IMPROVE-IT Published: Hotly Debated Ezetimibe Helpful When Added to Statin Therapy

On top of simvastatin therapy, the cholesterol-lowering agent ezetimibe may improve cardiovascular outcomes, according to data from the IMPROVE-IT study published online June 3, 2015, ahead of print in the New England Journal of Medicine. Additionally, the drug helps reduce LDL levels below current guideline-recommended targets better than the statin alone.

Results from IMPROVE-IT were previously presented at the 2014 American Heart Association Scientific Sessions in Chicago, IL.

Researchers led by Christopher P. Cannon, MD, of Brigham and Women’s Hospital (Boston, MA), looked at 18,144 moderate- to high-risk patients (mean age 63.6 years; 75.7% men) stabilized after a recent ACS event who had LDL levels below 125 mg/dL (or 100 mg/dL if on chronic statins).

Patients were randomized to 40 mg of simvastatin plus either 10 mg of ezetimibe (Vytorin; Merck; n = 9,067) or placebo (n = 9,077) at 1,147 sites in 39 countries between October 2005 and July 2010. After randomization, if 2 consecutive measurements showed LDL levels were greater than 79 mg/dL, the simvastatin dose was increased to 80 mg.

Benefit Parallels LDL Reduction

After a median of 6 years, 42% of patients in each group had discontinued the study medication without dying or having a primary endpoint event (cardiovascular death, nonfatal MI, rehospitalization for unstable angina, revascularization beyond 30 days, or stroke).

Median LDL over the course of follow-up was 53.7 mg/dL in the combination therapy group and 69.5 mg/dL in the simvastatin alone group; the difference appeared after 1 year (P < .001) and was accompanied by declines in triglycerides.

On Kaplan-Meier analysis, estimated event rates for the primary and secondary endpoints at 7 years were lower for the simvastatin plus ezetimibe group than for controls (table 1).

Cardiovascular death rates were similar between the study groups, although risk of MI (P = .002) and ischemic stroke (P = .008) each were lower with the combination therapy than with simvastatin alone. Also, the benefit of simvastatin plus ezetimibe was upheld across nearly all prespecified subgroups, although it was attenuated in patients with diabetes and those at least 75 years old.

There were no differences between the treatment groups with regard to elevation in alanine aminotransferase level or the rates of gallbladder-related adverse events, cholecystectomy, muscle-related adverse events, or cancer. Finally, discontinuation of the study drug due to an adverse event occurred in 10.1% of patients assigned to simvastatin alone and 10.6% of those assigned to combination therapy.

‘Additional Clinical Benefit’ With Ezetimibe

The IMPROVE-IT findings “are consistent with those in trials of intensive-dose versus standard-dose statin therapy,” Dr. Cannon and colleagues write. “However, significant reductions were observed in the rates of myocardial infarction and ischemic stroke.”

Previous studies have not clarified the benefit of lowering LDL cholesterol levels to below 70 mg/dL as recommended by practice guidelines, they say. “The benefit of ezetimibe in IMPROVE-IT suggests that there is an additional clinical benefit, and it appeared to be similar in patients with lower LDL cholesterol levels as well as in those with higher LDL cholesterol levels at baseline.”

Also, the authors note, “although cautions had been raised about the safety of ezetimibe, we observed no significant between-group difference in the incidence of cancer or cancer deaths during up to 7 years of follow-up and no significant difference in the incidence of rhabdomyolysis or myopathy.”

Limitations of IMPROVE-IT include its exclusive focus ACS patients, which means that the “results are most relevant to that population,” they say. However, since the treatment effect emerged at 1 year, most patients were then in the “chronic phase of their disease,” the researchers point out, adding “that greater benefits from ezetimibe might have been seen if baseline LDL cholesterol levels had been higher.”

Time to Improve the Guidelines?

In a telephone interview with TCTMD, Neal S. Kleiman, MD, of Methodist DeBakey Heart and Vascular Center (Houston, TX), said the results are “not dramatic… but very consistent with almost everything else we've seen in the lipid world.”

The incremental benefit achieved with the combination therapy has the cardiology community “very worked up,” he observed, but the ongoing struggle to reduce atherosclerotic complications is “multifactorial and every little bit we get counts.”

Dr. Kleiman said the results are “robust enough” to warrant changing current cholesterol guidelines, but “I'm sure there will be a lot of debate over it.”

IMPROVE-IT, however, should not inspire clinicians to prescribe ezetimibe to lower-risk patients on statins, he cautioned. “It's a small benefit in a higher-risk group, and that benefit is probably going to be less pronounced in a lower-risk group,” Dr. Kleiman said.

Other therapeutic directions to look to in the future, he suggested, include PCSK9 inhibitors and the combination of “ezetimibe with the more powerful generation of statins.”

Adopting an ‘LDL Principle’

In a similar vein, John A. Jarcho, MD, of Brigham and Women’s Hospital (Boston, MA), and John F. Keaney Jr, MD, of UMass Memorial Medical Center (Worcester, MA), write in an accompanying editorial that the trial “offers important new evidence in favor of the LDL hypothesis,” which they suggest might now come to be known as the “LDL principle.”

The “landmark,” first-of-its-kind study, they say, “suggests that reduction of LDL cholesterol levels per se explains the effect of statins on coronary heart disease.”

IMPROVE-IT offers “important hope to patients who have unacceptable side effects from statin therapy and to those who may not achieve adequate LDL reduction with statins,” Drs. Jarcho and Keaney write. “The 2013 guidelines do not recommend the use of specific targets for LDL cholesterol levels, but they 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.”

These results “should, at a minimum, reinforce such a recommendation and will undoubtedly rekindle arguments in favor of targets for LDL cholesterol levels,” they add.

Ultimately the trial “should not be interpreted as showing anything uniquely beneficial about the use of ezetimibe. Indeed, the real implication of IMPROVE-IT is to suggest that all reductions in LDL levels, regardless of mechanism, are of equivalent benefit,” the editorial authors write, adding that a patient on “40 mg of simvastatin would be expected to benefit just as much from a higher-intensity statin regimen… as from the addition of ezetimibe, assuming equivalent reductions in LDL cholesterol levels.”

What is “sobering” about IMPROVE-IT is that, consistent with other trials, 42% of patients discontinued the study medication prematurely, they conclude. “Since lipid-lowering is presumably intended to be a lifelong goal, this diminishment in long-term use is an important practical clinical concern, and one that suggests that treatment adherence to lipid-lowering therapy needs to be an ongoing focus of practitioner attention.”

1. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Eng J Med. 2015;Epub ahead of print.
2. Jarcho JA, Keaney JF Jr. Proof that lower is better—LDL cholesterol and IMPROVE-IT [editorial]. N Engl J Med. 2015;Epub ahead of print.

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