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Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational,
Bernadet T Santema1, Wouter Ouwerkerk2, Jasper Tromp3
1Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands.
Insights
Women with heart failure with reduced ejection fraction (HFrEF) may benefit from lower doses of ACE inhibitors or ARBs and beta blockers compared to men. This finding questions optimal medical therapy for HFrEF patients based on sex.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Medicine
Background:
- Guideline doses for ACE inhibitors/ARBs and beta blockers in heart failure with reduced ejection fraction (HFrEF) are similar for men and women.
- Known sex differences in drug pharmacokinetics suggest potential for sex-specific optimal dosing.
Purpose of the Study:
- To investigate potential sex differences in the optimal dosing of ACE inhibitors/ARBs and beta blockers for patients with HFrEF.
Main Methods:
- Post-hoc analysis of the BIOSTAT-CHF study, including patients with left ventricular ejection fraction <40%.
- Validation in the independent ASIAN-HF cohort.
- Primary outcome: composite of all-cause mortality or heart failure hospitalization.
Main Results:
- Women with HFrEF were older and had lower body weight and height than men.
- Optimal risk reduction for mortality or HF hospitalization in men occurred at 100% of guideline doses for ACE inhibitors/ARBs and beta blockers.
- Women achieved similar risk reduction at 50% of guideline doses, with no additional benefit at higher doses.
Conclusions:
- Women with HFrEF may require lower doses of ACE inhibitors/ARBs and beta blockers than men.
- This highlights a need to re-evaluate optimal medical therapy for HFrEF considering sex-based differences.
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.
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