Incidence of early tolerance to hemodynamic effects of continuous infusion of nitroglycerin in patients with coronary artery disease and heart failure

Abstract

Sustained therapy with nitroglycerin (NTG) has been reported to provoke the development of early tolerance. Because continuous intravenous NTG infusion is commonly used in patients with coronary artery diseases and heart failure, we evaluated the incidence of early tolerance developed within the first 24 hr of therapy in 31 responders to NTG. After documentation of response to NTG, defined as a 10 mm Hg or greater or a 30% or greater reduction in mean pulmonary arterial wedge pressure (PAWP), 16 patients were blindly, randomly assigned to receive placebo and 15 patients were continued on same-dose NTG. Both groups showed an identical fall in PAWP at peak NTG titration (11 ± 4 mm Hg). Discontinuation of NTG in the placebo group resulted in a rapid increase in PAWP to levels not significantly different from baseline (19 ± 5 mm Hg at 2 hr vs 23 ± 6 mm Hg at baseline; p = NS). In the NTG group, PAWP fell from 27 ± 9 to 14 ± 7 mm Hg, was 16 ± 9 mm Hg at 2 hr (p < .05 vs baseline), and continued to be significantly lower than baseline for 8 hr; however, due to attenuation of effect, PAWP values at 12, 20, and 24 hr were not significantly different from placebo or baseline values. Analysis of individual data showed there were eight patients (group A) who had a persistent effect and seven patients (group B) who developed tolerance, which was defined as an increase in PAWP to values within 10% of baseline or a greater than 34% increase (2 x coefficient of variation of PAWP in the placebo group 2 to 24 hr after discontinuation of NTG) from values measured at the end of NTG titration. These two groups differed only in their baseline systemic vascular resistance (2195 ± 765 vs 1517 ± 355 dyne-sec-cm-5; p < .05). No difference was found in any other baseline hemodynamic or hormonal variables or in the magnitude of hemodynamic change during peak NTG titration and hormonal changes during the study. This study therefore provides further evidence of the development of early tolerance to the hemodynamic effects of continuous NTG administration. Tolerance is developed in approximately half of patients with coronary artery disease and heart failure. The development of tolerance cannot be predicted by baseline hemodynamic and hormonal values or their changes during NTH therapy.