Cholesterol-lowering treatment with a combination of ezetimibe and simvastatin significantly decreases the likelihood of major atherosclerotic events in patients with chronic kidney disease (CKD), according to the findings of the five-year Study of Heart and Renal Protection (SHARP) trial.
CKD patients treated with the dual regimen experienced one sixth fewer heart attacks, strokes, and revascularization procedures, researchers reported. Had patients in the trial been fully compliant with treatment (about one third stopped taking their randomly assigned treatments), the dual regimen would have reduced the risk of these cardiovascular (CV) outcomes by about one quarter, thus avoiding 30-40 events per 1,000 patients over 5 years. Overall, the study revealed no increased risk of myopathy, liver and biliary disorders, cancer, or non-vascular mortality with this combination therapy.
“SHARP provides the first direct evidence that cholesterol-lowering is indeed effective in kidney patients, and that the benefits are substantial,” said principal trial investigator Colin Baigent, FRCP, a research scientist at the University of Oxford in the UK.
Dialysis and non-dialysis patients experienced similar proportional reductions in CV events, he said.
Previous large-scale randomized trials have shown that lowering LDL cholesterol level by about 40 mg/dL reduces the risk of coronary events and strokes by about one fifth in patients with pre-existing coronary heart disease (CHD). It has been unclear, however, whether lowering LDL cholesterol would decrease CV event risk in CKD patients, who systematically have been excluded from randomized, controlled clinical trials of cholesterol lowering treatments.
SHARP included 9,438 patients aged 40 and older with CKD recruited from 380 hospitals in 18 countries. All the patients had lost at least 50% of their normal kidney function, with a third of them requiring dialysis. None had experienced a previous heart attack or needed bypass surgery or stents to unblock clogged coronary arteries. Investigators randomized subjects to take a tablet containing ezetimibe 10 mg daily and simvastatin 20 mg daily, or matching placebo. The key endpoint was “major atherosclerotic event” during the five years, defined as non-fatal myocardial infarction or coronary death, non-hemorrhagic stroke, or revascularization. The study group had a mean age of 62 years and was 63% male. The mean systolic blood pressure was 139 mm Hg and the mean diastolic blood pressure was 79 mm Hg.
Patients allocated to receive ezetimibe plus simvastatin had one sixth fewer major atherosclerotic events, with similar reductions observed in all types of patient studied. During the five-year study period, about one third of patients stopped taking their allocated treatment, but this was not generally due to adverse effects and was the same for both the active treatment arm and the placebo arm. If taken without interruption, ezetimibe plus simvastatin could have even larger effects than observed in SHARP, potentially reducing the risk by about one quarter, according to the researchers.
The study showed no substantial effect on kidney disease progression, although further analyses will be exploring any possible renal effects in more detail. The two thirds compliance rate with the combination therapy reduced the risk of major atherosclerotic events by 17%, which was consistent with a meta-analysis of previous statin trials, Dr. Baigent said.