DENVER—In a trial of 9,270 patients, the combination of ezetimibe and simvastatin reduced the risk of major atherosclerotic events in kidney disease. The trial is the Study of Heart and Renal Protection (SHARP), which was presented during the late-breaking clinical trial session here at the American Society of Nephrology Renal Week 2010.
“It's the largest study ever done in the history of nephrology, and it's a landmark trial,” noted Rajiv Agarwal, MD, Professor of Medicine at Indiana University School of Medicine, who co-moderated the session during which the results were presented.
“It showed a 17-percent risk reduction in the major atherosclerotic events, and if you go back and look at the original endpoint they had proposed as the primary endpoint, even there you have a highly statistically significant 15-percent reduction in major vascular events, so by any criteria that's a positive trial.”
Ajay K. Singh, MBBS, MBA, Senior Nephrologist at Brigham and Women's Hospital, Associate Professor of Medicine at Harvard Medical School, and Chair of the Nephrology Times Editorial Board, agreed.
“I thought the study finally put to rest the idea that statins are not effective in modulating or in protecting patients from cardiovascular events in kidney disease, whether they're dialysis or non-dialysis patients. I think it was a remarkable study.”
There has been some discussion, though, about the effect of the treatment in the dialysis versus the non-dialysis population.
“They did not find heterogeneity of effect between dialysis and non-dialysis patients,” Dr. Agarwal said. “However, if you just look at dialysis in isolation, those patients did not have a statistically significant benefit.
“If you talk to a statistician, he'll tell you the dialysis patients will benefit as much as non-dialysis patients, but to a clinician this might not be true because dialysis patients don't have so many MIs [myocardial infarctions] compared with sudden deaths, whereas CKD [chronic kidney disease] patients have a lot more MIs than sudden deaths, so there are differences in the diseases between the two groups, and the drug may be less effective in those people who have more advanced kidney disease and are on dialysis.
“The authors obviously disagree with that and would say that both are effective, and they might be right, but, to me, in dialysis patients to reduce cardiovascular risk you also need to control volume and blood pressure risk besides using this drug, and the same is perhaps true in patients with chronic kidney disease, although we have never demonstrated that aggressive lowering of blood pressure protects people from cardiovascular disease any more than the average reduction in blood pressure.”
SHARP was sponsored, designed, run, and analyzed by the University of Oxford, and funding was received from Merck, the United Kingdom Medical Research Council, the British Heart Foundation, and the Australian National Health and Medical Research Council. Colin Baigent, MD, and Martin Landray, PhD, both of the University of Oxford, presented the results on behalf of the SHARP investigators.
‘A Strong Rationale’
Included in SHARP were patients with a history of chronic kidney disease who were at least 40 years old and did not have a history of myocardial infarction or coronary revascularization. Eligible patients also were those in whom lowering of low-density-lipoprotein cholesterol was neither definitely indicated nor contraindicated. Initially, 9,438 patients were randomized—4,193 to the ezetimibe and simvastatin arm, 1,054 to the simvastatin arm, and 4,191 to the placebo arm.
Later, 886 patients in the simvastatin arm were re-randomized into the other two arms, making a total of 4,650 patients in the ezetimibe/simvastatin arm and 4,620 in the placebo arm. Median follow-up was 4.9 years.
In addition to examining major atherosclerotic events, the trial also looked at renal outcomes, observing no difference in kidney disease progression between the two groups.
In terms of safety, there was no increase in risk of myopathy, liver and biliary disorders, cancer, or nonvascular mortality with the treatment.
“These results are incredibly reassuring,” Dr. Landray said during the presentation. “The SHARP results provide clear evidence that lowering cholesterol with ezetimibe and simvastatin safely reduces the risk of major atherosclerotic events.”
That evidence does have clinical implications, noted Josef Coresh, MD, PhD, Professor at Johns Hopkins Bloomberg School of Public Health, in a phone interview after the meeting.
“I think it resolves a long-standing controversy, and it provides a strong rationale that patients with severe CKD should be treated with statins if their risk of atherosclerotic events is high. In that sense, I think it has pretty major clinical implications. Now some physicians are already doing this and some aren't, so for the ones who aren't, it has major implications.”
More broadly speaking, the results of SHARP also demonstrate the benefit of conducting large-scale clinical trials in nephrology.
“I've always been impressed that the SHARP study was extremely well thought out, and I was quite pleased that the results showed a benefit for patients with chronic kidney disease, which is important because the number of therapies we have that are effective is not very large,” Dr. Coresh said.