There was little consolation for Schering-Plough and Merck & Co when results of the controversial ENHANCE study were reported yesterday at the American College of Cardiology (ACC) Annual Scientific Sessions in Chicago.
ENHANCE was a two-year study that compared the combination of Zetia (ezetimibe) and Zocor (simvastatin) — available in a single tablet as Vytorin — with Zocor alone in 720 patients with familial hypercholesterolaemia, an inherited disorder in which dangerously high levels of LDL or ‘bad’ cholesterol result in a high risk of premature cardiovascular disease.
Presenting the study, lead investigator Dr John Kastelein, Amsterdam Medical Centre, Netherlands, pretty much confirmed the results of ENHANCE released in January this year. The Zetia-Zocor combination was well tolerated and was more effective than Zocor alone in reducing LDL cholesterol and C-reactive protein, another marker of cardiovascular risk. But there was no statistically significant difference between the two treatments on the primary study endpoint, the mean change in carotid intima-media thickness, which measures build-up of atherosclerotic plaque in the arteries of the neck. There was also no difference in the risk of endpoints such as cardiovascular death or non-fatal heart attack, though the study was not designed to assess these clinical outcomes.
An imaging study in a relatively small number of patients with a rare inherited disorder would usually pass unnoticed at a meeting replete with large, hard-outcome studies. However, Zetia and Vytorin are widely prescribed in the USA, and S-P’s and Merck’s alleged actions in delaying release of ENHANCE data have resulted in investigation by US state and federal bodies including the Food and Drug Administration and a Congressional Sub-committee.
Both in his ACC presentation and a New England Journal of Medicine article, released online, Dr Kastelein suggested that ENHANCE’s surprising results might be due to the low-risk study population following recent improvements in treatment of familial hypercholesterolaemia. However, S-P and Merck were denied even this comfort by members of an ACC Expert Panel commenting in response to Dr Kastelein’s presentation.
According to Dr Harlan Krumholz, Yale University, USA: “The most likely explanation was that the compound [Zetia] did not work: it reduced LDL cholesterol but did not retard progression of atherosclerosis. This study provides no new evidence to support the use of this drug, and moves us to more uncertainty about its benefits.” He contrasted ENHANCE with similar studies showing that statins slow progression of atherosclerosis in familial hypercholestolaemia, and drew attention to other drugs that lower LDL cholesterol but do not improve outcomes, including Pfizer’s ill-fated torcetrapib.
Large clinical trials are currently under way to test whether Zetia can reduce the risk of heart attack, stroke and death, but they will not report for some years. In the meantime, events in Chicago can only add to S-P’s and Merck’s woes, especially as the ACC Expert Panel recommended that Zetia should be reserved only for the small number of patients who do not reach target LDL despite maximum–dose statins plus other proven cholesterol-lowering drugs such as niacin, fibrates or resins.
ENHANCE also has implications for industry as a whole. Any rebound increase in statin prescribing may not benefit other companies, since generic simvastatin is widely available and will look very attractive to cost-conscious health purchasers. In addition, since Zetia was approved on the basis of its effectiveness in LDL lowering alone, ENHANCE’s negative outcomes are likely to reinforce calls for positive outcome studies before future drugs are licensed. By Sue Lyon in Chicago
