Managing residual risk in patients receiving statin therapy

To the Editor: Evidence is beginning to accumulate on the effectiveness of the low-density lipoprotein (LDL) cholesterol-lowering medicine ezetimibe. While there are no completed trials investigating ezetimibe’s effect on clinically important end points, two recent trials investigating its effect on carotid intima media thickness (CIMT) have both reported disappointing results.1,2 After each of these trials, the Journal has published editorials by Hamilton-Craig, who offers reassurance about ezetimibe and encourages ongoing prescription of this drug to patients who have elevated LDL levels despite maximum-tolerated statin therapy.3,4 Such a sanguine opinion seems at odds with the negative trial evidence, and therefore worthy of debate.

Briefly, the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, which compared ezetimibe plus simvastatin with simvastatin treatment alone in 720 patients with familial hypercholesterolaemia, found no significant difference (and a trend in the direction of harm) with respect to the primary end point of CIMT.1 The ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 — HDL and LDL Treatment Strategies in Atherosclerosis) trial compared ezetimibe with extended-release niacin in statin-treated patients with coronary heart disease.2 Among 315 patients with available results, the group taking niacin showed a statistically significant reduction in CIMT, but the group taking ezetimibe showed no such reduction. Of concern, increased cumulative exposure to ezetimibe was associated with progression of CIMT (P = 0.05). Although far from definitive, the results of these two trials offer no reassurance of benefit from ezetimibe and, in my view, may portend harm.

It may seem counterintuitive that ezetimibe, which significantly lowers LDL cholesterol levels,1,2 could be ineffective or harmful. However, the history of medicine is replete with examples of interventions that improve numerical disease measures without benefit to patients. One recent example was torcetrapib, which, despite increasing high-density lipoprotein cholesterol and reducing LDL cholesterol levels in a promising manner, was found to cause serious adverse events, including death.5

I agree with Hamilton-Craig that we require trials measuring major cardiovascular events to really understand the effects of ezetimibe. Where we disagree is how to manage our patients during the period of uncertainty until publication of the results of these trials. While he argues for continued prescribing of ezetimibe, I suggest we should explicitly share our uncertainty about the safety and efficacy of this drug with our patients by discussing the existing research. Some patients will, like Hamilton-Craig, place their faith in the cholesterol hypothesis and be reassured by an assumption of cardiovascular protection as their LDL falls. Others will choose to wait until we have more robust evidence that ezetimibe is safe and effective. I would wait.