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

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Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study.
The Lancet ( IF 98.4 ) Pub Date : 2019-08-22 , DOI: 10.1016/s0140-6736(19)31792-1
Bernadet T Santema ₁ , Wouter Ouwerkerk ₂ , Jasper Tromp ₃ , Iziah E Sama ₁ , Alice Ravera ₄ , Vera Regitz-Zagrosek ₅ , Hans Hillege ₁ , Nilesh J Samani ₆ , Faiez Zannad ₇ , Kenneth Dickstein ₈ , Chim C Lang ₉ , John G Cleland ₁₀ , Jozine M Ter Maaten ₁ , Marco Metra ₁₁ , Stefan D Anker ₁₂ , Pim van der Harst ₁ , Leong L Ng ₆ , Peter van der Meer ₁ , Dirk J van Veldhuisen ₁ , Sven Meyer ₁₃ , Carolyn S P Lam ₃ , , Adriaan A Voors ₁

Affiliation

Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands.
National Heart Centre Singapore, Hospital Drive, Singapore; Deptartment of Dermatology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, Netherlands.
Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands; National Heart Centre Singapore, Hospital Drive, Singapore.
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.
Charité Universitaetsmedizin Berlin, Institute for Gender in Medicine, Centre for Cardiovascular Research, German Centre for Cardiovascular Research, Berlin, Germany.
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
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.
Department of Cardiology, Stavanger University Hospital, Stavanger, Norway.
School of Medicine Centre for Cardiovascular and Lung Biology, Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK.
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.
Institute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.
German Centre for Cardiovascular Research partner site Berlin, Charité Universitätsmedizin Berlin, Germany.
Heart Center Oldenburg, Department of Cardiology, European Medical School Oldenburg-Groningen, Carl von Ossietzky University Oldenburg, Oldenburg, Germany.

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.

中文翻译：

确定男性与女性相比心力衰竭药物的最佳剂量：一项前瞻性，观察性队列研究。

背景

患有心力衰竭且射血分数降低（HFrEF）的男女，血管紧张素转换酶（ACE）抑制剂或血管紧张素受体阻滞剂（ARBs）和β受体阻滞剂的推荐剂量相似这些药物的药代动力学。我们假设HFrEF患者的ACE抑制剂或ARB和β受体阻滞剂的最佳剂量可能存在性别差异。

方法

我们对BIOSTAT-CHF进行了事后分析，这是一项在欧洲11个心力衰竭患者国家中进行的前瞻性研究，在该研究中，协议鼓励使用ACE抑制剂或ARB和β受体阻滞剂进行启动和滴定。我们仅纳入左心室射血分数低于40％的患者，排除了在前3个月内死亡的患者。主要结果是因各种原因导致的死亡率或因心力衰竭住院的时间的综合。在ASIAN-HF中进行了验证，ASIAN-HF是一个独立的队列，共有3539名男性和961名女性患有HFrEF。

发现

在来自BIOSTAT-CHF的HFrEF的1308名男性和402名女性中，女性年龄较大（74 [12]岁对70 [12]岁，p <0·0001），并且体重较低（72 [16] kg对85 [18]）体重指数（p <0·0001）和身高（162 [7] cm vs 174 [8] cm，p <0·0001）比男性高，尽管身体质量指数没有显着差异。ACE抑制剂或ARB（99 [25％] vs 304 [23％]，p = 0·61）和β受体阻滞剂（57 [14％] vs168 [13％]，p = 0·54）。在男性中，心力衰竭的死亡或住院风险最低，发生在推荐剂量的ACE抑制剂或ARB和β受体阻滞剂的100％处，但是女性在推荐剂量的50％处发生的风险降低了约30％，并且没有进一步的降低降低高剂量水平的风险。在校正了年龄，体表面积等临床协变量后，这些性别差异仍然存在。在ASIAN-HF登记中，ACEI抑制剂或ARB和β受体阻滞剂的情况相似，女性在推荐剂量的50％时风险降低约30％，而在更高剂量水平时则没有进一步的获益。