Sex-related differences in treatment and outcome in patients with ACS

In Western countries, acute coronary syndrome (ACS) accounts for most cases of cardiovascular morbidity and mortality in both sexes. ACS encompasses a spectrum of clinical conditions. These include acute myocardial infarction (MI), which encompasses both ST-segment elevation MI (STEMI) and non-STEMI (NSTEMI), and unstable angina pectoris. The differences in presentation, awareness, diagnosis, treatment, and outcome between men and women with ACS have been widely investigated.^1-5 Some studies have found that although reperfusion therapy benefits all patients with ACS and has become standard practice, not all women who experience acute MI receive this treatment.

We investigated sex-related differences in management and in-hospital outcomes in a large, randomly selected population of patients (N = 26,452) admitted to hospitals in Switzerland for ACS between 1997 and 2007. We also assessed whether women with ACS are at a disadvantage compared with men regarding treatment and outcomes, something previous studies do not address.

Subjects and methods

In January 1997, the Steering Committee, consisting of members of the Swiss Societies of Cardiology, Intensive Care, and Internal Medicine, initiated the AMIS (Acute Myocardial Infarction in Switzerland) Plus project, a prospective cohort study of ACS patients admitted to academic and nonacademic hospitals in Switzerland. The project was approved by the Over-Regional Ethics Committee for Clinical Studies and the Swiss Board for Data Security.

Centers participated voluntarily, with coordinators at each institution providing deidentified data for patients using a standardized questionnaire administered electronically or on paper. All data were checked for plausibility and consistency, and incomplete questionnaires were returned to their respective enrollment centers for completion. Patients were included in the study if they met the following criteria for specific ACS conditions: STEMI, defined as ST-segment elevation or new left bundle branch block on initial electrocardiogram (ECG) and elevated cardiac enzymes (levels of total creatinine kinase [CK; normal, <2.8 μkat/L] or CK-MB fractions [normal, <5 μg/L] at least twice the upper limits of normal); NSTEMI, defined as symptoms and ECG changes or both compatible with ACS and elevated cardiac enzymes not meeting the criteria for STEMI; and unstable angina pectoris, defined as symptoms and ECG changes, or both compatible with ACS and normal cardiac enzymes.

AMIS Plus enrolled a cumulative 26,698 patients admitted to 74 Swiss hospitals between 1997 and 2007. The study included only those patients for whom valid data on their initial ECG and reperfusion therapy had been provided. Baseline characteristics between men and women were compared using t-test and chi-square tests (Table 1). Independent predictors of in-hospital mortality were calculated using logistic regression models that considered all variables available at hospital admission (Table 1): per year increase in age; history of coronary heart disease; presence of arterial hypertension, dyslipidemia, or diabetes; current smoking; delay >6 hours between symptom onset and hospital admission; left bundle branch block, ST-segment elevation, ST-segment depression, and Q-waves on initial ECG; Killip class, body mass index, heart rate, and systolic blood pressure at admission; and whether the patient underwent percutaneous coronary intervention (PCI). Variables significant at the 0.05 level were included in the stepwise logistic regression analysis using the backwards method. Statistical analyses were performed using SPSS software (Chicago, Illinois; Version 14.0).

Results

The 26,452 ACS patients included in the analysis comprise 7341 women and 19,111 men. The mean age of women in the study was 7 years greater than the mean age of the men. Women were more likely to have preexisting hypertension and diabetes, but less likely to have dyslipidemia, be overweight, or smoke. On average, women arrived at the hospital 1 additional hour after symptom onset compared with men.

At admission, more women than men were ranked Killip class II or III, and presented with dyspnea, ST-segment depression, left bundle branch block, or atrial fibrillation. Women were less likely to receive aspirin, clopidogrel (Plavix, Iscover, Clopilet), glycoprotein IIb/IIIa antagonists, beta blockers, and lipid-lowering drugs. Women were also less likely to undergo PCI than men, and even after adjusting for covariables, being of the female sex remained an independent factor that decreased a patient’s likelihood of undergoing PCI (odds ratio [OR], 0.83; 95% confidence interval [CI], 0.78-0.89; P <.001).

Crude in-hospital mortality was higher overall for women than men (9.8% vs 5.9%, respectively; P <.001). In-hospital mortality was also higher for more women than men with STEMI (12.0% vs 6.7%, respectively; P <.001) and NSTEMI (6.8% vs 4.7%, respectively; P <.001) and for women who underwent PCI (4.2% vs 3.1%; P = .009). After adjusting for covariables, it was determined that sex is not an independent predictor of in-hospital mortality for ACS patients (adjusted OR for men vs women, 1.07; 95% CI, 0.94-1.22). Table 2 provides unadjusted and adjusted ORs for in-hospital patient mortality for women, allocated by age group. For the most part, direct comparisons between men and women of the same age ranges indicate no significant differences between the sexes in the in-hospital mortality rates for ACS patients. However, the in-hospital mortality rate for women aged 51 to 60 years is statistically greater (P = .038) than the mortality rate for men of this age range, even after adjustment.

Discussion

Some studies have shown that even when women with ACS present with greater risk factors and have a higher in-hospital mortality risk than men, they receive less aggressive treatment.⁶ Data from AMIS Plus show that in addition to differences in baseline characteristics between men and women admitted for ACS between 1997 and 2007, their conditions were treated differently from the outset. For example, women in our study were less likely to receive certain drug treatments and reperfusion therapy. This finding supports other studies that have concluded women and men do not receive identical interventional treatment and women are less likely to receive PCI, although they have comparable or better outcomes than men following the procedure.^4,7

Routine PCI appears to be a safe revascularization procedure. It is associated with a low rate of clinical complications in patients with STEMI, NSTEMI, or unstable angina pectoris and has become the preferred treatment in Switzerland for patients with ACS. It is unclear why the women with ACS in our study underwent PCI less frequently than the men, and this should be investigated further.

The TACTICS—TIMI (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy—Thrombolysis in Myocardial Infarction)–18 trial found that employing an early invasive approach in ACS patients with non–ST-segment elevation benefitted both men and women.⁸ In contrast, the FRISC II (Fragmin and Fast Revascularization During Instability in Coronary Artery Disease) and RITA 3 (Third Randomized Intervention Trial of Unstable Angina) trials found that these women did not benefit from an early invasive approach.^9,10

Some studies have documented a higher mortality rate in women following interventional treatment,¹¹ which was attributed to differences in body size between men and women, anatomical differences, basic biological differences,^12,13 and/or the differing pathophysiology of ACS conditions dependent on patient age.¹⁴ On the whole, however, our study found similar rates of in-hospital mortality for men and women with ACS after adjustment for covariables, despite the less frequent use of interventional procedures in women.

The only exception was women aged 51 to 60 years, who demonstrated a marginally higher rate of in-hospital mortality than men of the same age. This corresponds with results from the USIC (Unité de Soins Intensifs Coronaires) French nationwide registries, which showed that women (30-67 years) had higher mortality following acute MI compared with men regardless of the patient’s clinical characteristics or treatment received.¹⁵

Conclusion

The AMIS Plus data show that among patients admitted to hospitals for ACS, women are less likely than men to receive specific drug treatments and PCI. Despite this, the men and women in our study had similar rates of in-hospital mortality overall, after adjustments were made to account for differences in their baseline characteristics and management.

We concluded that sex is not an independent predictor of in-hospital mortality, and simply being a woman does not increase the risk of dying in-hospital due to ACS. The only exception was observed in women aged 51 to 60 years, who had a higher rate of in-hospital mortality compared with men of the same age. Further investigation is needed to determine why this is the case and why women with ACS are less likely than men to receive interventional treatment, including PCI.

Disclosure

The AMIS Plus registry is funded by unrestricted grants from the Swiss Heart Foundation and from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Essex/MSD, GlaxoSmithKline, Guidant, INVATEC, Johnson & Johnson—Cordis Division, A Menarini, Medtronic, Mepha Pharma, Merck Sharp & Dohme-Chibret, Novartis, Pfizer, Sanofi-Aventis, Schering, Servier, SPSS, St. Jude Medical, and Takeda Pharma, all in Switzerland. The supporting institutions did not play any role in the design of the registry; in data collection, analysis, or interpretation; or in the preparation of the manuscript.