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(Circulation. 1996;93:691-696.)
© 1996 American Heart Association, Inc.

Articles

Effects of Diuretic Therapy on the Development of Tolerance to Nitroglycerin and Exercise Capacity in Patients With Chronic Stable Angina

John D. Parker, MD, FRCPC; Andrea B. Parker, MSc; Bernice Farrell, RN; John O. Parker, MD, FRCPC

From the Department of Medicine, Queen's University, Kingston (Ontario) General Hospital; the Department of Medicine, University of Toronto (Ontario), Mount Sinai Hospital, Toronto (J.D.P.); and SOCAR Research SA, Givrins, Switzerland (A.B.P.).

Correspondence to John D. Parker, MD, FRCPC, Department of Medicine, Mount Sinai Hospital, Suite 1609, 600 University Ave, Toronto, Ontario, M5G 1X5 Canada.

	Abstract

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Background Therapy with diuretics has been reported to prevent the development of nitrate tolerance. Importantly, diuretics may have independent antianginal effects through their effects on intravascular volume. The present investigation was designed to determine whether diuretic therapy could prevent the development of tolerance to continuous transdermal nitroglycerin. The study was also designed to examine whether diuretic therapy has an independent antianginal effect.

Methods and Results Twelve patients with chronic stable angina were studied in a randomized, double-blind, crossover trial. Patients received diuretic (hydrochlorothiazide plus amiloride) or placebo for 14 to 20 days. During each double-blind treatment period, patients underwent treadmill exercise testing on three separate occasions. The first exercise testing was performed after 7 to 10 days of single-blind, placebo transdermal nitroglycerin therapy. Subsequently, exercise testing was repeated on the first day of active transdermal nitroglycerin therapy and following 7 to 10 days of continuous transdermal nitroglycerin application. Therapy with a diuretic was associated with an increase in exercise capacity but had no effect on nitroglycerin tolerance. During therapy with placebo transdermal nitroglycerin, diuretic therapy caused an increase in treadmill walking time to the development of moderate angina compared with placebo (371±26 versus 288±16 seconds, diuretic versus placebo, P<.01). Similar results were obtained during both acute and sustained nitroglycerin therapy.

Conclusions The results of this study demonstrate that therapy with a diuretic has no effect on the development of tolerance to continuous transdermal nitroglycerin. Interestingly, diuretic therapy itself has important antianginal effects and improves exercise capacity in patients with stable angina.

Key Words: nitroglycerin • angina • diuretics

	Introduction

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The organic nitrates are widely used in the treatment of patients with angina pectoris; however, the development of tolerance remains an important problem. Nitrate administration designed to provide therapeutic effects throughout 24 hours each day is associated with tolerance.^{1 2 3 4 5 6 7} The development of tolerance has been documented with a variety of nitrate formulations and with all routes of administration.^{5 6 7} The exact mechanism of nitrate tolerance remains unknown, and several mechanisms have been proposed.⁸ Although a unifying hypothesis remains elusive, investigations have suggested that plasma volume expansion may be involved.^{9 10 11 12} It has been hypothesized that plasma volume expansion is associated with reversal of the preload-reducing effects of nitrates, with subsequent loss of hemodynamic and antianginal effects. Although the validity of this hypothesis remains in question, attempts have been made to prevent plasma volume expansion during nitrate therapy with diuretics.^{13 14} We have reported that diuretic therapy in normal volunteers did not prevent the development of hemodynamic tolerance.¹³ In contrast, in patients with stable angina, Sussex et al¹⁴ found that diuretic therapy prevented development of tolerance to isosorbide dinitrate, as assessed by exercise testing. Importantly, this investigation did not examine the effect of diuretic therapy alone on exercise performance, and it is possible that diuretic therapy could have primary antianginal effects. This is supported by observations of the effect of decreasing intravascular volume on the ischemic threshold in patients with coronary disease^{15 16} and clinical observations suggesting an antianginal effect of diuretic therapy.¹⁷ Given this background, the present investigation was designed to answer two questions: first, to determine whether diuretic therapy could prevent or modify the development of tolerance during continuous transdermal nitroglycerin (GTN) administration and second, to examine whether diuretic therapy has an independent antianginal effect in patients with stable angina.

	Methods

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Patient Population
Twelve male patients (mean age, 62±2 years) with stable angina were studied in a randomized, placebo-controlled, crossover-design trial. Eligible patients had stable angina for at least 3 months, with typical anginal symptoms during exercise. All had documented coronary artery disease, with angiographic evidence of a 75% stenosis of at least one major coronary artery or an unequivocally positive thallium exercise test. Subjects had a positive exercise test with chest pain and 1-mm horizontal or downsloping ST-segment depression when measured 80 ms after the J-point. None had a history of congestive heart failure or hypertension. All had a left ventricular ejection fraction of 50% by either two-dimensional echocardiography or contrast ventriculography. Other specific exclusion criteria were as follows: patients with valvular disease, hypertrophic cardiomyopathy, or vasospastic angina; unstable angina or myocardial infarction within 3 months; surgical or percutaneous revascularization within 6 months; exercise capacity limited by either claudication or noncardiac dyspnea; pacemaker dependency; clinically significant anemia or renal or hepatic disease; and patients taking ß-adrenergic receptor blockers, long-acting nitrates, calcium channel antagonists, angiotensin-converting enzyme inhibitors, diuretics, vasodilators, or digoxin.

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 GTN during the study period but not on the study days until after exercise testing was completed. Treadmill exercise testing was carried out using the standard Bruce protocol. Patients were instructed to indicate the onset of angina (P1) and to continue exercise to moderate angina (P2), the point at which they would normally discontinue activity. To confirm reproducibility, patients underwent another exercise test at least 1 day later using similar end points. Reproducibility was defined as the time to P2 during consecutive tests being within 15%. If reproducibility was not documented after four exercise tests on different days, the patient was excluded from further participation in the study. A standard 12-lead ECG monitoring system was used during all exercise testing procedures. A 12-lead ECG was recorded in the supine and standing positions before exercise and at 1-minute intervals throughout the exercise test. Blood pressure was recorded with the same sphygmomanometer in the sitting and standing positions before exercise testing, every 3 minutes during exercise, and at both P1 and P2.

The primary end point was treadmill walking time to P2. Other end points included the time to P1, treadmill walking time to the development of 1 mm of ST-segment depression, and heart rates and blood pressures at P1 and P2.

General Protocol Design
Patients were randomized to receive either a diuretic (50 mg hydrochlorothiazide combined with 5 mg amiloride) or matching placebo for a period of 14 to 20 days in a double-blind manner (Fig 1). Subsequently they crossed over to the other treatment period. During each of the two double-blind treatment periods, patients received single-blind placebo GTN patches (Ciba Geigy) for the first 7 to 10 days. These patches were applied at 8 AM daily and left in place for 24 hours. After this therapy period, patients returned to the cardiovascular laboratory at 7:30 AM and underwent treadmill exercise testing at 8 AM according to the protocol outlined above. After this test, the placebo GTN patch was changed and patients underwent repeat exercise testing at 12 noon and 4 PM. These exercise tests (testing day 1) were designed to determine whether diuretic therapy had an independent antianginal effect. Patients returned to the laboratory the following morning at 7:30. They underwent repeat treadmill exercise testing at 8 AM. Subsequently, they were given an active transdermal GTN patch (0.8 mg/h, Transderm-Nitro, Ciba Geigy) in a single-blind fashion and underwent repeat treadmill exercise testing at 12 noon and 4 PM. This day (testing day 2) was designed to document the patients' responses to acute therapy with transdermal GTN patches. Subsequently, patients received single-blind, transdermal GTN patches (0.8 mg/h) administered continuously for the next 5 to 7 days. Patches were changed daily at 8 AM. At the end of this treatment period, patients underwent another series of exercise tests (testing day 3). This testing day was designed to determine the response to sustained, continuous transdermal GTN patch therapy in the presence and absence of concomitant diuretic therapy.

View larger version (12K): [in this window] [in a new window]   Figure 1. Schematic of overall study design. TGTN indicates transdermal nitroglycerin.

The protocol was approved by the Ethics Committee of Queen's University, Kingston, Ontario, Canada.

Statistical Methods
The method of Hills and Armitage¹⁸ for analysis of a two-period crossover trial was used to determine whether there was a treatment effect (diuretic versus placebo) on treadmill walking times, heart rate, systolic blood pressure, and rate-pressure product. The analysis examined the data for the presence of an interaction between the two treatment arms. Such an interaction may be observed if one double-blind treatment period has significant effects on the subsequent treatment period. The analysis also examined for the presence of a period effect. A period effect is found when the observed result appears to be dependent on the order of treatment. Treadmill walking times on the 3 different testing days were compared by ANOVA for repeated measures with application of Scheffé's post hoc test. All data are presented as the mean±SEM.

	Results

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Effects of Diuretic Therapy on Treadmill Walking Times
Diuretic therapy was associated with a significant increase in treadmill walking time both to P1 and to P2 on all 3 testing days (Figs 2 and 3, Tables 1 and 2). On testing day 1, after 10 to 14 days of double-blind oral study medication, treadmill walking time to P1 at 8 AM was 296±21 versus 228±19 seconds (diuretic versus placebo, P<.01). This increase in time to P1 was also observed at 12 noon and at 4 PM (309±28 versus 233±16 seconds and 303±20 versus 220±15 seconds, P<.01 for both). The time to P2 at 8 AM was 371±26 versus 288±16 seconds (diuretic versus placebo; P<.01). This increase in total treadmill walking time was also observed at 12 noon and at 4 PM (388±31 versus 315±18 seconds and 372±25 versus 288±16 seconds, P<.01 for both). Similar findings were observed for treadmill walking time to the development of 1 mm of ST-segment depression (Fig 4).

View larger version (14K): [in this window] [in a new window]   Figure 2. Graph showing treadmill walking time to the onset of angina (P1) on each testing day. indicates placebo; , diuretic. *P<.05 compared with placebo in crossover analysis. P<.05 vs the same point on testing days 1 and 3 (ANOVA).

View larger version (14K): [in this window] [in a new window]   Figure 3. Graph showing treadmill walking time to the development of moderate angina (P2) on each testing day. indicates placebo; , diuretic. *P<.05 compared with placebo in crossover analysis. P<.05 vs the same point on testing days 1 and 3 (ANOVA).

View this table: [in this window] [in a new window]   Table 1. Treadmill Walking Time, Heart Rate, and Systolic Blood Pressure at Onset of Angina (P1)

View this table: [in this window] [in a new window]   Table 2. Treadmill Walking Time, Heart Rate, and Systolic Blood Pressure at Moderate Angina (P2)

View larger version (13K): [in this window] [in a new window]   Figure 4. Treadmill walking time to the development of 1 mm of ST-segment depression on each testing day. indicates placebo; , diuretic. *P<.05 compared with placebo in crossover analysis. P<.05 vs the same point on testing days 1 and 3 (ANOVA).

The improvement in exercise performance associated with diuretic therapy was also observed throughout the remainder of the study period (Figs 2 through 4, Tables 1 and 2). Although there appeared to be some attenuation in this effect over time, the ANOVA revealed no significant differences in treadmill walking time to P1, to P2, or to 1 mm of ST-segment depression on testing day 3 compared with testing day 1. These effects on exercise performance were observed in the absence of either a significant treatment interaction or period effect.

Effects of Diuretic Therapy on the Development of GTN Tolerance
On day 2, the acute administration of transdermal GTN patches caused an increase in treadmill walking time to both P1 and P2 at 12 noon and 4 PM. This response was seen during both the diuretic and placebo therapy periods (Figs 2 through 4, Tables 1 and 2). Importantly, on testing day 3, after sustained continuous transdermal GTN therapy, there was evidence of tolerance with treadmill walking times at 8 AM, 12 noon, and 4 PM similar to those observed on testing day 1.

Effects of Diuretic Therapy on Heart Rate and Blood Pressure
Standing heart rate and blood pressure at rest before exercise at 8 AM on each of the testing days are presented in Table 3. During the diuretic therapy period, standing systolic blood pressure tended to be lower and heart rate higher compared with the placebo period. The crossover analysis found that only the increase in heart rate at 8 AM on testing days 1 and 2 was statistically significant. A similar pattern was observed for standing systolic blood pressure and heart rate at the other time points (data not shown).

View this table: [in this window] [in a new window]   Table 3. Baseline, Standing Heart Rate, and Systolic Blood Pressure at 8 AM on Each Testing Day

Heart rate and systolic blood pressure responses at P1 and P2 are presented in Tables 1 and 2. During diuretic therapy, patients achieved a higher heart rate and blood pressure at both P1 and P2 compared with the placebo therapy period. This difference is most clearly seen when one examines the rate-pressure product achieved at P1 and P2 (Tables 1 and 2). At most (but not all) testing time points, the crossover analysis revealed that during diuretic therapy, patients achieved a significantly greater rate-pressure product at both P1 and P2. Importantly, at several of these time points, the crossover analysis identified a significant interaction between the two treatment periods, and thus, it is not possible to be certain that this represents an independent effect of diuretic therapy.

An additional two patients experienced adverse events and were withdrawn from the study protocol. One patient randomized to diuretic therapy was withdrawn from the study after developing nonsustained ventricular tachycardia during exercise testing. A second patient randomized to diuretic therapy developed atrial fibrillation and was withdrawn from further study. There was no evidence of an electrolyte disturbance in either case. Since no comparative data were available, information from these patients was not included in the analysis.

	Discussion

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Traditionally it was thought that nitrate tolerance developed because the vasodilatory effect of these agents attenuated during continuous use.^{8 19} Recently it has been recognized that neurohormonal activation and plasma volume expansion occur in response to nitrate therapy^{9 10 11 12 20 21} and that these counterregulatory responses may play a role in the development of tolerance. Plasma volume expansion is a consistent response to continuous therapy with GTN.^{9 10 11 12} In patients with stable angina, the antianginal effect of the organic nitrates is due, at least in part, to their ability to lower ventricular preload.²² Plasma volume expansion occurring in response to nitrate therapy may modify this preload effect and contribute to loss of antianginal efficacy.

Although both the cause and significance of plasma volume expansion during nitrate therapy remain unclear, both sodium retention and a transvascular fluid shift occurring secondary to changes in Starling's forces have been implicated.^{8 9 10 13} We previously reported that diuretic therapy did not prevent either the development of tolerance or evidence of plasma volume expansion during continuous transdermal GTN therapy in normal volunteers.¹³ Sussex et al¹⁴ reported that concurrent diuretic therapy prevented the development of tolerance to isosorbide dinitrate given four times daily. Importantly, that investigation did not examine the impact of diuretic therapy alone on exercise performance, and the observed result may represent a primary antianginal effect of the diuretic. The present investigation provides convincing evidence that diuretic therapy caused an improvement in exercise capacity but did not prevent the development of tolerance during continuous administration of transdermal GTN. This is not surprising, since most recent investigations have suggested that plasma volume expansion during sustained nitrate therapy occurs in the absence of any major changes in sodium balance.^{10 12}

Previous investigations have confirmed that blood volume is an important determinant of myocardial oxygen demand in patients with coronary disease and angina pectoris.¹⁵ The administration of furosemide was associated with an increase in exercise capacity in patients with coronary artery disease.¹⁶ In 1973, Floyd and Domenet¹⁷ reported that chlorthalidone reduced the number of anginal episodes and GTN consumption in a group of patients with stable angina pectoris. There have been no previous randomized trials of the use of diuretics in patients with angina pectoris, and the use of diuretics in patients with angina has generally been reserved for patients with concurrent hypertension or congestive heart failure.

The present study demonstrates that the combination of hydrochlorothiazide and amiloride has potent antianginal effects in patients with stable angina pectoris. The improvement in exercise performance with this drug regimen was substantial. The average increase in treadmill walking time to P2 during diuretic therapy was 65 seconds, a figure that compares favorably with other agents approved for the therapy of chronic stable angina.^{23 24 25} It is important to recognize that the patients in this study had no history of congestive heart failure and were normotensive. Furthermore, all of these patients had preserved left ventricular systolic function.

The mechanism of the antianginal effect of diuretic therapy remains uncertain. The results suggest that diuretic therapy caused a reduction in left ventricular preload during exercise. During the diuretic therapy period, patients were able to achieve a greater rate-pressure product at the onset of angina and at the development of moderate angina. The rate-pressure product is an imperfect indicator of myocardial oxygen requirements, because it does not assess the influence of changes in left ventricular volume or contractility. Despite this shortcoming, the ability to achieve a greater rate-pressure product most probably occurred secondary to a reduction in left ventricular preload, the other major determinant of myocardial oxygen demand.

It is possible that the observed antianginal effect of hydrochlorothiazide therapy would not be sustained during longer treatment periods if the preload-reducing effect were only transient. Although there has been considerable controversy concerning the mechanism of action of thiazides in hypertension,²⁶ most studies suggest that these agents are associated with a decrease in plasma volume during long-term therapy.^{27 28 29 30}

There are other potential mechanisms for the observed antianginal effect. Although thiazide diuretic therapy could have caused a reduction in coronary vascular resistance, we do not believe that this is the explanation for their antianginal effect. In fact, agents that dilate coronary resistance vessels may exacerbate angina in patients with epicardial coronary stenoses through the phenomenon of coronary steal.³¹ It is possible that the use of amiloride in this study may have had an impact on the results. Although thiazides are not believed to have any direct cardiac effects, amiloride has been shown to be cardioprotective in the setting of ischemia, particularly in models of reperfusion.^{32 33} Furthermore, in one report, amiloride was found to have negative inotropic effects in an in vitro animal model.³⁴ Although there have been no studies of the effect of amiloride on human myocardium, it is possible that the observed antianginal effect was mediated by a direct myocardial action of amiloride.

The role of diuretic therapy in the management of angina remains uncertain. In light of available therapeutic options, the authors do not suggest that diuretics be adopted as part of routine management in patients with angina. Diuretics can cause electrolyte disturbances and have potentially adverse metabolic effects. This concern has received considerable attention, since diuretics in the therapy of hypertension do not reduce the risk of death from coronary artery disease.³⁵ Whether this increase in risk was secondary to metabolic effects of thiazides or their effects on electrolyte balance remains unknown. However, these concerns mandate a conservative approach to the use of diuretics in the management of angina.

Despite these limitations, diuretic therapy may have an important role in certain circumstances. It is our belief that diuretics should be considered in the patient who has refractory symptoms or is intolerant to more traditional agents. The present study did not specifically address the question of whether diuretics could improve exercise tolerance in patients with symptoms despite treatment with other antianginal agents. Interestingly, the role of multiple drug therapy for angina remains controversial, with few convincing data supporting the use of multiple drug therapy in angina.³⁶ Despite this uncertainty, the present data would support a therapeutic trial of diuretics in the patient with angina who has symptoms despite optimal medical management when revascularization procedures are not feasible or have not been successful.

	Acknowledgments

 
Dr Parker is a scholar of the Medical Research Council of Canada. The authors are grateful to Ciba Geigy Canada for providing financial support for this investigation.

Received August 8, 1995; revision received September 19, 1995; accepted September 25, 1995.

	References

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