Biology and bias: do we have the will to improve cardiovascular disease outcomes for women?

SEX DIFFERENCES IN ACUTE MYOCARDIAL INFARCTION (AMI): BIOLOGY AND BIAS

Women with AMI have higher mortality than men with AMI, but multiple factors contribute to this sex difference, including biological variables related to sex such as older age at presentation and increased cardiovascular risk profile, as well as gender bias including disparities in reperfusion time and AMI treatment in women. Notably, the largest sex discrepancy in AMI survival is among young women <65 years when compared with similarly aged men¹; younger women are the only group with rising cardiovascular disease (CVD) death rates compared with declines in all others.^2,3 Understanding both biological sex differences and gender bias in AMI treatment is essential to improve CVD outcomes for all.

NEW FINDINGS

A new report⁴ using the recently developed and validated European Society of Cardiology Acute Cardiovascular Care Association (ACCA) Quality Indicators (QIs) for AMI offers insight into improving outcomes for women. These investigators found that women in England and Wales less frequently received guideline-indicated AMI care and had significantly higher mortality than men. Specifically, among 691 290 patients in the UK Myocardial Ischaemia National Audit Project, women less likely received timely reperfusion therapy for ST-Elevation Myocardial Infarction (STEMI), coronary angiography for Non-ST-elevation Myocardial Infarction (NSTEMI), dual antiplatelet therapy and secondary prevention therapies. Notably, this suboptimal care existed despite a more adverse biological 30-day Global Registry of Acute Coronary Events (GRACE) risk score adjusted mortality in women compared with men. The authors estimated that 8243 deaths in women were potentially preventable had care been equal between sexes.

WHY IS AMI CARE UNEQUAL? BIOLOGY DRIVES BIAS

Biological sex differences in AMI likely drive differences in administration of and response to guidelines-based therapy. For example, compared with men, women are less likely to have a culprit lesion identified at the time of angiography and more likely to have non-obstructive coronary artery disease,⁵ leading physicians to be less likely to pursue coronary angiography. Indeed, AMI with non-obstructive coronary arteries Myocardial Infarction with Non-obstructive Coronary Arteries (MINOCA) is more common in women than men, yet it is associated with an elevated 4.7% all-cause mortality at 1 year.⁶ A variety of mechanisms of MINOCA are understood including plaque rupture, plaque ulceration, coronary vasospasm, embolism, spontaneous coronary artery dissection and Takotsubo cardiomyopathy. The VIRGO investigators found that approximately one in eight young women with AMI are unclassified by the universal definition of myocardial infarction and proposed a new taxonomy to better phenotype patients and to ultimately determine optimal treatment strategies.⁷ A recent American College of Cardiology Think Tank on ischaemic heart disease in women recognised MINOCA knowledge gaps and recommended sex-specific examination of coronary pathophysiology and optimal diagnostic strategies to close the gap in AMI sex disparities.⁵ These knowledge gaps likely contribute to therapeutic inconsistency among practitioners in treating these women.

The lack of coronary angiography and/ or absence of anatomical obstructive coronary artery disease is associated with lower use of pharmacological therapies including dual antiplatelet therapy and secondary prevention therapies in women.⁵ Diagnostic uncertainty drives therapeutic uncertainty, as evidenced by the failure to provide evidence-based guidelines AMI therapy despite clear evidence of an AMI and elevated 30-day risk in women documented by Wilkinson and coauthors.⁴ While knowledge gaps exist regarding specific treatment of MINOCA, for example, statin and dual antiplatelet treatment of AMI due to coronary vasospasm, spontaneous coronary artery dissection and Takotsubo cardiomyopathy is controversial, current AMI acute and chronic pharmacological secondary prevention guidelines are based on randomised clinical trials in patients with AMI from prior decades with less coronary angiography, which most certainly included MINOCA patients.

SHOULD CARE BE EQUAL? PROTOCOLISED CARE AND OUTCOMES

Protocolised care to achieve evidence-based guidelines therapy improves AMI outcomes. We have demonstrated that a network focused on improving emergency service recognition of STEMI and protocols to facilitate rapid transfer to a percutaneous coronary intervention (PCI)-capable centre maximised STEMI outcomes for both women and men.⁸ We also demonstrated that prescriptions of guideline-based pharmacotherapies at discharge are equivalent in women and men with protocolised STEMI care.⁸ Protocolised care resulted in equivalent in-hospital and long-term (5 year) age-adjusted mortality (figure 1),⁸ suggesting that STEMI treatment disparities and mortality in women can be improved using protocols.

Figure 1.

Age-adjusted mortality to 5 years stratified by sex in 4918 consecutive STEMI patients presented to the Minneapolis Heart Institute at Abbott Northwestern Hospital regional STEMI system including 1416 (28.8%) women. Five-year follow-up confirmed absence of a sex disparity in survival post-STEMI⁸ (reprinted with permission).

WHY PROTOCOLS ARE NEEDED TO ADDRESS BIAS

While our network results indicate that outcomes for women (and men) can be improved with protocolised care, are protocols sufficient to address biology and bias? The answer appears to be yes. Specifically, the Cleveland Clinic recently implemented a four-step protocol that included: (1) emergency department catheterisation lab activation, (2) STEMI Safe Handoff Checklist; (3) immediate transfer to an immediately available catheterisation lab and (4) radial first approach to PCI, a protocol designed to minimise AMI care variability. Following protocol deployment, guideline-directed medical therapy before PCI, median door to balloon time, in-hospital adverse events and 30-day mortality all demonstrated elimination of sex differences in care and mortality.⁹ These results support that protocols can address bias, although further work is needed to understand the value of protocolised NSTEMI management, which currently is less guideline-driven than STEMI.

WHY DON’T WE USE PROTOCOLS IF THEY IMPROVE OUTCOMES?

After recognising inconsistency in his own practice as a surgeon due to the complexity of care, Atule Gawande MD, MPH, visited Boeing to see how they avoid deaths due to air flight error and noted they rely on ‘checklist’ protocols. Subsequent deployment of checklists implemented in eight medical centres reduced surgical mortality 47%.¹⁰ When Gawande’s team surveyed the doctors who used the checklist, 80% favoured continued use, but 20% were not (although 94% wanted the checklist if they were the patient). Why do some physicians disagree with a reminder that saves lives? As opined by Gawande, ‘Our great struggle in medicine these days is not just with ignorance and uncertainty’, but ‘with complexity: how much you have to make sure you have in your head and think about’, and ‘One of the things we have to grapple with is that we have to assume we are fallible, even as experts’.¹¹ Checklists help us (and pilots) overcome our fallibility to optimise outcomes.

SUMMARY

The new study by Wilkinson et al⁴ offers an explicit ACCA suite of QIs metrics that can be used as a checklist (figure 2) with goals to improve AMI outcomes for women (and men). Specifically, use of these metrics that are both measurable⁴ and achievable given prior experience with protocolised care^8,9 would likely close disparities in AMI that adversely impact women (and continue to improve outcomes for men). This AMI ‘Save Lives Checklist’ (figure 2) is not intended to be comprehensive; the initial goals reflect the metrics achieved in men,⁴ and additions and modifications to fit local practice are encouraged. Goals can be updated for further improvement with measured progress over time. It is clear from this new study⁴ and work of others^8,9 that protocols for the delivery of recommended AMI treatments for women can reduce the sex–AMI mortality gap. Accordingly, the question is: do we have the will to improve CVD outcomes for women?

Figure 2.

Acute myocardial infarction (AMI) ‘Save Lives Checklist’ from six quality indicators of the European Society of Cardiology Acute Cardiovascular Care Association suite of Quality Indicators (QIs) for AMI. The checklist is not intended to be comprehensive. Additions and modifications to fit local practice are encouraged. The initial goals reflect the metrics achieved in men⁴ and can be updated for further improvement with measured progress over time. ACEi, ACE inhibitor; ARB, angiotensin receptor blocker; ED, emergency department.