Author + information
- Brendan M. Everett, MD, MPH∗ (, )
- Maria Mori Brooks, PhD,
- Helen E.A. Vlachos, MS,
- Bernard R. Chaitman, MD,
- Robert L. Frye, MD,
- Deepak L. Bhatt, MD, MPH,
- BARI 2D Study Group
- ↵∗Division of Preventive Medicine, Harvard Medical School, Brigham and Women’s Hospital, 900 Commonwealth Avenue, Boston, Massachusetts 02115
Cardiac troponin is the preferred marker of myocardial necrosis in patients with suspected myocardial infarction (MI). Increasingly sensitive assays have allowed the detection of very low circulating troponin concentrations in ambulatory patients, and these low troponin levels are strong, independent predictors of major cardiovascular (CV) events and death (1). Women have lower troponin concentrations than men (2). However, the relationship between the lower troponin concentrations seen in women and the risk of major CV events, such as MI and heart failure (HF), is poorly understood (3).
In this Ancillary Study of the BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) trial, we followed 684 women and 1,601 men with type 2 diabetes (T2D) and stable ischemic heart disease for a median of 5 years for the primary endpoint of this substudy, which was the composite of the first occurrence of an MI, stroke, HF, or all-cause death. We measured baseline cardiac troponin T with a high-sensitivity assay (hsTnT; Roche Diagnostics, Indianapolis, Indiana) that has a limit of detection of 5 ng/l and a manufacturer’s recommended upper reference limit that is the same for both women and men (14 ng/l).
Median (interquartile range) hsTnT concentrations were significantly lower in women (9.1 ng/l [6.4 to 15.6 ng/l]) than in men (12.4 ng/l [8.7 to 20.8 ng/l]; p <0.0001), and a higher proportion of men (43.6%) than women (29.1%) were above the current established upper recommended limit of 14 ng/l (p <0.0001). Compared with men, women were of similar age, were more likely to be black and use insulin, have higher glycosylated hemoglobin and high-density lipoprotein cholesterol, a lower estimated glomerular filtration rate, and a longer duration of T2D. Women had similar prevalence of electrocardiographic abnormalities but less advanced coronary artery disease, and a lower proportion had a history of smoking, MI, or ejection fraction <50%. In linear regression models that adjusted for these possible confounders, female sex was associated with a statistically significant 27% lower hsTnT concentration (p <0.0001).
The rate of the primary composite outcome was significantly higher in women than in men (Figure 1A), although the adjusted risk was not significantly higher for women compared with men (hazard ratio: 1.18; 95% confidence interval: 0.99 to 1.41; p = 0.07) after accounting for baseline covariates and hsTnT. Random allocation to prompt coronary revascularization did not offer benefit compared with intensive medical therapy in either women or men in BARI 2D.
We divided hsTnT concentrations into quintiles based on the entire cohort, regardless of sex, and found that for all but the highest category of hsTnT (≥23 ng/l), the unadjusted rates of the primary composite were significantly higher among women than men (Figure 1B). When groups were created based on sex-specific hsTnT quintiles (e.g., the lowest 20% of women and the lowest 20% of men), event rates did not differ by sex. In models adjusted for baseline risk factors, we observed statistically significant evidence that sex modified the relationship between Ln-hsTnT and the primary composite outcome (p interaction = 0.018).
These results suggest that among patients with T2D and stable ischemic heart disease, women with circulating hsTnT concentrations that are within the “normal” range are at increased risk of serious CV events at rates that exceed those observed among men with similar hsTnT concentrations. For example, hsTnT concentrations <7.3 ng/l, well within the range considered normal, were still associated with a 24% 5-year rate of MI, stroke, HF, or death in women, compared with a 15% rate in men. hsTnT is also a powerful marker of risk in men, but hsTnT concentrations of ≥10 ng/l were required before men were at a similarly elevated absolute risk of the primary composite endpoint.
In conclusion, in a population of patients with T2D and stable ischemic heart disease, we found that the lower concentrations of hsTnT observed in women were nonetheless associated with an elevated risk of major CV events and death compared with men with similar hsTnT levels. Sex-specific thresholds for hsTnT, with lower thresholds in women than in men, may be appropriate to identify women at elevated risk of major cardiovascular events.
Please note: This research was supported by an investigator-initiated research grant from Roche Diagnostics (Indianapolis, Indiana) to Dr. Everett, as well as by grants (U01HL061744, U01HL061746, U01HL061748, U01HL063804, and R21HL121495) from the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.
The sponsors of the study had no role in the design and conduct of the study; the collection, management, analysis, or interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
Dr. Everett has received investigator-initiated research awards from Roche Diagnostics and Novartis; and serves as a consultant/advisor for Roche Diagnostics and Abbott Diagnostics. Dr. Brooks has received grant support from Gilead Sciences. Dr. Chaitman has received fees for serving on clinical events committees from Merck, Eli Lilly, Novo Nordisk, and Roche; and fees for serving on data safety monitoring boards from Pfizer and Sanofi. Dr. Bhatt has served on the advisory board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; served on the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care; has served as a chair for the American Heart Association Quality Oversight Committee; served on the data monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); has served as Deputy Editor for Clinical Cardiology; Vice-Chair for NCDR-ACTION Registry Steering Committee; chair for VA CART Research and Publications Committee; received research funding from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, The Medicines Company; received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as a site co-investigator for Biotronik, Boston Scientific, and St. Jude Medical; has served as a trustee for the American College of Cardiology; and has performed unfunded research for FlowCo, PLx Pharma, and Takeda. Ms. Vlachos and Dr. Frye have reported that they have no relationships relevant to the contents of this paper to disclose.
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