Hydralazine-isosorbide dinitrate heart failure

Cohn IN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure, [see comment]. N. Engl. J. Med. 1991 325 303-10. 

Clinical benefits and effects on mortality and hospitalization Whether used alone or in combination, hydralazine and isosorbide dinitrate decrease the preload and afterload, decrease mitral regurgitation, improve cardiac output, increase exercise capacity, modestly increase LVEF and prolong survival in patients with HF (63,64). V-Heart Failure Trial (HeFT) II (64) showed that enalapril had a major benefit on survival when compared with the combination of hydralazine-isosorbide dinitrate with enalapril in patients with predominantly NYHA class ll-lll. The African Americans in Heart Failure Trial (A-HeFT) (65) showed a beneficial effect of adding vasodilator therapy to African-American patients already treated with ACE inhibitors, (3 blockers, and spironolactone. There are no results with the same strategy in other patient groups. 

The CONSENSUS study was performed in 253 patients with severe congestive heart failure. They were randomized to receive either placebo (n = 126) or enalapril (n = 127), from 2.5 mg bid to 20 mg bid with a follow-up period that averaged 182 days. By the end of the study, there had been 68 deaths in the placebo group and 50 in the enalapril group (p =. 003) (313). Later, enalapril was shown to be superior to hydralazine-isosorbide dinitrate (314, 315). 

Severe postural hypotension has been observed in patients given both isosorbide dinitrate and hydralazine for chronic heart failure (26), although this has not been a problem in large studies (90). 

Massie B, Kramer B, Haughom F. Postural hypotension and tachycardia during hydralazine-isosorbide dinitrate therapy for chronic heart failure. Circulatiou 1981 63(3) 658-64. 

The beneficial effect of ACE inhibitors on mortality has been documented conclusively, with numerous trials showing a 20% to 30% relative reduction in mortality with ACE inhibitor therapy compared with placebo. A long-term (12-year) follow-up of the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials demonstrated sustained survival benefits in patients treated with enalapril. In addition to improving survival, ACE inhibitors also reduce the combined risk of death or hospitalization, slow the progression of heart failure, and reduce the rates of reinfarction.The benefits of ACE inhibitor therapy are independent of the etiology of heart failure (ischemic versus nonischemic) and are observed in patients with mild, moderate, or severe symptoms. ACE inhibitors clearly are superior to vasodilator therapy with hydralazine-isosorbide dinitrate. ... 

The rationale for the use of oral vasodilator drugs in the pharmacotherapy of CHF derived from the experience with the parenteral agents phentolamine and nitroprusside in patients with severe heart failure and elevated systemic vascular resistance. Although a number of vasodilators may improve symptoms in heart failure, only the hydralazine-isosorbide dinitrate combination and antagonists of the renin-angiotensin system (ACE inhibitors and ATj receptor blockers) have been shown to improve survival in prospective randomized trials. Table 33-1 summarizes some properties of vasodilators used to treat heart failure. 

Taylor AL, Ziesche S, Yancy C, Carson P, D Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn IN African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004 Nov ll 351(20) 2049-57. 

Direct Vasodilators Isosorbide dinitrate 20 mg and hydralazine 37.5 (BiDil) 1-2 tablets three times a day Minoxidil (Loniten) Hydralazine Heart failure (isosorbide dinitrate + hydralazine in African-Americans) A-HeFT66 Edema (minoxidil) Tachycardia Lupus-like syndrome (hydralazine) ... 

Vasodilators are effective in acute heart failure because they provide a reduction in preload (through venodilation), or reduction in afterload (through arteriolar dilation), or both. Some evidence suggests that long-term use of hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart. 

Taylor AL et al Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004 351 2049. [PMID 15533851]... 

Dilation of venous blood vessels leads to a decrease in cardiac preload by increasing venous capacitance arterial dilators reduce systemic arteriolar resistance and decrease afterload. Nitrates (see p. 175) are commonly employed venous dilators for patients with congestive heart failure. If the patient is intolerant of ACE inhibitors, the combination of hydralazine and isosorbide dinitrate is most commonly used. Amlodipine and felodipine (see p. 188) have less negative inotropic effect than other calcium channel blockers, and seem to decrease sympathetic nervous activity. 

Nitrates are the drugs of choice in patients with left ventricular impairment, in whom they are of benefit when used in combination with hydralazine (3), and they should be used in preference to the calcium antagonists, which cause deterioration in myocardial function by an as yet unknown mechanism (4). In black patients with congestive heart failure taking ACE inhibitors and beta-block-ers, a combination of isosorbide dinitrate plus hydralazine significantly reduced total mortality (5). 

The combination of isosorbide dinitrate with hydralazine is safe in systolic heart failure. Only headache and palpitation necessitated drug withdrawal and were more common than with enalapril (90). Headache and dizziness were more common with isosorbide dinitrate plus hydralazine than with placebo in patients taking ACE inhibitors and beta-blockers (5). 

One side effect unique to hydralazine is a dose-dependent drug-induced lupus-like syndrome. Hydralazine is eliminated by hepatic A-acetyltransferase. This enzyme displays genetic polymorphism, and slow acetylators are especially prone to develop drug-induced lupus with hydralazine. This syndrome is more common in women and is reversible on discontinuation. Drug-induced lupus may be avoided by using less than 200 mg hydralazine daily. Other side effects of hydralazine include dermatitis, drug fever, peripheral neuropathy, hepatitis, and vascular headaches. For these reasons, hydralazine has limited usefulness in the treatment of hypertension. However, it is still used with isosorbide dinitrate in patients with heart failure (especially African-Americans) and is useful in patients with severe chronic kidney disease and kidney failure. 

Discuss the benefits of combination therapy with hydralazine and isosorbide dinitrate (IDN) in heart failure. 

F. Vasodilators Vasodilator therapy with nitroprusside or nitroglycerin is often used for acute severe congestive failure. The use of these vasodilator drugs is based on the reduction in cardiac size and improved efficiency that can be realized with proper adjustment of venous return and reduction of resistance to ventricular ejection. Vasodilator therapy can be dramatically effective, especially in cases in which increased afterload is a major factor in causing the failure (eg, continuing hypertension in an individual who has just had an infarct). Chronic congestive heart failure sometimes responds favorably to oral vasodilators such as hydralazine or isosorbide dinitrate. 

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