Acute and chronic antianginal efficacy of continuous twenty-four-hour application of transdermal nitroglycerin

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To resolve the controversies surrounding the antianginal use of chronic, continuous 24-hour transdermal nitroglycerin therapy, a double-blind, placebo-controlled, randomized, parallel-group study was designed. Eligible patients had chronic angina pectoris with symptom-limited, reproducible treadmill tests and were responsive to sublingual nitroglycerin (n = 562). Patients were randomly assigned to placebo or 1 of 7 doses of active treatment (15, 30, 45, 60, 75, 90 and 105 mg/24 hours). In the active drug groups, treatment was initiated with 15 mg/24 hours during the first week of double-blind dosing with subsequent weekly increases until the assigned dose was reached, after which the dose was held constant. Treadmill tests were performed 0, 4 and 24 hours after the initial double-blind patches were applied, after each titration step and after 8 weeks. At the end of double-blind therapy, a sublingual nitroglycerin exercise challenge was repeated. Exercise tolerance in patients using the active patch increased 34 seconds (p < 0.05) over patients taking placebo 4 hours after the initial application of double-blind therapy, but there was no statistically significant difference in exercise time between placebo and active drug groups by 24 hours after the first application or for the remaining 8 weeks of the trial. Increasing the dose did not overcome the loss of effect. A partial attenuation of the response to a sublingual nitroglycerin challenge seen on exercise tolerance testing also occurred, with patients who received the highest dose showing the greatest attenuation. There were no differences in angina frequency among the groups, although in a post hoc analysis, patients with >7 attacks per week had a reduction in anginal frequency of 6 to 7 attacks per week with active treatment versus 2 attacks per week with placebo. The study showed that (1) tolerance to the exercise effects of continuous transdermal nitroglycerin develops within 24 hours after application; and (2) increasing the dose does not overcome this tolerance. The observation that symptomatic improvement may occur in the absence of increases in exercise tolerance seems deserving of further study.