Loss of effectiveness of dihydralazine in the long-term treatment of chronic heart failure.
The sustained effectiveness of the arteriolar vasodilator dihydralazine has not yet been established. Acute and long-term supplementary therapy with dihydralazine was therefore compared with placebo in 14 patients with severe congestive heart failure (classes III and IV) due to congestive cardiomyopathy. The heart failure had in most cases been refractory to treatment with digitalis and diuretics. Right and left ventricular filling pressures, cardiac output and systemic vascular resistance at rest and during exercise were measured by means of repeated right-heart catheterization. Left ventricular dimensions and contractility were measured with echocardiography, and heart volume determined by chest X-ray. Following the acute administration of 25 mg i.v. (n = 10) or 100 mg oral dihydralazine (n = 8), cardiac output increased significantly from 4.0 to 6.7 l min-1 and from 4.7 to 7.7 l min-1 respectively (2P less than 0.001). Systemic vascular resistance (SVR) decreased by about 50% (2P less than 0.02). The pulmonary artery diastolic pressure remained unchanged. At the same time, heart rate rose moderately, but significantly, and the arterial blood pressure fell slightly (approx. 7 mmHg). Shortening fraction increased from 12.5% to 17.0% (i.v.; 2P less than 0.01). During exercise, cardiac output reached about 11.7 l min-1 (i.v. and orally) as compared with 7.7 l min-1 before the administration of the vasodilator (2P less than 0.05). After a 12-week treatment period with 20 mg day-1 oral dihydralazine (n = 9), the haemodynamic effects were clearly diminished. In comparison with a placebo-period (4 weeks) following the study, only a moderate increase in cardiac output accompanied by a moderate decrease in SVR was found. In only 3 cases did the patients condition improve by one class (NYHA). All 3 had shown an initially extremely high SVR which could be effectively and persistently reduced under long-term therapy. Six patients remained unchanged, and 2 patients (class IV) worsened clinically, so that the medication had to be discontinued. Heart volume (chest X-ray) increased slightly during the 3 months of long-term therapy and notably during the one-month placebo period. According to these results, although patients with severe heart failure may show impressive haemodynamic improvement upon acute administration of dihydralazine, in most cases this improvement cannot be maintained under long-term therapy.