Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents
Author: Aviva Lev-Ari, PhD, RN
Real medical ethical dilemmas involved in physician assignment of patients to participate in Clinical Trials
Randomized controlled clinical trials have become the method of choice or the standard technique for obtaining scientific information to be used in changing diagnostic or therapeutic methods. The use of this technique creates an ethical dilemma (Hellman and Hellman, 1991).
Physicians using a randomized clinical trial are cast in two opposing roles at the same time: clinicians and researchers. As clinicians, they have an ethical commitment to individual patients: to practice professionally in an empathetic profession that is concerned with each patient as an individual. By entering into a relationship with an individual patient, the physician assumes obligations and commitments to act always in the patient’s best interest, derived from values of loyalty and the virtue of fidelity to his/her patients. Modifications of these relationships, otherwise dyadic relationship, occurs when a physician assumes legal obligations to report wounds of a suspicious nature and certain infectious diseases. Such obligations do not conflict with the physician’s ethical obligation to act in the best medical interests of his/her patient. Social concerns have pre-empted physician reporting of disease manifestations which are suspected to have public health bearing (Hellman and Hellman, 1991).
The other role assumed by a physician participating in randomized clinical trials, is that of a scientific researcher, committed to determine the validity of formally constructed hypotheses and their testing. Results of scientifically formulated studies using the methods developed in experimental design, derived from the disciplines of Statistics and Operations Research, are presumed to benefit humanity in general, and not only the individual patient participating in such a formally designed clinical trial. The goals of randomized clinical trials were stated by the Director of the National Institute of Allergy and Infectious Diseases, in these words: “It’s not to deliver therapy. It’s to answer a scientific question so that the drug can be available for everybody once you’ve established safety and efficacy” (as cited in Hellman and Hellman, 1991).
How do randomized clinical trials conflict with a physician’s duty towards his/her individual patients? It is a conflict between rights-based Moral Theories on one hand and Utilitarian Theory on the other. Moral theories by Immanuel Kant and John Rowls assert that human beings, by virtue of their unique capacity for rational thinking, are bearers of dignity and ought to be treated as ends in themselves not as means to an end. In contrast, Utilitarianism by Stuart Mills defines what is right as the greatest good for the greatest number, known as social utility (Hellman and Hellman, 1991). Pleasures among them, health and well-being, need be counterbalanced by pain. The morally correct act is the act that produces the most pleasure and the least pain overall. Respectively, believers in Moral theory oppose conduct and self participation in randomized clinical trials, while believers in Utilitarianism support them in earnest.
However, since the distribution of pleasure and pain does have moral consequences, physicians must care about that distribution, since they enter into relationships with many patients. They can’t be indifferent to whether it is these patients or others that suffer for the general benefit of society, even though society might gain from the suffering of a few, even if the physician believes that the suffering by a few is worth the benefit to society. The doctor-patient relationship requires doctors to see their patients as bearers of rights who cannot be merely used for the greater good of humanity.
Consider a new agent that promises more effectiveness of treatment. The control group must be given either an unsatisfactory treatment or a placebo. Even though the therapeutic value of the new agent is unproven, if physicians think it has promise, are they acting in the best interest of their patients in allowing them to be randomly assigned to the control group?
Ethical validity of the assignment of patients to randomized clinical trials involves the following three matters in medical ethics (Hellman and Hellman, 1991, Markman, 1992):
- If the physician has no opinion about whether the new treatment is acceptable, then random assignment is ethically acceptable. Lack of enthusiasm does not lore patients to participate or support the merit of conducting the study anyway. Treatment may show promise of beneficial results but also present undesirable complications (Markman paraphrased)
- Physician believes that the severity and likelihood of harm and good are evenly balanced, randomization may be ethically acceptable. If the physician has no preference for either treatment, he or she are in a state of equipoise (Freedman, 1992), then randomization is acceptable.
- If the physician believes that the new treatment may be either more or less successful or more or less toxic, the use of randomization is NOT consistent with fidelity to the patient.
After patient assignment to a Clinical Trial — What are the risks involved in participation in First-In-Man Stent Implantation as a treatment for cardiovascular diseases?
Dr. R. Stack, professor emeritus of medicine at Duke University, Durham, NC, and president of Synecor, a company developing Bioabsorbable stent, traced the evolution of interventional cardiology from inflation of the first angioplasty balloon to implantation of the first Bioabsorbable stent, in a Founders’ Lecture entitled, “How Can You Get Out of a Full-Metal Jacket?” at the Society for Cardiovascular Angiography and Interventions (SCAI), 29th Annual Scientific Sessions in Chicago, May, 2006, and said:
“In the early days of percutaneous transluminal coronary angioplasty (PTCA), each procedure took three to four hours to complete, and fully one in 20 patients suffered a heart attack in the catheterization laboratory. There was little an interventional cardiologist could do, other than rush the patient to surgery. Introduction of the steerable guidewire made PTCA easier to do and shortened procedure times. Development of the perfusion catheter meant that interventional cardiologists could re-establish blood flow to the heart and stabilize patients in case of a sudden arterial blockage. “(cited in David, 2006).
Risks of Participation in Randomized and Non-randomized Clinical Trials: Technology and Procedural Considerations
- Assignment to a “control group” means implantation of a stent that is gold standard, rather than having the chance of benefiting from an innovative technology such as bioabsorabable stents (Guidant Corporation, 2006) or bioengineered stents (Chadwick, 2006).
- During the clinical trials manufacturing defects in the device are identified after the device has been implanted in the participants but not in the control group. Wood (2006) reports that: Guidant Corporation has voluntarily stopped enrolling patients in several arms of the nonrandomized portion of its SPIRIT III clinical trial, because one out of every 100 Xience V everolimus-eluting stents may have been manufactured in substandard conditions. The Xience V everolimus-eluting stent received CE Mark approval in 1/2006. Earlier in March 2006, the company announced that it has completed enrollment of 1002 patients in the randomized US portion of the SPIRIT III trial, comparing the Xience V with the TAXUS paclitaxel-eluting stent. Company intents to restock investigators’ supplies and relaunch the trial.
- Shortcomings of an entire generation of stent technology which is the Gold Standard in major hospitals in US – Drug Eluting Stents (DES)
Drug-eluting stents, introduced just a few years ago, markedly reduce the risk of restenosis. These stents have quickly become a mainstay of interventional therapy, but their use to treat large segments of the coronary circulation has created new challenges. (ABSORB, 2006, Menichelli, 2006, Pfisterer, 2006, Simonton, 2006, Turco, 2006)
Pfisterer, P.E. (2006) at American College of Cardiology 55th Annual ScientificSession, March 11 – 14, 2006, Atlanta, Georgia in his presentation on Basel Stent Cost-Effectiveness Trial-Late Thrombotic Events (BASKET LATE) Trialcompared Drug-eluting stents (DES) with Bare metal stents (BMS) and told the largest audience of interventional cardiologists in the US that
“The results of this small study and the conclusions reached by the authors are certainly a cause for concern. As has been demonstrated by previous studies, the rate of late stent thrombosis after DES implantation was not significantly higher than the rate associated with BMS, but, nevertheless, the consequences are dire. What I find especially troublesome is the fact that we cannot predict with certainty which patients are prone to develop late stent thrombosis and when stent thrombosis is likely to occur — the latter of which is extremely variable in relation to clopidogrel discontinuation. I am not completely convinced that we should advise all patients treated with a DES to continue dual antiplatelet therapy indefinitely, especially when considering high costs and the potential for bleeding complications. This issue generated plenty of debate at the ACC meeting and is far from being resolved” (Pfisterer, 2006).
Does his message have any impact on Cath Labs in US where thousand of drug-eluting stents are stocked and implanted everyday in thousands of cardiovascular patients, and patients with peripheral vascular diseases?
Risk Sources for Complication during Cardiac Catheterization: Patient participation in a randomized or non-randomized Clinical Trial for a new generation of stent devices
- Clinical – iatrogenic, induced inadvertently by the medical treatment or procedures or activity of a physician
- Procedural – no change in practice induced, though scientific evidence is available
- Idiopathic,of the nature of an idiopathy, self originated, of unknown causation.
The first two risk types are addressed, below.
Clinical – iatrogenic, induced inadvertently by the medical treatment or procedures or activity of a physician
- Access site complications
The most frequently observed complications are related to access site. Such complications, albeit rarely life-threatening, may require additional treatment, including further compression or thrombin injection (for pseudoaneurysms), blood transfusions or vascular surgery. Access site complications may also expose patients to further discomfort, a longer hospital stay and higher hospital costs. For local vascular complications, established predictors are older age, female gender, body surface area, peripheral vascular disease, some antithrombotic regimens and access site (Agostoni, et al. 2006).
- Expertise level of the physician operator
A recent paper from a non-university hospital showed that expert operators (> 500 procedures performed) had an overall complication rate lower than cardiologists-in-training (despite the fact that it is not clear if they were cardiology fellows or interventional cardiologists-in-training), with a relative risk reduction of approximately 40%, Ammann, et al.(2003). This result is not confirmed by our report. Indeed, fellows, whose maximum caseload is around 300 procedures during the training period, can safely perform cardiac catheterizations, with a complication rate very similar to that of attending physicians. We focused, in particular, on local vascular complications, as arterial puncture is the first procedure step in the training of fellows and usually the only part of the examination they perform alone. An attending physician, who is directly responsible for the whole procedure, supervises the rest. In a recent registry on postcatheterization complications, it was stated: “the involvement of fellows-in-training may have contributed to some complications, especially local” according to Chandrasekar, B., et al.(2001). A study may well complement that report, suggesting the opposite conclusions (Agostoni, et al. 2006).
We report that for Procedural and during Procedure – no change in practice introduced though scientific evidence is available.
- Extensive use of antithrombotic therapy
The majority of the patients reported in Agostoni, et al.(2006), underwent left heart catheterization because of suspected or known CAD. Thus, they were taking at least one antiplatelet drug despite the fact that it is common practice at our institution to administer a double antiplatelet regimen (aspirin associated with either ticlopidine or clopidogrel) at least 2 days prior to coronary angiography. And for patients with unstable symptoms, they routinely administer subcutaneous unfractionated or low-molecular-weight heparin, which has been shown to significantly increase the risk of local complications. Moreover, in these unstable patients, intravenous heparin was always administered during the procedure, irrespective of the concomitant administration of subcutaneous heparin. Nevertheless, the complication rate in catheterizations performed for reasons other than CAD remained particularly high (3.1%) (Agostoni, et al., 2006).
In terms of arterial access site, the radial approach clearly reduced the rate of local complications, with an overall incidence of 0.8% compared to 3.4% after transfemoral catheterizations. A recently published meta-analysis comparing the radial versus the femoral approach for percutaneous coronary diagnostic and interventional procedures, including patients with similar overall characteristics, yielded results comparable to those of the present study. The radial artery approach was electively performed by one senior cardiologist and only occasionally by the others, while cardiology fellows did not perform any transradial procedures (Agostoni, et.al. 2006) [italics added].
If radial artery is implicated with less site access-related complications, why is radial artery used in 30% of the cases, and femoral artery in 70% of percutaneous coronary interventions (PCI)?
- Additional Risk Factors for Complication during Cardiac Catheterization that are not routinely Checked or Used Peri-procedure.
Percutaneous left heart catheterization, including pressure measurements, left ventriculography, coronary angiography and percutaneous coronary interventions (PCI), is nowadays considered the gold standard for the diagnosis, evaluation and treatment of several cardiac diseases (coronary artery disease [CAD], valvular and congenital heart diseases, cardiomyopathies, status post-heart transplant) (Agostoni, et al. 2006).
Other variables may increase the probability of complication during Cardiac Catheterization.
These intermediate variables are not routinely checked or used. Thus, they compromise the patient’s chance of achieving the optimal medical results and the best of care. That is after playing the odds of obtaining an assignment in the clinical trial to the “Treatment Group” if a patient was not assigned to either the “Control Group” to be implanted a traditional device or to the “Placebo Group” calling for no device implantation on this round.
Among these variable one finds:
- antithrombotic regimens other than GP IIb/IIIa inhibitors
- body surface area calculation
- identification and consideration of presence of peripheral vascular disease
- absence of testing for systematic screening of serum CK-MB levels needed for detection of postprocedural myocardial infarction.
- absence of cardiac enzymes measurement: before, after, follow up: 2 weeks, 1 month, 6 month, 12 month
Discussion
The first part of the paper deals with the physician’s medical dilemma of assigning patients to randomized clinical trials. The Moral Theory was contrasted with the Utilitarian one. My chosen side/stand on this matter is to identify my values with the Utilitarian group that will participate in randomized clinical trials if medical conditions so require.
In the second part of the paper, I dealt with a realm of risk factors the patient is exposed to after he/she has signed an informed consent and has no longer control. Noteworthy, the risk factors discussed in the paper are not included on any informed consent form. These risks call for modifications to current practices involved in stent implantation technology requiring an immediate consideration.
Two sources of risks were addressed: Clinical and Procedural. These sets of risks are identical for any patient in the Cath Lab, regardless of being assigned to the Treatment Group or to the Control Group. One may not assume that the implantation procedure for a traditional device vs. a new generation device, carries similar risk. Though the risk of complication during the procedure is very low, when it occurs to someone you care for or to yourself, it is very dire.
Major adverse cardiovascular and cerebrovascular events (MACCE: death, myocardial infarction, cerebrovascular event) were also assessed. The overall access site complication rate was 2.6%. On multivariate regression analysis, the only two predictors of local complications were female gender (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.6–6.5) and femoral approach (OR 3.9, 95% CI 1.2–12.1). The rate of MACCE (major cardiovascular and cerebrovascular events was 1.2%, mainly after percutaneous coronary interventions, with only 1 death overall (0.07%)(Agostoni, et.al. 2006).
Like most medical ethics issues, there is no single right answer. I would recommend every Cath Lab to revisit every risk factor listed above, discuss them with the Ethics Committee in the Hospital and initiate new procedures to address the clinical and procedural risk factors identified in the context of First-In-Man Stent Implantation.
As other interventional cardiologists, we are looking forward to Generation Five of Stenting Technology that will include the following innovations:
(a) Stents eluding Nitric Oxide (Verma and Marsden, 2005);
(b) stents with coating of an antibody specific (anti-CD34) to the antigen cells that are in the blood, therefore capturing the patient’s circulating endothelial progenitor cells (cEPCs) in order to accelerate the natural healing process (Chadwick, 2006),(Aoki et al., 2005), (Ben-Shoshan & George, 2007), and
(c) EPC-covered intravascular stents deployed for prevention of stent thrombosis and restenosis as well as for rapid formation of normal tissue architecture (Shirota et al., 2003).
Patient safety will be improved if the risk factors identified will raise awareness and will be addressed — preferably, before the next procedure starts in Angiography/Angioplasty Suite #14, ten minutes from now!
According to Rogers & Edelman (2006), “the spectacular success of drug-eluting stents is still plagued by an aura of unease and an insistent drumbeat demanding evidence of success and safety…dramatic reduction in restenosis attended by enhanced rates of thrombosis.” The performance of the two FDA-approved drug-eluting stents (Taxus and Cypher) varies. Cypher is associated with lower restenosis risk. Both devices are pushed into very complex settings to include patients diagnosed with diabetes (different diabetic states may affect restenosis after stenting in different ways). Percutaneous interventions routinely performed in small-vessels, multilesions, diffuse disease, acute coronary syndrome settings and stent-inside-stent as followed up therapy to restenosis. Other failure modes are stent thrombosis, post-procedural myonecrosis, plaque rupture, enhanced disease at a distance and excitation of patients’ already heightened immune state. Other predictors of device failure include lesion type, patient demographics, prior history of coronary bypass surgery, calcification, degree of pre-stent and post-stent stenosis. The variation in performance is critical for patient care decisions and physician’s discrimination between alternative therapies. In most cases the device is selected by the interventional cardiologist with little or no input from the patient.
Research of Clinical/Ethical issues, to emerge in the context of development of clinical trials for First-In-Man Stents, as well as medical ethical issues, to arise during the implantation procedure of the device, and during the period of follow up of the installed base of the device in humans, requires formalization of the data collection and standardization of the statistical analysis procedures. The two leading conferences, where research findings are reported, in the US in 2006 [American College of Cardiology, Annual Scientific Session] and in Europe in 2006 [The European Paris Course on Revascularization (EuroPCR)] are currently presenting challenges for comparative analysis of safety and efficacy.
Development of a schematic rubric, a conceptual proposal for a future study on the “Ethical Medical Issues involved in Clinical Trials for Next Generation Stent Technology.” Implementation of such a study will be most beneficial to all parties involved: physicians, patients, FDA, device manufacturers and medical ethicists. It will involve the following comparative criteria:
- Medical Ethical Issue
- Clinical Trial Name
- Stent Type
- Number of Patients
- Major adverse cardiac events
- Treatment Efficacy
- Follow up Studies
- Clinical Trial Sites
- Safety of Risk Factors
- Study Discontinued
REFERENCES
ABSORB (2006). Everolimus Eluting Coronary Stent System First in Man Clinical Investigation. ClinicalTrials.gov Identifier: NCT00300131
Study start: March 2006; Expected completion: June 2011
Last follow-up: March 2011; Data entry closure: May 2011
http://www.clinicaltrials.gov/ct/gui/show/NCT00300131?order=1
Agostoni, P., Anselmi, M., Gasparini, G., Morando, G., Tosi, P., De Benedictis, M.L., Quintarelli, S., Molinari, G., Zardini, P., Turri, M. (2006). Safety of percutaneous left heart catheterization directly performed by cardiology fellows: A cohort analysis. The Journal of Invasive Cardiology, 18 (6), 248-252.
Ammann, P., Brunner-La Rocca H.P., et al. (2003). Procedural complications following diagnostic coronary angiography are related to the operator’s experience and the catheter size. Catheter Cardiovasc Interv , 59, 13–18.
Aoki, J., Serruys, P.W., van Beusekom, H., Ong, A.T., McFadden, E.P., Sianos, G., et al. (2005). Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry. J Am Coll Cardiol 45 (10), 1574–1579.
Ben-Shoshan, J. George, J. (2007). Endothelial progenitor cells as therapeutic vectors in cardiovascular disorders: From experimental models to human trials. Pharmacology & Therapeutics, 115, 25-36.
Chadwick , D.(2006) OrbusNeich’s Genous Bioengineered R-stent . Cath Lab Digest, 14 (1), 20-26
Chandrasekar, B., Doucet, S., Bilodeau, L., et al. (2001). Complications of cardiac catheterization in the current era: A single-center experience. Catheter Cardiovasc Interv , 52, 289–295.
David, K.B. (2006). Impressive Progress In Interventional Cardiology – From 1st Balloon Inflation To First Bioabsorbable Stent, Society for Cardiovascular Angiography and Interventions, http://www.scai.org, http://www.medicalnewstoday.com/medicalnews.php?newsid=43313
Freedman, B. (1992). A response to a purported ethical difficulty with randomized clinical trials involving cancer patients.Journal of Clinical Ethics, 3 (3), 231-234.
Guidant Corporation, (2006). Guidant Announces Enrollment of First Patient in Clinical Trial of the World’s First Fully Bioabsorbable Drug Eluting Coronary Stent, 3/9/2006, Source: Guidant Corporation, Indianapolis, IN, www.guidant.com
Hellman, S. and D.S. Hellman (1991). Of mice but not men: Problems of the randomized clinical trial. New England Journal of Medicine, 324 (22), 1589-1592.
Markman, M. (1992). Ethical difficulties with randomized clinical trials involving cancer patients: Examples from the field of gynecologic oncology. Journal of Clinical Ethics, 3 (3), 193-193.
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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