THERAPY AND PREVENTION CONGESTIVE HEART FAILURE Dose requirements and hemodynamic effects of transdermal nitroglycerin compared with placebo in patients with congestive heart failure

The dose requirements and duration of effect of transdermal nitroglycerin in patients with heart failure are not clearly established. In a first series of eight patients with chronic heart failure we gave transdermal nitroglycerin in incremental doses until pulmonary capillary wedge pressure fell at least 30% within 4 hr in three consecutive patients. Thus we found that a single dose of 60 mg/24 hr (120 cm2) was the minimal effective dose. Transdermal nitroglycerin or placebo was then given as a single application of 60 mg/24 hr in random double-blind fashion to 15 additional patients with heart failure (eight received transdermal nitroglycerin and seven received placebo), and hemodynamics were monitored for up to 24 hr. After administration of transdermal nitroglycerin, the control pulmonary capillary wedge pressure of 22 + 7 mm Hg fell by 6 + 6 mm Hg at 2 hr (p < .05) and reached maximal reduction of 8 + 6 mm Hg (p < .01) at 4 hr. The reduction in wedge pressure remained significant through 12 hr but was no longer statistically significant by 18 hr after administration of the drug. Transdermal nitroglycerin also significantly reduced pulmonary arterial and right atrial pressures as well as pulmonary vascular resistance from 4 through 12 hr but did not affect systemic hemodynamics. No significant hemodynamic changes occurred after administration of placebo. Thus transdermal nitroglycerin is an effective vasodilator in patients with heart failure, but a dose of at least 60 mg/24 hr is needed. Even with this dose, hemodynamic effects do not last beyond 18 hr, suggesting altered absorption or development of tolerance. Circulation 71, No. 5, 980-986, 1985. VASODILATORS are commonly used for the treatment of acute and chronic congestive heart failure. Among the presently available vasodilator agents, only nitrates and angiotensin-converting enzyme inhibitors have produced sustained hemodynamic improvement along with increased exercise tolerance in placebo-controlled trials in patients with chronic heart failure.1-6 Both captopril and nitrates require frequent dosing, so that practical problems related to drug delivery and patient compliance still exist. The duration of action of sublingually administered nitroglycerin is far From the Cardiovascular Clinical Research Center, Cardiovascular Division, Veterans Administration Medical Center, and University of Arkansas for Medical Sciences, Little Rock. Supported by grants from the Medical Research Service of the Veterans Administration, Washington, DC, and from the Ciba-Geigy Corp., Summit, NJ. Address for correspondence: Joseph A. Franciosa, M.D., Cardiovascular Division, Mail Slot 532, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR 72205. Received Jan. 2, 1985; accepted Feb. 14, 1985. Presented in part at the 57th Annual Scientific Sessions of the American Heart Association, Miami Beach, November 1984. too short to be of practical value for long-term therapy. Orally administered isosorbide dinitrate and topically applied nitroglycerin ointment produce significant hemodynamic effects for as long as 4 to 8 hr, but still require multiple daily dosing.7' The recent introduction of transdermal delivery systems for nitroglycerin has raised the possibility of once-daily dosing.9' 10 However, the dose requirements and duration of effect of these preparations are not clearly established.9-12 Early claims of a prolonged duration of action were based on uncontrolled studies that did not account for spontaneous changes in hemodynamics. 13 Recent studies have suggested a duration of action of transdermal nitrate delivery systems of less than 24 hr and have raised the possibility of early tolerance or altered absorption." 12, 14 This study was designed to assess the dose responsiveness and pharmacodynamics of a single transdermal dose of nitroglycerin compared with placebo in patients with chronic congestive heart failure. CIRCULATION 980 by gest on Sptem er 5, 2017 http://ciajournals.org/ D ow nladed from THERAPY AND PREVENTION-CONGESTIVE HEART FAILURE