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IMPROVE-IT: Ezetimibe added to statin therapy improved CV outcomes
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CHICAGO — The addition of ezetimibe to simvastatin was associated with better clinical outcomes in high-risk patients with ACS compared with simvastatin alone, according to the results of the IMPROVE-IT trial presented at the American Heart Association Scientific Sessions.
This trial is the first to demonstrate clinical benefit of a lipid-modifying therapy added to statin therapy, Christopher P. Cannon, MD, said here.
Christopher P. Cannon
Cannon and colleagues conducted the randomized, double blind, multicenter IMPROVE-IT trial to investigate whether the addition of ezetimibe (Zetia, Merck) to simvastatin (Zocor, Merck) improved CV outcomes relative to statin monotherapy in patients after ACS. The researchers enrolled 18,144 moderate-to-high risk patients (mean age, 64 years; 25% women) within 10 days of ACS onset at 1,158 centers in 39 countries. All patients were aged 50 years or older and had LDL ≤125 mg/dL if not already on statin therapy, or ≤100 mg/dL if already on statin therapy. Approximately 5,000 of the patients had STEMI and the rest had non-STEMI or unstable angina.
Patients were assigned either 40 mg/day of simvastatin (n=9,077) or 10 mg/day of ezetimibe and 40 mg/day of simvastatin (Vytorin, Merck; n=9,067). The patients were up-titrated to 80 mg/day of simvastatin if they had LDL >79 mg/dL.
The primary endpoint was a composite of CV death, MI, hospitalization for unstable angina, stroke and coronary revascularization at least 30 days after randomization. Patients were followed for a minimum of 2.5 years; average follow-up was approximately 6 years.
Mean LDL in both groups was 95 mg/dL. At 1 year, mean LDL was 69.9 mg/dL in the simvastatin group and 53.2 mg/dL in the simvastatin/ezetimibe group; the difference of 16.7 mg/dL was slightly greater than the anticipated 15 mg/dL difference, Cannon, physician at Brigham and Women’s Hospital, professor of medicine at Harvard Medical School and executive director of cardiometabolic trials at Harvard Clinical Research Institute, said during a press conference.
“Would this … translate into a greater clinical benefit? The answer was yes,” Cannon said.
In the intention-to-treat population, the simvastatin/ezetimibe group had a 32.7% rate of the primary outcome compared with 34.7% for the simvastatin group (HR=0.936; 95% CI, 0.887-0.988; P=.016; number needed to treat=50), Cannon said.
The simvastatin/ezetimibe group also had better outcomes than the simvastatin group for the following prespecified secondary outcomes: all-cause death, MI, hospitalization for unstable angina, coronary revascularization or stroke (40.3% vs. 38.7%; HR=0.948; P=.034); CHD, MI or urgent coronary revascularization (18.9% vs. 17.5%; HR=0.912; P=.034); CVD, MI, unstable angina, all revascularization or cerebrovascular accident (36.2% vs. 34.5%; HR=0.945; P=.035), according to the researchers.
The following endpoints also favored the simvastatin/ezetimibe group over the simvastatin group: MI (14.8% vs. 13.1%; HR=0.87; P=.002); ischemic stroke (4.1% vs. 3.4%; HR=0.79; P=.008); and CVD, MI or stroke (22.2% vs. 20.4%; HR=0.9; 95% CI, 0.84-0.97; P=.003). There was a trend toward favorable rate of all stroke in the simvastatin/ezetimibe group (4.8% vs. 4.2%; HR=0.86; P=.052) and no significant differences between the groups in individual endpoints of all-cause death, CVD, CHD, unstable angina or coronary revascularization at least 30 days after randomization, according to the researchers.
There were no differences between the groups in cancer, muscle-related and gallbladder-related events, or other safety endpoints, Cannon said.
Ezetimibe did not have as strong a recommendation as statins for LDL-lowering therapy in the 2013 American College of Cardiology/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults because clinical outcome data for ezetimibe were unavailable at the time. The guidelines “put an emphasis on statins because that is where the evidence is,” Cannon said at the press conference.
“These findings in well-treated patients reaffirm the LDL hypothesis: Reducing LDL prevents CVD,” Cannon said. “These [data] are the evidence the guidelines are looking for.” – by Erik Swain
For more information:
Cannon CP. LBCT.02: Anti-Lipid Therapy and Prevention of CAD. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.
Disclosure: The study was funded by Merck. Cannon reports receiving research grants from Accumetrics, Arisaph, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen Pharmaceuticals, Merck and Takeda, and honoraria from Bristol-Myers Squibb, CSL, Essentialis, GlaxoSmithKline, LipoMedix, Merck, Pfizer, Regeneron, Sanofi and Takeda.
Perspective
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Neil J. Stone, MD, MACP, FAHA, FACC
Ten years ago, the PROVE-IT trial showed us that intensive therapy with statins that lowered LDL below 70 mg/dL gave important benefit to patients with ACS. Now comes IMPROVE-IT, a large-scale, robust, randomized, controlled trial looking at that same group of patients and asking the question whether adding ezetimibe 10 mg to simvastatin 40 mg could make a difference, with the caveat that there were increases in the comparator arm more so than in the intervention arm to simvastatin 80 mg until 2011. The study took 9 years, the follow-up was a mean of 6 years. The point is, this was a long-scale trial that is very important for safety. And now we see for the first time two groups that are under what is considered by many an arbitrary LDL goal of 70 mg/dL and, as was pointed out, they found out that lower was better in this trial. More specifically, that there were improvements in the hard endpoints of MI and ischemic stroke.
The study affirms the central role of intensive LDL reduction in the prevention of recurrent cardiac events. It expands the options for additional proven lipid-lowering therapies. The recent guidelines refuse to say “lower is better.” They said “lower is better with proven therapy,” that therapy shown to provide incremental benefit and to be safe. The trial might suggest that we do not even know what further LDL lowering could obtain in this very high-risk group.
Does this change the current guidelines? The guidelines expressly stated that clinicians treating high-risk patients with less-than-anticipated response to statins, unable to tolerate the recommended intensity of a statin or completely statin intolerant, may consider the addition of non-statin cholesterol-lowering therapy. This is a direct quote: “In this situation, the guideline recommends clinicians preferentially prescribe drugs that have been shown in randomized controlled trials to provide reduction of [atherosclerotic] CVD benefits that outweigh the potential for adverse effects and drug-drug interactions, and consider patient preferences.” So now ezetimibe can show that.
What take-home points for the clinician can we make? I have three principles of practice that I borrowed from Oliver Wendell Holmes, Sr., MD, one of the early deans at Harvard in the 1840s: Not to guess when you can know, not to take authority when you have the facts and don’t prescribe just because somebody’s ill: Consider the net benefit. It was pointed out that lower is not better, always. Estrogen, progesterin and torcetrapib showed negatives that obliterated the benefit of LDL lowering. AIM-HIGH and HPS2-THRIVE showed no support for niacin.
In terms of safety, that is what I am most impressed with. This was a longer-term trial for ezetimibe than we have had before. And that makes a big difference, particularly when you’re pushing to lower values.
In terms of considering net benefit, there is still evidence for high-intensity statin therapy as secondary prevention in multiple randomized trials. So a high-intensity statin and lifestyle changes to achieve the lowest LDL level that a safe and tolerated regimen can provide still seems reasonable. But if a high-intensity statin is not tolerated, or a response to therapy is judged not adequate — that was the language — the data support using a moderate-intensity statin, to which a non-statin such as ezetimibe can be added. Importantly, these data don’t speak to the use of ezetimibe in patients with low risk for primary prevention.
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