Differences in the Management and Prognosis of Women and Men Who Suffer From Acute Coronary Syndromes

Methods

We conducted a post-hoc analysis of data from the CURE trial. Details of the CURE trial have been reported previously (10). Briefly, the trial enrolled men and women who presented within 24 h of symptoms onset with ACS, including UA and NSTEMI as previously described (10). Patients with contraindications to antithrombotic/antiplatelet therapy, who were at high risk of bleeding, who had severe heart failure (class IV), who had an ongoing long-term need for oral anticoagulants, and who had percutaneous transluminal coronary angioplasty (PTCA)/stent, or coronary artery bypass graft (CABG) within three months before randomization were excluded. Patients were recruited between December 1998 and September 2000 from 482 centers in 28 countries. The protocol was approved by the institutional review board of each hospital, and all patients provided written informed consent.

Results

Risk stratification

Patients were stratified into low-, intermediate-, and high-risk categories using the previously validated TIMI risk score. As expected, with increasing risk, the rate of cardiovascular death, MI, stroke, and refractory coronary ischemia increased significantly among all patients; surprisingly, however, the rate of coronary angiography did not differ. Across all risk strata, angiography rates were significantly lower among women compared to men. Among low- and moderate-risk patients, women were less likely to have significant CAD on angiography compared to men, whereas among high-risk patients, women had a similar proportion of “significant” coronary disease compared to men (60.8% vs. 59.4%; p = 0.68), and the rates of PTCA or CABG surgery among those with significant CAD were similar (64.9% vs. 65.1%; p = 0.97) (Table 4).The incidence of cardiovascular death, MI, stroke was not increased among high-risk women compared to men (19.5% vs. 17.8%; p = 0.40), but the incidence of refractory angina and rehospitalization for chest pain during follow-up was significantly higher (23.9% vs. 15.3%; p = 0.0001) (Fig. 1,Table 4). A significant interaction between the TIMI risk strata and gender for the outcome of refractory angina and rehospitalization was present (p_interaction= 0.0001) (Fig. 2).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

High-risk acute coronary syndrome patients. Open bars= women; solid bars= men. Significant coronary artery disease (CAD) by angiography indicates triple-vessel disease or left main disease. *p < 0.005. CABG = coronary artery bypass graft surgery; CVD = cardiovascular disease; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

Refractory ischemia and rehospitalization by gender and Thrombolysis In Myocardial Infarction (TIMI) risk. Adjusted for treatment allocation and region. Solid line= women; dashed line= men. *Note: p for interaction between TIMI risk and gender = 0.001.

View this table:

• View inline
• View popup

Table 4

Gender Differences in Invasive Procedures and Clinical Outcomes by TIMI Risk

Discussion

Our findings demonstrate that, after ACS, women are less likely to undergo angiography, PTCA, and CABG compared to men, and while they have no differences in cardiovascular death, MI, or stroke, they do suffer an increased rate of refractory angina and rehospitalization for UA. This is especially true among high-risk women.

Our study is consistent with the results of previous investigators who have reported that, compared with men, women with NSTEMI/UA are generally older, have more comorbidities at the time of presentation, and undergo fewer coronary interventions (13–15). However, the lower rate of invasive cardiac procedures has not been convincingly linked to differences in prognosis after the acute coronary episode, nor has it been linked to any systematic biases (5,7,13–15). Explanations for the differences in the rates of coronary invasive procedures between women and men are multiple, and include differences in the presentation of ACS (e.g., reporting of typical versus atypical symptoms) (3), patient preferences to undergo invasive cardiac procedures (8,16–18), and physician practices in the referral of women for cardiac catheterization (8).

Our analysis differs from previous reports because it includes the largest number of women enrolled into an ACS clinical trial to date (n = 4,836); it includes patients from a broad representation of countries (e.g., North and South America, and Europe), and it examines procedure use and prognosis according to the TIMI risk score. Surprisingly in the CURE trial cohort, the decision to perform angiography was notlinked to the risk status of patients, and in all risk groups women were less likely to have angiography. Among women who did undergo angiography, those in the low- or moderate-risk TIMI categories were less likely to have significant CAD, whereas women in the high-risk stratum had a similar proportion of significant CAD compared to men. The lower angiography rates among high-risk women likely “underidentified” women with significant CAD who required coronary revascularization, and this difference in angiography may be particularly important to address given that high-risk women suffered a significantly higher incidence of refractory angina and rehospitalization for ACS over the long-term compared to men (Fig. 2). However, it is not clear from existing clinical trials whether an early invasive strategy is as beneficial in reducing hard clinical outcomes such as death and MI among women as it is among men.

Recently, subgroup analyses of the Fragmin and Fast Revascularization during InStability in Coronary artery disease (FRISC)-2 (n = 749 women) (13) and Randomized Intervention Trial of unstable Angina (RITA)-3 (n = 648 women) (14) randomized clinical trials reported worsened outcomes among women who underwent invasive management of ACS, which has raised doubt as to whether the management approach toward women and men should be similar. The results from these trials conflict with the more recent Treat Angina With Aggrastat and Determine Cost of Therapy With Invasive or Conservative Strategy (TACTICS)-TIMI 18 trial report (n = 757 women) in which women appeared to benefit as much as men from an early invasive strategy (32% risk reduction in death and MI; p = 0.02), especially women with elevated troponin T levels at baseline (15). This is supported by the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines Quality Improvement Initiative (CRUSADE) prospective registry of 17,926 ACS patients from 248 U.S. hospitals in which women who were 14% less likely to receive early invasive management after ACS had a significantly higher in-hospital mortality (no early invasive vs. early invasive: 8.9% vs. 4.7%) (19). Whether the differences observed across studies reflect differences in the clinical characteristics of women, differences in health system approaches to the treatment of men and women with ACS, retrospective methodology, or the unreliable nature of subgroup analyses remains unclear. Despite the fact that our trial included the largest number of women enrolled into an ACS trial to date (n = 4,836), an examination of the reasons for sex/gender differences is limited because detailed information regarding presentation, symptoms, center characteristics (i.e., cath lab facilities), changes in risk factors and medication use over time, referral patterns, and patient preferences was not collected. The only way to definitively determine if differences in early intervention rates between women and men with NSTEMI/UA, including those at high risk, are associated with differences in their long-term prognosis, especially hard outcomes such as cardiovascular death, MI, and stroke, is to randomize women to different intervention strategies and collect long-term follow-up data.

The medical management of men and women with ACS appears to be equivalent as the use of aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitors increased significantly during the initial hospitalization among all patients in our trial, although significantly fewer women were prescribed beta-blockers at the time of discharge compared to men. This may be appropriate given that fewer women had suffered from a previous MI. More women were taking angiotensin-converting enzyme inhibitors at the time of admission, which is likely due to the greater proportion of women with diabetes, who were on angiotensin-converting enzyme inhibitors for renal protection. In the CURE trial, the risk reduction with clopidogrel was not significantly heterogeneous between women compared to men. This is consistent with data for a number of other pharmacologic treatments that indicate that antiplatelets, beta-blockers, angiotensin-converting enzyme inhibitors, and lipid-lowering therapies clearly reduce the risk of future vascular events by approximately a quarter in both women and men (20). Therefore, as the incidence of cardiovascular death, MI, and stroke was between three to four times greater among high-risk patients compared to low-risk patients in our trial, it appears especially important that all high-risk patients—men andwomen—receive optimal medical management, and are considered for coronary angiography with possible revascularization when their coronary anatomy warrants it (15,20,21).