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 Landray, Christina Reith, Joanthan Emberson, David Wheeler, Charles Tomson, Wanner Christoph, Vera Krane, Alan Cass, Jonathan Craig, Bruce Neal, Lixin Jiang, Lai Hooi, Adeera Levin, Lawrence Agodoa, Michael Gaziano, Bertram Kasiske, Robert Walker, Ziad Massy

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: 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.

    Methods: 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.

    Findings: 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).

    Interpretation:
    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.

    Funding: Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.
    Original languageEnglish
    Pages (from-to)2181-2192
    Number of pages12
    JournalLancet
    Volume377
    Issue number9784
    DOIs
    Publication statusPublished - 2011

    Fingerprint

    Simvastatin
    Chronic Renal Insufficiency
    LDL Cholesterol
    Randomized Controlled Trials
    Placebos
    Kidney
    Myocardial Infarction
    Stroke
    Kidney Diseases
    Biomedical Research
    Dialysis
    Hydroxymethylglutaryl-CoA Reductase Inhibitors
    Intention to Treat Analysis
    Ezetimibe
    Gallstones
    Muscular Diseases
    Hepatitis
    Compliance
    Coronary Disease
    Safety

    Cite this

    Baigent, Colin ; Landray, Martin ; Reith, Christina ; Emberson, Joanthan ; Wheeler, David ; Tomson, Charles ; Christoph, Wanner ; Krane, Vera ; Cass, Alan ; Craig, Jonathan ; Neal, Bruce ; Jiang, Lixin ; Hooi, Lai ; Levin, Adeera ; Agodoa, Lawrence ; Gaziano, Michael ; Kasiske, Bertram ; Walker, Robert ; Massy, Ziad. / 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. In: Lancet. 2011 ; Vol. 377, No. 9784. pp. 2181-2192.
    @article{72f603b7167d4e46a16202ad193599c5,
    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 = "Background: 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.Methods: 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.Findings: 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).Interpretation: 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.Funding: Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.",
    author = "Colin Baigent and Martin Landray and Christina Reith and Joanthan Emberson and David Wheeler and Charles Tomson and Wanner Christoph and Vera Krane and Alan Cass and Jonathan Craig and Bruce Neal and Lixin Jiang and Lai Hooi and Adeera Levin and Lawrence Agodoa and Michael Gaziano and Bertram Kasiske and Robert Walker and Ziad Massy",
    year = "2011",
    doi = "10.1016/S0140-6736(11)60739-3",
    language = "English",
    volume = "377",
    pages = "2181--2192",
    journal = "Lancet",
    issn = "0140-6736",
    publisher = "The Lancet Publishing Group",
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    Baigent, C, Landray, M, Reith, C, Emberson, J, Wheeler, D, Tomson, C, Christoph, W, Krane, V, Cass, A, Craig, J, Neal, B, Jiang, L, Hooi, L, Levin, A, Agodoa, L, Gaziano, M, Kasiske, B, Walker, R & Massy, Z 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. 2181-2192. 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; Reith, Christina; Emberson, Joanthan; Wheeler, David; Tomson, Charles; Christoph, Wanner; Krane, Vera; Cass, Alan; Craig, Jonathan; Neal, Bruce; Jiang, Lixin; Hooi, Lai; Levin, Adeera; Agodoa, Lawrence; Gaziano, Michael; Kasiske, Bertram; Walker, Robert; Massy, Ziad.

    In: Lancet, Vol. 377, No. 9784, 2011, p. 2181-2192.

    Research output: Contribution to journalArticleResearchpeer-review

    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

    AU - Reith, Christina

    AU - Emberson, Joanthan

    AU - Wheeler, David

    AU - Tomson, Charles

    AU - Christoph, Wanner

    AU - Krane, Vera

    AU - Cass, Alan

    AU - Craig, Jonathan

    AU - Neal, Bruce

    AU - Jiang, Lixin

    AU - Hooi, Lai

    AU - Levin, Adeera

    AU - Agodoa, Lawrence

    AU - Gaziano, Michael

    AU - Kasiske, Bertram

    AU - Walker, Robert

    AU - Massy, Ziad

    PY - 2011

    Y1 - 2011

    N2 - Background: 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.Methods: 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.Findings: 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).Interpretation: 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.Funding: Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.

    AB - Background: 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.Methods: 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.Findings: 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).Interpretation: 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.Funding: 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 - Article

    VL - 377

    SP - 2181

    EP - 2192

    JO - Lancet

    JF - Lancet

    SN - 0140-6736

    IS - 9784

    ER -