Mini review: The clinical avenues of combined hydralazine-nitrate in subjects with heart failure with reduced ejection fraction

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Asim Ahmed Elnour
Adel Sadeq
Azza Ramadan
Abdalla Alamoodi
Alin Alkawarit
Asma Faisal Alshammari
Israa Yousif Elkhidir
Nouf Eid Alrashidi
Parisa kouhgard
Mariam Mohamed Al Qahtani
Semira Abdi Beshir
Khalid Awad Al-Kubaisi
Nadia Al Mazrouei
Maisoun Alkaabi
Afaf Ashoor


hydralazine-nitrate; heart failure with reduced ejection fraction (HFrEF), hydralazine, isosorbide dinitarte, randomized clinical trials, Vasodilator Heart Failure Trial I (V-HeFT I), the Vasodilator Heart Failure Trial II (V-HeFT II), New York Heart Association (NYHA)


Background: Combined hydralazine-nitrate has an avenue in the management of subjects with heart failure with reduced ejection fraction. Exploring the pharmacotherapy in this context will facilitate the clinical utility of the combined therapy. Objective: The main objective of this mini-review was to evaluate the role of combined hydralazine-nitrate in subjects with heart failure with reduced ejection fraction. Methods: We conducted a literature search on Google scholar, MEDLINE, and PubMed to identify the randomized clinical trials on combined hydralazine-nitrate, in subjects with heart failure with reduced ejection fraction. 2760 articles were returned initially out of which 10 trials were conforming to the inclusion criteria. However, three trails were the focus for the current mini-review. Key findings: The current mini-review lends support to the use of combined hydralazine-nitrate in subjects with heart failure with reduced ejection fraction (HFrEF). The combination may offer subjects who have remained symptomatic with HFrEF despite optimum dosing of standard therapy. Black subjects with HFrEF have proved to benefit from combined hydralazine-nitrate. The combination (e.g. small dose of hydralazine 12.5-25 mg twice a day and isosorbide mononitrate 10 mg twice a day) may provide alternative clinical utility in subjects with contraindications (renal artery stenosis, creatinine clearance less than 30 mL/minute, sustained hyperkalemia) to the use of ACEinh, ARBs, and/or ARNI. Subjects with HFrEF on combined hydralazine-nitrate should be assessed and monitored for systolic BP (keep >120 mmHg) and subjects with chronic kidney disease (keep eGFR > 30 mL/min/1.73 m2). Hydralazine-nitrate was inferior to ACEinh (higher all-cause mortality and cardiovascular mortality. Conclusion: The current minireview provides the key points to support the use of hydralazine-nitrate in subjects with heart failure with reduced ejection fraction..

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1. Cotton JM, Kearney MT, Shah AM. Nitric oxide and myocardial function in heart failure: friend or foe? BMJ Journal. 2002;88(6):564-566.
2. Jugdutt BI. The Role of Nitric Oxide in Heart Failure. Kluwer Academic Publishers. 2004;81-88.
3. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314(24):1547-1552.
4. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325(5):303-310.
5. Yusuf S, Pitt B, Davis CE, et al. 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.
6. Carson P, Ziesche S, Johnson G, et al. Racial differences in response to therapy for heart failure: analysis of the vasodilatorheart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail. 1999;5(3):178-187.
7. Exner DV, Dries DL, Domanski MJ, et al. Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med. 2001;344(18):1351-1357. https://doi.
8. Taylor AL, Ziesche S, Yancy C, et al. African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351(20):2049-57.
9. Turgeon RD, Barry AR, Hawkins NM, et al. Pharmacotherapy for heart failure with reduced ejection fraction and health-related quality of life: a systematic review and meta-analysis. Eur J Heart Fail. 2021;23(4):578-589.
10. Mullens W, Abrahams Z, Francis GS, et al. Usefulness of Isosorbide Dinitrate and Hydralazine as add-on therapy in patients discharged for advanced decompensated heart failure. Am J Cardiol. 2009;103(8):1113-1119.
11. Ziaeian B, Fonarow GC, Heidenreich PA. Clinical Effectiveness of Hydralazine-Isosorbide Dinitrate in African-American Patients with Heart Failure. JACC Heart Fail. 2017;5(9):632-639.
12. Farag M, Mabote T, Shoaib A, et al. Hydralazine and nitrates alone or combined for the management of chronic heart failure: A systematic review. Int J Cardiol. 2015;196(1):61-9.
13. Ponikowski P, Voors AA, Anker SD, et al. ESC Scientific Document Group. 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):2129-2200.
14. Real J, Cowles E, Wierzbicki AS; Guideline Committee. Chronic heart failure in adults: summary of updated NICE guidance. BMJ. 2018;362:k3646.
15. Henrik Wiggers, Lars Køber, Gunnar Gislason, et al. The DANish randomized, double-blind, placebo-controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic
heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT). AHJ. 2021;23(1):137-146.
16. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure (PARADIGM). N Engl J Med. 2014;371:993-1004.
17. Moulis F, Rousseau V, Chebane L, et al. Serious adverse drug reactions with sacubitril/valsartan Entresto®: a French pharmacovigilance survey. Eur J Clin Pharmacol. 2018;74(7):983-984.
18. Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004;17(2):103-11.
19. Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002;106(8):920-6.
20. John JV, McMurray, Scott D, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008.
21. FDA approves new treatment for a type of heart failure ( website). 2020. Available at: press-announcements/fda-approves-new-treatment-type-heart-failure. Accessed 04/11/2021.
22. Paul W. Armstrong, Burkert Pieske, Kevin J. Anstrom, et al. VICTORIA Study Group. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med. 2020;382(20):1883-93.
23. Teerlink JR, Diaz R, Felker GM, et al. GALACTIC-HF Investigators. Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure. N Engl J Med. 2021;384(2):105-116.

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