Intermittent transdermal nitroglycerin therapy. Decreased anginal threshold during the nitrate-free interval

Intermittent transdermal nitroglycerin therapy is effective in the treatment of stable angina and prevents the development of tolerance. Previous investigations have suggested that removal of nitroglycerin patches may be associated with a decrease in anginal threshold. This study examines the effect of nitroglycerin patch removal on anginal threshold in a group of patients with stable angina.

Twelve patients with stable angina were enrolled in a randomized, double-blind, placebo-controlled, crossover study. These patients had reproducible treadmill walking times and were taking no other long-acting antianginal medications or vasodilators. They received 0.8 mg/h transdermal nitroglycerin or wore a matching placebo patch for 5 to 7 days and then crossed over to the other treatment arm of the study. Transdermal nitroglycerin was applied at 8:00 PM and removed at 8:00 AM each day. On the last day of each treatment period, patients underwent treadmill exercise testing at 8:00 AM (before patch removal) and at 2, 4, and 6 hours after patch removal. The primary end point was the treadmill walking time until moderate angina (P2). Other end points included the treadmill walking time until onset of angina (P1), the amount of ST segment depression at P1 and P2, and treadmill walking time until the development of 1 mm ST depression. Heart rate, systolic blood pressure, and the rate-pressure product were determined at rest before exercise and at P1 and P2. At 8:00 AM P1 and P2 were not significantly affected by active nitroglycerin compared with placebo, indicating the development of tolerance. Removal of the active transdermal nitroglycerin patch was associated with a significant decrease in the time to P1 at 2, 4, and 6 hours after patch removal compared with placebo. There was also a decrease in the time to P2 after active patch removal that was statistically significant compared with placebo at 2 and 4 hours and was of borderline significance at 6 hours. There were no differences in heart rate, blood pressure, or amount of ST segment depression at either P1 or P2 after active compared with placebo patch removal.

In patients with stable angina pectoris, intermittent transdermal nitroglycerin therapy is associated with a decrease in anginal threshold for 4 to 6 hours after patch removal. Although the cause of this phenomenon remains uncertain, it may be due to counterregulatory responses that develop during nitroglycerin patch application.