CV Risk Factors Largely Explain Sex Gap in NSTE ACS Outcomes: TIMI Trials

At first glance, women with NSTE ACS have poorer outcomes than men treated for the same condition. But an analysis of data from 10 trials in the TIMI Study Group shows that, after adjustment for differences in baseline cardiovascular risk, female patients in fact have a lower likelihood of not only MACE but also all-cause death compared with their male counterparts.

Yet despite the fact that women in the trial setting presented at an older age and with more comorbidities, as has been seen in real-world data sets, they were less likely than men to receive guideline-directed medical therapy and to undergo angiography.

The idea that heart disease manifests and is managed differently in male and female patients isn’t new, nor is the recognition that women tend to fare more poorly. But the exact reason why women face worse outcomes has proven elusive, lead author Amy A. Sarma, MD (Massachusetts General Hospital, Boston, MA), and colleagues point out in the December 17           , 2019, issue of the Journal of the American College of Cardiology.

“In light of the multitude of recognized differences in baseline comorbidities and disparities in treatment use between women and men, it has remained unclear whether sex itself is an independent risk factor for death and MACE after NSTE ACS,” they explain.

Sarma told TCTMD that even though the current findings can’t be directly extrapolated to the clinical setting, the analysis’ strength comes from the fact that the TIMI “patients were very well phenotyped because they were very carefully tracked.”

Michael E. Farkouh, MD, and Wendy Tsang, MD (both from University of Toronto, Canada), writing in editorial, say the study “underscores the lack of progress made in addressing sex inequality in the care for women with ACS. That this care gap for women with cardiovascular diseases continues to persist, even in well-run contemporary landmark ACS trials, highlights how challenging it is to address.”

To improve women’s health outcomes, they point to the need for research to clarify the best means of prevention and diagnosis as well as provide insight on differences in response to therapy. “We desperately need strategies to enhance the enrollment of women in these randomized trials, and this should be a high priority for funding agencies and industry sponsors,” the editorialists stress.

Detailed Database

For their study, the investigators homed in on 68,730 patients with NSTE ACS (29% women) who had been enrolled across 10 TIMI trials.

“The study population was multinational and diverse, with a database that allowed for detailed patient characterization, including data on coronary angiography, medication use, adjudicated cardiovascular outcomes, and rigorous long-term follow-up,” they explain.

The median age of female study participants was 5 years higher than that of the male participants (67 vs 62 years; P < 0.001), and the women also had a greater prevalence of hypertension, diabetes, prior heart failure, and renal impairment. The men, on the other hand, were more likely to be current smokers, to have had a prior MI, and to have previously undergone PCI.

There were many differences in how male and female patients were managed during hospitalization. Women were less likely to receive aspirin, P2Y12 inhibitors, or a statin but more likely to be given ACE inhibitors or angiotensin receptor blockers, though beta-blocker use was similar regardless of sex. Notably, women were less likely to undergo coronary angiography compared to men (69.7% vs 76.2%) and to undergo PCI (49.2% vs 59.0%; P < 0.001 for both); these imbalances remained even when excluding patients with the less-severe presentation of unstable angina. When angiography was performed, women had more nonobstructive CAD than men (10.9% vs 4.4%) and thus were less likely to proceed to PCI (70.4% vs 77.1%; P < 0.0001 for both).

In unadjusted comparisons, women had a MACE rate matching that of men but were at higher risk of all-cause death (HR 1.12; 95% CI 1.01-1.24). Adjustment for baseline differences shifted the balance, however—from this perspective, women had a lower risk of MACE compared with men (HR 0.93; 95% CI 0.89-0.98) as well as a lower risk of all-cause death (HR 0.84; 95% CI 0.78-0.90). Stroke and MI risks did not differ by sex.

We need to be very mindful of including sex-specific characteristics in data collection. Amy A. Sarma

Further adjustment for imbalances in guideline-based therapy on top of the baseline risk-factor differences didn’t incrementally change these results, Sarma observed to TCTMD.

Greater focus on women in studies of guideline-directed therapies may tease out some nuances to help determine ways to optimize their use and know whether their efficacy is the same in men and women, she suggested. Another thing that’s not fully understood, Sarma added, is not only why trials don’t enroll more women but also why women might decline to participate in them.

When designing trials, “we need to be very mindful of including sex-specific characteristics in data collection,” she advised. For example, details on reproductive history, such as whether a trial participant experienced preeclampsia, could be relevant, as could menopausal state and use of hormone therapy.

Farkouh and Tsang, for their part, also point out that women are not a homogeneous cohort. “Although they are generally studied as one subgroup, women are a heterogeneous and diverse group. Pregnancy and menopause are two unique life events that alter women’s risk of cardiovascular disease and response to treatment. Premenopausal and postmenopausal women and young, middle-age, and older women have different cardiovascular disease subtypes and risk profiles,” they note.

“Ultimately, sex- and age-specific strategies for the diagnosis of ACS in women should be developed to improve women’s health outcomes,” they conclude.