Sustained antianginal efficacy of transdermal nitroglycerin patches using an overnight 10-hour nitrate-free interval

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      The antianginal efficacy of the transdermal nitroglycerin patch may be limited by the rapid development of tolerance during uninterrupted exposure. To address this problem, we investigated the role of intermittent therapy was investigated, using a daily nitroglycerin patch-free Interval in 13 patients with chronic stable angina. Concomitant antianginal medications were permitted. Entry criteria required reproducible exercise times to both onset of angina and 1 mm of ST-segment depression. In each patient the highest tolerated nitroglycerin patch dose was determined by a dose-titration phase, which was then used in a double-blind crossover trial comprising 2 randomized treatment arms: 1 week of active nitroglycerin patch and 1 week of matching placebo. All patches were worn only from 8 a.m. to 10 p.m. daily. Exercise testing was repeated before patch application and then 4 and 8 hours after application on both the first and the last day of each treatment arm. Eleven patients completed the randomized crossover phase. Exercise time to the onset of angina and to the onset of 1 mm of ST-segment depression was significantly prolonged during the first day of therapy at both 4 and 8 hours after active nitroglycerin patch application compared with placebo (p < 0.01). During sustained use, the benefit at 4 and 8 hours after nitroglycerin patch application was still evident (p < 0.001 and p < 0.05, respectively). No evidence of a overnight rebound or withdrawal phenomenon was observed by history or by ambulatory Hotter monitoring calibrated for ST-segment analysis. The results suggest that tolerance to the antianginal effects of the nitroglycerin patch can be avoided by providing a dosing regimen using interrupted exposure to nitroglycerin.
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