Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events The ODYSSEY OUTCOMES Trial

被引：139

作者：

Szarek, Michael ^{[1
,1411
]}

White, Harvey D. ^{[2
,63
,1407
]}

Schwartz, Gregory G. ^{[3
]}

Alings, Marco ^{[4
]}

Bhatt, Deepak L. ^{[5
,6
]}

Bittner, Vera A. ^{[7
]}

Diaz, Rafael ^{[10
,30
,1405
]}

Edelberg, Jay M. ^{[11
]}

Goodman, Shaun G. ^{[12
,13
]}

Hanotin, Corinne ^{[14
]}

Harrington, Robert A. ^{[15
]}

Jukema, J. Wouter ^{[16
]}

Kimura, Takeshi ^{[17
,679
]}

Kiss, Robert Gabor ^{[18
,51
]}

Lecorps, Guillaume ^{[14
]}

Mahaffey, Kenneth W. ^{[15
]}

Moryusef, Angele ^{[11
]}

Pordy, Robert ^{[19
]}

Roe, Matthew T. ^{[20
,21
,84
,94
]}

Tricoci, Pierluigi ^{[21
,94
]}

Xavier, Denis ^{[22
,23
,24
,25
,52
]}

Zeiher, Andreas M. ^{[26
]}

Steg, Gabriel ^{[27
,28
,29
]}

Schwartz, Gregory G. ^{[3
]}

Steg, Ph. Gabriel ^{[475
]}

Bhatt, Deepak L. ^{[5
,6
]}

Bittner, Vera A. ^{[7
]}

Diaz, Rafael ^{[10
,30
,1405
]}

Goodman, Shaun G. ^{[12
,13
]}

Harrington, Robert A. ^{[15
]}

Jukema, J. Wouter ^{[16
]}

Szarek, Michael ^{[1
,1411
]}

Zeiher, Andreas M. ^{[26
]}

Tricoci, Pierluigi ^{[21
,94
]}

Roe, Matthew T. ^{[20
,21
,84
,94
]}

Mahaffey, Kenneth W. ^{[15
]}

Edelberg, Jay M. ^{[11
]}

Hanotin, Corinne ^{[14
]}

Lecorps, Guillaume ^{[14
]}

Moryusef, Angele ^{[11
]}

Pordy, Robert ^{[19
]}

Sasiela, William J.

Tamby, Jean-Francois

Aylward, Philip E. ^{[31
,160
]}

Drexel, Heinz ^{[32
,180
]}

Sinnaeve, Peter ^{[33
,189
,1408
]}

Dilic, Mirza ^{[34
]}

Gotcheva, Nina N. ^{[35
,263
]}

Goodman, Shaun G. ^{[12
,13
]}

Prieto, Juan-Carlos ^{[36
]}

机构：

[1] SUNY, Downstate Sch Publ Hlth, Brooklyn, NY USA

[2] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand

[3] Univ Colorado, Div Cardiol, Sch Med, Aurora, CO USA

[4] Amphia Ziekenhuis Molengracht, Breda, Netherlands

[5] Brigham & Womens Hosp, Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA

[6] Harvard Med Sch, Boston, MA USA

[7] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL 35294 USA

[8] Taipei Vet Gen Hosp, Gen Clin Res Ctr, Taipei, Taiwan

[9] Natl Yang Ming Univ, Taipei, Taiwan

[10] Inst Cardiovasc Rosario, Estudios Cardiol Latinoamer, Rosario, Santa Fe, Argentina

[11] Sanofi, Bridgewater, MA USA

[12] Univ Alberta, Canadian VIGOUR Ctr, Edmonton, AB, Canada

[13] Univ Toronto, St Michaels Hosp, Toronto, ON, Canada

[14] Sanofi, Paris, France

[15] Stanford Univ, Dept Med, Stanford Ctr Clin Res, Stanford, CA 94305 USA

[16] Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands

[17] Kyoto Univ, Grad Sch Med, Kyoto, Kyoto, Japan

[18] Magyar Honvedseg Egeszsegugyi Kozpont, Budapest, Hungary

[19] Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA

[20] Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC 27706 USA

[21] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA

[22] St Johns Med Coll, Dept Pharmacol, Bangalore, Karnataka, India

[23] St Johns Med Coll, Div Clin Res, Bangalore, Karnataka, India

[24] St Johns Res Inst, Dept Pharmacol, Bangalore, Karnataka, India

[25] St Johns Res Inst, Div Clin Res, Bangalore, Karnataka, India

[26] Goethe Univ, Dept Med 3, Frankfurt, Germany

[27] Hop Bichat Claude Bernard, AP HP, Paris, France

[28] Paris Diderot Univ, Sorbonne Paris Cite, FACT, INSERM U1148, Paris, France

[29] Royal Brompton Hosp, Imperial Coll, Natl Heart & Lung Inst, London, England

[30] Estudios Cardiol Latinoamer, Rosario, Argentina

[31] Flinders Univ S Australia, South Australian Hlth & Med Res Inst, Med Ctr, Adelaide, SA, Australia

[32] Landeskrankenhaus Feldkirch, Feldkirch, Austria

[33] UZ Leuven, Leuven, Belgium

[34] Univ Clin Ctr Sarajevo, Sarajevo, Bosnia & Herceg

[35] MHAT Nat Cardiol Hosp EAD, Sofia, Bulgaria

[36] Univ Chile, Hosp Clin, Santiago, Chile

[37] Peking Univ, First Hosp, Beijing, Peoples R China

[38] Fundac Oftalmol Santander FOSCAL, Floridablanca, Colombia

[39] Univ Zagreb, Univ Hosp Ctr Zagreb, Zagreb Sch Med, Zagreb, Croatia

[40] Univ Zagreb, Univ Ctr Zagreb, Sch Med, Zagreb, Croatia

[41] Na Homolce Hosp, Prague, Czech Republic

[42] Aarhus Univ Skejby, Aarhus, Denmark

[43] North Estonia Med Ctr, Tallinn, Estonia

[44] Heart & Lung Ctr, Div Cardiol, HUCH, Helsinki, Finland

[45] Hop Europeen Georges Pompidou, FACT, F CRIN network, Paris, France

[46] Chapidze Emergency Cardiol Ctr, Tbilisi, Georgia

[47] Univ Aachen, Aachen, Germany

[48] Univ Gen Hosp Ioannina, Ioannina, Greece

[49] Unidad Diagnost Cardiol, Clin privada, Guatemala City, Guatemala

[50] Univ Hong Kong, Queen Mary Hosp, Hong Kong, Peoples R China

来源：

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY | 2019年 / 73卷 / 04期

关键词：

acute coronary syndrome; alirocumab; total events; ACUTE CORONARY SYNDROMES; STATIN THERAPY; REDUCTION;

D O I：

10.1016/j.jacc.2018.10.039

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths. OBJECTIVES This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES. METHODS Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death. RESULTS With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk. CONCLUSIONS In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS. (c) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

引用

页码：387 / 396

页数：10

共 11 条

[1] Comparison of 80 versus 10 mg of Atorvastatin on Occurrence of Cardiovascular Events After the First Event (from the Treating to New Targets [TNT] Trial) [J].

LaRosa, John C. ;

Deedwania, Prakash C. ;

Shepherd, James ;

Wenger, Nanette K. ;

Greten, Heiner ;

DeMicco, David A. ;

Breazna, Andrei .

AMERICAN JOURNAL OF CARDIOLOGY, 2010, 105 (03) :283-287

[2] Shared frailty models for recurrent events and a terminal event [J].

Liu, L ;

Wolfe, RA ;

Huang, XL .

BIOMETRICS, 2004, 60 (03) :747-756

[3] Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome The IMPROVE-IT Trial [J].

Murphy, Sabina A. ;

Cannon, Christopher P. ;

Blazing, Michael A. ;

Giugliano, Robert P. ;

White, Jennifer A. ;

Lokhnygina, Yuliya ;

Reist, Craig ;

Im, KyungAh ;

Bohula, Erin A. ;

Isaza, Daniel ;

Lopez-Sendon, Jose ;

Dellborg, Mikael ;

Kher, Uma ;

Tershakovec, Andrew M. ;

Braunwald, Eugene .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2016, 67 (04) :353-361

[4] Reduction in Recurrent Cardiovascular Events With Intensive Lipid-Lowering Statin Therapy Compared With Moderate Lipid-Lowering Statin Therapy After Acute Coronary Syndromes From the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) Trial [J].

Murphy, Sabina A. ;

Cannon, Christopher P. ;

Wiviott, Stephen D. ;

McCabe, Carolyn H. ;

Braunwald, Eugene .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2009, 54 (25) :2358-2362

[5] Prasugrel versus Clopidogrel for Acute Coronary Syndromes without Revascularization [J].

Roe, Matthew T. ;

Armstrong, Paul W. ;

Fox, Keith A. A. ;

White, Harvey D. ;

Prabhakaran, Dorairaj ;

Goodman, Shaun G. ;

Cornel, Jan H. ;

Bhatt, Deepak L. ;

Clemmensen, Peter ;

Martinez, Felipe ;

Ardissino, Diego ;

Nicolau, Jose C. ;

Boden, William E. ;

Gurbel, Paul A. ;

Ruzyllo, Witold ;

Dalby, Anthony J. ;

McGuire, Darren K. ;

Leiva-Pons, Jose L. ;

Parkhomenko, Alexander ;

Gottlieb, Shmuel ;

Topacio, Gracita O. ;

Hamm, Christian ;

Pavlides, Gregory ;

Goudev, Assen R. ;

Oto, Ali ;

Tseng, Chuen-Den ;

Merkely, Bela ;

Gasparovic, Vladimir ;

Corbalan, Ramon ;

Cinteza, Mircea ;

McLendon, R. Craig ;

Winters, Kenneth J. ;

Brown, Eileen B. ;

Lokhnygina, Yuliya ;

Aylward, Philip E. ;

Huber, Kurt ;

Hochman, Judith S. ;

Ohman, E. Magnus .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 367 (14) :1297-1309

[6] Joint frailty models for recurring events and death using maximum penalized likelihood estimation: application on cancer events [J].

Rondeau, Virginie ;

Mathoulin-Pelissier, Simone ;

Jacqmin-Gadda, Helene ;

Brouste, Veronique ;

Soubeyran, Pierre .

BIOSTATISTICS, 2007, 8 (04) :708-721

[7] Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome [J].

Schwartz, G. G. ;

Steg, P. G. ;

Szarek, M. ;

Bhatt, D. L. ;

Bittner, V. A. ;

Diaz, R. ;

Edelberg, J. M. ;

Goodman, S. G. ;

Hanotin, C. ;

Harrington, R. A. ;

Jukema, J. W. ;

Lecorps, G. ;

Mahaffey, K. W. ;

Moryusef, A. ;

Pordy, R. ;

Quintero, K. ;

Roe, M. T. ;

Sasiela, W. J. ;

Tamby, J. -F. ;

Tricoci, P. ;

White, H. D. ;

Zeiher, A. M. ;

Aylward, Philip E. ;

Drexel, Heinz ;

Sinnaeve, Peter ;

Dilic, Mirza ;

Lopes, Renato D. ;

Gotcheva, Nina N. ;

Goodman, Shaun G. ;

Prieto, Juan-Carlos ;

Yong, Huo ;

Lopez-Jaramillo, Patricio ;

Pecin, Ivan ;

Reiner, Zeljko ;

Ostadal, Petr ;

Poulsen, Steen Hvitfeldt ;

Viigimaa, Margus ;

Nieminen, Markku S. ;

Danchin, Nicolas ;

Chumburidze, Vakhtang ;

Marx, Nikolaus ;

Liberopoulos, Evangelos ;

Montenegro Valdovinos, Pablo Carlos ;

Tse, Hung-Fat ;

Kiss, Robert Gabor ;

Xavier, Denis ;

Zahger, Doron ;

Valgimigli, Marco ;

Kimura, Takeshi ;

Kim, Hyo Soo .

NEW ENGLAND JOURNAL OF MEDICINE, 2018, 379 (22) :2097-2107

[8] Early, intensive statin treatment reduces 'hard' cardiovascular outcomes after acute coronary syndrome [J].

Schwartz, Gregory G. ;

Fayyad, Rana ;

Szarek, Michael ;

DeMicco, David ;

Olsson, Anders G. .

EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY, 2017, 24 (12) :1294-1296

[9] Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial [J].

Schwartz, Gregory G. ;

Bessac, Laurence ;

Berdan, Lisa G. ;

Bhatt, Deepak L. ;

Bittner, Vera ;

Diaz, Rafael ;

Goodman, Shaun G. ;

Hanotin, Corinne ;

Harrington, Robert A. ;

Jukema, J. Wouter ;

Mahaffey, Kenneth W. ;

Moryusef, Angele ;

Pordy, Robert ;

Roe, Matthew T. ;

Rorick, Tyrus ;

Sasiela, William J. ;

Shirodaria, Cheerag ;

Szarek, Michael ;

Tamby, Jean-Francois ;

Tricoci, Pierluigi ;

White, Harvey ;

Zeiher, Andreas ;

Steg, Philippe Gabriel .

AMERICAN HEART JOURNAL, 2014, 168 (05) :682-689

[10] Total Cardiovascular Disease Burden: Comparing Intensive With Moderate Statin Therapy Insights From the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) Trial [J].

Tikkanen, Matti J. ;

Szarek, Michael ;

Fayyad, Rana ;

Holme, Ingar ;

Cater, Nilo B. ;

Faergeman, Ole ;

Kastelein, John J. P. ;

Olsson, Anders G. ;

Larsen, Mogens Lytken ;

Lindahl, Christina ;

Pedersen, Terje R. .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2009, 54 (25) :2353-2357

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