Bernadet T Santema1, Wouter Ouwerkerk2, Jasper Tromp3, Iziah E Sama1, Alice Ravera4, Vera Regitz-Zagrosek5, Hans Hillege1, Nilesh J Samani6, Faiez Zannad7, Kenneth Dickstein8, Chim C Lang9, John G Cleland10, Jozine M Ter Maaten1, Marco Metra11, Stefan D Anker12, Pim van der Harst1, Leong L Ng6, Peter van der Meer1, Dirk J van Veldhuisen1, Sven Meyer13, Carolyn S P Lam3, Adriaan A Voors14. 1. Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands. 2. National Heart Centre Singapore, Hospital Drive, Singapore; Deptartment of Dermatology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, Netherlands. 3. Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands; National Heart Centre Singapore, Hospital Drive, Singapore. 4. Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands; Institute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy. 5. Charité Universitaetsmedizin Berlin, Institute for Gender in Medicine, Centre for Cardiovascular Research, German Centre for Cardiovascular Research, Berlin, Germany. 6. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. 7. Clinical Investigation Center 1433, French Clinical Research Infrastructure Network, Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Centre Hospitalier Regional et Universitaire de Nancy, Vandoeuvre les Nancy, France. 8. Department of Cardiology, Stavanger University Hospital, Stavanger, Norway. 9. School of Medicine Centre for Cardiovascular and Lung Biology, Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK. 10. National Heart & Lung Institute, Royal Brompton & Harefield Hospitals, Imperial College, London, UK; Robertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, Glasgow, UK. 11. Institute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy. 12. German Centre for Cardiovascular Research partner site Berlin, Charité Universitätsmedizin Berlin, Germany. 13. Heart Center Oldenburg, Department of Cardiology, European Medical School Oldenburg-Groningen, Carl von Ossietzky University Oldenburg, Oldenburg, Germany. 14. Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands. Electronic address: a.a.voors@umcg.nl.
Abstract
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.
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.
Authors: Xavier Rossello; João Pedro Ferreira; Francisca Caimari; Zohra Lamiral; Abhinav Sharma; Cyrus Mehta; George Bakris; Christopher P Cannon; William B White; Faiez Zannad Journal: Clin Res Cardiol Date: 2021-04-30 Impact factor: 5.460
Authors: Anubha Agarwal; Sanne A E Peters; Chanchal Chandramouli; Carolyn S P Lam; Gemma A Figtree; Clare Arnott Journal: Curr Heart Fail Rep Date: 2021-07-02
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