TY - JOUR
T1 - Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events
T2 - individual patient-data meta-analysis of statin outcome trials
AU - Willeit, Peter
AU - Ridker, Paul M.
AU - Nestel, Paul J.
AU - Simes, John
AU - Tonkin, Andrew M.
AU - Pedersen, Terje R.
AU - Schwartz, Gregory G.
AU - Olsson, Anders G.
AU - Colhoun, Helen M.
AU - Kronenberg, Florian
AU - Drechsler, Christiane
AU - Wanner, Christoph
AU - Mora, Samia
AU - Lesogor, Anastasia
AU - Tsimikas, Sotirios
N1 - Funding Information:
PW reports consultancy fees from Novartis Pharmaceuticals during the conduct of the study; and travel expenses from Bayer, Daiichi Sankyo, and Sanofi-Aventis outside the submitted work. PMR reports grants from AstraZeneca during the conduct of the study; grants from Novartis, Kowa, Pfizer, and the National Heart, Lung, and Blood Institute outside the submitted work; and personal fees from Novartis and Sanofi outside the submitted work. AMT reports personal fees from Amgen, Bayer, Merck, and Pfizer outside the submitted work; and non-financial support from Bayer outside the submitted work. TRP reports personal fees from Amgen and Sanofi Regeneron outside the submitted work. GGS reports grants from Pfizer during the conduct of the study; and grants from Cerenis, Roche, Sanofi, and The Medicines Company outside the submitted work. HMC reports grants from AstraZeneca, Boehringer Ingelheim, and Roche Pharmaceuticals during the conduct of the study; grants, non-financial support, and travel expenses from Eli Lilly and Regeneron during the conduct of the study; personal fees from Eli Lilly during the conduct of the study; institutional fees from Novartis Pharmaceuticals during the conduct of the study; grants and speaker fees from Pfizer during the conduct of the study; grants and travel expenses from Sanofi Aventis and Novo Nordisk during the conduct of the study; honorarium and speakers' bureau fees from Sanofi during the conduct of the study; and holds shares in Bayer and Roche Pharmaceuticals. CW reports personal fees from Boehringer Ingelheim and Sanofi-Genzyme outside the submitted work. SM reports institutional support from the National Institutes of Health (NIH; grants R01 HL117861 , R01 HL134811 , and K24 HL136852 ) outside the submitted work; non-financial support from Quest Diagnostics for measuring lipoprotein(a) in the JUPITER trial outside the submitted work; personal fees from Quest Diagnostics outside the submitted work; and an institutional research grant from Atherotech Diagnostics outside the submitted work. The JUPITER trial was funded by AstraZeneca. AL is an employee of Novartis Pharma AG. ST declares research support from the NIH (grants R01-HL119828 , R01-HL078610 , R01 HL106579 , R01 HL128550 , R01 HL136098 , P01 HL136275 , and R35 HL135737 ) and is supported by a grant to the Leducq Epigenetics of Atherosclerosis Network from the Fondation Leducq; currently has a dual appointment at the University of California San Diego and Ionis Pharmaceuticals; is a co-inventor and receives royalties from patents owned by the University of California San Diego on oxidation-specific antibodies; and is a co-founder of Oxitope. PJN, JS, AGO, FK, and CD declare no competing interests.
Funding Information:
This work was funded by Novartis through a grant to PW to conduct the meta-analysis. We thank Lena Tschiderer for advice on data management for this project, Georgina Bermann for providing detailed feedback on the statistical analysis plan and on the execution of the analysis, and Elizabeth H Barnes for work on data management of the LIPID trial.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/10/13
Y1 - 2018/10/13
N2 - Background: Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain. Methods: Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL, vs <15 mg/dL), before pooling estimates using multivariate random-effects meta-analysis. Findings: Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change −39% [95% CI −43 to −35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs <15 mg/dL) were 1·04 (95% CI 0·91–1·18) for 15 mg/dL to less than 30 mg/dL, 1·11 (1·00–1·22) for 30 mg/dL to less than 50 mg/dL, and 1·31 (1·08–1·58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0·94 (0·81–1·10), 1·06 (0·94–1·21), and 1·43 (1·15–1·76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p=0·010) and was more pronounced at younger ages (interaction p=0·008) without effect-modification by any other patient-level or study-level characteristics. Interpretation: In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials. Funding: Novartis Pharma AG.
AB - Background: Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain. Methods: Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL, vs <15 mg/dL), before pooling estimates using multivariate random-effects meta-analysis. Findings: Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change −39% [95% CI −43 to −35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs <15 mg/dL) were 1·04 (95% CI 0·91–1·18) for 15 mg/dL to less than 30 mg/dL, 1·11 (1·00–1·22) for 30 mg/dL to less than 50 mg/dL, and 1·31 (1·08–1·58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0·94 (0·81–1·10), 1·06 (0·94–1·21), and 1·43 (1·15–1·76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p=0·010) and was more pronounced at younger ages (interaction p=0·008) without effect-modification by any other patient-level or study-level characteristics. Interpretation: In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials. Funding: Novartis Pharma AG.
UR - http://www.scopus.com/inward/record.url?scp=85054439798&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(18)31652-0
DO - 10.1016/S0140-6736(18)31652-0
M3 - Article
C2 - 30293769
AN - SCOPUS:85054439798
SN - 0140-6736
VL - 392
SP - 1311
EP - 1320
JO - The Lancet
JF - The Lancet
IS - 10155
ER -
