nature reviews cardiology https://doi.org/10.

1038/s41569-024-00996-1

Review article Check for updates

Sex-related similarities and

differences in responses to
heart failure therapies
Janice Y. Chyou1,6, Hailun Qin 2,6
, Javed Butler3,4, Adriaan A. Voors 2
& Carolyn S. P. Lam 5

Abstract Sections

Although sex-related differences in the epidemiology, risk factors, Introduction

clinical characteristics and outcomes of heart failure are well known, Response to pharmacological
investigations in the past decade have shed light on an often overlooked therapy for HF

aspect of heart failure: the influence of sex on treatment response. Response to device therapy
for HF
Sex-related differences in anatomy, physiology, pharmacokinetics,
pharmacodynamics and psychosocial factors might influence the Response to cardiac
rehabilitation in HF
response to pharmacological agents, device therapy and cardiac
Challenges and opportunities
rehabilitation in patients with heart failure. In this Review, we discuss
the similarities between men and women in their response to heart Conclusions

failure therapies, as well as the sex-related differences in treatment

benefits, dose–response relationships, and tolerability and safety
of guideline-directed medical therapy, device therapy and cardiac
rehabilitation. We provide insights into the unique challenges faced
by men and women with heart failure, highlight potential avenues for
tailored therapeutic approaches and call for sex-specific evaluation
of treatment efficacy and safety in future research.

1
Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 2Department of Cardiology,
University of Groningen, University Medical Centre Groningen, Groningen, Netherlands. 3Department of Medicine,
University of Mississippi School of Medicine, Jackson, MS, USA. 4Baylor Scott and White Research Institute, Dallas,
TX, USA. 5National Heart Centre Singapore and Duke-NUS Medical School, Singapore, Singapore. 6These authors
contributed equally: Janice Y. Chyou and Hailun Qin. e-mail: carolyn.lam@duke-nus.edu.sg

Nature Reviews Cardiology

Review article
Key points
•• Men and women with heart failure with reduced ejection
fraction derive similar benefits from pharmacotherapy with
renin–angiotensin system inhibitors, angiotensin receptor–neprilysin
inhibitors, β-blockers, mineralocorticoid receptor antagonists and
sodium–glucose cotransporter 2 inhibitors.
•• In patients with heart failure with preserved ejection fraction,
treatment heterogeneity by sex has been observed with angiotensin
receptor–neprilysin inhibitors and spironolactone, whereby women
seem to derive greater benefit than men.
•• Optimal doses of renin–angiotensin–aldosterone system
inhibitors and β-blockers might be lower in women than in men,
whereas adverse effects, such as dry cough and angio-oedema with
angiotensin-converting enzyme inhibitors, might be more common in
women than in men.
•• Among patients with left bundle branch block, women derive greater
benefit from cardiac resynchronization therapy at a shorter QRS
duration for reducing mortality than men.
•• In relation to the patient-oriented outcomes of quality of life and
functional status, women derive similar benefits from baroreceptor
activation therapy but less benefit from mitral valve intervention
compared with men.
•• Women with heart failure might derive greater benefit from cardiac
rehabilitation than men but have lower rates of enrolment and
adherence.
Introduction
The sex-related differences in heart failure (HF) are well known1,2. Tra-
ditional risk factors such as hypertension, diabetes mellitus, obesity
and smoking have a more potent influence on the risk of HF in women
than in men3–7. Additional sex-specific risk factors in women are related
to sex hormones, pregnancy and gestational complications, propen-
sity and treatment for breast cancer, as well as autoimmune diseases
and the associated inflammatory and immune system milieu8. HF in
women is marked by pathophysiological predominance of endothelial
inflammation and microvascular dysfunction compared with HF in
men9–11. The epidemiology of HF is notable for a higher prevalence of
HF with preserved ejection fraction (HFpEF) in women, higher preva-
lence of non-ischaemic cardiomyopathy among women with HF, female
preponderance in Takotsubo cardiomyopathy, and the sex-specific
entity of peripartum cardiomyopathy12–14. Compared with men with
HF, women with HF are generally older, more likely to be physically
frail, more symptomatic and have worse self-reported health status,
yet better survival15,16. Therefore, although among patients with HF,
women outlive men, their additional years of life are of poorer quality17.
Extensive research has been dedicated to understanding these
sex-related differences in epidemiology, risk factors, clinical char-
acteristics and outcomes in HF, but investigations in the past decade
have shed light on an often-overlooked aspect: the influence of sex on
treatment responses. In this Review, we comprehensively evaluate the
current literature on sex-related differences in treatment response in
Nature Reviews Cardiology
patients with HF. By examining studies focused on the efficacy and
safety of pharmacological interventions, device-based therapies
and cardiac rehabilitation (Fig. 1), we provide insights into the unique
challenges faced by male and female patients with HF and highlight
potential avenues for tailored therapeutic approaches.
Response to pharmacological therapy for HF
The cornerstone of HF guideline-directed medical therapy (GDMT) in
both men and women includes renin–angiotensin system (RAS) inhibi-
tors or angiotensin receptor–neprilysin inhibitors (ARNI), β-blockers,
mineralocorticoid receptor antagonists (MRAs) and sodium–glucose
cotransporter 2 (SGLT2) inhibitors18–20. Sex-specific differences in
anatomy and physiology can influence the pharmacokinetics and
pharmacodynamics of these HF medications21,22.
Sex-related differences in pharmacokinetics and
pharmacodynamics
Sex-related differences exist in the pharmacokinetics of HF medica-
tions, including drug absorption, distribution, metabolism and elimina-
tion (Fig. 2). For drug absorption, women have a higher gastric pH and
slower gastric emptying time than men, which can delay and/or reduce
the absorption of drugs that require an acidic environment21. Body
composition, organ blood flow, plasma volume and protein binding all
influence how drugs are distributed throughout the body. In general,
women have lower body weight, lower total body water (intracellular
and extracellular) content, lower plasma volume and smaller organ
size than men, but have a higher proportion of body fat23. These differ-
ences might contribute to a larger volume of distribution, faster onset
and longer duration of action for lipophilic drugs in women than in
men (and, conversely, a smaller volume of distribution and relatively
higher concentrations for hydrophilic drugs in women than in men).
Sex-related differences in the activity of hepatic enzymes might also
influence treatment responses, given that many HF drugs are metab­
olized by cytochrome P450 (CYP) isoenzymes, and some CYP isoen-
zymes have been shown to differ by sex (particularly CYP3A4, which
has higher activity levels in women)24,25. Women generally have lower
renal blood flow, estimated glomerular filtration rate, and tubular secre-
tion, transport and reabsorption than men26,27. Therefore, drugs that
are primarily inactivated or excreted by the kidneys might be cleared
more slowly in women than in men.
In healthy volunteers given a single oral dose (5 mg) of the RAS inhib-
itor ramipril, women showed a higher area under the concentration–
time curve (AUC/kg) of the active metabolite ramiprilat than men28.
Plasma concentrations of the RAS inhibitor losartan were approxi-
mately two times higher in women than in men with hypertension,
but the concentrations of the active metabolites of losartan were
similar across both sexes29. Although the pharmacokinetics of the
RAS inhibitor irbesartan were not affected by sex in healthy partici-
pants, women with hypertension had higher plasma irbesartan lev-
els than men29,30. Among healthy young men and women receiving
irbesartan 75 mg for 4 weeks, which increased to 150 mg for a further
4 weeks, women had increased sensitivity to RAS modulation and
thus might require lower dosages of irbesartan than men to achieve
a similar response31.
Compared with men, women have a lower activity of the CYP2D6
enzyme, which metabolizes the β-blocker metoprolol, and thus a slower
body clearance, greater exposure and higher plasma levels of metopro-
lol after normalizing for body weight32–34. In healthy individuals receiv-
ing metoprolol 100 mg twice daily for a total of nine doses, women had
Review article

a Pharmacological therapy b Device therapy c Cardiac rehabilitation

Counselling

Autonomic Electrical conduction Mental health Education

Medication
• ACE inhibitors, nervous system • Defibrillation
ARBs, ARNI • Modulation • Pacing
• β-Blockers • Resynchronization
• MRAs Stress Physical activity
• SGLT2 inhibitors
Anatomical remodelling
• Modification Lifestyle modification
• Haemodynamic support

Women have: Anatomy:
• Lower body weight
• Lower total body water content
• Greater body fat percentages
• Smaller organ size
• Smaller body surface area
Pharmacokinetics and pharmacodynamics:
• Higher gastric pH
• Slower gastric emptying time
• Different enzyme activity levels
Cardiac electrical system: • Lower self-reported physical function
• Narrower QRS complexes • Increased prevalence of frailty
• Longer QTc interval • Increased fear of exercise
Anatomy: • More comorbidities
• Smaller LV mass and volume • Older age at heart failure diagnosis
• Thinner myocardial walls • Greater psychological burdens
• Predisposition to LV concentric remodelling
Cardiac autonomic nervous system:
• Higher resting heart rates
• Lower sympathetic activities

Fig. 1 | Sex-specific considerations in heart failure therapy. Women are under-
represented in randomized clinical trials and some therapies for heart
failure are underutilized in women. Encouragingly, these gaps have gradually
narrowed over time. In approximately 70% of trials on heart failure therapies,
outcome data were reported by sex, and only a minority (5%) of the trials
detected significant variation in treatment effects by sex. a, The cornerstone
of heart failure guideline-directed medical therapy in both men and women
includes loop diuretics, renin–angiotensin system inhibitors, angiotensin
receptor–neprilysin inhibitors (ARNI), β-blockers, mineralocorticoid
receptor antagonists (MRAs) and sodium–glucose cotransporter 2 (SGLT2)
inhibitors. Sex-related differences in anatomy and physiology can influence the
pharmacokinetics and pharmacodynamics of heart failure medications.
b, The three major domains of therapeutic targets for device therapies in heart
failure are the electrical conduction system, anatomical remodelling and the
autonomic nervous system. Therapeutic interventions have primary targets
but can have additional effects on other domains. c, Cardiac rehabilitation is a
comprehensive non-pharmacological intervention that is underutilized among
women and adherence is particularly low in women. ACE, angiotensin-converting
enzyme; ARB, angiotensin-receptor blocker; LV, left ventricular.

higher maximum plasma concentrations (146 ng/ml versus 85.5 ng/ml)
and AUC values (867 µg/h/l versus 417 µg/h/l) of metoprolol than men32.
Similarly, a clinical trial simulation model found that, after receiving
100 mg of metoprolol, healthy men had a faster metoprolol absorption
and clearance rates than women35. The pharmacokinetics of 100 mg of
metoprolol in men were roughly similar to the pharmacokinetics
of 50 mg of metoprolol in women35.
Importantly, in prospective, randomized, controlled trials (RCTs)
assessing GDMT in patients with HF, achieved doses of ARNI 36,37,
β-blockers38 and vericiguat39 were similar between men and women.
Therefore, pharmacokinetic and pharmacodynamic differences
between men and women do not seem to translate into clinically mean-
ingful differences in achievable doses of GDMT for HF, at least in the
context of prospective clinical trials.
Sex-related differences in treatment benefit with GDMT
Although sex differences in the response to pharmacological HF ther-
apy are important to consider, the similarities are equally important.
In the big picture, GDMT for HF with reduced ejection fraction (HFrEF)
is strongly indicated in both men and women on the basis of consist-
ent overall treatment benefits in both sexes demonstrated in large
outcomes trials40–47, including for angiotensin-converting enzyme
(ACE) inhibitors47, angiotensin-receptor blockers (ARBs)48, ARNI42,
β-blockers49, MRAs50, SGLT2 inhibitors44,51 and ivabradine52. Similarly,
in patients with HFpEF, no significant treatment heterogeneity by sex
has been observed for the primary outcomes in large clinical trials
of ACE inhibitors or ARBs53–55, or SGLT2 inhibitors56 (Fig. 3; Table 1).
However, in the CHARM programme, women seemed to derive benefit
from treatment with the ARB candesartan up to a higher left ventricular
ejection fraction (LVEF) range than men57.
A significant differential treatment response between men and
women was found in two trials in patients with HF with LVEF ≥45%. In the
PARAGON-HF trial36, sex was an independent treatment effect modifier
(unadjusted P for interaction 0.017), wherein women derived greater
benefit from sacubitril–valsartan versus valsartan for the primary com-
posite outcome of total HF hospitalizations and cardiovascular death
(rate ratio for the primary outcome 0.73, 95% CI 0.59–0.90) compared
with men (rate ratio 1.03, 95% CI 0.84–1.25). However, men had a greater
improvement in the Kansas City Cardiomyopathy Questionnaire clini-
cal summary score than women in response to sacubitril–valsartan
treatment, and similar improvements in New York Heart Association
(NYHA) class and renal function were observed between women and
men36. No sex-related differences in the effect of spironolactone on
the primary composite outcome (death from cardiovascular causes,
aborted cardiac arrest or HF hospitalization) were found in the overall
TOPCAT population (P for interaction 0.99)58. However, when restricted
to the TOPCAT-Americas cohort (which included only the participants
from Argentina, Brazil, Canada and the USA), sex was found to signifi-
cantly modify the treatment effect of spironolactone on all-cause death
(P for interaction 0.024); when compared with placebo, spironolactone
reduced all-cause death in women (by 34%), but not in men59.
In the PARAGON-HF trial36, sex-specific spline analyses of treat-
ment effect across the LVEF spectrum showed that the benefit of
sacubitril–valsartan treatment seemed to extend to a higher LVEF
range in women than in men, both for the primary composite end point
and for total HF hospitalizations (Table 1). By contrast, in men, the

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Higher in men Fig. 2 | Sex-related differences in

Factors affecting drug distribution
and metabolism
• Body surface area, organ size and
blood flow
• Total body water content and
plasma volume
• Volume of distribution for
water-soluble drugs
Factors affecting drug distribution
and metabolism
• Cardiac output, lung volume
• Functional capacity
• Levels of CYP1A2, CYP2D6, CYP2E1
enzyme activity
• Levels of UGTs, methyltransferase,
sulfotransferase
Factors affecting drug elimination
• Liver metabolism
• Renal blood flow, eGFR
• Tubular secretion and reabsorption
Factors affecting drug absorption
• Gastric acid secretion and gastric
emptying
• Gastrointestinal transit time and rate
Drug
therapy
Higher in women
Factors affecting drug metabolism
• CYP2A6, CYP2B6, CYP3A4
enzyme activity
• Xanthine oxidase,
N-acetyltransferases
Factors affecting drug elimination
• Elimination half-life
Factors affecting drug distribution
• Body fat content
• Volume of distribution for
lipophilic drugs
pharmacokinetics. In general, compared
with men, women have lower body weight,
total body water content and cardiac output,
higher gastric pH and slower gastric emptying
time, smaller organ size and body surface
area, and greater body fat percentages, all of
which affect the absorption and distribution
of drugs. The sex-specific differences in the
activity of metabolizing enzymes in the liver
and the lower glomerular filtration rate in
women might also affect drug elimination.
CYP, cytochrome P450; eGFR, estimated
glomerular filtration rate; UGTs, uridine
diphosphate glucuronosyltransferases.

drug was only beneficial in those with a lower LVEF36. In the TOPCAT
trial60, the interaction between treatment and LVEF (stronger benefit
in patients with a lower LVEF) for the primary outcome also seemed to
differ by sex, wherein women across the LVEF spectrum benefited from
spironolactone treatment, whereas in men, the benefit was limited
to those with a lower LVEF (P for interaction 0.077). A similar pattern
was observed in the CHARM-Preserved trial with candesartan for the
primary composite outcome of first occurrence of HF hospitalization
or cardiovascular death57. These observed sex-related differences in
treatment response across the LVEF spectrum in patients with HF, which
were consistent across different neurohormonal drugs (ARNI, MRAs
and ARBs), have been postulated to be related to known sex differences
in cardiac remodelling with age and risk factors such as hypertension.
Greater concentric cardiac remodelling in women resulted in smaller
left ventricular volumes and higher LVEF (higher stroke volume for a
given left ventricular end-diastolic volume) in women than in men61.
Indeed, in the general population, the distribution of LVEF is shifted
towards higher values in women than in men16,62,63, with a normal LVEF in
older women being closer to 60% compared with 55% in men. Therefore,
women with HF and a LVEF of 50% have more adverse cardiac remodel-
ling or contractile dysfunction than men, and thus might derive more
benefit from neurohormonal inhibitor therapies whose mechanism
of action is promoting reverse cardiac remodelling64. Indeed, in the
PARAMOUNT trial65, women with HFpEF had greater systolic dysfunc-
tion (lower tissue S′ velocity), despite having a higher LVEF, than men
with HFpEF.
Important sex-related differences in the response to pharma-
cological HF therapy have also been shown with digoxin. A post hoc,
sex-specific subgroup analysis of the DIG study66 found that treatment
with digoxin significantly increased all-cause mortality among women
but not among men (P for interaction 0.034). Women had greater serum
digoxin concentrations than men at 1 month after treatment initiation
(1.05 ng/ml versus 0.96 ng/ml; P = 0.003), and serum digoxin concen-
trations exceeding the upper limit of therapeutic range (>2.0 ng/ml)
were found in 4% of women, twice the percentage found in men67. How-
ever, the serum digoxin concentration was only tested in a subgroup
of patients in the DIG study, among whom only 20% were women, and
thus statistical power was insufficient for further sex-specific analyses.
Although the sex-related differences described above are nota-
ble, some of these findings are from post hoc subgroup analyses of
trials that had neutral results for their primary outcome analyses
(PARAGON-HF, TOPCAT and CHARM-Preserved)36,57,58. Furthermore,
the overwhelming evidence from large clinical trials of neurohormonal
agents in patients with HF across the LVEF spectrum indicate similar
effect modification by LVEF in men and women (greater benefit at
lower LVEF) for the primary end point, calling into question the clini-
cal significance of sex-related differences in component or secondary
end points. Conversely, the under-representation of women in clinical
trials, especially in smaller HF studies (CONSENSUS68, US Carvedilol
HF study69 and RALES70) might limit the ability to detect sex-related
differences by interaction testing.
In aggregate, the evidence suggests that sex modifies the response
to ARNI and spironolactone in patients with HFpEF. Indeed, there are
now sex-specific considerations for GDMT in patients with HFpEF in
the most recent American College of Cardiology Expert Consensus
statement19, which recommends that the use of ARNI and spirono-
lactone be considered across the entire LVEF spectrum in women
with HFpEF.
Sex-related differences in dose–response relationships with
GDMT
In a large, prospective, multinational, observational HF study con-
ducted in patients across Europe, the lowest risk of the composite of
hospitalization for HF or all-cause death was observed in women with
HFrEF who had received ~40% of the recommended target doses of
ACE inhibitors and ARB, whereas in men with HFrEF, the lowest risk
was found in those who achieved 100% of the recommended target
doses71. For β-blockers, women with HFrEF had the lowest risk of the
composite outcome at ~60% of the recommended target doses, whereas
the lowest risk in men with HFrEF was observed at 100% of the target
doses71. These findings were validated in a separate prospective, mul-
tinational, observational HF study in patients across Asia71. Although

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hypothesis-generating, these observational, non-randomized results
should be interpreted with caution.
Two RCTs compared the effects of a low dose versus a high dose of
an ACE inhibitor and an ARB on clinical outcomes in patients with HFrEF.
The ATLAS trial72 compared a low dose (2.5–5.0 mg per day) versus a
high dose (32.5–35 mg per day) of lisinopril in patients with HFrEF.
Patients receiving the higher dose had a significant 12% lower risk of
death or hospitalization for any reason and 24% fewer hospitalizations
for HF. Interestingly, no additional benefit of the high dose of lisinopril
was found in women compared with the low dose, and the positive
results were completely driven by the effects seen in men. The HEAAL
trial73 compared the effects of losartan 50 mg versus losartan 150 mg
on death or HF hospitalization in patients with HFrEF. Patients who
were assigned to the higher dose had a significantly lower event rate
than those assigned to the lower dose, and this result was completely
driven by a beneficial effect of the higher dose in men but not in women
(P for interaction 0.018)73.
In aggregate, these data suggest that the optimal doses of ACE
inhibitors or ARBs and β-blockers might be lower in women than in
men with HF. However, given that the trials that formed the evidence
base for HF management guideline recommendations used the same
target doses for men and for women, sex-specific target doses cannot
be recommended at this time. Nonetheless, future trials should be
designed with the consideration of potential sex-specific differences
in target doses to best optimize the benefit–risk ratio in both women
and men with HF.
Tolerability of GDMT in men and women
Women are known to experience more adverse effects from cardiovas-
cular medications and generally have a higher rate of hospital admis-
sions for adverse drug reactions than men74–77. The increased risk of
adverse drug reactions in women might be attributable to sex-related
differences in the pharmacokinetics and pharmacodynamics of the
drug treatments, resulting in higher doses of drugs per kilogram of
body weight in women than in men; to biological differences, such as
longer corrected QT interval in women or differences in circulating
hormone levels; or to greater polypharmacy in women, with the asso-
ciated increased potential for drug–drug interactions76,78. Indeed, a
report published in 2023 highlighted that more women than men with
HF were prescribed medications that might cause or exacerbate HF
(such as inhaled sympathomimetics, diltiazem and antidepressants)79.
Despite a 1.5 to 1.7 times higher likelihood of adverse drug reactions
in women than in men80, only 11 (7%) clinical trials of pharmacological HF
therapies have found sex-specific adverse drug reactions21,74,81. Among
them, three studies found that women have a higher risk of adverse reac-
tions with ACE inhibitors81. In a post hoc analysis from the SOLVD trial82,
dry cough after taking enalapril occurred approximately 1.4 times more
frequently in women than in men. In a retrospective cohort study from
the USA, the cumulative incidence of new-onset angio-oedema with
ACE inhibitor treatment in patients with HF was more than twofold
higher in women than in men83. No sex-related differences in adverse
drug reactions were observed in clinical trials of ARBs and β-blockers81.
A pooled analysis of three landmark trials of MRAs (RALES, EMPHASIS-HF
and TOPCAT) showed no sex-specific differences in adverse drug reac-
tions (all P for interaction >0.1), including worsening renal function and
hyperkalaemia43. Moreover, a small study including 134 patients with HF
found that a comparable number of men and women treated with
spironolactone withdrew from the study because of hyperkalaemia or
worsening renal function (and gynaecomastia in men)84. In the DAPA-HF
and DELIVER trials, which assessed SGLT2 inhibitors, men treated with
dapagliflozin were more likely to experience severe adverse events,
but women were more likely to experience adverse events leading to

Men Similarities between men and women Women

• Sacubitril–valsartan reduced the risk
of hospitalization for heart failure to a
lesser degree in men with HFpEF
than in women with HFpEF
• Spironolactone did not reduce
all-cause death in men with HFpEF,
but reduced all-cause death in
women with HFpEF
• Similar response to ACE inhibitors,
ARBs, ARNI, β-blockers, MRAs and
SGLT2 inhibitors in HFrEF
• Similar response to ACE inhibitors,
ARBs and SGLT2 inhibitors in HFpEF
• Largely similar in achieved dose and
adherence
• Predominantly similar in adverse
drug reactions
• Higher mortality with digoxin
• Lower optimal dose for ACE inhibitors,
ARBs and β-blockers
• Higher incidence of dry cough and
angio-oedema with ACE inhibitors
• Lower rate of enrolment and adherence
in cardiac rehabilitation
• Might benefit more from cardiac
rehabilitation

Fig. 3 | Sex-based considerations in the response to pharmacological and
non-pharmacological therapies for heart failure. Men and women with
heart failure with reduced ejection fraction (HFrEF) have similar treatment
response to angiotensin-converting enzyme (ACE) inhibitors or angiotensin-
receptor blockers (ARBs), angiotensin receptor–neprilysin inhibitors (ARNI),
β-blockers, mineralocorticoid receptor antagonists (MRAs) and sodium–glucose
cotransporter 2 (SGLT2) inhibitors. No evidence of treatment heterogeneity
by sex has been observed for the primary outcomes of large clinical trials of
ACE inhibitors or ARBs and SGLT2 inhibitors in patients with heart failure
with preserved ejection fraction (HFpEF). However, the responses to ARNI
and spironolactone therapies in men and women with HFpEF are different.
The achieved dose and adherence to heart failure guideline-directed medical
therapies are largely similar in men and women. Women have lower optimal
doses of ACE inhibitors, ARBs and β-blockers than men. Adverse drug reactions
are predominantly similar in both sexes. However, women have a higher
incidence of dry cough and angio-oedema with ACE inhibitors than men.
In general, women have lower rates of enrolment into clinical trials and treatment
adherence than men, but women might derive more benefit from cardiac
rehabilitation than men.

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Table 1 | Landmark clinical trials of drug therapy in men and women with HF

Trial (year) Drug Number Mean Mean Primary end point RR or HR (95% CI) P for interaction
of patients age LVEF
(% women) (years) (%) Men Women Sex Treatment Treatment,
or sex and sex and
LVEF LVEF

ACE inhibitors
CONSENSUS (1987)a Enalapril 253 (30) 71 ≤35 Mortality 0.41 (0.16–0.58) 1.01 (0.59–1.73) NA NA NA
(refs. 68,231)
SOLVD-Treatment Enalapril 2,569 (20) 61 25 Mortality Favourable treatment outcomes in NA NA
(1991)232,233 both sexes, but the effect seemed
to be greater in men
Meta-analysis of ACE inhibitors 7,105 (22) NA NA Mortality 0.76 (0.65–0.88) 0.79 NA NA NA
32 RCTs (1995)47 (0.59–1.06)
Mortality or 0.63 (0.55–0.73) 0.78 NA NA NA
hospitalization (0.59–1.04)
Angiotensin-receptor blockers
Val-HeFT (2005)234 Valsartan 5,010 (20) 63 27 Mortality and 0.84 (0.67–1.06) 0.87 NS NA NA
morbidity (0.78–0.98)
Non-fatal morbidity 0.74 (0.56–0.99) 0.72 NS NA NA
(0.61–0.84)
Hospitalization 0.78 (0.59–1.04) 0.71 NS NA NA
for HF (0.60–0.83)
CHARM Candesartan 7,599 (32) 66 39 Cardiovascular 0.84 (0.76–0.92) 0.84 0.9939 0.0146b; 0.0649
programme death (0.73–0.97) 0.73c
(2007)53,57
Hospitalization Reference 0.83
for HF group (0.76–0.91)
Mortality Reference 0.77 NA 0.65c NA
group (0.69–0.86)
I-PRESERVE Irbesartan 4,128 (60) 71 60 Mortality or 0.96 (0.83–1.12) 0.94 0.78 NA NA
(2008)54,235 hospitalization (0.82–1.08)
for specified
cardiovascular cause
Angiotensin receptor–neprilysin inhibitors
PARADIGM-HF Sacubitril– 8,399 (22) 64 29 Cardiovascular Significant Significant 0.63 NA NA
(2014)42 valsartan death or benefitd benefitd
hospitalization
for HF
Cardiovascular Significant Trend towards 0.92 NA NA
death benefitd benefitd
PARAGON-HF Sacubitril– 4,769 (52) 72 57 Cardiovascular 1.02 (0.83–1.24) 0.73 0.0225 NA NA
(2020)36 valsartan death or (0.60–0.90)
hospitalization
for HF
Mortality 0.95 (0.77–1.17) 0.99 0.8703 NA NA
(0.79–1.24)
Pooled analysis Sacubitril– 13,195 (33) 67 39.7 Cardiovascular 0.86 (0.79–0.93) 0.79 0.3452 0.0424b 0.032
(PARADIGM and valsartan death or (0.70–0.91)
PARAGON-HF) hospitalization
(2020)57,236 for HF
β-Blockers
US Carvedilol HF Carvedilol 1,094 (23) 58 22 Mortality 0.41 (0.22–0.80) 0.23 NS NA NA
Study (1996)69 (0.07–0.69)
CIBIS II (2001)237 Bisoprolol 2,647 (19) 61 28 Mortality Reference 0.64 NA NA NA
group (0.47–0.86)
MERIT-HF Metoprolol 3,991 (22.5) 64 28 Mortality Risk reduction Risk reduction NS NA NA
(1999)49,238 18% 21%
COPERNICUS Carvedilol 2,289 (20) 63 20 Mortality 0.65 0.65 NS NA NA
(2001)239

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Table 1 (continued) | Landmark clinical trials of drug therapy in men and women with HF

Trial (year) Drug Number Mean Mean Primary end point RR or HR (95% CI) P for interaction
of patients age LVEF
(% women) (years) (%) Men Women Sex Treatment Treatment,
or sex and sex and
LVEF LVEF

β-Blockers (continued)
Pooled data β-Blockers 8,927 (NA) NA NA Mortality Similar survival benefit in men and women
(CIBIS II, MERIT-HF
and COPERNICUS)
(2002)49
MRAs
RALES (1999)70 Spironolactone 1,663 (27) 65 25 Mortality Significant Significant NS NA NA
reductiond reductiond
EMPHASIS-HF Eplerenone 2,737 (22) 69 26 Cardiovascular Significant Significant 0.36 NA NA
(2011)50 death or hospitaliza­ reductiond reductiond
tion for HF
TOPCAT- Spironolactone 1,767 (49.9) 71 58 Cardiovascular 0.85 (0.67–1.08) 0.81 0.84 NA NA
Americas (2019)59 death, aborted (0.63–1.05)
cardiac arrest, or
hospitalization
for HF
Mortality 1.06 (0.81–1.39) 0.66 0.024 NA NA
(0.48–0.90)
Pooled analysis MRAs 6,167 (31) 69 35.3 Cardiovascular 0.70 (0.63–0.77) 0.71 0.8089 0.0074b 0.0682
(RALES, death or (0.60–0.84)
EMPHASIS-HF hospitalization
and TOPCAT- for HF
Americas) (2020)57
SGLT2 inhibitors
DAPA-HF Dapagliflozin 4,744 (23) 66 31 Cardiovascular 0.73 (0.63–0.85) 0.79 0.67 NA NA
(2019)44,240 death or (0.59–1.06)
worsening HF
EMPEROR- Empagliflozin 3,730 (24) 67 27 Cardiovascular 0.80 0.59 NS NA NA
Reduced (2020)51 death or (0.68–0.93) (0.44–0.80)
hospitalization
for worsening HF
EMPEROR- Empagliflozin 5,988 (45) 72 54 Cardiovascular 0.81 (0.69–0.96) 0.75 0.536 Men, 0.878
Preserved (2022)241 death or (0.61–0.92) 0.402b;
hospitalization women,
for worsening HF 0.587b
DELIVER (2022)242 Dapagliflozin 6,263 (44) 71 54 Cardiovascular 0.82 (0.71–0.96) 0.81 NS NA NA
death or (0.67–0.97)
worsening HF
Pooled analysis Dapagliflozin 11,007 (35) 70 44 Cardiovascular 0.78 (0.70–0.86) 0.80 0.77 0.71b 0.86
(DAPA-HF death or (0.68–0.94)
and DELIVER) worsening HF
(2022)85,243
Meta-analysis (five SGLT2 20,725 (36) NA NA Cardiovascular 0.78 (0.73–0.85) 0.74 0.45 NA NA
RCTs) (2022)56 inhibitors death or (0.66–0.84)
hospitalization
for HF
Digoxin
DIG (1997)66,244 Digoxin 6,800 (22) 63 28 Mortality 0.93 (0.85–1.02) 1.23 0.014 NA NA
(1.02–1.47)
DIG-PEF (2006)245 Digoxin 988 (41) 67 55 Mortality Reference 0.59 NA NA NA
group (0.43–0.82)
Hospitalization Reference 1.06 NA NA NA
for HF group (0.75–1.51)
ACE, angiotensin-converting enzyme; HF, heart failure; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NA, not available; NS, not significant; RCT,
randomized controlled trial; RR, relative risk; SGLT2, sodium–glucose cotransporter 2. aAt 6 months, 66 of the 178 men and 22 of the 75 women had died; enalapril reduced mortality by 51%
in men and 6% in women (small number of women and wide confidence intervals). bInteraction between treatment and LVEF. cInteraction between sex and LVEF. dResults of sex subgroup
analyses were reported in forest plots; quantitative data were not provided.

Nature Reviews Cardiology

Review article
study drug cessation as well as study drug cessation for any reason85.
No sex-related differences in adverse events were observed in the
dapagliflozin group (all P for interaction >0.1)85.
Notably, for the vast majority of HF clinical trials, sex-stratified
adverse events were not reported, and this aspect has not improved
over time81. Data safety monitoring in future clinical trials in patients
with HF should account for potential sex-related differences in adverse
events and they should be reported in a sex-disaggregated manner86.
Response to device therapy for HF
Sex-related differences in device therapies for HF might relate to dif-
ferences in biology, prevalence of associated conditions, therapeutic
responses, adverse procedural events and systemic barriers in thera-
peutic adoption. Therapeutic targets for device-based therapies for HF
fall into three major domains: the cardiac electrical system, anatomical
remodelling and the autonomic nervous system (Fig. 1). Sex-based
considerations in HF device therapy incorporate domain-specific bio-
logical differences as well as cross-domain differences in risk factors,
pathophysiology, epidemiology, outcomes, symptoms, quality of life
(QoL), functional capacity and challenges in clinical trial representation
and therapeutic adoption (Fig. 4).
Sex-related biological differences
Cardiac electrical conduction system. Sex differences exist in cellular
electrophysiology and in surface electrocardiography. On the cellular and
tissue level, sex differences exist in the expression of ion channels,
which are further modulated by sex hormones. Human cardiac tissues
from donor hearts revealed reduced expression of potassium channel
subunits involved in cardiac repolarization in the heart of female indi-
viduals compared with the heart of male individuals87. Sex hormones
(most notably oestradiol and testosterone) differentially influence
the ion channels, with implications for cardiac repolarization and
excitability88. On surface electrocardiography, women have a shorter
PR interval, a shorter effective refractory period of the atrioventricular
node, and a narrower QRS complex than men89–91. QT intervals cor-
rected for resting heart rates are approximately 20 ms longer in women
than in men92. Significant sex differences in the QTc interval start to be
seen after puberty, persist through adulthood but attenuate in older
age, suggestive of the influence of sex hormones92–94.
ain differe
-dom nc
oss es
Cr Cardiac electrical conduction
ic al differe
g nc
olo es • Cardiac resynchronization therapy
Bi • Implantable cardioverter–defibrillator
i ce the rap
ev ie
D
• Narrower QRS complexes
Domains of • Longer QTc (premenopause)
therapeutic
target
• Risk factors • Pathophysiology
• Epidemiology • Outcomes
Fig. 4 | Factors influencing sex-related differences in device therapies for
heart failure. Sex-based considerations in response to device therapy for heart
failure incorporate considerations of domain-specific baseline differences as
Nature Reviews Cardiology
Anatomical size and anatomical remodelling. Sex-related differences
exist in anatomical size and anatomical remodelling. In the general pop-
ulation, women have smaller left ventricular cavities, greater diastolic
dysfunction, and more concentric hypertrophy on echocardiography
studies than men95–97. Cardiac MRI data reveal that left ventricular vol-
umes indexed to body surface area are smaller in women than in men,
and that women have higher LVEF due to a higher stroke volume for a
given left ventricular end-diastolic volume61. Cardiac remodelling in
the setting of HF is also influenced by older age and higher proportions
of non-ischaemic aetiology in women than in men12.
Cardiac autonomic nervous system. Premenopausal women have
higher resting heart rates than men, consistently seen between the ages
of 20 and 50 years and attenuating thereafter93,98. In healthy volunteers
aged <40 years, women had lower sympathetic activity (quantified
by low-frequency component of heart rate variability) than men99.
In a middle-aged population (age 50 ± 6 years), baroreflex sensitivity
was lower in women without oestrogen therapy than in men, but was
not significantly different between women taking oestrogen therapy
and men100,101.
Sex-related differences in response to device therapies
Implantable cardioverter–defibrillator. Implantable cardioverter–
defibrillators (ICDs) are indicated for primary and secondary preven-
tion of sudden cardiac death102,103. Among eligible patients with HF,
ICDs are underutilized in all sexes104,105, but even more so in women16,
even after accounting for age39 and comorbidities106–111. Low referral
rates, financial concerns and inadequate knowledge about ICDs have
been reported as potential reasons for ICD underutilization104,112,113. ICD
counselling and strategies to improve referral might help to address
sex-related differences in utilization. Among patients with HF who are
eligible for an ICD, women received ICD counselling less frequently
than men (19.3% versus 24.6%; P < 0.001); however, among those who
received counselling, women and men received an ICD at similar
rates (63.1% versus 62.3%)114, suggesting that equitable ICD counsel-
ling might be a potential tool to address sex-related disparities in
ICD utilization. The use of a screening tool115 or electronic health
record alert116 has been shown to improve referral of ICD-eligible
patients, among whom point-of-care alerts through electronic health
Anatomical Autonomic modulation
• LV assist device • Baroreflex activation therapy
• Mitral valve procedure • Vagal nerve stimulation
• Smaller LV mass • Higher resting heart rates
• Smaller LV volume (premenopause)
• Thinner myocardial walls • Lower sympathetic activity
• Predisposition to LV concentric (healthy volunteers,
remodelling premenopause)
• Symptoms • Therapeutic adoption
• Quality of life • Clinical trial representation
well as cross-domain differences in risk factors, pathophysiology, epidemiology,
outcomes, symptoms, quality of life, functional capacity and challenges in
clinical trial representation and therapeutic adoption. LV, left ventricular.
Review article
records had a modestly greater effect in improving referral rates in
women than in men, mitigating the sex-based gap otherwise seen
with under-referral of women (in the study comparison group without
electronic alert)116.
In landmark studies of the efficacy and indication for ICD thera-
pies for primary prevention in patients with HFrEF, women comprised
only 10–29% of the study populations117–123 (Table 2). Sex-specific data
from the MADIT II trial118 and secondary analyses of the MUSTT124,
SCD-HeFT125 and DEFINITE126 trials found no significant sex-specific
differences in the benefit derived from ICD. Although pooled analyses
of several landmark studies have questioned the benefit of ICDs for
reducing all-cause mortality in women127–129, a definitive interpreta-
tion of findings from these pooled analyses127–129 has been difficult
given the heterogeneity of the included trials, particularly with regard
to the length of follow-up and the study population composition
(especially concerning ischaemic versus non-ischaemic aetiology and
concomitant use of cardiac resynchronization therapy (CRT)).
A retrospective analysis of 14 European registries of ICD use for
primary prevention revealed that women had lower mortality and fewer
appropriate ICD shocks than men after adjusting for age, ischaemic
cardiomyopathy, LVEF ≤25% and concomitant CRT130. In a comparison
of an older US patient population from the National Cardiovascular
Data Registry of ICD for primary prevention with propensity-matched
patients from the GWTG-HF registry without ICD, similar rates of reduc-
tion in mortality were found in men and women with ICDs compared
with matched counterparts without ICDs, highlighting the similar
benefit of ICD treatment in both sexes131. Appropriate shock was a
strong predictor of mortality in both men (HR 2.61, 95% CI 1.82–3.74;
P < 0.0001) and women (HR 5.99, 95% CI 2.75–13.02; P <0.0001)132.
Of note, women received fewer inappropriate therapies than men
(9.2% versus 13.5%; P = 0.006)132.
Finally, although the initial RCTs establishing efficacy of ICDs
as primary prevention therapy in patients with HF were based on
transvenous ICD systems, the subcutaneous ICD system is a contem-
porary alternative for ICD therapy in individuals without need for
pacing. Data from the PRAETORIAN trial133 established that the sub-
cutaneous ICD was non-inferior to the transvenous ICD with respect
to device-related complications and the number of inappropriate
shocks. The UNTOUCHED trial134 demonstrated high safety and effi-
cacy, and a low rate of inappropriate shocks with contemporary
second-generation and third-generation subcutaneous ICD systems.
No significant differences in survival or inappropriate shock rates were
seen between men and women in the IDE or EFFORTLESS registries135.
Cardiac resynchronization therapy. CRT can be part of a pacemaker
system (CRT-P) or part of a defibrillator system (CRT-D). Guideline
recommendations for CRT are currently sex-neutral. In HFrEF, CRT
is indicated in patients with NYHA class II, III or ambulatory IV HF
despite optimal pharmacological treatment, LVEF ≤35%, left bundle
branch block (LBBB) with a prolonged QRS duration of ≥150 ms, and in
sinus rhythm as a class I recommendation in both the American136 and
European137 guidelines. Class IIa recommendations in the American
guidelines136 include a QRS duration of 120–149 ms in sinus rhythm,
or atrial fibrillation that requires ventricular pacing or meets CRT
criteria; atrioventricular nodal ablation or pharmacological rate con-
trol will allow near complete ventricular pacing with CRT. Class IIa
recommendations in the European guidelines137 include a QRS duration
of 130–149 ms in sinus rhythm or ≥130 ms in atrial fibrillation with a
strategy in place to ensure biventricular pacing.
Nature Reviews Cardiology
Landmark RCTs evaluating CRT for HFrEF collectively established
the benefits of CRT in improving clinical outcomes and reducing mor-
tality, HF hospitalizations and HF symptoms, and improving QoL,
6-min walking distance (6MWD)138–142 and left ventricular reverse
remodelling143 (Table 3). However, definitive RCT-level evidence for
sex-specific treatment response to CRT is not feasible because none of
the studies was powered to assess treatment response by sex specifi-
cally given that women were under-represented (17–33% of the study
population in the landmark CRT trials)138–144. Although men and women
both benefit from CRT, data from post hoc analyses and registry studies
suggest that women might derive more benefit than men, in terms of
both clinical outcomes145–147 and left ventricular reverse remodelling148.
Baseline patient characteristics in trials of CRT are notable, with women
having shorter stature, smaller left ventricular end-diastolic diameter,
more LBBB and more non-ischaemic cardiomyopathy (less often ischae-
mic cardiomyopathy) than men144,145,149. An analysis of the MADIT-CRT
study148 identified six baseline characteristics predictive of a favourable
CRT response: female sex, LBBB, no previous myocardial infarction,
BMI <30 kg/m2 and smaller left atrial volume index. However, in a
meta-analysis of five RCTs (CARE-HF, MIRACLE, REVERSE, MIRACLE
ICD and RAFT), QRS duration was the only independent predictor
of a reduction in all-cause mortality with CRT, and QRS duration and
height were independent predictors of CRT benefits in the composite
outcome of all-cause mortality or HF hospitalization149.
The extent and mitigation of left ventricular electrical delay are
central to the considerations for CRT150,151. Longer QRS duration in
LBBB (especially ≥150 ms) is associated with increased survival with
CRT-D in both sexes147. Among recipients of CRT-D in large national
databases, women with LBBB had even greater mortality reduction
than men with LBBB147,152. Women with LBBB derive benefit at a shorter
QRS duration than men with LBBB153,154, prompting ongoing discus-
sions for further sex-specific considerations for recommendations
for CRT155,156. The AdaptResponse RCT utilized sex-specific inclusion
criteria for QRS duration, which is likely to have contributed to the high
portion of women (43.4%) in the trial157, paving the way for utilization
of sex-specific criteria158 in future clinical trials and in clinical practice.
With regard to the aetiology of the cardiomyopathy, a meta-
analysis revealed that, whereas no sex-based differences were seen in
CRT recipients with ischaemic cardiomyopathy, among CRT recipients
with non-ischaemic cardiomyopathy, women had greater observed
benefit than men149. A retrospective analysis of CRT recipients with
non-ischaemic cardiomyopathy and LBBB suggests that the com-
plex interplay between QRS duration and heart size might explain
the observed sex-based differences in CRT response, in which a more
favourable CRT response (defined in this study as an increase in LVEF,
as determined by echocardiography) was seen in women, but women
also had a larger baseline index of QRS duration to heart size (with
generally smaller heart size than men), such that normalization of QRS
duration for heart size resolved the sex-based differences associated
with the response to CRT159. A subsequent study extended this concept,
noting that normalization of QRS duration to left ventricular dimension
improved the prediction of survival after CRT implantation160.
Despite the benefits and indications, CRT is under-implemented
in both men and women161–166. Estimates of European inhabitants with
HFrEF and LBBB167 qualifying for CRT and statistics of utilization of
cardiac implantable electronic devices (CIED)168 suggest that up to
two-thirds of CRT-eligible patients are not receiving CRT166. The multi-
national ESC CRT survey II noted that referral from non-implanting cen-
tres accounted for only 25% of CRT referrals, suggesting that patients
Review article

Table 2 | Clinical trials of implantable cardioverter–defibrillators in men and women with HF

Trial (year) Device Patient cohort Number of Mean Follow-up Primary Main results Interaction by sex or end
therapy patients age (months) end point point data
(% women) (years)

MUSTT EPS-guided LVEF ≤40%, CAD, 704 (10) 67 39 Cardiac EPS-guided therapy with ICD Primary end point in
(1999)117,124 antiarrhythmic NSVT and inducible arrest or reduced cardiac arrest or death comparator groups did not
therapy sustained VT at EPS death from from arrhythmia compared differ by sex; the interaction
(AAD or ICD arrhythmia with EPS-guided therapy between treatment and
if failed AAD) without defibrillator (HR 0.24, sex was not significant for
versus no 95% CI 0.13–0.45; P < 0.001) the secondary end point of
antiarrhythmic and compared with no all-cause death (P = 0.12)
therapy antiarrhythmic therapy (HR 0.27,
95% CI 0.15–0.47; P < 0.001)
EPS-guided therapy with
ICD reduced all-cause death
compared with EPS-guided
therapy without defibrillator
(HR 0.40, 95% CI 0.27–0.59;
P < 0.001) and compared with no
antiarrhythmic therapy (HR 0.45,
95% CI 0.32–0.63; P < 0.001)
MADIT II ICD or medical LVEF ≤30%, 1,232 (16) 64 20 All-cause Compared with medical No significant interaction by
(2002)118 therapy ischaemic death therapy, ICD reduced the sex for primary end point
cardiomyopathy, rate of the primary end point
previous MI (HR 0.69, 95% CI 0.51–0.93;
P = 0.016)
SCD-HeFT Placebo or LVEF ≤35%, 2,521 (23) 52 45.5 All-cause Compared with placebo, ICD P for interaction by sex for
(2005)121,125 amiodarone or ischaemic or death reduced the primary end point primary end point 0.54; ICD
ICD (on top of non-ischaemic (HR 0.77, 95% CI 0.62–0.96; versus placebo adjusted HR
conventional cardiomyopathy, P = 0.007) 0.71 (95% CI 0.57–0.88) in men
therapy) NYHA class II–III and 0.90 (95% CI 0.56–1.43)
in women; lower mortality in
women than in men; the
differences in mortality were
most accentuated in the
placebo group
DINAMIT ICD or medical LVEF ≤35%, recent 674 (24) 62 30 All-cause Similar rates of the primary end P for interaction by sex for
(2004)120 therapy MI (6–40 days), death point in the ICD and medical primary end point 0.82
heart rate ≥80 bpm, therapy groups (HR 1.08, 95%
SDNN ≤70 ms CI 0.76–1.55; P = 0.66)
IRIS ICD or medical LVEF ≤40%, recent 898 (23) 63 37 All-cause Similar rates of the primary end P for interaction by sex for
(2009)122 therapy MI (5–31 days), death point in the ICD and medical primary end point 0.85
heart rate ≥90 bpm, therapy groups (HR 1.04, 95%
with or without CI 0.81–1.35; P = 0.78)
Holter monitoring
with NSVT
≥150 bpm
DEFINITE ICD or medical LVEF ≤35%, 458 (29) 58 29 All-cause Similar rates of the primary end P for interaction by sex
(2004)119,126 therapy non-ischaemic death point in the ICD and medical (univariate) 0.11; primary
cardiomyopathy, therapy groups (HR 0.65, 95% end point HR 0.49 (95% CI
NYHA class I–III, CI 0.40–1.06; P = 0.08) 0.27–0.90; P = 0.018) in men
Holter monitoring and 1.14 (95% CI 0.50–2.64;
NSVT ≥120 bpm or P = 0.75) in women; sex
≥10 PVC/h was not an independent
predictor of primary end
point in multivariable
analysis adjusting for NYHA
class, LVEF, age and race
(P = 0.18)
DANISH ICD or no ICD LVEF ≤35%, 1,116 (27.5) 63 67.6 All-cause Similar rates of the primary P for interaction by sex 0.66;
(2016)123 non-ischaemic death end point in the ICD and primary end point HR 0.85
cardiomyopathy, non-ICD groups (HR 0.87, 95% (95% CI 0.64–1.12; P = 0.24)
NYHA class II–IV CI 0.68–1.22; P = 0.28); there in men and 1.03 (95% CI
was high background cardiac 0.57–1.87; P = 0.92) in women
resynchronization therapy (58%)
AAD, antiarrhythmic drug; CAD, coronary artery disease; EPS, electrophysiology studies; HF, heart failure; ICD, implantable cardioverter–defibrillator; LVEF, left ventricular ejection fraction;
MI, myocardial infarction; NSVT, non-sustained ventricular tachycardia; NYHA, New York Heart Association; PVC, premature ventricular complexes; SDNN, standard deviation of normal-to-
normal RR intervals (a measure of heart rate variability); VT, ventricular tachycardia.

Nature Reviews Cardiology

Review article

Table 3 | Clinical trials of cardiac resynchronization therapy in men and women with HF

Trial (year) Device Patient cohort Number Mean Follow- Primary end Main results Interaction by sex or
therapy of patients age up point end point data
(% women) (years)
MIRACLE CRT-P LVEF ≤35%, ischaemic 453 (32) 64 6 months 6MWD, QoL, Compared with no pacing, CRT Interaction with CRT
(2002)138 randomized or non-ischaemic NYHA class improved 6MWD (P = 0.005), by sex not reported in
to CRT cardiomyopathy, QoL (P = 0.001) and NYHA main manuscript
on or no NYHA class III–IV, class (P < 0.001) and reduced
pacing QRS ≥130 ms, LVEDD hospitalizations for worsening
≥55 mm, 6MWD HF (HR 0.5, 95% CI 0.28–0.88;
≤450 m P = 0.02)
COMPANION CRT-P, LVEF ≤35%, ischaemic 1,520 (33) 67 11.9–16.2 All-cause Reduced 12-month rate of the Interaction with CRT
(2004)139 CRT-D or or non-ischaemic months death or primary end point with CRT-P by sex not reported in
OMT cardiomyopathy, all-cause (HR 0.81, 95% CI 0.69–0.96; main manuscript
NYHA class III–IV, hospitalization P = 0.014) or CRT-D (HR 0.80,
QRS ≥120 ms, sinus 95% CI 0.68–0.95; P = 0.010)
rhythm, PR ≥150 ms compared with OMT
CARE-HF CRT-P or LVEF ≤35%, ischaemic 813 (27) 66 29 months All-cause CRT-P reduced the rate of the Primary end point HR
(2005)140 OMT or non-ischaemic death or primary end point compared 0.62 (95% CI 0.49–0.79)
cardio­myopathy, hospitalization with OMT (HR 0.63, 95% CI in men and 0.64 (95%
NYHA class III–IV; for cardio­ 0.51–0.77; P < 0.001) CI 0.42–0.07) in women
QRS ≥120 ms, LVEDDi vascular
≥30 mm causes
REVERSE CRT (± ICD) LVEF ≤40%, 610 (21) 63 12 months HF clinical CRT-on did not significantly Primary end point OR
(2008)143 randomized ischaemic or composite reduce the rate of the primary 0.69 (95% CI 0.43–1.11)
to CRT on non-ischaemic response end point compared with in men and 0.75 (95% CI
or off cardiomyopathy, CRT-off (OR 0.70, 95% CI 0.26–2.19) in women
NYHA class I–II, QRS 0.45–1.07; P = 0.10); CRT-on
≥120 ms, LVEDD reduced LVESVI (P < 0.0001) and
>55 mm time to first HF hospitalization
(HR 0.47; P = 0.03) compared
with CRT-off
MADIT-CRT CRT-D or LVEF ≤30%, ischaemic 1,820 (25) 65 2.4 years All-cause CRT-D reduced the rate of the P for interaction by
(2009)141 ICD cardiomyopathy death or primary end point compared sex 0.01; primary end
(NYHA class I–II) non-fatal with ICD-only (HR 0.66, 95% CI point HR 0.76 (95% CI
or non-ischaemic HF event 0.52–0.84; P = 0.001) 0.59–0.97) in men and
cardiomyopathy 0.37 (95% CI 0.22–0.61)
(NYHA class II), QRS in women
≥130 ms, sinus rhythm
RAFT CRT-D or LVEF ≤30%, ischaemic 1,798 (17) 66 40 months All-cause CRT-D reduced the rate of the P for interaction by sex
(2010)142 ICD or non-ischaemic death or HF primary end point compared 0.09
cardiomyopathy, hospitalization with ICD-only (HR 0.75, 95% CI
NYHA class II–III, 0.64–0.87; P < 0.001)
intrinsic QRS ≥120 ms
(or paced QRS
≥200 ms)
Pooled CRT-P or MIRACLE, MIRACLE 3,782 (22) 66 See All-cause Compared with no CRT (OMT, All-cause death HR 0.68
analysis CRT-D ICD, CARE-HF, individual death; ICD, back-up pacing), CRT (95% CI 0.57–0.80) in
(2013)246 versus OMT REVERSE, RAFT; trials all-cause (CRT-P or CRT-D) reduced men and 0.58 (95% CI
or ICD or see individual death or HF all-cause death (HR 0.66, 0.41–0.84) in women;
back-up trials; excluded hospitalization 95% CI 0.57–0.77) and the all-cause death or HF
pacing NYHA class I, atrial composite of all-cause death hospitalization HR 0.69
fibrillation, existing or HF hospitalization (HR 0.65, (95% CI 0.60–0.79) in
pacemaker 95% CI 0.58–0.74) men and 0.50 (95% CI
0.37–0.66) in women
Pooled CRT-D or REVERSE, MADIT-CRT, 4,076 (22) 65 See Death or HF; With LBBB and QRS ≥150 ms, CRT-D reduced clinical
analysis ICD RAFT individual death end points compared with ICD-alone in women (death
(2014)153 trials or HF, HR 0.33, 95% CI 0.21–0.52; death, HR 0.36,
95% CI 0.16–0.82) and men (death or HF, HR 0.47, 95% CI
0.37–0.59; death, HR 0.65, 95% CI 0.47–0.91)
With LBBB and QRS 130–149 ms, CRT-D reduced clinical
end points compared with ICD-alone in women (death
or HF, HR 0.24, 95% CI 0.11–0.53; death, HR 0.24, 95% CI
0.06–0.89), but not in men (death or HF, HR 0.85, 95% CI
0.60–1.21; death, HR 0.86, 95% CI 0.49–1.52)
6MWD, 6-min walking distance; CRT, cardiac resynchronization therapy; CRT-D, CRT plus defibrillator; CRT-P, CRT plus pacemaker; HF, heart failure; ICD, implantable cardioverter–defibrillator;
LBBB, left bundle branch block; LVEDD, left ventricular end-diastolic diameter; LVEDDi, LVEDD indexed for height; LVEF, left ventricular ejection fraction; LVESVI, left ventricular
end-systolic volume index; NYHA, New York Heart Association; QoL, quality of life; OMT, optimal medical therapy.

Nature Reviews Cardiology

Review article

outside university or teaching hospital settings have more limited
access to CRT169. In an analysis of a HF registry from Sweden, female
sex and advanced age were independent predictors of non-referral
for CRT161. Strategies to improve implementation of CRT are needed,
especially in eligible women in light of the evidence showing that they
derive greater benefit than men. Such strategies include overcoming
barriers in referral166,170, which includes increasing awareness of the
indications and benefits of CRT among clinicians169, leveraging elec-
tronic health records for identification of eligible patients, and engag-
ing patients and support organizations to address misconceptions,
promote information dissemination and increase therapeutic uptake166.
Together with advances in pharmacological therapies for HF,
new approaches to pacing and resynchronization are also emerging.
In particular, conduction system pacing171–174 (targeting the His bun-
dle or the left bundle branch area) as a form of cardiac physiological
pacing175 is emerging as an alternative to conventional resynchroni-
zation (with placement of a coronary sinus lead to pre-excite the left
ventricle). The RCT funded by the Patient-Centered Outcomes Research
Insitute176 will evaluate the comparative effectiveness of His bundle
or left bundle branch pacing in patients with a LVEF ≤50% and with
either a wide QRS (≥130 ms), or with an anticipated pacing of >40% who
are already receiving current standard HF pharmacological therapy.
Sex-specific data in conduction system pacing will be needed to guide
further consideration.
Interventions for mitral valve regurgitation. Sex-related differences
in outcomes exist after mitral valve intervention for mitral regurgita-
tion in patients with HF (Table 4). In a secondary analysis of sex-based
differences177 from the Cardiothoracic Surgical Trials Network SIMR
trial178,179, women had a smaller left ventricular volume and a smaller
mitral valve effective regurgitant orifice area (EROA) but proportionally
larger EROA-to-left ventricular end-diastolic volume ratio than men177. At
2 years after mitral valve surgery, although the degree of reverse left ven-
tricular remodelling was similar in both sexes, women had higher rates
of all-cause death and major adverse cardiovascular and cerebrovascular
events and worse QoL and functional status than men177.
A sex-specific analysis of the COAPT trial assessed the influence of sex
on the response to device therapy in patients with HF and severe secondary
mitral regurgitation. Although transcatheter mitral valve repair with the
MitraClip resulted in improved clinical outcomes compared with GDMT
alone for both sexes, the relative reduction in HF hospitalizations was less
pronounced in women (HR 0.78, 95% CI 0.57–1.05) than in men (HR 0.43,
95% CI 0.34–0.54; P for interaction 0.002), especially beyond the first year
of treatment. Women also derived less benefit from transcatheter mitral
valve repair than men with regard to QoL scores and 6MWD180.
Mechanical circulatory support. With respect to left ventricular
assist device (LVAD) therapy, female sex was independently associated
with higher inpatient mortality after implantation in those implanted

Table 4 | Select clinical trials of mitral valve interventions and neuromodulation in men and women with HF

Trial (year) Device Patient cohort Number Mean Follow-up Primary end Main results Interaction by sex or end point data
therapy of patients age (months) point
(% women) (years)

Mitral valve interventions

COAPT TMVR LVEF 20–50%, 614 (36) 72 24 HF TMVR reduced the P for interaction by sex 0.05; primary
(2018)180,247 plus ischaemic or hospitalization primary end point of end point HR 0.44 (95% CI 0.32–0.61)
GDMT or non-ischaemic HF hospitalization in men and 0.77 (95% CI 0.49–1.21) in
GDMT cardiomyopathy, (HR 0.53, 95% CI women
alone moderate-to- 0.40–0.70; P < 0.001)
severe or severe as well as all-cause
secondary mitral death (HR 0.62, 95% CI
regurgitation, 0.46–0.82; P < 0.001)
NYHA class II–IV

Autonomic nervous system modulation

BeAT-HF BAT plus LVEF ≤35%, 264 (20) 62 6 6MWD, QoL, BAT improved No significant interaction by sex for
(2020)187,248 GDMT NYHA class II–III NT-proBNP 6MWD (P < 0.001), 6MWD, QoL and NYHA; BAT showed
or GDMT QoL (P < 0.001) and benefits in women and men; significant
alone NT-proBNP (P < 0.001) interaction by sex for NT-proBNP (P for
at 6 months of interaction 0.05), significant reduction
follow-up in plasma NT-proBNP levels with BAT in
women (P < 0.01) but less pronounced
and not significant in men (P = 0.08)

INOVATE-HF VNS plus LVEF ≤40%, NYHA 707 (21) 61 16 All-cause Similar rates of the P for interaction by sex 0.03; primary
(2016)188 GDMT or class III, mortality or HF primary end point in end point HR 0.99 (P = 0.93) in men
GDMT LVEDD 50–80 mm event the VNS and control and 2.43 (P = 0.02) in women; sex was
groups (HR 1.14, 95% no longer an independent predictor
CI 0.86–1.53; P = 0.37); of outcome (P = 0.17) in multivariate
compared with analysis incorporating sex-based
control, VNS improved differences (women were younger, with
6MWD (P < 0.01), QoL smaller left ventricular volume, shorter
(P < 0.01) and NYHA QRS duration and more likely to have
class (P < 0.01) non-ischaemic cardiomyopathy)
6MWD, 6-min walking distance; BAT, baroreflex activation therapy; GDMT, guideline-directed medical therapy; HF, heart failure; LVEDD, left ventricular end-diastolic diameter; LVEF, left
ventricular ejection fraction; NT-proBNP, amino‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; QoL, quality of life; TMVR, transcatheter mitral valve repair;
VNS, vagal nerve stimulation.

Nature Reviews Cardiology

Review article
during the pulsatile-flow LVAD era, but not in those implanted during
the continuous-flow LVAD era181. However, although the number of
women undergoing LVAD implantation has increased, a utilization gap
remains, with less utilization in women than in men182. Women have
greater left ventricular reverse remodelling after implantation of LVAD
than men183. A retrospective analysis of 355 patients who underwent
LVAD implantation (167 with a HeartMate II and 188 a HeartMate VAD)
revealed that, compared with men, women had a greater reduction in
left ventricular dimensions and a greater increase in LVEF in response
to unloading by the LVAD early after implantation and up to 5 years of
follow-up, regardless of LVAD type183.
Extending the consideration of mechanical circulatory sup-
port to patients with cardiogenic shock in the setting of acute myo-
cardial infarction, women derived greater benefit than men from
early mechanical circulatory support (in this study, percutaneous
mechanical circulatory support before the percutaneous coronary
intervention)184.
Neuromodulation in HF. Baroreflex activation therapy (BAT), via
stimulation of the carotid baroreceptor by an implanted impulse gen-
erator, results in a centrally mediated decrease in sympathetic activity
and an increase in parasympathetic flow185,186. Sex-specific data from
the randomized BeAT-HF study187, which compared BAT combined with
GDMT versus GDMT alone, showed that women undergoing BAT had a
significant improvement in 6MWD, QoL and NYHA functional class at
6 months, similar to men, and that women had an additional benefit of
significant reduction in plasma amino‐terminal pro‐B‐type natriuretic
peptide (NT-proBNP) levels (Table 4).
The INOVATE-HF trial188, which is the largest trial on vagal nerve
stimulation (VNS)188–191, compared high-amplitude, low-frequency
VNS plus GDMT versus GDMT alone in patients with chronic, symp-
tomatic HFrEF. A significant treatment-by-subgroup interaction was
seen for sex (HR 0.99 in men versus HR 2.43 in women for the primary
efficacy end point of a composite of death from any cause or first event
for worsening HF; P for interaction by sex 0.03). However, sex was no
longer an independent predictor of the primary efficacy end point in a
multivariate analysis incorporating sex-based differences (women were
younger, more likely to have a non-ischaemic aetiology of HF and had a
smaller left ventricular volume and a shorter QRS duration than men),
underscoring the importance of considering underlying sex-related
differences in epidemiology, pathophysiology and electroanatomical
remodelling. Further sex-specific analyses are needed to assess whether
the optimal dose, intensity and duration of stimulation vary by sex.
Sex-related differences in adverse procedural events
Adverse procedural events related to CIEDs. Among US Medicare-
covered recipients of single-chamber or dual-chamber transvenous
ICDs for primary prevention, women had more comorbidities, more
advanced HF at the time of ICD implantation and higher odds of
6-month procedural complications than men (OR 1.39, 95% CI 1.26–1.53;
P < 0.001), even after adjusting for differences in baseline characteris-
tics and device type192. Among recipients of a transvenous ICD device
(including for a primary or secondary prevention indication, and with
device systems ranging from single-chamber to dual-chamber, to
CRT-D systems) from the Ontario ICD Database, women were more
likely than men to experience 45-day and 1-year implant-related com-
plications, after adjusting for baseline characteristics, comorbid con-
ditions and prevention indication, regardless of ICD type or implant
site193. Beyond recipients of ICDs, an analysis of adult recipients of a
Nature Reviews Cardiology
new CIED in Australia and New Zealand reported more 90-day major
device-related complications in women than in men, and the difference
remained significant after adjusting for age, procedural acuity and
comorbidities (OR 1.10, 95% CI 1.04–1.16; P < 0.001)194. Multivariable
analyses of the population-based Danish Pacemaker and ICD Register
similarly found that female sex was a predictor of increased risk of
complications after device implantation195. The postulated reasons
for the higher implant-related complications observed in women with
transvenous CIEDs than in men include more difficult vascular access,
thinner myocardial walls and smaller coronary sinus diameter196,197. In
contrast to this higher rate of implant-related complications associated
with transvenous CIED systems192–194, an analysis of the IDE and EFFORT-
LESS registries involving recipients of subcutaneous ICD systems found
no sex-related differences in 360-day complications with these devices,
which do not require vascular access for implantation198.
Adverse procedural events related to mitral valve procedures. In
patients with severe ischaemic mitral valve regurgitation undergoing
mitral valve surgery, the rate of 2-year major adverse cardiac and cer-
ebrovascular events (stroke, worsening HF, rehospitalization for HF and
mitral valve reoperation) was higher in women than in men (49.0% ver-
sus 38.1%; HR 1.58, 95% CI 1.06–2.37; P = 0.02)177. In patients with HF and
severe secondary mitral regurgitation undergoing transcatheter mitral
valve repair, procedural success rates were high and device-related
complications were infrequent, irrespective of sex180,199,200.
Adverse procedural events related to mechanical circulatory sup-
port. An analysis of 966 LVAD recipients (815 men and 151 women,
median follow-up 1.26 years) from the European EUROMACS registry
(which includes a broad range of LVAD types) found that women expe-
rienced significantly more major bleeding events (P = 0.0012), arrhyth-
mias (P = 0.022) and right ventricular failure with need for additional
right ventricular support (P < 0.001) than men201. Although the rates
of pump thrombosis were not significantly different between men and
women, the occurrence of pump thrombosis was even more strongly
related to mortality in women than in men (HR 10.01 in women (95% CI
4.44–22.55; P < 0.001) and HR 3.27 in men (95% CI 2.07–5.16; P < 0.001);
P for interaction for sex 0.028)201. An analysis of the US National Inpa-
tient Sample including 3,511 patients with HF who received an LVAD
between 2009 and 2014 found no sex-related differences in periproce-
dural complications182; however, the National Inpatient Sample dataset
is primarily an administrative dataset that is not specifically developed
for HF (in contrast to the EUROMACS registry) and does not specifically
capture INTERMACS (Interagency Registry for mechanically assisted
circulatory support) profiles or the need for right ventricular support.
Adverse procedural events related to neuromodulation. In the
BeAT-HF trial187, high rates of freedom from system-related and
procedure-related major adverse neurological and cardiovascular
events were seen in the 125 patients (101 men and 24 women) who
underwent BAT with an implanted impulse generator, with no appar-
ent sex-specific differences (97% in men and 96% in women; P = 0.57).
With regard to VNS, the rate of freedom from procedure-related and
system-related adverse events in the INOVATE-HF trial188 was 90.6%
(95% CI 87.7–93.5%), without specification by sex.
Response to cardiac rehabilitation in HF
HF guidelines strongly recommend non-pharmacological interven-
tions, including multidisciplinary team care, exercise training and
Review article

associated with a non-significant overall reduction in the primary

Box 1 end point of all-cause mortality or hospitalizations (HR 0.93, 95% CI
0.84–1.02), with 64% of women and 68% of men experiencing the pri-
mary outcome (hazard ratios adjusted only for cause 0.83 (95% CI
Challenges and opportunities 0.68–1.00) in women and 0.97 (95% CI 0.87–1.09) in men; P for interac-
tion 0.17). A further analysis that adjusted for baseline covariates found
in sex-based considerations sex-related differences in outcomes, wherein women with LVEF ≤35%

for HF therapies in the exercise training group had a significant 26% reduction in the
primary composite outcome compared with no reduction in men with
LVEF ≤35% (adjusted HR 0.74 (95% CI 0.59–0.92) in women and 0.99
Challenges and opportunities exist when addressing sex-related (95% CI 0.86–1.13) in men; P for interaction 0.027)212,213. Although the
considerations in the design and conduct of clinical trials and the mechanisms behind this preferential benefit of exercise training in
implementation of heart failure therapies (see the table). Complex women are still unclear, these results are consistent with the findings
interactions of sex with other sociodemographic characteristics of other trials in patients with coronary conditions and patients with
pose additional challenges and opportunities for the optimization HF214,215. Among US Medicare beneficiaries who were hospitalized
of clinical trials and therapeutic adoption. for coronary conditions or cardiac revascularization procedures,
the reduction in 5-year mortality among cardiac rehabilitation users
Areas Challenges and Complex interaction (versus non-users) was greater in women than in men214. Moreover, in
opportunities between sex and
sociodemographic
the REHAB-HF trial215 in 349 older patients (52% women) hospitalized
characteristics with HF, an early, tailored and multidomain physical rehabilitation
programme clearly improved physical function among women, with
Clinical trial Study population, inclusion Gender
design and exclusion criteria an increase in the primary end point of Short Physical Performance
Race and ethnicity
Dose selection Battery score by a mean of 1.9 (95% CI 1.1–2.7) compared with 1.0 (95% CI
Urbanity versus rurality
Powered to detect 0.1–1.8) among men. A post hoc analysis of the REHAB-HF trial showed
Psychological factors
sex-specific effects that compared with patients with HFrEF, those with HFpEF were more
Social determinants of
At each stage of the therapy health often women (43% versus 61%) and had more frailty and depression and
development process, the worse baseline physical function and QoL216. The benefits of the multi-
influence of sex on the safety
domain physical rehabilitation intervention were numerically larger in
and efficacy of the treatment
should be assessed patients with HFpEF than in those with HFrEF, although the P values for
interaction for the 3-month outcomes were not significant216.
Conduct of Trial leadership
clinical trials Recruitment to ensure
representation of both sexes Challenges and opportunities
Participant engagement and Numerous opportunities exist to address sex-related differences in clin-
retainment during the study ical trials and therapeutic adoption, but they are not without challenges
Implementation Counselling and education (Box 1). In clinical trial design, sex-related considerations are relevant in
Shared decision-making the determination of inclusion and exclusion criteria, treatment dose
Adherence selection, protocol design, sample size calculation (ideally powered to
generate sex-specific data), and data and safety monitoring plan (cog-
nizant of potential sex-related differences in biological response and
adverse events)86. Women remain under-represented in clinical trials217.
cardiac rehabilitation18,202,203. Cardiac rehabilitation is safe, reduces Addressing this challenge calls for a multilevel approach, including
the rate of HF-related hospitalizations and improves functional capac- ensuring representation of women in clinical trial leadership218, educa-
ity, QoL and psychosocial wellbeing204,205. However, cardiac rehabili- tion of recruiting personnel on the importance of enrolling women and
tation is remarkably underutilized, particularly in women206,207. An of sharing their experience on enrolling women86, tailored recruitment
analysis of data from two meta-analyses showed that women were 36% (including outreach to community settings frequented by women and
less likely to enrol in cardiac rehabilitation programmes than men, and the involvement of family members and primary care providers)86
adherence was 3.6% lower among women than among men207,208. The and retention strategies that take into account logistical barriers to
reasons for these sex-related differences might be because women participation (such as offering flexible hours and at-home follow-up
with HF tend to be older, have more comorbidities and have lower and provision or reimbursement for concomitant childcare or family
levels of social support and functional capacity, and have greater care-giving responsibilities)86.
psychological burden than men with HF209. Up to 30% of patients Therapeutic adoption has been hindered by differential access
with HF have depression, and even more patients have depressive and counselling among women in particular. Approaches to improve
symptoms, particularly women with HFpEF210,211. Paradoxically, these the implementation of HF therapies will need to assess and address
challenges faced by women make it all the more necessary to encour- systemic and individual barriers to access as well as adherence to thera-
age participation and increase adherence to cardiac rehabilitation pies, and further consider differences in decision-making. Digital
among women with HF. health tools might have increasing roles in facilitating remote interac-
In the large HF-ACTION trial212, 2,331 outpatients (28% women) with tions between patients and clinicians, improving standardization of
HFrEF were randomly assigned to receive standard care or standard HF care, and promoting adherence to evidence-based guidelines219.
care with supervised aerobic exercise training. Exercise training was Electronic health record alerts can improve referral of ICD-eligible

Nature Reviews Cardiology

Review article
patients, thereby mitigating the observed sex-based gaps, with
under-referral in women116. Decision support tools (such as with order
sets and triggered alerts) serve as opportunities to increase adher-
ence to GDMT220–222. Increasing the readability and comprehensibility
of patient-facing guideline materials has been helpful in promoting
patient partnership and empowering patients to make decisions
regarding their own therapies223. Given the known sex-related differ-
ences in the decision-making processes (women might take longer to
make decisions, require more sources of input and be more susceptible
to external influences than men)224, such patient-facing tools can be
tailored for optimal sex-specific decision-making. Multi-stakeholder
engagement (patients, care-givers, health-care practitioners, payers
and public-health and policy makers, across multiple cultures)225 will
be important to promote implementation and sustainability among
both women and men.
Additionally, the exploration of how sex (biological domain),
gender (psychosocial domain) and sex hormones and exogenous
hormones contribute to HF are needed in future research. Gender
interacts with sex, and its properties are fluid and not binary terms226.
Traits of masculinity or femininity coexist and are expressed to vary-
ing degrees in the general population. Gender has been related to the
development and progression of cardiovascular diseases227. Feminine
gender, independent of sex, has been shown to be a strong predictor
of recurrent acute coronary syndrome, and patients with feminine
personality traits have poorer access to care than patients with mas-
culine traits228,229. In a large cohort study, feminine characteristics were
associated with an increased risk of cardiovascular diseases, especially
in men230. However, much less is known about the association between
gender and HF. Notably, no gold standard exists for gender assessment.
The measurement of gender in a reliable way (for example, current
theory-driven methods include the Bem Sex-Role Inventory and the
Masculine Gender Role Stress scale, and data-driven methods include
the gender index) is the first challenging step for future research.
Conclusions
Sex differences in anatomy, physiology, pharmacokinetics, pharma-
codynamics and psychosocial factors might influence the response to
pharmacological agents, device therapy and cardiac rehabilitation in
patients with HF (Fig. 1). The response to pharmacological therapies
for HF in men and women are generally similar, except the response to
ARNI and spironolactone in those with higher LVEF (Fig. 3). Sex-related
differences and similarities in clinical outcomes in response to device
therapies for HF have been reported. CRT is associated with a reduction
in mortality at a shorter QRS duration in women with LBBB than in men
with LBBB. For the patient-oriented outcomes of QoL and functional
status, women derive similar benefits from BAT to men, but less benefit
from mitral valve interventions. Women might also be more prone to
adverse effects of some HF medications (such as ACE inhibitors) and
to procedural complications than men. Conversely, cardiac rehabilita-
tion might be particularly beneficial among women with HF. In general,
however, sex-specific evidence on therapeutic efficacy and safety in
patients with HF is still limited given the historical under-representation of
women in clinical trials, as well as the lack of sex-specific evaluation
of therapeutic efficacy and safety in these trials. Such deficiencies also
represent opportunities to address sex-related disparities in HF and
develop tailored approaches to improve outcomes for both women
and men with HF.
Published online: xx xx xxxx
Nature Reviews Cardiology
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Author contributions
The authors contributed substantially to all aspects of the article.
Competing interests
J.B. has received consultancy and/or research fees from Abbott, American Regent, Amgen,
Applied Therapeutics, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston
Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Behring, CVRx,
Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse
Dynamics, Imbria, Inventiva, Ionis, Lexicon, Eli Lilly, LivaNova, Janssen, Medtronics, Merck,
Occlutech, Owkin, Novartis, Novo Nordisk, Pharmacosmos, Pharmain, Pfizer, Prolaio,
Regeneron, Renibus, Roche Diagnostics, Salamandra, Sanofi, SC Pharma, Secretome,
Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. A.A.V. has received
consultancy and/or research fees from Anacardio, AstraZeneca, Bayer, Bristol Myers Squibb,
Boehringer Ingelheim, Cytokinetics, Corteria, Eli Lilly, Moderna, Novartis, Novo Nordisk,
Pfizer and Roche Diagnostics. C.S.P.L. is supported by a Clinician Scientist Award from the
National Medical Research Council of Singapore; has received research support from Novo
Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering
Committee/Executive Committee for Alleviant Medical, Allysta Pharma, Amgen, AnaCardio
AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific,
Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc., EchoNous Inc, Eli Lilly, Impulse
Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development
LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento, Quidel
Corporation, Radcliffe Group, Recardio, ReCor Medical, Roche Diagnostics, Sanofi, Siemens
Healthcare Diagnostics and Us2.ai; and serves as co-founder and non-executive director of
Us2.ai. J.Y.C. has received consultancy fees from Medtronic. H.Q. has no competing interests.
Additional information
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McDonagh, and the other, anonymous, reviewer(s) for their contribution to the peer review
of this work.
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