Women With Non-STEMI ACS Underrepresented, Undertreated

Batya Swift Yasgur, MA, LSW

December 09, 2019

Women may be at lower risk of adverse cardiac outcomes following
non–ST-segment elevation acute coronary syndromes (NSTEACS) compared with men, but even high-risk women receive fewer evidence-based treatments, a new study shows.

Investigators analyzed close to 69,000 patients with NSTEACS, of whom roughly one fifth were female.

Women were initially found to be at similar risk for major adverse cardiovascular events (MACE) as their male counterparts, but at higher risk of mortality. However, after baseline differences such as age, comorbidities, and smoking status were taken into account, women were found to be at lower risk of MACE compared to men.

On the other hand, they were less likely than men to receive evidence-based drugs or undergo coronary angiography or treatment with percutaneous coronary intervention (PCI).

"Before accounting for baseline characteristics, women seemed more likely to die after NSTEACS than men, but after accounting for these differences, women, if anything, tended to fare better than men — and, overall, some of this news is encouraging," senior investigator Michelle O'Donoghue, MD, MPH, associate professor of medicine, Brigham and Women's Hospital, Cardiovascular Division, Boston, Massachusetts, told theheart.org | Medscape Cardiology.

"However, there were also concerning findings, which is that women were less likely than men to be treated with many of the evidence-based therapies that should be used, compared to a man, and were also less likely to go for cardiac catheterization and receive coronary stenting," she said.

The study was published online today in the Journal of the American College of Cardiology.

Women's Risk Disputed

For years it has been disputed whether women have worse outcomes than men after myocardial infarction (MI), or whether differences in outcomes might be explained by differences in baseline risk factors, O'Donoghue said. "For instance, women are often older and have many more comorbidities at the time of their first heart attack than a man, so that may account for the worse prognosis," she noted.

To address this question, researchers analyzed patients enrolled in trials conducted by the Thrombolysis in Myocardial Infarction (TIMI) Study group.

MACE (defined as the composite of cardiovascular death, MI, or stroke) was the primary outcome of interest of the current study, but each outcome was also examined individually.

The analysis included 10 trials (mean follow-up time, 676 days, N = 68,730 patients, of whom 29% were women).

Female participants were older than men (median [IQR] 67 [59 – 74] vs 62 [55 – 70] years) and also had a higher prevalence of comorbidities at baseline, such as hypertension, diabetes mellitus, prior heart failure (HF), and renal impairment.

Conversely, women were less likely than men to be current smokers. They were also less likely to have experienced a prior MI and to have undergone prior PCI.

Understudied and Underdiagnosed

Compared with men, women were less likely to receive aspirin, P2Y12 inhibitors, and statin therapy; however, they were more likely to receive angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). There were no differences between women and men in treatment with beta-blockers.

Moreover, fewer women than men underwent coronary angiography or were treated with PCI (69.7% vs 76.2% and 49.2% vs 59%, respectively, both Ps < .001).

Even after the researchers excluded patients with unstable angina, women continued to be less likely than men to undergo coronary angiography or PCI despite a diagnosis of non-STEMI. They also obtained similar findings when examining high-risk patient groups.

"Unfortunately, it remains unknown whether women remain undertreated for valid reasons or whether there is conscious or unconscious bias that may influence clinician decisions," O'Donoghue commented.

Additionally, there is a "growing appreciation that women and men may manifest heart disease differently."

She noted that women are less likely to have classic cholesterol plaque build-up in their epicardial coronary arteries, but may be more likely to experience other related types of heart disease that mimic an MI, such as coronary dissection, spasm, plaque erosion, or microvascular disease.

The challenge still is that many types of related heart disease more commonly associated with women "remain understudied and underdiagnosed," she said.

Baseline Characteristics

In unadjusted analyses, women were at similar risk of MACE as men following NSTEACS (hazard ratio [HR], 1.04; 95% confidence interval [CI]: 0.99 to 1.09; P = .16),

However, when each adverse outcome was looked at individually, women were found to be at increased risk of:

  • Cardiovascular death (HR, 1.16; 95% CI, 1.02 - 1.32; P = .03)

  • All-cause mortality (HR, 1.12; 95% CI, 1.01 - 1.24; P = .03)

  • Stroke (HR, 1.19; 95% CI, 1.03 - 1.37; P = .02)

MI risk was similar, irrespective of patient sex.

After the researchers adjusted for baseline risk predictors, women were found to have a 7% lower risk of MACE compared with men (adjusted HR, 0.93; 95% CI, 0.89 - 0.98; P = .005).

Women also had a 15% lower risk of cardiovascular death (adjusted HR, 0.85; 95% CI, 0.76 - 0.96; P = .008) and a 16% lower risk of all-cause mortality (adjusted HR, 0.84; 95% CI, 0.78 - 0.90; P < .0001).

"We looked at outcomes for both women and men who had been enrolled in clinical trials with a diagnosis of NSTEACS — heart attack or unstable angina — and before accounting for baseline differences, it confirmed what had been previously observed, namely that women were more likely to die after NSTEACS than men," O'Donoghue reported.

"However, we determined that this appeared to be explained entirely by differences in baseline characteristics," she added.

High-Risk Group

Commenting on the study for theheart.org | Medscape Cardiology, Raffaele Bugiardini, MD, professor of cardiology in the Department of Experimental, Diagnostic and Specialty Medicine at University of Bologna in Italy, said that recent studies in STEMI "found unexplained higher mortality rates in women, even after adjusting for medications, primary PCI, and other coexisting comorbidities."

He noted that his own research showed that "women are more likely than men to have congestive heart failure at hospital presentation, and women with heart failure have worse survival than do their male counterparts."

Heart failure, therefore, "is a key feature to explain the mortality gap after STEMI among women and men," said Bugiardini, who was not involved with the study.

He described women with heart failure as a "high-risk group deserving more research into prevention of sex-specific risks of mortality."

Care Gap

Also commenting for theheart.org | Medscape Cardiology, Nanette K. Wenger, MD, professor of medicine (cardiology), Emory University School of Medicine, and founding consultant, Emory Women's Heart Center, Atlanta, Georgia, called it "an extremely well-done study."

It is "worthy of emphasis that only 29% of the NSTEACS patients were women — an underrepresentation in the trials — and the obvious issue is that patients in clinical trials do not represent patients in the community," said Wenger, who was not associated with the current research.

An accompanying editorial written by Michael Farkouh, MD, and Wendy Tsang, MD, of the University of Toronto in Canada, referred to the discrepancy between the treatment of men and women with NSTEACS as a "care gap" that they describe as "sobering."

"Overall, this study by Sarma et al underscores the lack of progress made in addressing sex inequality in the care for women with ACS," they write. "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."

Strategies to improve the underuse of guideline-directed therapy in women are needed, they add, and point out that the information on outcomes in women is limited to those enrolled in large clinical trials.

"More studies are needed on the overall population of women with NSTEACS to improve disease prevention, diagnosis, and response to therapy," they conclude. "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. Ultimately, sex-, and age-specific strategies for the diagnosis of ACS in women should be developed to improve women's health outcomes."

O'Donoghue added, "Moving forward, it's critical that clinical trials and registries capture greater detail as to why women and men are being treated differently, and why women remain largely underrepresented in clinical trials."

No funding source was listed for this study. O'Donoghue has received research grants from Amgen, Merck, Eisai, AstraZeneca, GlaxoSmithKline, and The Medicines Company. Financial disclosures for the other study authors are listed in the original article. Farkouh has received research support from Amgen and Novo Nordisk. Tsang is supported by a National New Investigator award from the Heart and Stroke Foundation of Canada.

Wenger and Bugiardini have disclosed no relevant financial relationships.

JACC. Published online December 9, 2019. Abstract, Editorial

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