SHARP trial shows that combination statin therapy in patients with CKD reduces risk of heart attack and stroke without raising cancer risk.
Results from the world’s largest randomized trial involving patients with kidney disease show that lowering cholesterol through long-term combination therapy using ezetimibe and simvastatin could prevent up to one-quarter of heart attacks and strokes experienced by patients with chronic kidney disease (CKD).
Speaking at Renal Week 2010, the American Society of Nephrology 43rd Annual Meeting and Scientific Exposition, principal investigator Colin Baigent, BM, BCh, said research confirms that cholesterol-lowering regimens for CKD patients are equally as valuable as those for people with normally functioning kidneys, contradicting earlier beliefs that high cholesterol was not an important contributor to heart disease or stroke in this patient population.
Confusion over the utility of lowered LDL cholesterol in kidney disease patients had formed the basis of patient participation in the ambitious trial. “The chief criterion for entry into the study was if their doctor was uncertain whether to treat with LDL-lowering therapy,” explained Baigent.
The double-blind, placebo-controlled Study of Heart and Renal Protection (SHARP) involved nearly 9,500 patients recruited from 380 hospitals in 18 countries. Volunteers age 40 or over had lost at least 50% of their normal kidney function. A third of them were on dialysis. None had experienced previous heart attacks or were diagnosed as bypass surgery or stent candidates.
Patients in the active group took 10 mg of ezetimibe and 20 mg of simvastatin daily, with treatment and follow-up continuing for an average of five years. Evidence showed that the drug combination safely produced a large reduction in LDL cholesterol.
While 17% of patients on the therapy experienced fewer major atherosclerotic events than patients in the placebo group, researchers factored in the approximately one-third of patients in both the active and placebo groups who stopped the treatment for reasons other than detrimental side effects, and estimated that the true measure of risk reduction was closer to one-quarter of the patient population.
“The SHARP trial is apt to provide clear evidence that lowering cholesterol with ezetimibe with statin safely reduces the risk of atherosclerotic events,” said co-investigator Martin Landray, PhD. “These highly significant treatment effects are actually an underestimate of what would be the true value if patients actually took the tablets. During the course of this study, around two-thirds of the patients took the tablets.”
The trial revealed no evidence that the combination therapy could retard the progression of CKD. “The study included about six and a half thousand people who were not on dialysis at the beginning of the study,” Landray said. “During the course of the study, many of those people did of course go onto dialysis. There had been a hope that perhaps lowering LDL cholesterol would not only reduce the risk of major atherosclerotic events, but also would slow the progression to end stage renal disease.”
Results did, however, indicate the therapy is not associated with adverse events related to muscle or liver problems, myopathy, hepatitis, gall stones, or other complications. And researchers found no detrimental impact of the drugs on existing cancers.
“The key question that we had about safety, particularly with a combination that included both a statin and ezetimibe, was what would happen to cancer, said Landray. “There were 850 cancers which occurred after randomization in this trial. There was no significant difference in the number of cancers that occurred in those on active treatments and those on the placebo treatment.”
The SHARP results are also relevant to people who don’t have CKD in that the combination of ezetimibe and a statin produced similar benefits to those resulting from similar LDL cholesterol reductions achieved with high doses of statin only. Since the lower the cholesterol the bigger the risk reduction, these results suggest that patients who remain at high risk of major atherosclerotic events despite maximal statin therapy may benefit further from adding ezetimibe to their current statin regimen.