General (including evidence of efficacy)
These agents are generally used in combination in heart failure and most of the large trials of vasodilators in heart failure pertain to this combination.
Differences between drugs within the class
Refer to the discussion on hydralazine, a primary afterload-reducing agent, and nitrates, primarily preload-reducers.
The dose range and final dose selection of this combination is the same as that noted under hydralazine administration and under oral nitrate administration. The final dose is generally hydralazine 25 to 100 mg combined with isosorbide dinitrate (ISDN) at 20 to 40 mg, administered in a TID or QID schedule to avert the potential for nitrate tolerance.
These agents can be administered as two separate drugs (but given at the same time), allowing independent dose adjustment of each. For patient convenience, a commercial product, BiDil, combines the two agents into one tablet containing hydralazine 37.5 mg and isosorbide dinitrate (ISDN) 20 mg.
With proper dose selection, the hydralazine-nitrate combination provides balanced afterload-preload reduction with a lowering of ventricular filling pressure, and systemic and pulmonic vascular resistance.
The combination reduced mortality in heart failure compared to a placebo and the alpha-adrenergic blocker, prazosin (V-HeFT trial). In the V-HeFT II trial, enalapril had a more beneficial effect on survival than the hydralazine-ISDN combination.
But a retrospective analysis of the V-HeFT II data showed that African-Americans had a comparable survival time to enalapril and hydralazine-ISDN, but with a better quality of life and improved peak oxygen consumption with hydralazine-ISDN. The A-HeFT trial compared hydralazine-ISDN with a placebo in African-American patients with symptomatic heart failure despite standard background therapy that included angiotensin-converter enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs); hydralazine-ISDN improved survival time, quality of life, and the rate of first rehospitalization.
Indications and contraindications
Hydralazine-ISDN is indicated for all patients with heart failure who remain symptomatic while on optimal dosing of ACE inhibitors or ARBs, beta-adrenergic blockers, and diuretics. This combination is also useful in patients with heart failure who cannot tolerate or who experience adverse effects (e.g., angioedema, renal dysfunction) from ACE inhibitors and ARBs.
Intolerance or adverse effects to either hydralazine or ISDN may limit the use of this combination.
These have been presented under the undesirable effects of hydralazine and ISDN separately. ISDN appears to have a protective effect for hydralazine when administered to patients with extensive coronary artery disease and ischemic cardiomyopathy.
If the hydralazine-ISDN is not tolerated as a combination, treatment with either component alone is reasonable (except in critical coronary disease where hydralazine can increase angina and ischemia). Thereafter, continued optimization of ACE inhibitors or ARBs, diuretics, and beta-blockers is encouraged.
What's the Evidence?
Cohn, JN, Archibald, DG, Ziesche, S. ” Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of the Veterans Administration Cooperative Study”. N Engl J Med. vol. 314. 1986. pp. 1547-1552.
Taylor, AL, Ziesche, S, Yancy, C. “Combination of isosorbide dinitrate and hydralazine in blacks with heart failure”. N Engl J Med. vol. 351. 2004. pp. 2049-2057. (These are some of the major trials showing favorable outcomes to combination isosorbide dinitrate – hydralazine in patients with chronic congestive heart failure.)
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