Publish in this journal
Journal Information
Vol. 75. Issue 8.
Pages 636-648 (August 2022)
Visits
Not available
Vol. 75. Issue 8.
Pages 636-648 (August 2022)
Original article
Full text access
Gender differences in drug titration among heart failure patients with reduced ejection fraction in the ETIFIC trial
Diferencias de género en la titulación de fármacos de pacientes con insuficiencia cardiaca y fracción de eyección reducida del ensayo ETIFIC
Visits
578
Juana Oyangurena,b,
Corresponding author
juanaoy@hotmail.com

Corresponding author: Labeaga Auzoa, 48960 Galdakao, Bizkaia, Spain.
, Beatriz Díaz-Molinac, Iñaki Lekuonaa, José González-Costellod, Silvia López-Fernándeze, José M. García-Pinillaf, Lluisa Garcia-Garridog, Gracia López-Moyanoh, Nicolás Manitod, Marta Cobo-Marcosi, Magdalena Nebot-Margalefd, Pedro Latorre-Garcíab, Eunate Arana-Arrib, Silvia Pérez-Fernándezb, Jesús Torcal-Lagunab, on behalf of the ETIFIC research team group
a Servicio de Cardiología, Hospital Universitario Galdakao, Usansolo, OSI Barrualde-Galdakao, Osakidetza, Servicio Vasco de Salud, Galdakao, Bizkaia, Spain
b BIOCRUCES, Instituto de Investigación Sanitaria, Barakaldo, Bizkaia, Spain
c Unidad de Insuficiencia Cardiaca Avanzada y Trasplante Cardiaco, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain
d Unidad de Insuficiencia Cardiaca Avanzada y Trasplante Cardiaco, Servicio de Cardiología, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain
e Unidad de Insuficiencia Cardiaca, Hospital Universitario Virgen de las Nieves, Granada, Spain
f Unidad de Insuficiencia Cardiaca, Servicio de Cardiología, Hospital Virgen de la Victoria, Málaga, Spain
g Unidad de Insuficiencia Cardiaca, Servicio de Cardiología, Hospital Universitario Dr. Josep Trueta, Girona, Spain
h Unidad de Insuficiencia Cardiaca, Hospital Alto del Guadalquivir, Andújar, Jaén, Spain
i Unidad de Insuficiencia Cardiaca Avanzada y Trasplante Cardiaco, Servicio de Cardiología, Hospital Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain
Ver más
This item has received
Article information
Abstract
Full Text
Bibliography
Download PDF
Statistics
Figures (4)
Show moreShow less
Additional material (1)
Abstract
Introduction and objectives

Optimal medical therapy decreases mortality and heart failure (HF) hospitalizations in HF patients with reduced left ventricular ejection fraction. Women have been underrepresented in clinical trials and not specifically evaluated. This study aimed to compare the safety and effectiveness of drug titration in women vs men.

Methods

This post hoc gender study of the ETIFIC multicenter randomized trial included hospitalized patients with new-onset HF with reduced ejection fraction and New York Heart Association II-III and no contraindications to beta-blockers. A structured 4-month titration process was implemented in HF clinics. The primary endpoint was the mean relative dose (% of target dose) of beta-blockers achieved by women vs men. Secondary endpoints included the mean relative doses of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists, adverse events, and other clinical outcomes at 6 months.

Results

A total of 320 patients were included, 83 (25.93%) women and 237 (74.06%) men (76 vs 213 analyzed). The mean±standard deviation of the relative doses achieved by women vs men were as follows: beta-blockers 62.08%±30.72% vs 64.4%±32.77%, with a difference of−2.32% (95%CI,−10.58-5.94), P = .580; and mineralocorticoid receptor antagonists 79.85%±27.72% vs 67.29%±31.43%, P =.003. No other differences in drug dosage were found. Multivariate analysis showed nonsignificant differences. CV mortality was 1 (1.20%) vs 3 (1.26%), P=1, and HF hospitalizations 0 (0.00%) vs 10 (4.22%), P=.125.

Conclusions

In a post hoc analysis from the HF-titration ETIFIC trial, we found nonsignificant gender differences in drug dosage, cardiovascular mortality, and HF hospitalizations.

Trial registry number: NCT02546856.

Keywords:
Titration
Drug
Heart failure
Women
Female
Gender
Sex
Differences
Abbreviations:
ACEI
ARB
BB
HF
HFrEF
MRA
Resumen
Introducción y objetivos

El tratamiento óptimo disminuye la mortalidad y hospitalizaciones por insuficiencia cardiaca (IC) en pacientes con IC y fracción de eyección reducida. En los ensayos clínicos las mujeres estuvieron infrarrepresentadas y no fueron evaluadas específicamente. Este estudio buscó comparar la seguridad y efectividad de titulación (ajuste de dosis), de fármacos en mujeres y varones.

Métodos

Estudio post hoc de género del ensayo aleatorizado multicéntrico ETIFIC. Se incluyeron pacientes hospitalizados con IC de novo y fracción de eyección reducida. Proceso estructurado de titulación en unidades de IC. Objetivo principal: la dosis relativa media de bloqueadores beta (% de la dosis objetivo) alcanzada por mujeres frente a varones. Objetivos secundarios: dosis relativas medias de otros fármacos de IC, eventos adversos y resultados clínicos a 6 meses.

Resultados

Se incluyeron 320 pacientes, 83 (25,93%) mujeres y 237 (74,06%) varones. (76 frente a 213 analizados). Media±desviación estándar de dosis relativa de bloqueadores beta mujeres frente a varones: 62,08±30,72% frente a 64,4±32,77%; diferencia −2,32%; IC95%, −10,58-5,94; p=0,580, antagonistas del receptor de mineralocorticoides 79,85±27,72% comparado con 67,29±31,43%; p=0,003, sin diferencias significativas en dosificación de otros fármacos. El análisis multivariante no encontró diferencias significativas. Mortalidad cardiovascular 1 (1,20%) frente a 3 (1,26%), p=1 y 0 hospitalizaciones por IC (0,00%) frente a 10 (4,22%), p=0,125.

Conclusiones

En un análisis post hoc del ensayo ETIFIC de titulación en IC no encontramos diferencias de género significativas en dosificación, mortalidad cardiovascular y hospitalizaciones por IC.

Número de registro: NCT02546856.

Palabras clave:
Titulación
Fármaco
Insuficiencia cardiaca
Mujer
Género
Sexo
Diferencias
Full Text
INTRODUCTION

Heart failure (HF) has a high prevalence, mortality, hospital admissions, and social and health system impacts. To improve prognosis and reduce mortality and HF hospitalizations, clinical practice guidelines recommend administration of beta-blockers (BB), renin angiotensin system inhibitors, mineralocorticoid receptor antagonists (MRA) and education and follow-up programs with multidisciplinary teams of specialized nurses and cardiologists in HF patients with reduced ejection fraction (HFrEF). Careful drug titration is recommended.1–3 However, dose optimization is deficient in clinical practice. Women have been underrepresented in most original HFrEF trials. Their clinical characteristics, prescription, achieved dose and adverse events associated with titration have not been specifically analyzed. Few trials have evaluated the effects on mortality and hospitalization based on sex4–10 (see references 1-42 of the supplementary data).

There is limited evidence on the differences between women and men from meta-analyses, systematic reviews, and observational studies.4,11–23 It is recommended that sex and gender analysis be carried out in studies to deepen knowledge of possible differences, avoid harm due to inappropriate generalization of results, and increase the applicability of treatments in women.4,12,16 To our knowledge, no results of the HF drug titration process in women vs men have been published within the framework of a clinical trial with a structured titration protocol and follow-up. The limited available evidence raises the need to deepen study of this topic.

ETIFIC was a multicenter randomized trial, which demonstrated noninferiority in the safety and effectiveness of drug titration by HF-nurses vs HF-cardiologists in patients with de novo HFrEF.24,25 This post hoc analysis aimed to compare gender differences in drug titration, selection process, characteristics, prescription, achieved dose, adverse events and clinical results in women vs men.

METHODSStudy design and participants

ETIFIC was a randomized controlled open label trial carried out in 20 Spanish hospitals with HF units (2015-2018) to compare the safety and effectiveness of HF drug titration by HF-nurses vs HF-cardiologists. Its design and results have been previously published.24,25

Patients with de novo HFrEF and New York Heart Association (NYHA) II-III were included after hospitalization in a cardiology ward. Exclusion criteria were planned surgery, contraindication to BB or already receiving target or maximum tolerated dose, home or terminal care, or inability for self-care.

An active supervision system for recruitment, with centralized randomization, 4-month titration period, and a 6-month follow-up period after inclusion were established. A safety and clinical adjudication committee, blinded to the group assignment, monitored the safety of the research activity and evaluated all adverse events. Written informed consent forms were signed. The study was approved by the Clinical Research Ethics Committee of the Basque Country and complied with the Declaration of Helsinki.

ETIFIC confirmed the noninferiority safety and effectiveness of drug titration by HF-nurses vs drug titration by HF-cardiologists.

Study protocol

The previously published study protocol24 was based on clinical practice guidelines.1,2 The titrating professional was the HF-nurse vs the HF-cardiologist. In both cases, drug prescription was the responsibility of the cardiologist. HF-nurse tasks also included clinical assessment, education on self-care, psychosocial support, and care coordination. All HF-nurses and half of the HF-cardiologists were women.

The main objective of this post hoc substudy was to compare the safety and effectiveness of drug titration in women vs men from the ETIFIC study and to assess the possible factors associated with any differences.

Primary endpoint

To compare the achieved BB mean relative dose (% relative to target dose) after 4 months of titration in women vs men. The % of target dose was defined according to ESC HF guidelines.24

Secondary endpoints

To compare the following between women and men: a) patient selection process and baseline characteristics; b) mean relative doses of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), and MRA at 4 months; c) percentage of patients with 100% and ≥ 50% of the target dose; d) mean relative doses and number of visits according to type and gender of the professional; e) percentage of adverse events associated with titration; f) variables influencing target dose achievement; g) rates of cardiovascular mortality and readmissions at 6 months; and h) changes in left ventricular ejection fraction (LVEF), NYHA class, 6-minute walk distance, N-terminal pro b-type natriuretic peptide (NT-proBNP) levels and quality of life scores throughout the study. Variables are shown in the design article.2 Definitions of sex and gender are provided in the supplementary data.

Statistical analysis

The analysis was performed on an intention-to-treat basis. Both the Student t-test (or nonparametric Wilcoxon test if continuous data were not normally distributed) and the chi-square test (or Fisher exact test) were used to compare the baseline sociodemographic and clinical characteristics of patients in the 2 groups (women vs men). The effect attributable to the intervention was estimated by comparing the differences in the relative dose of BB, ACEI, ARB and MRA achieved between the groups, assessed at 4 months after the start of titration, and the 95% confidence interval was calculated. We performed a multivariate analysis for the primary and secondary endpoints as predefined in the original study design.24 The model was adjusted by the variables established as relevant related factors with a possible effect on dosing, based on a review of the literature, shown in table 1 of the supplementary data. All analyses were performed considering the 2 target populations (women and men). All variables with a P value<.20 were included as explanatory variables in the multivariate model, with the relative dose as the response variable. The multivariate analysis was conducted using ANCOVA within the framework of a linear mixed regression analysis. To take into account the difference between baseline and end of the titration period at 4 months, mixed linear regression models with fixed effects and random effects (specific effect of each participant and center and the effect of time expressed as visit 1 (baseline) and visit 2 (at 4 months) were used. The models were adjusted for women, men, and the total number of patients. These models took into account the longitudinal structure of the 2 repeated measurements, as well as the hierarchical structure of the data. All the statistical analyses were performed using R (version 4.0.4): R Foundation (Statistical Computing, Vienna, Austria). Statistical significance was set at P<.05.

RESULTSPatient population

A total of 824 patients with de novo HFrEF, 221 women and 603 men, were evaluated, and 320 patients were included, 83 women and 237 men. Finally, 289 patients (76 women and 213 men) were analyzed at 4 months, and 274 (74 women, 200 men) were analyzed at 6 months. The selection process and causes for exclusion are shown in figure 1, and in table 2 and 3 of the supplementary data.

Figure 1.

Patient flowchart. HF, heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

(0.34MB).

Patient characteristics were generally well-balanced between the 2 groups, without significant differences in LVEF, ischemic heart disease, or NT-proBNP (table 1). However, women were older (4 years), had a higher proportion of systolic blood pressure (SBP) ≤ 100mmHg, lower hemoglobin level, lower 6-minute walk distance, and worse quality of life. In contrast, men had a higher proportion of smokers, alcohol abuse, atrial fibrillation/flutter, and worse scores on the Lawton Instrumental Activities of Daily Living Scale and age-adjusted Charlson index.

Table 1.

Baseline patient characteristics

Variables (at hospital discharge)  Women n=83  Men n=237  P 
Demographics  83 (25.93)  237 (74.06)  <.001 
Age, y  64.83±12.27  60.04±11.95  .002 
Education level, ≤ 10 y  31 (37.25)  77 (32.63)  .434 
Patients ≥ 70 y  30 (36.14)  53 (22.36)  .0137 
Memory impairment screening ≤ 4  4 (14.29)  8 (17.02)  .755 
Lawton test: inability to administer medication  10 (38.46)  23 (46.94)  .482 
Cardiovascular risk factors
Hypertension  41 (49.4)  125 (52.74)  .600 
Smoker  14 (16.87)  83 (35.02)  .002 
Alcohol consumption>2 units/d  7 (8.43)  87 (36.71)  .001 
Diabetes  19 (22.89)  76 (32.07)  .115 
Heart disease
Ischemic heart disease  18 (21.69)  70 (29.54)  .168 
Atrial fibrillation/flutter  14 (18.42)  78 (34.98)  .007 
NYHA       
II  64 (77.11)  203 (85.65)  .071 
III  19 (22.89)  34 (14.35)  .071 
Left ventricular ejection fraction, %  28.02±7.05  27.59±6.9  .6232 
Comorbidities
Peripheral arterial disease  2 (2.41)  20 (8.44)  .062 
Stroke  6 (3.66)  10 (6.41)  .259 
Chronic respiratory disease  9 (10.84)  32 (13.5)  .533 
Charlson index, adjusted by age  5.11±1.65  4.69±2.03  .048 
Vital signs
SBP mmHg  112.95±18.65  116.39±18.48  .147 
SPB ≤ 100 mmHg  24 (28.92)  44 (18.64)  .049 
Heart rate beats/min  72.41±14.4  72.75±13.84  .851 
Laboratory tests
NT-proBNP pg/mL  75; 1901 [1042; 4642]  207; 1590 [860; 3196]  .231 
BNP pg/mL  5; 358 [126;404]  24; 352.5 [193.8; 835.2]  .544 
Creatinine mg/dL  0.91±0.39  1.14±0.52  .001 
eGFR mL/min/1.73 m2  72.21±22.75  75.55±21.71  .234 
eGFR<60 mL/min/1.73 m2  16 (19.28)  49 (20.68)  .735 
Potassium>5 mEq/L  7 (8.43)  29 (12.24)  .345 
Hemoglobin g/dL  13.52±1.99  14.3±2.03  .0025 
Anemia  22 (26.51)  60 (25.32)  .831 
6-minute walk test, meters  318.29±96.82  383.28±102.85  .001 
Meters ≤ 300  38 (46.34)  37 (16.23)  .001 
European HF Self-care Behavior Scale (12-60)  37.6±11.98  35.78±11.68  .229 
Question 10 Irregular medication intake (score 3-5)  18 (21.95)  26 (11.06)  .014 
Quality of life
Minnesota Living with HF Questionnaire (0-105)  52.76±21.14  46.76±22.83  .038 
Physical dimension (0-40)  25.68±10.32  20.77±11.11  .001 
Emotional dimension (0-25)  11.49±7.35  9.49±6.77  .025 
EQ-5 D index  0.66±0.24  0.76±0.23  .001 
Daily living tasks, score 2-3  43 (51.80)  75 (31.64)  .040 
Anxiety and depression score 2-3  52 (62.65)  109 (45.99)  .002 
VAS EQ-5D (0-100)  53.89±17.73  58.94±20.21  .047 
Drugs
BB  78 (93.98)  232 (97.89)  .078 
ACEI  70 (84.34)  196 (82.7)  .732 
ARB  9 (10.84)  23 (9.7)  .766 
MRA  63 (75.9)  186 (78.48)  .627 
Psychotropic drugs  32 (38.55)  43 (18.14)  .001 
Antidepressants  17 (20.48)  21 (8.86)  .005 
Anxiolytics  19 (22.89)  24 (10.13)  .003 
Hypnotics  6 (7.23)  4 (1.69)  .013 
Neuroleptics  3 (3.61)  2 (0.84)  .080 

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blockers; BNP, B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; EQ-5D, EuroQol-5 Dimension; HF, heart failure; MRA, mineralocorticoid receptor blocker; NT-proBNP, N-terminal probrain natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; VAS, Visual analogue scale.

The data are expressed as No. (%), mean±standard deviation, or No.; median [interquartile range].

Baseline prescription of HF guideline-recommended drugs did not differ significantly. Women more frequently took psychotropic drugs (table 4 of the supplementary data shows other baseline characteristics).

Primary endpointBB dosage

There were no significant differences between women and men in the mean relative doses of BB at 4 months or in the percentage of patients with 100% and ≥ 50% of target dose (table 2). Equally, there were also no differences between women and men in each group of titrating professional (table 3), or in the number of visits for women vs men (table 4).

Table 2.

Dosage: baseline to 4 months (titration period)

  Womenn=76  Menn=213  Diff. (95%CI)  P
BB
At baseline  76  213     
Relative dose %  34.54±17.95  34.90±19.89  0.36 (−5.46 to 4.75)  .890 
At 4 mo  76  213     
Relative dose %  62.08 (30.72)  64.4 (32.77)  2.32 (−10.58 to 5.94)  .580 
Patients with 100% target dose  24 (31.57)  83 (38.96)  7.38 (−19.7 to 4.94)  .252 
Patients with ≥ 50% target dose  54 (71.05)  149 (69.95)  1.09 (−10.8 to 13.01)  .857 
ACEI
At baseline  63  176     
Relative dose %  40.58±27.61  43.93±27.91  3.35 (−11.40 to 4.70)  .413 
At 4 mo  57  173     
Relative dose %  57.67±48.81  66.21±62.05  8.54 (−18.42 to 1.35)  .089 
Patients with 100% target dose  19 (33.33)  64 (36.99)  3.66 (−17.85 to 10.53)  .617 
Patients with ≥ 50% target dose  37 (64.91)  138 (79.76)  14.85 (−28.61 to1.09)  .023 
ARB
At baseline  16     
Relative dose %  30.70±19.55  35.39±17.55  4.69 (−13.03 to 22.40)  .577 
At 4 mo  13  23     
Relative dose %  34.11±24.46  49.62±35.62  15.51 (−36.80 to 5.78)  .147 
Patients with 100% target dose  1 (7.69)  6 (26.08)  18.39 (−41.45 to 4.66)  .180 
Patients with ≥ 50% target dose  3 (23.07)  12 (52.17)  29.09 (−59.77 to 1.58)  .089 
MRA
At baseline  67  185     
Relative dose %  72.01±36.55  59.10±31.50  12.91 (3.66 to 22.16)  .006 
At 4 mo  67  185     
Eplerenone  30/67 (44.77)  131/185 (70.81)  26.03 (−40.64 to -11.43)  <.001 
Relative dose %  79.85±27.72  67.29±31.43  12.55 (4.46 to 20.65)  .003 
Patients with 100% target dose  42 (62.68)  81(43.78)  18.90 (4.28 to 33.53)  .012 
Patients with ≥ 50% target dose  65 (97.01)  161 (87.02)  9.9 (2.64 to 17.33)  .039 

95%CI, 95% confidence interval; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; Diff., difference; MRA, mineralocorticoid receptor blocker.

The data are expressed as No. (%) or mean±standard deviation.

* P value of the interaction between treatment and each subgroup.

Table 3.

Mean relative dose by intervention group. Baseline to 4 months (titration period)

DrugNo.Titrating professionalRelative dose (%) at 4 moMean±SWomenn=76  Menn=213  Diff. (95%CI)  P
BB
No.  76  213     
HF-nurse group (all women)  40  104     
Relative dose, %  68.44±30.7  72.48±31.7  4.03 (−15.54 to 7.46)  .486 
HF-cardiologist group  36  109     
Relative dose, %  55.03±29.5  56.71±32  1.67 (−13.25 to 9.91)  .774 
Female cardiologist  18  47     
Relative dose, %  65.28±33.09  62.37±33.34  2.91 (−15.83 to 21.65)  .754 
Male cardiologist  18  62     
Relative dose, %  44.79±17.53  52.42±30.52  7.63 (−20.69 to 5.43)  .244 
ACEI
No.  57  173     
HF-nurse group  30  85     
Relative dose, %  68.75±32.3  73.2±28.7  4.45 (−17.90 to 8.93)  .504 
HF-cardiologist group  27  88     
Relative dose, %  45.37±30.6  59.43±29.7  14.06 (−27.57 to0.55)  .042 
Female cardiologist  14  39     
Relative dose, %  48.21±32.84  61.35±29.20  13.14 (−33.82 to 7.56)  .201 
Male cardiologist  13  49     
Relative dose, %  42.31±30.17  57.91±30.27  15.6 (34.74 to 3.54)  .104 
ARB
No.  13  23     
HF-nurse group  12     
Relative dose, %  36.85±30.8  48.93±35.5  12.08 (−45.26 to 21.09)  .448 
HF-cardiologist group  11     
Relative dose, %  30.92±22.8  50.38±37.5  19.46 (−50.78 to 11.85)  .205 
Female cardiologist     
Relative dose, %  22.75±14.50  43.75±44.19  21 (−299.93 to 257.92)  .622 
Male cardiologist     
Relative dose, %  35±27.1  51.85±38.76  16.85 (−59.69 to 25.99)  .393 
MRA
No.  67  185     
HF-nurse group  34  91     
Relative dose, %  83.82±26.7  66.21±32.8  17.61 (6.19 to 29.04)  .003 
HF-cardiologist group  33  94     
Relative dose, %  75.76±28.3  68.35±30.5  7.41 (−4.28 to19.1)  .210 
Female cardiologist  17  38     
Relative dose, %  70.59±30.92  63.82±39.50  6.77 (−12.10 to 25.65)  .471 
Male cardiologist  16  56     
Relative dose, %  81.25±25.00  71.43±34.04  9.82 (−5.13 to 24.77)  .189 

95%CI, 95% confidence interval; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; Diff., difference; HF, heart failure; MRA, mineralocorticoid receptor blocker.

Unless otherwise indicated, the results are expressed as No. or mean±standard deviation (SD).

* P value of the interaction between treatment and each subgroup.

Table 4.

Visits according to titrating professional

Visits/professional(n women/n men)  Womenn=76  Menn=213  Diff. (95%CI)  P 
HF-nurse and HF-cardiologist, n *75/*211  4.57±2.97  4.63±2.91  0.05 (−0.84 to 0.73)  .895 
HF-nurse (all women), n *39/*103  6.28±2.95  6.50±2.80  0.21 (−1.30 to 0.88)  .698 
HF-cardiologist, n 36/*108  2.72±1.56  2.84±1.60  0.12 (−0.72 to 0.48)  .692 
Male cardiologist, n 18/47  3.22±1.77  3.43±1.65  0.20 (−1.17 to 0.77)  .670 
Female cardiologist, n 18/*61  2.22±1.17  2.30±1.33  0.07 (−0.73 to 0.59)  .823 
Patients with ≤ 2 visits according to the titrating professional
HF-nurse and HF cardiologist  *23/75 (30.67)  *62/211 (29.38)  1.28 (−11.73 to 14.30)  .950 
HF-nurse  *3/39 (7.69)  *4/103 (3.88)  3.81 (−7.12 to 14.73)  .616 
HF-cardiologist  20/36 (55.55)  *58/108 (53.70)  1.85 (−18.76 to 22.46)  .999 
Male cardiologist  8/18 (44.44)  18/47 (38.30)  6.15 (−24.53 to 36.82)  .865 
Female cardiologist  12/18 (66.67)  *40/61 (65.57)  1.09 (−24.83 to 27.01)  .999 

Diff., difference; HF, heart failure.

Unless otherwise indicated, the data are expressed as No. (%) or mean±standard deviation.

*

There were 3 patients (1 woman and 2 men) with the number of missing visits.

However, women achieved significantly higher BB doses when titration was performed by a female HF-cardiologist compared with a male HF-cardiologists (P=.037) and higher BB doses, when comparing HF-nurses vs HF-cardiologists, and this result was almost significant (P=.057). This was associated with a higher number of visits (tables 5 and 6 of the supplementary data).

Secondary endpointsACEI/ARB dosage

There were no significant differences between women and men in the relative ACEI and ARB doses achieved at 4 months (table 2). However, relative doses of ACEI were significantly lower in women vs men (P=.042) when titration was performed by HF-cardiologists but not by HF-nurses (table 3).

Women achieved significantly higher ACEI doses on comparison of titration by HF-nurses vs H-cardiologists, P=.007 (table 5 of the supplementary data).

The percentage of patients receiving ≥ 50% of the target dose of ACEI was significantly higher in men, P=.0226 (table 2).

MRA dosage

The relative MRA doses, the percentage of patients with 100% and ≥ 50% of the target dose at 4 months, were significantly higher in women vs men (table 2). Women achieved higher MRA doses vs men when titration was performed by HF-nurses, P=.003 (table 3).

Variables potentially associated with higher drug doses at the end of the up-titration period

Significant differences were found between women and women. Women showed slightly better self-care, while men showed lower NYHA class and a lower proportion of patients with body mass index ≤ 19.

Moreover, the type and gender of the titrating professional, associated with their respective number of visits, influenced the achievement of higher doses, both among men and among women.

Although women had significantly lower creatinine at baseline and 4 months, estimated glomerular filtration rates (eGFR) showed no significant differences. No differences were found in other clinical variables or prescription (tables 5-10 of the supplementary data).

Multivariate analysis

A multivariate analysis disaggregated by sex was carried out, using mixed linear regression models with fixed effects and following the recommendations for Sex and Gender Equity in Research SAGER guidelines.12 Factors related to the relative dose of BB, ACEI, MRA achieved by women, men and the total number of patients are shown in table 5.

Table 5.

Multivariate linear mixed regression models

  Estimate  95%CI  P 
Beta-blockers, all patients, n=289
Intercept  −53.02  (−146.97 to 40.92)  .269 
Female sex  2.01  (−10.16 to 14.19)  .746 
Time (baseline vs 4 mo)  29.29  (−29.71 to 88.28)  .331 
Time (baseline vs 4mo), female sex*  −1.87  (−9.55 to 5.81)  .634 
BB relative dose at baseline  0.83  (0.73 to 0.93)  <.001 
Baseline heart rate, bpm  0.29  (0.16 to 0.41)  <.001 
Visits with the titrating professional  1.23  (0.42 to 2.04)  .003 
HF-nurse vs HF-cardiologist  4.63  (0.61 to 8.65)  .024 
Beta-blockers, women, n=76
Intercept  −59.23  (−163.61 to 45.15)  .268 
BB relative dose at baseline  0.83  (0.64 to 1.02)  <.001 
Baseline heart rate, bpm  0.35  (0.12 to 0.58)  .004 
Visits with the titrating professional  2.4  (1.15 to 3.66)  <.001 
Time (baseline vs 4 mo)  27.42  (−37.29 to 92.12)  .408 
Beta-blockers, men, n=213
Intercept  −45.76  (−151.84 to 60.32)  .398 
BB relative dose at baseline  0.82  (0.71 to 0.92)  <.001 
Baseline heart rate, bpm  0.29  (0.14 to 0.44)  <.001 
HF-nurse vs HF-cardiologist  7.78  (3.72 to 11.85)  <.001 
Atrial fibrillation  −5.44  (−9.99 to−0.88)  .02 
Time (baseline vs 4 mo)  29.13  (−37.51 to 95.76)  .392 
ACEI, all patients, n=239
Intercept  −31.77  (−119.52 to 55.98)  .478 
Sex: female  4.09  (−8.5 to 16.68)  .525 
Time (baseline vs 4 months)  22.83  (−31.98 to 77.65)  .415 
Time (baseline vs 4 months) *Sex: female  −4.26  (−12.34 to 3.81)  .301 
ACEI relative dose at baseline  0.7  (0.64 to 0.77)  <.001 
SBP (baseline, mmHg)  0.26  (0.16 to 0.36)  <.001 
eGFR<60 (no vs yes)  −6.56  (−11.31 to−1.81)  .007 
HF-nurse vs HF-cardiologist  7.1  (3.52 to 10.68)  <.001 
Age, y  −0.18  (−0.33 to−0.02)  .025 
ACEI, women, n=63
Intercept  −46.71  (−130.67 to 37.26)  .278 
ACEI relative dose at baseline  0.72  (0.58 to 0.86)  <.001 
SBP (baseline, mmHg)  0.31  (0.1 to 0.52)  .004 
HF-nurse vs HF-cardiologist  11.14  (3.69 to 18.58)  .004 
Diabetes mellitus  −12.08  (−22.15 to−2.02)  .02 
Time (baseline vs 4 mo)  18.37  (−32.59 to 69.32)  .481 
ACEI, men, n=176
Intercept  −27.17  (−105.39 to 51.04)  .999 
ACEI relative dose at baseline  0.71  (0.64 to 0.78)  <.001 
SBP (baseline, mmHg)  0.25  (0.14 to 0.36)  <.001 
eGFR<60 (no vs yes)  −5.65  (−10.95 to−0.34)  .038 
HF nurse vs HF cardiologist  5.72  (1.65 to 9.79)  .006 
Age, y  −0.23  (−0.41 to−0.05)  .012 
Time (baseline vs 4 mo)  22.83  (−25.6 to 71.25)  .999 
MRA, all patients, n=252
Intercept  14.71  (−29.88 to 59.3)  .999 
Sex: female  3.03  (−10.17 to 16.24)  .653 
Time (baseline vs 4 mo)  8.51  (−19.5 to 36.52)  .999 
Time (baseline vs 4 mo) *Sex: female  −0.68  (−8.97 to 7.61)  .873 
MRA relative dose at baseline  0.75  (0.68 to 0.83)  <.001 
eGFR<60 (no vs yes)  −6.28  (−11.15 to−1.41)  .012 
K (≥ 5.5 mEq/L vs<5.5 mEq/L)  −14.09  (−27.47 to−0.7)  .04 
Combination of 3 drugs, baseline  −8.65  (−14.64 to−2.66)  .005 
MRA, women, n=67
Intercept  14.5  (−75.86 to 104.86)  .754 
MRA relative dose at baseline  0.69  (0.59 to 0.79)  <.001 
Time (baseline vs 4 mo)  7.84  (−49.15 to 64.82)  .788 
MRA, men, n=185
Intercept  31.28  (−148.71 to 211.27)  .999 
MRA relative dose at baseline  0.77  (0.68 to 0.85)  <.001 
K (≥ 5.5 mEq/L vs<5.5 mEq/L)  −22.88  (−38.21 to−7.55)  .004 
Combination of 3 drugs, baseline  −9.09  (−16.47 to−1.71)  .016 
NYHA at baseline  −8.18  (−14.15 to−2.22)  .008 
Time (baseline vs 4 mo)  8.43  (−105.05 to 121.9)  .999 

95%CI, 95% confidence interval; ACEI, angiotensin-converting enzyme inhibitors; BB, beta-blockers; eGFR, estimated glomerular filtration; HF, heart failure; K, potassium; n, number of patients; MRA, mineralocorticoid receptor antagonists; NYHA, New York Heart Association; SBP, systolic blood pressure.

*

Time and sex interaction.

Adverse events

There were no significant differences in terms of the occurrence of overall or individual adverse events between groups (figure 2).

Figure 2.

Adverse events associated with titration. 95%CI, 95% confidence interval; bpm, beats per minute; Diff., difference; HF, heart failure; HR, heart ratio; K, potassium; worsening renal function, creatinine>50% baseline, creatinine>3mg/dL, estimated glomerular filtration rate<25mL/min/1.73 m2; N total number of patients, No. (%), number of cases. * P value for difference between treatment groups.

(0.24MB).
Serious adverse events at 6 months

There were no statistically significant differences between women and men in all-cause and cardiovascular mortality or cardiovascular hospitalizations. No HF hospitalizations were observed in women, but this difference was not statistically significant. However, unplanned noncardiovascular hospitalizations were significantly more frequent in women (figure 3).

Figure 3.

Serious adverse events. Mortality and hospitalizations evaluated at 6 months. 95%CI, 95% confidence interval; CV, cardiovascular; Diff., differences; HF, heart failure; N total number of patients, No. (%), number of cases. * P value for difference between treatment groups.

(0.24MB).
Clinical outcomes at 6 months

There were significant improvements in all clinical outcomes at 6 months, but without significant differences in the change from baseline to 6 months between the 2 groups, except in NYHA class, with men having better functional class at 6 months (table 6).

Table 6.

Outcomes at 6 months

Variables  Womenn=74Menn=200Difference of change from baselineto 6 monthsbetween groups(95%CI)  P 
  Baseline  6 months  Baseline  6 months     
LVEF %  28.23±7.17  43.09±11.29  27.26±6.94  42.58±12.32  0.46 (−3.80 to 2.87)  .786 
LVEF<35%  57 (77.03)  15(20.27)  161 (80.50)  48 (24.00)  0.26 (−13.21 to 13.73)  .999 
LVEF>40%  44 (59.46)  96 (48.00)  11.46 (−2.62 to 25.54)  .121 
NT-proBNP, pg/mL n 68/176  1654 [952-3850]  611 [195-1017]  1476 [789-2954]  526 [152-1277]  182 (−650 to 92)  .158 
BNP, pg/ml, n 3/19  358 [200-381]  160 [155-166]  333 [188-762]  162 [71- 490]  33.5 (−967 to 992)  .999 
NYHA classa
18 (24.32)  84 (41.00)  16.68 (−30.53 to4.82)  .011 
II  57 (77.03)  53 (71.62)  171 (85.50)  110 (55.00)  25.09 (−34.22 to 15.97)  <.001 
III  16 (21.62)  2 (2.70)  29(14.50)  6 (3.00)  7.42 (−3.47 to 18.30)  .163 
6-minute-walk test, meters  315.9±94.59  359.59±99.86  382.25±97.41  433.20±117.64  7.25 (−30.29 to 15.80)  .535 
Minnesota scoreb  52.81±21.48  26.07±19.60  46.5±22.73  21.11±20.01  1.34 (−7.83 to 5.14)  .683 
Physical dimension  25.42±10.28  10.94±9.08  20.8±11.32  7.4±8.66  1.08 (−14.48 to 2.40).  .540 
Emotional dimension  11.60±7.30  6.81±6.08  9.46±6.54  5.21±5.91)  0.60 (−2.47 to 1.27).  .524 
Euroqol-5 dimension index  0.65±0.24  0.74±0.24  0.77±0.21  0.82±0.21  0.04 (−0.02 to 0.11)  .210 
Visual analogue scale  53.52±18.50  66.19±20.28  58.78±19.85  71.65±18.93  0.19 (−6.32 to 5.93)  .950 

95%CI, 95% confidence interval; BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal probrain natriuretic peptide; NYHA, New York Heart Association.

Unless otherwise indicated, the data are expressed as No. (%), mean±standard deviation, or No.; median [interquartile range].

a

There was 1 patient (woman) with NYHA missing.

b

Minnesota Living with HF Questionnaire (0 better-105 worse).

DISCUSION

In this post hoc study of HF drug titration in the ETIFIC trial, nonsignificant gender differences were found in BB/ACEI/MRA dosage in the multivariate analysis, cardiovascular mortality, HF hospitalizations, and other clinical outcomes at 6 months (figure 4).

Figure 4.

Post hoc analysis of the HF-titration ETIFIC trial: There were no significant gender differences regarding dosage of HF medications in the multivariate analysis, cardiovascular mortality or HF hospitalizations. ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; BB, beta-blockers; CV, cardiovascular; HF, heart failure; HFrEF, heart failure patients with reduced ejection fraction; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor blocker; RAS, renin-angiotensin system.

(0.31MB).
Differences between women and men in the selection process and baseline characteristics

The possible barriers to women's participation were analyzed.4,12 The proportion of women in ETIFIC (25.93%) could be considered underenrolment, given the established reference (< 32%) in a systematic review of 317 HFrEF trials.4 However, participation was higher than that in trials of BB (23%), ACEI (21%), ARB (26%) and MRA (21%) (see references of the supplementary data: BB,1-20; ACEI 21-23; ARB 24,25 MRA 26-28), but lower than that in observational optimization studies (30%)5–10 (see references 29-42 of the supplementary data). This may have been influenced by recruitment in cardiology wards (lower proportion of elderly patients or with comorbidity). The lower proportion of women in cardiology services vs other services is also reflected in the literature20–26 (see references 43-46 of the supplementary data).

Some baseline differences between women vs men were observed in ETIFIC (table 1). No clinical trial or observational optimization study has evaluated the baseline characteristics of women.5–10 (see references 1-42 of the supplementary data). These were analyzed by 2 meta-analyses17,18 and 6 studies with other objectives.15,19–23 The HFrEF women generally had similar characteristics to those in ETIFIC (table 1): they were 1 to 4 years older,15,17,18,20–22 had a lower proportion of smokers,15,18,21 lower alcohol consumption,15 less frequently had atrial fibrillation,15,18,20,21 a lower 6-minute walk distance,22 worse quality of life,22,23 a higher proportion of NYHA III-IV,17,18,20,21 and minimal differences in LVEF (0.5-2%) vs men.15,17–19,21

Drug prescription in ETIFIC showed no significant differences, except for greater prescription of psychotropic drugs in women. A lower prescription of BB15,18 and ACEI in women vs men has been reported in the literature.15,20

Primary endpointBB relative dose

No gender differences were found in the mean relative doses of BB reached by all patients at 4 months (table 2) or in the multivariate analysis (table 5). Factors associated with dose were the relative dose of BB and heart rate at baseline for both women and men, and atrial fibrillation only for men (table 5), probably associated with a higher prevalence (table 1).

Both women and men achieved higher BB doses when they were titrated by HF-nurses vs HF-cardiologists. All HF-nurses were female. Female patients achieved higher BB doses when titrated by female cardiologists vs male cardiologists. In both cases, this was associated with a higher number of visits. The multivariate analysis also reflected the influence of these organizational issues (table 5, and tables 5 and 6 of the supplementary data). The association of the achieved dose with the titrating professional, and the number of visits was previously demonstrated in ETIFIC patients.25 The possible influence of the professional's gender on the doses achieved by women has also been mentioned previously.16

No original BB trial has evaluated optimal doses for women or analyzed their prescription and the mean relative doses achieved (see references 1-20 of the supplementary data). These doses in women in ETIFIC, 62%, were lower (−15%), as with men, than the mean doses achieved by all patients in BB trials (more selected patients), although they were in the high dose range of observational optimization studies (33-63%)5–10 (see references 29-42 of the supplementary data).

We found limited and heterogeneous information on the BB doses achieved by women vs men in other types of studies. As in ETIFIC, some studies found no dose differences, namely a meta-analysis,17 a trial on exercise (see reference 47 of the supplementary data), and 3 observational studies,9,10,21 while others reported lower target doses in women, namely, a HF program trial (see reference 48 of the supplementary data) and 2 observational studies5 (see reference 40 of the supplementary data).

Secondary endpoints

No gender differences were found in the relative doses of ACEI/ARB (table 2). Equally, there were no significant differences between women and men during titration in SBP or eGFR (table 10 of the supplementary data), in symptomatic hypotension events (figure 2), or the mean relative dose of ACEI (table 2). However, there was a lower proportion of women with ≥ 50% the target dose of ACEI (table 2).

The multivariate analysis showed that the relative dose of ACEI at baseline and SBP were associated with the achieved doses of ACEI in both women and men (table 5). The association of achieved ACEI dose with the titrating professional, and the number of visits previously demonstrated in ETIFIC25 was also confirmed for women, as shown in table 3 and table 5 (see also table 5 of the supplementary data).

Women achieved significantly higher relative MRA doses at 4 months, associated with higher use of spironolactone and lower use of eplerenone (table 2). No gender differences were found in the multivariate analysis including all patients (table 5). However, there were no differences in the potassium level at baseline and 4 months (table 10 of the supplementary data) or in adverse events associated with potassium levels (figure 2), but potassium ≥ 5 mEq/L was associated with a lower dose only in men in the multivariate analysis (table 5).

No original ACEI, ARB and MRA trial has reported the prescription and mean relative dose achieved disaggregated by gender. Both women and men achieved lower ACEI/ARB doses in ETIFIC than those achieved by all patients in trials. This difference could be explained by the selected population, a higher SBP and a lower prescription of MRA and BB in these trials compared with ETIFIC (see references 21-28 of the supplementary data).

We found limited and heterogeneous information from some observational studies, 2 of them showing lower ACEI and ARB doses achieved by women6,10 but no other.21 In contrast, higher MRA doses have been reported in women.7

The drug prescription rate in the ETIFIC trial was high for both women and men, without significant differences. In addition, the joint prescription of 3 groups of drugs (BB, renin angiotensin system inhibitors and MRA) was 84% in women vs 78% in men, far higher than in trials and observational studies5–10 (see tables 7-9 and references 1-42,49 of the supplementary data).

Both women and men showed good self-care and adherence, although women showed slightly better results. Previous studies of adherence in HF have reported contradictory results in relation to gender (see table 10 and references 50, 51 of the supplementary data).

There were no differences between women and men in adverse events associated with titration (figure 2). Clinical trials and observational optimization studies did not report adverse events disagregated by sex5–10 (see references 1-42 of the supplementary data).

Differences in pharmacodynamics and pharmacokinetics have been described in women that could lead to higher blood levels at the same drug dose, lower tolerance of higher doses or beneficial effects with lower doses. Moreover, differences in renal function could lead to greater adverse events, suggesting that optimal doses in women should be lower.13,16,21 However, the ETIFIC trial showed no significant differences in women vs men in dosage and adverse events.

Other secondary endpoints

No gender differences were found in the mortality rate or cardiovascular admissions. Both were lower than in the literature, probably because the patients in this study had novo HF, received therapeutic optimization, close follow-up by the HF program, and showed good self-care and adherence.1,3

Although it did not reach statistical significance, probably due to the small number of events, it could be clinically relevant that there were no HF admissions in women, considering that there were no significant differences in cardiovascular mortality either (figure 3).

Three meta-analyses have shown the effectiveness of BB, ACEI and MRA in reducing mortality and admissions in women.17,18,27 The BB and MRA meta-analysis17,18 and the European Long-Term registry28 observed fewer serious adverse events in women.

A substudy of BIOSTAT21 observed a 30% reduction of death or hospitalization with 50% of the recommended doses of ACEI, ARB and 60% of BB, without finding a greater reduction with higher doses, although the authors reported that the optimal doses for women are unknown. No titration protocol, adverse events, number of visits or reasons for not reaching the target dose were described. Moreover, the BB and MRA prescription and BB doses achieved were significantly lower than in the ETIFIC trial.

A clear improvement in LVEF (14.86% vs 15.32%), NT-proBNP, NYHA, 6-minute walk test and quality of life, with no significant differences between women and men, was shown, except in NYHA class, where men had a better functional class at 6 months than women (table 6).

LVEF recovery has been associated with being female, nonischemic etiology, atrial fibrillation, adherence to BB and shorter duration of HF19 (see references 52-54 of the supplementary data).

Similar improvements in women vs men have also been described in quality of life and 6-minute walk test, associated with the use of BB, ACEI, ARB, and a close follow-up in clinical studies.22

A paradox previously reported in the literature15,20,29 was also observed in women who, despite being older, more symptomatic and having worse quality of life, had lower mortality and HF hospitalization. According to previous publications, this may be due to possible late diagnoses, less access to health care, socioeconomic and educational factors, and physicians’ misperception of women's symptoms and consequent undertreatment.

Limitations

The ETIFIC clinical trial was not designed with the aim of evaluating gender differences in drug titration. Therefore, the sample in this post hoc analysis was not calculated for this purpose.

CONCLUSIONS

In a post hoc analysis of the HF-titration ETIFIC trial, multivariate analysis identified nonsignificant gender differences in the dosage of HF medications at 4 months after discharge. There were also nonsignificant differences in cardiovascular mortality, HF hospitalizations, and other clinical outcomes at 6 months.

To our knowledge, ETIFIC is the first study to show that a controlled environment such as a randomized trial in HF clinics, with a structured protocol, close follow-up and patient education allows women to tolerate a prescription and dosage without significant differences vs men, without a higher mortality rate or cardiovascular admissions and a clear improvement in clinical outcomes. Higher dosage was associated with HF-nurse involvement, female gender of the titrating professional, and the number of visits.

Sex and gender analysis should be carried out in clinical trials to gain greater in-depth knowledge of the possible differences and increase the applicability of treatments in women.

WHAT IS KNOWN ABOUT THE TOPIC?

  • -

    Women have been underrepresented in HFrEF trials. No original BB, ACEI, ARB, MRA trial has prospectively evaluated optimal doses by sex on a continuous scale, or specifically evaluated the characteristics, prescription, achieved doses and adverse events in women. Few trials have evaluated their effects on mortality and hospitalizations.

  • -

    Some studies (meta-analyses, systematic reviews, observational studies) have described differences between women and men in characteristics, drug prescription, dosage, and effects, but this evidence is limited by their design.

WHAT DOES THIS STUDY ADD?

  • -

    To our knowledge, ETIFIC is the first study to show that a controlled environment such as a randomized trial in a HF unit, with a structured protocol, close follow-up and patient education allows women to tolerate prescription and dosage without significant differences vs men, without a higher mortality rate or cardiovascular admissions and a clear improvement in LVEF, NT-proBNP, 6-minute-walk test, and quality of life.

  • -

    Higher dosage was associated with HF-nurse involvement, female gender of the titrating professional, and the number of visits.

FUNDING

This work was supported by grants from Carlos III Health Research Institute (FIS PI14/01208) in coordination with the European Regional Development Fund, and the Government of the Basque Country (Exp. 2014111143). Neither funding source was an industry sponsor, and both are public institutions. ETIFIC researchers were independent from funders in the study design, collection, analysis, and interpretation of the data, drafting of the report and in the decision to submit the article for publication.

AUTHORS’ CONTRIBUTIONS

All authors had full access to all the data (including statistical reports and tables) in the study and take responsibility for data integrity and data analysis. All authors participated in the study design, writing and review of this manuscript and approval of the final version. P. Latorre-García, E. Arana-Arri, S. Pérez-Fernández were responsible for its methodological accuracy and statistical analysis. J. Oyanguren is the guarantor and attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

CONFLICTS OF INTEREST

None declared.

Appendix A
APPENDIX. SUPPLEMENTARY DATA

Supplementary data associated with this article can be found in the online version available at https://doi.org/10.1016/j.rec.2021.11.002

References
[1]
P. Ponikowski, A.A. Voors, S.D. Anker, et al.
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
Eur Heart J., 37 (2016), pp. 2129-2200
[2]
P. Ponikowski, A.A. Voors, S.D. Anker, et al.
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2016 -Web Addenda.
Eur Heart J., 37 (2016), pp. 2129-2200
[3]
J. Oyanguren, P.M. Latorre-García, J. Torcal-Laguna, et al.
Effectiveness and Factors Determining the Success of Management Programs for Patients with Heart Failure: A Systematic Review and Meta-analysis.
Rev Esp Cardiol., 69 (2016), pp. 900-914
[4]
S. Whitelaw, K. Sullivan, Y. Eliya, et al.
Trial characteristics associated with under-enrolment of females in randomized controlled trials of heart failure with reduced ejection fraction: a systematic review.
Eur J Heart Fail., 23 (2021), pp. 15-24
[5]
M. Komajda, S.D. Anker, M.R. Cowie, et al.
Physicians’ adherence to guideline-recommended medications in heart failure with reduced ejection fraction: data from the QUALIFY global survey.
Eur J Heart Fail., 18 (2016), pp. 514-522
[6]
W. Ouwerkerk, A.A. Voors, S.D. Anker, et al.
Determinants and clinical outcome of up-titration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.
Eur Heart J., 38 (2017), pp. 1883-1890
[7]
S.J. Greene, J. Butler, N.M. Albert, et al.
Medical Therapy for Heart Failure with Reduced Ejection Fraction: The CHAMP-HF Registry.
J Am Coll Cardiol., 72 (2018), pp. 351-366
[8]
M.G. Crespo-Leiro, J. Segovia-Cubero, J. Gonzalez-Costello, et al.
Adecuación en España a las recomendaciones terapéuticas de la guía de la ESC sobre insuficiencia cardiaca: ESC Heart Failure Long-term Registry.
Rev Esp Cardiol., 68 (2015), pp. 785-793
[9]
G. Poelzl, J. Altenberger, R. Pacher, et al.
Dose matters! Optimisation of guideline adherence is associated with lower mortality in stable patients with chronic heart failure.
Int J Cardiol., 175 (2014), pp. 83-89
[10]
R. Carroll, A. Mudge, J. Suna, C. Denaro, J. Atherton.
Prescribing and up-titration in recently hospitalized heart failure patients attending a disease management program.
Int J Cardiol., 216 (2016), pp. 121-127
[11]
C.S.P. Lam, C. Arnott, A.L. Beale, et al.
Sex differences in heart failure.
Eur Heart J., 40 (2019), pp. 3859-3868
[12]
S. Hiedari, T.F. Babor, P.D. Castro, S. Torte, M. Curno.
Sex and gender equity in research: rationale for the SAGER recommendations and use.
Res Integr Peer Rev., 1 (2016), pp. 2
[13]
V. Regitz-Zagrosek, S. Oertelt-Prigione, E. Prescott, et al.
Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes The EUGenMed, Cardiovascular Clinical Study Group.
Eur Heart J., 37 (2016), pp. 24-34
[14]
G. Mentzer, E.M. Hsich.
Heart Failure with Reduced Ejection Fraction in Women: Epidemiology Outcomes, and Treatment.
Heart Fail Clin., 15 (2019), pp. 19-27
[15]
P. Dewan, R. Rørth, P.S. Jhund, et al.
Differential Impact of Heart Failure with Reduced Ejection Fraction on Men and Women.
J Am Coll Cardiol., 73 (2019), pp. 29-40
[16]
J. Tamargo, G. Rosano, T. Walther, et al.
Gender differences in the effects of cardiovascular drugs.
Eur Heart J Cardiovasc Pharmacother., 3 (2017), pp. 163-182
[17]
D. Kotecha, L. Manzano, H. Krum, et al.
Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis.
BMJ., 353 (2016), pp. i1855
[18]
X. Rossello, J.P. Ferreira, S.J. Pocock, et al.
Sex differences in mineralocorticoid receptor antagonist trials: a pooled analysis of three large clinical trials.
Eur J Heart Fail., 22 (2020), pp. 834-844
[19]
A. Aimo, G. Vergaro, V. Castiglione, et al.
Effect of Sex on Reverse Remodelling in Chronic Systolic Heart Failure.
JACC Heart Fail., 5 (2017), pp. 735-742
[20]
D. Stolfo, A. Uijl, O. Vedin, et al.
Sex-Based Differences in Heart Failure Across the Ejection Fraction Spectrum Phenotyping, and Prognostic and Therapeutic Implications.
JACC Heart Fail., 7 (2019), pp. 505-515
[21]
B.T. Santema, W. Ouwerkerk, J. Tromp, et al.
Identifying Optimal Doses of Heart Failure Medications in Men Compared with Women. A Prospective, Observational.
Cohort Study. Lancet., 394 (2019), pp. 1254-1263
[22]
A. Ravera, B.T. Santema, I.E. Sama, et al.
Quality of life in men and women with heart failure: association with outcome, and comparison of the Kansas City Cardiomyopathy Questionnaire and the EuroQol 5 dimensions questionnaire.
Eur J Heart Fail., 23 (2021), pp. 567-577
[23]
J. Comín-Colet, M. Anguita, F. Formiga, et al.
Calidad de vida relacionada con la salud de los pacientes con insuficiencia cardiaca crónica sistólica en España: resultados del estudio VIDA-IC.
Rev Esp Cardiol., 69 (2016), pp. 256-271
[24]
J. Oyanguren, Ll. García-Garrido, M. Nebot-Margalef, et al.
ETIFIC research group Design of a multicentre randomized controlled trial to assess the safety and efficacy of dose titration by specialized nurses in patients with heart failure. ETIFIC study protocol.
ESC Heart Fail., 4 (2017), pp. 507-519
[25]
J. Oyanguren, García-Garrido Ll, M. Nebot-Margalef, et al.
Noninferiority of heart failure nurse titration versus heart failure cardiologist titration ETIFIC multicentre randomized trial.
Rev Esp Cardiol., 74 (2021), pp. 533-543
[26]
I. Gómez-Otero, A. Ferrero-Gregori, A. Varela-Román, et al.
(REDINSCOR II). La fracción de eyección intermedia no permite estratificar el riesgo de los pacientes hospitalizados por insuficiencia cardiaca.
Rev Esp Cardiol, 70 (2017), pp. 338-346
[27]
P.G. Shekelle, M.W. Rich, S.C. Morton, et al.
Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials.
J Am Coll Cardiol., 41 (2003), pp. 1529-1538
[28]
M. Lainščak, I. Milinković, M. Polovina, et al.
Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry.
Eur J Heart Fail., 22 (2020), pp. 92-102
[29]
M.N. Walsh, M. Jessup, J. Lindenfeld.
Women with Heart Failure Unheard Untreated, and Unstudied.
J Am Coll Cardiol., 73 (2019), pp. 41-43

The ETIFIC research team can be consulted in the supplementary data.

Copyright © 2021. Sociedad Española de Cardiología
Idiomas
Revista Española de Cardiología (English Edition)

Subscribe to our newsletter

View newsletter history
Article options
Tools
Supplemental materials
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?