Abstract
Purpose of Review
Over the last decades, several classes of drugs have been introduced for the treatment of patients with heart failure with reduced ejection fraction (HFrEF). Their use has been supported by randomized controlled trials that have demonstrated improved patient outcomes. However, these trials enrolled a small number of female patients and sometimes have reported gender-related differences regarding the efficacy of the treatments. The aim of this review is to revise the available data about the influence of gender on the optimal treatment and drug dose in patients with HFrEF.
Recent Findings
Several gender-related differences in terms of pharmacokinetic and pharmacodynamic characteristics of the drugs have been described. These characteristics could be responsible for a different response and tolerability in men and women also when current recommended treatment of HFrEF is considered. Some studies have shown that, in women, lower doses of beta-blockers and inhibitors of renin angiotensin aldosterone system could be equally effective than higher doses in men, whereas sacubitril/valsartan could exert its favorable effect at greater values of left ventricular ejection fraction.
Summary
Although there is evidence about differences in the response to treatment of HFrEF in men and women, this has not been sufficient for differentiating current recommended therapy. Further studies should better clarify if the treatment of HFrEF should be based also on the patients’ gender.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Over the last decades, several randomized controlled trials (RCTs) have demonstrated the efficacy of several classes of drugs in improving the prognosis of patients with heart failure with reduced ejection fraction (HFrEF) [1–18]. Consequently, European and American guidelines have recommended these drugs for the treatment of patients with chronic heart failure (CHF) [19, 20].
However, all trials that evaluated the efficacy of the current therapeutic approaches for CHF had a small number of female patients [21.••, 22]. This issue is even more relevant considering that female patients are naturally different from male patients and that these differences may affect the pharmacokinetics and pharmacodynamics of drugs [23.••, 24.••].
These differences could be related also to the body composition, which represents one of the other relevant aspects influencing the effectiveness of any therapeutic approach [25]. This is due to the influence of the body’s composition on drug distribution and clearance as well as on hemodynamic properties such as the clearance of natriuretic peptides [25, 26].
Hence, the aim of this review is to revise the available data about the influence of gender on the optimal drug dose for heart failure patients.
Pharmacokinetic and Pharmacodynamic Differences According to Gender and Body Composition
Several gender-related differences have been demonstrated to affect a drug’s pharmacokinetics. In women, the higher plasma concentration of drugs is due to differences in absorption (slower gastrointestinal motility and transit time, lower absorption, and less drug enzymes and transporters), metabolism, distribution, and excretion (lower renal blood flow and glomerular filtration rate, slower clearance, and longer half-life) [23.••, 24.••]. Figure 1 summarizes the pharmacokinetic and pharmacodynamic differences according with the gender.
Gender-Related Differences Affecting Drug Metabolism
Gender-related differences in phase I drug metabolism are evident in cytochrome P (CYP) activity. In women, CYP450 activity is lower [23.••, 24.••], which can be attributed to the fact that endogenous hormones, including estrogens and progestins, are also metabolized by this enzyme [23.••, 24.••]. Additionally, activity of CYP450 isoenzymes as well as those of CYP1A2 and CYP2E1 are higher in men, whereas CTP2A6, CYP2B6, and CYP3A4 have higher activity in women [23.••]. There are conflicting results about the activity of CYP2D6 in men and women [27]. In phase II drug metabolism, methyltransferase and sulfotransferase activity is higher in men, whereas uridine diphosphate glucuronosyltransferase and N-acetyl-transferase activity is higher in women [23.••, 24.••].
Gender, Body Composition, and Pharmacokinetics
Other relevant gender-related differences that may affect drug pharmacokinetics are body surface area, body weight, and body composition [23.••, 25]. Generally, women weigh less and are shorter but have a higher proportion of body fat than men, which result in slower drug clearance due to a lower glomerular and hepatic filtration rate, leading to higher drug plasma concentrations. On the other hand, the increased adipose tissue can influence drug distribution, particularly of lipophilic drugs. Hydrophilic drugs generally have a smaller volume of distribution in adipose tissue and a higher plasma concentration, whereas lipophilic drugs have greater distribution in adipose tissue, which could result in lower plasma concentrations when there is increased adipose tissue [25]. Another aspect relative to body composition is related to drug clearance [22, 23.••, 25]. Hepatic metabolism, which is dependent on cardiac output and liver blood flow, is lower in women, whereas gender differences in renal excretion are related to body weight.
Gender-Related Pharmacodynamic Differences in Heart Failure Therapy
Aside from drug pharmacokinetics, drug pharmacodynamics could be also influenced by gender-related differences related to hormonal and non-hormonal factors.
Estrogens inhibit the renin-angiotensin system. After an initial increase in the angiotensin II (ATII) plasma levels, angiotensin converting enzyme (ACE) and renin activity decrease due to negative feedback, resulting in a reduced expression of type-1 ATII receptors with a net inhibitory effect [28–30]. Moreover, after menopause, lower ACE activity is improved by hormone replacement therapy [31].
Differences have also been observed when sympathetic activity is considered. The expression of beta-1 adrenergic receptors could be influenced by estrogen [32–34], which can explain the greater reduction of arterial blood pressure and heart rate in women than in men despite receiving similar doses of the same drug [35, 36].
The Evidence in RCT According to Gender
The current evidence regarding gender-related differences in HF therapy is influenced by the under-enrollment of female patients. The under-enrollment of female patients is evident in most of the RCTs that have demonstrated benefits of HF drugs [21.••, 22]. In a systematic review of RCTs involving 183,097 patients with HFrEF, only 25.5% were female [21.••]. Moreover, female patients were under-enrolled in 71.6% of the RCTs; this proportion did not increase significantly between 2000 and 2019. Furthermore, many trials do not separately report gender-related risk factors and comorbidities as well as the adverse effects of drugs according to gender. Aside from the under-enrollment of female patients, another concern is the gender-related benefits of drugs for patients with heart failure. Figure 2 summarizes the subgroup analyses of the RCTs which are described below and current recommended HFrEF therapy is based on.
Renin–Angiotensin–Aldosterone System Blockade
Two meta-analyses that evaluated ACE inhibitors in patients with CHF showed that men benefited more from ACE inhibitor therapy than women [37, 38], with mortality and/or hospitalization reduced by 37% in men vs. 22% in women [37]. However, after a myocardial infarction complicated by left ventricular dysfunction, no gender-related differences were observed in a meta-analysis of most of the available trials [39]. Regarding ACE inhibitors, women have a greater incidence of cough than men [40], whereas no gender-related difference was observed when angioedema was considered [41].
Additionally, the ELITE II, Val-HeFT, and CHARM trials demonstrated that there were no gender-related differences for ARBs [42–44].
Spironolactone and eplerenone have demonstrated their ability in reducing mortality among patients with HFrEF and affect both genders equally [10, 11]. Moreover, the Randomized ALdactone Evaluation Study and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study, wherein there was a low percentage of female patients (27% and 28%, respectively), revealed that mineralocorticoid receptor antagonists (MRA) had similar benefits in both genders [45]. A recent meta-analysis [46], including TOPCAT, confirmed that spironolactone had similar benefits for both male and female patients with heart failure with preserved ejection fraction (HFpEF).
In this analysis, analogous to a real-world study [47], women were different from men because they were older and had a higher body mass index, poorer renal function, and fewer comorbidities except for essential hypertension. However, MRA treatment had a similar effect in both men and women in terms of cardiovascular death and hospitalization due to HF, cardiovascular death alone, and all-cause death regardless of the possible confounding factors. Analogously, MRA-related hyperkalemia as well as worsening renal function did not vary by gender.
Beta-Blockers
Some data suggest that the pharmacokinetic and pharmacodynamic differences in men and women could be related to the different efficacies of metoprolol and carvedilol as demonstrated by the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure [6, 48] and Carvedilol Prospective Randomized Cumulative Survival [4]. On the other hand, CIBIS-II did not demonstrate differences between male and female patients [7, 49]. These results could be related to the metabolism of carvedilol and metoprolol, which, differently from that of the bisoprolol, is CYP2D6 dependent (Table 1) [50]. However, as above mentioned, the results of the studies evaluating CYP2D6 in men and women are conflicting [27]. The other possible explanation is related to the small proportion of enrolled female patients in these trials. This hypothesis is strengthened by a meta-analysis that pooled the results of these trials and demonstrated a similar effect of these drugs in reducing mortality in women [49].
Sacubitril/Valsartan
Possible gender-related differences have been suggested in the response to therapy with sacubitril/valsartan, which are recommend for patients with HFrEF [13]. Sacubitril and valsartan inhibit ATII and neprilysin, respectively. Neprilysin is an endothelial endopeptidase involved in the degradation of natriuretic peptides that counteracts the overactivation of RAAS and sympathetic nervous system by inducing natriuresis and diuresis as well as exerts an antifibrotic effect at the cardiac level [51]. Sacubitril/valsartan also showed a strong effect on cardiac remodeling, which is related to the reduction of serum levels of natriuretic peptides [52, 53]. Notably, the degree of reverse remodeling and the reduction of NT-proBNP levels were greater in women with HFrEF after sacubitril/valsartan therapy [54]. The possibility that sacubitril/valsartan exert different effects in male and female patients has been strengthened by the results of PARAGON-HF [55, 56.••]. PARAGON-HF compared treatment between sacubitril/valsartan with valsartan alone in patients with CHF and a left ventricular ejection fraction (LVEF) ≥ 45%, evidence of structural heart disease (left atrial enlargement or left ventricular hypertrophy), New York Heart Association classes II–IV, and elevated levels of natriuretic peptides. The results of PARAGON-HF demonstrated that sacubitril/valsartan reduced hospitalizations due to HF and cardiovascular mortality, albeit without statistical significance (rate ratio: 0.87; 95% confidence interval [CI]: 0.75–1.01; P = 0.06) [56.••]. Among the pre-specified sub-groups, heterogeneity was observed in the subgroup of female patients who benefited more from sacubitril/valsartan therapy.
The differential benefits of sacubitril/valsartan in female patients have also been suggested by an analysis that combined data from PARADIGM-HF and PARAGON-HF [57]. When the population of the two studies was combined, a benefit was evident in patients with an LVEF < 55%. However, in female patients, the benefit was greater in patients with higher LVEF values. The explanation for this gender-based relationship between LVEF and the beneficial effects of sacubitril/valsartan is unclear. One is that systolic dysfunction in female patients is already present at a higher LVEF [58–60]. The varied response to neurohormonal modulation at a greater LVEF among women is further supported by the results of the TOPCAT and CHARM trials on the effects of spironolactone and candesartan, respectively [61].
Another possible explanation may be attributed to the differences in the natriuretic peptide system between male and female patients, particularly in those with HFrEF or HFpEF. Among these patients, women had lower levels of natriuretic peptides despite a similar severity of HF. This is probably due to the increased clearance of natriuretic peptides related to greater visceral obesity as well as to the reduced levels of natriuretic peptides after menopause, which lead to a relative insufficiency of natriuretic peptides in women that may be improved by sacubitril/valsartan [61].
Type 2 Sodiun-Glucose Cotrasporter Inhibitors
A possible gender-related influence in the efficacy of SGLT2i was hypothesized in diabetic patients [62, 63]. In DAPA-HF [14] and in EMPEROR-reduced [15], the proportion of female patients was 19.6 and 22.8%, respectively. Interestingly, in a meta-analysis of the two trials [64], a similar reduction of the primary endpoint was observed in men (hazard ratio [HR]: 0.76; 95% CI: 0.68–0.85) and in women (HR: 0.68; 95% CI: 0.56–0.84).
Digoxin
The first evidence of possible gender-related differences was derived from the analysis of the DIG trial, which showed a significant interaction between digoxin administration and events among male and female patients [65]. The general results of the trial demonstrated that digoxin was associated with increased mortality in female patients. Moreover, in women, a smaller digoxin-associated reduction in the rate of hospitalization due to heart failure was observed. Interestingly, the mean daily dose of digoxin was not different between men and women (p = 0.28), but the median serum digoxin level at 1 month was slightly higher in a subgroup of women than in a subgroup of men (p = 0.007). This suggests the possibility of differences in pharmacokinetics between men and women that could be attributed to an interaction between hormone replacement therapy and digoxin. Progestin may increase serum digoxin levels by inhibiting P glycoprotein, thus reducing the renal excretion of digoxin through the renal tubules [65]. This interaction is supported by the Heart and Estrogen/Progestin Replacement Study, wherein it was observed that the interaction between digoxin and hormone replacement therapy was associated with a higher rate of cardiovascular events [66].
Differences in the Dose/Effectiveness of HFrEF Treatment According to Gender
Although the classes of drugs currently recommended for the treatment of HFrEF show similar efficacy regardless of gender, beneficial effects were noted depending on the doses of drugs.
The ATLAS study [67] was a randomized controlled trial aimed to compare the effects of a high dose (32.5 to 35 mg daily) with those of a low dose (2.5 to 5.0 mg daily). Among more than 3000 patients with heart failure, LVEF ≤ 30% and NYHA classes II–IV only 26% in low-dose group and 20% in the high-dose group were female. The trial did not show a significant effect of high dose on death, but a significant lower occurrence of hospitalizations related to heart failure was observed. However, when gender was considered in the subgroup analysis, a trend toward a greater beneficial effect in men than in women was observed.
In the HEAAL study [68], the effects of a high dose of losartan (150 mg/daily) versus a low dose (50 mg/daily) were compared in a group of patients with HFrEF (LVEF at the enrollment ≤ 40%). No differences were found among groups in the occurrence of the combined end-point death or admission for heart failure. Like most of the other RCTs in heart failure, HEAAL study was also characterized by an underenrollment of female patients (30% in the high dose group and 29% in low dose group). Interestingly, in the subgroup analysis, women showed a less beneficial effect form high dose of losartan than men, with a p for interaction near to the statistical significance (p: 0.10).
More recently, the possibility that lower doses of HFrEF diseases modifier drugs can be effective in female like the higher in males has been further supported by a post hoc analysis of BIOSTAT-CHF [69.••], which was a prospective study involving centers of 11 European countries that was aimed to evaluate the initiation and up-titration of ACE inhibitors or ATII receptor blockers and beta-blockers among patients with HFrEF. Among the 1710 patients with HFrEF, 30.7% were female and were older; there was no difference in BMI between male and female patients. The percentage of male and female patients in whom the target dose of ACE inhibitors or ATII receptor blockers and beta-blockers was reached was similar. However, the benefit observed in female patients in terms of mortality reduction was significant at doses lower than those in men. The differences between male and female patients remained significant after correcting for covariates, including age and body surface area. Interestingly, despite differences in baseline characteristics and ethnicity, similar results were observed among patients enrolled in the ASIAN-HF registry.
Conclusions
Studies have demonstrated gender-related differences in the pharmacokinetic and pharmacodynamic properties of drugs currently recommended for patients with HFrEF, which is related to the difference in body composition between men and women. Moreover, although most of the RCTs have demonstrated that drugs have similar efficacy in male and female patients, some evidence suggests the possibility that a lower dosage could be as effective in women.
Despite this evidence, current European and American guidelines [19, 20] do not recommend personalized treatment based on gender and body composition in HFrEF therapies. Further studies should better clarify if HFrEF treatment should be tailored based on gender and body composition.
Abbreviations
- ACE:
-
Angiotensin-converting enzyme
- ATII:
-
Angiotensin II
- CHF:
-
Chronic heart failure
- CYP:
-
Cytochrome P
- HFpEF:
-
Heart failure with preserved ejection fraction
- HFrEF:
-
Heart failure with reduced ejection fraction
- LVEF:
-
Left ventricular ejection fraction
- MRA:
-
Mineralocorticoid receptor antagonists
- RAAS:
-
Renin-angiotensin-aldosterone system
- RCTs:
-
Randomized controlled trials
References
Papers of particular interest, published recently, have been highlighted as: • Of importance
CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429–35.
SOLVD Investigators, Yusuf S, Pitt B, Davis CE, Hood WB Jr, Cohn JN. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685–91.
SOLVD Investigators, Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.
Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349–55.
Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–8.
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001–7.
Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194–9. https://doi.org/10.1161/01.cir.0000035653.72855.bf.
CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9–13.
Flather MD, Shibata MC, Coats AJS, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215–25. https://doi.org/10.1093/eurheartj/ehi115.
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.
Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21. https://doi.org/10.1056/NEJMoa1009492.
Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, CHARM Investigators and Committees, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772–6. https://doi.org/10.1016/S0140-6736(03)14284-5.
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, PARADIGM-HF Investigators and Committees, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004. https://doi.org/10.1056/NEJMoa1409077.
McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, DAPA-HF Trial Committees and Investigators, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008. https://doi.org/10.1056/NEJMoa1911303.
Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190.
Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, SOLOIST-WHF Trial Investigators, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384:117–28. https://doi.org/10.1056/NEJMoa2030183.
Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med. 2020;382:1883–93. https://doi.org/10.1056/NEJMoa1915928.
Ponikowski P, Kirwan BA, Anker SD, McDonagh T, Dorobantu M, Drozdz J, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020;396:1895–904. https://doi.org/10.1016/S0140-6736(20)32339-4.
Authors/Task Force Members, McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, ESC Scientific Document Group, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2022;24:4–131. https://doi.org/10.1002/ejhf.2333.
Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79:1757–80. https://doi.org/10.1016/j.jacc.2021.12.011.
Whitelaw S, Sullivan K, Eliya Y, Alruwayeh M, Thabane L, Yancy CW, 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. 2021;23:15–24. https://doi.org/10.1002/ejhf.2034. The authors underline the underenrollment of females patients in randomized controlled trials.
DeFilippis EM, Van Spall HGC. Is it time for sex-specific guidelines for cardiovascular disease? J Am Coll Cardiol. 2021;78:189–92. https://doi.org/10.1016/j.jacc.2021.05.012.
Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2009;48:143–57. https://doi.org/10.2165/00003088-200948030-00001. The review summarizes the differences related to gender in pharmacokinetics and pharmacodynamics.
Rosano GM, Lewis B, Agewall S, Wassmann S, Vitale C, Schmidt H, et al. Gender differences in the effect of cardiovascular drugs: a position document of the Working Group on Pharmacology and Drug Therapy of the ESC. Eur Heart J. 2015;36:2677–80. https://doi.org/10.1093/eurheartj/ehv161. The position paper of the European Society of Cardiology about gender differences for cardiovascular drugs.
Barras M, Legg A. Drug dosing in obese adults. Aust Prescr. 2017;40:189–93. https://doi.org/10.18773/austprescr.2017.053.
Díez J. Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy. Eur J Heart Fail. 2017;19:167–76. https://doi.org/10.1002/ejhf.656.
JochmannN Stangl K, Garbe E, Baumann G, Stangl V. Female-specific aspects in the pharmacotherapy of chronic cardiovascular diseases. Eur Heart J. 2005;26:1585–95. https://doi.org/10.1093/eurheartj/ehi397.
Fischer M, Baessler A, Schunkert H. Renin angiotensin system and gender differences in the cardiovascular system. Cardiovasc Res. 2002;53:672–7. https://doi.org/10.1016/s0008-6363(01)00479-5.
Harrison-Bernard LM, Schulman IH, Raij L. Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity. Hypertension. 2003;42:1157–63. https://doi.org/10.1161/01.HYP.0000102180.13341.50.
Harvey PJ, Morris BL, Miller JA, Floras JS. Estradiol induces discordant angiotensin and blood pressure responses to orthostasis in healthy postmenopausal women. Hypertension. 2005;45:399–405. https://doi.org/10.1161/01.HYP.0000157161.78721.5c.
Schunkert H, Danser AH, Hense HW, Derkx FH, Kurzinger S, Riegger GA. Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. Circulation. 1997;95:39–45. https://doi.org/10.1161/01.cir.95.1.39.
Kam KW, Qi JS, Chen M, Wong TM. Estrogen reduces cardiac injury and expression of beta1-adrenoceptor upon ischemic insult in the rat heart. J Pharmacol Exp Ther. 2004;309:8–15. https://doi.org/10.1124/jpet.103.058339.
Luzier AB, Killian A, Wilton JH, Wilson MF, Forrest A, Kazierad DJ. Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther. 1999;66:594–601. https://doi.org/10.1053/cp.1999.v66.103400001.
Thawornkaiwong A, Preawnim S, Wattanapermpool J. Upregulation of beta 1-adrenergic receptors in ovariectomized rat hearts. Life Sci. 2003;72:1813–24. https://doi.org/10.1016/s0024-3205(02)02473-6.
Gilmore DA, Gal J, Gerber JG, Nies AS. Age and gender influence the stereoselective pharmacokinetics of propranolol. J Pharmacol Exp Ther. 1992;261:1181–6.
Walle T, Byington RP, Furberg CD, McIntyre KM, Vokonas PS. Biologic determinants of propranolol disposition: results from 1308 patients in the beta-Blocker Heart Attack Trial. Clin Pharmacol Ther. 1985;38:509–18. https://doi.org/10.1002/ejhf.2034.
Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA. 1995;273:1450–6.
Shekelle PG, Rich MW, Morton SC, Atkinson W, Tu W, Maglione M, 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. J Am Coll Cardiol. 2003;41:1529–38. https://doi.org/10.1016/s0735-1097(03)00262-6.
Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, for the ACE inhibitor myocardial infarction collaborative group, et al. Long-term ACE inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. Lancet. 2000;355:1575–81. https://doi.org/10.1016/s0140-6736(00)02212-1.
Mackay FJ, Pearce GL, Mann RD. Cough and angiotensin II receptor antagonists: cause or confounding? Br J Clin Pharmacol. 1999;47:111–4. https://doi.org/10.1046/j.1365-2125.1999.00855.x.
Pillans PI, Coulter DM, Black P. Angiooedema and urticaria with angiotensin converting enzyme inhibitors. Eur J Clin Pharmacol. 1996;51:123–6. https://doi.org/10.1007/s002280050171.
Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial—the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355:1582–7. https://doi.org/10.1016/s0140-6736(00)02213-3.
Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–75. https://doi.org/10.1056/NEJMoa010713.
Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, Michelson EL, CHARM investigators and committees, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-overall programme. Lancet. 2003;362:759–66. https://doi.org/10.1016/s0140-6736(03)14282-1.
Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21. https://doi.org/10.1056/NEJMoa030207.
Rossello X, Ferreira JP, Pocock SJ, McMurray JJV, Solomon SD, Lam CSP, et al. Sex differences in mineralocorticoid receptor antagonist trials: a pooled analysis of three large clinical trials. Eur J Heart Fail. 2020;22:834–44. https://doi.org/10.1002/ejhf.1740.
Stolfo D, Uijl A, Vedin O, Strömberg A, Faxén UL, Rosano GM, Sinagra G, Dahlström U, Savarese G. Sex-based differences in heart failure across the ejection fraction spectrum: phenotyping, and prognostic and therapeutic implications. JACC Heart Fail. 2019;7:505–15. https://doi.org/10.1016/j.jchf.2019.03.011.
Ghali JK, Pina IL, Gottlieb SS, Deedwania PC, Wikstrand JC. Metoprolol CR/XL in female patients with heart failure: analysis of the experience in metoprolol extended-release randomized intervention trial in heart failure (MERIT-HF). Circulation. 2002;105:1585–91. https://doi.org/10.1161/01.cir.0000012546.20194.33.
Simon T, Mary-Krause M, Funck-Brentano C, Jaillon P. Sex differences in the prognosis of congestive heart failure: results from the Cardiac Insufficiency Bisoprolol Study (CIBIS II). Circulation. 2001;103:375–80. https://doi.org/10.1161/01.cir.103.3.375.
Kalibala J, Pechère-Bertschi A, Desmeules J. Gender differences in cardiovascular pharmacotherapy-the example of hypertension: a mini review. Front Pharmacol. 2020;11:564. https://doi.org/10.3389/fphar.2020.00564.
Buggey J, Mentz RJ, DeVore AD, Velazquez EJ. Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact. J Card Fail. 2015;21:741–50. https://doi.org/10.1016/j.cardfail.2015.07.008.
Januzzi JL Jr, Prescott MF, Butler J, Felker GM, Maisel AS, McCague K, PROVE-HF Investigators, et al. Association of change in N-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA. 2019;322:1085–95. https://doi.org/10.1001/jama.2019.12821.
Desai AS, Solomon SD, Shah AM, Claggett BL, Fang JC, Izzo J, EVALUATE-HF Investigators, et al. Effect of sacubitril-valsartan vs enalapril on aortic stiffness in patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2019;322:1077–84. https://doi.org/10.1001/jama.2019.12843.
Ibrahim NE, Pina I, Camacho A, Bapat D, Felker MG, Maisel AS, et al. Sex-based differences in biomarkers, health status, and reverse cardiac remodelling in patients with heart failure with reduced ejection fraction treated with sacubitril/valsartan. Eur J Heart Fail. 2020;22:2018–25. https://doi.org/10.1002/ejhf.2005.
Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381:1609–20. https://doi.org/10.1056/NEJMoa1908655.
McMurray JJV, Jackson AM, Lam CSP, Redfield MM, Anand IS, Ge J, et al. Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction: insights from PARAGON-HF. Circulation. 2020;141:338–51. https://doi.org/10.1161/CIRCULATIONAHA.119.044491. The paper analyzes the different effects of sacubitril/valsartan in men and women affected by chronic heart failure with left ventricular ejection fraction >45%.
Solomon SD, Vaduganathan M, Claggett BL, Packer M, Zile M, Swedberg K, et al. Sacubitril/valsartan across the spectrum of ejection fraction in heart failure. Circulation. 2020;141:352–61. https://doi.org/10.1161/CIRCULATIONAHA.119.044586.
Lin FY, Devereux RB, Roman MJ, Meng J, Jow VM, Jacobs A, et al. Cardiac chamber volumes, function, and mass as determined by 64-multidetector row computed tomography: mean values among healthy adults free of hypertension and obesity. JACC Cardiovasc Imaging. 2008;1:782–6. https://doi.org/10.1016/j.jcmg.2008.04.015.
Echocardiographic Normal Ranges Meta-Analysis of the Left Heart Collaboration. Ethnic-specific normative reference values for echocardiographic LA and LV size, LV mass, and systolic function: the EchoNoRMAL study. JACC Cardiovasc Imaging. 2015;8:656–65. https://doi.org/10.1016/j.jcmg.2015.02.014.
Kraigher-Krainer E, Shah AM, Gupta DK, Santos A, Claggett B, Pieske B, PARAMOUNT Investigators, et al. Impaired systolic function by strain imaging in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2014;63:447–56. https://doi.org/10.1016/j.jacc.2013.09.052.
Dewan P, Jackson A, Lam CSP, Pfeffer MA, Zannad F, Pitt B, et al. Interactions between left ventricular ejection fraction, sex and effect of neurohumoral modulators in heart failure. Eur J Heart Fail. 2020;22:898–901. https://doi.org/10.1002/ejhf.1776.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28. https://doi.org/10.1056/NEJMoa1504720.
Mahmoud AN, Elgendy IY, Saad M, Elgendy AY, Barakat AF, Mentias A, et al. Does gender influence the cardiovascular benefits observed with sodium glucose co-transporter-2 (SGLT-2) inhibitors? A meta-regression analysis. Cardiol Ther. 2017;6:129–32. https://doi.org/10.1007/s40119-016-0075-1.
Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396:819–29. https://doi.org/10.1016/S0140-6736(20)31824-9.
Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med. 2002;347:1403–11. https://doi.org/10.1056/NEJMoa021266.
Furberg CD, Vittinghoff E, Davidson M, Herrington DM, Simon JA, Wenger NK, et al. Subgroup interactions in the Heart and Estrogen/Progestin Replacement Study: lessons learned. Circulation. 2002;105:917–22. https://doi.org/10.1161/hc0802.104280.
Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. 1999;100:2312–8. https://doi.org/10.1161/01.cir.100.23.2312.
Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M, Martinez FA, HEAAL Investigators, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet. 2009;374:1840–8. https://doi.org/10.1016/S0140-6736(09)61913-9.
Santema BT, Ouwerkerk W, Tromp J, Sama IE, Ravera A, Regitz-Zagrosek V, Voors AA, ASIAN-HF investigators, et al. Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study. Lancet. 2019;394:1254–63. https://doi.org/10.1016/S0140-6736(19)31792-1. The study demonstrates the differences in effective doses of heart failure medications according with gender.
Funding
Open access funding provided by Università di Foggia within the CRUI-CARE Agreement.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Massimo Iacoviello received honoraria as speaker or consultant by AstraZeneca, Boehringer Ingelheim, Lilly, Merck-Serono, Novartis, and Viphor Pharma. Rosanna Pugliese, Michele Correale, and Natale Daniele Brunetti declare that they have no conflict of interest for this review.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Clinical Heart Failure
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Iacoviello, M., Pugliese, R., Correale, M. et al. Optimization of Drug Therapy for Heart Failure With Reduced Ejection Fraction Based on Gender. Curr Heart Fail Rep 19, 467–475 (2022). https://doi.org/10.1007/s11897-022-00583-w
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11897-022-00583-w