A recent spate of observational or registry analyses have challenged conventional wisdom derived from randomized clinical trials (RCTs). Both RCTs and registries have inherent flaws, but both provide important information in regard to drug efficacy in the search for "truth."
RCTs examine therapeutic effects in highly selected patient populations by focusing on one clinical entity, thereby excluding many patients with comorbidities that could influence or blunt the effect of the intervention. In a sense, RCTs do not represent the real-world expression of disease, since diseases rarely exists in isolation.
Registry trials collect large numbers of patients with a particular diagnosis within a large database. They include unselected patients and examine the effect of therapy in one disease regardless of comorbidities and are subject to both doctor and patient bias and confounding by comorbidities like chronic renal and pulmonary disease and, above all, are not randomized. Using a contemporary analogy, RCTs are a rifle shot whereas registries are more of a shotgun blast.
There have been two recent important targets for clinical research in heart failure. One is the search for better therapy for heart failure patients with preserved ejection fraction (HFPEF). The other is a search for drugs or devices that can provide added benefit to contemporary therapy for heart failure with reduced ejection fraction (HFREF)
The observation that many HFPEF patients develop heart failure despite current therapy with renin angiotensin aldosterone system (RAAS) antagonists and beta-blockers has led to a search for better therapy. RCTs with newer agents. including focused therapy with new RAAS antagonists, have failed to affect mortality in HFPEF (Lancet 2003;362:759-66). In contrast, a recent publication using the Swedish Heart Failure Registry (JAMA 2012;308:2108-17) found that patients treated with RAAS antagonists benefited compared with patients not taking them. The failure of the newer drugs to reach significance was attributed to flawed patient selection in RCTs that led to lower mortality rates and rendered the trials underpowered.
Similar discordance was observed between RCT and registry data in patients with HFREF who were treated with aldosterone antagonist (AA) in addition to contemporary RAAS antagonists and beta-blocker therapy. Using the Medicare database (JAMA 2012;308:2097-107), the investigators failed to observe any treatment benefit of AA on mortality that had previously been reported (N. Engl. J. Med. 1999;341:709-17). They did observe a decrease in rehospitalization for heart failure associated with an increase in rehospitalization for hyperkalemia. The authors attributed the reported benefit in the RCT to the exclusion of older and diabetic patients in addition to those with renal impairment, who were included in the registry analysis and reflected the real world of HFREF.
One registry study examining the benefit of ICDs in heart failure patients (JAMA 2013;309:55-62) from the analysis by the National Cardiovascular Registry did support the mortality benefit observed in the RCT (N. Engl. J. Med. 2002; 346:877-83).
As RCTs have developed over the last half-century, they have changed from investigations of therapeutic concepts to assessments of the efficacy of new and, often, expensive drugs. Much of this search has been supported by the pharmaceutical and device industries, which are intent on more focused research because of their concern about the "noise" generated by comorbidities that could obscure the benefit of their product. As a result, RCTs have identified lower-risk, homogeneous patient populations that may not reflect the real-world experience. Nevertheless, registry studies suffer from the major effect of bias, which is influenced by the physicians’ therapeutic choices and can distort the observed outcome. Unfortunately, the search for "truth" in clinical research remains often out of our reach.
Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.