The differences between men and women with acute coronary syndromes are of great interest to scientists and clinicians. Women have traditionally been underrepresented in clinical trials that evaluate the presentation, management, and outcome of acute coronary syndromes, despite the fact that coronary artery disease (CAD) is the leading cause of death in women. In 2002, 241 622 women died from CAD, a figure accounting for 49% of all CAD deaths.¹

Women’s Health Initiative
There has been an effort on multiple fronts to study sex differences in acute coronary syndromes, with the ultimate goal of improving care for women and men. In 1991, the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) launched the Women’s Health Initiative (WHI), a 15-year research program to address the most common causes of death and disability for postmenopausal women. The WHI consisted of a set of clinical studies and an observational trial that together included more than 160 000 women.²

In August 2003, the final results of the estrogen-progestin study were published. Hormone replacement therapy (HRT) did not confer cardiac protection and may have increased the risk of CAD. Combined HRT was associated with a hazard ratio for CAD of 1.24 (nominal 95% confidence interval [CI], 1.00-1.54).³

In April 2004, the results of the study using estrogen alone were published. No difference in the risk of CAD was shown using single-agent HRT.⁴ This confirmed that there is no role for HRT in the prevention of CAD in women.

In the observational trial of the WHI, predictors of angina pectoris versus myocardial infarction (MI) were evaluated. In a multivariate analysis of women with angina pectoris or MI, high cholesterol level (odds ratio [OR] for MI vs angina pectoris, 0.62) and prior coronary disease (OR, 0.70) predicted angina pectoris, whereas current cigarette smoking (OR, 1.60), diabetes (OR, 1.44), and hypertension (OR, 1.26) predicted MI.⁵

Women’s Ischemia Syndrome Evaluation
The Women’s Ischemia Syndrome Evaluation (WISE) study was started by the NHLBI in August 1996. The purpose was to evaluate diagnostic methods in the evaluation of ischemic heart disease in women.⁶ In 1 substudy of 864 women referred for angiography on the basis of ischemic symptoms, hemoglobin level was found to be an independent predictor of ad­verse cardiovascular outcomes. Anemic wom­en, with a hemoglobin level < 12 g/dL, had a higher risk of death from any cause than nonanemic women (10.3% vs 5.4%, respectively; P = .02) and a higher risk of total adverse outcome (26% vs 16%, respectively; P < .01). Adverse outcome was de­fined as a composite of hospitalization for nonfatal MI, congestive heart failure, stroke, other vascular events, or death.⁷

Guidelines
The American Heart Association (AHA) and American College of Car­diology (ACC) have also ad­dressed sex differences in acute coronary syndromes. The 2002 AHA/ACC committee guidelines for the management of patients with unstable angina pectoris and non–ST-elevation MI (NSTEMI) include a section on the treatment of women. A class I recommendation is that women with unstable an­gina/NSTEMI should be treated in a manner similar to men. Specifically, they should receive aspirin and clopidogrel (Plavix) and undergo invasive and noninvasive testing for the same indications.⁸

The guidelines recognize that CAD presents somewhat differently in women than in men, but they stress the importance of treating women just as aggressively as men and using the same treatments, including percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery.

Outcomes
The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Im­plementation of the ACC/AHA Guide­lines (CRUSADE) registry was the first large-scale trial to evaluate the effect of the updated AHA/ACC guidelines with respect to the treatment of wom­en with unstable angina/NSTEMI. A substudy of the trial focused on sex disparities.⁹ The analysis included 35 875 patients, of which 14 552 (41%) were women. In the registry, women were older than men and had higher rates of diabetes and hypertension, but were less likely to smoke or to have hyperlipidemia. Fewer women had a history of MI, CABG surgery, or PCI.

Compared with men, women were less likely to have an electrocardiogram performed within 10 minutes of hospital presentation (29.3% vs 25.2%, respectively) and less likely to be cared for by a cardiologist during their inpatient stay (63.4% vs 53.4%, respectively). Pharmacologic therapy likewise differed according to sex. Women were less likely than men to receive acute heparin, angiotensin-converting enzyme (ACE) inhibitors, and glycoprotein IIb/IIIa inhibitors. They were equally likely to receive aspirin, clopidogrel, and beta blocking agents within 24 hours of presentation. At discharge, women were less likely than men to receive aspirin, ACE in­hibi­tors, and HMG-CoA reductase inhibi­tors (statins). The rates of beta blocking agent and clopidogrel use were similar between men and women at discharge.

The rate of invasive procedures was also different between men and women. Cardiac catheterization, PCI, and CABG surgery were performed less frequently for women. After ac­counting for use of diagnostic angiography and extent of coronary disease, the PCI rate was similar between women and men. This suggests that differences in angiography and extent of disease account for the sex differences in the use of revascularization procedures.

Another substudy of the CRUSADE registry focused on elderly pa­tients.¹⁰ Treatment of elderly patients bears special relevance to acute coronary syndromes in women, given that women tend to present with acute coronary syndromes at an older age than men. In the CRUSADE trial, patients were divided into 4 quartiles based on age: < 65 years, 65-74 years, 75-85 years, and > 85 years. The percentage of patients who were women increased with advancing age: 30.9%, 39.5%, 48.4%, and 62%, respectively.

Elderly patients were more likely to have positive cardiac markers (91.6% for patients > 85 years vs 86.7% for patients < 65 years) and congestive heart failure (41.4% for patients > 85 years vs 12.5% for patients < 65 years) at presentation. Elderly patients had a declining prevalence of diabetes, hy­perlipidemia, and smoking, but an in­creasing prevalence of history of known cardiac disease (prior congestive heart failure, MI, or CABG surgery).

Medication use varied with age. Early use of aspirin and beta blocking agents (within 24 hours) was somewhat less common with age > 65 years. Clopidogrel and glycoprotein IIb/IIIa inhibitors were less commonly used in elderly patients. For patients < 65 years, 45.2% received early clopidogrel, compared with 29.9% of patients > 85 years (OR, 0.82; 95% CI, 0.76-0.87). For patients < 65 years, 44.6% received early glycoprotein IIb/IIIa inhibitors, compared with 12.8% of patients > 85 years (OR, 0.39; 95% CI, 0.35-0.44). The rates of invasive procedures, cardiac ca­theterization, PCI, and CABG sur­gery all decreased with age. The risk of death, repeat MI, stroke, and congestive heart failure all increased with age. The in-hospital mortality rate for patients < 65 years was 1.9% compared with 11.5% for patients > 85 years (OR, 3.00; 95% CI, 2.53-3.55).

Cardiac biomarkers
A substudy of the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Con­servative Strategy–Thrombolysis in Myocardial Infarction (TACTICS–TIMI) 18 study evaluated differences between men and women in cardiac biomarkers for patients presenting with unstable angina/NSTEMI.¹¹

Women were found to have lower levels of creatine kinase-MB, troponin I, and troponin T and higher levels of high-sensitivity C-reactive protein (hsCRP) and brain natriuretic protein (BNP) compared with men. Women were older, had hypertension more often, were less likely to smoke, and were less likely to have a prior MI, CABG surgery, or documented CAD. Among patients who underwent an­gio­graphy, women were more likely to have no significant CAD. Despite these baseline differences, the sex differences persisted after multivariable analyses for troponin I, troponin T, hsCRP, and BNP. Increased levels of biomarkers predicted adverse outcomes for both sexes. There was no correlation between sex and positive biomarkers and death or death and MI, indicating that the predictive value of positive biomarkers is the same for men and women.

Lipid lowering
In the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study, high-dose atorva-statin (Lipitor; 80 mg) was compared with standard-dose pravastatin (Pra­vachol; 40 mg).¹² Of 4162 patients, 22% were women. The median low-density lipoprotein (LDL) cholesterol level at the start of the study was 106 mg/dL for both groups, which de­creased to 95 mg/dL in the pravastatin group and 62 mg/dL in the atorva-statin group. The primary end point was death from any cause, MI, documented unstable angina pectoris re­quiring hospitalization, revascularization with either PCI or CABG surgery, and stroke. At 2 years, 27% of the women in the pravastatin group and 20.3% of the women in the atorva-statin group reached the primary end point. For men, 26.2% in the pravastatin group compared with 23.0% in the atorvastatin group reached the primary end point. The benefit from intensive lipid lowering was seen as early as 30 days.

In the Treating to New Targets (TNT) study, the effect of intensive lipid lowering in patients with stable CAD was evaluated.¹³ A total of 10 001 patients with clinically evident CAD were assigned to either 10 mg or 80 mg daily of atorvastatin. Women accounted for 20% of the trial participants. The mean LDL cholesterol level during the study was 77 mg/dL in the group receiving 80 mg of atorva-statin and 101 mg/dL in the group receiving 10 mg of atorvastatin. A primary event, defined as death from CAD, nonfatal non–procedure-related MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke, occurred in 8.7% of patients receiving 80 mg of atorvastatin compared with 10.9% of patients receiving 10 mg of atorva-statin (hazard ratio, 0.78; P < .001). There was no difference in all-cause mortality between the 2 groups and no difference in outcomes between men and women.

Early invasive versus selectively invasive strategy
A number of studies have addressed the issue of a routine invasive strategy, in which all patients with unstable angina pectoris or NSTEMI are re­ferred for invasive procedures, versus a selective approach, in which such patients are treated with aggressive pharmacologic intervention and only those with refractory or inducible ischemia are referred.^14-16 These studies have had conflicting results regarding which strategy is better and whether there is a sex difference.

In the Fast Revascularization During Instability in Coronary Artery Disease (FRISC II) trial of acute coronary syndromes, patient sex was prospectively selected for subgroup analysis of outcomes at 1 year among 747 women and 1706 men.¹⁴ An invasive strategy was beneficial for men but not for women. For men, the primary end point of death or MI was significantly reduced at 1 year, from 15.8% in the conservative-treatment group to 9.6% in the invasive-treatment group (risk ratio [RR], 0.61). For women, the event rate was not significantly different in the conservative and invasive arms—10.5% vs 12.4%, respectively (RR, 1.18). Similar results were observed for the single end point of death. The study was underpowered to detect differences in women because of the low event rate—43 women with death or infarction in the invasive-treatment group and 42 women with these events in the conservative-treatment group.

A subgroup analysis of the TACTICS–TIMI 18 results, however, showed a similar benefit for both women and men treated with an early invasive strategy.¹⁷ The study included 2220 patients (757 women, 1463 men) with acute coronary syndrome. All patients received a glycoprotein IIb/IIIa inhibitor. Compared with men, women were older and more frequently had hypertension, but they were less likely to have a prior MI or CABG surgery and less frequently had increased levels of cardiac markers. Women had a 28% odds reduction in the primary end point of death, MI, or rehospitalization for acute cor­onary syndrome at 6 months (adjusted OR, 0.72; 95% CI, 0.47-1.11), similar to the benefit for men (adjusted OR, 0.64; 95% CI, 0.47-0.88; P = .⁶⁰ for sex interaction).

In a recent Dutch study, the benefit of an early-invasive strategy was compared with a selectively invasive strategy in 1200 patients, of which 26.5% were women.¹⁶ At 1 year, there was no significant difference in the primary end point of death, MI, or re-hospitalization for angina pectoris symptoms for the early-invasive group compared with the selectively invasive group (22.7% vs 21.2%, respectively; RR, 1.07; 95% CI, 0.87-1.33; P = .33). Individual end points did differ be­tween the 2 groups. The cumulative risk of MI was higher in the early-invasive group compared with the selectively invasive group (15% vs 10%, respectively; RR, 1.50; P = .005), and rehospitalization was less frequent (7.4% vs 10.9%, respectively; RR, 0.68). There was no difference in mortality. Subgroup analysis did not show any significant difference in frequency of the primary end point according to sex.

Antiplatelet drug resistance
Resistance to antiplatelet drug thera­py is an area of active research with important implications for the treatment of cardiovascular disease. A recent study of 326 patients (22.3% women) with cardiovascular disease assessed the prevalence and clinical significance of resistance to the effects of aspirin, as measured by optical platelet aggregation.¹⁸ Of the 326 patients, 17(5.2%) were aspirin resistant. Of those who were aspirin resistant, 47% were women compared with 21% women in the aspirin-sensitive group. After a mean follow-up period of 679 days, the primary end point, which was a composite of death, MI, or cerebrovascular accident, was reached by 24% of patients in the aspirin-resistant group versus 10% of patients who were not aspirin re-sistant (P = .03).

An analysis of patients from the Heart Outcomes Prevention Evalua­tion (HOPE) study assessed the relationship between aspirin resistance and the risk of adverse cardiovascular outcomes.¹⁹ Patients in the study had a history of CAD, stroke, peripheral vascular disease, or diabetes, plus at least one other cardiovascular risk factor. Case subjects (n = 488) were de­fined as aspirin-treated patients who subsequently developed MI, stroke, or cardiovascular death. Control subjects (n = 488) were defined as aspirin-treated patients who did not develop MI, stroke, or cardiovascular death. Women made up 15.8% of both cases and controls. Aspirin resistance was determined by measuring urinary levels of 11-dehydro-thromboxane B2, a stable metabolite of thromboxane A2. The higher the level of 11-dehydro-thromboxane B2, the greater was the resistance to aspirin. Baseline urinary levels of 11-dehydro-thromboxane B2 were significantly higher among patients who developed MI, stroke, or cardiovascular death compared with those who did not (24.5 ng/mmol creatinine vs 21.5 ng/mmol creatinine, respectively; P = .01). Female sex was found to be independently associated with higher baseline levels of 11-dehydrothromboxane B2, indicating that women may be inherently more resistant to aspirin.

Conclusions
Cardiovascular disease is the number one killer of women, and half of all deaths from CAD occur in women. Proven treatment strategies should be employed with the same frequency in both sexes. Despite the existence of evidence-based guidelines for the treatment of acute coronary syndromes, women continue to be undertreated with pharmacologic therapy and invasive procedures, even though they receive the same benefits of therapy as men. The older age of women with acute coronary syndromes adds complexity to clinical decision making. Available data indicate that an aggressive medical or interventional approach to acute coronary syndrome is often warranted in elderly patients, with particular attention to appropriate medication dosing dictated by patient size, comorbidity, and renal function.

The percentage of women enrolled in clinical trials of acute coronary syndromes has increased over the past decade, but women are still underrepresented relative to the prevalence of disease in the population. Initiatives from the NIH have helped to remedy some of the disparity. Some evidence exists showing that there are inherent differences between men and women with regard to CAD, such as resistance to antiplatelet drugs and the benefit of an early-invasive versus conservative treatment strategy, but more research is needed before firm conclusions can be drawn. For now, the primary goal should be increasing the number of women treated with proven effective therapies according to established evidence-based guidelines.

References
1. American Heart Association. Women and Cardiovascular Diseases – Statistics (Revised). 2005. Available at: http://www.americanheart.org/presenter.jhtml?identifier=3000941. Accessed January 25, 2006.

2. Design of the Women’s Health Initiative Clinical Trial and Observational Study. The Women’s Health Initiative Study Group. Control Clin Trials. 1998;19(1):61-109.

3. Manson JE, Hsia J, Johnson KC, et al for the Women’s Health Initiative Investi­gators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349(6):523-534.

4. Anderson GL, Limacher M, Assaf AR, et al for the Women’s Health Initiative Steering Committee. Effects of Conjugated Equine Estrogen in Postmenopausal Wom­en with Hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-1712.

5. Hsia J, Aragaki A, Bloch M, et al for the WHI Investigators. Predictors of angina pectoris versus myocardial infarction from the Women’s Health Initiative Observation Study. Am J Cardiol. 2004;93(6):673-678.

6. Merz CNB, Kelsey SF, Pepine CJ, et al for the WISE Study Group. The Women’s Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report. J Am Coll Cardiol. 1999; 33(6):1453-1461.

7. Arant CB, Wessel TR, Olson MB, et al. Hemoglobin level is an independent predictor for adverse cardiovascular outcomes in women undergoing evaluation for chest pain: results from the National Heart, Lung, and Blood Institute women’s ische­mia syndrome evaluation study. J Am Coll Cardiol. 2004;43(11):2009-2014.

8. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Man­age­ment of Patients With Unstable Angina). 2002. Available at: http://www.acc.org/clinical/guidelines/unstable/unstable.pdf. Accessed January 25, 2006.

9. Blomkalns AL, Chen AY, Hochman JS, et al for the CRUSADE Investigators. Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. J Am Coll Cardiol. 2005;45: 832-837.

10. Alexander KP, Roe MT, Chen AY, et ala for the CRUSADE Investigators. Evo­lu­tion in cardiovascular care for elderly patients with non–ST-segment elevation acute coronary syndromes. Results from the CRUSADE National Quality Improve­ment Initiative. J Am Coll Cardiol. 2005;46(8):1479-1487.

11. Wiviott SD, Cannon CP, Morrow DA, et al. Differential expression of cardiac biomarkers by gender in patients with unstable angina/non–ST-elevation myocardial infarction. A TACTICS–TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Con­ser­vative Strategy–Thrombolysis In Myo­cardial Infarction 18) substudy. Circula­tion. 2004;109(5):580-586.

12. Cannon CP, Braunwald E, McCabe CH,et al for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Throm­bolysis in Myocardial Infarction 22 In­vestigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15): 1495-1504.

13. LaRosa JC, Grundy SM, Waters DD, et al for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14): 1425-1435.

14. Wallentin L, Lagerqvist B, Husted S, et al. Outcome at 1 year after an invasive compared with a noninvasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial. FRISC II Investi­gators. Fast Revasculari­zation during In­stability in Coronary artery disease. Lancet. 2000;356(9223):9-16.

15. Cannon CP, Weintraub WS, Demopoulos LA, et al for the TACTICS (Treat An-gina with Aggrastat and Determine Cost of Therapy with an Invasive or Con­servative Strategy)—Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa in­hibitor tirofiban. N Engl J Med. 2001;344(25): 1879-1887.

16. de Winter RJ, Windhausen F, Cornel JH, et al for the Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) Investigators. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med. 2005;353(11):1095-1104.

17. Glaser R, Herrmann HC, Murphy SA, et al. Benefit of an early invasive management strategy in women with acute coronary syndromes. JAMA. 2002;288(24):3124-3129.

18. Gum PA, Kottke-Marchant K, Welsh PA, et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol. 2003;41(6):961-965.

19. Eikelboom JW, Hirsh J, Weitz JI, et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation. 2002;105(14):1650-1655.