SHARP: Ezetimibe/simvastatine combi verlaagt vasculair risico bij CNS

SHARP: Ezetimibe/simvastatin combo cuts atherosclerotic and vascular events in kidney disease patients

November 20, 2010

Denver, CO - Final results of the Study of Heart and Renal Protection (SHARP) trial show that cholesterol lowering with a combination of simvastatin and ezetimibe (Vytorin, Merck) in patients with kidney disease significantly reduced the risk of "major atherosclerotic events" by 17%, and the primary end point for the study, major vascular events, by almost the same degree.

Lead investigators Drs Colin Baigent and Martin Landray (Clinical Trials Service Unit, Oxford, UK) presented the results today here at the American Society of Nephrology's Renal Week 2010.

After a median follow-up of 4.9 years, patients randomized to the ezetimibe/simvastatin combination experienced a 17% reduction in major atherosclerotic events compared with the placebo group, a statistically significant difference (p=0.0022).

For the prespecified primary end point of major vascular events, patients in the active treatment group experienced a statistically significant 15.3% reduction (p=0.0012), as compared with placebo.

Controversial trial tweaks
The similar findings for both "atherosclerotic" and "major vascular events" may help put to rest controversy that has dogged this study in advance of its presentation, namely the announcement by investigators that they would not be "emphasizing" the prespecified primary end point of major vascular events when presenting the final results, as reported by heartwire. That decision was taken after the trial sponsors rejected a request to formally change the trial's primary endpoint—something that would surely have opened the credibility of the trial results to major scrutiny had the 'new' end point proved positive, and the pre-specified had not.

The SHARP steering committee's stated reasons for changing their "emphasis" was 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 was diluted by nonatherosclerotic events. As designed, the SHARP trial's primary end point had included hemorrhagic stroke, which is unlikely to be altered by LDL lowering, Baigent explained to heartwire last month. "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," he said.

SHARP enrolled 9438 patients with chronic kidney disease either on dialysis, or with a creatinine >1.7 mg/dL for men or >1.5 mg/dL for women, all with no history of MI or coronary revascularization. As Baigent observed in presenting the results, the main entry criteria had to be that a patient's doctor was uncertain whether or not the patient should be on cholesterol-lowering drugs: previous studies of LDL-lowering in CKD patients have been "inconclusive," he noted.

In the first year of the study, patients were randomized to either ezetimibe/simvastatin (10 mg/20 mg) versus placebo, with an additional 1000 patients randomized to simvastatin alone. After one year, patients in the simvastatin alone arm were rerandomized, so that the comparison presented today was the outcomes in patients randomized to placebo, versus ezetimibe/simvastatin.

SHARP results
As noted, both major atherosclerotic events and major vascular events were reduced in the active treatment group after almost five years of treatment.

For the secondary end point of progression to end-stage renal disease, no differences were seen between groups, with roughly one-third of patients in both arms progressing to dialysis or transplantation. Subgroup analyses, including an analysis of patients on or off dialysis, found no difference between groups.

Importantly, said Baigent and Landray, no difference in incidence of cancer was seen between groups, at roughly 9.5% in both. Other safety end points including rates of myopathy, hepatitis, gallstones, etc, were no different between groups.

Of note, one-third of SHARP patients discontinued treatment over the course of the trial, with similar rates of "noncompliance," as investigators put it, between groups. According to investigators, this implies the results would actually be even stronger in the real world, where patients and physicians could be confident that taking their meds would actually be beneficial.

"Full compliance would reduce the risk of major atherosclerotic events by one quarter, avoiding 30-40 events per 1000 patients treated for five years," they estimated.

Clearing confusion
Commenting on the study for heartwire, Dr James Stein pointed out that while SHARP is being touted as the first trial to show a benefit of cholesterol lowering in CKD patients, it is not. The Deutsche Diabetes Dialyse Studie (4D) also showed significant reductions in stroke and all cardiac events with a statin only (atorvastatin 20mg), although all cardiac events was a secondary, not primary, end point in 4D.

Of note, 4D found opposite results from A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA), which saw no benefit of cholesterol lowering in CKD patients, fostering confusion over the question of lipid-lowering in CKD patients.

"I think most kidney docs were still treating patients with statins despite the AURORA study, and this just proves to them that they were right after all," Stein told heartwire. "I would point out that the absolute benefits [in SHARP] were quite small—you have to treat a lot of people to prevent one event. But most of these patients are already being treated with statins and this is going to help cement that."

Answers, and more questions
But for Stein, at least two questions are not answered in SHARP. For one, he says, he is not reassured on the ezetimibe cancer findings—an issue debated in the past. "This is a small and short study. . . . This just doesn't tell us anything about cancer: a five year study in people with advanced kidney disease is not a place to study the cancer safety of a drug."

As well, he says, SHARP does not speak to the role of ezetimibe on top of a statin. "This tells us really nothing at all about the efficacy of ezetimibe and whether ezetimibe had anything to do with the results. It's perfectly possible that they would have gotten the same results if they'd used simvastatin 20 mg or simvastatin 40 mg a day." To understand the role of ezetimibe, SHARP would also have needed a statin-only arm—something SHARP had only for the first year of the study.

Addressing this complaint in a morning press conference, Baigent noted that the three-way randomization in the first year was to make sure ezetimibe was safe—something not well known at the study outset. And he pointed out that to continue the three-way randomization would have required a sample size of 30 000 to 40 000 participants. "We struggled to recruit 9000, so you can imagine how hard it would have been to recruit 40 000."

And Baigent pointed out that the amount of LDL lowering seen in SHARP, and the reduction in events it produced, was similar to that seen for other trials that have used statins alone. "So my guess is that no, it's not something special that ezetimibe is doing, just lowering LDL cholesterol the same way that statins do."

But he also thought the questions about ezetimibe's contributions were somewhat beside the point. "We thought the key question was, does a large reduction in LDL cholesterol benefit kidney patients? This trial shows very clearly that it does."