The Effects of Lowering LDL Cholesterol With Simvastatin Plus Ezetimibe in Patients With Chronic Kidney Disease (Study of Heart and Renal Protection): A Randomised Placebo-Controlled Trial

Study Questions:

What is the efficacy and safety of the combination of simvastatin plus ezetimibe in patients with moderate to severe kidney disease?

Methods:

This randomized double-blind trial included 9,270 patients with chronic kidney disease (3,023 on dialysis and 6,247 not) with no known history of myocardial infarction or coronary revascularization. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (nonfatal myocardial infarction or coronary death, nonhemorrhagic stroke, or any arterial revascularization procedure). All analyses were by intention to treat. Time-to-event analyses used log-rank methods to calculate two-sided p values, event rate ratios, and 95% confidence intervals.

Results:

A total of 4,650 patients were assigned to receive simvastatin plus ezetimibe and 4,620 to receive placebo. Allocation to simvastatin plus ezetimibe yielded an average low-density lipoprotein (LDL) cholesterol difference of 0.85 mmol/L (standard error, 0.02; with about two-thirds compliance) during a median follow-up of 4.9 years, and produced a 17% proportional reduction in major atherosclerotic events (526 [11.3%] simvastatin plus ezetimibe vs. 619 [13.4%] placebo; rate ratio [RR], 0.83; 95% CI, 0.74-0.94; log-rank p = 0.0021). Nonsignificantly fewer patients allocated to simvastatin plus ezetimibe had a nonfatal myocardial infarction or died from coronary heart disease (213 [4.6%] vs. 230 [5.0%]; RR, 0.92; 95% CI, 0.76-1.11; p = 0.37) and there were significant reductions in nonhemorrhagic stroke (131 [2.8%] vs. 174 [3.8%]; RR, 0.75; 95% CI, 0.60-0.94; p = 0.01) and arterial revascularization procedures (284 [6.1%] vs. 352 [7.6%]; RR, 0.79; 95% CI, 0.68-0.93; p = 0.0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary RR in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only 2 per 10,000 patients per year of treatment with this combination (9 [0.2%] vs. 5 [0.1%]). There was no evidence of excess risks of hepatitis (21 [0.5%] vs. 18 [0.4%]), gallstones (106 [2.3%] vs. 106 [2.3%]), or cancer (438 [9.4%] vs. 439 [9.5%], p = 0.89) and there was no significant excess of death from any nonvascular cause (668 [14.4%] vs. 612 [13.2%], p = 0.13).

Conclusions:

The authors concluded that reduction of LDL cholesterol with simvastatin plus ezetimibe safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.

Perspective:

The study shows that lowering LDL cholesterol with the combination of simvastatin plus ezetimibe safely reduces the risk of major atherosclerotic events in a wide range of patients with chronic kidney disease. As in people without kidney disease, the proportional reduction in major atherosclerotic events produced by a given absolute reduction in LDL cholesterol was broadly similar irrespective of age, sex, diabetes, history of vascular disease, and presenting lipid profile. The results would, therefore, apply to most patients with chronic kidney disease. Overall, the results suggest that widespread use of any LDL-cholesterol-lowering therapy in patients with chronic kidney disease would result in a worthwhile reduction in cardiovascular disease complications in this high-risk population.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Statins

Keywords: Myocardial Infarction, Stroke, Neoplasms, Follow-Up Studies, Hepatitis, Vascular Diseases, Lipoproteins, Gallstones, Coronary Disease, Simvastatin, Cholesterol, Renal Dialysis, Renal Insufficiency, Kidney Diseases, Azetidines, Cardiovascular Diseases, Confidence Intervals, Muscular Diseases, Diabetes Mellitus


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