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Heart failure (HF) affects women and men differently, in part due to sex-related differences in disease aetiology and pathophysiology, which may ultimately impact treatment response and outcomes. Sex differences in HF outcomes may be further exacerbated by differences in medication pharmacokinetics and pharmacodynamics, with female-specific physiological factors including lower body mass, as well as decreased renal excretion and gastrointestinal enzymatic activity, leading to higher medication bioavailability. As a result, the administration of sex-neutral medication doses leads to greater drug exposure in female patients, which may subsequently lead to a higher incidence of adverse drug reactions.1 This raises the possibility of sex-based HF treatments to improve clinical outcomes. However, current guidelines adopt a ‘one size fits all’ approach, with an emphasis on target-dosed therapy. In this era of precision medicine, is it time to redefine optimal HF therapy based on the sex of the patient?
Bots and colleagues2 evaluated the associations between prescription practice and survival of patients with HF in a community setting using electronic health record data from the Cardiology Centre of the Netherlands database. This well-designed study included over 1000 patients with de novo HF treated with at least one guideline HF medication with a median follow-up time of 3.7 years. The main outcome was all-cause mortality in relation to the prescribed HF medication dose (reference ≥50% target dose), stratified by sex and HF type. The authors concluded that lower angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) dose was associated with improved survival in women, but not in men, with HF with reduced ejection fraction (HFrEF). In contrast, no ACEI/ARB dose–survival association was observed in patients with HF with preserved ejection fraction (HFpEF) of either sex. No association was observed between beta-blocker dose and mortality in any of the prespecified subgroups.
One of the first striking observations in this study is that the vast majority of patients, irrespective of sex, received less than 100% of the target-dosed therapy, highlighting the differences between populations included in clinical trials that inform guidelines and those in ‘real world’ community settings. Older patients and women are consistently under-represented in HF trials, and in particular HFrEF and acute HF trials, and gender disparities in inclusion in research are amplified among racial/ethnic groups.3 Therapeutic dose targets are thus extrapolated from results obtained in trial populations that do not reflect the general HF population, which may at least partially account for this finding.
Do the results of this study reflect sex-specific (biological) differences in HF medical optimisation? Probably. However, the results are likely influenced by the inclusion of only patients with de novo HF referred to cardiology care, which highlights important gender (sociocultural) factors that may have influenced the study findings. A nationwide Danish study recently reported that patients with lower socioeconomic status had more severe HF but were less likely to be referred to specialty care follow-up,4 even with a universal healthcare system similar to that found in the Netherlands. After adjustment for confounders, lower socioeconomic status was most strongly linked with female sex and associated with greater risk of morbidity and mortality. While not able to account for socioeconomic status in this study, by only studying an HF population referred to specialty care, the authors may have mitigated the impact of gender factors on the outcome in the current study.2
In the Swedish Heart Failure Registry population, women were older, more symptomatic, and more likely to have hypertension and kidney disease but less likely to have diabetes and ischaemic heart disease.5 In the present study,2 while women were older and more likely to have hypertension compared with men, they were less likely to have diabetes, coronary heart disease or have undergone a coronary procedure compared with men. Both women and men had similarly preserved kidney function. Patients were considered to have a new HF diagnosis on referral to the Cardiology Centre of the Netherlands if the cardiologist registered the diagnosis, although it remains possible that many had pre-existing HF managed by the referring physician. The authors acknowledge that overall the study population was healthier than Western European HF populations, and in particular the female population included in the study may not be completely reflective of the general population with HF.
Previous studies support the present study findings where lower ACEI/ARB dosages were associated with improved survival compared with higher dosages in women with HFrEF, but not in men. Emerging evidence suggests that sex differences in renin–angiotensin–aldosterone system (RAAS) activity contribute to sex differences in cardiovascular disease. Women, at least in the premenopausal years, exhibit a shift in the RAAS towards cardioprotective counter-regulatory pathways mediated by the hormone angiotensin-(1-7), which may be modulated, in part, by interactions with oestrogen. In young healthy women and men on a controlled sodium and protein diet, women exhibited no pressor response to angiotensin II challenge after only 4 weeks of treatment with irbesartan 75 mg daily.6 Conversely, men continued to demonstrate a significant increase in blood pressure in response to angiotensin II challenge even after doubling the irbesartan dose for an additional 4 weeks. Angiotensin type 1 receptor expression at baseline did not differ between men and women, but after 8 weeks of irbesartan treatment was significantly decreased in women and unchanged in men. Epidemiological data support a sex-specific dose of ACEI/ARBs. In a post-hoc analysis of a prospective study in 11 European countries of patients with HFrEF in whom initiation and uptitration of ACEI or ARBs were encouraged by protocol, the risk of death was significantly lower in men prescribed 100% of the recommended dose of ACEI or ARBs, while women showed approximately 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels.
While sex-specific reporting of safety data for HF medications is rare, previous studies have highlighted the increased risk of adverse effects in women with use of guideline-recommended HF treatment,1 and relevant to the present study, specifically ACEI, but not ARBs or beta-blockers. While the authors were unable to discern the reasons behind prescriptions of lower HF medication doses in the current study,2 a decreased risk of adverse drug reactions with lower doses of ACEI may have played a role.
In contrast to ACEI/ARB use, no association between beta-blocker dosage and survival was observed in patients with HFrEF or HFpEF of either sex. This finding is in contrast to recent studies in the HFrEF population which have reported improved outcomes in women with 50% of the recommended dose, while optimal outcomes were observed in men on 100% of the target dose.7 The fact that the population in the present study may have been healthier than other HF study populations may account for these differences. Among patients with hypertension who had no history of cardiovascular disease, women previously treated with beta-blockers had significantly higher risk of HF than did men at hospital presentation for an acute coronary syndrome.8 Conversely, the rate of HF was similar among women and men who did not receive beta-blockers. In the study by Bots and colleagues,2 beta-blockers were a newly prescribed medication for HF rather than pre-existing hypertension, which may at least partially explain the lack of sex differences observed in the study.
The findings of this important study highlight that a sex-specific approach to medical optimisation of early compensated HF may have important implications for survival in this population. Due to the nature of the data set, the authors were not able to comment on other patient-identified important measures of HF burden, such as symptom severity or hospitalisations. The findings of this study should prompt investigators to design and analyse future studies through a sex and gender lens to enable guideline committees to provide tailored recommendations for diagnosis and management of HF. The study conducted by Bots et al 2 is an important reminder that ‘one size does not fit all’ in healthcare, particularly in this era of precision medicine. HF is a global epidemic and the prevalence is only expected to increase in parallel with the world’s ageing population. Is it time to redefine optimal HF therapy by sex? Large prospective studies with prespecified endpoints stratified by sex and HF type, in addition to other important intersectional factors, are necessary to answer this important question. Only with this framework will the medical community be able to achieve the ultimate precision medicine goal of providing the best possible care to ‘the right patient with the right treatment at the right time’.
Patient consent for publication
Contributors RH and SA both contributed to the planning, conduct and reporting of the work described in the article.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Commissioned; externally peer reviewed.
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