Hydralazine plus nitrate therapy in patients with heart failure with reduced ejection fraction
- Wilson S Colucci, MD
Wilson S Colucci, MD
- Section Editor — Heart Failure
- Professor of Medicine
- Boston University School of Medicine
Hydralazine plus nitrate therapy provides symptomatic and mortality benefit in selected patients with heart failure with reduced ejection fraction (HFrEF; also known as HF due to systolic dysfunction or systolic HF) .
Recommendations for use of hydralazine plus nitrates in patients with HFrEF and data supporting the efficacy of this drug combination will be presented here. An overview of the treatment of HFrEF is presented separately (figure 1). (See "Overview of the therapy of heart failure with reduced ejection fraction".)
A hemodynamic rationale for the combined use of hydralazine and nitrate therapy is to reduce cardiac preload and afterload by achieving both venous and arterial vasodilation. Hydralazine is an arterial vasodilator and nitrates are predominantly venodilators. These vasodilatory effects can reduce intracardiac filling pressures, which may reduce adverse cardiac remodeling. (See "Cardiac remodeling: Basic aspects".)
It has also been hypothesized that combined hydralazine and nitrate therapy enhances nitric oxide bioavailability since nitrates serve as nitric oxide donors and hydralazine is an antioxidant that reduces consumption of nitric oxide [1-3]. It has been postulated that this protective mechanism can be recruited even in the presence of neurohormonal blockade (eg, use of angiotensin converting enzyme inhibitors).
Indications — For select patients with heart failure with reduced ejection fraction (HFrEF), we recommend hydralazine plus oral nitrate as a component of therapy. Our recommendations are similar to major society guidelines (figure 1) and are based on the clinical trial evidence discussed below. The strength of the evidence for benefit is somewhat stronger in black patients than in other patient groups, as reflected in our recommendations. (See 'Major society guidelines and regulations' below and 'Evidence of benefit' below.)
- Cole RT, Kalogeropoulos AP, Georgiopoulou VV, et al. Hydralazine and isosorbide dinitrate in heart failure: historical perspective, mechanisms, and future directions. Circulation 2011; 123:2414.
- Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004; 351:2049.
- Taylor AL, Ziesche S, Yancy CW, et al. Early and sustained benefit on event-free survival and heart failure hospitalization from fixed-dose combination of isosorbide dinitrate/hydralazine: consistency across subgroups in the African-American Heart Failure Trial. Circulation 2007; 115:1747.
- Fonarow GC, Yancy CW, Hernandez AF, et al. Potential impact of optimal implementation of evidence-based heart failure therapies on mortality. Am Heart J 2011; 161:1024.
- Cheng JW. A review of isosorbide dinitrate and hydralazine in the management of heart failure in black patients, with a focus on a new fixed-dose combination. Clin Ther 2006; 28:666.
- http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4145B2_02_01-NitroMed-Background.htm (Accessed on April 01, 2016).
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128:1810.
- Heart Failure Society of America, Lindenfeld J, Albert NM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail 2010; 16:e1.
- McMurray JJ, Adamopoulos S, Anker SD, et al. 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 2012; 33:1787.
- Anand IS, Win S, Rector TS, et al. Effect of fixed-dose combination of isosorbide dinitrate and hydralazine on all hospitalizations and on 30-day readmission rates in patients with heart failure: results from the African-American Heart Failure Trial. Circ Heart Fail 2014; 7:759.
- Anand IS, Tam SW, Rector TS, et al. Influence of blood pressure on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine in the African-American Heart Failure Trial. J Am Coll Cardiol 2007; 49:32.
- 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; 314:1547.
- Cohn JN, Ziesche S, Smith R, et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study Group. Circulation 1997; 96:856.
- 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; 103:1113.
- 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; 325:303.
- Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail 1999; 5:178.
- Loeb HS, Johnson G, Henrick A, et al. Effect of enalapril, hydralazine plus isosorbide dinitrate, and prazosin on hospitalization in patients with chronic congestive heart failure. The V-HeFT VA Cooperative Studies Group. Circulation 1993; 87:VI78.
- Bloche MG. Race-based therapeutics. N Engl J Med 2004; 351:2035.
- Kalinowski L, Dobrucki IT, Malinski T. Race-specific differences in endothelial function: predisposition of African Americans to vascular diseases. Circulation 2004; 109:2511.
- Stein CM, Lang CC, Nelson R, et al. Vasodilation in black Americans: attenuated nitric oxide-mediated responses. Clin Pharmacol Ther 1997; 62:436.
- Granger CB, McMurray JJ, Yusuf S, 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.
- McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003; 362:767.
- Our approach
- - Indications
- - Contraindications
- - Evaluation prior to initiation of therapy
- - Administration
- - Management of adverse effects
- Major society guidelines and regulations
- EVIDENCE OF BENEFIT
- In addition to standard therapy
- Earlier trials
- Unresolved issues
- - Racial subgroups
- - NYHA class II or IV heart failure
- SUMMARY AND RECOMMENDATIONS