INTRODUCTION — There are significant differences between women and men in the epidemiology, diagnosis, response to therapy, and prognosis of coronary heart disease (CHD) that should be taken into account in the care of women with known or suspected disease. In addition, women are generally underrepresented in cardiovascular randomized studies and data suggest that women are not referred as often as men for appropriate therapeutic procedures in clinical practice [1,2].
The success rate of therapy for CHD is similar in women and men; however, the complication rates differ, resulting in a sex specific profile of benefit. Although unadjusted outcomes with therapies such as an early invasive strategy in non-ST elevation acute coronary syndromes, and fibrinolytic therapy or primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction, are often worse in women than men, these differences are almost entirely due to confounding risk factors (eg, older age, more diabetes, more hypertension), not female sex [3-7].
The management of CHD in women will be reviewed here. The clinical features, including diagnosis, the outcome after acute myocardial infarction, and issues in younger individuals are discussed separately. (See "Clinical features and diagnosis of coronary heart disease in women" and "Coronary artery disease and myocardial infarction in young people".)
SECONDARY PREVENTIVE INTERVENTIONS — All women and men with established cardiovascular disease have a high risk of subsequent cardiovascular events, including myocardial infarction, stroke, and death. Therapeutic lifestyle changes such as increased physical activity, dietary modification/weight loss, and smoking cessation are of proven benefit and are likely to improve outcomes beginning within a matter of months. Adjunctive drug therapies of proven benefit include aspirin and statins, and in patients with myocardial infarction or heart failure, include beta blockers and angiotensin converting enzyme inhibitors or angiotensin receptor blockers. In addition, other adjunctive therapies of value, such as influenza vaccination, should be recommended to the patient. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)
Cardiac rehabilitation — Although cardiac rehabilitation benefits women after an acute coronary syndrome (ACS) event , women are less likely to be referred to cardiac rehabilitation. For example, according to a study of Medicare claims, only 14.3 percent of women, compared with 22.1 percent of men, utilize these programs . (See "Cardiac rehabilitation programs" and "Cardiac rehabilitation: Indications, efficacy, and safety in patients with coronary heart disease".)
Medications — A variety of medications are used in the treatment of coronary heart disease (CHD). Women are more likely to receive nitrates, calcium channel blockers, diuretics, and sedatives than men and some studies suggest that women are less likely to receive aspirin, beta blockers, and statins. In a review of almost 3800 patients with stable angina, women were as likely to be treated with a beta blocker as men, but significantly less likely to be treated with aspirin (73 versus 81 percent) and a statin (45 versus 51 percent) . The underuse of statins in secondary prevention in women has been well documented [11,12]. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Women of childbearing age'.)
The following medications are used in secondary prevention:
●Antiplatelet therapy – When used for secondary prevention of CHD, an overview of randomized trials from the Antiplatelet Trialists' Collaboration found that aspirin (75 to 162 mg/day) was beneficial in women . Among patients with an ACS, aspirin (162 to 325 mg) should be part of initial management of all patients, both men and women. Despite the clear efficacy of aspirin therapy in all patients with ACS, women undergoing percutaneous coronary intervention are less likely to receive aspirin than men (adjusted odds ratio [OR] 0.86; 95% CI 0.83-0.88) . (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)
●Some evidence suggests that women with ACS are less often treated with P2Y12 inhibitors than men, but such therapy, including the high-potency agents such as prasugrel, ticagrelor, and cangrelor, are as safe and efficacious in women as they are in men . (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients".)
●Beta blockers – The benefit of beta blockers after myocardial infarction is well demonstrated in women and is at least equivalent to that in men [16,17]. (See "Acute myocardial infarction: Role of beta blocker therapy".)
●ACE inhibitors – The benefits of angiotensin converting enzyme (ACE) inhibition after acute myocardial infarction have been demonstrated in a number of trials that included some women . Although efficacy in women has not been specifically studied, the criteria for ACE inhibitor therapy should be the same as in men. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use".)
●LDL-C lowering drugs – Analyses of four trials of lipid lowering for secondary prevention in different patient populations support a beneficial effect of statins in women with CHD [19-23]. The FOURIER trial, which studied PCSK9 inhibitor therapy in patients with atherosclerotic cardiovascular disease and low density lipoprotein cholesterol ≥70 mg/dL on statin therapy, found no difference in efficacy of the therapy by sex . Similarly, there was no difference in the effect of ezetimibe added to statin therapy by sex in the IMPROVE-IT trial . (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
Hormone replacement therapy is not recommended for cardiac protection in women with CHD since the HERS trials showed no evidence of benefit [26,27]. (See "Menopausal hormone therapy and cardiovascular risk".)
STABLE ANGINA — Women with stable angina pectoris should receive beta blockers and have calcium channel blockers or nitrates added as necessary to manage chest pain. (See "Chronic coronary syndrome: Overview of care", section on 'Antianginal therapy'.)
NSTEACS — The non-ST elevation acute coronary syndromes (NSTEACS) include unstable angina and non-ST elevation myocardial infarction (see "Diagnosis of acute myocardial infarction", section on 'Definitions'). Women with NSTEACS tend to be older than men and have more comorbidities such as diabetes and hypertension . In general, women with positive troponin(s) are treated the same as men [28,29]. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction".)
Early invasive strategy — We utilize an early invasive strategy similarly in women and men. Although there is some evidence that Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores are not as predictive of risk in women as in men, they have both been validated in women and are clinically useful [30-32].
An invasive strategy of early catheterization and revascularization, if indicated, improves the outcome of men with a NSTEACS when compared with a noninvasive approach (see "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization"). However, in women, the benefit of early invasive therapy appears to be more nuanced. A meta-analysis of contemporary trials suggested that while an early invasive strategy had a survival benefit in men, there was no such benefit in women . However, when the subgroup of women with elevated troponin levels was examined, a clear benefit in six-month outcomes emerged (adjusted odds ratio 0.47, 95% CI 0.26-0.83) . A subsequent meta-analysis of eight trials, with over 3000 women and over 7000 men, found that an early invasive strategy had a similar benefit in high-risk (biomarker-positive) women as it did in men, but that benefit could not be shown for lower-risk (biomarker-negative) women .
In practice, women with a NSTEACS are treated less aggressively than men. In a review from the CRUSADE National Quality Improvement Initiative of almost 36,000 such patients (41 percent women), women were treated less aggressively than men . They were significantly less likely to undergo catheterization within 24 hours of admission (42 versus 49 percent in men) and less likely to undergo percutaneous coronary intervention within this time (44 versus 52 percent). Women had higher rates of in-hospital mortality, reinfarction, and heart failure but, after adjustment, the rates were similar to those in men. Similarly, in an evaluation of all patients with first ACS in Denmark between 2005 and 2011, diagnostic angiography was performed less frequently in women compared with men, both at one day (31 versus 42 percent, p<0.001), and within 60 days (67 versus 80 percent, p<0.001) . Data from two large academic health systems in the United States between 2000 and 2016 demonstrated that women with a first MI before the age of 50 were less likely than men to undergo coronary revascularization (82.1 versus 92.6 percent, p<0.001) .
STEMI — Women with ST-elevation myocardial infarction (STEMI) should generally be treated similarly to men. (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the nonacute management of ST-elevation myocardial infarction".)
Coronary reperfusion — Coronary reperfusion after acute STEMI can be achieved by fibrinolysis or, preferably, primary percutaneous coronary intervention (PCI) and should be offered to most patients. (See "Acute ST-elevation myocardial infarction: Selecting a reperfusion strategy", section on 'Summary and recommendations'.)
While studies discussed below have noted a higher rate of bleeding, particularly from the gastrointestinal tract, with coronary reperfusion therapies, the mechanism(s) is unclear. We believe that our understanding of the optimal dosing of anticoagulants and antiplatelet agents in patients with smaller BMI is incomplete. Women should receive these therapies in most cases despite the concern for an increased bleeding risk.
Fibrinolysis — In most studies, women were somewhat less likely to receive fibrinolysis, even if eligible, and were likely to experience a greater delay in being treated [5,38-41]. Although definitive data are not available, it appears that fibrinolysis reduces mortality in acute myocardial infarction (MI) by the same proportion in both sexes [5,42]. (See "Acute ST-elevation myocardial infarction: The use of fibrinolytic therapy".)
Women receiving fibrinolysis have a higher rate of mortality and morbidity compared with men [5,6,43-46]. These differences are primarily due to worse baseline characteristics, such as older age and significantly higher rates of diabetes mellitus, hypertension, and prior heart failure [5,6,43,45,46]. There are conflicting data as to whether the increase in mortality disappears  or persists after correction for these factors [6,46]. In a review from GUSTO IIb, for example, there was a nonsignificant trend toward an increased risk of death or infarction at 30 days in women after adjustment for baseline variables (odds ratio 1.27, p = 0.07) .
Women have a modestly increased risk of bleeding, including hemorrhagic stroke, after fibrinolysis [5,45]. An additional bleeding concern is the use of fibrinolytic agents in menstruating women. Data on this issue are limited. Among 12 menstruating women in GUSTO-I, there was no significant increase in severe bleeding compared with non-menstruating women . A significant increase in moderate bleeding was found that was offset by the benefits of fibrinolytic therapy. Thus, menstruating women should not automatically be excluded from fibrinolytic therapy.
Primary percutaneous coronary intervention — Women undergoing primary PCI have had higher rates of in-hospital and longer-term mortality than men in both retrospective observational studies [48-51] and subset analyses of randomized trials [45,52]. However, as with fibrinolysis, this difference was no longer present on multivariate analysis in almost all of these studies since women tended to be older and have more comorbidities [45,48,50-55].
The magnitude of these effects was illustrated by a review from the CADILLAC trial, which compared primary stenting with primary angioplasty . At one year, women had significantly higher rates of mortality (7.6 versus 3.0 percent in men), target vessel revascularization (16.7 versus 12.1 percent), and major adverse cardiac events (23.9 versus 15.3 percent) . These differences were largely due to a higher prevalence of clinical risk factors in women (older age and more frequent diabetes, hypertension, and renal insufficiency) and smaller body size, which may be associated with more frequent procedural complications and perhaps lack of weight adjustment of pharmacologic therapy, especially anticoagulants. After adjustment, female sex was not an independent risk factor for mortality in the CADILLAC trial.
In a single-center observational study of patients with acute MI treated predominantly with PCI, women had a significantly lower mortality at one year after adjustment for older age and a greater prevalence of diabetes and hypertension . A possible explanation for this finding is a greater benefit from PCI. Support for this hypothesis comes from a study that measured the degree of myocardial salvage after primary PCI in 502 women and 1435 men . The amount of myocardium at risk or initial perfusion defect was similar in women and men (22 and 24 percent of the left ventricle). However, final infarct size, measured on follow-up scintigraphy, was smaller in women, and the percent of myocardium that was salvaged by PCI was greater in women (64 versus 50 percent). Why this might occur is not clear. Contributing factors may include more reactive platelets and therefore a greater response to aggressive antiplatelet therapy and a higher incidence of preinfarction angina, which may limit infarct size by ischemic preconditioning . (See "Myocardial ischemic conditioning: Clinical implications".)
Observational studies and subset analyses of randomized trials suggest that women with STEMI (similar to men) have better outcomes with primary PCI than fibrinolysis [45,53]. In an analysis from the GUSTO-IIb trial of patients treated with primary PCI (without stenting) or fibrinolytic therapy, the adjusted odds ratio for reaching a clinical end point at 30 days (death or nonfatal MI or stroke) was significantly lower with primary PCI compared with fibrinolysis with similar benefit as in men (odds ratio 0.69 versus 0.57 in men) . In a meta-analysis of randomized controlled trials showed that in women, similar to men, 30-day outcome after STEMI was significantly better after PCI compared with after fibrinolysis (odds ratio 0.50; 95% CI, 0.36 to 0.72) .
Cardiogenic shock — Women are somewhat more likely than men to develop cardiogenic shock after STEMI (see "Prognosis and treatment of cardiogenic shock complicating acute myocardial infarction"). The magnitude of this effect was illustrated in a report from the American College of Cardiology – National Cardiovascular Data Registry (2004 to 2006), in which women had a higher incidence than men of cardiogenic shock (11.6 versus 8.3 percent, p<0.01) . A higher rate of cardiogenic shock in female versus male STEMI patients has been consistent between 2003 and 2010 .
Among STEMI patients who develop cardiogenic shock, women are significantly less likely than men to be treated with an intraaortic balloon pump (43 versus 55.1 percent, adjusted odds ratio 0.73; 95% CI 0.72-0.75). Women also have a higher likelihood of in-hospital mortality with cardiogenic shock (44.4 versus 34.5 percent; adjusted odds ratio 1.11; 95% CI 1.08-1.14; p<0.001). However, use of circulatory support (Impella) during emergent PCI in such patients clearly improves outcomes in women, perhaps more so than in men . (See "Prognosis and treatment of cardiogenic shock complicating acute myocardial infarction", section on 'Intraaortic balloon pump'.)
INVASIVE PROCEDURES — Cardiac catheterization and coronary revascularization in selected patients are fundamental to the management of coronary artery disease. Some but not all studies have noted lower rate of utilization of these procedures in women, suggesting possible sex bias [10,60,61]. However, women often are older and have a greater burden of risk factors than men [62-64].
Access to procedures — Women are less likely than men to undergo cardiac catheterization, but this difference has, in many studies, been appropriate when the difference in risk is taken into account [65-68]. This was illustrated in a review of over 143,000 Medicare patients who were admitted for an acute myocardial infarction between 1994 and 1996 . Women had significantly lower unadjusted rates of cardiac catheterization (35.7 versus 46.5 percent in men), but this difference largely disappeared with multivariable adjustment (risk-standardized rates 40.3 versus 41.9 percent). There was no difference between men and women with strong indications for catheterization; the lower utilization in women was primarily seen in those with equivocal indications, raising the suggestion of overuse of the procedure in men. In contrast, a study of over 78,000 ST elevation myocardial infarction patients between 2001 and 2006 revealed that women were less likely to receive acute reperfusion therapy with primary percutaneous coronary intervention (PCI) or fibrinolytic therapy than men (56.3 versus 73.0 percent, p<0.0001), and this disparity persisted after adjustment for clinical factors .
Women may have a different pattern of access to revascularization compared with men [67,68]. This was illustrated in a report from the Nationwide Independent Sample in the United States that compared 500,000 men with over 300,000 women . After adjustment, women were nearly as likely as men to undergo angioplasty or stenting (prevalence ratio [PR] 0.98 and 0.96, respectively); women remained less likely to undergo CABG (PR 0.78). It is unclear whether this represents bias or appropriate medical treatment given the higher mortality of women following CABG. (See 'Coronary artery bypass graft surgery' below.)
Data from the CURE trial of clopidogrel therapy in non-ST elevation acute coronary syndromes suggested that outcomes are worse in some women in whom intervention is not performed . Although the rate of angiography, PCI, and CABG was significantly lower in women than men (48 versus 61 percent), there were no significant differences in cardiovascular death, myocardial infarction, or stroke between women and men. However, women were more likely to develop refractory ischemia and to be rehospitalized for chest pain (16.6 versus 13.9 percent).
This increase in risk was most prominent in women at high risk as determined by the TIMI risk score (calculator 1). Thus, high-risk women should, as in high-risk men, be considered for coronary angiography and, if appropriate, revascularization. (See "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization".)
Cardiac catheterization — Women have a slightly higher risk of death after diagnostic catheterization than men. In a report from a Canadian registry of over 37,000 patients undergoing catheterization between 1995 and 2000, women had a higher unadjusted mortality rate at one year (5.6 versus 4.6 percent for men) . However, the excess risk appeared to be concentrated in the early post-catheterization period. After adjusting for women being older and having higher rates of comorbidity, the mortality risk was significantly increased for women compared with men at 30 days, especially for those undergoing CABG or PCI (odds ratios [OR] 2.22 and 1.70 versus 1.40 for those not undergoing revascularization). After 30 days, there was a progressive decrease in the relative risk to equivalence before one year.
Percutaneous coronary intervention — Women undergoing PCI are older and have a greater burden of risk factors than men [3,62-64,72-76]. They have a slightly higher periprocedural risk but long-term survival is better . Most strategies to avoid bleeding are similar in women as in men and include preprocedural risk assessment, use of radial access, aim for a lower activated clotting time, and consideration of bivalirudin in high-risk cases .
The following findings were noted in a study using data on 426,996 patients ≥65 years (42.3 percent women) in the United States National Cardiovascular Data Registry CathPCI Registry (2004 to 2008) and linking to United States Medicare inpatient claim data :
●Compared with men, women had a higher rate of in-hospital complications including death (2.2 versus 1.6 percent; adjusted odds ratio [OR] 1.41, 95% CI 1.33-1.49), myocardial infarction (1.3 versus 1.2 percent; adjusted OR 1.10, 95% CI 1.11-1.27), bleeding (4.4 versus 2.3 percent; OR 1.86, 95% CI 1.79-1.93), and vascular complications (1.3 versus 0.7 percent, OR 1.85, 95% CI 1.73-1.99).
●At 20.4 months, women had a lower adjusted risk of death (hazard ratio 0.92, 95% CI 0.90-0.94).
Adjustment for body surface area has been a presumed surrogate for coronary artery size , but women may have smaller coronary arteries independent of body size . Small coronary artery diameter is associated with worse outcomes after PCI . (See "Percutaneous coronary intervention of specific coronary lesions", section on 'Small coronary arteries'.)
In trials comparing late-generation DES (eg, everolimus or zotarolimus) with early-generation DES, late-generation DES showed trends to greater safety and efficacy. In a study of the nearly 25 percent of women enrolled in many of these randomized trials, outcomes were similar to the broad population . (See "Intracoronary stents: Stent types", section on '2012 comparison of drug-eluting stents'.)
Coronary artery bypass graft surgery — A high burden of comorbidities exists in women undergoing CABG. Although there has been a significant and similar reduction in in-hospital mortality in women and men , women still have a greater likelihood of procedural complications (new neurologic event, heart failure, perioperative infarction, and hemorrhage) and death at 30 days [82-92].
In an analysis from the Society of Thoracic Surgery national database of 416,347 patients undergoing CABG in 1996 and 1997, women had a higher 30-day mortality than men (5.7 versus 3.5 percent) . The increase in mortality compared with men may be most pronounced in patients under age 50 . The overall increase in short-term mortality in women has been attributed primarily to patient-related factors, including age and coronary risk factors [85,86]. As noted above with regard to PCI (see 'Percutaneous coronary intervention' above), another factor that may account for increased in-hospital mortality after CABG is smaller body size with consequently smaller coronary artery size [86,93]. During CABG, smaller vessel size may impose more technical difficulties and may be associated with a higher risk of graft failure .
In a 2013 meta-analysis of 20 studies of CABG reported through 2012, women (n = 277,783) were more likely to be older and have more comorbidities than men (n = 966,492) . Short-term, mid-term and long-term mortality were independently associated with female sex in propensity score-matched analyses. However, women appear to have better survival at 10 years after CABG compared with PCI .
RECOMMENDATIONS OF OTHERS — The 2014 American College of Cardiology/American Heart Association guideline for the management of patients with non-ST elevation myocardial infarction recommended that women be treated in a similar manner to men with the same indications for noninvasive and invasive testing . Similar cautionary advice to adhere to guidelines without specifying differences between men and women is contained in the European Society of Cardiology guidelines .
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
Basics topics (see "Patient education: Coronary artery disease in women (The Basics)")
●There are significant differences between women and men in the epidemiology, presentation, response to therapy, and prognosis of coronary heart disease (CHD) that should be taken into account in the care of women with known or suspected disease. These include but are not limited to:
•After ST-elevation myocardial infarction (STEMI), women have a higher rate of cardiogenic shock and high in-hospital mortality with shock, even after adjustment for baseline differences. (See 'STEMI' above.)
●Recommendations for the management of CHD are similar in women and men. A few sex-based recommendations can be made, including:
•Hormone replacement therapy is not recommended for cardiac protection in women with CHD. (See 'Medications' above.)
•For non-ST elevation acute coronary syndromes, an early invasive strategy is particularly beneficial in women who are high risk (eg, troponin positive). For men, the level of risk does not appear to affect the benefit of an early invasive strategy. However, for STEMI, the benefit of early revascularization is similar in women and men. (See 'Early invasive strategy' above and 'Primary percutaneous coronary intervention' above.)
•After fibrinolysis or primary percutaneous coronary intervention, women have a somewhat higher risk of bleeding but still benefit from these therapies. (See 'Coronary reperfusion' above.)
•Secondary prevention with statin therapy is underused in women, despite evidence that the benefits are similar to those in men. (See 'Secondary preventive interventions' above.)
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