Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study

Summary

Background

Guideline-recommended doses of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), and β blockers are similar for men and women with heart failure with reduced ejection fraction (HFrEF), even though there are known sex differences in pharmacokinetics of these drugs. We hypothesised that there might be sex differences in the optimal dose of ACE inhibitors or ARBs and β blockers in patients with HFrEF.

Methods

We did a post-hoc analysis of BIOSTAT-CHF, a prospective study in 11 European countries of patients with heart failure in whom initiation and up-titration of ACE inhibitors or ARBs and β blockers was encouraged by protocol. We included only patients with left ventricular ejection fraction less than 40%, and excluded those who died within the first 3 months. Primary outcome was a composite of time to all-cause mortality or hospitalisation for heart failure. Findings were validated in ASIAN-HF, an independent cohort of 3539 men and 961 women with HFrEF.

Findings

Among 1308 men and 402 women with HFrEF from BIOSTAT-CHF, women were older (74 [12] years vs 70 [12] years, p<0·0001) and had lower bodyweights (72 [16] kg vs 85 [18] kg, p<0·0001) and heights (162 [7] cm vs 174 [8] cm, p<0·0001) than did men, although body-mass index did not differ significantly. A similar number of men and women reached guideline-recommended target doses of ACE inhibitors or ARBs (99 [25%] vs 304 [23%], p=0·61) and β blockers (57 [14%] vs 168 [13%], p=0·54). In men, the lowest hazards of death or hospitalisation for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and β blockers, but women showed approximately 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels. These sex differences were still present after adjusting for clinical covariates, including age and body surface area. In the ASIAN-HF registry, similar patterns were observed for both ACE inhibitors or ARBs and β blockers, with women having approximately 30% lower risk at 50% of the recommended doses, with no further benefit at higher dose levels.

Interpretation

This study suggests that women with HFrEF might need lower doses of ACE inhibitors or ARBs and β blockers than men, and brings into question what the true optimal medical therapy is for women versus men.

Funding

European Commission.

Introduction

Angiotensin-converting-enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), and β blockers are the cornerstone of therapy for patients with heart failure with reduced ejection fraction (HFrEF).¹ Heart failure guidelines recommend up-titration of ACE inhibitors or ARBs and β blockers to the same target doses in men and women (table 1). These sex-neutral target doses were recommended despite findings from several pharmacological studies indicating that with the same dose, the maximum plasma concentrations of ACE inhibitors, ARBs, and β blockers were up to 2·5 times higher in women than in men.2, 3, 4 Women generally have a lower bodyweight, higher proportion of body fat, and lower plasma volume. These factors can contribute to a longer duration of action of lipophilic drugs and higher peak plasma concentrations of hydrophilic drugs in women.4, 5 Moreover, lower cardiac output in women results in lower hepatic flow and lower glomerular filtration rate, and women have lower expression of some drug-specific cytochrome P450 isoenzymes, which could also contribute to higher plasma levels of both hydrophilic and lipophilic drugs in women.6, 7 Supporting these considerations, studies with β blockers showed different pharmacodynamic effects with a greater reduction in heart rate and blood pressure in women than with men using similar doses.8, 9 In addition, women have a 50–70% increased risk in experiencing adverse drug reactions compared with men, and these adverse events are generally more serious in women than in men.4, 5, 9 We tested the hypothesis that there might be sex differences in the optimal dose of ACE inhibitors or ARBs and β blockers in patients with HFrEF in the prospective multinational European chronic heart failure cohort of BIOSTAT-CHF10, 11 and validated our findings in the independent multinational chronic heart failure cohort of ASIAN-HF.¹²

Research in context

Evidence before this study

We searched PubMed from Jan 1, 1980, to Jan 31, 2019, with the search terms “heart failure”, “sex differences”, “gender differences”, “women”, “men”, “outcome”, “mortality”, “hospitalization”, “drugs”, “medication”, “dose”, “angiotensin-converting enzyme inhibitors”, “angiotensin-receptor blockers”, and “beta-blockers”. There were no studies that directly compared the optimal dose levels of current evidence-based drugs on a continuous scale, in relation to clinical outcome of men and women with heart failure with reduced ejection fraction separately. We did not limit the search to English language publications.

Added value of this study

To our knowledge, this is the first study to show that there are striking sex differences in the optimal dose levels of angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers and β blockers in patients with heart failure with reduced ejection fraction, in which women had the lowest risk of death or hospitalisation for heart failure at half the guideline-recommended doses compared with men.

Implications of all the available evidence

Because of the under-representation of women with heart failure with reduced ejection fraction in all previous clinical drug trials, and in the absence of prospective sex-specific dose-finding clinical trials of current therapies, this is the best available evidence with regards to the optimal dose levels of medication for heart failure in men and women separately. These findings should also prompt similar studies in other cardiovascular disease areas.