Informed consent and STEMI research participants controversy
Expectations "likely do not match clinical realities"
An ethical controversy erupted regarding a "delayed-consent" approach used in the recent how effective are antithrombotic therapies in primary PCI (HEAT/PPCI) trial. In the study, researchers compared outcomes in ST-elevation myocardial infarction (STEMI) patients treated with bivalirudin versus heparin.1
"The HEAT trial is a really important case for several reasons," says Neal Dickert Jr., MD, PhD, assistant professor of medicine in the Division of Cardiology at Emory University School of Medicine in Atlanta.
Dickert commends the investigators for "addressing head-on" the issue of consent in acute MI trials, and acknowledging that full informed consent is likely not possible in the context of this situation.
"In the modern era, this is the first time that delayed consent has been used in the setting of STEMI," says R.H. Stables, MA, DM, BMBCH, the study’s lead investigator. Stables is research lead for Interventional Cardiology at Liverpool Heart and Chest Hospital’s Institute of Cardiovascular Medicine and Science.
Ideal approach isn’t established
The management of STEMI with primary percutaneous coronary intervention (PCI) demands a fast response, Stables notes, as each additional minute of delay before reperfusion is associated with less favorable outcomes.
In the HEAT trial, 50% of patients were randomized within five minutes of hospital arrival. The median time from hospital arrival to the first use of a device in the coronary artery to restore blood flow was just 29 minutes.
During that time period, the diagnosis was made and patients were informed about the diagnosis and the need for emergent catheterization. "Most patients were likely significantly symptomatic, scared, and anxious," says Dickert.
When true informed consent cannot be obtained, available therapies have been approved and proper oversight has been obtained, some trials should be possible without informed consent, argues Spencer B. King, MD, a cardiologist at Emory St. Joseph’s Hospital in Atlanta and Professor of Medicine Emeritus at Emory University School of Medicine. "I am not sure that delayed consent’ is a logical concept. But a consent to remain in a trial that the patient has been enrolled in does makes sense," he says
Expectations for full, valid informed consent "likely do not match the clinical reality" of these situations, says Dickert.
Because the risks were low, and because the expectation of full informed consent of a surrogate or patient in this context for a randomized clinical trial is unreasonable, Dickert says the investigators properly pursued alternative strategies.
"The issue of what the best approach is for trials like this — when patients are conscious and not obviously incapacitated, but where barriers to consent like time constraints, stress, and physical symptoms likely limit potential involvement of patients in decisions — has not been worked out," says Dickert.
Right to refuse participation
In almost all prior studies of STEMI, patients have been consented prior to randomization, so they have the chance not to participate, says Gregg W. Stone, MD, co-director of The Cardiovascular Research Foundation’s Medical Research and Education Division in New York, NY.
"To me, the overriding principle is that the rights of human beings to refuse to participate in an experiment must be preserved," argues Stone.
In the HEAT trial, patients were randomly assigned and treated in the acute phase, with no mention of the trial upfront. They were approached for full informed consent once the acute phase was over.
"Some say that the occasional patient doesn’t remember entering into the study," says Stone. "In my experience of running numerous STEMI trials for more than two decades, almost all patients do recall agreeing to participate in the study, and do not feel they were pressured."
Using these processes, when consent in the emergency department is obtained prior to sedation, Stone usually finds that about 60% of STEMI patients decline participation; about 40% join the study.
"Consenting the patient after randomization takes away the patient’s right to not participate in an experiment, compromising the rights of the 60%," argues Stone. This is most concerning if the patient dies in the cardiac catheterization lab, he says — after randomization, but before even having the chance to hear about the study.
Stone says that the fact that 99% of patients in the study accepted the randomization after being told about it the day afterward, is in itself proof this type of process doesn’t work. "It means that the patients feel helpless, having already been exposed to the experiment," he explains.
Stone acknowledges that this type of trial design results in much faster enrollment a more generalizable study cohort. "To me, these advantages don’t nearly make up for the ethical concerns of experimenting on human beings without their knowledge and consent," he says.
Some form of consent might be feasible
There is essentially a universal agreement that one cannot obtain full, informed consent before emergency PCI, according to Stables. The special circumstances of the HEAT trial were also critical, he adds, as the study involved a comparison of two established medications.
Alternative approaches have included the use of an "abbreviated consent" process, usually involving the reading out of some basic information about the study and often verbal assent by the patient.
"We reasoned that it may be unethical to burden a patient with a question of this nature, in this setting, when they have no prospect of reaching an informed and mature conclusion in the time available," says Stables.
Franklin G. Miller, PhD, senior faculty in the Department of Bioethics at National Institutes of Health in Bethesda, MD, acknowledges that standard methods of obtaining informed consent would not have been feasible for patients in the HEAT trial.
"However, it does not follow that no form of advance consent would be feasible," he says.
Patients might have been offered a very simple explanation of the study and asked to agree or refuse participation. "When a simple, informal consent process is used for initial enrollment, patients could be subsequently given a more detailed account of the research, including a written consent document, and asked whether they are willing to provide consent for continuing in the study," Miller suggests.
Conducting the study without prospective consent has the scientific merit of facilitating a representative sample of eligible patients, which is not modified by any selection bias that can come from a proportion of eligible patients refusing to participate, acknowledges Miller.
"However, it is doubtful that overriding the principle of respect for persons justifies waiving advance consent entirely, when prospective subjects are capable of giving some form of meaningful consent," he says.
- Stables R, Shahzad A. HEAT PPCI: How effective are antithrombotic therapies in PPCI? Program and abstracts of the American College of Cardiology Scientific Session; Washington, DC; March 29-31, 2014.
- Neal Dickert Jr., MD, PhD, Assistant Professor of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta. E-mail: firstname.lastname@example.org.
- Spencer B. King, MD, Emory St. Joseph’s Hospital, Atlanta. E-mail: Spencer.King@emoryhealthcare.org.
- Franklin G. Miller, PhD, Department of Bioethics, National Institutes of Health, Bethesda. Phone: (301) 435-8719. E-mail: FMiller@cc.nih.
- R.H. Stables, MA, DM, BMBCH, Research Lead, Interventional Cardiology at Liverpool Heart and Chest Hospital’s Institute of Cardiovascular Medicine and Science. E-mail: email@example.com.
- Gregg W. Stone, MD, Co-Director, Medical Research and Education Division, The Cardiovascular Research Foundation, New York, NY. Phone: (646) 434-4134. E-mail: firstname.lastname@example.org.