November 17th, 2014
IMPROVE-IT Meets Endpoint and Demonstrates Real But Modest Clinical Benefit for Ezetimibe
After all the waiting and all the controversy it turned out to be pretty simple. The IMPROVE-IT trial did what it set out to do and reached its primary endpoint. The benefit wasn’t very big or impressive but it will be enough to put to rest concerns that ezetimibe might have been an expensive placebo or that LDL might not be a reliable surrogate endpoint. The IMPROVE-IT results will also provide comfort to companies developing the next generation of cholesterol drugs, since their approval may have depended on validation of LDL as a surrogate endpoint.
The Improved Reduction of Outcomes: Vytorin Efficacy International Trial, presented Monday morning at the American Heart Association meeting in Chicago, randomized 18,144 high-risk patients within 10 days of an acute coronary event to either ezetimibe or placebo on top of a statin. These patients had LDL levels between 50-125 mg/dL, or between 50-100 mg/dL if on a prior cholesterol drug. Patients were followed for an average of six years. The trial ended after there were 5,250 primary endpoint events (CV death, MI, hospital admission for unstable angina, coronary revascularization more than a month after randomization, or stroke).
Primary endpoint events occurred in 34.7% of the control group versus 32.7% of the treatment group, representing a 6.4% reduction in risk (HR 0.936, CI 0.887-0.988, p=0.016). The investigators calculated that 50 patients would need to be treated for seven years to prevent one event. There was no difference between the groups in overall deaths, coronary deaths, or cardiovascular deaths, but there were significant reductions in MI (13%, p =0.002), stroke (14%, p=0.052), and ischemic stroke (21%, p=0.008). The effect was significant across subgroups, except for diabetics, who had a larger benefit than nondiabetics.
The results came about even though 42% of patients in each arm discontinued taking the study drug before the end of the trial. A secondary analysis, presenting the results of only the patients who stayed on the study drug, is scheduled for presentation on Tuesday.
As expected, LDL was significantly different throughout the trial; median levels were 69.9 mg/dL in the control group versus 53.2 mg/dL in the treatment group. No safety issues were found during the trial and there were no significant differences in cancer or muscle-related events.
In his presentation of the results, Chris Cannon said the trial provided a positive answer to three questions that have been hanging for more than a decade:
- Whether lowering LDL with the non-statin ezetimibe can lower cardiac events?
- Is it worthwhile to take an already low LDL cholesterol (65 mg/dL) even lower (50 mg/dL)?
- Is ezetimibe safe?
Cannon added that the trial “reaffirms the LDL hypothesis, that reducing LDL prevents cardiovascular events” and that the results should be incorporated in future guidelines.
A Modest Proposal
Despite its history of divisive controversy, the discussion about IMPROVE-IT fell within a fairly narrow range of views. Most experts agreed that the trial results were trustworthy and genuine, but that the benefit seen in the trial was “modest.” Lipid experts in particular expressed relief that the trial did not invalidate the lipid hypothesis.
The result, said James Stein, “makes perfect sense and fits with the physiology just presented last week in the NEJM. Any drug that lowers LDL-C safely, given for a long enough time, will reduce cardiovascular disease risk. The key issues are extent of LDL-C lowering, duration, and baseline level of CVD risk. I am very glad to see these long overdue results as they give us another tool to help prevent heart attacks and strokes. They also help refocus us on the physiology — bad cholesterol — and away from the statin class of drugs as the only treatment for heart disease. It really is about the risk factors. And I can’t emphasize it enough. Anything that lowers LDL-C safely, when used for a long enough amount of time, will reduce CVD risk.”
Sekar Kathiresan, who was the senior author of the NEJM paper cited by Stein, was even more enthusiastic: “These results are a home-run for patients. In human genetics studies for heart-attack risk, LDL has always emerged as the key causal risk factor. And now, we have two medicine options for patients — statins and ezetimibe — proven in clinical trials to lower LDL as well as heart attacks. The question for LDL lowering and cardiovascular disease prevention now moves from ‘how low’ to ‘how long’.”
Kathiresan also argued that the NNT (number needed to treat) of 50 was “outstanding for a drug that basically has no side effects.” But Steven Nissen, a vocal critic of ezetimibe in the past, pointed out that the NNT occurred over seven years, so the yearly NNT was actually 350.
But Nissen also said that the trial result was trustworthy and that the trial was well conducted, but he emphasized the modest effect and asked “when have you ever seen a risk reduction as small as 6%?” He noted that the trial was powered to detect a 9% difference but got only a 6% reduction.
Nissen said he thought the results were strong enough to support the approval of the PCSK9 inhibitors for the limited indications of familial hypercholesterolemia and for those who are truly statin intolerant.
At the AHA press conference, Neil Stone, the chairman of the AHA/ACC cardiovascular guidelines committee, said that ezetimibe should now be viewed as a proven therapy. The results, he said, expand the options for additional proven lipid lowering therapies that have been shown to add incremental benefit.
Stone, Cannon, and others warned that the results of IMPROVE-IT should not be applied to lower-risk groups using ezetimibe for primary prevention. Cardiologist Melissa Walton-Shirley noted that most patients who now take ezetimibe are, in fact, low-risk patients taking it for primary prevention. Cardiologist Karol Watson pointed out that “the NNT goes up with low-risk patients but the NNH (number needed to harm) remains constant.”
Cannon said that the long length of the trial was at least partly a reflection of the excellent state-of-the-art treatment received by study patients. This was “good for the patients but bad” for those who wanted results sooner.
Cannon also pointed out that the 42% drop-out rate over the seven years of the trial worked out to 7% per year, which is actually better than other similar trials in the past.
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