Hemodynamic Characterization of Tolerance to Long-Term Hydralazine Therapy in Severe Chronic Heart Failure

We performed hemodynamic studies in 11 patients with severe chronic heart failure whose symptoms had returned to their pretreatment status after 37±15 weeks (mean ±S.E.M.) of therapy with the vasodilator hydralazine. The cardiac index increased from 1.85 to 3.47 liters per minute per square meter of body-surface area, and systemic vascular resistance decreased from 1748 to 754 dyn · sec · cm^-5 (both P<0.01) during initial hydralazine administration but returned to pretreatment values on repeat evaluation; withdrawal of the drug produced no hemodynamic deterioration. Responsiveness to hydralazine could not be restored by doubling the oral dose or by intravenous administration; tolerance was associated with fluid retention in five patients but was not reversed by intensive diuresis. In contrast, the responses to nitroprusside evaluated before and after the development of hydralazine tolerance were unaltered; other oral vasodilators were still effective. We conclude that drug-specific tolerance may account for the lack of clinical improvement in some patients with severe heart failure who receive long-term treatment with hydralazine. (N Engl J Med. 1982; 306:57–62.) By reducing impedance to left ventricular ejection, hydralazine can produce substantial short-term improvement in cardiac performance in patients with severe chronic heart failure.^{1 2 3 4} Although a number of reports have noted an amelioration of dyspnea and fatigue after the institution of hydralazine therapy,^{1 2 3 4} a randomized clinical trial showed no significant differences between patients receiving long-term drug treatment and placebo-treated controls.⁵ The lack of effectiveness of hydralazine in this study may have been due to the administration of subtherapeutic doses of the drug⁶ or to the inclusion of patients without notable dilatation of the left ventricular chamber, who were unlikely to respond.