Nitrate use in Heart Failure

Isosorbide dinitrate can be used with hydralazine in heart failure as an alternative to ACE-inhibitors or ARBs.  The medications act complementary to dilate the blood vessels.  Hydralazine reduces afterload by decreasing both pulmonary and systemic vascular resistance.  Its effects on vasodilation are not completely understood.  It also has some moderate inotropic effects.  It reduces renal vascular resistance, though not by as much as ACE-inhibitors.¹ 

Nitrates like isosorbide dinitrate relax blood vessels by releasing NO.  Isosorbide dinitrate improves exercise capacity in patients with heart failure^1,2.  Nitrates can inhibit vascular and myocardial remodeling³.  Nitrates must be dosed so that there is a six to eight hour period of negligible drug levels or tolerance may develop.  Hydralazine may decrease nitrate tolerance. ^1,3

The V-HeFT trial in 1986 showed decreased mortality with the use of hydralazine and isosorbide dinitrate compared to prazosin ².  The V-HeFT II trial compared isosorbide dinitrate to enalapril in patients with moderate heart failure and found decreased survival due to a higher incidence of sudden death in the isosorbide dinitrate-hydralazine arm.  There was no difference in mortality rate in African Americans taking isosorbide dinitrate-hydralazine compared to enalapril. ²   

The A-HeFT trail in 2004 compared the addition of isosorbide dinitrate with hydralazine or placebo to standard heart failure treatment in patients of African descent in NYHA stage III or IV heart failure.  The trial was terminated early due to increased survival in patients taking hydralazine with isosorbide dinitrate.  The target dosing used in this trial was 75mg hydralazine and 40mg isosorbide dinitrate three times daily for a total daily dose of 225mg hydralazine and 120mg isosorbide dinitrate.⁴

Compliance is more difficult with a regimen containing isosorbide dinitrate and hydralazine because these medications are dosed three to four times a day.  The new product, BiDil, contains both medications but is about twice as expensive and must also be taken multiple times per day.  There is also a high discontinuation rate due to incidence of headache and GI upset.³

There is a lack of trials evaluating the use of isosorbide dinitrate without hydralazine in heart failure; these medications should be used together³.   The ACC/AHA guidelines recommend to consider the addition of hydralazine with isosorbide dinitrate in African Americans.  However, hydralazine with isosorbide should not be considered before an ACE-inhibitor if the patient has no history or ACE-inhibitor intolerance or if they are tolerating ACE-inhibitor therapy.³  The HFSA guidelines recommend to consider the use of hydralazine and isosorbide dinitrate in African Americans in standard therapy, as they do not respond as well to ACE-inhibitors as white patients.  The HFSA also recommends to consider the addition of hydralazine with isosorbide dinitrate in African Americans with stage II or III heart failure and LV dysfunction even if their regimen includes an ACE-inhibitor or beta-blocker.⁵

*Note: images are not of heart failure but are of the beach

References:

1. Brunton LL, Lazo JS, Parker KL, editors.  Goodman & Gilman’s: the pharmacological basis of therapeutics.  11th ed.  New York: McGraw-Hill Companies, Inc.; 2006.
2. Elkayam U, Bitar F.  Effects of nitrates and hydralazine in heart failure: clinical evidence before the African American heart failure trial.  American Journal of Cardiology 2005;96(suppl):37i-43i.
3. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG et al.  ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult.  Circulation 2005;112:e154-e235.
4. Taylor AL, Ziesche S, Yancy C, Carson P,  D’Agostino R, Ferdinand K et al.  Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.  The New England Journal of Medicine 2004;351(20):2049-2057.
5. Adams KF, Lindenfeld J, Arnold JMO, Baker DW, Barnard DH, Baughman KL et al.  Executive summary: HFSA 2006 comprehensive heart failure practice guideline.  Journal of Cardiac Failure 2006; 12(1):10-38.