Long-term oral administration of amrinone for congestive heart failure: lack of efficacy in a multicenter controlled trial.

Abstract

A number of uncontrolled studies have indicated that oral administration of amrinone, a phosphodiesterase inhibitor with potent positive inotropic effects in experimental preparations, may be beneficial in patients with chronic congestive heart failure. The present multicenter trial was designed to prospectively evaluate clinical response and change in exercise tolerance during 12 weeks of amrinone therapy in a double-blind, placebo-controlled protocol. Ninety-nine patients with NYHA functional class 3 or 4 congestive heart failure on digitalis and diuretics, of whom 31 were also receiving captopril, were enrolled. After baseline clinical assessment and determination of exercise tolerance, radionuclide left ventricular ejection fraction, and roentgenographic cardiothoracic ratio, patients were randomly assigned to receive amrinone or placebo, beginning at 1.5 mg/kg tid and increasing to a maximum dosage of 200 mg tid. After 12 weeks of therapy or at the last blinded evaluation in patients who did not complete this protocol, there were no significant differences from baseline values between treatment with amrinone or placebo with regard to symptoms, NYHA functional class, left ventricular ejection fraction, cardiothoracic ratio, frequency and severity of ventricular ectopy, or mortality. Exercise tolerance improved significantly from baseline by 37 + 10% (mean 163 sec) in patients on amrinone and 35 ± 11 % (mean 149 sec) in patients on placebo, but there was no significant difference between treatments. Adverse reactions were significantly more frequent and more severe on amrinone, occurring in 83% of patients and necessitating withdrawal in 34%. Downward adjustment of amrinone dosage because of side effects was responsible for a significantly lower mean total daily dose of 355 vs 505 mg for placebo (p < .001). These findings indicate that oral administration of amrinone is not clinically effective in patients with chronic congestive heart failure, in part because of frequent adverse effects. Circulation 71, No. 5, 96-971, 1985. IN THE LAST DECADE there has been growing interest in new approaches to drug treatment of refractory congestive heart failure. Early investigations centered on drugs that altered the loading conditions of the left ventricle. More recently, agents possessing positive inotropic activity with chemical structures and mechanisms of action different from those of digitalis glycosides or catecholamines have been investigated. ' Amrinone, a bipyridine derivative,2 was the first of these to undergo extensive clinical evaluation. Shortterm therapy with amrinone administered intravenous-*Participating centers and investigators are listed in an appendix to

ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult

“…The hypothesis underlying this approach suggests that changes in therapy to optimize LV filling pressure may improve outcomes in HF patients (414,415). (435,436), long-term oral therapy with these drugs has not improved symptoms or clinical status (292,(437)(438)(439)(440)(441)(442)(443)(444)(445)(446)(447) and has been associated with a significant increase in mortality, especially in patients with advanced HF (445,(448)(449)(450)(451)(452)(453). Despite these data, some physicians have proposed that the regularly scheduled intermittent use of intravenous positive inotropic drugs (e.g., dobutamine or milrinone) in a supervised outpatient setting might be associated with some clinical benefits (41)(42)(43)454).…”

2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults

“…Although positive inotropic agents can improve cardiac performance during short-and long-term therapy, 185,186 long-term oral therapy with these drugs has not improved symptoms or clinical status 131,[187][188][189][190][191][192][193][194][195][196][197] and has been associated with a significant increase in mortality, especially in patients with advanced HF. 195,198 -203 Despite these data, some physicians have proposed that the regularly scheduled intermittent use of intravenous positive inotropic drugs (e.g., dobutamine or milrinone) in a supervised outpatient setting might be associated with some clinical benefits.…”

Beneficial effect of amrinone on murine cardiac allograft survival

“…As described in the Introduction, long-term oral administration of amrinone has been shown to be complicated by a number of side effects as well as limited effectiveness. However, it is important to note that the mean daily dose of orally administered amrinone in the clinical study was 355mg or 1-6 mg/kg tid (4-8 mg/kg per day) and the maximal daily dose was 600mg [6]. These doses may be a little too high for immunosuppressive use, since the dose used in this study appears to be equivalent to a daily dose of 244mg (3-3 mg/kg per day) in humans.…”