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The Vytorin Controversy and Surrogate Markers

The big news at the American College of Cardiology annual meeting in Chicago March 29-April 1 was the controversy caused by the ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) trial result, essentially ending a 2 billion dollar annual market overnight. 
Vytorin, distributed by Merck/Schering-Plough, combines a statin with ezetimibe (Zetia), a drug that reduces intestinal lipid absorption. Ironically, an American College of Cardiology publication in 2002 (Davidson MH, McGarry T,Bettis R, et al, on behalf of the Ezetimige Study Group. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. JACC 2002;40:2125-34) was typical of studies that gave Vytorin its momentum to begin with. Coadministration of ezetimibe and simvastatin reduced low-density lipoprotein cholesterol by 44% to 57% and triglycerides 20% to 28%. The combination also raised high density lipoprotein cholesterol 8% to 11%, depending on the simvastatin dose. Concurrent studies illustrated the drug combination was safe.

ENHANCE, however, was conducted using 720 patients with heterozygous familial hypercholesterolemia, prevalence 0.2%. The endpoint was mean change in intima-media thickness measured at three sites in the carotid arteries between patients treated with ezetimibe/simvastatin 10/80 mg versus patients treated with simvastatin alone over a two year period. There was no significant difference between artery wall thcknesses between treatment groups. It was this result that prompted an ACC panel to state, “This study provides no new evidence to support the use of this drug and moves us to more uncertainty about using it.”

There are currently no outcomes studies comparing adverse cardiovascular outcomes between combination and statin therapy. Laboratorians know it is risky to base therapy on surrogate outcomes, be they plasma or tissue-based.

The key issue in this instance was, should we treat for better laboratory values or for clinical outcomes, but it is interesting how surrogate measures have started, and now ended Vytorin’s market.

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