Is Informed Consent Needed in STEMI Trials? Ethical Questions From the HEAT-PPCI Fallout

May 07, 2015

SAN DIEGO, CA — Is informed consent necessary to randomize patients with ST-segment elevation MI (STEMI) into clinical trials?

That was the question two experts grappled with this week at the Society for Cardiac Angiography and Interventions (SCAI) 2015 Scientific Sessions [11], a debate that had its origins in the How Effective Are Antithrombotic Therapies in Primary PCI (HEAT-PPCI) clinical trial presented in early 2014.

According to Dr Roxana Mehran (Icahn School of Medicine at Mount Sinai, New York), in arguing her position in the debate, informed consent is absolutely necessary to protect vulnerable patients. While there might be advantages behind eliminating informed consent in certain situations, the bottom line is that physicians do not have an ethical right to interfere with a patient's right to choose.

"As much as I love clinical research and I want the very best patients and I want the research to translate into real-world practice, are we empowered to take away a patient's right to choose to be part of a study?" she asked. "I don't think so."

Dr Michael Lim (St Louis University, MO), who took the opposing side of the argument, said that he would never argue against the ethical obligation to patients. However, in STEMI patients, many of whom are compromised with impaired consciousness and decreased cerebral perfusion due to low blood pressure, there is a psychological desire to assist in the care of their own condition.

As a result, informed consent itself can be compromised, as these patients will "consent to pretty much anything."


The SCAI debate over informed consent was not an arbitrary discussion between two expert clinical researchers but rather was intended to address an issue that emerged from one of the most notable studies in recent years, the HEAT-PPCI study led by Drs Adeel Shahzad and Rod Stables (Liverpool Heart and Chest Hospital, UK).

The HEAT-PPCI trial was a single-center randomized trial of unfractionated heparin vs bivalirudin (Angiomax, the Medicines Company) in 1829 STEMI patients. As reported by heartwire from Medscape, the results showed that the primary efficacy end point— major adverse cardiac events (MACE), defined as all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target lesion revascularization—occurred in 8.7% of bivalirudin-treated patients and in 5.7% of heparin-treated patients, an absolute increased risk of 3% with bivalirudin.

If you really believe .  .  .  that one [drug] is less than the other, the patient needs to be informed of that, even if it's an approved therapy.

While the results were surprising—and hotly debated—the fallout from the design of trial reverberated long after the results were presented at the American College of Cardiology (ACC) 2014 Scientific Sessions. HEAT-PPCI utilized "delayed consent," wherein all patients were randomized and treated with either therapy without first consenting to be in the study. Consent was obtained during the patient's recovery period and reconfirmed at 28 days. The HEAT-PPCI trial, as reported by heartwire , received full ethics approval by three separate national bodies, given that both treatments—bivalirudin and unfractionated heparin—are used routinely in STEMI patients undergoing PCI.

The lack of informed consent made sense, "given that the two treatment arms in this particular trial were ones that were well established with respect to their safety and their efficacy for ST-segment elevation myocardial infarction," said Lim. "We're not bringing forward a new, untested, untried, or potentially unsafe treatment for these patients, which I think gives an opening for the delayed-consent process."

In rebuttal, Mehran argued that the HEAT-PPCI investigators approached the trial with the hypothesis bivalirudin was inferior to unfractionated heparin. "That to me is an issue, even though both therapies are available," she said. Mehran noted that the catheterization lab where the study was performed used very little bivalirudin, meaning they likely favored one treatment over the other.

"If you really believe in your research premise that one [drug] is less than the other, then the patient needs to be informed of that, even if it's an approved therapy," said Mehran.

The Limitations of Informed Consent

During the SCAI debate, Lim said that a priori informed consent can result in physician and patient selection biases, skewing the data that physicians and clinical-guideline writing committees use to establish treatment protocols. As a result, clinical trials, even large-scale randomized trials, are often not applicable to real-world clinical practice.

Lim said informed consent assumes the patients are competent and informed to make a decision and their consent is freely given. With respect to the standard of competence, patients need to understand they have a choice, meaning they can opt out without their decision affecting their clinical care. They should also have an understanding of the treatment offered and be able to "rationally manipulate" the information they are being presented with.

These are easy things to put forward on a slide in talks like this, but when we talk about a patient with [STEMI], they are in discomfort and they might be throwing up.

"These are easy things to put forward on a slide in talks like this, but when we talk about a patient with ST-segment elevation MI, they are in discomfort and they might be throwing up," said Lim. "And I've never seen an ST-segment-elevation-MI patient without at least six people hovering over them. When you start interpreting these simple statements [in terms of what is required of the patient in informed consent], it becomes very difficult."

Lim said there have been at least seven studies that have addressed the issue of informed consent in STEMI patients, all with different results. In a 2004 Swedish study, for example, 86% of physicians felt that patients were unable to understand the information presented to them and 25% of them felt the patients would not understand the information at any time[2]. Other studies have shown different levels of understanding among patients during the initial examination period and an assessment 24 hours later.

Mehran conceded that STEMI patients are vulnerable and not always capable of giving informed consent. In the STEMI setting, "the clock is ticking," she said, questioning whether it was truly possible to obtain informed consent from a patient entrusting his/her life to the physician and team asking for his or her signature. Moreover, the "delayed-consent" process used in HEAT-PPCI allowed investigators to include nearly 2000 "real-world" STEMI patients.

"But you know what, there is no question these patients are in a vulnerable psychological state and physicians are in charge, but the rights of a human being to refuse to participate in an experiment must be preserved," said Mehran. "I stand by that. If we start doing this, we can expand this to all PCI patients. If you bring PCI patients back and tell them, 'By the way, we put you in the ISCHEMIA trial, do you understand the risks and benefits?' most of them would not."

For Mehran, eliminating informed consent in STEMI, while it might lead to studying populations more like a general, real-world STEMI population and lead to larger clinical trials, does not trump the "ethical concerns."

For instances where the patient is sedated or with impaired consciousness, informed consent can be obtained by a legal representative, such as a family member. The Declaration of Helsinki, in fact, has even been updated to allow for delayed consent if specific conditions are met, such as the patient being unable to provide consent, no family member is available to sign, and the research can't be delayed.

Mehran noted that other trials in STEMI patients, including HORIZONS-AMI, EUROMAX, TAPAS, TASTE, and EXAMINATION, were all able to effectively randomize patients with informed consent (or informed consent from a family member/next of kin).

During the debate, Lim agreed with many of these arguments but pointed out physicians and researchers also have an obligation to further their knowledge. In the STEMI guidelines, for example, there are few clinical recommendations supported by the strongest evidence (level of evidence A). If physicians want to advance care, "we have to not only look out for the patients to make sure they're treated and taken care of openly in an ethical and correct manner, we do have an obligation to try to push the envelope further and advance our knowledge," said Lim.

Lim has reported he has no relevant financial relationships. Mehran reports consulting for Abbott Vascular, AstraZeneca, Boston Scientific, Bristol-Myers Squibb, Covidien, Janssen, Maya Medical, Merck, Regado Biosciences; grant/research support from Bristol Myers-Squibb/Sanofi, CardioKinetix, Lilly/Daiichi Sankyo, and the Medicines Company; and serving on the advisory board of CSL Behring and Sanofi.


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