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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Sex Differences in Therapies for Heart Failure

Author(s): Davor Miličić*, Maria Bergami and Saša Pavasović

Volume 28, Issue 16, 2022

Published on: 12 May, 2022

Page: [1295 - 1303] Pages: 9

DOI: 10.2174/1381612828666220301125514

Price: $65


Heart failure (HF) is a common cause of morbimortality with different etiopathogenesis and prognosis between men and women. This review provides a brief overview of gender-based differences in response to pharmacological therapies of heart failure with or without reduced ejection fraction (EF). It focuses on the differences in therapy outcomes with angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), angiotensin neprilysin inhibitors (ARNI), beta-adrenergic blockers, mineralocorticoid/ aldosterone receptor antagonists, diuretics, ivabradine and digoxin. The baseline data originate from randomised controlled trials (RCTs) and large registries. We conclude that current guidelines recommending similar therapeutic approaches for both men and women are appropriate, while additional consideration should be given to different approaches regarding the use of ARBs, ACEi, and digoxin. Based on the available data, the ARBs might be considered a first-line therapy of HR for women instead of ACEi. Moreover, female patients should have stricter digoxin monitoring due to higher sensitivity and increased risk of complications. Finally, women are underrepresented in current clinical trials, and therefore future trials should aim to balance the gender recruitment disparity allowing sub-group analysis and comparisons between genders to guide individualised therapeutic strategies and appropriately targeted preventative steps.

Keywords: Heart failure, sex differences, HFpEF, digoxin, women, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, randomized controlled trial.

Next »
Fox KF, Cowie MR, Wood DA, et al. Coronary artery disease as the cause of incident heart failure in the population. Eur Heart J 2001; 22(3): 228-36.
[] [PMID: 11161934]
He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med 2001; 161(7): 996-1002.
[] [PMID: 11295963]
Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev 2017; 3(1): 7-11.
[] [PMID: 28785469]
Tan LB, Williams SG, Tan DKH, Cohen-Solal A. So many definitions of heart failure: Are they all universally valid? A critical appraisal. Expert Rev Cardiovasc Ther 2010; 8(2): 217-28.
[] [PMID: 20136608]
Braunwald E. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 4th ed. Saunders 1992.
Azad N, Kathiravelu A, Minoosepeher S, Hebert P, Fergusson D. Gender differences in the etiology of heart failure: A systematic review. J Geriatr Cardiol 2011; 8(1): 15-23.
[] [PMID: 22783280]
Strömberg A, Mårtensson J. Gender differences in patients with heart failure. Eur J Cardiovasc Nurs 2003; 2(1): 7-18.
[] [PMID: 14622644]
Ho KKL, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: The Framingham study. J Am Coll Cardiol 1993; 22(4)(Suppl. A): 6A-13A.
[] [PMID: 8376698]
Mehta PA, Cowie MR. Gender and heart failure: A population perspective. Heart 2006; 92(Suppl. 3): iii14-8.
[] [PMID: 16614262]
López-Vilella R, Marqués-Sulé E, Laymito Quispe RDP, et al. The female sex confers different prognosis in heart failure: Same mortality but more readmissions. Front Cardiovasc Med 2021; 8: 618398.
[] [PMID: 33748194]
Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL. Women’s participation in cardiovascular clinical trials from 2010 to 2017. Circulation 2020; 141(7): 540-8.
[] [PMID: 32065763]
Whitelaw S, Sullivan K, Eliya Y, 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(1): 15-24.
[] [PMID: 33118664]
Lindenfeld J, Krause-Steinrauf H, Salerno J. Where are all the women with heart failure? J Am Coll Cardiol 1997; 30(6): 1417-9.
[PMID: 9362395]
Ghali JK. A clinician’s perspective on clinical trials. J Card Fail 2001; 7(1): 1-3.
[] [PMID: 11264543]
Heiat A, Gross CP, Krumholz HM. Representation of the elderly, women, and minorities in heart failure clinical trials. Arch Intern Med 2002; 162(15): 1682-8.
[] [PMID: 12153370]
Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European society of cardiology (ESC) developed with the special contribution of the heart failure association (HFA) of the ESC. Eur Heart J 2016; 37(27): 2129-200.
[] [PMID: 27206819]
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American college of cardiology foundation/American heart association task force on practice guidelines. J Am Coll Cardiol 2013; 62(16): e147-239.
[] [PMID: 23747642]
Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: An update of the 2013 ACCF/AHA guideline for the management of heart failure: A report of the American college of cardiology/American heart association task force on clinical practice guidelines and the heart failure society of America. J Am Coll Cardiol 2016; 68(13): 1476-88.
[] [PMID: 27216111]
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(23): 1429-35.
[] [PMID: 2883575]
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(5): 293-302.
[] [PMID: 2057034]
Limacher MC, Yusuf S. Gender differences in presentation, morbidity and mortality in the Studies of left ventricular dysfunction (SOLVD): A preliminary report. In: Wenger NK, Speroff L, Packard B, Eds. Cardiovascular Health and Disease in Women. Greenwich: Le Jacq Communications 1993; pp. 345-8.
Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995; 273(18): 1450-6.
[] [PMID: 7654275]
Shekelle PG, Rich MW, Morton SC, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: A meta-analysis of major clinical trials. J Am Coll Cardiol 2003; 41(9): 1529-38.
[] [PMID: 12742294]
Flather MD, Yusuf S, Køber L, 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(9215): 1575-81.
[] [PMID: 10821360]
Keyhan G, Chen S-F, Pilote L. Angiotensin-converting enzyme inhibitors and survival in women and men with heart failure. Eur J Heart Fail 2007; 9(6-7): 594-601.
[] [PMID: 17462947]
Khan MS, Fonarow GC, Khan H, et al. Renin-angiotensin blockade in heart failure with preserved ejection fraction: A systematic review and meta-analysis. ESC Heart Fail 2017; 4(4): 402-8.
[] [PMID: 28869332]
Cleland JGF, Tendera M, Adamus J, et al. Perindopril for elderly people with chronic heart failure: The PEP-CHF study. Eur J Heart Fail 1999; 1(3): 211-7.
[] [PMID: 10935667]
Mujib M, Patel K, Fonarow GC, et al. Angiotensin-converting enzyme inhibitors and outcomes in heart failure and preserved ejection fraction. Am J Med 2013; 126(5): 401-10.
[] [PMID: 23510948]
Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet 2003; 362(9386): 759-66.
[] [PMID: 13678868]
Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345(23): 1667-75.
[] [PMID: 11759645]
Majahalme SK, Baruch L, Aknay N, et al. Comparison of treatment benefit and outcome in women versus men with chronic heart failure (from the valsartan heart failure trial). Am J Cardiol 2005; 95(4): 529-32.
[] [PMID: 15695147]
Hudson M, Rahme E, Behlouli H, Sheppard R, Pilote L. Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure--a population study. Eur J Heart Fail 2007; 9(6-7): 602-9.
[] [PMID: 17383932]
Pitt B, Poole-Wilson PA, Segal R, 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(9215): 1582-7.
[] [PMID: 10821361]
Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349(20): 1893-906.
[] [PMID: 14610160]
Konstam MA, Neaton JD, Dickstein K, 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(9704): 1840-8.
[] [PMID: 19922995]
Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008; 359(23): 2456-67.
[] [PMID: 19001508]
Mentzer G, Hsich EM. Heart failure with reduced ejection fraction in women: Epidemiology, outcomes, and treatment. Heart Fail Clin 2019; 15(1): 19-27.
[] [PMID: 30449377]
McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371(11): 993-1004.
[] [PMID: 25176015]
Levinsson A, Dubé M-P, Tardif J-C, de Denus S. Sex, drugs, and heart failure: A sex-sensitive review of the evidence base behind current heart failure clinical guidelines. ESC Heart Fail 2018; 5(5): 745-54.
[] [PMID: 29916560]
Bozkurt B, Khalaf S. Heart failure in women. Methodist DeBakey Cardiovasc J 2017; 13(4): 216-23.
[] [PMID: 29744014]
Kotecha D, Manzano L, Krum H, et al. Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: Individual patient data meta-analysis. BMJ 2016; 353: i1855-5.
[] [PMID: 27098105]
Shah RU, Chang TI, Fonarow GC. Comparative effectiveness research in heart failure therapies: Women, elderly patients, and patients with kidney disease. Heart Fail Clin 2013; 9(1): 79-92.
[] [PMID: 23168319]
MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in-congestive heart failure (MERIT-HF). Lancet 1999; 353(9169): 2001-7.
[] [PMID: 10376614]
Ghali JK, Piña 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(13): 1585-91.
[] [PMID: 11927527]
Ghali JK, Lindenfeld J. Sex differences in response to chronic heart failure therapies. Expert Rev Cardiovasc Ther 2008; 6(4): 555-65.
[] [PMID: 18402544]
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(3): 375-80.
[] [PMID: 11157688]
Packer M, Fowler MB, Roecker EB, 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(17): 2194-9.
[] [PMID: 12390947]
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(3): 215-25.
[] [PMID: 15642700]
Bugiardini R, Yoon J, Kedev S, et al. Prior beta-blocker therapy for hypertension and sex-based differences in heart failure among patients with incident coronary heart disease. Hypertension 2020; 76(3): 819-26.
[] [PMID: 32654558]
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341(10): 709-17.
[] [PMID: 10471456]
Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364(1): 11-21.
[] [PMID: 21073363]
Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014; 370(15): 1383-92.
[] [PMID: 24716680]
Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial. Circulation 2015; 131(1): 34-42.
[] [PMID: 25406305]
Merrill M, Sweitzer NK, Lindenfeld J, Kao DP. Sex differences in outcomes and responses to spironolactone in heart failure with preserved ejection fraction: A secondary analysis of TOPCAT trial. JACC Heart Fail 2019; 7(3): 228-38.
[] [PMID: 30819379]
Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336(8): 525-33.
[] [PMID: 9036306]
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(18): 1403-11.
[] [PMID: 12409542]
Adams KF Jr, Patterson JH, Gattis WA, et al. Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: A retrospective analysis. J Am Coll Cardiol 2005; 46(3): 497-504.
[] [PMID: 16053964]
Dewan P, Rørth R, Jhund PS, et al. Differential impact of heart failure with reduced ejection fraction on men and women. J Am Coll Cardiol 2019; 73(1): 29-40.
[] [PMID: 30621948]
Shin JJ, Hamad E, Murthy S, Piña IL. Heart failure in women. Clin Cardiol 2012; 35(3): 172-7.
[] [PMID: 22389122]
Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010; 376(9744): 875-85.
[] [PMID: 20801500]
Hsich EM. Sex differences in advanced heart failure therapies. Circulation 2019; 139(8): 1080-93.
[] [PMID: 30779645]
Nicolaou PA. Sex differences in heart failure medications targeting the renin-angiotensin-aldosterone system. Eur J Pharmacol 2021; 897: 173961.
[] [PMID: 33617824]
Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2009; 48(3): 143-57.
[] [PMID: 19385708]
Ghali JK. Sex-related differences in heart failure and beta-blockers. Heart Fail Rev 2004; 9(2): 149-59.
[] [PMID: 15516863]

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