Ethical issues in cardiovascular research involving humans.

This component of the series “Careers in Cardiovascular Research: A Primer for New Investigators” will address ethical conduct of research involving humans. The dramatic decline in cardiovascular mortality (Figure) provides testimony to the societal benefits of research leading to new therapies and systems of care.1 In concert with these rapid developments, changing expectations have resulted in the emergence of ethical issues with highly publicized examples of concern over conduct of research in humans.2–5 Whereas professional ethics should, and for most physicians do, “regulate” conduct of biomedical research, “self-regulation” does not always meet societal expectations. Dr Barry Coller6 has pointed out that science lacks intrinsic morality. Thus, the laudable goals of improving patient care, understanding mechanisms of disease, or protecting society from perceived external threats do not justify ignoring fundamental human rights that guide (and regulate) the conduct of research. At the same time it is important to reflect on the importance of physicians participating in research and providing the opportunity for their patients to do so. Although some have argued this compromises the basic physician responsibility to a patient,7 we believe the best interest of the patient can and must be protected in the research setting. Two brief examples demonstrate the fundamental changes in understanding that may arise from direct involvement of physicians in research. As late as the 1970s, the prevailing wisdom to explain the presence of intracoronary thrombus on postmortem examination of patients after myocardial infarction was simply wrong; pathologists studying hearts in this setting found evidence to “suggest that coronary thrombi are consequences rather than causes of acute myocardial infarction”8 and “consideration is given to the possibility that some thrombi may follow rather than precede myocardial necrosis.”9 The primary role of thrombus in the genesis of acute myocardial infarction was subsequently established by physicians caring for their patients and by the observations from coronary arteriography and coronary artery bypass surgery during the acute phase of the event.10 The subsequent proof that intervention early in the course of myocardial infarction with thrombolysis or primary angioplasty reduces mortality could not have been accomplished without individual physicians on the front line of practice involving their patients in those investigations. A dramatic reduction in mortality with acute myocardial infarction has been achieved. A more recent example of a clinical trial that had a fundamental impact on practice and that depended on physicians involving their patients as subjects in research is the Cardiac Arrhythmia Suppression Trial (CAST).11 It was known that cardiac death was related to ventricular arrhythmias and that drugs were widely used that reduced ventricular premature contractions. The assumption had been made clinically that treatment of ventricular premature contractions with antiarrhythmic drugs would therefore decrease mortality. Many patients received these drugs in anticipation of benefit. Finally, CAST was performed as a large clinical trial, which documented that the drugs used clinically to prevent cardiac death actually increased mortality. This research has dramatically changed practice and saved lives. We use these examples to emphasize the critical role of physicians caring for their own patients also engaging in the effort to advance knowledge and improve care. In both examples, the established opinion influencing care was proved to be wrong, confirming the need for continued questioning of established dogma. At the same time we believe that rights of patients and subjects must be respected. The National Institutes of Health Roadmap12 recognizes the importance of clinical research and the need to “reengineer” the process with an emphasis on collaboration and translation of new knowledge to the community. An essential element will be specific training of clinicians in research methodology, the ethics of research, and the regulations that govern these activities. New discoveries such as gene and cell repair therapy, the patent process, and physician involvement in the biotechnology industry introduce the potential for a multiplicity of potential conflicts of interest.13 Our goal is to provoke reflection by investigators on the basis for current regulations governing research in humans and to urge careful attention to these regulations in the planning and conduct of their own research.