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The authors are with the Duke Clinical Research Institute and the Division of Cardiovascular Medicine, Department of Medicine, Duke University School of Medicine, Durham, NC
Correspondence to: Dr. Adrian F. Hernandez, Duke Clinical Research Institute, PO Box 17969, Durham NC 27715, USA; fax 919 668-7063; adrian.hernandez{at}duke.edu
Although large randomized clinical trials remain the foundation for informing evidence-based prescribing, vast data sources can provide insight into complex questions that arise in clinical decision-making. Using tens of thousands to millions of patients, registries and administrative databases now serve as the "living textbooks" envisioned more than 40 years ago.1 Common clinical questions can now be readily addressed because of the marked advances in clinical data informatics and the application of information technology to clinical care. As an example of this wealth of data, in this issue of CMAJ, Pilote and colleagues2 use administrative databases of hospital discharges and prescription claims to study the comparative effectiveness of angiotensin-converting-enzyme (ACE) inhibitors in the treatment of congestive heart failure.
The value of renin–angiotensin–aldosterone inhibition in reducing mortality and morbidity among patients with heart failure and left ventricular systolic dysfunction has been well established in multiple large randomized clinical trials.3,4 With evidence indicating about a 25% decrease in mortality and a 35% decrease in mortality or admission to hospital, ACE inhibitors are used universally in the treatment of heart failure in a broad range of patients.4 Over the last several decades, our understanding of ACE inhibition has evolved from a theory based on simple hemodynamic effects of vasodilatation to beneficial effects on mechanisms throughout the cardiorenal and cardiovascular systems.5
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Are all ACE inhibitors the same? |
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ACE inhibitors have not been studied uniformly in patients with heart failure and left ventricular dysfunction. Indeed there are no large clinical trials comparing the efficacy of one ACE inhibitor with another to determine which one best improves survival. Once the early ACE inhibitors were shown to be beneficial, the later studies compared them mainly with other vasodilators; comparisons with more specific angiotensin-receptor blockers occurred later. Unfortunately, because patents on ACE inhibitors ended, the incentives for funding head-to-head trials of ACE inhibitors never materialized. Instead, manufacturers chose to gain market share by looking for previously unstudied indications or by focusing on advertising rather than on comparative studies. In addition, initial regulatory approval of a new ACE inhibitor required only that the new agent be shown to be "safe and effective."
However, there are some lessons to be learned from ACE inhibitor studies. The results of successful trials, particularly the Heart Outcomes Prevention Evaluation (HOPE) trial,13 led many physicians to believe that class effect was so powerful that any ACE inhibitor would be beneficial in any of the indications that had been studied with specific individual agents. The failure of the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial16 challenged this concept of class effect; however, some argued that differences in the patient population or other treatments could explain the lack of benefit.
Earlier work from Pilote and colleagues also suggests that ACE inhibitors may not have a class effect.18 Similar to the current analysis, the previous study analyzed data from an administrative database, and the results suggested that ramipril was associated with lower mortality compared with most other ACE inhibitors. At the time, both the study and the accompanying commentary19 noted the limitations of administrative databases and the potential for unknown confounding. Simply stated, were the observed benefits attributable to the drug or to some other aspect of care or characteristic that occurred more often when prescribing ramipril? In follow-up, Hansen and colleagues20 published an observational analysis of ACE inhibitors involving more than 16 000 patients who had myocardial infarction. They found no differences in mortality between ramipril and other ACE inhibitors, including captopril and enalapril.
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What does the new evidence show us? |
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As with any observational study that predominantly uses administrative data, there are 2 potential interpretations. First, the results are valid because confounding and bias have been limited and, based on known data, the hypothesis is biologically and clinically plausible. The alternative explanation is that residual confounding and bias remain and can never be adequately adjusted, despite careful analytical technique, because of limitations inherent to the administrative databases.
Unlike large clinical trials in which randomization balances both the known (measured) and unknown (unmeasured) differences among groups, in the analysis of treatment comparisons using nonrandomized data we must rely on appropriate adjustment for known confounders and restriction of population cohorts to limit bias. Although it is certainly conceivable that ramipril may be superior to other ACE inhibitors based on characteristics of the drug and on prior analyses, there are some important potential sources of error that cannot be fully addressed by the methods used by Pilote and colleagues.
First, prescription patterns may vary significantly between an ACE inhibitor popularized by the HOPE trial and ACE inhibitors traditionally used to treat heart failure. That is, ramipril may be prescribed more readily to lower-risk patients who fit HOPE-like criteria, whereas other ACE inhibitors may be prescribed more readily to higher-risk patients similar to those enrolled in the trials that originally assessed the efficacy of those drugs. Second, physicians' prescribing habits of ramipril may be related to other care activities (e.g., cardiovascular procedures, other medications) that influence beneficial outcomes, not necessarily to the effects of ramipril.21 Third, additional patient characteristics may differ among various study populations; however, because data were unavailable (i.e., not collected) they could not be used in the adjustment models.
In the study by Pilote and colleagues, ejection fraction appears to be the most prominent missing characteristic. Beyond being one of the most important risk factors in establishing prognosis among patients with heart failure, left ventricular dysfunction also establishes true eligibility for an ACE inhibitor based on professional guidelines and measures of quality-of-care performance. Furthermore, ejection fraction would help further limit bias by restricting the population to patients with left ventricular dysfunction, among whom the benefit of ACE inhibition is already known. Thus, these limitations, especially the potential differential use of ACE inhibitors based on knowledge of the ejection fraction, could be the fatal flaw of their analysis.
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The way forward |
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Although the number of comparative effectiveness studies will likely continue to grow — especially when payers make choices about whether to list therapies on formularies based on their cost-effectiveness — we hope much more can be done. At the very least, professional societies and government agencies should continue to guide improvement in methodologies and standards for reporting results in comparative effectiveness studies. However, the stakes are too large to risk so many lives without conducting the large, practical clinical trials that can establish more definitive evidence in support of the best therapy. All stakeholders, including clinicians, should demand reinvention of the clinical research enterprise to fund and conduct large, practical clinical trials. Moving forward, practical clinical trials will be the best way to know which agent is the true "ace" and to deliver the best care possible.
@ See related article page 1303
Key points
• Every day, clinicians choose drugs from classes of therapy to treat many conditions. To determine which drug is best, researchers often perform observational studies comparing the efficacy of drugs.
• There may be critical differences in outcomes among groups of ACE inhibitors commonly used to manage heart failure, but further studies comparing their efficacy are needed to validate this finding.
• Moving forward, physicians, payers, professional societies and government agencies should invest in large, practical trials to answer these important questions.
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Footnotes |
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Contributors: Both of the authors contributed to the conception and design of the manuscript, drafted and revised the article and approved the final version for publication.
Competing interests: Adrian Hernandez has received speaker fees from Novartis. Robert Harrington has received consulting fees from the Annenberg Center for Health Sciences, AstraZeneca, Baxter, Bayer AG, Bristol Myers Squibb, Indigo Pharmaceuticals, NicOx, OLG Research, Sanofi-Aventis, Schering-Plough Corporation, Seredigm and WebMD/theheart.org; received speaker fees from the Schering-Plough Corporation; and received honoraria or other compensation for research related to the article from AstraZeneca, Bristol Myers Squibb, CanAm Bioresearch, Johnson & Johnson, KAI Pharmaceuticals, Medicure, Merk Group, Millennium Pharmaceuticals, Novartis AG Group, Pfizer, Schering-Plough Corporation and The Medicines Company.
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