Results of IMPROVE-IT Trial, and Editorial, Affirm Benefits of Lower LDL Cholesterol

Long-term results of the IMPROVE-IT trial, which were first presented in November 2014 at the American Heart Association annual meeting, were published yesterday in the New England Journal of Medicine, and confirmed that adding ezetimibe (Zetia) to a statin would reduce the risk of cardiovascular events by a rate of 6.4%.¹

The bigger news was the accompanying editorial that supported the cause of aggressive treatment to lower low-density lipoprotein (LDL) or “bad” cholesterol.² The writers specifically mentioned the anticipated arrival of PCSK9 inhibitors, which trials have shown can reduce LDL cholesterol levels by as much as 60%, while also providing cardiovascular benefits. Two entrants in this new class face FDA deadlines in July and August.

"Indeed, the real implication of IMPROVE-IT is to suggest that all reductions in LDL levels, regardless of mechanism, are of equivalent benefit," wrote John A. Jarcho, MD, and John F. Keaney Jr, MD.

IMPROVE-IT, which stood for Improved Reduction Outcomes: Vytorin Efficacy International Trial, gathered data on 18,144 patients who had been hospitalized for acute coronary syndrome. Patients had LDL cholesterol levels of 50 to 100 mg / dL and were followed for a median of 6 years. The trial compared a group receiving 40 mg simvastatin and 10 mg ezetimibe with a group receiving 40 mg simvastatin plus placebo. (Vytorin is the name of the combination statin and ezetimibe therapy.)

Cardiovascular deaths or events—including myorcardial infarction, unstable angina requiring hospitalization, coronary vascularization, or stroke—occurred in 32.7% of the patients who received the combination therapy, compared with 34.7% of those who had the statin alone.

That’s good news to those who take ezetimibe, but to hear Drs Jarcho and Kearney tell it, patients might be as well off with other high-intensity therapies on the market: the issue is getting the LDL cholesterol down, not necessarily which medication is used.

Indeed, at the recent meeting of the American College of Cardiology in March, presenters who touted the benefits of the PCSK9 inhibitors said thus far, researchers have yet to find a floor for lowering cholesterol, below which patients won’t find a benefit.

Still, the writers of the editorial credit IMPROVE-IT with being the first trial to show the safety and effectiveness of lowering cholesterol with a non-statin agent added to a statin, which gave hope to those patients who had been unable to get to safe cholesterol targets with statins alone. They note that the 2013 AHA/ACC guidelines, which were controversial in their recommendations for use of statins for so many patients, do not recommend specific cholesterol goals but do acknowledge that some patients simply cannot tolerate statins.

References

1. Cannon CP, Blazing MA, Guigliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

2. Jarcho JA, Keaney JF. Proof that lower is better—LDL cholesterol and IMPROVE-IT. N Engl J Med [published online June 3, 2015]. 2015; DOI: 10.1056.NEJMoa1410489