TY - JOUR
T1 - The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection)
T2 - A randomised placebo-controlled trial
AU - Baigent, Colin
AU - Landray, Martin J.
AU - Reith, Christina
AU - Emberson, Jonathan
AU - Wheeler, David C.
AU - Tomson, Charles
AU - Wanner, Christoph
AU - Krane, Vera
AU - Cass, Alan
AU - Craig, Jonathan
AU - Neal, Bruce
AU - Jiang, Lixin
AU - Hooi, Lai Seong
AU - Levin, Adeera
AU - Agodoa, Lawrence
AU - Gaziano, Mike
AU - Kasiske, Bertram
AU - Walker, Robert
AU - Massy, Ziad A.
AU - Feldt-Rasmussen, Bo
AU - Krairittichai, Udom
AU - Ophascharoensuk, Vuddidhej
AU - Fellström, Bengt
AU - Holdaas, Hallvard
AU - Tesar, Vladimir
AU - Wiecek, Andrzej
AU - Grobbee, Diederick
AU - De Zeeuw, Dick
AU - Grönhagen-Riska, Carola
AU - Dasgupta, Tanaji
AU - Lewis, David
AU - Herrington, William
AU - Mafham, Marion
AU - Majoni, William
AU - Wallendszus, Karl
AU - Grimm, Richard
AU - Pedersen, Terje
AU - Tobert, Jonathan
AU - Armitage, Jane
AU - Baxter, Alex
AU - Bray, Christopher
AU - Chen, Yiping
AU - Chen, Zhengming
AU - Hill, Michael
AU - Knott, Carol
AU - Parish, Sarah
AU - Simpson, David
AU - Sleight, Peter
AU - Young, Alan
AU - Collins, Rory
N1 - Funding Information:
We thank the participants in SHARP and the local clinical centre staff, regional and national coordinators, steering committee, and data monitoring committee. The study was funded by Merck/Schering-Plough Pharmaceuticals (North Wales, PA, USA), with additional support from the Australian National Health Medical Research Council, the British Heart Foundation, and the UK Medical Research Council. JE acknowledges support from the British Heart Foundation Centre of Research Excellence (Oxford, UK; RE/08/04).
PY - 2011
Y1 - 2011
N2 - Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. 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 (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607. 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 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). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal 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 non-haemorrhagic stroke (131 [2·8] vs 174 [3·8]; RR 0·75, 95 CI 0·60-0·94; p=0·01) and arterial revascularisation 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 rate ratio 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 two 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 non-vascular cause (668 [14·4] vs 612 [13·2], p=0·13). Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease. Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.
AB - Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. 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 (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607. 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 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). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal 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 non-haemorrhagic stroke (131 [2·8] vs 174 [3·8]; RR 0·75, 95 CI 0·60-0·94; p=0·01) and arterial revascularisation 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 rate ratio 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 two 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 non-vascular cause (668 [14·4] vs 612 [13·2], p=0·13). Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease. Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.
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U2 - 10.1016/S0140-6736(11)60739-3
DO - 10.1016/S0140-6736(11)60739-3
M3 - Article
C2 - 21663949
AN - SCOPUS:79959746706
SN - 0140-6736
VL - 377
SP - 2181
EP - 2192
JO - The Lancet
JF - The Lancet
IS - 9784
ER -
