Secondary Prevention of Cardiovascular Disease in Women: Closing the Gap

Cardiovascular disease (CVD) is the leading cause of death among women in the US and globally. Although the overall death rates from CVD have decreased in recent years, rates of acute MI (AMI) and CVD mortality have actually been increasing among young US women aged <65 years. One analysis found that the prevalence of AMI among young women aged 35–54 years increased from 21% in 1995 to 31% in 2004; in comparison, the prevalence of AMI in men over the same time period increased from 30% to 33%. Between 2011 and 2017, middle-aged women, defined as those aged 45–64 years, had a 7% increase in death rates, compared with a 3% increase among men during this time period. Women are at risk of a broad spectrum of CVDs, including, but not limited to, CHD including AMI, stroke and heart failure (HF).

Women typically present with atherosclerotic CVD (ASCVD) approximately a decade later than men during their postmenopausal period due to decreases in oestrogen and a loss of its protective effects. Loss of the protective effects of oestrogen leads to worsening of traditional risk factors: weight gain, insulin resistance and higher blood pressures. Thus, older women presenting with CVD are also more likely to present with comorbid conditions such as diabetes and hypertension. Available evidence suggests that some traditional risk factors, such as diabetes and smoking, confer a greater relative risk of ASCVD in women than men.

In addition, women are at risk of CVD due to female-specific risk factors (e.g. adverse pregnancy outcomes, polycystic ovary syndrome and premature menopause) or factors that are more prevalent in women (e.g. autoimmune disorders, including lupus and rheumatoid arthritis, and radiation or chemotherapies for breast cancer). These added risks are often unaccounted for, leading to underestimation of cardiovascular risk and the under-treatment of women. Recognition of the multitude of factors that predispose women to CVD can be instrumental in addressing the burden of disease. However, current risk scores do not take into account such comorbidities, although some guidelines do consider them ‘risk-enhancing’ factors.

Both primary prevention (before initial presentation of disease) and secondary prevention (after initial presentation of disease) strategies are crucial to decrease the burden of CVD for women. Primary prevention of CVD in women has been covered in other recent reviews. Given space limitations, this review will focus primarily on secondary prevention strategies and guidelines. This review serves to highlight multidisciplinary guidelines for women across a broad spectrum of CVD, including known atherosclerotic disease, HF and post-MI, post-cardiac catheterisation and post-coronary artery bypass grafting (CABG) surgery.

Outcomes After MI and CABG

Women across all age groups are susceptible to poor outcomes from CVD. Older women are more likely to experience mortality after a percutaneous intervention for an ST-elevation MI (STEMI), but not after non-ST-elevation MI (NSTEMI). Younger women <55 years who experience AMI are less likely to receive guideline-directed medical therapy (GDMT), have a greater likelihood of readmission within 1 year, have worse self-reported recovery outcomes and have higher rates of all-cause mortality. Women have also been shown to be less likely to undergo CABG than men and to have worse outcomes after CABG. This discrepancy is thought to be due to women presenting at older ages, with more comorbidities and with later-stage CVD. Despite women being at such high risk for secondary cardiovascular events, most cardiovascular trials to date have been predominantly male, with females being under-represented in trials for CHD, acute coronary syndrome (ACS) and HF relative to their disease burden in the population. This limits the knowledge base of the efficacy and safety of cardiovascular preventive interventions and limits generalisability of trial results into clinical practice. Even so, available evidence does indicate that women derive a nearly similar benefit from existing secondary prevention pharmacological treatment modalities such as statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and icosapsent ethyl as men, as discussed further below.

Mitigating Risk and Improving Outcomes in Women with Cardiovascular Disease

Thus, more attention for secondary CVD prevention in women is sorely needed, with additional attention to mental health and social determinants of health. Figure 1 outlines some strategies for mitigating risk and improving outcomes after CVD in women. It should be further noted that there are knowledge gaps on how to reduce cardiovascular risk among transwomen and transmen, which warrants further study.

Atypical Presentations and Obstacles to Treatment

Difficulty in treating women with GDMT for CVD begins with the initial diagnosis. Compared with men, women describe overall milder symptoms and are more likely to describe weakness, shortness of breath and fatigue as opposed to squeezing pressure, heart burn and palpitations. Women are also more likely to report pain in the chest, back or jaw without chest pain. In the setting of AMI, women do experience chest discomfort to a similar degree as men (~90% of cases), but are more likely to report three or more additional symptoms that may distract patients and their clinicians from initial recognition of the true diagnosis. As a result of these different presentations and overall lower perceived risk of CVD, women often have delayed diagnoses and are less likely to get urgent revascularisation of their MI.

One study examining revascularisation times of young individuals (<55 years of age) presenting with AMI found that 35% of women presented more than 6 hours after any initial symptoms, compared with 23% of men. In that study, women had 1.72-fold (95% CI [1.28–2.33]) the odds of exceeding the reperfusion time goal, and 2.31-fold (95% CI [1.32–4.06]) the odds of not receiving reperfusion at all. After the cardiovascular event, despite the strong evidence behind secondary prevention guidelines, women are not placed on appropriate GDMT and have worse patient-reported outcomes. For example, women are less likely to be treated with statin or aspirin therapy and have controlled hypertension, and, overall, are less likely to be linked to appropriate cardiac rehabilitation (CR) programmes. Disparities in access to care for women extend throughout all ages and stages of CVD. Previous reviews have demonstrated that minimising modifiable risk factors at every aspect of care from diagnosis to treatment can help close the gap and improve outcomes.

Sex Differences in Medication Side-effects

Women often report greater overall medication side-effects than men, which often leads patients or their clinicians to stop medications or decrease dosages to a more tolerable side-effect profile. Side-effect profiles of cardiovascular medications for women are variable and stem from differences in gastrointestinal absorption, body composition, metabolic consumption and kidney excretion. For example, one large US survey found that women were 28% more likely to have new or worsening muscle symptoms with statin therapy (adjusted OR 1.28; 95% CI [1.16, 1.42]) and 48% more likely to discontinue their statin therapy due to muscle symptoms (adjusted OR 1.48; 95% CI [1.25–1.75]) than men. This is worrisome in light of the substantial benefit that women derive from statin therapy. As another example, women have greater hospitalisations as a result of side-effects from torsemide, with higher circulating plasma concentrations of the drug. There are certainly many more examples.

In such cases of intolerability, often a lower dose of medication can still provide benefit without the added risk. In situations where a reduced dosage is used due to side-effects, clinicians should consider titrating up to the maximum tolerated dose to make best use of benefits. Acknowledging and educating both clinicians and patients on the side-effect profile of cardiovascular medications is crucial in mitigating the risk of such medications and helping tailor the appropriate medication regimen. These discrepancies further highlight the need for increased representation of women in pharmacological cardiovascular trials.

MINOCA, INCOCA and Coronary Microvascular Dysfunction

Women presenting with AMI are also twice as likely to present with MI with non-obstructive coronary arteries (MINOCA) over obstructive coronary artery disease (CAD). Women who present with MINOCA more often present with NSTEMI as a result of plaque erosion or rupture, coronary embolus or thrombosis, microvascular dysfunction, coronary artery dissection or spasm. Plaque erosions are thought to evolve from endothelial apoptosis, whereas plaque rupture is the result of inflammation. Both are associated with some coronary evidence of atherosclerotic burden. Women who are predisposed to a hypercoagulable state from antiphospholipid syndrome or inherited thrombophilia are at risk for MINOCA from coronary thrombosis and embolism of the microcirculatory system.

Another cause of MINOCA results from spontaneous coronary artery dissection (SCAD), where there is separation of the layers of the epicardial coronary artery wall from an intimal tear or an intramural haemorrhage, which results in decreased arterial flow. SCAD may account for up to one-third of MIs among young women aged <50 years. SCAD is managed differently than other atherosclerotic-type MIs and thus is not discussed here; however, the topic has been comprehensively reviewed elsewhere. Although the underlying pathophysiology of each of the above causes of MINOCA is distinct, all result in decreased forward flow and poor perfusion of myocardial tissue, thus leading to ischaemia and infarct.

Modalities for the Secondary Prevention of Cardiovascular Disease in Women

A combination of coronary optical coherence tomography (OCT) or intravascular ultrasound (IVUS) plus cardiac MRI may help elucidate the aetiology of MINOCA in the vast majority of women. IVUS/OCT has been shown to be useful in detecting plaque disruption, coronary embolus or thrombus and SCAD. Despite overall better outcomes for individuals with MINOCA than those with complete occlusive disease, young women have higher mortality and adverse events from MINOCA than young men. The cause of this differential in mortality has not been studied, but is thought to be due, in part, to failure of placing women on appropriate goal-directed therapy. Preliminary studies from the SWEDEHEART registry indicate beneficial effects of statins, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), and β-blockers for women with MINOCA.

Whereas MINOCA reflects AMI, women can also have stable angina and/or evidence of coronary ischaemia with non-obstructive coronary arteries (INOCA). Among individuals with stable angina and evidence of ischaemia, one study found that 65% of women had no obstructive CAD, compared with 32% of men. Among individuals with moderate to severe ischaemia discovered on stress testing who were screened for eligibility to participate in the ISCHEMIA trial, 66% of those found to have no obstructive disease (the population enrolled in CIAO-ISCHEMIA registry) were female, compared with 26% of those with obstructive CAD (the population enrolled in the main ISCHEMIA trial). The frequency of angina symptoms and the amount of abnormalities seen on stress echocardiography testing (i.e. inducible wall motion abnormalities) were actually surprisingly similar between patients with and without obstructive CAD (i.e. patients enrolled in the ISCHEMIA trial versus those enrolled in the CIAO-ISCHEMIA registry). Furthermore, the degree of ischaemia on stress testing was not significantly correlated with symptom burden (i.e. angina). One may have assumed that the more ischaemia, the more symptoms and that if one could reduce ischaemia, that would reduce symptoms, but that is not the case. Ischaemia and angina were found to be not that well correlated.

Secondary Prevention of Cardiovascular Disease in Women

Nevertheless, INOCA in women is not benign and is associated with an elevated 5-year risk of major adverse cardiovascular events (MACE) compared with women without angina. Non-obstructive plaque is prognostic of MACE risk in women and should not be ignored when detected on imaging evaluation, and plaques with high-risk features may confer even greater relative risk in women than in men.

INOCA can be the result of coronary microvascular dysfunction, vasospastic angina (VSA) or a combination of both, but is often underdiagnosed and undertreated and often has a poor prognosis. INOCA from microvascular dysfunction is defined as typical chest pain, non-obstructive coronary arteries and impaired flow specifically seen through one of the following: poor coronary flow reserve (CFR); spasm during provocative testing; or decreased coronary blood flow.

Both anatomical and functional testing are frequently used for the work-up of women with suspected angina, and provide complementary information. Anatomical approaches (e.g. invasive coronary angiography or coronary CT angiography) rule out obstructive disease and can identify non-obstructive atherosclerotic plaque that warrants implementation of preventive therapies. Functional testing is used to evaluate for ischaemia. Ischaemia can be first identified through a number of non-invasive methods, including PET scans or dobutamine stress echocardiography. PET can be useful in detecting microvascular dysfunction and thus CFR, which is a strong indicator of prognosis. However, nuclear PET scans cannot identify coronary vasomotor disorders, which are common causes of INOCA in women.

Elucidating coronary artery spasm requires acetylcholine to test vasoreactivity, which can only be administered during invasive coronary angiography. Thus, once non-invasive methodologies have ruled out obstructive disease, the European Society of Cardiology (ESC) guidelines specify diagnostic guidewire coronary function testing as a Class IIa recommendation to assess CFR, and further recommend intracoronary acetylcholine testing for microvascular spasm as a Class IIb recommendation. If VSA is considered, the ESC notes acetylcholine testing as a Class IIa recommendation.

There is a paucity of clinical trials specifically relating to treatment and risk mitigation for patients with INOCA; however, medications should be tailored to specifically target the underlying cause. Women with INOCA identified to have plaque on imaging should be treated with anti-atherosclerotic therapies (i.e. statins and ACEI/ARB) to reduce the risk of MACE. Anti-anginal therapies are used to control symptoms. For individuals with microvascular dysfunction, β-blockers, calcium channel blockers or ACEI/ARB may help decrease workload and improve microvascular perfusion. Ranolazine may also significantly improve symptoms and quality of life in women with microvascular angina. Individuals with INOCA from VSA derive greater benefit from calcium channel blockers or long-acting nitrates.