Statins evidence: when answers also raise questionsBMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i4963 (Published 14 September 2016) Cite this as: BMJ 2016;354:i4963
- Harlan M Krumholz, professor
- Section of Cardiovascular Medicine and the Robert Wood Johnson Foundation Clinical Scholars Program, Department of Internal Medicine, Yale School of Medicine, 1 Church Street, Suite 200, New Haven, CT 06510, USA
Statins are likely to have contributed to the large reductions in cardiovascular disease that have occurred in North America and Europe. Clinical trials of these affordable drugs have a remarkable record of showing benefit, with side effects mostly uncommon and minor and resolving after discontinuation of the drug.1 Moreover, many complaints among statin users are misattributed to the drug.
Nevertheless, some scientists have raised persistent concerns.2 They have asked questions about the effectiveness and adverse effects of statins, particularly in low risk populations and those not well represented in the trials. Advocates for statins equate the dissent to yelling “Fire” in a crowded theatre when no fire exists, and causing harm with words.3 Others defend the rights of well intentioned scientists and clinicians to question evidence.4
Into this fray comes a publication from some prominent clinical scientists—a review article with an attitude. The authors’ intent is to provide “the appropriate interpretation of evidence.”5 The review, which consolidates previously published information, aims to explain “how evidence from randomized trials yields reliable information about both the efficacy and safety of statin therapy.” Moreover, “it discusses how claims that statins commonly cause adverse effects reflect a failure to recognize the limitations of other sources of evidence about the effects of treatment.” Their findings strongly support the benefits of statins in comparison to very modest risks. The article concludes that, “It is, therefore, of concern that exaggerated claims about side effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events.”
The review raises an important question about the value of observational data. It provides a useful perspective and argues persuasively for the use of statins based on the trial evidence. However, there is little consideration of the limitations of the trial evidence, which also deserve attention. The trial populations do not fully reflect the diversity of patients seen in contemporary practice across the world. For example, few trials have included people over 80 years old, a growing population that has an increased susceptibility to adverse drug effects. And few people from China were enrolled, even though there is evidence that risks of adverse events may be higher in this population.
The individual trials were also underpowered to detect many relevant harms. Moreover, the comparability of harm data is not clear and may be an impediment to combining data. The timing of the trials is another concern since, even without statins, the experience of patients with cardiovascular disease even a decade ago is much different from that today. Finally, the trials leave other questions unanswered, including the comparative effectiveness and safety of individual statins.6 There are few head-to-head comparisons.
The statin review authors question whether observational data are good enough for inferences about benefit and harm. The predicament is that the only readily available contemporary evidence is observational and these remaining questions about statins are unlikely to be addressed soon by future trials. Their review comes at a time of increasing emphasis on real world evidence by regulatory bodies—and there are challenges to reconcile these two views and the path forward.
This fray raises another uncomfortable question about scientific debate. When should we shut down debate on a topic in the interest of the public’s health. The review was prompted by concerns that press reports of scientific articles questioning the safety of statins led some patients to abandon the drugs and resulted in avoidable cardiovascular events. The instinct to correct misinformation should be encouraged, but the adverse effects of quieting dissent can also be consequential. The question in the end is whether we are debating indisputable facts or disputable interpretations of the evidence. In many cases, a person’s perspective may depend on where he or she stands on the issue.
The new review is powerful, and it is useful that these experts have made their case and used evidence to advocate for a verdict. For consensus to emerge it may have been even more useful if the publication were accompanied by an announcement that the data from the statin trials were being made publicly available for others to analyse.
We are rapidly entering an era where sharing will become the norm. Many international organisations have already endorsed it, and the International Committee of Medical Journal Editors “believes that there is an ethical obligation to responsibly share data generated by interventional clinical trials because participants have put themselves at risk.”7 Some people fear that data sharing could produce poor science that spreads misinformation. But science should be self correcting when there are no limitations on access to data.
Sharing the individual patient level data from the statin trials would be another fine contribution by this highly respected group of research leaders and a strong message that no single person or group should have exclusive access to trial data. In the end, the sharing of these data by the trialists may do more to advance their interpretation of the data and promote consensus than anything else they could do.
Competing interests: I have read and understood BMJ policy on declaration of interests and declare that I am a recipient of research agreements from Medtronic and Johnson & Johnson (Janssen), through Yale University, to develop methods of clinical trial data sharing; I am the recipient of a grant from the Food and Drug Administration and Medtronic to develop methods for post-market surveillance of medical devices; work under contract with the Centers for Medicare & Medicaid Services to develop and maintain performance measures; chair a cardiac scientific advisory board for UnitedHealth; and am the founder of Hugo, a personal health information platform.
Provenance and peer review: Commissioned; not externally peer reviewed.