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EDITORIAL |
Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610, Email: shepsds@medicine.ufl.edu, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, Department of Psychiatry, University of North Carolina, Chapel Hill, NC, Maryland Psychiatric Research Center, Baltimore, MD
Ever since the negative results of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial were presented at the American Heart Association meeting over a year ago, there has been widespread concern in the behavioral medicine community about the impact that this disappointing outcome might have on future clinical trials. As of this writing, the primary results have still not been published, and this has heightened these concerns.
Unlike ENRICHD, the results of the Sertraline Antidepressant Heart Attack Trial (SADHART) have been published (1), but like ENRICHD, some of the SADHART findings have produced disappointment and concern. The results suggest that sertraline is a safe treatment for major depression in patients with a recent myocardial infarction or unstable angina, and they even raise the possibility that sertraline might help to prevent recurrent cardiac events. Unfortunately, the SADHART findings also show that sertraline is not a highly efficacious treatment for depression in these patients. In the overall sample, there was virtually no difference in Hamilton depression change scores between the sertraline and placebo groups. Sertraline did have a statistically significant effect in the subgroup of patients with severe, recurrent depression, but the difference was only about three points on the Hamilton scale.
ENRICHD was one of the first multicenter clinical trials in behavioral medicine and the first that was sponsored by the National Heart, Lung, and Blood Institute (NHLBI). Many investigators were concerned from the beginning of this trial that negative findings would doom NIH sponsorship of any further major research efforts in our field. We do not believe that these fears will be realized. Indeed, there is good reason for optimism.
The primary aim of ENRICHD was to determine whether treatment of depression and low perceived social support increases reinfarction-free survival after acute myocardial infarction. Although the intervention had no effect on this endpoint and modest effects on depression and social support, a variety of secondary analyses are in progress and are yielding many important findings. Furthermore, ENRICHD demonstrated that a cognitive-behavioral intervention can be implemented in collaboration with cardiologists and can be done effectively in a multicenter trial despite the inherent challenges in ensuring uniform adherence to a common protocol, recruiting a large sample of depressed and socially isolated patients, and retaining them for the study’s duration. ENRICHD tested an important hypothesis and was carefully designed and implemented. The investigators are to be complimented on their successful completion of the protocol.
Still, it should be acknowledged that few of the ENRICHD investigators, indeed few researchers in the entire field of behavioral medicine, have extensive experience in clinical trials. As a research and clinical community, we need to educate ourselves in this important research arena. Circulation recently published two valuable series of articles entitled "Lessons Learned From Recent Cardiovascular Clinical Trials," Parts I and II, and "Principles from Clinical Trials Relevant to Clinical Practice," Parts I and II (2–5). We encourage all behavioral researchers to read these richly informative papers. They point out that negative trials are common in cardiology and that a single negative trial cannot definitively answer any important question. A number of cardiology trials that were much larger than ENRICHD and SADHART combined had negative findings. In addition, a large scale, multicenter, NIH-sponsored study of St. John’s wort for depression also failed to show a significant difference on the primary outcome measure between a placebo and the selective serotonin reuptake inhibitor (SSRI) sertraline (6). These experiences tell us that ENRICHD and SADHART enjoy a lot of company as well-designed, large-scale trials that yielded results less favorable than investigators had anticipated. They also tell us that these trials should be recognized as landmark beginnings of a line of research, not as the end.
We should not abandon this form of investigation, but instead set our sights on the appropriate design of future studies that will add to our research database. There are many possible reasons why the ENRICHD and SADHART depression outcomes fell short of expectation, and why the ENRICHD intervention failed to prolong reinfarction-free survival. We believe the best approach is to learn as much as possible from these experiences and to move forward with further research.
How shall the field progress? It is likely that at some point, NIH will issue another request for proposals (RFP) for a behavioral clinical trial in heart disease. Perhaps this will occur in cooperation and collaboration with the pharmaceutical industry. However, the form that it will take remains to be determined, and because of the inherent lag time in the NIH system, such an RFP may not be issued for several years. We believe that researchers interested in moving the field forward should not wait. Instead, they should propose investigator-initiated research to answer timely and important clinical questions. In particular, they should consider proposing small clinical trials that could build the foundation for the next large, multicenter trial.
Although we have much to learn from clinical trials in "mainstream" medicine, clinical trials in behavioral medicine can pose some unique methodologic challenges. In studies such as ENRICHD, the aim is to affect a medical endpoint by manipulating an intermediary psychosocial endpoint (eg, depression). We have to be aware in designing these trials of the potential confound between an intervention’s direct physiologic effects and its indirect effects on the medical endpoint (via changing the intermediate psychosocial endpoint). For instance, if we design a trial employing sertraline or another SSRI, the drug, if effective, will reduce depression, but independent of its effects on the mood disorder also block platelet serotonin receptors. If we see a reduction in cardiac events, is it because of the antiplatelet effects of sertraline or because sertraline reduced depression? Similarly, exercise can reduce depression, but it also has direct, beneficial effects on the lipoprotein profile (7). This is one of the reasons why interventions such as cognitive behavior therapy will continue to have an important place in this kind of research. They can change psychosocial risk factors without having any known direct physiological effects on the cardiovascular system or on other organ systems.
We have much to learn about the treatment of psychiatric disorders and other psychosocial problems in medically ill patients. Many important research questions, with clear clinical relevance, remain unanswered. We strongly believe that it is imperative to build on our experiences with ENRICHD and SADHART, rather than to become discouraged by them.
NOTES
Drs. Sheps and Freedland were involved with the ENRICHD study, Dr. Freedland as an investigator and Dr. Sheps as a consultant to the coordinating center.
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