CHICAGO (FRONTLINE MEDICAL NEWS) – Adding ezetimibe to a midpotency statin in high-risk cardiovascular patients to drive their LDL cholesterol into the low 50s resulted in a further significant reduction in major cardiovascular events, compared with statin alone, in the 18,144-patient IMPROVE-IT study.

In IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), 7 years of double-blind therapy with ezetimibe 10 mg/simvastatin 40 mg (Vytorin) achieved a 6.4% lower relative risk of the primary composite endpoint, compared with patients randomized to simvastatin alone (P = 0.016).

The 7-year rate of this composite outcome – comprised of cardiovascular death, nonfatal MI, rehospitalization for unstable angina, stroke, or coronary revascularization – was 32.7% with ezetimibe/simvastatin and 34.7% with simvastatin alone, for an absolute difference of 2%, Dr. Christopher P. Cannon reported at the American Heart Association scientific sessions.

Patients on dual therapy showed relative risk reductions of 13% for MI and 21% for ischemic stroke. The number needed to treat was 50, meaning that treating 100 patients with ezetimibe/simvastatin for 7 years should prevent 2 patients from having an ischemic stroke or MI who would have had such an event on simvastatin alone. That NNT is “well within the range of our standard therapies,” noted Dr. Cannon, professor of medicine at Harvard Medical School, Boston.

Patients in IMPROVE-IT began double-blind therapy within 10 days of hospitalization for an ST-elevation MI or non-STEMI/unstable angina. Participants also had to have at least one additional high-risk feature, such as a previous MI, diabetes, or coronary artery bypass surgery.

Observers hailed IMPROVE-IT as a major study for several reasons. It’s the first-ever study to demonstrate added clinical benefit when a nonstatin having a different mechanism of action is added to a statin. Thus, it provides physicians with a new, solidly evidence-based treatment option for high-risk acute coronary syndrome patients. Also, the trial emphatically affirms the LDL hypothesis that lowering LDL prevents cardiovascular events: The mean LDL at 1 year was 53.7 mg/dL in the dual-treatment group and 69.9 mg/dL in the simvastatin arm. And, as Dr. Karol Watson noted, IMPROVE-IT, with 7-plus years of careful follow-up, confirms the safety of ezetimibe, which had been questioned earlier on the basis of smaller studies that were far smaller.

“That’s one of the most important things to me to come from this study,” said Dr. Watson, professor of medicine and codirector of the program in preventive cardiology at the University of California, Los Angeles.

Once IMPROVE-IT has been published in a peer-reviewed journal it will be reviewed by the expert panel responsible for the AHA/American College of Cardiology cholesterol management practice guidelines, which in 2013 famously abolished specific LDL target goals.

Just what impact IMPROVE-IT ought to have on the guidelines was a point of considerable contention at the Chicago AHA meeting. Late-breaking clinical trials session cochair Dr. Sidney C. Smith noted that the current guidelines (J. Am. Coll. Cardiol. 2014;63:2889-934), on the basis of very solid evidence, call for high-intensity statin therapy, such as atorvastatin at 80 mg/day, as the first-line therapy for high-risk patients such as those with acute coronary syndrome.

“There are people who can’t take atorvastatin at 80 mg or atorvastatin at all. It seems to me that these IMPROVE-IT data fit very nicely with the guidelines: In such patients, you would start with 40 mg of simvastatin along with ezetimibe because of the proven outcome you’ve demonstrated,” suggested Dr. Smith, professor of medicine at the University of North Carolina, Chapel Hill.

Dr. Cannon indicated that he sees a broader role than that for statin/ezetimibe combination therapy. Since IMPROVE-IT has now shown that the lower a patient’s LDL the better the clinical outcomes, it makes sense to consider starting high-risk patients on maximal statin therapy – atorvastatin 80 mg/day or its equivalent – along with ezetimibe, he said.

“If you’re starting out at a high baseline risk, you might go straight to both. That’s what I hope the revised guidelines will say. Whereas, if someone was at a more moderate baseline LDL level they might get a very good response with just the high-intensity statin,” the cardiologist asserted.

Dr. Neil J. Stone, chair of the cholesterol guidelines panel, wasn’t buying that argument.

“That strategy simply wasn’t tested in terms of safety and efficacy in this trial. I’m not willing to make a leap of faith. I’d like to stay as close to the evidence as we can,” said Dr. Stone, professor of medicine at Northwestern University in Chicago. He cited several fairly recent examples in which lower proved not to be better in terms of LDL reduction: Niacin, fenofibrate, estrogen/progestin for women, and torcetrapib all went down in flames in randomized trials.

“If we had made a leap of faith that lower is better, we wouldn’t have done those trials,” he observed.

Also, it’s important to recognize that the IMPROVE-IT data don’t speak to the use of ezetimibe for primary prevention in lower-risk patients. “This study is not a signal that everyone should be on ezetimibe,” Dr. Stone emphasized.

It’s estimated that, in clinical practice, up to 25% of patients are statin intolerant to varying degrees. Dr. Watson said that, after seeing the IMPROVE-IT results, “I would absolutely try to persist with statin therapy, but there are some patients who are truly statin intolerant, and for them I might add ezetimibe to a low-dose statin.”

Indeed, like many other physicians, she has been doing that all along in selected cases on the basis of clinical judgment and biologic plausibility while anxiously awaiting the IMPROVE-IT findings, which come as a great relief, she added.

IMPROVE-IT was initially planned to include 10,000 randomized patients and a minimum of 2.5 years of on-treatment follow-up. Over the years, however, it underwent four protocol amendments. As IMPROVE-IT kept growing larger and longer, some observers quipped that it appeared the organizers would just keep the trial going until it produced a positive result, although, in fact, the study leaders remained blinded to the interim safety and efficacy data.

Merck, which sponsored the study, announced that it will use the data in petitioning the Food and Drug Administration next year for a new indication for reduction of major cardiovascular events for Vytorin and ezetimibe (Zetia).

Dr. Cannon reported receiving research grants from Merck and half a dozen other pharmaceutical companies. Dr. Watson reported participating in the clinical trials adjudication committee for Merck. Dr. Smith and Dr. Stone had no disclosures.


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