Prior Oral Contraceptive Use and Longer Term Mortality Outcomes in Women with Suspected Ischemic Heart Disease

Abstract

Background: Previous Women's Ischemia Syndrome Evaluation (WISE) work demonstrated prior oral contraceptive (OC) use was associated with lower coronary artery disease (CAD) in women with suspected ischemia. The association of prior OC use with longer term all-cause and cardiovascular disease (CVD) mortality is unclear. Materials and Methods: WISE women undergoing coronary angiography for suspected ischemia (enrolled 1996-2001) with prior OC use history and 10-year follow-up data were analyzed. A blinded core laboratory assessed atherosclerotic CAD severity. Kaplan-Meier analyses evaluated prior OC use relative to all-cause and CVD mortality. Cox regression analyses adjusted for baseline differences. Mediation, interaction, and multicollinearity were analyzed. Results: Our 686 women had a mean age 62.5 ± 9.6 years, multiple cardiac risk factors, and 39% previously used OC. Prior OC users were younger, with less lipid-lowering medication use and lower atherosclerotic CAD severity scores (all p < 0.05). Prior OC use was associated with lower 10-year all-cause (p = 0.007) and CVD mortality (p = 0.019). After adjustment, this was no longer significant (p = 0.77 and p = 0.90, respectively). Atherosclerotic CAD severity score mediated one-third of the observed association. Prior OC use was associated with increased CVD mortality among women with very elevated menopausal systolic blood pressure (SBP). Conclusions: Unadjusted prior OC use was associated with lower longer-term all-cause and CVD mortality. One-third of this observed effect appears mediated by the atherosclerotic CAD severity score. Prior OC was adversely associated with CVD mortality in women with very elevated menopausal SBP. Additional investigation is needed to understand the potential benefits and harms of prior OC use. Clinical Trial Number: NCT00000554, or https://www.clinicaltrials.gov/ct2/show/NCT00000554.

Keywords: WISE; mortality; nonobstructive coronary artery disease; oral contraceptive.

Conflict of interest statement

N.B.M. reports personal fees from iRhythm, other from Sanofi, other from Abbott Diagnostics, during the conduct of the study. E.H. reports grants from NIH/NHLBI, during the conduct of the study; grants from Aastom Biosciences, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Brigham and Women's Hospital, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Duke Clinical Research Institute, East Carolina University, Everyfit, Inc., Gilead, Ionis, Medtronic, Merck & Co., Mesoblast, PCORI, Relypsa, Sanofi Aventis, outside the submitted work. C.J.P. reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NCATS, grants from BioCardia BC-14-001-02; Mesoblast, Inc., MSB-MPC-CHF001; Ventrix, Inc.; Athersys, Inc., AMI MultiStem; Verily Life Sciences LLC-Project Baseline OSMB; Ironwood MSB-MPC-CHF00-DMC, Imbria Pharmaceuticals, Inc.; Milestone Pharmaceuticals, Inc.; Caladrius Biosciences, Inc.; Gatorade Trust; and McJunkin Family Foundation, outside the submitted work. V.B. serves on the Executive Steering Committee of the ODYSSEY OUTCOMES trial (Sanofi), as National Coordinator for STRENGTH (Astra Zeneca), DalGene (Dalcor), CLEAR (Esperion), as local site investigator for ORION IV (The Medicines Company) and was a local site investigator for ARTEMIS (Astra Zeneca) and COMPASS (Bayer Healthcare), both completed. All activities are contracted through the University of Alabama at Birmingham. She has served as a consultant for Sanofi. All other authors report no disclosures.

Figures

FIG. 1.

(A) Unadjusted prior OC use was associated with reduced all-cause mortality when compared with no history of OC use (log rank p = 0.007). (B) Unadjusted prior OC use was associated with reduced CVD mortality when compared with no history of OC use (log rank p = 0.019). CVD, cardiovascular disease; OC, oral contraceptive.

FIG. 2.

Predicted probability of CVD mortality based on the final model, including interaction between prior OC use status and SBP. For women with very high SBP (i.e., with SBP = 175, HR = 2.36 [95% CI, 1.1–5.3], p = 0.036), prior OC use had a harmful association, but for women with very low SBP (i.e., with SBP = 100, HR = 0.26 [95% CI, 0.07–0.92], p = 0.037), prior OC use had a protective association (overall p = 0.013 for this interaction analysis). CI, confidence interval; HR, hazard ratio; SBP, systolic blood pressure.