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.
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.
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DOI：
10.1016/s0140-6736(11)60739-3
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发表时间：
2011-06-25
期刊：
影响因子：
168.9
通讯作者：
Collins, Rory
中科院分区：
文献类型：
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作者：
Baigent, Colin;Landray, Martin J.;Reith, Christina;Emberson, Jonathan;Wheeler, David C.;Tomson, Charles;Wanner, Christoph;Krane, Vera;Cass, Alan;Craig, Jonathan;Neal, Bruce;Jiang, Lixin;Hooi, Lai Seong;Levin, Adeera;Agodoa, Lawrence;Gaziano, Mike;Kasiske, Bertram;Walker, Robert;Massy, Ziad A.;Feldt-Rasmussen, Bo;Krairittichai, Udom;Ophascharoensuk, Vuddidhej;Fellstrom, Bengt;Holdaas, Hallvard;Tesar, Vladimir;Wiecek, Andrzej;Grobbee, Diederick;de Zeeuw, Dick;Gronhagen-Riska, Carola;Dasgupta, Tanaji;Lewis, David;Herrington, William;Mafham, Marion;Majoni, William;Wallendszus, Karl;Grimm, Richard;Pedersen, Terje;Tobert, Jonathan;Armitage, Jane;Baxter, Alex;Bray, Christopher;Chen, Yiping;Chen, Zhengming;Hill, Michael;Knott, Carol;Parish, Sarah;Simpson, David;Sleight, Peter;Young, Alan;Collins, Rory
他汀类药物降低低密度脂蛋白胆固醇可降低心肌梗死、缺血性卒中的风险，并减少无肾病患者冠状动脉血运重建的需要，但其对中重度肾病患者的影响尚不确定。SHARP试验旨在评估辛伐他汀联合依折麦布治疗此类患者的疗效和安全性。这项随机双盲试验纳入了9270例无心肌梗死或冠状动脉血运重建病史的慢性肾脏疾病患者（3023例接受透析，6247例未接受透析）。患者被随机分配至辛伐他汀20 mg+依折麦布10 mg每日一次组，与匹配的安慰剂组相比。预先规定的关键结局是首次重大动脉粥样硬化事件（非致死性心肌梗死或冠状动脉死亡、非出血性卒中或任何动脉血运重建术）。所有分析均按意向治疗进行。该试验在ClinicalTrials.gov、NCT 00125593和ISRCTN 54137607上注册。4650例患者被分配接受辛伐他汀加依折麦布治疗，4620例患者接受安慰剂治疗。辛伐他汀+依折麦布组的平均LDL胆固醇差异为0.85 mmol/L（SE 0.02;约三分之二的依从性），主要动脉粥样硬化事件比例降低17（辛伐他汀+依折麦布组526例[11.3%] vs安慰剂组619例[13.4%];率比[RR] 0.83，95%CI 0.74 - 0.94;对数秩p= 0.0021）。辛伐他汀+依折麦布组发生非致死性心肌梗死或死于冠心病的患者较少，但无显著性差异（213例[4.6%] vs 230例[5.0%]; RR 0.92，95%CI 0.76 - 1.11; p= 0.37），非出血性卒中显著减少（131 [2.8%] vs 174 [3.8%]; RR 0.75，95% CI 0.60 - 0.94; p= 0.01）和动脉血运重建术（284 [6.1%] vs 352 [7.6%]; RR 0.79，95% CI 0.68 - 0.93; p= 0.0036）。在对亚组特异性LDL胆固醇降低进行加权后，没有很好的证据表明对主要动脉粥样硬化事件的比例效应与所检查的任何亚组的汇总率比不同，特别是在透析患者和未透析患者中相似。肌病的额外风险仅为2/10000例患者/年（9 [0.2%] vs 5 [0.1%]）。 没有证据表明肝炎的风险过高（21例[0·5%] vs 18例[0·4%]），胆结石（106 [2.3%] vs 106 [2.3%]），或癌症（438例[9.4%] vs 439例[9.5%]，p= 0.89），任何非血管原因导致的死亡均无显著增加（668例[14.4%] vs 612例[13.2%]，p= 0.13）。辛伐他汀20 mg+依折麦布10 mg每日降低LDL胆固醇可安全降低大部分晚期慢性肾脏疾病患者的主要动脉粥样硬化事件发生率。默克/先灵葆雅制药公司;澳大利亚国家健康和医学研究理事会;英国心脏基金会;英国医学研究理事会。
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.