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The Canadian Women’s Heart Health Alliance Atlas on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women — Chapter 6: Sex- and Gender-Specific Diagnosis and Treatment
Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, CanadaDepartment of Medicine, McMaster University, Hamilton, Ontario, CanadaPopulation Health Research Institute, Hamilton, Ontario, CanadaDepartment of Health Research Methods, Evidence, and Impact, Research Institute of St. Joe’s, Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
Division of Cardiology, Dalhousie University, Halifax, Nova Scotia, CanadaDepartment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, CanadaKITE, Toronto Rehab, University Health Network, Toronto, Ontario, Canada
Corresponding author: Dr Colleen M. Norris, Faculty of Nursing, 3rd Floor ECHA, University of Alberta, Edmonton, Alberta T6G 1C9, Canada. Tel.: +1-780-492-0784; fax: +1-780-492-2551.
This chapter summarizes the sex- and gender-specific diagnosis and treatment of acute/unstable presentations and nacute/stable presentations of cardiovascular disease in women. Guidelines, scientific statements, systematic reviews/meta-analyses, and primary research studies related to diagnosis and treatment of coronary artery disease, cerebrovascular disease (stroke), valvular heart disease, and heart failure in women were reviewed. The evidence is summarized as a narrative, and when available, sex- and gender-specific practice and research recommendations are provided. Acute coronary syndrome presentations and emergency department delays are different in women than they are in men. Coronary angiography remains the gold-standard test for diagnosis of obstructive coronary artery disease. Other diagnostic imaging modalities for ischemic heart disease detection (eg, positron emission tomography, echocardiography, single-photon emission computed tomography, cardiovascular magnetic resonance, coronary computed tomography angiography) have been shown to be useful in women, with their selection dependent upon both the goal of the individualized assessment and the testing resources available. Noncontrast computed tomography and computed tomography angiography are used to diagnose stroke in women. Although sex-specific differences appear to exist in the efficacy of standard treatments for diverse presentations of acute coronary syndrome, many cardiovascular drugs and interventions tested in clinical trials were not powered to detect sex-specific differences, and knowledge gaps remain. Similarly, although knowledge is evolving about sex-specific difference in the management of valvular heart disease, and heart failure with both reduced and preserved ejection fraction, current guidelines are lacking in sex-specific recommendations, and more research is needed.
Résumé
Ce chapitre présente un résumé sur le diagnostic et le traitement des tableaux cliniques aigus/instables et non aigus/stables des maladies cardiovasculaires chez les femmes, et les différences propres à chacun des deux sexes. Les lignes directrices, les énoncés scientifiques, les revues systématiques/méta-analyses et les études de recherche originale sur le diagnostic et le traitement des coronaropathies, des maladies vasculaires cérébrales (AVC), des valvulopathies cardiaques et de l’insuffisance cardiaque chez les femmes ont été examinés. Les données probantes sont résumées sous forme narrative et, lorsqu’elles sont disponibles, des recommandations en matière de pratique et de recherche pour chacun des deux sexes sont présentées. Les tableaux cliniques du syndrome coronarien aigu et les délais d’attente à l’urgence sont différents selon qu’une femme ou un homme en est atteint. L’angiographie coronarienne reste l’examen de référence pour le diagnostic des coronaropathies obstructives. D’autres examens d’imagerie diagnostique (p. ex. la tomographie par émission de positons, l’échocardiographie, la tomographie d'émission à photon unique, la résonance magnétique cardiovasculaire, l’angiographie coronarienne par tomodensitométrie) se sont avérés utiles pour la détection des cardiopathies ischémiques chez les femmes. Le recours à ces modalités dépend de l’objectif de l’évaluation personnalisée et des ressources disponibles. La tomodensitométrie sans agent de contraste et l’angiographie par tomodensitométrie sont utilisées pour le diagnostic des AVC chez les femmes. Malgré les différences entre les sexes quant à l’efficacité des traitements de référence des divers tableaux cliniques du syndrome coronarien aigu, bon nombre des médicaments et des interventions cardiovasculaires qui ont fait l’objet d’essais cliniques n’avaient pas la puissance statistique nécessaire pour détecter des différences selon les sexes, de sorte que les connaissances restent fragmentaires sur ce sujet. De même, malgré l’évolution des connaissances sur les différences sexuelles quant à la prise en charge des valvulopathies cardiaques et de l’insuffisance cardiaque avec fraction d’éjection réduite ou préservée, on ne trouve pas de recommandations pour chaque sexe dans les lignes directrices actuelles, d’où la pertinence d’études supplémentaires portant sur cette question.
Cardiovascular disease (CVD) presentation and emergency department delays vary between women and men. These differences are attributable to the biology of being a male or female (ie, biological sex) as well as the sociocultural norms ascribed to women in their roles, identities, opportunities/expectations, and interactions with others (gender). Sex and gender differences necessitate sex- and gender-specific approaches to the diagnosis and treatment of CVD. This Atlas chapter aims to summarize these differences across ischemic heart disease (inclusive of both coronary artery disease [CAD] involving the epicardial coronary arteries, and small vessel disease, involving the microvasculature), cerebrovascular disease (stroke), valvular heart disease (VHD), and heart failure (HF). A heterogenous approach is used to present the evidence in this chapter, across the various manifestations of CVD in women, based on the depth and breadth of the evidence. Table 1 summarizes the guidelines and scientific statements related to the diagnosis and treatment of CAD, cerebrovascular disease (stroke), VHD, and HF, and notes where sex-specific analysis/recommendations are included. This chapter focuses on the following: (i) acute or unstable presentations—diagnosis and treatment; and (ii) nonacute or stable presentations—diagnosis and treatment of various manifestations of CVD in women. Sex and gender summary statements are provided at the end of each section, and key messages are summarized in Figure 1.
Table 1Summary of guidelines and scientific statements related to the diagnosis and treatment of coronary artery disease, cerebrovascular disease (stroke), valvular heart disease, heart failure, and cardiac rehabilitation/secondary prevention in women
Condition
Guideline/scientific statement
Sex-specific analysis / recommendations
Coronary artery disease
•
AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain (2021)
2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the ACC/AHA Task Force on Practice Guidelines (2014)
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology/Canadian Society of Cardiac Surgery position statement on revascularization—multivessel coronary artery disease.
Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
Percutaneous Coronary Intervention and Adjunctive Pharmacotherapy in Women: A Statement for Healthcare Professionals From the American Heart Association (2005)
Percutaneous coronary intervention and adjunctive pharmacotherapy in women: a statement for healthcare professionals from the American Heart Association.
Canadian Stroke Best Practice Recommendations: Rehabilitation, Recovery, and Community Participation Following Stroke. Part One: Rehabilitation and Recovery Following Stroke; 6th Edition Update (2020)
Canadian stroke best practice recommendations: rehabilitation, recovery, and community participation following stroke. Part one: rehabilitation and recovery following stroke; 6th edition update 2019.
ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the ACC/AHA Joint Committee on Clinical Practice Guidelines (2021)
2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure: Developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the ESC With the Special Contribution of the HFA of the ESC (2021)
2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC.
How to Diagnose Heart Failure With Preserved Ejection Fraction: The HFA-PEFF Diagnostic Algorithm: A Consensus Recommendation From the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) (2019)
How to diagnose heart failure with preserved ejection fraction: the HFA–PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).
Sex differences in cardiac arrhythmia: a consensus document of the European Heart Rhythm Association, endorsed by the Heart Rhythm Society and Asia Pacific Heart Rhythm Society.
ACCF/AHA/HRS Focused Update Incorporated Into the ACCF/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the ACCF/AHA Task Force on Practice Guidelines and the HRS (2013)
2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Society Position Statement: CCS/CAS/CHRS Joint Position Statement on the Perioperative Management of Patients With Implanted Pacemakers, Defibrillators, and Neurostimulating Devices (2012)
Society position statement: Canadian Cardiovascular Society/Canadian Anesthesiologists' Society/Canadian Heart Rhythm Society joint position statement on the perioperative management of patients with implanted pacemakers, defibrillators, and neurostimulating devices.
CCS Consensus Conference Guidelines on Heart Failure, Update 2009: Diagnosis and Management of Right-Sided Heart Failure, Myocarditis, Device Therapy and Recent Important Clinical Trials (2009)
Canadian Cardiovascular Society Consensus Conference guidelines on heart failure, update 2009: diagnosis and management of right-sided heart failure, myocarditis, device therapy and recent important clinical trials.
ACC, American College of Cardiology; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; APHRS, Asia Pacific Heart Rhythm Society; ASE, American Society of Echocardiography; CAIC, Canadian Association of Interventional Cardiology; CAS, Canadian Anesthesiologists' Society; CCS, Canadian Cardiovascular Society; CHEST, American College of Chest Physicians; CHFS, Canadian Heart Failure Society; CHRS, Canadian Heart Rhythm Society; CPS, Canadian Pain Society; CSCS, Canadian Society of Cardiac Surgery; EHRA, European Heart Rhythm Association; ESC, European Society of Cardiology; HFA, Heart Failure Association; HRS, Heart Rhythm Society; SAEM, Society for Academic Emergency Medicine; SCCT, Society of Cardiovascular Computed Tomography; SCMR, Society for Cardiovascular Magnetic Resonance.
Figure 1Summary of sex- and gender-specific diagnosis and treatment considerations for coronary artery disease, cerebrovascular disease, valvular heart disease, and heart failure; including appropriate referrals for cardiovascular rehabilitation.
Table 1 summarizes the current guidelines and scientific statements related to the diagnosis and management of CAD, stroke, HF, and VHD and indicates whether they provide any sex and/or gender analyses or recommendations. Table 2 presents the key sex and gender considerations in the diagnosis and treatment of acute presentations of CVD reviewed herein.
Table 2Key takeaways regarding sex and gender considerations in the diagnosis and treatment of acute presentations of cardiovascular disease
Evidence
•
80% of CAD, 63% of HF, and no stroke-related guidelines or position statements provided sex-specific analysis or recommendations
Diagnosis
•
ACS and stroke presentations are different in women, compared with those in men, which can lead to delayed diagnosis and treatment
•
In women, an initial normal or non-diagnostic ECG should be followed by serial ECGs based on symptoms, serial biomarkers, and further diagnostic imaging
•
Emerging evidence indicates that using sex-specific high-sensitivity cTn cutoffs in the setting of ACS, especially in younger women, improves detection of ischemic heart disease
•
Coronary angiography remains the preferred imaging modality for confirming and/or characterizing the diagnosis of ACS in women as obstructive or nonobstructive CAD
Treatment
•
Early invasive stratification by coronary angiography with intention to perform revascularization is recommended for women who present with STEMI as well as NSTEMI with positive troponins
•
Technical success rates of PCI are similar in women and men, but differ for CABG surgery
•
Women less frequently receive appropriate pharmacologic treatment during an ACS, compared with men
•
In the setting of acute HF, NT-proBNP sex-specific cutoffs are not recommended
•
Sex-specific evidence is lacking for effects of tissue plasminogen activator and endovascular treatment on stroke outcomes
•
Women are much less likely to be referred to and participate in secondary prevention/cardiovascular rehabilitation programs following an acute CVD event/diagnosis due to gender-related barriers, despite experiencing similar or greater benefit, compared with men
Women have a varied pattern and distribution of cardiovascular pain symptoms associated with both CAD and stroke that are distinct from those of men. These have historically been described as “anginal equivalents” or “atypical,”
2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
Scirica BM, Moliterno DJ, Every NR, et al. Differences between men and women in the management of unstable angina pectoris (The GUARANTEE Registry). The GUARANTEE Investigators. Am J Cardiol 1999;84:1145-1150.
The 2021 American Heart Association/American College of Cardiology/American Society of Echocardiography/American College of Chest Physicians/Society for Academic Emergency Medicine/Society of Cardiovascular Computed Tomography/Society for Cardiovascular Magnetic Resonance (AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR) Guideline for the Evaluation and Diagnosis of Chest Pain recommends describing chest pain as “cardiac,” “possibly cardiac,” or “noncardiac,” as these terms more explicitly describe the potential underlying diagnosis.
2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
Chest pain is reported to be the most common presenting symptom in 91% of men (1081 of 1185) and 92% of women (698 of 756) diagnosed with acute coronary syndrome (ACS).
Women are more likely than men (61.9% vs 54.8%, P < 0.001) to report accompanying symptoms, such as nausea, unusual fatigue, indigestion, dizziness, and palpitations.
The patient's interpretation of myocardial infarction symptoms and its role in the decision process to seek treatment: the MONICA/KORA Myocardial Infarction Registry.
Sex specific impact of prodromal chest pain on pre-hospital delay time during an acute myocardial infarction: findings from the multicenter MEDEA study with 619 STEMI patients.
In the International Survey of Acute Coronary Syndromes in Transitional Countries (ISACS-TC), the time from symptom onset to emergency department arrival was longer in women (median: 270 minutes [range: 130-776 minutes]) compared with that in men (median: 240 minutes [range: 120-600 minutes]), which resulted in increased 30-day mortality for women, even after controlling for baseline variables (odds ratio: 1.58; 95% confidence interval [CI], 1.27-1.97).
Treatment for acute presentations of CAD depends on accurate and timely diagnosis, with imaging being critical to the process. The initial tests for women presenting with a possible ACS are an electrocardiogram (ECG) and biomarkers, which, based on the results, may trigger further diagnostic imaging. An initial normal or nondiagnostic ECG should be followed by serial ECGs based on symptoms, serial biomarkers, and further diagnostic imaging.
2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
The evidence for using sex-specific biomarker cutoffs (ie, high-sensitivity cardiac troponin [cTn]) for the diagnosis and management of ACS is unclear, with emerging evidence to suggest its clinical value in younger women.
In the setting of ACS, the preferred diagnostic/therapeutic imaging is invasive coronary angiography for both women and men. However, evidence suggests that the underappreciation of ACS in women (based on anginal equivalent symptoms/ECGs/biomarkers) leads to sex- and gender-based differences in referral for coronary angiography in the setting of ACS.
Scirica BM, Moliterno DJ, Every NR, et al. Differences between men and women in the management of unstable angina pectoris (The GUARANTEE Registry). The GUARANTEE Investigators. Am J Cardiol 1999;84:1145-1150.
Developments in the invasive diagnostic–therapeutic cascade of women and men with acute coronary syndromes from 2005 to 2011: a nationwide cohort study.
Important to note is that up to 15% of those presenting with acute myocardial infarction (MI) have MI with nonobstructive CAD (MINOCA), which disproportionately affects women.
The etiology of MINOCA includes stress-induced cardiomyopathy, myocarditis, underappreciated plaque rupture, coronary thrombosis/emboli, coronary spasm, microvascular disease, and spontaneous coronary artery dissection. Based on a meta-analysis of studies using cardiovascular magnetic resonance (CMR) as a diagnostic tool in the setting of suspected MINOCA, a diagnosis can be made in 87% of cases when CMR is done early,
Echocardiography and CMR also should be performed when considering stress-induced cardiomyopathy or when looking for evidence of an infarct that may have occurred secondary to plaque rupture, coronary emboli, or spasm. Whereas CMR provides a thorough evaluation of the myocardium, intravascular ultrasonography and optical coherence tomography can be used to assess the coronary arteries in further detail when trying to determine alternate mechanisms of MINOCA. A recently published study examining coronary optical coherence tomography and CMR in the workup of MINOCA suggested a cause in 84.5% of patients when one or both imaging modalities were used.
Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of myocardial infarction with nonobstructive coronary arteries in women.
An ischemic etiology was identified in 63.8% of women (most commonly plaque disruption, such as plaque rupture), whereas a nonischemic cause was discovered in 20.7 %.
Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of myocardial infarction with nonobstructive coronary arteries in women.
Coronary computed tomography angiography (CCTA) also can be considered as a noninvasive test to assess the coronary arteries and the presence of vulnerable plaque in intermediate- and low-risk patients presenting with ACS. The sensitivity and specificity of CCTA for the diagnosis of spontaneous coronary artery dissection (SCAD) have not yet been defined. However, noninvasive follow-up with CCTA may be useful in patients with SCAD in proximal or large-caliber coronary arteries
The Canadian Women's Heart Health Alliance atlas on the epidemiology, diagnosis, and management of cardiovascular disease in women; chapter 5: sex- and gender-unique manifestations of cardiovascular disease.
New-onset acute HF diagnostic workup begins with a thorough patient history, assessment of clinical signs and symptoms, and investigations that include an ECG, echocardiography, cTn concentration, and levels of natriuretic peptides (brain natriuretic peptide [BNP], N-terminal pro b-type natriuretic peptide [NT-proBNP], and mid-regional pro atrial natriuretic peptide [MR-proANP]).
2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC.
and vary by HF phenotype (ie, is lower in patients with HF with preserved ejection fraction [HFpEF], compared with that in patients with HF with reduced injection fraction [HFrEF]).
N-terminal pro brain natriuretic peptide-guided management in patients with heart failure and preserved ejection fraction: findings from the Trial of Intensified Versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-CHF).
The Canadian Women's Heart Health Alliance atlas on the epidemiology, diagnosis, and management of cardiovascular disease in women; chapter 5: sex- and gender-unique manifestations of cardiovascular disease.
On admission for acute HF, women have a higher prevalence of dementia, hypertension, and gastrointestinal bleeding, and a lower prevalence of MI and peripheral vascular disease. Women report a poorer quality of life than men during hospitalization,
Effect of patient-centered transitional care services on patient-reported outcomes in heart failure: sex-specific analysis of the PACT-HF randomized controlled trial.
Evaluation of patients presenting with symptoms possibly consistent with stroke warrants emergent neuroimaging to exclude hemorrhage as a cause, determine the vascular territory responsible for the deficit, and determine which patients will benefit from thrombolytic therapy. Stroke can present with nontraditional symptoms in women that may be interpreted as less significant (eg, tingling, numbness, short-duration visual or speech disturbances), This interpretation can delay stroke recognition and lead to a missed diagnosis.
However, once stroke is recognized, the approach to diagnostic imaging among women and men is similar, with early noncontrast computed tomography (CT) to exclude hemorrhage.
When possible, this imaging should include simultaneous CT perfusion imaging and CT angiography, which together show improved detection of acute infarction, compared with noncontrast CT alone.
The multimodal CT approach provides additional information relating to the site of vascular occlusion, infarct core, salvageable brain tissue, and extent of collateral circulation.
In the acute setting, there appear to be sex-specific differences in the efficacy of standard treatments for diverse presentations of ACS. For ST-elevation MI (STEMI), women have a more favourable outcome with percutaneous coronary intervention (PCI), compared with thrombolytic therapy, and they seem to benefit more from an early invasive approach in the setting of a non ST-elevation MI (NSTEMI).
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
However, as demonstrated in the Canadian Gender and Sex Determinants of Cardiovascular Disease: From Bench to Beyond Premature Acute Coronary Syndrome (GENESIS-PRAXY) study of patients with ACS aged 18-55 years, women with STEMI are less likely than men to receive reperfusion therapy.
Debate remains as to whether women and men respond differently to pharmacologic therapies during an ACS event. For example, in a large meta-analysis of glycoprotein IIb/IIIa inhibitors and intravenous antiplatelet therapy used at the time of primary PCI, a reduction in the risk of death or recurrent ACS events was seen in men but not in women. However, when the analysis was limited to only those with biomarker-confirmed ACS, the sex-associated effect was no longer observed.
Similarly, anticoagulant (unfractionated heparin, low-molecular weight-heparins, bivalrudin) and oral antiplatelet (P2Y12 receptor inhibitors) agents have been shown to reduce adverse outcomes in both women and men with ACS who have undergone PCI.
Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
Percutaneous coronary intervention and adjunctive pharmacotherapy in women: a statement for healthcare professionals from the American Heart Association.
and it may be due to sex-related differences in body surface area, drug metabolism, and pharmacokinetics; weight and renal dose corrections must be considered. In premenopausal women who are still menstruating, antiplatelet therapy may substantially increase menstrual bleeding.
Indeed, the long-term benefits of aspirin, beta-blockers, ACEIs, and statins after MI are similar in both women and men, with risk reductions for major adverse cardiac events of 20%-30% for both sexes in each of these drug classes.
Despite a definite role for these medications in the treatment of ACS, women are 10%-15% less likely than men to be treated acutely and/or prescribed these medications upon discharge from the hospital.
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.
Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: large-scale observations from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines) National Quality Improvement Initiative.
A point of note is that specific cautions are in place regarding medical therapy for cardiovascular syndromes in pregnant women: ACEIs and angiotensin II receptor blockers (ARBs) are in pregnancy category C (meaning animal studies have demonstrated an adverse effect on the fetus) for the first trimester of pregnancy and are labeled as being in pregnancy category D (meaning human fetal risk has been demonstrated) during the second and third trimesters.
Similarly, all statins are in pregnancy category X, indicating that studies in animals or humans have demonstrated associated fetal abnormalities, so they must be avoided during pregnancy.
Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: a retrospective review of 39 pregnancies.
Of additional consideration in women diagnosed with ACS is the discontinuation of harmful medications or medications that are of no benefit. Other pregnancy-related medication recommendations have been published in Chapter 4 of this Atlas.
Menopausal hormone therapy, either estrogen plus progestin or estrogen alone, has been linked to an increased incidence of recurrent infarction and should not be given for the prevention of coronary events. For those women already receiving menopausal hormone therapy at the time of their ACS event, its discontinuation is recommended.
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
In 23,473 patients undergoing cardiac catheterization for ACS in an Ontario cohort, a significantly lower proportion of women, compared with men, received coronary revascularization during the index hospitalization (51.8% vs 66.0%). In women diagnosed with STEMI, primary PCI was linked to lower numbers of major adverse cardiovascular events, including target revascularization.
Women who undergo PCI in this setting, compared with fibrinolytic therapy, have a lower risk of major bleeding, including intracranial bleeding, and lower mortality.
Interestingly, variables related to gender including time-to-presentation, time-to-diagnosis, and door-to-device times are longer in women, and they may contribute to excess mortality.
Sex differences persist in time to presentation, revascularization, and mortality in myocardial infarction treated with percutaneous coronary intervention.
In women presenting with NSTEMI with high-risk features, such as a positive troponin test, early invasive stratification by coronary angiography with intention to perform revascularization is recommended (class I recommendation).
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
However, compared with men in a population-based cohort in Canada, women who had coronary revascularization following an NSTEMI had higher risk for recurrent cardiovascular events. Sex-based differences in outcomes following coronary angiography for NSTEMI-ACS persisted despite revascularization.
Additionally, evidence suggests that invasive angiography and PCI are associated with a higher risk of bleeding, vascular complications, and renal insufficiency in women.
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Low-risk women with a negative troponin test are at higher risk of periprocedural complications, and an early-invasive approach is not recommended (class III).
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Newer-generation drug-eluting stents (DESs) are associated with a reduction in death and recurrent MI, compared with bare-metal stents and older-generation stents. More recently, in a pooled analysis of 2 all-comers randomized controlled trials (RCTs; n = 4605), Bjerking et al.
Drug-eluting stents in large coronary vessels improve both safety and efficacy compared with bare-metal stents in women: a pooled analysis of the BASKET-PROVE I and II trials.
reported that DESs are associated with enhanced safety in terms of cardiac death and nonfatal MI, compared with bare-metal stents in women. Specifically, they report that a DES is safe and more effective and should be considered as the stent of choice for large coronary arteries in women.
Drug-eluting stents in large coronary vessels improve both safety and efficacy compared with bare-metal stents in women: a pooled analysis of the BASKET-PROVE I and II trials.
The Canadian Cardiovascular Society’s position statement on revascularization for multivessel CAD recommends CABG in patients who are acceptable surgical candidates and have multivessel CAD and diabetes, as well as those with complex multivessel CAD (strong recommendation, high-quality evidence).
Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology/Canadian Society of Cardiac Surgery position statement on revascularization—multivessel coronary artery disease.
Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials.
Although the subgroup analysis by sex was nonsignificant, the signal suggests that differences between men and women, and female data, may have been statistically attenuated due to the low proportion of women in the RCTs.
Systematic incorporation of sex-specific information into clinical practice guidelines for the management of ST-segment-elevation myocardial infarction: feasibility and outcomes.
mortality after CABG surgery. In comparison to men, women present for CABG surgery with a higher preoperative risk profile that may include the following: older age at diagnosis, and significant comorbidities (hypertension, diabetes, respiratory disease, HF); more urgent/emergent surgery; less-extensive disease, needing less revascularization; and shorter cross-clamp times.
Filardo et al. reinforced the association of female sex and higher short-term mortality risk in isolated CABG using propensity-adjusted analysis (n = 13,327), which equated to a reported 392 “excess” female deaths in the US each year.
More recently, Hara and colleagues revealed that female patients had a greater 10-year mortality rate, compared with that of male patients (32.8% vs 24.7%; log-rank P = 0.002), but female sex was not an independent predictor of mortality (adjusted hazard ratio[HR]: 1.02; 95% confidence interval [CI], 0.76 to 1.36).
Mortality at 10 years was lower after CABG, compared with PCI, with a similar treatment effect for female vs male patients (adjusted HR for female patients: 0.90 [95% CI, 0.54 to 1.51]; adjusted HR for male patients: 0.76 [95% CI, 0.56 to 1.02]; P for interaction = 0.952).
However, although bilateral ITA grafting demonstrated improved medium-term and late survival in both sexes, woman were less likely to receive this procedure, and when they did, it was less effective.
Finally, the evidence indicates that following CABG surgery, women experience added postoperative complications, such as renal failure, neurologic complications, and postoperative MI. Evidence also indicates that women have more difficulty recovering following CABG surgery, with less improvement in physical functioning and more depressive symptomatology.
The etiology and treatment of acute HF vary based on the signs of congestion and/or peripheral hypoperfusion—acute decompensated HF, acute pulmonary edema, isolated right ventricular failure, and cardiogenic shock.
2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC.
Decompensated HF is responsible for 50%-70% of acute HF presentations and is most commonly treated with loop diuretics, and inotropic agents and vasopressors for peripheral hypoperfusion and/or hypotension.
2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC.
Sex differences in stroke symptoms and door-to-imaging times can result in inappropriate treatments and/or missed opportunities for treatment within the recommended therapeutic window for women.
Tissue plasminogen activator is less frequently used in women than in men, resulting in a lack of evidence on sex-specific effects of tissue plasminogen activator on stroke outcomes.
Evidence suggests that women have a higher prevalence of anterior and intracranial large-artery occlusion, and this may be related to a higher prevalence of atrial fibrillation in women, compared with men.
Data related to sex differences in access and outcomes related to endovascular treatment are scarce, and more research is needed.
Nonacute Presentations: Diagnosis and Treatment
Table 3 presents a summary of the key sex and gender considerations in the diagnosis and treatment of nonacute or chronic presentations of CVD reviewed herein.
Table 3Key takeaways regarding sex and gender considerations in the diagnosis and treatment of nonacute/chronic presentations of cardiovascular disease
Evidence
•
There are no current sex-specific guidelines for valvular heart disease, revascularization in women with stable angina, or device therapies for women with HF
Diagnosis
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Diagnostic and prognostic evaluation of CAD in women via exercise treadmill testing can be improved by integrating multiple parameters (eg, exercise time, changes in the ST-segment, presence of angina)
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In symptomatic women with intermediate CVD risk and the ability to exercise adequately (> 5 METS), either functional assessment that includes stress echocardiography, SPECT or PET myocardial perfusion imaging, or stress cardiac MRI, or alternatively, anatomic assessment with coronary CT angiography, are reasonable diagnostic strategies depending upon local resources.
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Evidence suggests rates of referral to surgery for MR are lower in women, and outcomes worse in women with severe MR, compared with men
Treatment
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Women with both obstructive and nonobstructive CAD continue to be under-prescribed ASA, beta-blockers, calcium-channel blockers, and ACEIs
•
Sex differences in the administration and effects of statins remain under constant debate, although evidence suggests an increased risk of diabetes in women taking statins and a higher risk of statin-induced myotoxicity compared to men
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Women with HF often demonstrate greater symptom burden than men, including more dyspnea and poorer quality of life
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Women with HF are less likely than men to be prescribed ACEIs
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Women are underrepresented in CIED studies; evidence suggests that there are sex-differences in referrals and outcomes for pacemakers, ICDs, and CRTs
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When aortic valve replacement is required, TAVR may be preferred to SAVR in women
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Women are more likely than men to present with postoperative HF following mitral valve repair
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Novel secondary prevention approaches including home-based, online/virtual programs, community programs, and women-only programs may provide alternatives to reduce barriers and enable ongoing support for chronic CVD in women
Clinical presentation, traditional and nontraditional risks, and the life course of CVD are different for women, compared with men. This difference makes the accurate diagnosis of nonacute or stable presentations of CAD in women challenging.
Insights from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies.
A higher prevalence of nonobstructive CAD in women results in lower diagnostic accuracy, compared with obstructive CAD with conventional testing in women.
Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
Various noninvasive imaging modalities are now available to assist in diagnosing CAD in women and are reviewed here. In addition, many sex-specific evaluations and outcomes have been reported in VHD and HF, important CVD diagnoses in women.
Coronary artery disease
Exercise treadmill testing can be obtained rapidly, is inexpensive, and is the most common noninvasive evaluation for suspected ischemia. However, its diagnostic value is limited in women by its lower sensitivity and specificity, which range between 31% and 71%, and 66% and 86%, respectively.
Diagnostic and prognostic evaluation of CAD in women via exercise treadmill testing can be improved by integrating multiple parameters (eg, exercise time, changes in the ST-segment, presence of angina). Additional risk correlates include heart rate and blood pressure response and recovery. Women with intermediate risk should be referred for additional imaging studies for risk stratification.
Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
Despite its false positives and lower accuracy in women, exercise treadmill testing demonstrates similar negative predictive value in both women and men, and it is recommended as a first-line diagnostic test in ruling out CAD in women who are at low risk and can exercise adequately ( > 5 metabolic equivalents). In women with an intermediate risk, and the ability to exercise adequately ( > 5 metabolic equivalents), functional assessment using stress echocardiography, stress single-photon emission computed tomography (SPECT) or positron emission tomography (PET) myocardial perfusion imaging, or stress cardiac magnetic resonance imaging may be considered.
State of the art in noninvasive imaging of ischemic heart disease and coronary microvascular dysfunction in women: indications, performance, and limitations.
Imaging (echocardiographic or nuclear) stress tests are recommended if the resting electrocardiogram is abnormal, if there is a history of known ischemic heart disease, or in the event of limited exercise capacity; imaging is an essential component of pharmacologic stress testing. In addition to evaluating the presence of myocardial ischemia, stress echocardiography provides additional information with regard to systolic and/or diastolic dysfunction, pulmonary hypertension, and VHD. Sensitivity (79%) and specificity (83%) have been reported for the detection of obstructive CAD in women.
Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
Dobutamine stress echocardiography is recommended for women who are unable to perform exercise, with sensitivity and specificity ranges of 75%-93% and 79%-92%, respectively.
Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
Observational data suggest that stress echocardiography may be more cost-effective than exercise treadmill testing in that it can appropriately diagnose and avoids unnecessary angiography, especially in younger women. However, stress echocardiography cannot distinguish between coronary microvascular dysfunction and obstructive CAD.
State of the art in noninvasive imaging of ischemic heart disease and coronary microvascular dysfunction in women: indications, performance, and limitations.
Gated myocardial perfusion SPECT improves the predictive value in women, with a higher sensitivity range of 80%-91%, and a specificity range of 64%- 91%.
Insights from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies.
Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
Abnormal perfusion on nuclear medicine imaging is predictive of adverse cardiac events in women, and severe abnormalities on pharmacologic stress SPECT testing are predictive of annual cardiovascular mortality in women with diabetes (8.5% per year) and without diabetes (6.1% per year).
Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
Meta-analysis data suggest that sensitivity (92%) and specificity (85%) are higher than they are with SPECT, with significant improvement of diagnostic accuracy.
Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
Quantification of coronary flow reserve using rubidium is possible and is predictive of prognosis, as PET-measured coronary flow reserve < 2.0 is associated with an increased risk of cardiac death, MI, revascularization, and HF in both men and women and can be diagnostic of coronary microvascular dysfunction in the absence of obstructive CAD.
State of the art in noninvasive imaging of ischemic heart disease and coronary microvascular dysfunction in women: indications, performance, and limitations.
Stress cardiac magnetic resonance imaging (cMRI), most often performed with vasodilator-induced coronary hyperemia (adenosine or regadenoson) allows for assessment of structural abnormalities, stress-induced wall-motion abnormalities, systolic dysfunction, myocardial edema, scarring, and fibrosis.
Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
An additional advantage of stress cMRI is the ability to assess subendocardial perfusion qualitatively, which is of specific interest in women with angina and no obstructive CAD.
Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
Cardiac magnetic resonance myocardial perfusion reserve index is reduced in women with coronary microvascular dysfunction. A National Heart, Lung, and Blood Institute-sponsored study from the Women's Ischemia Syndrome Evaluation.
Myocardial perfusion reserve index, a quantitative measure of subendocardial perfusion, correlates with and is predictive of coronary microvascular dysfunction on invasive coronary reactivity testing.
Cardiac magnetic resonance myocardial perfusion reserve index is reduced in women with coronary microvascular dysfunction. A National Heart, Lung, and Blood Institute-sponsored study from the Women's Ischemia Syndrome Evaluation.
cMRI is particularly useful in women with obesity, owing to its high spatial and temporal resolution. However, it is relatively contraindicated in end-stage renal disease.
State of the art in noninvasive imaging of ischemic heart disease and coronary microvascular dysfunction in women: indications, performance, and limitations.
Some cardiac centres have determined that combining entities of cMRI and SPECT allows for improved diagnostic and prognostic value of myocardial perfusion.
CCTA provides anatomic coronary artery information and is diagnostically useful in symptomatic intermediate-risk patients. It may be considered as an initial anatomic diagnostic strategy alternative to functional exercise stress testing, or for further evaluation of an abnormal exercise stress test in the context of no known CAD.
2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
Plaque progression and high-risk plaque can be assessed using CCTA. In a secondary analysis of the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial, women with evidence of moderate to severe ischemia were less likely than men to have extensive CAD on CCTA (36% women vs 47% men with 3-vessel disease; 32% vs 31% with 2-vessel disease) and more likely to have 1-vessel disease (31% women vs 22% men).
Association of sex with severity of coronary artery disease, ischemia, and symptom burden in patients with moderate or severe ischemia: secondary analysis of the ISCHEMIA randomized clinical trial.
Noninvasive fractional flow reserve can also be determined in some centres. Radiation exposure is also a consideration, and patients require beta-blocker therapy pretest to slow heart rate and enhance image quality.
State of the art in noninvasive imaging of ischemic heart disease and coronary microvascular dysfunction in women: indications, performance, and limitations.
Coronary angiography remains the gold standard test for diagnosis of obstructive CAD. Use of coronary angiography should be considered when noninvasive tests demonstrate high-risk features, or when symptoms persist despite optimal medical therapy (strong recommendation, high-quality evidence).
Typical chronic HF symptoms include dyspnea, orthopnea, paroxysmal nocturnal dyspnea, fatigue, reduced exercise tolerance, and ankle swelling. Although the signs and symptoms of HF are similar for women vs men, women often demonstrate greater symptom burden, including more dyspnea and poorer quality of life.
Effect of patient-centered transitional care services on patient-reported outcomes in heart failure: sex-specific analysis of the PACT-HF randomized controlled trial.
HFpEF is defined as a normal EF (ie, EF > 50%), a nondilated left ventricle with concentric remodelling, or a hypertrophied left ventricle with left atrial enlargement.
How to diagnose heart failure with preserved ejection fraction: the HFA–PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).
2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC.
12-lead ECG, transthoracic echocardiography, chest X ray, and other routine blood tests to assess for comorbidities. Cardiac catheterization is recommended when an intermediate probability of HFpEF is determined to exist after history, physical examination, and other recommended diagnostic evaluations (eg, natriuetic peptide determination, echocardiography) have been performed.
In cases in which access to specialized tests is limited, a more simplified pragmatic approach to diagnosing HFpEF is recommended. This includes assessment of the following: (i) signs/symptoms of HF; (ii) a left ventricular ejection fraction (LVEF) ≥ 50%; and (iii) objective evidence of cardiac structural and/or functional abnormalities consistent with LV diastolic dysfunction/raised LV filling pressures. With this approach, the greater number of objective noninvasive measures increases the probability of an HFpEF diagnosis.
2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC.
The Canadian Women's Heart Health Alliance atlas on the epidemiology, diagnosis, and management of cardiovascular disease in women; chapter 5: sex- and gender-unique manifestations of cardiovascular disease.
In aortic stenosis, the concomitance of a low flow rate despite a normal EF (ie, paradoxical low flow or HFpEF associated with aortic stenosis) is reported to be higher in women.
Paradoxical low-flow, low-gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival.
The first issue with paradoxical low flow is linked to the assessment of aortic stenosis severity. Indeed, as the gradient and velocity across the stenosed aortic valve are dependent on the flow rate, a decrease in flow rate will lead to a decrease in gradient and velocity, which may underestimate the degree of stenosis severity. On the other hand, a moderately stenosed valve may not open fully, due to a lower flow rate, thus presenting a small valve area, which overestimates the degree of stenosis severity. Therefore, a discordance between gradient/velocity (in the moderate range) and aortic valve area (in the severe range) at rest echocardiography in these patients is not uncommon.
The use of multidetector-computed tomography has been validated to assess aortic valve calcification (Agatston method), with sex-specific thresholds identifying severe aortic stenosis as ≥ 1200 Agatston units (AU) in women and ≥ 2000 AU in men.
The complex nature of discordant severe calcified aortic valve disease grading: new insights from combined Doppler-echocardiographic and computed tomographic study.
2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
Moreover, the presence of low flow is an independent predictor of adverse outcomes, and these patients should be considered to have at least intermediate risk.
Evaluation of patients with mitral regurgitation (MR) requires comprehensive echocardiographic assessment, including evaluation of MR severity and signs of volume overload. Current guidelines suggest absolute measurements of left ventricular (LV) size as surgical cutoff criteria
2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
impacting timely diagnosis and intervention in asymptomatic women.
Treatment
Coronary artery disease
In Canada, more women die each year of CAD than of chronic lower respiratory disease, Alzheimer’s disease, diabetes, breast cancer, and all female gynecological cancers combined.
Pharmacologic and nonpharmacologic treatment strategies reduce morbidity and mortality and improve health-related quality of life (HRQoL).
Pharmacologic
Patients with stable CAD are maintained on a combination of evidenced-based drugs, including acetylsalicylic acid (ASA; aspirin), statins, beta-blockers, ACEIs, ARBs, digoxin, diuretics, and anti-thrombotic drugs.
However, the possibility that the “one size fits all” sex-agnostic approach is not appropriate is becoming apparent. A point now recognized is that cardiovascular (CV) medications have been tested predominantly in clinical trials that were not powered for sex-specific analyses. Nonetheless, experiences in the use of these drugs in chronic conditions indicate the presence of sex differences. Further details are described below.
The maintenance care of stable CAD generally focuses on blood pressure and blood lipid levels. The renin-angiotensin system is one mechanism that regulates blood pressure. Methods of inhibiting the renin-angiotensin system include used of 2 drug classes that operate on different stages in the system. ACEIs act by inhibiting the conversion of angiotensin I to angiotensin II. ARBs function by binding to the angiotensin receptor, thus blocking the angiotensin II access to the binding site. Studies have shown that women are more likely to be ACEI intolerant (odds ratio [OR] 1.70; 95% CI, 1.65-1.75).
However, pharmacokinetic differences have been identified with the use of ARBs, such as the finding that women’s maximum serum concentrations (given the same dosage) of losartan and telmisartan were twice that in men.
Beta-blockers are used in men and women with CAD to decrease the harmful effects of excessive adrenergic stimulation to the heart (ie, angina symptoms in men and women with stable CAD).
Beta-blockers provide a differential survival benefit in patients with coronary artery disease undergoing contemporary post-percutaneous coronary intervention management.
The Canadian Cardiovascular Society 2014 guidelines for the diagnosis and management of stable ischemic heart disease recommend beta-blockers as first-line therapy for chronic stable angina post-MI, and beta-blockers or long-acting calcium channel blockers for uncomplicated chronic stable angina.
In Canada, use of beta-blockers in obstructive and nonobstructive CAD did not differ by sex 3 months post-angiography. However, only 67.5% of women with obstructive CAD, and 41.9% of women with nonobstructive CAD, were prescribed beta-blockers.
Sex differences in cardiac medication use post-catheterization in patients undergoing coronary angiography for stable angina with nonobstructive coronary artery disease.
Women with obstructive and nonobstructive CAD are more commonly prescribed CCBs (P < 0.001), although only 38.3% of women with obstructive CAD, and 31% of women with nonobstructive CAD, are prescribed CCBs 3 months post-coronary angiography.
Sex differences in cardiac medication use post-catheterization in patients undergoing coronary angiography for stable angina with nonobstructive coronary artery disease.
Results from the Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery disease (CLARIFY) international registry across 45 countries suggest that, in addition to calcium-channel blockers, women are more frequently prescribed long-acting nitrates for stable CAD, compared with men (P < 0.001).
Although the mechanism of action is not completely understood, ranolazine (recently approved for use in Canada) does not affect heart rate or blood pressure, and it acts on late inward sodium current in myocardial cells, possibly reducing oxygen demand by inhibiting intracellular calcium overload.
Effects on potassium currents may cause QT prolongation, and monitoring is warranted when initiating ranolazine. Ranolazine is metabolized by cytochrome P450 family 3 subfamily A member 4 (CYP3A4), and care must be taken to avoid drug-drug interactions with other drugs metabolized or inhibiting CYP3A4, and those causing QT prolongation.
Use of ranolazine has been associated with a reduction in angina frequency, nitroglycerin consumption, and total exercise duration in patients with stable CAD,
Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial.
available through special access programs requiring approval by Health Canada, also has been used for patients with refractory symptoms or vasospastic angina, on a case-by-case basis, but robust trials are lacking.
However, the platelet inhibition effect of ASA varies among patients, and the underlying reasons for this are not clear. In the Physician’s Health Study, a 44% reduction in risk of MI in men occurred (relative risk [RR], 0.56, 95% CI , 0.45-0.70, P < 0.00001) in the aspirin group, compared with the placebo group, with inconclusive benefit for stroke and cardiovascular deaths.
The risk reduction in MI was evident in men aged > 50 years (P = 0.02). Aspirin appears to have greatest benefit in women of reducing risk of mortality from cardiovascular disease (CAD and stroke; RR, 0.62, 95% CI, 0.55-0.71), with this effect most pronounced within the first 5 years of use and in older women (P < 0.001).
Statins are a group of drugs used to lower blood cholesterol in both men and women. The inconclusive results from studies of sex differences in the administration and effects of statins are under constant debate. The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial showed an increased risk of diabetes in women taking statins, compared with that in men.
A Dutch cohort study examined adherence to guidelines-based medications after STEMI/NSTEMI by following 52,672 individuals for 12 months after discharge.
Findings revealed that use of indicated drugs (ASA, P2Y12-inhibitor, statin, beta-blocker, ACE-/AT2-inhibitor) was higher in male patients, compared with that in female patients, regardless of MI subtype (STEMI male 61% vs female 57%, P ≤ 0.001; NSTEMI male 43% vs female 37%, P ≤ 0.001).
Nonpharmacologic
Revascularization can be performed during angiography for obstructive lesions when indicated.
State of the art in noninvasive imaging of ischemic heart disease and coronary microvascular dysfunction in women: indications, performance, and limitations.
Currently, no sex-specific guidelines have been developed regarding revascularization in patients with stable angina.
Chronic heart failure
Women are underrepresented relative to disease prevalence as participants in clinical trials of HF; drug dosing protocols, as well as estimates of treatment efficacy and adverse events, are derived from trials with primarily men as trial participants.
Trial characteristics associated with under-enrolment of females in randomized controlled trials of heart failure with reduced ejection fraction: a systematic review.
Trials often are inadequately powered for sex-specific analysis, and subgroup analyses, when reported, often do not include testing for sex-treatment interactions.
Trial characteristics associated with under-enrolment of females in randomized controlled trials of heart failure with reduced ejection fraction: a systematic review.
Trial characteristics associated with under-enrolment of females in randomized controlled trials of heart failure with reduced ejection fraction: a systematic review.
Sex-specific eligibility criteria; trial leadership by male investigators; and drug, device, or surgical interventions are independently associated with underenrollment of women with HF, highlighting areas that can be targeted to increase enrollment of women.
Trial characteristics associated with under-enrolment of females in randomized controlled trials of heart failure with reduced ejection fraction: a systematic review.
The recent Canadian Cardiovascular Society/Canadian Heart Failure Society (CCS/CHFS) guidelines for HFrEF recommend 4 classes of medications, as follows
: (i) angiotensin receptor-neprilysin inhibitor (ARNI) as first-line therapy (preferably) or following titration of an ACEI/ARB; (ii) beta-blocker; (iii) MRA; and (iv) sodium glucose transport 2 inhibitor. Other medical therapies may be used based on individual patient characteristics. Women and men are commonly prescribed diuretics, beta-blockers, and MRAs at similar rates, but women are less likely to receive ACEIs.
The response and effect of beta-blockers, MRAs, ACEIs, and ARBs appear to be similar between the sexes, although women may require lower doses of ACEI to receive mortality benefit.
A post hoc subgroup analysis of the Digitalis Investigation Group (DIG) trial, which originally showed that digoxin use was associated with an overall decrease in hospitalizations, revealed that female patients prescribed digoxin had a 5.8-fold higher absolute risk of all-cause mortality, compared with male patients (interaction P = 0.034), raising concerns about using digoxin therapy in female patients.
Most eligible women and men with HFrEF do not receive target doses of medical therapy (including ARNIs, beta-blockers, ACEIs, ARBs, and MRAs) following hospitalization, and only a minority have guideline-directed serial incremental dose adjustments over time.
No known drug therapies reduce the risk of CV mortality in HFpEF, although a few reduce the risk of HF hospitalization. PARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor–neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF With Preserved Ejection Fraction), a trial assessing the efficacy of neprilysin inhibition in HFpEF, was associated with lower rates of the composite primary outcome of death or HF hospitalizations, driven by a reduction in HF hospitalizations; a treatment interaction was noted with sex and LVEF such that women derived benefit from sacubitril-valsartan at a higher LVEF than men.
The Preserved, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trial assessed the efficacy of empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with class II-IV heart failure and an ejection fraction > 40%.
Emplagliflozin reduced the combined risk of cardiovascular death or HF hospitalization by 21% (HR, 0.79 [95% CI, 0.69-0.90] in both female and male patients, with the effect due largely to reduced HF hospitalizations. Increasing evidence indicates that LVEF should be treated as a continuum, as therapies effective in HFrEF also appear to be effective in HF with mildly reduced EF (HFmrEF) and HFpEF. The management of HFpEF should include the following: (i) identification and treatment of underlying etiologies, such as hypertensive heart disease, with exclusion of mimickers of HFpEF; (ii) identification and treatment of comorbid conditions that account for an increasing proportion of hospitalizations and deaths as LVEF increases; (iii) use of pharmacotherapies to reduce the burden of HF hospitalization; (iv) management of volume overload; and (v) lifestyle modification, including caloric reduction among obese patients, and exercise to improve functional capacity and quality of life.
Society position statement: Canadian Cardiovascular Society/Canadian Anesthesiologists' Society/Canadian Heart Rhythm Society joint position statement on the perioperative management of patients with implanted pacemakers, defibrillators, and neurostimulating devices.
Indications for CIED use continue to increase. Presently, evidence regarding CIEDs is predominantly only available in retrospective, observational, and registry studies. By and large, women are underrepresented in CIED studies, thereby limiting evidence-based conclusions. Consequently, the available research regarding sex- and gender-specific observations on the outcomes of CIED is presented below.
Nonpharmacologic: Pacemakers
Sick sinus syndrome and atrial fibrillation with bradyarrhythmias have been shown to be the main indications for permanent pacemaker implantation in women, whereas the main indication in men is atrioventricular block.
Expert Committee 'Pacemaker' Institute of Quality Assurance Hessen, et al. Do gender differences exist in pacemaker implantation?—results of an obligatory external quality control program.
found no significant differences in the selection of pacemakers based on sex, whereas others have reported that women are less likely than men to receive dual-chamber pacemakers.
Sex may also impact outcomes after device insertion. In a 30-year follow-up study examining the prognostic importance of baseline patient characteristics impacting survival post-permanent pacemaker implantation, women survived longer than men, despite being older at the time of the procedure.
Complications such as pneumothorax and pocket hematoma are more common in women, and hospitalizations for device-related infections are more common in men.
Implantable cardioverter defibrillators (ICDs) are the gold standard of treatment for primary prevention (patients at risk for ventricular tachyarrhythmias) and secondary prevention (patients who have survived a life-threatening ventricular arrhythmia or sudden cardiac arrest) in both women and men.
2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Canadian Cardiovascular Society Consensus Conference guidelines on heart failure, update 2009: diagnosis and management of right-sided heart failure, myocarditis, device therapy and recent important clinical trials.
Several studies have shown improved survival rates with the use of these devices in high-risk patients with CAD, ventricular dysfunction, and inducible ventricular tachycardia.
2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Canadian Cardiovascular Society Consensus Conference guidelines on heart failure, update 2009: diagnosis and management of right-sided heart failure, myocarditis, device therapy and recent important clinical trials.
Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators.
However, a recent meta-analysis of 6 RCTs, including the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) trial, revealed that women did not attain significant survival benefit from primary preventive ICDs, but men did.
Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators.
Sex differences in cardiac arrhythmia: a consensus document of the European Heart Rhythm Association, endorsed by the Heart Rhythm Society and Asia Pacific Heart Rhythm Society.
Sex differences in cardiac medication use post-catheterization in patients undergoing coronary angiography for stable angina with nonobstructive coronary artery disease.
Female sex may also influence decisions to implant an ICD. Curtis et al. reported that men were 3.2 times more likely than women to receive ICD therapy in a Medicare sample of > 230,000 patients.
Subgroup analyses performed on data from the Multicenter Unsustained Tachycardia Trial (MUSTT) and the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) trial indicated that mortality does not differ between men and women
Effectiveness of implantable cardioverter-defibrillators for the primary prevention of sudden cardiac death in women with advanced heart failure: a meta-analysis of randomized controlled trials.
Survival in women versus men following implantation of pacemakers, defibrillators, and cardiac resynchronization therapy devices in a large, nationwide cohort.
also have shown discrepant effects of sex on ICD benefit in primary and/or secondary prevention populations.
The National Cardiovascular Data Registry (NCDR) ICD registry reported that women had a higher rate of periprocedural complications than men (7.2% vs 4.8%; 95% CI, 1.25-1.53; P < 0.001).
Canadian Cardiovascular Society Consensus Conference guidelines on heart failure, update 2009: diagnosis and management of right-sided heart failure, myocarditis, device therapy and recent important clinical trials.
2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Canadian Cardiovascular Society Consensus Conference guidelines on heart failure, update 2009: diagnosis and management of right-sided heart failure, myocarditis, device therapy and recent important clinical trials.
It is a class I recommendation for patients with HF (New York Heart Association (NYHA)/CCS class II, III, and IV), reduced ejection fraction (EF ≤ 35%) despite maximally tolerated doses of guideline-directed medical therapies, and electrocardiographic evidence of ventricular dysynchrony (left bundle branch block [LBBB] and QRS > 150 ms).
In the landmark Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial, CRT-D reduced mortality by 36%, compared with medical therapy, with significant reduction in hospitalization and improvement in functional status.
CRT implantation should be performed only when the LVEF meets guideline criteria for nonischemic cardiomyopathy (NICM) for patients who have received > 3 months of medical therapy or those with ischemic cardiomyopathy > 40 days post MI.
2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Canadian Cardiovascular Society Consensus Conference guidelines on heart failure, update 2009: diagnosis and management of right-sided heart failure, myocarditis, device therapy and recent important clinical trials.
Association between demographic, organizational, clinical, and socio-economic characteristics and underutilization of cardiac resynchronization therapy: results from the Swedish Heart Failure Registry.
Association between demographic, organizational, clinical, and socio-economic characteristics and underutilization of cardiac resynchronization therapy: results from the Swedish Heart Failure Registry.
female sex and age were independent predictors of non-referral for CRT. CRT-D may confer greater benefits to women than to men in the setting of NICM and LBBB.
Cardiac resynchronization therapy is more effective in women than in men: the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) trial.
Sex-specific clinical outcomes after cardiac resynchronization therapy in left bundle branch block-associated idiopathic nonischemic cardiomyopathy: a NEOLITH II substudy.
Effectiveness of cardiac resynchronization therapy by QRS morphology in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT).
Subgroup analysis of the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) study identified women as exceptional responders to CRT, with a 72% decrease in all-cause mortality and greater reduction in left atrial and ventricular volumes.
Despite men typically being younger at diagnosis, in a retrospective study conducted by Wang et al., women were found to have a lower risk of death, compared with men in LBBB-associated NICM, after controlling for age at diagnosis.
Sex-specific clinical outcomes after cardiac resynchronization therapy in left bundle branch block-associated idiopathic nonischemic cardiomyopathy: a NEOLITH II substudy.
Women have a shorter baseline QRS duration (QRSd) and smaller LV volumes than men. Therefore, women have relatively more dysynchrony for any prolonged QRSd, which may contribute to a better outcome with CRT.
Cardiac resynchronization therapy is more effective in women than in men: the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) trial.
Sex-specific, stricter QRSd criteria recommendations (QRSd > 140 for men and > 130 for women) have been proposed and evaluated, with no significant difference in echocardiographic response to CRT between men and women at 12-month follow-up.
Effectiveness of cardiac resynchronization therapy by QRS morphology in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT).
In summary, women appear to be “super-responders” to CRT, but they are under-referred for CRT, relative to men.
Valvular heart disease
When aortic valve replacement is required, transcatheter aortic valve replacement (TAVR) may be preferred to surgical aortic valve replacement (SAVR) in women, given the following: (i) TAVR may be safer for low-flow patients, with evidence of lower operative mortality
; and (iii) women at intermediate/high risk enrolled in the Women's International Transcatheter Aortic Valve Implantation (WIN-TAVI) all-female registry had reduced incidence of early mortality and stroke.
Acute and 30-day outcomes in women after TAVR. Results From the WIN-TAVI (Women's INternational Transcatheter Aortic Valve Implantation) Real-World Registry.
Finally, sex was the only subgroup in which a significant interaction with treatment occurred, with a trend toward superiority of TAVR vs SAVR in women.
An unfortunate point to note is that RCTs comparing TAVR to SAVR have not stratified randomization by sex.
Earlier cohorts of MR patients suggested lower rates of referral to surgery in women, with worse outcomes in women with severe MR, compared with outcomes in men.
Mitral valve repair is less often successfully performed in women, attributable to a higher occurrence of rheumatic disease and anterior/bileaflet valve prolapse.
Transcatheter mitral valve repair with the edge-to-edge approach may have less impact in women, compared with men, as the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) trial demonstrated no superiority of the transcatheter intervention over standard therapy in women and an interaction between sex and treatment with regard to HF rate at 24 months.
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