Skip to main content
SpringerLink
Log in

Combination of Hydralazine and Isosorbide-Dinitrate in the Treatment of Patients with Heart Failure with Reduced Ejection Fraction

  • Chapter
  • First Online:
Book cover Heart Failure: From Research to Clinical Practice

Part of the book series: Advances in Experimental Medicine and Biology ((AIM,volume 1067))

Abstract

The use of direct acting vasodilators (the combination of hydralazine and isosorbide dinitrate -Hy+ISDN-) in heart failure with reduced ejection fraction (HFrEF) is supported by evidence, but rarely used.

However, treatment with Hy+ISDN is guideline-recommended for HFrEF patients who cannot receive either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers due to intolerance or contraindication, and in self-identified African-American HFrEF patients who are symptomatic despite optimal neurohumoral therapy.

The Hy+ISDN combination has arterial and venous vasodilating properties. It can decrease preload and afterload, decrease left ventricular end-diastolic diameter and the volume of mitral regurgitation, reduce left atrial and left ventricular wall tension, decrease pulmonary artery pressure and pulmonary arterial wedge pressure, increase stroke volume, and improve left ventricular ejection fraction, as well as induce left ventricular reverse remodelling. Furthermore, Hy+ISDN combination has antioxidant property, it affects endothelial dysfunction beneficially and improves NO bioavailability. Because of these benefits, this combination can improve the signs and symptoms of heart failure, exercise capacity and quality of life, and, most importantly, reduce morbidity and mortality in well-defined subgroups of HFrEF patients.

Accordingly, this therapeutic option can in many cases play an essential role in the treatment of HFrEF.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Barbato A, Russo P, Siani A et al (2004) Aldosterone synthase gene (CYP11B2) C-344T polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population. J Hypertens 22:1895–1901

    Article  CAS  PubMed  Google Scholar 

  • Bauer JA, Fung HL (1991) Concurrent hydralazine administration prevents nitroglycerin- induced hemodynamic tolerance in experimental heart failure. Circulation 84:35–39

    Article  CAS  PubMed  Google Scholar 

  • Calderone A, Thaik CM, Takahashi N, Chang DL, Colucci WS (1998) Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts. J Clin Invest 101:812–818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carson P, Johnson G, Fletcher R, Cohn JN, for the V-HEFT Cooperative Study Group (1996) Mild systolic dysfunction in heart failure (left ventricular ejection fraction >35%): baseline characteristics, prognosis and response to therapy in the Vasodilator in Heart Failure Trials (V-HeFT). J Am Coll Cardiol 27:642–649

    Article  CAS  PubMed  Google Scholar 

  • Carson P, Ziesche S, Johnson G, Cohn JN, for the Vasodilator-Heart Failure Trial Study Group (1999) Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail 5:178–187

    Google Scholar 

  • Chatterjee K, Ports TA, Brundage BH, Massie B, Holly AN, Parmley WW (1980) Oral hydralazine in chronic heart failure: sustained beneficial hemodynamic effects. Ann Intern Med 92:600–604

    Article  CAS  PubMed  Google Scholar 

  • Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Hartson WE, Tristani FE et al (1986) Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 314:1547–1552

    Article  CAS  PubMed  Google Scholar 

  • Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F et al (1991) A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 325:303–310

    Article  CAS  PubMed  Google Scholar 

  • Cohn JN, Tam SW, Anand IS, Taylor AL, Sabolinski ML, Worcel M (2007) A-HeFT Investigators. Isosorbide dinitrate and hydralazine in a fixed-dose combination produces further regression of left ventricular remodeling in a well-treated black population with heart failure: results from A-HeFT. J Card Fail 13:331–339

    Article  CAS  PubMed  Google Scholar 

  • Daiber A, Mulsch A, Hink U, Mollnau H, Warnholtz A, Oelze M et al (2005) The oxidative stress concept of nitrate tolerance and the antioxidant properties of hydralazine. Am J Cardiol 96:25i–36i

    Article  CAS  PubMed  Google Scholar 

  • Damasceno A, Mayosi BM, Sani M, Ogah OS, Mondo C, Ojji D et al (2012) The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries. Arch Intern Med 172:1386–1394

    Article  CAS  PubMed  Google Scholar 

  • Elkayam U, Johnson JV, Shotan A, Bokhari S, Solodky A, Canetti M et al (1999) Double-blind, placebo-controlled study to evaluate the effect of organic nitrates in patients with chronic heart failure treated with angiotensin-converting enzyme inhibition. Circulation 99:2652–2657

    Article  CAS  PubMed  Google Scholar 

  • Exner DV, Dries DL, Domanski MJ, Cohn JN (2001) Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med 344:1351–1357

    Article  CAS  PubMed  Google Scholar 

  • Farag M, Mabote T, Shoaib A, Zhang J, Nabhan AF, Clark AL et al (2015) Hydralazine and nitrates alone or combined for the management of chronic heart failure: a systematic review. Int J Cardiol 196:61–69

    Article  PubMed  Google Scholar 

  • Franciosa JA, Pierpont G, Cohn JN (1977) Hemodynamic improvement after oral hydralazine in left ventricular failure: a comparison with nitroprusside infusion in 16 patients. Ann Intern Med 86:388–393

    Article  CAS  PubMed  Google Scholar 

  • Franciosa JA, Nordstrom LA, Cohn JN (1978a) Nitrate therapy for congestive heart failure. JAMA 240:443–446

    Article  CAS  PubMed  Google Scholar 

  • Franciosa JA, Blank RC, Cohn JN (1978b) Nitrate effects on cardiac output and left ventricular outflow resistance in chronic congestive heart failure. Am J Med 64:207–213

    Article  CAS  PubMed  Google Scholar 

  • Garg UC, Hassid A (1989) Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 83:1774–1777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gogia H, Mehra A, Parikh S, Raman M, Ajit-Uppal J, Johnson JV et al (1995) Prevention of tolerance to hemodynamic effects of nitrates with concomitant use of hydralazine in patients with chronic heart failure. J Am Coll Cardiol 26:1575–1580

    Article  CAS  PubMed  Google Scholar 

  • Golwala HB, Thadani U, Liang L, Stavrakis S, Butler J, Yancy CW, Bhatt DL, Hernandez AF, Fonarow GC (2013) Use of hydralazine-isosorbide dinitrate combination in African American and other race/ethnic group patients with heart failure and reduced left ventricular ejection fraction. J Am Heart Assoc 2:e000214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson W, Omland T, Hall C, Lucas C, Myking OL, Collins C et al (2002) Neurohormonal activation rapidly decreases after intravenous therapy with diuretics and vasodilators for class IV heart failure. J Am Coll Cardiol 40:1114–1119

    Article  PubMed  Google Scholar 

  • Jugdutt BI, Khan MI (1994) Effect of prolonged nitrate therapy on left ventricular remodeling after canine acute myocardial infarction. Circulation 89:2297–2307

    Article  CAS  PubMed  Google Scholar 

  • Khazanie P, Liang L, Curtis LH, Butler J, Eapen ZJ, Heidenreich PA et al (2016) Clinical effectiveness of hydralazine-isosorbide dinitrate therapy in patients with heart failure and reduced ejection fraction: findings from the Get With The Guidelines–Heart Failure Registry. Circ Heart Fail 9:e002444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Knowles HJ, Tian YM, Mole DR, Harris AL (2004) Novel mechanism of action for hydralazine: induction of hypoxia-inducible factor -1alpha, vascular endothelial growth factor, and angiogenesis by inhibition of prolyl hydroxylases. Circ Res 95:162–169

    Article  CAS  PubMed  Google Scholar 

  • Leier CV, Huss P, Magorien RD, Unverferth DV (1983) Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure. Circulation 67:817–822

    Article  CAS  PubMed  Google Scholar 

  • Lisy O, Redfield MM, Jovanovic S, Jougasaki M, Jovanovic A, Leskinen H et al (2000) Mechanical unloading versus neurohormonal stimulation on myocardial structure and endocrine function in vivo. Circulation 102:338–343

    Article  CAS  PubMed  Google Scholar 

  • Maggioni AP, Anker SD, Dahlström U, Filippatos G, Ponikowski P, Zannad F et al (2013) Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12 440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 15:1173–1184

    Article  CAS  PubMed  Google Scholar 

  • Marroni AS, Metzger IF, Souza-Costa DC, Nagassaki S, Sandrim VC, Correa RX et al (2005) Consistent interethnic differences in the distribution of clinically relevant endothelial nitric oxide synthase genetic polymorphisms. Nitric Oxide 12:177–182

    Article  CAS  PubMed  Google Scholar 

  • McMurray JJV, Adamopoulos S, Anker SD et al (2012) ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 33:1787–1847

    Article  Google Scholar 

  • McNamara DM, Tam SW, Sabolinski ML, Tobelmann P, Janosko K, Taylor AL et al (2006) Aldosterone synthase promoter polymorphism predicts outcome in African Americans with heart failure: results from the A-HeFT trial. J Am Coll Cardiol 48:1277–1282

    Article  CAS  PubMed  Google Scholar 

  • McNamara DM, Tam SW, Sabolinski ML, Tobelmann P, Janosko K, Venkitachalam L et al (2009) Endothelial nitric oxide synthase (NOS3) polymorphisms in African Americans with heart failure: results from the A-HeFT trial. J Card Fail 15:191–198

    Article  CAS  PubMed  Google Scholar 

  • McNamara DM, Taylor AL, Tam SW, Worcel M, Yancy CW, Hanley-Yanez K et al (2014) G-protein beta-3 subunit genotype predicts enhanced benefit of fix-dose isosorbide-dinitrate and hydralazine: results of A-HeFT. J Am Coll Cardiol 2:551–557

    Google Scholar 

  • Mullens W, Abrahams Z, Francis GS, Sokos G, Starling RC, Young JB et al (2009) Usefulness of Isosorbide Dinitrate and Hydralazine as Add-on Therapy in Patients Discharged for Advanced Decompensated Heart Failure. Am J Cardiol 103:1113–1119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Münzel T, Kurz S, Rajagopalan S, Thoenes M, Berrington WR, Thompson JA et al (1996) Hydralazine prevents nitroglycerin tolerance by inhibiting activation of membrane-bound NADH oxidase. A new action for an old drug. J Clin Invest 98:1465–1470

    Article  PubMed  PubMed Central  Google Scholar 

  • Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS 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 37:2129–2200

    Article  Google Scholar 

  • Rosskopf D, Manthey I, Siffert W (2002). Identification and ethnic distribution of major haplotypes in the gene GNB3 encoding the G-protein beta-3 subunit. Pharmacogenetics 12:209–220

    Article  CAS  PubMed  Google Scholar 

  • The SOLVD Investigators (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 325:293–302

    Google Scholar 

  • Stevenson LW (1999) Tailored therapy to hemodynamic goals for advanced heart failure. Eur J Heart Fail 1:251–257

    Article  CAS  PubMed  Google Scholar 

  • Stevenson WG, Stevenson LW, Middlekauff HR, Fonarow GC, Hamilton MA, Woo MA et al (1995) Improving survival for patients with advanced heart failure: a study of 737 patients. J Am Coll Cardiol 26:1417–1423

    Article  CAS  PubMed  Google Scholar 

  • Taylor AL (2016) Making medicine precise and personalized: what can we learn from the past? Circ Heart Fail 9:e002938

    PubMed  Google Scholar 

  • Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand K, et al, for the African-American Heart Failure Trial Investigators (2004) Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 351:2049–2057

    Article  CAS  PubMed  Google Scholar 

  • The CONSENSUS Trial Study Group (1987) Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 316:1429–1435

    Article  Google Scholar 

  • The SOLVD Investigators (1992) Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. N Engl J Med 327:685–691

    Article  Google Scholar 

  • Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y (1998) Randomized, double-blind, placebo-controlled study of carvedilol on the prevention of nitrate tolerance in patients with chronic heart failure. J Am Coll Cardiol 32:1194–1200

    Article  CAS  PubMed  Google Scholar 

  • Yancy CW, Ghali JK, Braman VM, Sabolinski ML, Worcel M, Archambault T et al (2007) Evidence for the continued safety and tolerability of fix-dose isosorbide dinitrate/hydralazine in patients with chronic heart failure (the extension to African-American Heart Failure Trial). Am J Cardiol 100:684–689

    Article  CAS  PubMed  Google Scholar 

  • Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH 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. Circulation 128:240–327

    Article  Google Scholar 

  • Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM 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 68:1476–1488

    Article  PubMed  Google Scholar 

  • Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM et al (2017) ACC/AHA/HFSA focused 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. Circulation 136(6):e137–e161

    Article  PubMed  Google Scholar 

  • Ziesche S, Cobb FR, Cohn JN, Johnson G, Tristani F (1993) Hydralazine and isosorbide dinitrate combination improves exercise tolerance in heart failure. Results from V-HeFT I and V-HeFT II. Circulation 87(Suppl VI):56–64

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department for Cardiology, Hungarian Defence Forces – Medical Centre, Budapest, Hungary

    Noémi Nyolczas, Miklós Dékány & Balázs Muk

  2. Heart-Lung Clinic, University Hospital Örebro, Örebro, Sweden

    Barna Szabó

Authors
  1. Noémi Nyolczas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miklós Dékány
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Balázs Muk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Barna Szabó
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Noémi Nyolczas .

Editor information

Editors and Affiliations

  1. Department of Clinical Sciences and Education, Karolinska Institutet, Stockholm, Sweden

    Md. Shahidul Islam

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Nyolczas, N., Dékány, M., Muk, B., Szabó, B. (2017). Combination of Hydralazine and Isosorbide-Dinitrate in the Treatment of Patients with Heart Failure with Reduced Ejection Fraction. In: Islam, M. (eds) Heart Failure: From Research to Clinical Practice. Advances in Experimental Medicine and Biology(), vol 1067. Springer, Cham. https://doi.org/10.1007/5584_2017_112

Download citation

  • DOI: https://doi.org/10.1007/5584_2017_112

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-78279-9

  • Online ISBN: 978-3-319-78280-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation