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

被引：1835

作者：

Baigent, Colin ^{[1
]}

Landray, Martin J. ^{[1
]}

Reith, Christina ^{[1
]}

Emberson, Jonathan ^{[1
]}

Wheeler, David C. ^{[2
]}

Tomson, Charles ^{[3
]}

Wanner, Christoph ^{[4
]}

Krane, Vera ^{[4
]}

Cass, Alan ^{[5
]}

Craig, Jonathan ^{[6
]}

Neal, Bruce ^{[5
]}

Jiang, Lixin ^{[7
,8
,9
]}

Hooi, Lai Seong ^{[10
,11
]}

Levin, Adeera ^{[12
]}

Agodoa, Lawrence ^{[13
]}

Gaziano, Mike ^{[14
]}

Kasiske, Bertram ^{[15
]}

Walker, Robert ^{[16
]}

Massy, Ziad A. ^{[17
,18
,19
]}

Feldt-Rasmussen, Bo ^{[20
]}

Krairittichai, Udom ^{[21
]}

Ophascharoensuk, Vuddidhej ^{[22
]}

Fellstrom, Bengt ^{[23
]}

Holdaas, Hallvard ^{[24
]}

Tesar, Vladimir ^{[25
,26
]}

Wiecek, Andrzej ^{[27
]}

Grobbee, Diederick ^{[28
]}

de Zeeuw, Dick ^{[29
]}

Gronhagen-Riska, Carola ^{[30
]}

Dasgupta, Tanaji ^{[31
]}

Lewis, David ^{[1
]}

Herrington, William ^{[1
]}

Mafham, Marion ^{[1
]}

Majoni, William ^{[32
]}

Wallendszus, Karl ^{[1
]}

Grimm, Richard ^{[33
]}

Pedersen, Terje ^{[34
,35
]}

Tobert, Jonathan ^{[36
]}

Armitage, Jane ^{[1
]}

Baxter, Alex ^{[1
]}

Bray, Christopher ^{[1
]}

Chen, Yiping ^{[1
]}

Chen, Zhengming ^{[1
]}

Hill, Michael ^{[1
]}

Knott, Carol ^{[1
]}

Parish, Sarah ^{[1
]}

Simpson, David ^{[1
]}

Sleight, Peter ^{[37
]}

Young, Alan ^{[1
]}

Collins, Rory ^{[1
]}

机构：

[1] Univ Oxford, Clin Trial Serv Unit, Oxford OX3 7LF, England

[2] UCL, London, England

[3] N Bristol NHS Trust, Bristol, Avon, England

[4] Univ Wurzburg, Dept Med 1, Div Nephrol, Wurzburg, Germany

[5] Univ Sydney, George Inst Global Hlth, Sydney, NSW 2006, Australia

[6] Univ Sydney, Childrens Hosp Westmead, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia

[7] Fuwai Hosp, China Oxford Ctr Int Hlth Res, Beijing, Peoples R China

[8] Chinese Acad Med Sci, Beijing, Peoples R China

[9] Peking Union Med Coll, Beijing, Peoples R China

[10] Sultanah Aminah Hosp, Dept Med, Johor Baharu, Malaysia

[11] Sultanah Aminah Hosp, Haemodialysis Unit, Johor Baharu, Malaysia

[12] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada

[13] NIDDK, NIH, Bethesda, MD USA

[14] Harvard Univ, Brigham & Womens Hosp, Sch Med, VA Boston, Boston, MA 02115 USA

[15] Univ Minnesota, Minneapolis, MN USA

[16] Univ Otago, Dunedin Sch Med, Otago, New Zealand

[17] Amiens Univ Hosp, Div Clin Pharmacol, Amiens, France

[18] Amiens Univ Hosp, Div Nephrol, Amiens, France

[19] Univ Picardie Jules Verne, INSERM, ERI 12, Amiens, France

[20] Univ Copenhagen, Rigshosp, DK-2100 Copenhagen, Denmark

[21] Rajavithi Hosp, Dept Med, Div Nephrol, Bangkok, Thailand

[22] Chiang Mai Univ, Fac Med, Dept Internal Med, Div Renal, Chiang Mai 50000, Thailand

[23] Univ Uppsala Hosp, Uppsala, Sweden

[24] Univ Oslo, Rikshosp, Oslo Univ Hosp, Dept Organ Transplantat,Renal Sect, N-0027 Oslo, Norway

[25] Charles Univ Prague, Sch Med 1, Dept Nephrol, Prague, Czech Republic

[26] Charles Univ Prague, Gen Univ Hosp, Prague, Czech Republic

[27] Med Univ Silesia, Dept Nephrol Endocrinol & Metab Dis, Katowice, Poland

[28] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands

[29] Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharmacol, NL-9713 AV Groningen, Netherlands

[30] Helsinki Univ Hosp, Helsinki, Finland

[31] Oxford Radcliffe Hosp NHS Trust, Oxford, England

[32] Royal Darwin Hosp, Darwin, NT, Australia

[33] Univ Minnesota, Hennepin Cty Med Ctr, Berman Ctr Outcomes & Clin Res, Minneapolis, MN 55415 USA

[34] Univ Oslo, Oslo, Norway

[35] Univ Oslo, Ulleval Hosp, Ctr Prevent Med, Oslo, Norway

[36] Tobert Med Consulting LLC, Warren, NJ USA

[37] John Radcliffe Hosp, Nuffield Dept Clin Med, Oxford OX3 9DU, England

来源：

LANCET | 2011年 / 377卷 / 9784期

基金：

英国医学研究理事会;

关键词：

REQUIRING PROLONGED OBSERVATION; UNITED-KINGDOM HEART; CARDIOVASCULAR EVENTS; EFFICACY; DESIGN; OUTCOMES; SAFETY;

D O I：

10.1016/S0140-6736(11)60739-3

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 I SRCTN54137607. 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.

引用

页码：2181 / 2192

页数：12

共 26 条

[1]

[Anonymous], 2002, American Journal of Kidney Disease, V39, pS46, DOI DOI 10.1053/AJKD.2002.30943

[2]

[Anonymous], 2008, NICE CLIN GUID

[3] Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double-blind randomised trial [J].

Armitage, Jane ;

Bowman, Louise ;

Wallendszus, Karl ;

Bulbulia, Richard ;

Rahimi, Kazem ;

Haynes, Richard ;

Parish, Sarah ;

Peto, Richard ;

Collins, Rory ;

Meade, T. ;

Sleight, P. ;

Collins, R. ;

Armitage, J. ;

Bowman, L. ;

Parish, S. ;

Peto, R. ;

Barton, J. ;

Bray, C. ;

Wincott, E. ;

Dayanandan, R. ;

Clarke, R. ;

Graham, I. ;

Simpson, D. ;

Warlow, C. ;

Wilken, D. ;

Tobert, J. ;

Mushner, T. ;

Doll, R. ;

Wilhelmsen, L. ;

Fox, K. ;

Hill, C. ;

Sandercock, P. ;

Webster, J. ;

Henderson, J. ;

Nixon, A. ;

Lackie, S. ;

Thompson, J. ;

Brown, M. ;

Blackwood, S. ;

Morgan, M. ;

Rhoden, W. ;

Saeed, B. ;

Houghton, M. ;

Nicholson, A. ;

Simpson, C. ;

Hoburn, B. ;

Cooper, I. ;

Gallivan, A. ;

Pickerell, E. ;

Hancock, J. .

LANCET, 2010, 376 (9753) :1658-1669

[4] First united kingdom heart and renal protection (UK-HARP-1) study: Biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease [J].

Baigent, C ;

Landray, M ;

Leaper, C ;

Altmann, P ;

Armitage, J ;

Baxter, A ;

Cairns, HS ;

Collins, R ;

Foley, RN ;

Frighi, V ;

Kourellias, K ;

Ratcliffe, PJ ;

Rogerson, M ;

Scoble, JE ;

Tomson, CRV ;

Warwick, G ;

Wheeler, DC .

AMERICAN JOURNAL OF KIDNEY DISEASES, 2005, 45 (03) :473-484

[5] Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease [J].

Baigent, C. ;

Landray, M. ;

Reith, C. ;

Dasgupta, T. ;

Emberson, J. ;

Herrington, W. ;

Lewis, D. ;

Mafham, M. ;

Collins, R. ;

Baigent, C. ;

Landray, M. ;

Bray, C. ;

Chen, Y. ;

Baxter, A. ;

Young, A. ;

Hill, M. ;

Knott, C. ;

Cass, A. ;

Feldt-Rasmussen, B. ;

Fellstroem, B. ;

Grobbee, R. ;

Groenhagen-Riska, C. ;

Haas, M. ;

Holdaas, H. ;

Hooi, L. S. ;

Jiang, L. ;

Kasiske, B. ;

Krairittichai, U. ;

Levin, A. ;

Massy, Z. ;

Tesar, V. ;

Walker, R. ;

Wanner, C. ;

Wheeler, D. ;

Wiecek, A. ;

Dasgupta, T. ;

Lewis, D. ;

Mafham, M. ;

Majoni, W. ;

Reith, C. ;

Simpson, D. ;

Strony, J. ;

Musliner, T. ;

Agodoa, L. ;

Armitage, J. ;

Chen, Z. ;

Craig, J. ;

de Zeeuw, D. ;

Gaziano, M. .

AMERICAN HEART JOURNAL, 2010, 160 (05) :785-U28

[6] Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials [J].

Baigent, C. ;

Blackwell, L. ;

Emberson, J. ;

Holland, L. E. ;

Reith, C. ;

Bhala, N. ;

Peto, R. ;

Barnes, E. H. ;

Keech, A. ;

Simes, J. ;

Collins, R. .

LANCET, 2010, 376 (9753) :1670-1681

[7] Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins [J].

Baigent, C ;

Keech, A ;

Kearney, PM ;

Blackwell, L ;

Buck, G ;

Pollicino, C ;

Kirby, A ;

Sourjina, T ;

Peto, R ;

Collins, R ;

Simes, J .

LANCET, 2005, 366 (9493) :1267-1278

[8] Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): Comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes [J].

Cannon, Christopher P. ;

Giugliano, Robert P. ;

Blazing, Michael A. ;

Harrington, Robert A. ;

Peterson, John L. ;

Sisk, Christine McCrary ;

Strony, John ;

Musliner, Thomas A. ;

McCabe, Carolyn H. ;

Veltri, Enrico ;

Braunwald, Eugene ;

Califf, Robert M. .

AMERICAN HEART JOURNAL, 2008, 156 (05) :826-832

[9] Excerpts from the United States Renal Data System 2002 Annual Data Report: Atlas of End-Stage Renal Disease in the United States - Preface [J].

Collins, AJ ;

Kasiske, B ;

Herzog, C ;

Chen, SC ;

Everson, S ;

Constantini, E ;

Grimm, R ;

McBean, M ;

Xue, J ;

Chavers, B ;

Matas, A ;

Manning, W ;

Louis, T ;

Ma, J ;

Pan, W ;

Liu, JN ;

Li, SY ;

Roberts, T ;

Dalleska, F ;

Snyder, J ;

Ebben, J ;

Frazier, E ;

Sheets, D ;

Johnson, R ;

Li, SL ;

Dunning, S ;

Berrini, D ;

Guo, HF ;

Palzer, M ;

Solid, C ;

Arko, C ;

Daniels, F ;

Wang, XY ;

Gilbertson, D ;

St Peter, W ;

Frederick, P ;

Eggers, P ;

Agodoa, L .

AMERICAN JOURNAL OF KIDNEY DISEASES, 2003, 41 (04) :V-IX

[10] Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia [J].

Davidson, MH ;

McGarry, T ;

Bettis, R ;

Melani, L ;

Lipka, LJ ;

LeBeaut, AP ;

Suresh, R ;

Sun, S ;

Veltri, EP .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2002, 40 (12) :2125-2134

← 1 2 3 →