TY - JOUR
T1 - Association of lipoprotein(a) with risk of recurrent ischemic events following acute coronary syndrome
T2 - Analysis of the dal-outcomes randomized clinical trial
AU - Schwartz, Gregory G.
AU - Ballantyne, Christie M.
AU - Barter, Philip J.
AU - Kallend, David
AU - Leiter, Lawrence A.
AU - Leitersdorf, Eran
AU - McMurray, John J.V.
AU - Nicholls, Stephen
AU - Olsson, Anders G.
AU - Shah, Prediman K.
AU - Tardif, Jean Claude
AU - Kittelson, John
N1 - Funding Information:
supported by a grant from F. Hoffmann–La Roche to the University of Colorado.
Funding Information:
completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Schwartz, through his institution, reported receiving research support from Cerenis, The Medicines Company, Resverlogix, Roche, and Sanofi. Dr Ballantyne reported receiving research support from Abbott Diagnostic, Amarin, Amgen, Eli Lilly, Esperion, Novartis, Pfizer, Otsuka, Regeneron, Roche Diagnostic, Sanofi-Synthelabo, Takeda, National Institutes of Health, American Heart Association, and American Diabetes Association. Dr Barter reported receiving research support from Merck, Pfizer, and the National Health and Medical Research Council of Australia, as well as honoraria from Amgen, AstraZeneca, CSL Behring, Eli Lilly, Merck, Novartis, Pfizer, and Sanofi-Regeneron. Dr Kallend reported being an employee of F. Hoffmann–La Roche at the time of the dal-Outcomes trial. Dr Leiter reported receiving research funding from Amgen, Esperion, Kowa, The Medicines Company, Merck, Pfizer, and Sanofi-Regeneron, as well as consulting or providing continuing medical education for Aegerion, Amgen, Merck, and Sanofi-Regeneron. Dr Leitersdorf reported consulting for Novartis, AstraZeneca, Sanofi, and Amgen. Dr McMurray, through his institution, reported receiving funding from AbbVie, Amgen, Cardiorentis, GlaxoSmithKline, Novartis, Pfizer, Roche, and Sanofi-Aventis. Dr Nicholls reported receiving research support from Amgen, Anthera, Eli Lilly, Cerenis, AstraZeneca, Novartis, Resverlogix, and Sanofi-Regeneron, as well as consulting for Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Merck, Takeda, Roche, Pfizer, and Sanofi-Regeneron. Dr Olsson reported receiving research grants from Amgen, AstraZeneca, Karobio, Merck, Pfizer, Roche, and Sanofi, as well as consulting fees from AstraZeneca, Merck KGaA, Merck (USA), Pfizer, and Roche. Dr Tardif reported receiving research support from Amarin, AstraZeneca, DalCor, Eli Lilly, Esperion, F. Hoffmann–La Roche, Merck, Pfizer, Sanofi, and Servier; receiving honoraria from F. Hoffmann–La Roche, Pfizer, Sanofi, and Servier; holding equity in DalCor; and authoring a paper about the genotype-dependent results of dalcetrapib on clinical outcomes on which a patent was based. Dr Kittelson reported receiving consulting fees for his work on the advisory and steering committees of Bayer Healthcare and Pfizer, as well as on the data and safety monitoring committees of Cystic Fibrosis Foundation Therapeutics, Novo Nordisk, Genentech, and BioMarin Pharmaceutical. No other disclosures were reported.
PY - 2018/2
Y1 - 2018/2
N2 - IMPORTANCE It is uncertain whether lipoprotein(a) [Lp(a)], which is associated with incident cardiovascular disease, is an independent risk factor for recurrent cardiovascular events after acute coronary syndrome (ACS). OBJECTIVE To determine the association of Lp(a) concentration measured after ACS with the subsequent risk of ischemic cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS This nested case-cohort analysiswas performed as an ad hoc analysis of the dal-Outcomes randomized clinical trial. This trial compared dalcetrapib, the cholesteryl ester transfer protein inhibitor, with placebo in patients with recent ACS and was performed between April 2008 and September 2012 at 935 sites in 27 countries. There were 969 case patients who experienced a primary cardiovascular outcome, and there were 3170 control patients who were event free at the time of a case event and had the same type of index ACS (unstable angina ormyocardial infarction) as that of the respective case patients. Concentration of Lp(a) was measured by immunoturbidimetric assay. Data analysis for this present study was conducted from June 8, 2016, to April 21, 2017. INTERVENTIONS Patients were randomly assigned to receive treatment with dalcetrapib, 600mg daily, or matching placebo, beginning 4 to 12 weeks after ACS. MAIN OUTCOMES AND MEASURES Death due to coronary heart disease, a major nonfatal coronary event (myocardial infarction, hospitalization for unstable angina, or resuscitated cardiac arrest), or fatal or nonfatal ischemic stroke. RESULTS The mean (SD) age was 63 (10) years for the 969 case patients and 60 (9) years for the 3170 control patients, and both cohorts were composed of predominantly male (770 case patients [79%] and 2558 control patients [81%]; P = .40) and white patients (858 case patients [89%] and 2825 control patients [89%]; P = .62). At baseline, the median (interquartile range) Lp(a) level was 12.3 (4.7-50.9)mg/dL. There was broad application of evidence-based secondary prevention strategies after ACS, including use of statins in 4030 patients (97%). The cumulative distribution of baseline Lp(a) levels did not differ between cases and controls at P = .16. Case-cohort regression analysis showed no association of baseline Lp(a) level with risk of cardiovascular events. For a doubling of Lp(a) concentration, the hazard ratio (case to control) was 1.01 (95%CI, 0.96-1.06; P = .66) after adjustment for 16 baseline variables, including assigned study treatment. CONCLUSIONS AND RELEVANCE For patients with recent ACS who are treated with statins, Lp(a) concentration was not associated with adverse cardiovascular outcomes. These findings call into question whether treatment specifically targeted to reduce Lp(a) levels would thereby lower the risk for ischemic cardiovascular events after ACS. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00658515.
AB - IMPORTANCE It is uncertain whether lipoprotein(a) [Lp(a)], which is associated with incident cardiovascular disease, is an independent risk factor for recurrent cardiovascular events after acute coronary syndrome (ACS). OBJECTIVE To determine the association of Lp(a) concentration measured after ACS with the subsequent risk of ischemic cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS This nested case-cohort analysiswas performed as an ad hoc analysis of the dal-Outcomes randomized clinical trial. This trial compared dalcetrapib, the cholesteryl ester transfer protein inhibitor, with placebo in patients with recent ACS and was performed between April 2008 and September 2012 at 935 sites in 27 countries. There were 969 case patients who experienced a primary cardiovascular outcome, and there were 3170 control patients who were event free at the time of a case event and had the same type of index ACS (unstable angina ormyocardial infarction) as that of the respective case patients. Concentration of Lp(a) was measured by immunoturbidimetric assay. Data analysis for this present study was conducted from June 8, 2016, to April 21, 2017. INTERVENTIONS Patients were randomly assigned to receive treatment with dalcetrapib, 600mg daily, or matching placebo, beginning 4 to 12 weeks after ACS. MAIN OUTCOMES AND MEASURES Death due to coronary heart disease, a major nonfatal coronary event (myocardial infarction, hospitalization for unstable angina, or resuscitated cardiac arrest), or fatal or nonfatal ischemic stroke. RESULTS The mean (SD) age was 63 (10) years for the 969 case patients and 60 (9) years for the 3170 control patients, and both cohorts were composed of predominantly male (770 case patients [79%] and 2558 control patients [81%]; P = .40) and white patients (858 case patients [89%] and 2825 control patients [89%]; P = .62). At baseline, the median (interquartile range) Lp(a) level was 12.3 (4.7-50.9)mg/dL. There was broad application of evidence-based secondary prevention strategies after ACS, including use of statins in 4030 patients (97%). The cumulative distribution of baseline Lp(a) levels did not differ between cases and controls at P = .16. Case-cohort regression analysis showed no association of baseline Lp(a) level with risk of cardiovascular events. For a doubling of Lp(a) concentration, the hazard ratio (case to control) was 1.01 (95%CI, 0.96-1.06; P = .66) after adjustment for 16 baseline variables, including assigned study treatment. CONCLUSIONS AND RELEVANCE For patients with recent ACS who are treated with statins, Lp(a) concentration was not associated with adverse cardiovascular outcomes. These findings call into question whether treatment specifically targeted to reduce Lp(a) levels would thereby lower the risk for ischemic cardiovascular events after ACS. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00658515.
UR - http://www.scopus.com/inward/record.url?scp=85043525971&partnerID=8YFLogxK
U2 - 10.1001/jamacardio.2017.3833
DO - 10.1001/jamacardio.2017.3833
M3 - Article
C2 - 29071331
AN - SCOPUS:85043525971
VL - 3
SP - 164
EP - 168
JO - JAMA Cardiology
JF - JAMA Cardiology
SN - 2380-6583
IS - 2
ER -