Efficacy, safety and duration of nitrate-free interval to prevent tolerance to transdermal nitroglycerin in effort angina

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Abstract
The magnitude of tolerance to the anti-anginal efficacy of transdermal nitroglycerin and the efficacy and safety of short (4h) and long (Wh) nitrate-free intervals for its prevention, were investigated in a randomized, double-blind, placebo-controlled crossover trial of 4 week-long treatment regimes: placebo, continuous therapy with a 50 mg patch (10 mg. 24 h−1), and 4 h and 10 h nitrate-free periods. Only patients showing>1 min increase in time to 1 mm ST depression after acute patch administration were eligible. Twelve men completed the study. One other anti-anginal medication (a beta-blocker in nine and calcium antagonist in two) was permitted in a constant dose throughout the study. Patients underwent exercise testing on days 1 and 7 of each treatment period, and 24 h ambulatory ECG monitoring on day 6. Compared to placebo, transdermal nitroglycerin on day 1 significantly improved time to 1 mm ST depression by 35%, and time to angina, exercise duration and maximal workload by 21 %, 13% and 9% respectively. These improvements were totally lost after 7 days' continuous therapy, but completely maintained by a 10 h nitrate-free period (improvements of 35%, 25%, 16% and 11% respectively) but not by a4h nitrate-free period (non-significant improvements of 15%, 2%, 4% and 1% respectively). The differences between 10 and 4 h nitrate-free were significant for each end-point. Neither duration of ambulatory ischaemia, nor the proportion of patients experiencing<5 min ischaemia during the scheduled nitrate-free interval differed between treatments. Thus, tolerance to transdermal nitroglycerin is complete after only 1 week of continuous therapy, but can be completely prevented by a 10 h nitrate-free period without an increase in spontaneous ischaemia, while a 4 h nitrate-free period is insufficient to prevent tolerance.

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