The long-awaited IMPROVE-IT trial was presented last month at the American Heart Association Scientific Sessions. Here are the presentation slides:
IMPROVE-IT was a trial that tested the ability of ezetimibe (Zetia) to lower the risk of heart attacks and strokes when added to simvastatin. See Larry Husten’s background post here, and if you type “ezetimibe” in the search box on this blog or on the Gooznews blog, you will find some previous posts of mine relating to ezetimibe. I admit I was a bit surprised that the trial was positive. I was expecting it to be negative, based on the negative results of the ENHANCE trial. Still, the benefit was small, a 6.4% reduction in risk of the primary endpoint (composed of cardiovascular death, heart attack, unstable angina requiring hospitalization, coronary revascularization, and stroke). In the high-risk trial participants — all patients who had been hospitalized for acute coronary syndrome within the 10 days before randomization — this translated to a 2% absolute benefit over 7 years. Of note, there was no reduction in all-cause or cardiovascular mortality.
I only want to make a few comments now, but I intend to write more when the trial is published. First, a 6.4% reduction is risk is a very small benefit, and many people would only consider that reduction in risk meaningful in a high risk population. Second, it is regrettable that we had to wait 12 years after the drug’s approval to find out whether it improves outcomes.
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.
David Rind recently revived his blog Evidence in Medicine and has a post up on the SHARP trial. The SHARP trial, which I discussed recently on this blog and on Gooznews, is the basis for Merck’s application for a new indication for its drugs Vytorin (ezetimibe/simvastatin) and Zetia (ezetimibe). David explains why the results in SHARP are consistent with previous evidence on the effect of statins in patients with chronic kidney disease, both pre-dialysis and on dialysis.
Kevin Lomangino has an article up on the “portfolio diet,” which is a diet that emphasizes foods that lower cholesterol. Kevin explains that most of the cholesterol-lowering from this diet comes from the inclusion of foods containing added plant sterols. As I previously discussed on this blog, while plant sterols lower LDL, their effect on cardiovascular events is unknown, making the portfolio diet a bit of a crapshoot healthwise.
I have a guest post up at Merrill Goozner’s blog explaining why Merck’s application for a new indication for its drugs Vytorin (simvastatin/ezetimibe) and Zetia (ezetimibe) should not be approved. The proposed indication is for the reduction of major cardiovascular events in patients with chronic kidney disease and is based on the results of the SHARP trial. However, because SHARP compared the combination of simvastatin and ezetimibe with placebo — there was no simvastatin arm — we have no way of knowing if ezetimibe contributed anything to the result. The FDA requires that combination drugs have additive effects over either drug alone. Merck has not shown that ezetimibe contributed anything to the effect in SHARP, so the new indication should not be approved.
Addendum January 25, 2012: Merck issued a press release today stating that the FDA did not approve the new indication. “Because SHARP studied the combination of simvastatin and ezetimibe compared with placebo, it was not designed to assess the independent contributions of each drug to the observed effect; for this reason, the FDA did not approve a new indication for VYTORIN or for ZETIA® (ezetimibe) and the study’s efficacy results have not been incorporated into the label for ZETIA.” The SHARP results were incorporated into the Vytorin label (see pages 27-28).
I just want to highlight this profile on my friend Harlan Krumholz in Yale Alumni Magazine. Harlan is a Yale cardiologist who is a leader in the field of outcomes research — figuring out what works in the real world and applying those lessons to improve outcomes for patients. In the process, he has not been afraid to take on powerful interests, as he did by testifying in the Vioxx trials (described in Snigdha Prakash’s new book All the Justice Money Can Buy) and publishing articles on how the Vioxx debacle happened and what we can learn from it (see here, here, here and here).
I first contacted Harlan after reading about his presentation on the ENHANCE trial at the March 2008 American College of Cardiology meeting. The ENHANCE trial was designed to test whether ezetimibe, a drug that lowers LDL, added any benefit to a statin in slowing the progression of atherosclerosis, as measured by carotid intima-media thickness. My daughter, who has heterozygous familial hypercholesterolemia, had been on ezetimibe at one point, so I was particularly interested in the trial. Unfortunately, ezetimibe added no benefit at all and Harlan, representing a panel of cardiologists, was not afraid to state that it is not enough to know a drug’s effect on laboratory markers such as LDL. Rather, we need to know whether a drug improves clinical outcomes, such as heart attacks, strokes and death. As Harlan put it,
There are 3 possibilities with this drug. Eventually—one day, when outcomes studies are finally done—we may recognize that it is an effective medication for reducing cardiovascular risk. The ENHANCE study makes that less likely, but it is not impossible.
It could be that ezetimibe is simply an expensive placebo, and its principal harm is that it drains precious resources from our health care system and possibly leads people to use fewer of the drugs that have been shown to be beneficial. The ENHANCE study suggests that this may be true.
Third, it could be harmful. We do not know enough about the clinical risks of this drug. It is well tolerated and there are no obvious safety problems, but we cannot say if there is an increased risk of acute myocardial infarction or death or another important health problem.
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This study heralds the need for clinical research to guide us in decisions for our patients; ideally, this work must be done early in the drug’s development. It is not right that we are this far down the line with this drug and we have so much uncertainty about its balance of risks and benefits. We must understand the effect of new drugs on people and that relying on a drug’s effect on a set of laboratory tests may not tell the whole story. We have learned this lesson before. It appears that we must learn it again.
Addendum: Just published in Circulation: Cardiovascular Quality and Outcomes, this editor’s perspective by Harlan Krumholz entitled “Patient-Centered Medicine: The Next Phase in Health Care.” Here’s an excerpt:
What matters most to patients are outcomes: Did I recover? Is my quality of life better? Patients want to know what has been accomplished by the tests and treatments they have undergone and what has been achieved by the time and resources that have been expended. It is time for us to fully embrace patient-centered medicine, which is ultimately outcomes oriented, with a focus on what patients experience and, among the range of medically reasonable options, gives precedence to what patients prefer.