IMPROVE-IT Published: Study Shows Benefit of Lowering LDL With Ezetimibe in ACS Patients

June 03, 2015

BOSTON, MA — The IMPROVE-IT study, the large cardiovascular-outcomes trial that showed a clinical benefit to adding ezetimibe (Zetia, Merck/Schering Plough) to statin therapy in post–acute coronary syndrome (ACS) patients, is now published[1].

First presented during the late-breaking clinical-trials session at the American Heart Association 2014 Scientific Sessions in Chicago, IL, the IMPROVE-IT investigators, led by Drs Christopher Cannon and Robert Giugliano(Brigham and Women's Hospital, Boston, MA), showed that adding ezetimibe 10 mg to simvastatin 40 mg resulted in an absolute 2.0% reduction in the primary end point over 7 years when compared with ACS patients who received simvastatin 40 mg alone.

As reported by heartwire from Medscape when the results were presented in November, the primary end point, a composite of cardiovascular death, MI, unstable angina requiring rehospitalization, coronary revascularization, or stroke, occurred in 32.7% of patients who received ezetimibe/simvastatin and in 34.7% of patients treated with simvastatin alone. This translated into a statistically significant 6.4% relative reduction in the risk of cardiovascular events with the combination therapy over 7 years.

The study is published June 3, 2015 in the New England Journal of Medicine, and the results are in line with the 2014 AHA presentation.

Nothing Unique About Ezetimibe

In an editorial[2], Drs John Jarcho and John Keaney (University of Massachusetts Medical School, Worchester, MA) say the study provides support for the LDL hypothesis that reducing LDL-cholesterol levels will reduce cardiovascular events and that IMPROVE-IT should not be interpreted to mean there is "anything uniquely beneficial" about ezetimibe.

"Indeed, the real implication of IMPROVE-IT is to suggest that all reductions in LDL levels, regardless of mechanism, are of equivalent benefit," they write. "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 or 20 to 40 mg of rosuvastatin [Crestor, AstraZeneca]) as from the addition of ezetimibe, assuming equivalent reductions in LDL-cholesterol levels."

In IMPROVE-IT, individuals randomized to ezetimibe/simvastatin achieved significantly lower LDL-cholesterol levels, down from 93.8 mg/dL at the index event to 53.7 mg/dL (time-weighted average). For the simvastatin-treated patients, LDL cholesterol was reduced to 69.5 mg/dL from 93.8 mg/dL. The event reduction in the trial is "precisely the same as that predicted by the Cholesterol Treatment Trialists' analysis of statin trials," say the editorialists, meaning the differential reduction in LDL-cholesterol levels likely explains the reduction in coronary heart disease events.

To heart wire , Giugliano said he agreed with the conclusions of the editorialists, adding the study "represents a major blow to the statin hypothesis." While statins have been credited with a number of beneficial effects not attributable to LDL lowering (the so-called pleiotropic effects), Giugliano said the value of the drug class is based on their ability to reduce LDL cholesterol.

In 2013, the new cholesterol guidelines abandoned LDL-cholesterol targets and instead urged clinicians to select a moderate- or high-intensity statin based on the patient's risk. As a result, simvastatin 40 mg, which is a moderate-intensity statin, is not frequently used in the post-ACS setting. Instead, US guidelines recommend high-dose statin therapy with atorvastatin 80 mg or rosuvastatin 40 mg.

Giugliano said he uses both approaches in ACS patients—using high-intensity statin therapy or using a moderate dose of statin plus ezetimibe—to achieve sufficient LDL lowering. He starts ACS patients with atorvastatin 80 mg, which he said is routine at their hospital and has been for a decade. If the patient fails to achieve an LDL-cholesterol target of <70 mg/dL, Giugliano said he will then add ezetimibe. "I think many of us still use targets, and I think the IMPROVE-IT trial may give another breath of air to those who support their use."

In their editorial, Jarcho and Keaney say IMPROVE-IT remains a landmark trial in that it was the first to show the safety and effectiveness of lowering LDL cholesterol with a nonstatin lipid-lowering agent added to a statin. The results also provide some hope to patients who have side effects from statins and those who are unable to lower their LDL cholesterol enough with a statin (the guidelines recommend a 50% reduction in LDL cholesterol in high-risk patients).

The story of ezetimibe, from its FDA approval until the AHA presentation of the IMPROVE-IT data, has been controversial, all of which has been documented by heartwire . A negative surrogate-end-point trial, known as ENHANCE, even got the attention of the US Congress, with representatives launching an investigation into why that 2008 study was delayed for so long.

Merck sponsored the IMPROVE-IT study. Cannon reports research grants from Accumetrics, Merck, Arisaph, AstraZeneca, GlaxoSmithKline, Janssen, Takeda, and Boehringer-Ingelheim and honoraria from Bristol-Myers Squibb, Pfizer, Takeda, Merck, GlaxoSmithKline, Essentialis, CSL Bering, Lipimedix, Regeneron, Kowa, and Sanofi. Giugliano reports receiving honoraria for CME lectures from and consulting for Merck and consulting for Amgen, Daiichi-Sankyo, Pfizer, CVS Caremark, Regeneron, and Sanofi. Disclosures for the coauthors are listed on the journal website. Jarcho is a deputy editor and Kearney an associate editor at the New England Journal of Medicine.

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