Is ezetimibe/simvastatin no better than simvastatin alone? Lessons learned and clinical implications
LESSONS LEARNED AND CLINICAL IMPLICATIONS
For Merck/Schering-Plough, missed opportunities
Although Dr. Krumholz (the spokesman for the ACC panel discussion) and I disagree on the clinical implications of the ENHANCE trial, we do agree on an important point. Dr. Krumholz posed the question that if the LDL-C-lowering hypothesis was already proven for ezetimibe, why was the ENHANCE trial conducted? After 6 years on the market, the efficacy of ezetimibe on cardiovascular outcomes should already have been established. It should not take this long to determine the clinical outcome benefit for a drug.
Merck/Schering-Plough’s outcome program for ezetimibe was inadequately designed to demonstrate the clinical value of this novel compound. Rather than assuming the LDL-C-lowering hypothesis was already established, they conducted another “lower-is-better” trial with the carotid intima-media thickness as the end point, and they succeeded only in raising doubt about the benefits of ezetimibe rather than showing that dual therapy is at least equivalent to high-dose statin therapy.
A preferable approach would have been to compare the effects of a statin in low doses plus ezetimibe vs high-dose statin monotherapy on either surrogate or hard outcomes. If the low-dose statin/ezetimibe combination, which should lower the LDL-C level as much as high-dose statin monotherapy, could provide similar or better outcomes with fewer side effects, this trial would change our practice.
One had hoped that dual therapy, by reducing both intestinal cholesterol absorption and hepatic synthesis of cholesterol, would improve outcomes by modifying postprandial chylomicron composition or by reducing plant sterol absorption.36 Unfortunately, other outcome trials of ezetimibe/simvastatin will not provide an answer regarding the potential advantages of dual therapy. The SEAS study is comparing the number of clinical events in patients with aortic stenosis who receive ezetimibe/simvastatin or placebo; SHARP is being conducted in patients with chronic kidney disease. Although both groups of patients have high rates of coronary events, these trials will not address whether adding ezetimibe provides additional benefits. In fact, if the results of these trials turn out neutral, as in ENHANCE, then ezetimibe will be blamed for potentially offsetting the benefits of simvastatin, and if the trials show a benefit, the simvastatin component of ezetimibe/simvastatin will be given the credit.
The answer may come in 3 to 4 years with the results of IMPROVE-IT, a study of 18,000 patients with acute coronary syndrome treated with ezetimibe/simvastatin or simvastatin. The simvastatin monotherapy group will have a target LDL-C level of less than 80 mg/dL and the ezetimibe/simvastatin group will have an LDL-C target about 15% less. Although this trial is testing the lower-is-better hypothesis with ezetimibe, if the study does not show a benefit, it may not be because ezetimibe lacks clinical efficacy but rather because the LDL-C effect is curvilinear, and there is minimal further benefit of lowering the LDL-C level past 70 mg/dL. If the results of the IMPROVE-IT trial are negative, it may mean the end of ezetimibe as an LDL-C-lowering drug.
Merck/Schering-Plough has lost valuable time in not demonstrating the benefits of ezetimibe on clinical events. In contrast, consider rosuvastatin, an AstraZeneca product. Rosuvastatin was approved about the same time as ezetimibe/simvastatin, and 6 years later it has already received a label change for the reduction of progression of atherosclerosis, based on positive outcomes in the METEOR trial,35 the ASTEROID intravascular ultrasonography trial,37 and the CORONA trial (an important trial that examined hard clinical end points).38 More importantly, the JUPITER trial was recently stopped early owing to a reduction in cardiovascular deaths. Initially, rosuvastatin received an unfair media portrayal as an unsafe drug. Now, because of its proven benefits in outcome trials, it will receive more widespread consideration for clinical use.
For preventive cardiologists, a painful reminder to focus on LDL-C
For the preventive cardiologist or lipidologist, the ENHANCE trial has been a painful reminder that despite overwhelming evidence, the mantra of “the lower the LDL-C the better” is still not universally accepted. We acknowledge the great benefits of statins, but the lure of “pleiotropic effects” distracts many of us from the necessity of more aggressive LDL-C reduction.
The pleiotropic benefits of statins were first raised as a means of supporting increased clinical use of pravastatin vis-a-vis other, more efficacious statins. It was not until the PROVE-IT study that pravastatin’s pleiotropic effects were found not to translate into a benefit equivalent to that of the more efficacious statin, atorvastatin.39
The success of ezetimibe was its ability to safely and easily lower LDL-C in combination with statins to achieve treatment goals. For many patients, a lower-dose statin and ezetimibe together provide a well-tolerated and efficacious approach to treating hyperlipidemia. The fallout from the ENHANCE trial is that many patients who were well treated or who could be better treated with ezetimibe in combination with a statin will not receive the best tolerated regimen. In fact, preliminary prescription data after the release of the ENHANCE study support our worse fear, ie, that patients at high risk will receive less aggressive LDL-C reduction. Since the ENHANCE data were released, more than 300,000 patients have stopped taking either ezetimibe/simvastatin or ezetimibe, and nearly all have continued on generic simvastatin or on a dose of statin with less overall efficacy.
An example is Senator John McCain, who, according to his recently released medical records, has a Framingham 10-year risk of more than 20% and was on ezetimibe/simvastatin to treat an elevated cholesterol level. After release of the ENHANCE trial, he was switched to generic simvastatin, and his LDL-C increased from 82 mg/dL to 122 mg/dL. He most likely has an LDL-C goal of less than 100 mg/dL according to the ATP III guidelines, and he is therefore no longer at his target.
