Najam A. Awan

BACKGROUND: The aim of the present study was to assess the short- and long-term effects of multiple doses of the angiotensin II receptor antagonist losartan in heart failure. METHODS AND RESULTS: A multicenter, placebo-controlled, oral, multidose (2.5, 10, 25, and 50 mg losartan once daily) double-blind comparison in patients with symptomatic heart failure and impaired left ventricular function (ejection fraction < 40%). Invasive 24-hour hemodynamic assessment was performed after the first dose and after 12 weeks of treatment. Clinical status and tolerability of treatment with losartan over the 12-week period were also evaluated. One hundred fifty-four patients were enrolled, of which 134 met the protocol criterion of baseline pulmonary capillary wedge pressure > or = 13 mm Hg. During short-term administration, systemic vascular resistance (SVR) (largest reduction against placebo of 197 dyne.s-1.cm-5 at 4 hours) and blood pressure fell significantly with 50 mg, lesser decreases were seen with 25 mg, and no discernible effects were seen with 2.5 and 10 mg. After 12 weeks of treatment, similar effects were seen on SVR and blood pressure (maximal fall in SVR against placebo, 318 dyne.s-1.cm-5 at 5 hours with 50 mg). In addition, pulmonary capillary wedge pressure fell with 2.5, 25, and 50 mg (largest reduction against placebo of 6.3 mm Hg at 6 hours with 50 mg), cardiac index rose with 25 and 50 mg, and heart rate was lower with all active treatment groups. Active treatment was well tolerated, and excess cough was not reported. CONCLUSIONS: This study showed that oral losartan administered to patients with symptomatic heart failure resulted in beneficial hemodynamic effects with short-term administration, with additional beneficial hemodynamic effects seen after 12 weeks of therapy. Clear effects were seen with both 25 and 50 mg, with the greatest effect seen with 50 mg.

To elucidate the hemodynamic effects of prazosin, an antihypertensive agent, in congestive heart failure, we studied 10 patients with ischemic cardiomyopathy and severe ventricular dysfunction. After an oral dose of 2 to 7 mg, heart rate was unchanged (P>0.05). One hour after prazosin administration, mean arterial pressure declined from 95 to 78 mm Hg (P<0.001); left ventricular filling pressure declined from 30 to 18 mm Hg (P<0.001), cardiac index increased from 2.1 to 2.9 liters per minute per square meter (P<0.001), and systemic vascular resistance fell from 2074 to 1156 dynes sec cm-5 (P<0.001). In both forearms vascular resistance and venous tone were reduced (86 to 48 mm Hg per ml per 100 g per minute, and 59 to 18 mm Hg per ml, respectively [P<0.001]). All responses persisted for at least six hours (P< 0.01). Prazosin benefits severe congestive heart failure by inducing a sustained fall of both cardiac preload and impedance. (N Engl J Med 297:303–307, 1977)

The long-term efficacy of the new oral vasodilator, prazosin (PZ), was evaluated in nine patients with refractory heart failure due to chronic coronary heart disease. Ventricular function was assessed by cardiac catheterization, echocardiography, and treadmill testing; symptomatic evaluation was carried out for two to four months. One hour following 2-7 mg PZ, control left ventricular filling pressure was reduced (32 to 18 mm Hg, P less than 0.001) and cardiac index was elevated (1.95 to 2.89 L/min/m2, P less than 0.001) for a 6-hour period. After two weeks of PZ 2 to 7 mg four times daily, echographic end-diastolic dimension fell (5.7 to 5.4 cm, P less than 0.001) while shortening fraction increased (27.6 to 30.2%, P less than 0.005). Treadmill exercise duration increased from 209 to 317 seconds (P less than 0.001). Symptoms diminished throughout the duration of follow-up (mean 94 days) with improvement in NYHA functional class (3.7 to 2.2, P less than 0.001). Thus, prazosin possesses sustained nitroprusside-like balanced dilator actions on the systemic arterial and venous systems and is effective in the ambulatory management of chronic severe heart failure.

The hemodynamic benefits of combining administration of dopamine with nitroprusside (NP) were evaluated in nine patients with chronic congestive heart failure due to ischemic, idiopathic myocardial or valvular cardiac disease. NP alone (68 microng/min) produced decline in left ventricular end-diastolic pressure (LVEDP) from 25.4 to 14.1 mm Hg (p less than 0.01) but modest increase in cardiac index (CI) from 2.41 to 3.02 L/min/m2 (P less than 0.05). Dopamine alone (6 microng/kg/min) caused an elevation of CI to 3.36 (P less than 0.01) but without decrease of LVEDP. Simultaneous infusion of the two agents resulted in favorable alterations in both hemodynamic variables: LVEDP decreased to 15.7 (P less than 0.01) and CI increased to 3.52 (P less than 0.01). It is concluded that dopamine substantially enhances the effectiveness of nitroprusside therapy in congestive heart failure by providing concomitantly the principal beneficial actions of the vasodilator and dopamine used separately. Thus combined dopamine with NP treatment considerably raises low CI while markedly reducing elevated LVEDP and provides a potentially efficacious pharmacologic modality for the treatment of severe congestive heart failure due to left ventricular dysfunction.