TY - JOUR
T1 - Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy
T2 - An analysis of primary and secondary prevention trials
AU - Mega, Jessica L.
AU - Stitziel, Nathan O.
AU - Smith, J. Gustav
AU - Chasman, Daniel I.
AU - Caulfield, Mark J.
AU - Devlin, James J.
AU - Nordio, Francesco
AU - Hyde, Craig L.
AU - Cannon, Christopher P.
AU - Sacks, Frank M.
AU - Poulter, Neil R.
AU - Sever, Peter S.
AU - Ridker, Paul M.
AU - Braunwald, Eugene
AU - Melander, Olle
AU - Kathiresan, Sekar
AU - Sabatine, Marc S.
N1 - Funding Information:
JUPITER was supported by AstraZeneca; ASCOT was supported by Pfizer; CARE was supported by Bristol-Myers Squibb; and PROVE IT-TIMI 22 was supported by Bristol-Myers Squibb and Sankyo. The Malmö Diet and Cancer Study was funded by The Swedish Research Council, The Swedish Heart and Lung Foundation, the European Research Council, and the Novo Nordisk Foundation. Research reported in this publication was supported by National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) under award number RC1 HL099634 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NOS was supported in part by a career development award from the NIH and the NHLBI ( grant K08 HL114642 ). This work was facilitated by the National Institute for Health Research (NIHR) Biomedical Research Unit at Barts (London, UK) and the NIHR Biomedical Research Centre at Imperial College (London, UK). MC, NP, and PS are recipients of NIHR Senior Investigator Awards.
Funding Information:
JLM has received research grant support through Brigham and Women's Hospital from Bristol-Myers Squibb and Sankyo during the study; grant support through Brigham and Women's Hospital from Janssen, Bayer, Bristol-Myers Squibb/Sanofi, Daiichi Sankyo, and AstraZeneca outside the submitted work; and personal fees from Janssen, American Genomics, and Boehringer Ingelheim outside the submitted work. NOS has received grants from the National Institutes of Health during the study; and personal fees from American Genomics outside the submitted work. DIC has received research support for genetic analysis in the JUPITER population from AstraZeneca. MC has received non-financial support (as a member of the board) from Genomics England. JJD is employed at Quest Diagnostics, a company that offers tests for cardiovascular disease, and has received personal fees from Quest Diagnostics outside the submitted work. CH is employed at Pfizer, and has received personal fees from Pfizer outside the submitted work. CPC has received research grant support through Brigham and Women's Hospital from Accumetrics, Arisaph, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Merck, Regeneron, Sanofi, and Takeda; personal fees from Accumetrics, CSL Behring, Essentialis, Merck, Regeneron, Sanofi, Takeda, Bristol-Myers Squibb, Lipimedix, and Pfizer; and has been on the advisory board for Bristol-Myers Squibb, Lipimedix, and Pfizer, outside the submitted work. FS has received grants from Bristol-Myers Squibb during the study, and has received consultation on a legal case from Pfizer, outside the submitted work. NP has received personal fees from Pfizer, and grants from Servier, Pfizer, and Amgen outside the submitted work. PS has received grant support through Imperial College London from Pfizer, and personal fees (honoraria) from Pfizer for lectures outside the submitted work. PMR has received research grants through Brigham and Women's Hospital from AstraZeneca and Amgen. Outside the submitted work, he has received grants through the Brigham and Women's Hospital from Novartis and Pfizer, and is listed as a co-inventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to AstraZeneca and Siemens. EB has received grants through Brigham and Women's Hospital from Merck and Bristol-Myers Squibb and uncompensated consultancies and lectures from Merck, related to the submitted work. Outside the submitted work, he has received grants from Daiichi Sankyo, Duke University, AstraZeneca, GlaxoSmithKline, Johnson and Johnson, and Sanofi Aventis; personal fees for consultancies from Genzyme, The Medicines Company, and Sanofi-Aventis; and personal fees for lectures from Menari International, Medscape, Bayer, and Daiichi Sankyo. SK has received grants from the National Institutes of Health during the conduct of the study; research grant support from Merck and Celera, outside the submitted work; and personal fees from Catabasis, Regeneron, Amgen, Amarin, and Eli Lilly outside the submitted work. MSS has received research grant support through Brigham and Women's Hospital from Abbott Laboratories, Accumetrics, Amgen, AstraZeneca, AstraZeneca–Bristol-Myers Squibb Alliance, BRAHMS, Bristol-Myers Squibb–Sanofi-Aventis Joint Venture, Critical Diagnostics, Daiichi-Sankyo, diaDexus, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, Nanosphere, Ortho-Clinical Diagnostics, Roche Diagnostics, Sanofi-Aventis, Singulex, and Takeda; and has acted as a consultant for Aegerion, Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo/Eli Lilly, GlaxoSmithKline, Intarcia, Merck, MyoKardia, Pfizer, Sanofi-Aventis, Vertex, Zeus, Cubist, and Quest Diagnostics. JGS, FN, and OM declare no competing interests.
Publisher Copyright:
© 2015 Elsevier Ltd.
PY - 2015/6/6
Y1 - 2015/6/6
N2 - Background Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy. Methods A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48 421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis. Findings When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55-1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT. Interpretation A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy. Funding National Institutes of Health.
AB - Background Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy. Methods A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48 421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis. Findings When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55-1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT. Interpretation A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy. Funding National Institutes of Health.
UR - http://www.scopus.com/inward/record.url?scp=84934277268&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(14)61730-X
DO - 10.1016/S0140-6736(14)61730-X
M3 - Article
C2 - 25748612
AN - SCOPUS:84934277268
VL - 385
SP - 2264
EP - 2271
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 9984
ER -