure (CHF) are affected by age and renal insufficiency (RI).This study evaluates the reference value for interpreting NT-proBNP concentrations. Increasing concentrations of NT-proBNP are associated with co-morbidities, not merely CHF, resulting in altered volume status or myocardial filling pressures.

Methods: NT-proBNP was measured in a population with normal trans-thoracic echocardiograms (TTE) and free of anemia or renal impairment.

Selection of Patients: Study participants were seen in acute care for symptoms of shortness of breath suspicious for CHF.

Results: The median NT-proBNP for patients under 50 years is 27.6 pg/ml with an upper limit of 445 pg/ml, and for patients over 50 years the median was 142.3 pg/ml with an upper limit of 475.3 pg/ml. We introduce a transformed NT-proBNP that normalizes for decrease in glomerular filtration rate and eliminates the age factor.

Conclusion: We suggest that NT-proBNP levels can be more accurately interpreted only after removal of the major co-morbidities that affect an increase in this peptide in serum. The PRIDE study guidelines should be applied until presence or absence of comorbidities is diagnosed. With no comorbidities, the reference range for normal over 50 years of age can be reduced below 800 pg/ml. The effect shown in previous papers likely is due to increasing concurrent comorbidity with age.

Key Words: Congestive Heart Failure, Natriuretic peptides, Anemia, Chronic renal insufficiency

Statistical treatment:

The combined acute and blood donor study sets were kept separate and each analyzed for central tendency, distribution and variability. The two were combined after the comorbidities described above were extracted from the acute care study group. This resulted in a population that should be representative of an unaffected study population that could be used to establish a most representative reference range. The database was replicated several times and then patient rows were randomly deleted until there was an expanded combined and mixed data set with 6,700 entries. All of the database sets were used for analyses.

The results are reported in means with p < 0.05 as the measure of significance for difference between means. Independent Student’s t-tests were applied comparing NT-proBNP and anemia. Univariate ANOVAs were used to compare NT-proBNP levels with varying ranges of hemoglobin and age using SPSS 15.0 (SPSS, Chicago, IL). A linear regression analysis with linear fitting and confidence interval was performed using SYSTAT 12 (SYSTAT, San Jose, CA). The results are reported in means with p < 0.05 as the measure of significance for difference between means. Linear regression analysis, Independent Student’s t and Mann-Whitney tests were applied comparing NT-proBNP for age intervals. Reference range was determined using MedCalc (Mariakerke, Belgium).

We observe the following changes with respect to NT-proBNP and age:
  • Sharp increase in NT-proBNP at over age 50
  • Increase in NT-proBNP at 7 percent per decade over 50
  • Decrease in eGFR at 4 percent per decade over 50
  • Slope of NT-proBNP increase with age is related to proportion of patients with eGFR less than 90
  •  NT-proBNP increase can be delayed or accelerated based on disease comorbidities
Adjustment of the NT-proBNP for eGFR and for age over 50 difference

We have carried out a normalization to adjust for both eGFR and for age over 50:

  • Take Log of NT-proBNP and multiply by 1000
  • Divide the result by eGFR (using MDRD[9] or Cockroft Gault[10])
  • Compare results for age under 50, 50-70, and over 70 years
  • Adjust to age under 50 years by multiplying by 0.66 and 0.56.

GFR (mL/min/1.73 m2) = 186 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African-American) (conventional units)

The equation does not require weight because the results are reported normalized to 1.73 m2 body surface area, which is an accepted average adult surface area.

Comparison of the mean + standard deviation of 607 blood donors and NYMH inpatients for the MDRD and Cockroft Gault (eCG), respectively gave 114.3, 43.7(MDRD); 105.0, 40.1 (eCG). The eCG is predicted by the regression: eCG = 0.059 + 0.918*MDRD. The mean + standard deviation for the age under 50 years and 50 or older is 106.5 + 14.7, 100.9 + 14.5 (MDRD); and 102.5 + 18.5, 98.4 + 20.8 (eCG). These differences are significant at < 0.0001, and 0.010, respectively.

The means comparison of the normalized NT-proBNP (NKLog[NT-proBNP]/eGFR) results in 23.4 and 18.7 for 307 non-donors and 300 donors, significant at p < 0.0001, assuming unequal variance). The difference is not significant for the MDRD normalized NT-proBNP (16.5, 6.6). The normalized by eCG result for 324 under age under 50 years and 283 age 50 years and older is 17.7 versus 18.2, significant at p = 0.0001. The MDRD calculated adjustment is 16.8 vs 16.9, which is not significant. The relationship between these is NKLog(NT-proBNP)/eCG = 4.47 + 0.948*NKLog(NT-proBNP)/MDRD. Figure 4 is a plot of the regression of NKLog(NTproBNP)/MDRD vs NKLog(NTproBNP)/eCG predicted over the full study population.

The reference range for the normalized Klog(NT-proBNP)/MDRD is described by a mean 13.99, median 13.12, and standard deviation 6.14 with a nonparametric upper limit of 24.7. A ROC curve is constructed comparing the NT-proBNP, the NKLog(NTproBNP)/MDRD and the ratio NTproBNP to NKLog(NTproBNP)/MDRD in the expanded full database. The area under the curve is 0.944 (0.938-0.950) for NKLog(NTproBNP)/MDRD with a base of 571 patients with early CHF and 6115 patients without. The reference range for NKLog(proBNP)/MDRD can be referenced to the percentiles as follows: 20, 8.78; 40, 11.92; 60, 14.85; 90, 21.10; 95, 24.73; 97.5, 29.54.

Conclusion: We suggest that NT-proBNP levels can be accurately assessed only after removal of the major confounding co-morbidities that increase this peptide in serum. We established our new range after establishing absence of co-morbidities. The value of this approach for screening purposes is an allowance for a considerably lower reference normal with a higher specificity based on the donor studies and the mixture model. This study finds that the reference range for NT-proBNP is age-dependent past age 50 years, mainly as the change relates to eGFR, and we introduce an age adjusted alternative measure, the normalized NT-proBNP using the MDRD transformation described.

NT-pro BNP reference range with blood donors and patients

Measure                                            NT-proBNP (pg/ml)                         After trimming extremes

Highest                                                    1110                                                                   599.4

Arithmetic mean                                   179.6                                                                   118.2

Geometric mean                                        68.7                                                                      54.4

Median                                                          52.6                                                                     42.6

Standard deviation                                250.5                                                                  150.6

D’Agostino-Pearson                          P = 0.0026                                                    P = 0.0091


< 50 years                                                  526.9                                                                 445.0

> 50 years                                                1000                                                                    565.0

Upper Limit of Normal                           772.9                                                                475.3

95% confidence interval                   637.1 – 873.73                                      442.7 – 531.0

Bernstein LH, Zions MY, Alam ME, Haq SA, Heitner JF, et al.  What is the best approximation of reference normal for NT-proBNP? Clinical Levels for Enhanced Assessment of NT-proBNP (CLEAN)

Renal Effect on NT-proBNP

NT-proBNP is excreted by the kidney.  Therefore, GFR has to be taken into account in adjusting the reference range.  BNP, unlike the propeptide, is eliminated 80% by vascular endothelium.  What would be the effect of vascular endothelium erosion?  We don’t know.

The Cockroft Gault equation is widely used in hospitals for adjusting medication doses in hospital patients. The MDRD equation was developed for patients with renal insufficiency and has been shown to be comparable to CG for the population the MDRD is applied. However, the MDRD is only reported to a CLCR of only 60 ml/min and is not validated for age over 65 years. On the other hand, the body weight and BMI, necessary for calculating the CG formula are not routinely done for all patients or in all hospitals. We used 307 inpatients and calculated the MDRD up to 100 ml/min/m2, then used the results to predict the CG. The regression for MDRD versus the CG resulted in an r = 0.884, and a regression equation: CG = -21.1 + 1.172*(MDRD). The initial prediction of CG from MDRDe from 198 of the patients is defined by the regression: CGe = -64.6 + 1.866*MDRDe. (Deming)(95% CI: Intercept -84.5 to -42.8; slope 1.40 to 2.33).  The means, medians, standard deviations, and 97.5th percentiles, respectively, of the age, MDRDe and CGe (calculated from weight data) for the 307 patients are: age- 61.2, 62.0, 17.4, 91.3; MDRD – 121.5, 107.5, 55.9, 212.3; CG – 111.7, 98.7, 51.4, 195.0.

The NT-proBNP was adjusted using a log transform and the estimated GFR (glomerular filtration rate by the original method of Levey et al.  The result for reference corrected Nt proBNP is shown in Table 2.

Table 2.

Kruskal-Wallis test

Factor codes MDRD60
Sample size




Average Rank







Test statistic


Corrected for ties  Ht


Degrees of Freedom (DF)


Significance level

P < 0.0001

[E]   Mid-region proANP in Emergency Room

Mid-region pro-hormone markers for diagnosis and prognosis in acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial.
J Am Coll Cardiol 2010 May 11;55(19):2062-76 (ISSN: 1558-3597)
Maisel A; Mueller C; Nowak R; Peacock WF; Landsberg JW; Ponikowski P; Mockel M; Hogan C; Wu AH; Richards M; Clopton P; Filippatos GS; Di Somma S; Anand I; Ng L; Daniels LB; Neath SX; Christenson R; Potocki M; McCord J; Terracciano G; Kremastinos D; Hartmann O; von Haehling S; Bergmann A; Morgenthaler NG; Anker SD
VA San Diego Healthcare System, San Diego, California 92161, USA. amaisel@ucsd.edu.
OBJECTIVES: Our purpose was to assess the diagnostic utility of midregional pro-atrial natriuretic peptide (MR-proANP) for the diagnosis of acute heart failure (AHF) and the prognostic value of midregional pro-adrenomedullin (MR-proADM) in patients with AHF. BACKGROUND: There are some caveats and limitations to natriuretic peptide testing in the acute dyspneic patient. METHODS: The BACH (Biomarkers in Acute Heart Failure) trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. A noninferiority test of MR-proANP versus B-type natriuretic peptide (BNP) for diagnosis of AHF and a superiority test of MR-proADM versus BNP for 90-day survival were conducted. Other end points were exploratory. RESULTS: MR-proANP (> or =120 pmol/l) proved noninferior to BNP (> or =100 pg/ml) for the diagnosis of AHF (accuracy difference 0.9%). In tests of secondary diagnostic objectives, MR-proANP levels added to the utility of BNP levels in patients with intermediate BNP values and with obesity but not in renal insufficiency, the elderly, or patients with edema. Using cut-off values from receiver-operating characteristic analysis, the accuracy to predict 90-day survival of heart failure patients was 73% (95% confidence interval: 70% to 77%) for MR-proADM and 62% (95% confidence interval: 58% to 66%) for BNP (difference p < 0.001). In adjusted multivariable Cox regression, MR-proADM, but not BNP, carried independent prognostic value (p < 0.001). Results were consistent using NT-proBNP instead of BNP (p < 0.001). None of the biomarkers was able to predict rehospitalization or visits to the emergency department with clinical relevance. CONCLUSIONS: MR-proANP is as useful as BNP for AHF diagnosis in dyspneic patients and may provide additional clinical utility when BNP is difficult to interpret. MR-proADM identifies patients with high 90-day mortality risk and adds prognostic value to BNP. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628). [Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.].
Comment In: RefSource:J Am Coll Cardiol. 2010 May 11; 55(19):2077-9/PMID:20447529


[A] Predictor of benefit of lowering CRP with statin

Sever PS, Poulter NR, Chang CL, et al; ASCOT Investigators. Evaluation of C-reactive protein prior to and on-treatment as a predictor of benefit from atorvastatin: observations from the Anglo-Scandinavian Cardiac Outcomes Trial. Eur Heart J. 2012;33:486-494

The theory that lowering the C-reactive protein (CRP) level with statin therapy is predictive of cardiovascular outcomes independent of lowering the low-density lipoprotein (LDL) cholesterol level was first advanced by the JUPITER investigators.[1]

  • This study further fueled the debate on whether CRP measurement should be routine for monitoring cardiovascular disease risk. The ASCOT investigators entered this debate when they analyzed data from their trial to determine whether on-statin C-reactive protein level was associated with cardiovascular outcomes.[4]
  • The data in the nested case-control study were from persons recruited to ASCOT in the United Kingdom and Ireland, 9098 of whom were randomly assigned in the blood pressure-lowering arm to receive either amlodipine with or without perindopril or atenolol with or without bendroflumethiazide.[5] Within the whole blood-pressure-lowering group, 4853 persons with a total cholesterol level of 6.5 mmol/L or less (≤ 250 mg/dL) were further randomized to receive atorvastatin or placebo as part of the lipid-lowering arm.[6]
  • For the case-control study, 485 cardiovascular cases were age- and sex-matched with 1367 controls. As expected, the investigators found that baseline LDL cholesterol and CRP levels both predicted cardiovascular events.
  • However, neither the baseline nor the on-treatment CRP level was related to the magnitude of statin efficacy in the prevention of cardiovascular events, whereas the on-treatment LDL cholesterol level was strongly predictive. Including CRP in the Framingham model resulted in a “modest” (2.1%) improvement in risk prediction overall.

The investigators noted that this finding was in line with other prospective studies that showed statistically significant, but modest, absolute improvements with the use of CRP in clinical risk prediction.[7,8] They concluded that “in this hypertensive population selected on the basis of traditional, common coexisting risk factors, CRP did not usefully improve the prediction of cardiovascular events and, critically, reduction in CRP associated with statin therapy was not a predictor of cardiovascular outcome alone or in combination with LDL-cholesterol.”

Eugene Braunwald downplayed the ASCOT investigators’ conclusions in observing “the ASCOT results, albeit quite limited in size, are in fact remarkably similar to those of the [CARE, AFCAPS/TexCAPS, REVERSAL, A to Z], and JUPITER trials, especially in light of the fact that the dose of atorvastatin [in ASCOT] was only 10 mg, while some of the other trials used considerably larger equivalent doses of statins.”

My own take on this is that for at least two decades, there was a belief that the LDL lowering was the main effect of statins, until the (deep frozen) specimens were reexamined from the Framingham study using a hs CRP assay.  The investigation was to determine whether there is a predictor of CVD that is present when the traditional features are not present (which would have to include diabetes and hypertension).  The basis for the use of hsCRP became to identify patients who had sufficient risk to be treated with a statin.  The essential focus seemed to turn on whether statin treatment has efficacy in view of the differential between the LDL or the CRP on the magnitude of the effect.  The muscular effect of a statin then comes into view with the size dose and length of treatment.  However, the CRP measurement identified a relationship between development of the vascular disease and the inflammatory process independently of the STATIN treatment benefit.

Prof. Sever (Medscape): The key result that we found in the initial paper was that CRP, although an independent predictor of cardiovascular events in the hypertensive population, was really only a weak predictor, which is confirmed by the meta-analyses. Furthermore, when you incorporate CRP into a Framingham-style model, it really does not add any benefit or give any more information than if it had not been included in the model. LDL cholesterol is a much more important biomarker. Our second important conclusion addressed the question of whether, after starting a patient on statin therapy, the magnitude of lowering CRP by the statin and the level to which CRP has been reduced predicts cardiovascular outcome. The simple answer from our analyses was that it did not and that the benefits were all related to lowering LDL cholesterol. Our population comprised patients with stable hypertension and no history of coronary disease; likewise, the diabetes population in CARDS had no history of coronary heart disease. Oddly, PROVE IT-TIMI 22 involved persons who were selected from a high-risk coronary heart disease population simply because they had a high level of an inflammatory marker. So, to a certain extent, this is like comparing apples and oranges, and to find some unifying hypothesis on the basis of widely heterogeneous patient populations seems to be a little naive.

[B] Predictor of cardiovascular disease

Acute Phase Reactants as Novel Predictors of Cardiovascular Disease  M. S. AhmedA. B. JadhavA. Hassan, and Qing H. Meng SRN Inflammation 2012; Article ID 953461, 18 pages. doi:10.5402/2012/953461

  • Acute phase reaction is a systemic response which usually follows a physiological condition that takes place in the beginning of an inflammatory process.
  • This physiological change usually lasts 1-2 days. However, the systemic acute phase response usually lasts longer.
  • The aim of this systemic response is to restore homeostasis.
  1. These events are accompanied by upregulation of some proteins (positive acute phase reactants) and
  2. downregulation of others (negative acute phase reactants) during inflammatory reactions.

Cardiovascular diseases are accompanied by the elevation of several positive acute phase reactants such as

  • C-reactive protein (CRP),
  • serum amyloid A (SAA),
  • fibrinogen,
  • white blood cell count,
  • secretory nonpancreatic phospholipase 2-II (sPLA2-II),
  • ferritin, and
  • ceruloplasmin.

Cardiovascular disease is also accompanied by the reduction of important transport proteins such as

  • albumin, transferrin,
  • transthyretin,
  • retinol-binding protein,
  • antithrombin, and
  • transcortin.

In this paper, we will be discussing the biological activity and diagnostic and prognostic values of acute phase reactants with cardiovascular importance.

The potential therapeutic targets of these reactants will be also discussed.


[C] CRP as an Inflammatory Biomarker

CRP is an acute phase protein [78] produced in the liver in response to interleukin- (IL-) 6 which is stimulated, in turn, by tumour necrosis factor-α (TNF-α) and IL-1 [89].

Recent studies suggest that CRP plays a pivotal role in many aspects of atherogenesis including

  • LDL uptake by macrophage,
  • release of proinflammatory cytokines,
  • expression of monocyte chemotactic protein-1,
  • intercellular adhesion molecule-1, and vascular cellular adhesion molecule-1 [1012].

Activation of inflammation and the acute phase reaction appear to play an important role, not only in the pathogenesis of atherosclerosis, but also in the initiation of the acute coronary syndrome (ACS) [13,14]. Cesari et al. suggested that the inflammatory markers CRP, IL-6, and TNF-α are independent predictors of cardiovascular events in older persons [14].

Diagnostic Value

CRP is also an early ischemic marker and elevated CRP is predictive of future adverse events [2223]. High-sensitivity CRP (hs-CRP) rises acutely after tissue injury, including myocardial infarction (MI). Intense cytokine production and inflammatory cell infiltration occur in the area of ischemia and necrosis. This increase of hs-CRP levels, in part, correlates with infarct size [2425]

CRP can be also used for patients screening in the primary prevention population [36]. Ockene et al. indicated that CRP is generally expressed at low levels (<1 mg/L) in healthy adults and levels remain relatively stable in the absence of an acute inflammatory stimulus [37].

Patients with unstable angina and CRP >3 mg/L at discharge are more likely to be readmitted for recurrent cardiovascular instability or MI within 1 year [38].

Pietilä et al. indicated that hs-CRP measurement is the strongest correlative factor for future clinical events due to arterial inflammation, myocardial infarction, unstable angina, stroke, and peripheral vascular disease in both diseased and apparently healthy asymptomatic patients [40].

The CRP plasma level also is the best risk assessment in patients with

  • either stable or unstable angina,
  • long term after myocardial infarction, and
  • in patients undergoing revascularization therapies [41].
  • One study showed the only independent cardiovascular risk indicators using multivariate, age adjusted and traditional risk analysis were CRP and Total/HDL cholesterol ratio.
  • If CRP, IL-6, and ICAM-1 levels are added to lipid levels, risk assessment can be improved over lipids alone.
  • Moreover, serum CRP may indicate the vulnerability of the plaque [40].

Prognostic Value

  • elevation of hs-CRP levels predicts a poor cardiovascular prognosis [42].
  • The extent of the inflammatory response to injury appears to have prognostic significance, which is independent of the extent of myocardial injury.
  • hs-CRP response after MI has been shown to predict future CHD morbidity and mortality independent of infarct size [43].
  • CRP is also a predictor of incident type 2 diabetes. As well, it adds a prognostic information on vascular risk at all levels of the metabolic syndrome [44].


III.  Troponin(s) and hs-TnI/cTnT

Comparison of diagnostic accuracy between three different rules of interpreting high sensitivity troponin T results. Francesco Buccelletti; Leonarda Galiuto; Davide Marsiliani; Paolo Iacomini; et al. Intern Emerg Med 2012; 7, 365


With the introduction of high sensitivity troponin-T (hs-TnT) assay, clinicians face more patients with ‘positive’ results but without myocardial infarction. Repeated hs-TnT determinations are warranted to improve specificity. The aim of this study was to compare diagnostic accuracy of three different interpretation rules for two hs-TnT results taken 6 h apart. After adjusting for clinical differences, hs-TnT results were recoded according to the three rules.

  • Rule1: hs-TnT >13 ng/L in at least one determination.
  • Rule2: change of >20 % between the two measures.
  • Rule3: change >50 % if baseline hs-TnT 14-53 ng/L and >20 % if baseline >54 ng/L.

The sensitivity, specificity and ROC curves were compared. The sensitivity analysis was used to generate post-test probability for any test result. Primary outcome was the evidence of coronary critical stenosis (CCS) on coronary angiography in patients with high-risk chest pain.

183 patients were analyzed (38.3 %) among all patients presenting with chest pain during the study period. CCS was found in 80 (43.7 %) cases.

The specificity was 0.62 (0.52-0.71), 0.76 (0.66-0.84) and 0.83 (0.74-0.89) for rules 1, 2 and 3, respectively (P < 0.01). Sensitivity decreased with increasing specificity (P < 0.01).

Overall diagnostic accuracy did not differ among the three rules (AUC curves difference P = 0.12). Sensitivity analysis showed a 25 % relative gain in predicting CCS using rule 3 compared to rule 1. Changes between two determinations of hs-TnT 6 h apart effectively improved specificity for CCS presence in high-risk chest pain patients.

There was a parallel loss in sensitivity that discouraged any use of such changes as a unique way to interpret the new hs-TnT results.

Advances in identifying NSTEMI biomarkers [Published 31 August 2012 | Article by Excerpta Medica | Tags: elderly, ami, biomarkers, diagnosis]

In the run-up to the ESC conference at the end of August, we review some recently published research on the hot topic of biomarkers for NSTEMI.

Prompt and accurate diagnosis of acute non-ST elevation myocardial infarction (NSTEMI) can be particularly challenging in elderly patients, as they often present with

  • atypical symptoms and/or have an inconclusive ECG.
  • the diagnostic value of cardiac troponin T (cTnT), an established marker of cardiac injury, is often limited as there is often non-coronary troponin elevation caused by concomitant conditions such as acute congestive heart failure.
  • Identifying new sensitive and specific biomarkers of NSTEMI in elderly patients is therefore important, and circulating microRNAs (miRs) are emerging as good candidates.

researchers evaluated the diagnostic potential of plasma levels of various miRs in elderly patients enrolled at presentation:

  • 92 acute NSTEMI patients (complicated by congestive heart failure in three-quarters of cases),
  • 81 patients with acute congestive heart failure without acute MI, and
  • 99 age-matched healthy people (the control group).

The researchers, from centers in Italy, found that levels of miR-1, miR-21, miR-133a, and miR-423-5p were 3-10 times higher in the patients with NSTEMI, compared with controls. Levels of miR-499-5p, meanwhile, were more than 80 times higher in the NSTEMI patients compared with the patients in the control group.

  • Levels of miR-499-5p and miR-21 were also significantly higher in the NSTEMI group compared with the group of patients with acute congestive heart failure without acute MI.
  • The researchers also found that miR-499-5p was similar to cTnT in being able to distinguish NSTEMI patients from the other two groups.
  • Also, a subgroup analysis of patients with a modest elevation in cTnT level at presentation (0.03-0.10 ng/mL) revealed that miR-499-5p had a diagnostic accuracy superior both to cTnT and to high sensitivity cTnT in differentiating NSTEMI from acute congestive heart failure.

International Journal of Cardiology


IV. Predicting cardiovascular mortality in NSTEMI patients

[A]  Japanese researchers studied 258 consecutive patients hospitalized for unstable angina and NSTEMI within 24 hours of the onset of chest symptoms, and followed them up for a median period of 49 months after admission. During this period there were 38 cardiovascular deaths (14.7%).

They reported that high-mobility group- box 1 (HMGB1), a nuclear protein and signaller of tissue damage, was “a potential and independent predictor of cardiovascular mortality in patients hospitalized for unstable angina and NSTEMI.

  • HMGB1,
  • cardiac troponin I,
  • Killip class greater than 1, and
  • age

were each independently and significantly associated with cardiovascular mortality.


[B]  William LaFramboise et al.       BMC Med. 2012 Dec 5;10(1):157)
see Report by Aviva Lev-Ari (pharmaceuticalintelligence.com)  Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles

Significant differences were detected in circulating proteins from patients requiring revascularization including increased apolipoprotein B100 (APO-B100), C-reactive protein (CRP), fibrinogen, vascular cell adhesion molecule 1 (VCAM-1), myeloperoxidase (MPO), resistin, osteopontin, interleukin (IL)-1beta, IL-6, IL-10 and N-terminal fragment protein precursor brain natriuretic peptide (NT-pBNP) and decreased apolipoprotein A1 (APO-A1). Biomarker classification signatures comprising up to 5 analytes were identified using a tunable scoring function trained against 239 samples and validated with 120 additional samples. A total of 14 overlapping signatures classified patients without significant coronary disease (38% to 59% specificity) while maintaining 95% sensitivity for patients requiring revascularization. Osteopontin (14 times) and resistin (10 times) were most frequently represented among these diagnostic signatures. The most efficacious protein signature in validation studies comprised osteopontin (OPN), resistin, matrix metalloproteinase 7 (MMP7) and interferon gamma (IFNgamma) as a four-marker panel while the addition of either CRP or adiponectin (ACRP-30) yielded comparable results in five protein signatures.


V.  Assessing Cardiovascular Risk

Agency for Healthcare Research and Quality (AHRQ)

Assessing Cardiovascular Risk: Guideline Synthesis

Agency for Healthcare Research and Quality (AHRQ) Authors and Disclosures Posted: 03/01/2012


The Third MI Definition: An Expert Interview With Joseph Alpert In the new definition, the diagnosis of acute MI remains unchanged: That is, it applies where there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. However, the criteria for diagnosis have been updated, with an emphasis on the biomarker cardiac troponin.

  1. The first essential criterion for diagnosis of MI is detection of a rise or fall in cardiac troponin, or CKMB if troponin is not available, with at least 1 value above the 99th percentile upper reference limit, plus at least 1 the following criteria:
  2. Symptoms of ischemia;
  3. ECG changes of new or presumed new ischemia (significant ST-segment T-wave changes or new left bundle branch block);
  4. Development of pathologic Q waves on ECG; or
  5. Imaging evidence of new loss of viable myocardium or new regional wall-motion abnormality.Other criteria include those for MI in sudden unexpected cardiac death and for MI during percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG).

The guidance document supports the use of high-sensitivity cardiac troponin assays, especially for distinguishing myocardial injury not related to myocardial ischemia, such as that associated with heart failure or renal failure. These assays are available in Europe, and not in the United States. MI is designated as ST-segment elevation MI or non- ST-segment elevation MI, and as in the 2007 version, it is classified into 5 types on the basis of pathologic, clinical, and prognostic differences. These types have been updated in the latest version.

  1. Type 1 MI (spontaneous MI) is related to atherosclerotic plaque rupture or other event leading to thrombus formation in ≥ 1 of the coronary arteries, leading to decreased myocardial blood flow with ensuing necrosis;
  2.  Type 2 MI arises from a condition other than CAD;
  3.  Type 3 MI is deemed to have occurred when cardiac death occurs with symptoms suggestive of myocardial ischemia, but without biomarker values having been obtained; and
  4. Type 4 and 5 MIs are related to PCI and CABG, respectively, and have been redefined since 2007.

The new document also describes situations in which troponin levels are elevated in conditions where myocardial injury with necrosis is associated with predominantly nonischemic myocardial injury, such as heart failure, renal failure, myocarditis, arrhythmias, or pulmonary embolism.


VI Statistical Problems

The normal or “bell shaped” curve is a plot of numerical values along the x-axis and the frequency of the occurrence on the y-axis.  If the set of measurements occurs as a random and independent event, we refer to this as parametric, and the distribution of the values is a bell shaped curve with all but 2.5% of the values included within both ends, with the mean or arithmetic average at the center, and with 67% of the sample contained within 1 standard deviation of the mean.  We view a reference range in terms of a homogeneous population.  This means that while all values might not be the same, the values are scattered within a distance from the mean that becomes less frequent as the distance is larger so that we can describe a mean and a 95% confidence interval around the mean.  In the problem we are discussing, the classic reference value could be determined with outliers removed, and it would most likely fit to a Receiver Operator Characteristic curve.  This became blurred when the high sensitivity assay was introduced, which included NOISE, which is really not noise but heterogeneous elements related to [a] vascular events that are not caused by plaque rupture, or [b] ischemia related to “piecemeal necrosis” which continued might predict a serious future event.  Hidden variables include – age, diurnal variation, racial factors, and disease (hypertension, CHF, type 2 diabetes, renal failure).

A majority have no ST elevation on EKG, considered definitive for AMI.  This makes the finding of elevated and increasing cardiac specific enzyme or protein in serum of paramount importance for specifying damaged cardiac muscle in a context of insufficient circulation.   We examine the classification of AMI using a combination of features of chest pain, EKG, and a sensitive cardiac marker, derived from the cardiac muscle filament.   An optimum value for a test cutoff is, such as cTnT, can be derived without using a prior determination of disease status. This is an alternative to first carrying out a study with a training set, and then repeating it with a validation set, provided there is sufficient information for classifying the data..  We have to construct a self-classifying table of ordered classes that have assigned measurable risks.   Haberman (4) discusses the underlying assumptions used by Magidson for association models of cross-classified data in calculating the maximum likelihood estimates (MLE) by using the log-likelihood ratio and a sum of squares representing deviations of parameters from their constraints. The Latent Class Analysis (LCA) developed by Magidson and Vermunt allows use of a traditional LCA or a regression model (Statistical Innovation. Belmont, MA).  .  The LCA model uses the variables – chest pain, EKG, and troponin T – to classify the data and to test the underlying structure using powerful fit measures, such as L2.  Chest pain has the value of “typical” or “other”.   EKG has the value ST depression or any other (for a non Q-wave study).  “cTnT” has the value  assigned by rank in the scaling intervals.   The results of such an analysis are displayed in Table 1.

Table 1. This LCA classification was constructed using the troponin T before hsTnT was available.

CTnT (mg/L) MI (6%)  Not MI (94%)
0-0.03 0.0008 0.8485
0.031-0.055 0.0009 0.0791
0.056-0.080 0.0009 0.0369
0.081-0.099 0.0010 0.0106
0.10-0.199 0.2026 0.0238
> 0.20 0.7939 0.0012

Eugene Rypka. Syndromic classification: A process for amplifying information using S-Clustering.  Nutrition 1996; 14(12: 827-829.

Stuart W Zarich, Keith Bradley, Inder Dip Mayall, Larry H Bernstein. Minor elevations in troponin T values enhance risk assessment in emergency department patients with suspected myocardial ischemia: analysis of novel troponin T cut-off values. Clin Chim Acta 2004; 343(1-2):223-229

Haberman SJ. Computation of maximum likelihood estimates in association models. J Am Stat Assoc 1995;90:1438-1446

Rudolph RA, Bernstein LH, Babb J.  Information Induction for the Diagnosis of  Myocardial Infarction. Clin Chem 1988; 34: 2031-8.

Vermoent JK, and Magidson J. Latent class cluster analysis. JA Hagenaars and AL McCutcheon (eds.), Advanced Latent Class Analysis. Cambridge, Cambridge University Press, 2000.

Bernstein LH, Qamar A, McPherson C, Zarich S. Evaluating a new graphical ordinal logit method (GOLDminer) in the diagnosis of myocardial infarction utilizing clinical features and laboratory data.   Yale J Biol Med 1999; 72: 259-268.


VII. Conclusions I have made a number of comments to follow up on.  The diagnosis of myocardial infarct has been extended as a result of the emergence of the high sensitivity troponins, but the laboratory methods have not caught up with the technology as the identification of myocardial ischemia is broken down with fine granularity in order to

  • identify the high risk patients early
  • and manage them effectively at the earliest stage of disease evolution

We no longer ponder over

  1. ECG findings of new Q-qave, not previously seen
  2. ST elevation
  3. T-wave inversion

These are an indication of plaque rupture. There are strong associations between CRP, hyperhomocysteinemia, and then add the troponins and b-type natriuretic  and the pro b-type peptides.  These associations have to be analyzed by “syndromic classification”, described by Eugene Rypka. The study first described found great value in the BNP and proBNP.  Despite having the creatinine clearance, the NT-proBNP can’t be adequately interpreted without adjusting for the estimated glomerular filtration rate, and using a log transform for the high fold-increase with age.

There is much more to be done with capturing the information from the data we are generating.  The problem of classification requires accurate data measurement, but it also requires that features in scaled data are combined in meaningful ways.  That job is far from completed.


Below I paste all discussions on this post that are taking place on LinkedIn Group: Innovations in Cardiology:

Kathy Dowd, AuD • I am an audiologist representing the Academy of Doctors of Audiology for an initiative of early identification of hearing loss in adults with chronic diseases, including cardiovascular disease, thyroid disease, diabetes, etc. I am working on a new product that will automatically screen hearing of patients with these conditions and route them to audiologists for evaluation, treatment and counseling. Hearing loss is unidentified for most adults for 7-10. The psychological impact of hearing loss includes depression, isolation, confusion and poor job performance. We are focused on educating healthcare professionals on the need to identify this ‘silent epidemic’ as a co morbidity with most major illnesses.

Aviva Lev-Ari, PhD, RN • Dr. William LaFramboise

Thank you for your comment above and the reference to your most recent publication. It is very helpful. We are on the same page on this topic.

May I bring to the attention of the readers three sources which are shading additional light on that matter.

To Stent or Not? A Critical Decision


Obstructive coronary artery disease diagnosed by RNA levels of 23 genes – CardioDx heart disease test wins Medicare coverage


Follow William
William LaFramboise • Thank you Aviva. The CardioDx approach is promising with heavy commercial support for use in a primary care practitioner’s office. However, RNA acquisition, purification and qRT-PCR expression analysis takes 2-3 days, is performed off-site, derives from a small subset of circulating inflammatory cells and is not yet directly correlated with functional proteomics. So its value in the Emergency Room and Chest Clinic is currently limited. The proteomics test we published revealed systemic serum changes in a small number of proteins known to be involved in atherosclerosis. It has a faster turnaround time (minutes to hours) that could be implemented in an emergency room or chest clinic. We are predominantly interested in using our test to “rule out” symptomatic patients who currently undergo coronary angiography but do NOT have clinically significant CAD. Our goal is to eliminate unecessary catheterizations while catching all patients that should undergo coronary angiography with a high probability of percutaneous intervention. Currently, the patients we are targeting all undergo catheterization; our test will hopefully allow us to identify at least some of these patients who do not have CAD and eliminate this expensive and risky procedure. However, we are in the pioneering stages of developing our test so there are miles to go before we establish and validate clinical efficacy.


Larry Bernstein • What you have indicated is practical proteomics. There is more to be done in line with what Dr Lev-Ari has indicated based on additional voluminous literature. What you have done with a not so large data set, and probably underpowered looks very interesting.

I f you were willing to share the data, now that it is publihed, I think that we can sharpen the results using a method of “identifying anomalies”, and even come up with estimated probabilities for meaningful classes. I think that the best you can get is defined by Kullback-Liebler distance.

Larry H Bernstein, MD

Biomarker classification signatures comprising up to 5 analytes were identified using a tunable scoring function trained against 239 samples and validated with 120 additional samples. A total of 14 overlapping signatures classified patients without significant coronary disease (38% to 59% specificity) while maintaining 95% sensitivity for patients requiring revascularization. Osteopontin (14 times) and resistin (10 times) were most frequently represented among these diagnostic signatures. The most efficacious protein signature in validation studies comprised osteopontin (OPN), resistin, matrix metalloproteinase 7 (MMP7) and interferon gamma (IFNgamma) as a four-marker panel while the addition of either CRP or adiponectin (ACRP-30) yielded comparable results in five protein signatures.

Proteins in the serum of CAD patients predominantly reflected (1) a positive acute phase, inflammatory response and (2) alterations in lipid metabolism, transport, peroxidation and accumulation.

Follow William
William LaFramboise • Our study (http://www.ncbi.nlm.nih.gov/pubmed/23216991) comprised discovery research using targeted immunochemical screening of retrospective patient samples using both Luminex and Aushon platforms as opposed to shotgun proteomics. Hence the costs constrained sample numbers. Nevertheless, our ability to predict outcome substantially exceeded available methods:

The Framingham CHD scores were statistically different between groups (P <0.001, unpaired Student’s t test) but they classified only 16% of the subjects without significant CAD (10 of 63) at a 95% sensitivity for patients with CAD. In contrast, our algorithm incorporating serum values for OPN, RES, CRP, MMP7 and IFNγ identified 63% of the subjects without significant CAD (40 of 63) at 95% sensitivity for patients with CAD. Thus, our multiplex serum protein classifier correctly identified four times as many patients as the Framingham index.

The addition of clinical variables to our scoring system should improve the acuity of our test as we move into the next phase. I appreciate your input and will contact you directly for further insights

Larry Bernstein • Bill La Fram..

our algorithm incorporating serum values for OPN, RES, CRP, MMP7 and IFNγ identified 63% of the subjects without significant CAD (40 of 63) at 95% sensitivity for patients with CAD

I think you can improve the algorithm with strong clinical features. The Goldman algorithm is stronger than the Framingham Index. Maybe its because the FI is epidemiological and is a measure of long term risk being present and does not indicate significant features at the time of presenting. The best features of the Goldman algorithm (without lab work) are – ECG (which may be arguable with NSEMI), but the presence of Afib or tachyarrhythmia could be added to that in weighting, and radiation actually should include symptoms of gall bladder (vagal nerve branch), and onset, characteristic and duration of pain, and SOB.

In your algorithm there isn’t any assessment of the hypercoagulable state, blood flow or Viscosity. There is a strong relationship between hyperhomocysteinemia and CVD, and the HHCys has ties to impaired methyl group transfers that maybe proinflammatory through more than one interaction: countering eNOS, related to Lp(a), un unknown relationship to iNOS (which becomes a counterpoise to eNOS), an effect on blood flow and viscosity, and a relationship to platelet aggregation.

Lp(a) was originally considered of less weight, except that it occurred in thin people from Asian Indian descent. The relationship to apo(B) and to dense LDL particles is now a factor. Sam Filligane uses Lp(a) in his ambulatory practice, and he also uses the PLAC test that Aviva has posted on.

The biggest problem we have is the amount of variability in the data physicians use. It makes metaanalysis a poor solution to the problem. The standardization of laboratory “panels” set up after CLIA 88 puts a real burden on the physician for unsubstantiated “cost benefits” in the light of today’s knowledge.


English: Four chamber view on cardiovascular m...

English: Four chamber view on cardiovascular magnetic resonance imaging. (Photo credit: Wikipedia)

Other related articles on Assessing Cardiovascular Disease with Biomarkers published on this Open Access Online Scientific Journal, include the following:


Dr. Lev-Ari’s research on Assessing Cardiovascular Disease with Biomarkers includes

  • Biomarkers in vascular biology,
  • Biomarkers in molecular cardiology and
  • circulating Endothelial Progenitor Cells (cEPCs) as a Biomarker for cardiovascular marcovascular disease risk


Lev-Ari, A., (2012U). Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs


Lev-Ari, A., (2012T). Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs


Lev-Ari, A., (2012S). Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs


Lev-Ari, A. (2012a). Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair


Lev-Ari, A. (2012b). Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes


Lev-Ari, A. (2012h). Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk


Lev-Ari, A. (2012xx). Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles


Lev-Ari, A. (2013a) forthcoming, based on:

Part III: (2006c) Biomarker for Therapeutic Targets of Cardiovascular Risk Reduction by cEPCs Endogenous Augmentation using New Combination Drug Therapy of Three Drug Classes and Several Drug Indications. Northeastern University, Boston, MA 02115

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment                                    Larry Bernstein

New Insights on Nitric Oxide donors – Part IV                Larry Bernstein

The Essential Role of Nitric Oxide and Therapeutic NO Donor Targets in Renal Pharmacotherapy             Larry Bernstein

A second look at the transthyretin nutrition inflammatory conundrum                                                                  Larry Bernstein

What is the role of plasma viscosity in hemostasis and vascular disease risk?                                                        Larry Bernstein

Biochemistry of the Coagulation Cascade and Platelet Aggregation – Part I                                                            Larry Bernstein

Laboratory, Innovative Technology, Therapeutics                                                                                                            Larry Bernstein

Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis                 Larry Bernstein

Overview of new strategy for treatment of T2DM: SGLT2 inhibiting oral antidiabetic agents                             aviralvatsa

Mitochondrial dynamics and cardiovascular diseases          ritusaxena

Nitric Oxide and it’s impact on Cardiothoracic Surgery        tildabarliya

Telling NO to Cardiac Risk                                                                  sjwilliamspa

Read Full Post »

Reporter and Curator: Aviva Lev-Ari, PhD, RN

WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulantion and Coronary Stenting): Get Rid Of The Aspirin In Triple Therapy

According to current guidelines and clinical practice, PCI patients already taking an oral anticoagulant generally end up on triple therapy comprising the anticoagulant plus clopidogrel and aspirin. However, there is no supporting evidence base for this approach and the triple therapy regimen is known to increase bleeding complications. Now a new study– the first randomized trial to address this situation, according to the investigators–  may have a large impact on clinical practice by demonstrating that the omission of aspirin in this context appears to be safe and may reduce adverse events.

Results of the WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulantion and Coronary Stenting) trial were presented by Willem Dewilde at the ESC in Munich today. Investigators in the Netherlands and Belgium randomized 573 patients to triple therapy or dual therapy of an anticoagulant plus clopidogrel for at least one month after implantation of a bare-metal stent or one year after a drug-eluting stent. Two-thirds of the patients were receiving oral anticoagulation for atrial fibrillation.

The primary endpoint, the total number of bleeding events, was dramatically reduced in the dual therapy group at one year:

  • 44.9% in the triple therapy group versus 19.5% (HR 0.36, CI 0.26-0.50)

There were 3 intracranial bleeds in each group. Most of the difference in bleeding occurred in TIMI minor and minimal bleeding. The difference in TIMI major bleeding (3.3% versus 5.8%) did not achieve statistical significance.

Clinical events, the trials’s secondary endpoint, were numerically lower in the dual therapy group. The difference in mortality achieved statistical significance.

  • Mortality: 7 deaths (2.6%) in the dual therapy group versus 18 deaths (6.4%) in the triple therapy group, p=0.027
  • MI: 3.3% versus 4.7%, p=0.382
  • TVR: 7.3% versus 6.8%, p=0.876
  • Stroke: 1.1% versus 2.9%, p=0.128)
  • Stent thrombosis: 1.5% versus 3.2%, p=0.165

“The WOEST study demonstrates that omitting aspirin leads to less bleedings but does not increase the risk of stent thrombosis, stroke or myocardial infarction,” said Dewilde in an ESC press release. “Although the number of patients in the trial is limited, this is an important finding with implications for future treatment and guidelines in this group of patients known to be at high risk of bleeding and thrombotic complications.”

David Holmes said the trial addressed “an incredibly important issue” and predicted that it would “change the way we practice medicine, it will change practice right away.” Keith Fox said that the evidence base prior to WOEST was extremely limited and that the trial showed that there was no hazard in doing without aspirin. The ESC discussant, Marco Valgimigli, said the trial showed it was safe to drop aspirin and provided another demonstration that “we have hit the wall” with anticoagulation.

Republished with permission from CardioExchange, a NEJM group publication.


European Society of Cardiology: Prasugrel Can’t Top Clopidogrel in ACS

 By Todd Neale, Senior Staff Writer, MedPage Today

Published: August 26, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

MUNICH — For patients with unstable angina or non-ST-segment elevation myocardial infarction (non-STEMI) who do not undergo revascularization, increasing platelet inhibition may not improve outcomes, a randomized trial showed.

Added to a background of low-dose aspirin, prasugrel (Effient) did not significantly reduce the rate of MI, stroke, or cardiovascular death compared with clopidogrel (13.9% versus 16%, HR 0.91, 95% CI 0.79 to 1.05), according to Matthew Roe, MD, of Duke University in Durham, N.C.

The risk of severe bleeding was similar with both drugs, although minor and moderate bleeding were increased with prasugrel, Roe reported at the European Society of Cardiology meeting here. The findings were published simultaneously online in the New England Journal of Medicine.

“I think the outcome is a bit surprising because we think usually that more aggressive antiplatelet therapy, conceivably, in the face of an acute coronary syndrome and non-ST-elevation would lead to lesser adverse outcome from acute myocardial infarction or death,” said William Zoghbi, MD, from Methodist DeBakey Heart Center in Houston and president of the American College of Cardiology.

But he said clinicians need to respect the data “and start thinking about pathogenesis and what we’re trying to do with any of our new interventions.”

In patients with unstable angina or non-STEMI, practice guidelines call for angiography within 48 to 72 hours with provisional revascularization. Many of these patients do not ultimately undergo revascularization, placing them at greater risk compared with those who have their arteries opened with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG).

Recommended medical therapy is with clopidogrel and aspirin, which is an approach that will not change from the current findings, Zoghbi said.

The purpose of the TRILOGY ACS trial was to explore whether using a more powerful platelet inhibitor — prasugrel — would improve outcomes compared clopidogrel (Plavix) in this high-risk patient subset.

The primary analysis involved 7,243 patients younger than 75 (mean age 62) who were receiving aspirin and were randomized to prasugrel 10 mg daily (or 5 mg daily for those weighing less than 132 pounds) or to clopidogrel 75 mg daily. The researchers recommended a daily aspirin dose of 100 mg or less.

A secondary, exploratory analysis involved 2,083 patients, 75 or older, who were randomized to prasugrel 5 mg daily or to clopidogrel 75 mg daily.

The lack of efficacy seen in the primary analysis of patients younger than 75 remained when patients of all ages were combined. There were no between-group differences for any of the components of the primary endpoint.

A prespecified secondary analysis taking multiple recurrent ischemic events into consideration showed a lower risk of MI, stroke, and cardiovascular death with prasugrel in the younger patients (HR 0.85, 95% CI 0.72 to 1.00, P=0.04), a finding consistent with the main results of the TRITON-TIMI 38 trial, which involved patients treated with PCI. The apparent benefit appeared after 12 months of treatment.

“Although this observation is exploratory, it raises the question of whether investigation of the multiplicity of ischemic events is warranted in future secondary-prevention trials, rather than solely analyzing the time to the first event, as has been traditional in studies involving patients who have had an acute coronary event,” the researchers wrote.

Rates of GUSTO severe or life threatening bleeding and TIMI major bleeding — as well as intracranial hemorrhage — were similar in the two groups in both the younger patients and in the overall study population. When minor and moderate bleeding events were added, the bleeding rate was higher with prasugrel.

There were no widespread differences between the groups in rates of nonhemorrhagic serious adverse events, but heart failure was more frequent with clopidogrel (1.8% versus 1.3%, P=0.045).

Douglas Weaver, MD, of Henry Ford Health System, said that he does not think the findings will have any impact on the use of prasugrel, which is not indicated for the patient population included in the study.

“It just doesn’t pass muster in improving value over clopidogrel,” said Weaver, a past president of the American College of Cardiology.

From a clinical perspective, he said, an important message from the study is the evidence of the safety of a reduced dose of prasugrel in the patients 75 and older, which is a consideration when prescribing prasugrel for patients undergoing PCI.

In comments following Roe’s presentation, Raffaele De Caterina, MD, PhD, of the G. d’Annunzio University in Chieti, Italy, provided context about how the findings fit in with the rest of the literature.

He compared the current results to those of a substudy of the PLATO trial, which involved ticagrelor (Brilinta).

In that trial, ticagrelor significantly reduced vascular death, MI, and stroke (HR 0.85, 95% CI 0.73 to 1.00, P=0.045) — the primary endpoint — and all-cause death (HR 0.75, 95% CI 0.61 to 0.93).

He then highlighted the ESC guidelines on treating patients with acute coronary syndromes without persistent ST-segment elevation.

In those, ticagrelor is recommended for all patients at moderate-to-high risk of ischemic events, regardless of initial treatment strategy and including those pre-treated with clopidogrel, and prasugrel is recommended for those who have not taken another P2Y12 inhibitor, who have a known coronary anatomy, and who are proceeding to PCI.

“I believe such statements and recommendations of the guidelines should not be changed,” De Caterina said.

TRILOGY ACS was funded by Eli Lilly and Daiichi Sankyo.

Roe reported relationships with Daiichi Sankyo, Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck, Hoffmann-La Roche, and sanofi-aventis. The other authors reported numerous relationships with industry.

Primary source: New England Journal of Medicine

Prematurely halted ALTITUDE trial showed When added to monotherapy with either an ACE inhibitor or an angiotensin receptor blocker (ARB), aliskiren (Tekturna) did not improve outcomes in patients with type 2 diabetes who had high cardiovascular and renal risk

ESC: Aliskiren Onboard No Help in T2D

By Todd Neale, Senior Staff Writer, MedPage Today

Published: August 26, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

MUNICH — When added to monotherapy with either an ACE inhibitor or an angiotensin receptor blocker (ARB), aliskiren (Tekturna) did not improve outcomes in patients with type 2 diabetes who had high cardiovascular and renal risk, the prematurely halted ALTITUDE trial showed.

Through an average follow-up of 32 months, a composite of various cardiovascular and renal outcomes occurred in 17.9% of patients receiving the direct renin inhibitor and 16.8% of those receiving placebo (HR 1.08, 95% CI 0.98 to 1.20), according to Hans-Henrik Parving, MD, DMSc, of the University of Copenhagen and Aarhus University in Denmark.

As a Hot Line presentation European Society of Cardiology meeting here, Parving reported that there were no significant differences on any of the individual components of the endpoint — cardiovascular death, resuscitated sudden death, MI, stroke, unplanned hospitalization for heart failure, doubling of baseline serum creatinine, and onset of end-stage renal disease — or all-cause death.

The rate of stroke — mostly ischemic stroke — was numerically higher with aliskiren, although the result fell short of statistical significance (3.4% versus 2.8%; HR 1.25, 95% CI 0.98 to 1.60,P=0.07).

Thus, Parving said, using aliskiren with ACE inhibitors or ARBs in these high-risk patients “is not recommended and may even be harmful.”

The data monitoring committee for the ALTITUDE trial decided to stop the study early in December 2011 both for futility and for adverse events. Then, earlier this year, the FDA issued a warning about using aliskiren with ACE inhibitors or ARBs and changed the drug label to reflect a contraindication for such combinations in patients with diabetes or renal impairment.

The trial included 8,561 patients with type 2 diabetes who had a high risk of cardiovascular or renal disease who were randomized to aliskiren — at 150 mg daily for 1 month followed by 300 mg daily thereafter — or placebo in addition to monotherapy with either an ACE inhibitor or an ARB (but not both).

Adding aliskiren did not improve outcomes, and in fact, may have caused harm, Parving said, as indicated by the apparent increase in stroke risk.

He said that could be explained by the impaired autoregulation of patients with diabetes or by chance, as there are no indications of a stroke risk in other studies of the drug.

Johannes Mann, of Friedrich Alexander University in Erlangen, Germany, and McMaster University in Hamilton, Ontario, who served as the discussant following Parving’s presentation, agreed that it could be a chance finding, but said that it could also be a direct effect of aliskiren itself.

He concluded that the stroke risk was not explained, however, by dual renin system inhibition, because such a signal was not seen in the ONTARGET trial, which compared the combination of ramipril (an ACE inhibitor) and telmisartan (an ARB) with each drug as monotherapy.

As noted when the trial was halted last year, adverse events were more frequent in the aliskiren group.

The percentage of patients who had a potassium level of 5.5 to less than 6.0 mmol/L was greater with active treatment (21% versus 16%), as was the percentage of those with a potassium level of 6.0 mmol/L or greater (8.8% versus 5.6%).

Aliskiren carried higher risks of hyperkalemia (38.7% versus 28.6%), hypotension (12.1% versus 8%), diarrhea (9.6% versus 7.2%), and falls (2.8% versus 2.6%). There was one death caused by hyperkalemia.

Douglas Weaver, MD, of the Henry Ford Health System in Detroit, said that the findings were disappointing, but that they likely wouldn’t change how aliskiren is used in practice.

“I don’t think this is going to have a negative or a positive effect on it,” said Weaver, who is a past president of the American College of Cardiology.

ALTITUDE was sponsored by Novartis Pharma AG.

The executive committee and other investigators or their institutions received a consultancy fee. Some of the authors are employees of Novartis and therefore eligible for stock and stock options.

Primary source: European Society of Cardiology
Source reference:
Parving H-H, et al “The Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE)” ESC 2012; Abstract 399.


From Wikipedia, the free encyclopedia
Systematic (IUPAC) name
Aliskiren (INN) (trade names Tekturna, U.S.; Rasilez, U.K. and elsewhere) is the first in a class of drugs called direct renin inhibitors. Its current licensed indication is essential (primary) hypertension.

Aliskiren was co-developed by the Swiss pharmaceutical companies Novartis and Speedel.[1][2] It was approved by the U.S. Food and Drug Administration in 2007 for the treatment of primary hypertension.[3]

In December 2011, Novartis had to halt a clinical trial of the drug after discovering increased incidence of non-fatal stroke, renal complications, hyperkalemia and hypotension in patients with diabetes and renal impairment.[4]

The following recommendations are being added to the drug labels for aliskiren-containing products as of 4/20/12:

I) A new contraindication against the use of aliskiren with ARBs or ACEIs in patients with diabetes because of the risk of renal impairment, hypotension, and hyperkalemia. II) A warning to avoid use of aliskiren with ARBs or ACEIs in patients with moderate to severe renal impairment (i.e., where glomerular filtration rate [GFR] < 60 mL/min).

Mechanism of Action

Renin is the first enzyme in the renin-angiotensin-aldosterone system which plays a role in blood pressure control. Renin cleaves angiotensinogen to angiotensin I, which is in turn converted by angiotensin-converting enzyme (ACE) toangiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure. Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following thereby increasing plasma volume and blood pressure.

Aliskiren binds to the S3bp binding pocket of renin, essential for its activity.[5] Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I.
Aliskiren is also available as combination therapy with hydrochlorothiazide.[6]

Many drugs control blood pressure by interfering with angiotensin or aldosterone. However, when these drugs are used chronically, the body increases renin production, which drives blood pressure up again. Therefore, doctors have been looking for a drug to inhibit renin directly. Aliskiren is the first drug to do so.[7][8]

Aliskiren may have renoprotective effects that are independent of its blood pressure−lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. According to the AVOID study, researchers found that treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). Furthermore, the AVOID trial shows that treatment with 300 mg of aliskiren daily reduces albuminuria in patients with hypertension, type 2 diabetes, and proteinuria who are receiving the recommended maximal renoprotective treatment with losartan and optimal antihypertensive therapy. Therefore, direct renin inhibition will have a critical role in strategic renoprotective pharmacotherapy, in conjunction with dual blockade of the renin−angiotensin−aldosterone system with the use of ACE inhibitors and angiotensin II–receptor blockers, very high doses of angiotensin II−receptor blockers, and aldosterone blockade.[9]

Adverse effects

  • Angioedema
  • Hyperkalemia (particularly when used with ACE inhibitors in diabetic patients)
  • Hypotension (particularly in volume-depleted patients)
  • Diarrhea and other GI symptoms
  • Headache
  • Dizziness
  • Cough
  • Rash
  • Elevated uric acidgout, and renal stones
  • Rarely: allergic swelling of the face, lips or tongue and difficulty breathing


  • Pregnancy: other drugs such as ACE inhibitors, also acting on the renin-angiotensin system have been associated with fetal malformations and neonatal death[10]
  • Breast feeding: during animal studies, the drug has been found present in milk.[10]

Aliskiren has not yet been evaluated in patients with significantly impaired renal function.

Drug interactions

Aliskiren is a minor substrate of CYP3A4 and, more important, P-glycoprotein:

  • Reduces furosemide blood concentration.
  • Atorvastatin may increase blood concentration, however no dose adjustment needed.
  • Possible interaction with ciclosporin (the concomitant use of ciclosporin and aliskiren is contraindicated).
  • Caution should be exercised when aliskiren is administered with ketoconazole or other moderate P-gp inhibitors (itraconazole, clarithromycin, telithromycin, erythromycin, amiodarone).
  • Doctors should stop prescribing aliskiren-containing medicines to patients with diabetes (type 1 or type 2) or with moderate to severe kidney impairment who are also taking an ACE inhibitor or ARB, and should consider alternative antihypertensive treatment as necessary.[11]


  1. ^ Gradman A, Schmieder R, Lins R, Nussberger J, Chiang Y, Bedigian M (2005). “Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients”. Circulation 111 (8): 1012–8. doi:10.1161/01.CIR.0000156466.02908.EDPMID 15723979.
  2. ^ Straessen JA, Li Y, and Richart T (2006). “Oral Renin Inhibitors”Lancet 368 (9545): 1449–56. doi:10.1016/S0140-6736(06)69442-7PMID 17055947.
  3. ^ “First Hypertension Drug to Inhibit Kidney Enzyme Approved”CBC. 2007-03-06. Retrieved 2007-03-14.[dead link]
  4. ^ Healthzone.ca: Blood-pressure drug reviewed amid dangerous side effects
  5. ^ “Chemistry & Biology : Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin”. ScienceDirect. Retrieved 2010-01-20.
  6. ^ Baldwin CM, Plosker GL.[1]doi:10.2165/00003495-200969070-00004. Drugs 2009; 69(7):833-841.
  7. ^ Ingelfinger JR (June 2008). “Aliskiren and dual therapy in type 2 diabetes mellitus”N. Engl. J. Med. 358 (23): 2503–5. doi:10.1056/NEJMe0803375.PMID 18525047.
  8. ^ PharmaXChange: Direct Renin Inhibitors as Antihypertensive Drugs
  9. ^ Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. “Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy,” N Engl J Med 2008;358:2433-46.
  10. a b Drugs.com: Tekturna
  11. ^ European Medicines Agency recommends new contraindications and warnings for aliskiren-containing medicines.

External links


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Reporter: Aviva Lev-Ari, PhD, RN

Updated 3/10/2013

Since August 25, 2012, when the ESC: New Definition of MI Unveiled was reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco as was reported  By Chris Kaiser, Cardiology Editor, MedPage Today,  a new discussion emerged by ACC asking if FFR CT is Ready for prime time or not?

By Lisa Fratt
Mar 09, 2013

SAN FRANCISCO—Is there a better way to measure fractional flow reserve (FFR), Bon-Kwon Koo, MD, of Seoul National University queried a crowded room March 9 during an educational session at the American College of Cardiology (ACC) scientific session.

The current model is good for patients, safe and effective, Koo said. However, it requires an invasive procedure and is expensive. FFR CT may provide a method to measure FFR without an invasive procedure.

FFRCT extracts geometry from a CT scan to determine boundary conditions and fluid properties. In addition, velocity and pressure can be calculated. The hitch is that a supercomputer is required to solve the blood flow equation, said Koo. The results provide anatomical and functional data, thus giving a possible answer to the question at hand.

FFRCT may change daily practice in several ways. Most importantly, it may be a novel, fast, risk-free, noninvasive cost-saving way to measure FFR and identify patients who may not need to be sent to the cath lab for stenting or PCI. It can provide information to help surgeons plan strategies before invasive procedures, bypass procedures or interventional procedures. Noninvasive CT-derived FFR also can predict the functional significance of coronary lesions.

Despite its promise, however, FFR CT is not ready for prime time, Koo said. FFR CT depends on the diagnostic accuracy of coronary CT angiography stenosis, which is less than true stenosis. With current technologies, true stenosis provides the required diagnostic accuracy.

FFRCT is promising, but further development of the technology is required, Koo concluded.


ESC: New Definition of MI Unveiled

By Chris Kaiser, Cardiology Editor, MedPage Today

Published: August 25, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

MUNICH — An international, multispecialty task force has published a new definition of myocardial infarction that was prompted by the new generation of highly sensitive cardiac troponin (cTn) assays.

The highly sensitive assays are capable of detecting cTn in conditions other than MI, such as pulmonary embolism, cardiomyopathy, and left bundle branch block, and so result in false positives, according to the task force writing group.

The expert consensus document dips into a controversial area by setting levels of cTn for MI associated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG).

“This is one of the most controversial areas in the definition of myocardial infarction,” Anthony DeMaria, MD, from the University of California in San Diego and editor-in-chief of the Journal of the American College of Cardiology, told MedPage Today.

“There are a large number of people undergoing PCI in the setting of an acute MI. It’s almost impossible to know whether a subsequent increase in troponin was part and parcel of the acute MI or related to the procedure itself,” DeMaria said.

The consensus document, titled “Third Universal Definition of Myocardial Infarction,” set the cTn levels for MI associated with PCI as elevation of troponin greater than 5 times the 99th percentile upper reference limit (URL) in patients with normal baseline levels or a rise in troponin values greater than 20% if the baseline values are elevated and are stable or falling.

“Some people speculate that troponin may be too sensitive in this situation and what is needed is evidence that an elevation of some degree of troponin following a procedure actually results in some alteration of the natural history of the patient,” DeMaria said. “In other words, the definition of acute MI after a procedure really is of significance if it increases the risk of subsequent events such as death.”

In CABG, the task force set the troponin values as greater than 10 x 99th percentile URL during the first 48 hours when baseline values are normal.

DeMaria said there are several ongoing studies examining the correlation of elevated cTn with subsequent events. As this is the third definition of MI since 2000, there most likely will be more refinements as new data emerge, he said.

The document is being copublished online in several journals including the Journal of the American College of CardiologyCirculation, the European Heart Journal, and Global Heart.

The task force was in touch with the FDA during the development of this new definition, which means it could be used as the basis for clinical trial protocols designed according to FDA regulations.

“A universal definition for MI is of great benefit for clinical studies, since it will allow a standardized approach for interpretation and comparison across different trials,” the task force writing group explained.

When different definitions have been used in trials, it hampers “comparison and generalization between these trials,” they said.

Also of significance in this document is the inclusion of imaging as a means to identify or confirm an MI. The document spells out the strengths of echocardiography, nuclear imaging, MRI, and CT in the setting of acute MI.

“Imaging is playing an increasingly important role,” DeMaria said. “In the absence of focal symptoms or with an inconclusive ECG, it’s important to recognize the concomitant potential of ancillary measures, primarily imaging, to help with the diagnosis of a myocardial infarction.”

Thygesen reported relationships with Edwards Lifesciences, Servier, St. Jude Medical, Roche Pharma, and Roche Diagnostics. Her co-authors and reviewers reported relationships with Bayer Healthcare, Daiichi Sankyo, Johnson & Johnson, sanofi aventis, Servier, Novartis, Boehringer-Ingelheim, Genzyme, Eli Lilly, OrthoClinical Diagnostics, Abbott Laboratories, Alere, Brahms, Siemens Healthcare, Roche Pharma, Radiometer, BioRad, Diagenics, Response Medical, Takeda Pharmaceuticals, Regado Biosciences, Bristol-Myers Squibb, Merck Sharp and Dohme, GlaxoSmithKline, Merck, Portola Pharmaceuticals, AstraZeneca, Regado Biosciences, Scios, Ortho-Biotech, Pfizer, Kai Pharmaceuticals, Iroko Cardio, Philips, GE Healthcare, Boston Scientific, Lantheus, Medtronic, St. Jude Medical, Biotronik, Impulse Dynamics, Edwards Lifesciences, Health System Networks, Health Station Networks, Insight Telehealth Systems, Elsevier Sciences, Gilead, Evolva, Medicines Company, F. Hoffman La Roche, Torrent, Vifor International, Corthera, Nanosphere, Bayer Schering Pharma, Cardiorentis, Molecular Insight Pharmaceuticals, Berlin Chemie, Menarini, Cordis, Beckman Coulter, Amgen, Critical Diagnostics, Tethys Bioscience, Roche Diagnostics, bioMérieux, Genentech, Ikaria, Singulex, BG Medicine, Shionogi, Amylin, DiaDexus, Orion, WebMD, theheart.org, Pozen, Maquet, BHFZ, Covidien, Rapidscan, Actelion, Athera, Symetis, Schering-Plough, OrbusNeich, Terumo, Cardio3 Biosciences, Micell, Ablynx, Therabel, Kowa, Zentiva, Chugai Pharma, Automedics Medical Systems, Essentialis, Biosensors, Vascular Solutions, Zoll Medical, JaBA Recordati, Actavis, PharmaSwiss, Eisai, Medscape, Accumetrics, Bial Portela, AGA, Novo-Nordisk, Janssen-Cilag, Valtech, Otsuka Pharmaceuticals, Meda Pharma, CEPHALON, Intracellular Therapies USA, Santhera, TROPHOS, Pierre-Fabre, and Lundbeck.

DeMaria reported relationships with Gilead, ResMed Foundation, Lantheus, Cardiovascular Biotherapeutics, Angioblast Systems, General Electric Medical Systems, and Cardionet.

Primary source: European Heart Journal

Source reference:
Thygesen K, et al “Third universal definition of myocardial infarction” Eur Heart J 2012; DOI: 10.1093/eurheartj/ehs184.

ESC: FFR CT Has Potential for Tagging Ischemia

By Chris Kaiser, Cardiology Editor, MedPage Today

Published: August 26, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

MUNICH — Using CT imaging to assess the hemodynamic significance of coronary lesions is “promising” but needs more research before it displaces conventional invasive fractional flow reserve (FFR), researchers said.

Using FFR as the reference standard, FFRCTplus CT angiography (CTA) had good sensitivity (90%) and negative predictive value (84%) on a per patient basis for detecting ischemia, which indicates a low rate of false-negative studies, according to James K. Min, MD, of Cedars-Sinai Heart Institute in Los Angeles, and colleagues.

Although FFRCT plus CTA were superior to CTA alone, the specificity (54%) and negative predictive value (67%) of the combination remained low compared with conventional FFR, indicating that a considerable number of false-positive studies would endure, Min reported here during a Hot-Line session at the European Society of Cardiology meeting.

The results of this proof of concept study show that FFRCT can “impart considerable discriminatory power” to detect and exclude ischemia in patients with suspected CAD, Min said.

However, future studies should be conducted to determine the cost-effectiveness of FFRCT in guiding decisions to stent, particularly given the potentially high false-positive rate, he added.

“Non-invasive FFR is a dream for all interventional cardiologists,” said study discussant Jean-Pierre Bassand, MD, of the University Hospital Jean-Minjoz in Besançon, France. Although Bassand praised the DeFACTO study, he expressed concern about the discrepancy between the accuracy of FFR versus FFRCT.

For example, compared with FFR, the sensitivity and specificity of FFRCT in cases of greater than 90% or less than 30% stenosis were 83% and 76%, respectively. The per-vessel correlation of FFRCT to FFR was 0.63.

“What matters is the correlation with FFR,” he concluded.

A single non-invasive imaging test that can identify obstructive coronary artery disease (CAD) and determine the physiological significance of those lesions would be ideal. At present, nuclear stress imaging fulfills the first part, but it cannot label stenoses as hemodynamically significant or not. Also, nuclear stress testing suffers from high rates of both false-negative and false-positive studies, Min said.

The results of this study are in line with stress imaging: per patient diagnostic accuracy of 73% (95% CI 67% to 78%). Min said that studies are being designed to compare FFRCT plus CTA with stress imaging.

“For patients considered for invasive therapy, this type of test could help exclude those who don’t need to be stented,” Spencer King III, MD, of St. Joseph’s Hospital in Atlanta told MedPage Today.

“The excitement about this CT approach is that it moves things closer to being able to assess physiology and anatomy in a single non-invasive test,” added King, who is also a past president of the American College of Cardiology.

However, the process of calculating the FFR values from CT data currently takes about 6 hours, Min told MedPage Today. The CT data are sent offsite to HeartFlow, the company that makes the software. Whether such processing would be done onsite in the future is not yet determined, Min said. He also expects the processing time to drop to about 2 hours by the year’s end.

HeartFlow has already received EU mark to use the software in Europe and is in the process of applying for FDA approval, Min said.

Conventional FFR uses a pressure wire inserted through the groin to the coronary arteries to determine the hemodynamic significance of lesions. The same data can be gleaned during a typical CTA exam with software that calculates computational fluid dynamics,without additional radiation exposure. The median radiation exposure among the study centers was 6.4 mSv (range 4.4 to 15 mSv).

The original FAME study found the use of FFR to guide stenting was better than relying on angiography alone in patients with multivessel disease. A second study, FAME II, was stopped early because of the overwhelming benefit seen in patients with stable CAD when FFR guided stenting versus patients randomized to optimal medical therapy.

Because FFRCT is a novel technique, it has not been adequately evaluated in its ability to identify patients with ischemia, Min said.

The researchers therefore designed the DeFACTO (Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography) study, which sought to evaluate the accuracy of FFRCT while using invasive FFR as the reference standard.

The study was also simultaneously published online in the Journal of the American Medical Association.

The 252 patients with suspected or known CAD were recruited from 17 centers in five countries between October 2010 and October 2011. They were scheduled to undergo diagnostic catheter angiography.

The mean age of patients was 63, 70% were men, and a majority were white. Nearly half of the patients had obstructive CAD (>50% stenosis).

Among 615 study vessels, 271 had less than 30% stenosis and 101 had at least 90% stenosis. Invasive coronary angiography and FFR identified 46.5% of 408 vessels with obstructive CAD, while CT and FFRCT identified 52.3% of 406 vessels.

A total of 172 patients had an FFR value <0.80, which indicates an ischemic lesion.

The diagnostic accuracy of FFRCT plus CT was 73% (95% CI 67% to 78%), but this did not meet the prespecified primary endpoint of greater than 70% of the lower bound of the 95% confidence interval, Min said.

However, Min emphasized that FFRCT was superior to CTA alone in all categories.

The researchers concluded that the results show the potential of FFRCT as a “promising” non-invasive tool to identify ischemia.

King added that despite not meeting the prespecified primary endpoint, “it’s an encouraging early study.”

This study was funded by HeartFlow

Min reported relationships with GE Healthcare and Philips Medical. Some of his co-authors reported relationships with GE Healthcare, Siemens Medical Systems, Lantheus Medical Imaging, Boston Scientific, Merck, Abbott Vascular, Medtronic, Cordis, Eli Lilly, Daiichi Sankyo, Bristol-Myers Squibb, and sanofi-aventis.

King reporeted relationships with Merck & Company, Wyeth Pharmaceuticals, Celonova Biosciences, and Northpoint Domain.


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