SHARP Tweaked: "Statistical Plan" Changed in Ongoing Ezetimibe/Simvastatin Trial

October 06, 2010

October 6, 2010 (Oxford, United Kingdom) — The evaluation of the efficacy of lipid-lowering therapy with ezetimibe/simvastatin (Vytorin, Merck) in the Study of Heart and Renal Protection (SHARP) trial will no longer focus on the primary end point of major vascular events but instead will emphasize the effect on major atherosclerotic events, defined as the combination of coronary death, MI, ischemic stroke, or any revascularization procedure [1].

The change in emphasis, according to investigators, is to reduce the possibility of a "false-negative" trial, where the potential benefit of LDL-lowering therapy on atherosclerotic outcomes in patients with chronic kidney disease is diluted by nonatherosclerotic events.

"The steering committee was concerned about the primary end point, because it includes both noncoronary cardiac death, which is a frequent cause of death in patients like those included in SHARP, and hemorrhagic stroke, which the most recent meta-analyses suggest is not prevented by LDL lowering," study coordinator and lead investigator Dr Colin Baigent (Clinical Trials Service Unit, Oxford, UK) explained to heartwire . "Therefore, we wanted an end point that would be as sensitive as possible to any real benefit, which is reflected in nonfatal myocardial infarction and coronary cardiac death, revascularization, and ischemic stroke."

The trial sponsor denied a request from investigators to have the primary end point changed, hence the "change in emphasis." Details on the changes, as well as some early safety and efficacy data, are published online September 20, 2010 in the American Heart Journal.

4D and AURORA Throw a Wrench

Briefly, the SHARP trial includes more than 9000 chronic kidney disease patients, including approximately 3000 patients on dialysis, randomized to lipid-lowering treatment with ezetimibe/simvastatin or placebo. Although LDL-lowering therapy with statins has been shown to be beneficial in a wide variety of patients, the effect of treatment in chronic kidney disease patients is unknown.

Two trials, Deutsche Diabetes Dialyse Studie (4D) and A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA), both failed to show a benefit of statin therapy in patients with end-stage renal failure undergoing dialysis. As a result of these two studies, as well as evidence from epidemiologic studies and studies of heart-failure patients, Baigent told heartwire that investigators felt that the SHARP trial needed to be readjusted.

"Remember, SHARP was being designed in the early part of 2000, before 4D and AURORA had emerged, and we thought that some major vascular events might be nonatherosclerotic, might just simply be attributable to hypertensive heart disease or sudden death, and so on," he said. "What we've learned from those trials is that these patients frequently die suddenly and that coronary heart disease might actually be a much less frequent cause of death than we originally anticipated."

As part of their regular statistical checks on the trial, SHARP investigators noted that the primary end point of major vascular events was 4.3% per year, slightly higher than anticipated, and that 33% of these events were noncoronary cardiac deaths and hemorrhagic strokes, two outcomes known to not be affected by reductions in LDL cholesterol. In addition, blinded review showed that reductions in LDL cholesterol were smaller than expected among the simvastatin/ezetimibe-treated patients: 33 mg/dL vs an expected 39-mg/dL reduction.

As a result of the discrepancy with their underlying assumptions, the SHARP steering committee, still blinded to the effects of study treatment, decided in October 2009 to change the primary outcome to major atherosclerotic events and approached the sponsor, as required in the contract, to seek approval for the change. Merck, however, declined to approve the changes. Unable to change the trial's primary end point, the investigators changed the study's statistical analysis plan, focusing instead on major atherosclerotic events.

Baigent stressed that investigators are still blinded to the treatment effects, and the change in statistical analysis has been published prior to the introduction of the study's results, so as to refute any accusations of possible bias.

Safety and LDL Changes

In addition to reporting their change of focus, the SHARP investigators also published one-year and 30-month safety data with ezetimibe. Baigent noted that the study protocol includes a three-way randomization--comparison of placebo vs simvastatin vs ezetimibe/simvastatin--so as to assess the safety of ezetimibe after 12 months of treatment. Compared with placebo or simvastatin alone, patients treated with ezetimibe/simvastatin had no increased risk of myopathy, excess toxicity, or biliary complications during follow-up. In the overall trial, patients were rerandomized to placebo or simvastatin/ezetimibe.

"If there had been any safety issues, it would have been reasonable for that to have been picked up in the first year," said Baigent.

As noted, the average LDL reduction among ezetimibe/simvastatin patients was 43 mg/dL at one year and 33 mg/dL at 30 months. Baigent told heartwire that there is no accepted management of cardiovascular disease in chronic kidney disease patients and that it's likely these patients have substantially modified atherosclerosis, possibly with more calcification, vascular stiffness, or left ventricular disease. "So unless you focus on what you can do for their atherosclerotic disease, you're going to miss whatever is going on," he said.


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