What action is often recommended to help reduce tolerance to transdermal nitroglycerin therapy?

Abstract

Background 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.

Methods and Results 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.

Conclusions 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.

The organic nitrates are commonly used in the therapy of chronic angina. Despite their broad application, it is now known that nitrate administration designed to provide therapeutic effects 24 hours a day is associated with tolerance and loss of hemodynamic and antianginal effects.1234567 The development of tolerance has been documented with a variety of nitrate formulations and with all routes of administration.567 The exact cause of nitrate tolerance remains unknown, and several potential mechanisms have been proposed.8 Strategies for the prevention of nitrate tolerance have been suggested, but the only approach that has achieved wide clinical acceptance involves the use of dosage regimens that provide a nitrate-free interval. Such intermittent nitrate therapy allows for a period of nitrate washout that presumably prevents or reverses the influences responsible for the development of tolerance.9101112 Although intermittent nitrate therapy can prevent tolerance, the potential for adverse clinical events during the nitrate-free interval has caused some concern. Munitions workers exposed to large concentrations of organic nitrates in the workplace have an increased incidence of acute coronary syndromes during 24- to 72-hour periods away from the work environment.13 Similar reports of rebound events during nitrate withdrawal have been reported in two recent trials of intermittent nitroglycerin therapy in angina pectoris.1415 Furthermore, trials of intermittent transdermal nitroglycerin therapy have indicated that there may be a decrease in anginal threshold during the nitrate-free interval.1416

The present study was done to examine the effect of nitrate withdrawal on exercise capacity and anginal threshold during intermittent transdermal nitroglycerin therapy in a group of patients with stable angina. The hypothesis tested was that this therapy would be associated with a decrease in exercise capacity during the nitrate-free period. To make serial measurements of exercise performance during the patch-off period, a study design was adopted in which transdermal nitroglycerin was applied during the night and removed each morning. Although this dosing regimen is not the norm in clinical practice, it was used so we could test the study hypothesis.

Methods

Subjects

Twelve patients were studied in a randomized, placebo-controlled, crossover design trial. All were male, with a mean age (±SEM) of 60±2 years. Eligible patients had a history of stable angina for at least 3 months with typical anginal symptoms during exercise. All had documented coronary artery disease with either angiographic evidence of at least 75% stenosis of one or more major coronary artery or an unequivocally positive thallium exercise test. Eligible subjects also had chest pain and ≥1 mm horizontal or downsloping ST segment depression when measured 80 milliseconds after the J-point. Exclusion criteria were valvular heart disease, hypertrophic cardiomyopathy, or vasospastic angina; a history of unstable angina or myocardial infarction within the past 3 months; surgical or percutaneous revascularization within the past 6 months; congestive heart failure; exercise capacity limited by either claudication or noncardiac dyspnea; pacemaker dependency; and clinically significant anemia, renal or hepatic disease. Patients taking the following drugs were also excluded when these agents could not be safely discontinued for the duration of the study: β-adrenergic receptor blockers, long-acting nitrates, calcium channel antagonists, angiotensin-converting enzyme inhibitors, diuretics, vasodilators, digoxin, nonsteroidal anti-inflammatory drugs, or more than 325 mg/day acetylsalicylic acid.

The protocol was approved by the Ethics Committee of Queen’s University, Kingston, Ontario, Canada, and written informed consent was obtained in all cases.

Exercise Testing Reproducibility and Nitrate Responsiveness

After informed consent was obtained, all antianginal and other medications excluded by the protocol were discontinued. Patients were allowed to use sublingual nitroglycerin during the study period but not on the study days until exercise testing was completed. Screening exercise testing was carried out using the standard Bruce protocol. Each patient was instructed to indicate the time of onset of angina (P1) and to continue to exercise until such time as he experienced moderate angina (P2), the point at which he would normally discontinue activity. To confirm reproducibility, at least 1 day later the patient underwent another exercise test with the same end points. Reproducibility was defined as a difference of 15% or less between consecutive P2 measurements. If this criterion was not met, the patient returned on another day for repeat exercise testing. If reproducibility was not documented after four exercise tests, the patient was excluded from further participation in the study. When reproducibility was documented, each patient underwent another treadmill exercise test 5 minutes after the administration of 0.4 mg sublingual nitroglycerin to determine whether he was a nitrate responder. Nitrate responsiveness was defined as an increase of ≥20% in P2 from the average of the two qualifying exercise tests. Only nitrate responders participated further in the trial. A standard 12-lead ECG monitoring system (Marquette) was used during all exercise testing procedures. An ECG was recorded with the patient in the supine and standing positions before exercise and at 1-minute intervals throughout the exercise test and during the first 6 minutes of recovery. Blood pressure was recorded, with the same sphygmomanometer throughout, in the sitting and standing positions before exercise testing, every 3 minutes during exercise, and at P1 and P2.

The primary end point was P2. Other end points included P1, the amount of ST segment depression at P1 and P2, and treadmill walking time until the development of 1 mm ST segment depression. Heart rate, systolic blood pressure, and rate-pressure product were determined at rest before exercise and at P1 and P2.

Definitive Protocol

Patients who qualified for the investigation were then randomized to receive either active nitroglycerin patches (0.8 mg/h) (Transderm-Nitro, Ciba-Geigy) or matching placebo patches for the first part of the study. Patches were applied at 8:00 pm each day and removed at 8:00 am each morning. After 7 to 10 days, patients returned to the cardiovascular laboratory at 7:30 am. They underwent repeat treadmill exercise testing at 8:00 am according to the protocol and end points previously described. After completion of this exercise test, the transdermal preparation was removed. Patients then underwent repeat exercise testing at 10:00 am, noon, and 2:00 pm. When the final test was completed, patients crossed over to the other treatment arm of the study to receive the type of patch (placebo or active nitroglycerin) they had not used previously. They were given a new supply of patches and instructed to apply them as before. After 7 to 10 days, patients returned to the cardiovascular laboratory and underwent the same four-part exercise testing protocol described above. When the second set of four exercise tests was completed, patients returned any remaining study medications and resumed their normal treatment regimens.

Statistics

The method of Hills and Armitage17 for analysis of a two-period crossover trial was used to determine whether there was a treatment effect, compared with placebo, of the active transdermal nitroglycerin on treadmill walking time, heart rate, systolic blood pressure, rate-pressure product, and ST segment deviation. This analysis also tested for an interaction between the observed treatment effect and the order of randomization into the two treatment arms. Treadmill walking times at 8:00 am were compared with those observed at 10:00 am, noon, and 2:00 pm by means of two-tailed, paired t tests. For the latter comparisons, the statistical significance of differences was tested using the Bonferroni correction for repeated measures, such that a value of P <.05/n was required for statistical significance, where n represents the number of comparisons performed. All data are mean±SEM.

Results

P1 at 8:00 am, before patch removal, was similar during the two treatment periods (254±17 seconds and 252±16 seconds, active compared with placebo; Fig 1). During subsequent exercise testing there was a small increase in P1 during therapy with placebo, but during active therapy there was a significant decrease in P1 at 2, 4, and 6 hours after patch removal (Fig 1). The crossover analysis revealed that the decrease in P1 was significant 2 and 4 hours after patch removal (at 10:00 am, active compared with placebo, 230±15 and 264±19 seconds, respectively; at noon, 233±17 and 264±16 seconds; P<.05) and approached statistical significance 6 hours after patch removal (active compared with placebo, 231±21 and 266±22 seconds, respectively; P=.06). The crossover analysis revealed no evidence of an interaction between treatment effect and the order of randomization.

P2 was also similar during the two treatment periods at 8:00 am, before patch removal (active compared with placebo, 341±17 and 327±18 seconds, respectively; Fig 2). During the active therapy period there was a significant decrease in P2 at 10:00 am, noon, and 2:00 pm, while during placebo treatment there was an insignificant increase in treadmill walking time during the same time period (Fig 2). The crossover analysis revealed a significant treatment effect during therapy with active transdermal nitroglycerin, with a decrease in exercise performance at 2 and 4 hours after patch removal (P2 at 10:00 am, active compared with placebo, 311±20 and 335±18 seconds, respectively; P2 at noon, 308±14 and 352±16 seconds; P<.05 for both). There was also a decrease in exercise performance 6 hours after patch removal during active nitroglycerin therapy; however, this difference was not statistically significant (active compared with placebo, 302±20 and 327±14 seconds, respectively; P=.15). There was no evidence of a period effect in the crossover analysis, suggesting that the observed results were not affected by the order of randomization.

The time until 1 mm ST segment depression was similar during the two treatment periods at 8:00 am, before patch removal. There was no significant change in the time until 1 mm ST depression after placebo patch removal. After removal of the active patch, there was a significant decline in the time until 1 mm ST depression at 10:00 am, noon, and 2:00 pm (Fig 3), although the crossover analysis revealed that the differences between the two treatment periods were not statistically significant.

There were no differences in standing heart rate, systolic blood pressure, rate-pressure product, or ST segment depression before any of the exercise testing periods during active and placebo patch therapy (Table 1). During exercise, the crossover analysis revealed no significant differences in heart rate, systolic blood pressure, rate-pressure product, or ST segment depression at P1 (Table 2). Heart rate and the rate-pressure product were slightly higher at P2 at 8:00 am in the active therapy group (Table 3). There were no differences in heart rate, systolic blood pressure, rate-pressure product, or ST segment depression at P2 during exercise testing 2, 4, and 6 hours after patch removal.

All patients randomized into the study remained stable during both treatment periods. No patient developed an unstable ischemic syndrome during the trial or reported an increase in anginal symptoms during placebo or active therapy. One patient withdrew from the study for personal reasons a day after randomization. Because no double-blind exercise testing data were obtained, he was not one of the 12 patients whose data were included in the analysis.

Discussion

The cause of nitrate tolerance remains uncertain and is likely multifactorial. There is evidence that tolerance to the organic nitrates develops because their vasodilatory effect is attenuated during continuous use.818 We192021 and others8222324 have suggested that both neurohormonal activation and plasma volume expansion occur during nitrate therapy and that these responses may play a role in the loss of nitrate effects over time. These counterregulatory responses develop rapidly during transdermal nitroglycerin therapy and are activated during the 12-hour patch-on period used in most intermittent nitroglycerin therapy regimens.19

At present, the only method of preventing nitrate tolerance involves the use of dosing schedules that provide low or absent plasma nitrate levels for a portion of the day. A number of investigations have demonstrated that intermittent therapy with transdermal nitroglycerin preparations is effective in angina,9101112141516 and intermittent dosing of transdermal nitroglycerin is now widely practiced.

There are potential problems associated with intermittent nitroglycerin therapy. A patient receiving monotherapy with nitrates will have no prophylactic therapy against ischemia for the nitrate-free portion of the day. However, for the patient with stable exertional angina, being nitrate-free overnight may be of no consequence, and for the patient with nocturnal angina the clinician has other therapeutic options. There is also concern that anginal symptoms may be exacerbated during the nitrate-free period because of a phenomenon that has been termed “rebound angina.” Although the cause of rebound angina remains obscure, the acute withdrawal of nitrates may be associated with some form of vascular hypersensitivity or exposure to vasoconstrictor stimuli. In two investigations of intermittent transdermal nitroglycerin therapy, an increase in angina during the nitrate-free interval was seen. In one study, 9 patients experienced increased frequency of rest angina during the nitrate-free interval.14 All were receiving active nitroglycerin therapy at the time, and increased frequency of rest angina was not seen during placebo patch therapy. In the other study, intermittent therapy with transdermal nitroglycerin was also associated with increased frequency of angina during the period of patch removal.15

The other evidence suggesting adverse effects during intermittent nitroglycerin therapy is the so-called “zero-hour effect.” In one intermittent transdermal nitroglycerin study, there was a progressive improvement in treadmill walking time during the 8:00 am exercise test performed 12 hours after patch removal.14 The patients on placebo treatment showed greater improvement in this morning exercise test than the patients who were receiving active nitroglycerin therapy. Similar observations were made in another large trial of intermittent transdermal nitroglycerin therapy.16 These results, along with reports of increased episodes of rest angina during the nitrate-free period, suggest that rebound may be a clinically relevant problem.

Trials of intermittent nitroglycerin patch therapy have generally shown antianginal efficacy for 8 hours1416 ; the effects at 12 hours have been variable.1425 In the present study, there was no difference in P2 between patients with the active and placebo patches at 8:00 am, before patch removal, indicating the development of tolerance. Although there was no apparent therapeutic effect of transdermal nitroglycerin 12 hours after application, removal of the patch was followed by a decrease in exercise performance over the subsequent 6-hour period. We hypothesize that the counterregulatory responses that developed during the patch-on period are responsible for this effect and that these responses (plasma volume expansion, neurohormonal activation, or both) have an effect on treadmill exercise after nitroglycerin patch removal. Plasma levels of nitroglycerin fall quickly after patch removal,2627 but it is suggested that the counterregulatory phenomenon persists for 4 to 6 hours. A recent study revealed that plasma volume is expanded for up to 8 hours after patch removal, an observation that supports the hypothesis that counterregulatory responses continue for some time after nitrate withdrawal (J.D.P., unpublished data, 1994).

There have been no investigations of the hemodynamic response to nitroglycerin patch removal in the setting of angina. In a study of normal volunteers, the removal of transdermal nitroglycerin after 48 hours of application caused no change in heart rate or blood pressure at rest.26 In patients with congestive heart failure, removal of transdermal nitroglycerin after 24 hours of therapy was associated with increases in pulmonary artery and systemic arterial pressure to levels above those recorded before nitroglycerin application, suggesting rebound.28 These observations in patients with angina and heart failure provide evidence that, despite tolerance as assessed by exercise testing or hemodynamic variables, there are continuing nitrate effects. It appears from the present study that, 12 hours after patch application, there was a balance between nitrate effects and the counterregulatory forces, whether vasoconstrictor, volume expansion, or both. The rapid decline in plasma nitroglycerin levels after patch removal was accompanied by expression of the counterregulatory influences on exercise performance.

Our original hypothesis was that exercise performance would be diminished after removal of active nitroglycerin patches, and it was anticipated that the rate-pressure product at the onset of angina would be less than that seen after removal of placebo patches. This was not the case, because the rate-pressure product at both P1 and P2 was identical after removal of the active and placebo patches. The rate-pressure product is, of course, an imperfect indicator of myocardial oxygen requirements because it does not assess the influence of changes in left ventricular volume or contractility, factors that may be of major importance if our concept of the role of counterregulatory factors in tolerance is correct.

The present study was specifically designed to test the hypothesis that withdrawal of transdermal nitroglycerin would lead to a decrease in exercise performance in patients with stable angina pectoris. To make serial observations during the patch-off period, the normal dosing schedule was reversed, with patients wearing the patch at night and removing it in the morning. A potential weakness of this study design is that counterregulatory responses may be different during the day than in the evening because many hormonal axes are subject to circadian variation. It is therefore possible that our observations would have been different if patches had been applied in the usual manner.

We believe that the design of the study prevents us from drawing strong clinical conclusions concerning the results. Our intention was to examine the effect of nitroglycerin withdrawal on anginal threshold in patients with stable angina pectoris. Because the majority of patients wear the patch during the day and remove it in the evening, exercise performance may not be of clinical importance. Nevertheless, the findings of the study may provide an explanation for some of the adverse effects that have been reported during intermittent transdermal nitroglycerin therapy.

The most important observation made in this study is that nitrate tolerance, as measured by treadmill exercise performance, does not indicate that there is no longer a nitrate effect. Indeed, the fact that exercise performance deteriorates after patch removal confirms the hypothesis that nitrates continue to exert vascular effects despite tolerance as assessed by hemodynamic end points or exercise testing.

Figure 1. Plot of treadmill walking time (in seconds) until the onset of angina (P1) during the two treatments (nitroglycerin and placebo) at 8:00 am (0800), 10:00 am (1000), noon (1200), and 2 pm (1400). Patches were removed after the 8:00 am exercise test. Open square indicates active transdermal nitroglycerin; closed triangle, placebo therapy. *P<.05 compared with treadmill walking time at 8:00 am; +P<.05, effect of treatment in crossover analysis; #P=.06, effect of treatment in crossover analysis.

Figure 2. Plot of treadmill walking time (in seconds) until moderate angina (P2) during the two treatments (nitroglycerin and placebo) at 8:00 am (0800), 10:00 am (1000), noon (1200), and 2 pm (1400). Patches were removed after the 8:00 am exercise test. Open square indicates active transdermal nitroglycerin; closed triangle, placebo therapy. *P<.05 compared with treadmill walking time at 8:00 am; +P<.05, effect of treatment in crossover analysis.

Figure 3. Plot of time (in seconds) to 1 mm ST segment depression during the two treatments (nitroglycerin and placebo) at 8:00 am (0800), 10:00 am (1000), noon (1200), and 2 pm (1400). Patches were removed after the 8:00 am exercise test. Open square indicates active transdermal nitroglycerin; closed triangle, placebo therapy. *P<.05 compared with time to 1 mm ST depression at 8:00 am.

The authors are grateful to Ciba-Geigy Canada for generously supplying the placebo and active nitroglycerin patches used in this investigation.

Footnotes

References

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