Saturday, April 4, 2015

IMPROVE-IT trial of Vytorin

Missed this when it came out last November. The much awaited results of the 18,000-patient, 7-year, randomized, controlled, double-blind, mulitcenter study of Vytorin are out. Ezetimibe (in conjunction with simvastatin) isn't a complete lemon after all as the ENHANCE study showed (although that trial used a surrogate endpoint rather than outcomes of real interest to patients and doctors).

The primary endpoint of IMPROVE-IT is a mishmash of cardiovascular events including death. The absolute risk reduction is 2%. But what's interesting to me is that there is zero reduction in mortality rates--ezetimibe doesn't reduce death rates. What it does clearly do is reduce LDL and the implication (as the researchers reveal) is that having an even lower LDL is better given the reduction in CV events compared to simvastatin alone.

The primary and secondary endpoints, being composites, do not paint a clear picture of what Vytorin exactly improves. Looking at the forest plot of the individual components of the composite reveals that there are only two--heart attack (MI) and ischemic stroke--which showed unambiguous risk reductions (p = 0.002 and p = 0.008, respectively). The improvements in both events are modest. For MI the absolute reduction is 1.7% while for ischemic stroke it's a mere 0.7%, both for a period of 7 years. In other words, we'd have to put 59 people on Vytorin for 7 years to reduce the number of heart attack incidents by 1 and the number of patients we'd have to give Vytorin, again for 7 years, to reduce ischemic strokes by 1 would be 143.

Moreover, as has been highlighted by some critics, coronary heart deaths (CHD), cardiovascular deaths (CVD), and all-cause mortality are the same for those on statin alone and on Vytorin (the 95% CI includes HR = 1). It's quite clear ezetimibe does nothing for mortality rates.

Ultimately, whether the benefits outweigh the cost (which includes harms and not just financial burden) will be a judgment call both by doctors and patients.


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