IMPROVE-IT: Can It Improve Heart Guidelines?

Lowering lipid levels beyond typical targets by adding ezetimibe (Zetia) to a statin modestly boosted the cardiovascular protection afforded, the IMPROVE-IT trial showed.

The combination reduced the composite primary endpoint at 7 years by a relative 6% compared with simvastatin (Zocor) alone (P=.016), Christopher Cannon, MD, of Brigham and Women’s Hospital in Boston, and colleagues found.

The rate for that composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization 30 or more days after randomization, or nonfatal stroke was 32.7% in the simvastatin plus ezetimibe group and 34.7% with simvastatin alone.

The findings, published online in The New England Journal of Medicine, matched the initial report at last year’s American Heart Association meeting.

Cannon argued that the wait for publication represented simply a normal, rather than accelerated publication schedule for the data, which had been locked just weeks before his November 2014 presentation.

Many clinicians contacted by MedPage Todayat the time weren’t too impressed by the data in terms of increasing their use of ezetimibe, and an editorial accompanying the publication agreed there was no indication of anything uniquely beneficial about the drug.

“Indeed, the real implication of IMPROVE-IT is to suggest that all reductions in LDL levels, regardless of mechanism, are of equivalent benefit,” wrote editorialists John A. Jarcho, MD, of Brigham and Women’s Hospital in Boston and deputy editor for NEJM, and John F. Keaney Jr, MD, of the University of Massachusetts Medical School in Worcester.

“Thus, a patient who is currently being treated with 40 mg of simvastatin would be expected to benefit just as much from a higher-intensity statin regimen (eg, 40 to 80 mg of atorvastatin [Lipitor] or 20 to 40 mg of rosuvastatin [Crestor]) as from the addition of ezetimibe, assuming equivalent reductions in LDL cholesterol levels.”

And that proof that lower is better regardless of the agent used to achieve it makes the trial a landmark one with the potential to change guidelines, they argued.

The controversial shift in AHA/American College of Cardiology guidelines away from cholesterol treatment targets toward simply treating with a statin for elevated cholesterol was predicated at least in part on prior failure of other lipid lowering agents to impact outcomes.

In IMPROVE-IT, the 18,144 acute coronary syndrome patients randomized to moderate-dose simvastatin (40 mg) plus ezetimibe (10 mg) had an additional 24% lowering in LDL (16.7 mg/dL) than those assigned to the same dose of simvastatin plus placebo.

Getting the combination group down to a median 54 mg/dL averaged across the duration of the trial clearly was better than the 70 mg/dL for the control group, which had been the guideline-based target at the time of trial initiation, Cannon noted.

“This would likely push the target, at least for these high-risk patients, even lower,” he told MedPage Today, predicting that the guidelines would change.

Also, using the combination of endpoints used in the Cholesterol Treatment Trialists’ (CTT) huge meta-analysis of statin trials, the addition of ezetimibe had the same incremental impact per unit LDL reduction as seen with statins.

This finding “suggests that reduction of LDL cholesterol levels per se explains the effect of statins on coronary heart disease,” rather than some pleiotropic benefit specific to statins, the editorialists wrote.

“It’s nice to have all the different options for patients,” Cannon said.

Ezetimibe is due to go generic soon and could be a cost-effective way to drive down LDL even if the PCSK9 class (with roughly twice the LDL reduction achieved by ezetimibe) gets approved in the coming months, he suggested.

IMPROVE-IT showed no significant differences in adverse events between groups, including for prespecified muscle, gallbladder, and hepatic adverse effects and cancer.

“These results offer important hope to patients who have unacceptable side effects from statin therapy and to those who may not achieve adequate LDL reduction with statins,” Jarcho and Keaney noted.

“The 2013 guidelines . . . do acknowledge that some patients may have an ‘insufficient response to statin therapy’ and that in such patients the addition of a nonstatin agent may be considered,” they added. “The results of IMPROVE-IT should, at a minimum, reinforce such a recommendation and will undoubtedly rekindle arguments in favor of targets for LDL cholesterol levels.”

Action Points

 ♦ Lowering lipid levels beyond typical targets by adding ezetimibe to a statin modestly boosted the cardiovascular protection afforded.

 ♦ Note that the study suggests that all reductions in LDL levels, regardless of mechanism, may be of equivalent benefit.

The trial was supported by Merck.

Cannon disclosed relevant relationships with Merck, Accumentrics, Arisaph, AstraZeneca, Janssen, Boehringer Ingelheim, GlaxoSmithKline, Takeda, Bristol-Myers Squibb, CSL Behring, Essentialis, Kowa, Lipimedix, Pfizer, Regeneron, and Sanofi.

Jarcho and Keaney disclosed relevant relationships with the NEJM.

Reviewed by Robert Jasmer, MD, Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner.

last updated 06.04.2015

Primary Source

New England Journal of Medicine

Source Reference: Cannon CP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

Secondary Source

New England Journal of Medicine

Source Reference: Jarcho JA, Keaney JF. Proof that lower is better-LDL cholesterol and IMPROVE-IT. N Engl J Med. 2015; doi:10.1056/NEJMe1507041.

This article was first published on MedPage Today and reprinted with permission.

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