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

Colin Baigent; Martin J Landray; Christina Reith; Jonathan Emberson; David C Wheeler; Charles Tomson; Christoph Wanner; Vera Krane; Alan Cass; Jonathan Craig; Bruce Neal; Lixin Jiang; Lai Seong Hooi; Adeera Levin; Lawrence Agodoa; Mike Gaziano; Bertram Kasiske; Robert Walker; Ziad A Massy; Bo Feldt-Rasmussen; Udom Krairittichai; Vuddidhej Ophascharoensuk; Bengt Fellström; Hallvard Holdaas; Vladimir Tesar; Andrzej Wiecek; Diederick Grobbee; Dick de Zeeuw; Carola Grönhagen-Riska; Tanaji Dasgupta; David Lewis; William Herrington; Marion Mafham; William Majoni; Karl Wallendszus; Richard Grimm; Terje Pedersen; Jonathan Tobert; Jane Armitage; Alex Baxter; Christopher Bray; Yiping Chen; Zhengming Chen; Michael Hill; Carol Knott; Sarah Parish; David Simpson; Peter Sleight; Alan Young; Rory Collins; SHARP Investigators

doi:10.1016/S0140-6736(11)60739-3

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

Colin Baigent, Martin J Landray, Christina Reith, Jonathan Emberson, David C Wheeler, Charles Tomson, Christoph Wanner, Vera Krane, Alan Cass, Jonathan Craig, Bruce Neal, Lixin Jiang, Lai Seong Hooi, Adeera Levin, Lawrence Agodoa, Mike Gaziano, Bertram Kasiske, Robert Walker, Ziad A Massy, Bo Feldt-RasmussenUdom Krairittichai, Vuddidhej Ophascharoensuk, Bengt Fellström, Hallvard Holdaas, Vladimir Tesar, Andrzej Wiecek, Diederick Grobbee, Dick de Zeeuw, Carola Grönhagen-Riska, Tanaji Dasgupta, David Lewis, William Herrington, Marion Mafham, William Majoni, Karl Wallendszus, Richard Grimm, Terje Pedersen, Jonathan Tobert, Jane Armitage, Alex Baxter, Christopher Bray, Yiping Chen, Zhengming Chen, Michael Hill, Carol Knott, Sarah Parish, David Simpson, Peter Sleight, Alan Young, Rory Collins, SHARP Investigators

1674 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Lancet
Volume	377
Issue number	9784
Pages (from-to)	2181-92
Number of pages	12
ISSN	0140-6736
DOIs	https://doi.org/10.1016/S0140-6736(11)60739-3
Publication status	Published - 2011

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10.1016/S0140-6736(11)60739-3

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Baigent, C., Landray, M. J., Reith, C., Emberson, J., Wheeler, D. C., Tomson, C., Wanner, C., Krane, V., Cass, A., Craig, J., Neal, B., Jiang, L., Hooi, L. S., Levin, A., Agodoa, L., Gaziano, M., Kasiske, B., Walker, R., Massy, Z. A., ... SHARP Investigators (2011). 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. Lancet, 377(9784), 2181-92. https://doi.org/10.1016/S0140-6736(11)60739-3

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. / Baigent, Colin; Landray, Martin J; Reith, Christina et al.
In: Lancet, Vol. 377, No. 9784, 2011, p. 2181-92.

Research output: Contribution to journal › Journal article › Research › peer-review

Baigent, C, Landray, MJ, Reith, C, Emberson, J, Wheeler, DC, Tomson, C, Wanner, C, Krane, V, Cass, A, Craig, J, Neal, B, Jiang, L, Hooi, LS, Levin, A, Agodoa, L, Gaziano, M, Kasiske, B, Walker, R, Massy, ZA, Feldt-Rasmussen, B, Krairittichai, U, Ophascharoensuk, V, Fellström, B, Holdaas, H, Tesar, V, Wiecek, A, Grobbee, D, de Zeeuw, D, Grönhagen-Riska, C, Dasgupta, T, Lewis, D, Herrington, W, Mafham, M, Majoni, W, Wallendszus, K, Grimm, R, Pedersen, T, Tobert, J, Armitage, J, Baxter, A, Bray, C, Chen, Y, Chen, Z, Hill, M, Knott, C, Parish, S, Simpson, D, Sleight, P, Young, A, Collins, R & SHARP Investigators 2011, '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', Lancet, vol. 377, no. 9784, pp. 2181-92. https://doi.org/10.1016/S0140-6736(11)60739-3

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title = "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",

abstract = "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.",

author = "Colin Baigent and Landray, {Martin J} and Christina Reith and Jonathan Emberson and Wheeler, {David C} and Charles Tomson and Christoph Wanner and Vera Krane and Alan Cass and Jonathan Craig and Bruce Neal and Lixin Jiang and Hooi, {Lai Seong} and Adeera Levin and Lawrence Agodoa and Mike Gaziano and Bertram Kasiske and Robert Walker and Massy, {Ziad A} and Bo Feldt-Rasmussen and Udom Krairittichai and Vuddidhej Ophascharoensuk and Bengt Fellstr{\"o}m and Hallvard Holdaas and Vladimir Tesar and Andrzej Wiecek and Diederick Grobbee and {de Zeeuw}, Dick and Carola Gr{\"o}nhagen-Riska and Tanaji Dasgupta and David Lewis and William Herrington and Marion Mafham and William Majoni and Karl Wallendszus and Richard Grimm and Terje Pedersen and Jonathan Tobert and Jane Armitage and Alex Baxter and Christopher Bray and Yiping Chen and Zhengming Chen and Michael Hill and Carol Knott and Sarah Parish and David Simpson and Peter Sleight and Alan Young and Rory Collins and Bo Feldt-Rasmussen",

year = "2011",

doi = "10.1016/S0140-6736(11)60739-3",

language = "English",

volume = "377",

pages = "2181--92",

journal = "Lancet",

issn = "0140-6736",

publisher = "TheLancet Publishing Group",

number = "9784",

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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): 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

AU - SHARP Investigators

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.

U2 - 10.1016/S0140-6736(11)60739-3

DO - 10.1016/S0140-6736(11)60739-3

M3 - Journal article

SN - 0140-6736

VL - 377

SP - 2181

EP - 2192

JO - Lancet

JF - Lancet

IS - 9784

ER -

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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