A controversial study has finally delivered a verdict on the effects of adding Merck & Co’s ezetimibe to statin therapy in patients with acute coronary syndrome (ACS), revealing a small reduction in cardiovascular events.
The IMPROVE-IT trial was designed to compare the effects of Vytorin (simvastatin and ezetimibe) versus Zocor (simvastatin) on cardiovascular complications and death in 18,000 post-ACS patients and got under way nine years ago – shortly after Vytorin was first launched onto the market.
Results presented at the American Heart Association (AHA) meeting showed that 32.7% of Vytorin-treated patients suffered a major cardiovascular event over a median seven-year follow-up period, compared to 34.7% of the Zocor group, a difference that was statistically significant. There was no impact on all-cause mortality.
The study reinforces the view that the lower LDC-cholesterol levels can be driven, the better the outcome for the patient, according to study co-chairs Eugene Braunwald of Harvard Medical School and Robert Califf of Duke University.
“The addition of ezetimibe to a statin resulted in a further reduction in cardiovascular events compared to statin therapy alone, which is the first time this has been directly shown in a study of a non-statin cholesterol-lowering medicine,” they pointed out.
Vytorin and ezetimibe monotherapy Zetia got off to a strong start in the market but were quickly enveloped in controversy when the results of another study – called ENHANCE – failed to show any impact on the development of atherosclerosis when ezetimibe was added to statin therapy.
The results led to suggestions by some cardiologists that it was pointless using the combination if a reduction in LDL-cholesterol was not followed by an improvement in cardiovascular outcomes, and sales momentum for the products started to tail off. Nevertheless, the drugs remain big earners for Merck, with sales still topping $1bn a quarter.
A delay in reporting the results of ENHANCE sparked claims that Merck had tried to bury the results and a class action suit by investors – which the company eventually settled for $688m in 2013. Meanwhile, IMPROVE-IT was threatened with early termination after an interim analysis revealed a possible safety signal, although an independent review subsequently indicated it should continue to the end.
Despite the positive outcome of IMPROVE-IT, the debate seems set to continue, with critics arguing that the size of the benefit would be inconsequential in real-world clinical practice outside the parameters of the large-scale clinical trial.
Undeterred, Merck has said it will now file for approval of updated labelling for Vytorin and Zetia based on the results of IMPROVE-IT next year.
The company has also been trying to get approval for a combination of ezetimibe and atorvastatin and resubmitted a marketing application to the FDA last year after being knocked back in 2012 and 2009 by requests for more data.