For the past several years I have been following the ezetimibe controversy (see these posts on Gooznews and this blog here, here, here, here, here, here, here, here, here, here, here, here, here, here, and here). In my view, we continue to lack evidence of ezetimibe’s clinical benefit, or even safety, 10 years after FDA approval.
I have a Google Scholar Alert for ezetimibe, so often links to articles on ezetimibe arrive in my email inbox. Recently, two review articles on ezetimibe were published that were a study in contrasts. The first, by Sheila Doggrell, takes a skeptical view toward ezetimibe and reaches the following conclusion:
The comparison of clinical trials with simvastatin and ezetimibe alone and together has clearly shown that simvastatin decreases LDL-cholesterol and this is associated with improved clinical outcomes. Also, ezetimibe alone or in the presence of simvastatin lowers LDL-cholesterol. However, ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on clinical outcomes. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes, and ezetimibe should not be used routinely in everyday practice.
The second, by Binh An Phan, Thomas Dayspring and Peter Toth, takes a much more optimistic view:
In the current treatment of cardiovascular disease, many subjects fail to reach LDL-C targets or remain at high risk for CHD events despite optimal statin and medical therapy. Ezetimibe inhibits intestinal cholesterol absorption and is effective in lowering cholesterol as monotherapy or in combination with statins in several populations, including those with FH, sitosterolemia, and insulin resistance. Significant controversy has been generated regarding the clinical effectiveness of ezetimibe, particularly after the publication of ENHANCE and ARBITER-6 despite both trials having significant methodological flaws that limited their ability to evaluate the benefit of ezetimibe. Growing data suggest that ezetimibe in combination with statin has a positive effect on the progression of atherosclerosis and reduces cardiovascular events in subjects at risk for CHD, including those with chronic kidney disease. Results from IMPROVE-IT are forthcoming and may help to guide better the use of ezetimibe in very high-risk CHD populations. Until that time and based upon the current available data, ezetimibe should remain a viable adjunct to statin therapy in the treatment of hypercholesterolemia.
Dr. Phan and colleagues find reasons to dismiss the negative results of ENHANCE and ARBITER 6-HALTS as due to “methodological flaws” and use copious amounts of hand-waving to find support for ezetimibe in the SEAS and SHARP trials, even though those trials compared the combination of simvastatin and ezetimibe with placebo and thus can tell us nothing about what, if anything, ezetimibe added to those results. Could the differing views of Doggrell and Phan et al. have anything to do with the fact that Dr. Doggrell declares no conflicts of interest relating to ezetimibe, while Phan, Dayspring and Toth declare the following conflicts:
Binh An Phan is a speaker for Abbott. Thomas Dayspring consults for Abbott, GSK, Health Diagnostic Labs, Kowa Company, Eli Lilly, Merck, Genentech, The Roche Group, Genzyme, and Omthera. He is on the Lecture Bureau for Abbott, GSK, Health Diagnostic Labs, Kowa, Eli Lilly, LipoScience, Merck. Peter P Toth is a speaker for Abbott, AstraZeneca, Amylin, Boehringer-Ingelheim, GSK, Kowa, Merck and consults for Abbott, Aegerion, AstraZeneca, Atherotech, Genzyme, Genentech, Kowa, and Merck.
It is not too surprising that authors who are consultants and on the speaker’s bureau for Merck would take a favorable view of ezetimibe. What is surprising is that anyone would take their word for it.
Doggrell SA. The ezetimibe controversy — can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together? Expert Opin. Pharmacother. (2012) 13(10):1469-1480.
Phan BAP, et al. Ezetimibe therapy: mechanism of action and clinical update. Vascular Health and Risk Management 2012:8:415-427.
Section 6002 of the Patient Protection and Affordable Care Act requires disclosure of payments by the drug and device industry to physicians and teaching hospitals. On December 14, 2011, the Centers for Medicare and Medicaid Services proposed regulations that would implement these “sunshine” provisions. See this Pharmalot post for background. I also recommend this commentary by Robert Steinbrook and Joseph Ross. The comment period closed on February 17, and I submitted a comment, excerpted below. You can access the proposed regulations and comments by going to www.regulations.gov and searching on “CMS-5060-P.”
Re: Transparency Reports and Reporting of Physician Ownership or Investment Interests; CMS-5060-P
Dear Ms. Tavenner:
I am writing to support the adoption of the above-referenced proposed rules implementing section 6002 of the Patient Protection and Affordable Care Act of 2010 (PPACA). As you know, this section of the PPACA requires drug, device, biological, or medical supply manufacturers to report certain payments and transfers of value to covered recipients, entities, individuals and teaching hospitals. The reported information would be available on a public website.
I believe the rules should be adopted substantially as proposed. In particular, I believe it is essential for the rules to require disclosure of both direct and indirect payments. Indirect payments include those a company makes to a third party, such as a medical society, contract research organization, or medical education and communication company, but that are ultimately intended for a physician or other covered recipient. The reporting of indirect payments is essential to meet the goals of transparency and completeness and to prevent the institution or continuation of arrangements that impede full disclosure of the financial relationships between industry and the medical profession.
In addition, I urge you to give careful consideration to the design of the proposed website. It should be designed to make possible it easy for members of the general public to find all payments to a particular provider or entity in one search regardless multiple addresses or variations in names (e.g., with or without a middle initial). I urge CMS to provide an opportunity for public discussion and comment on the proposed website design, such as through a public forum and/or focus groups.
Finally, I urge CMS to provide greater detail on specific enforcement mechanisms to ensure that manufacturers comply promptly and completely with the reporting requirements.
Thank you for the opportunity to comment on this important proposed regulation.
A review article in a medical journal is an attempt to summarize the current state of research on a particular topic. A review article does not present original research but rather collects and interprets the research that has been done, describes gaps in the research and controversies that exist, and how to apply the research in clinical practice. A review article can be a good starting point to get a grasp of a topic. However, because the authors are generally experts on the topic they are discussing, they often have a point of view that may not be obvious to someone not expert in the field.
But what if the agenda for the article were out in the open? What if, say, a drug company sponsored a review article on its own drug and paid a medical journal to publish it? That appears to have happened with this review article on fibrates in a journal called Reviews in Cardiovascular Medicine, published by MedReviews, LLC. The acknowledgment discloses the following:
Abbott Laboratories, Inc., provided funding to MedReviews, LLC. No funding was provided to authors. Abbott Laboratories, Inc. had the opportunity to review and comment on the publication content; however, all decisions regarding content were made by the authors.
So, while it is unclear who produced the initial draft of the article, Abbott Laboratories reviewed and commented on the article before publication and paid the publisher for publishing the article. Abbott just happens to sell two fibrates, TriCor and Trilipix.
Never having heard of this journal, I looked at the journal’s website and confirmed that it is a peer-reviewed journal and is indexed in PubMed and Medline. It’s editorial board includes some well-known academic physicians. The website also discloses that MedReviews has formed a partnership with the California Chapter of the American College of Cardiology.
I’m having a hard time understanding why anyone would want to spend their time reading a medical journal that publishes review articles that have such a high level of involvement from a commercial enterprise with a vested interest in the topic. I’m also having a hard time understanding why the California Chapter of the ACC and the members of the editorial board would want to be associated with this journal.
H/T Harlan Krumholz.
Addendum January 7, 2012: Howard Brody has weighed in on the Hooked: Ethics, Medicine, and Pharma blog.
Addendum January 10, 2012: Also see this post on Pharmalot blog.
Addendum August 16, 2012: See this followup post by Kevin Lomangino on the Health News Watchdog blog.