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(Chest. 2003;124:1652-1657.)
© 2003 American College of Chest Physicians

Safety of Nitrate Withdrawal in Angina-Free and Hemodynamically Stable Patients With Coronary Artery Disease*

Jacob George, MD; Ilan Kitzis, MD; David Zandorf, MD; Michal Golovner, MD; Itzhak Shapira, MD; Shlomo Laniado, MD and Arie Roth, MD

* From the Department of Cardiology, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University; and SHL Medical Services, Tel-Aviv, Israel.

Correspondence to: Arie Roth, MD, Department of Cardiology, Tel-Aviv Sourasky Medical Center, 6 Weizman St, Tel-Aviv, 64239 Israel; e-mail: arieroth{at}tasmc.health.gov.il


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To assess the consequences of nitrate withdrawal in angina-free and hemodynamically stable coronary patients.

Design: Prospective, open, intervention study.

Setting: Cardiology outpatient clinic of a university-affiliated municipal hospital.

Patients: Angina-free patients who were hemodynamically stable for at least 3 months before study onset were enrolled. They were all regularly receiving nitrates for symptom control. Those with significant reasons to avoid stopping nitrates, such as heart failure (ejection fraction <35%) or high BP (> 160 mm Hg systolic and/or > 100 mm Hg diastolic), and noncompliant patients were excluded.

Interventions: After providing informed consent and undergoing an exercise test (whenever possible), the participants were randomized to abruptly discontinue (study group) or continue (control group) nitrate treatment. Follow-up continued for at least 3 months after study entry.

Measurements and results: Eighty patients were randomized to the study group and 40 patients to the control group (mean age [± 1 SD], 65.5 ± 11 years and 66.1 ± 10.9 years, respectively; p = not significant). The first month, eight study patients (10%) had a recurrence of anginal symptoms, compared with one control subject (2.5%) [p = not significant]. All eight patients responded promptly and favorably to the resumption of nitrate administration.

Conclusions: Nitrate administration can be safely discontinued in angina-free and hemodynamically stable coronary patients who receive this medication on a regular basis. If relapse of anginal symptoms occurs, it will be within 1 month following nitrate withdrawal, and will resolve satisfactorily with reinstatement of treatment.

Key Words: angina pectoris • myocardial infarction • nitrates


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Organic nitrates are widely employed for the treatment of patients with coronary artery disease.1 Although there are no conclusive data to show long-term favorable effects on mortality, nitrates improve quality of life by inducing a significant improvement in and relief from anginal pains.1 2 The mechanisms of action of nitrates are probably multifactorial, consisting of vasodilating effects,3 reduction in platelet adhesion and aggregation,4 as well as control of endothelial function and vascular growth3 and myocardial contractility.5 These effects result from biodegradation of the drugs that involve their denitration with subsequent liberation of nitric oxide.6

One of the major limitations of the use of nitrates is the development of tolerance,7 8 although the drug apparently remains active despite a loss of effects on exercise tolerance when it is used chronically.9 10 Interestingly, the occurrence of myocardial infarction was shown to increase among workers of the munitions industry after their withdrawal from an occupational environment that involves exposure to nitrates.11 12 Moreover, it has been suggested that there is a rise in the incidence of rest angina and myocardial infarction in patients undergoing intermittent (ie, over a 24-h period with the intention of avoiding tolerance) nitrate treatment compared to those in whom the use is continuous,13 14 although these contentions were refuted by a subsequent large trial.15

Some physicians may hesitate to withdraw nitrates in patients who have been receiving them for years, and tend to continue prescribing them for an unlimited period in spite of any current clear-cut clinical justification. This carries special meaning in recent times, since sustained treatment with nitrates limits and even prohibits the concomitant use of a number of medications, among them sildenafil, which is prescribed for sexual dysfunction.16 This has changed nitrate withdrawal from an occasional minor problem to a frequent minor problem. In the present study, we sought to evaluate the consequences of nitrate withdrawal in nitrate-treated patients with coronary artery disease who had remained angina-free and hemodynamically stable throughout the 3 months prior to the initiation of this study.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Individuals with coronary artery disease proven by coronary angiography (91 of 120 patients, 76%), or clinical and noninvasive means (24%) who were receiving long-term nitrates for manifestations of angina or its equivalents were eligible for this study. Those who were hemodynamically stable and had been free of anginal symptoms requiring short-acting nitrates during a period of at least 3 months prior to the initiation of this study were enrolled.

Eligibility
Patients were excluded if they had significant angina (Canadian Cardiothoracic Society functional classes III-IV) at any time prior to recruitment, significant heart failure (ejection fraction [EF] < 35%) or uncontrolled hypertension, or if they were noncompliant.

Study Design
The study protocol was approved by the institutional ethics committee and, after giving informed consent, patients were randomized consecutively with a 2:1 distribution between groups. Nitrates were abruptly withdrawn from the patients in the study group, while the others continued to observe their usual medication regimen and served as control subjects. A baseline 12-lead ECG was recorded and, whenever possible, a symptom-limited Bruce protocol exercise stress test was performed (without altering the medications) at baseline and at the follow-up visit. A thallium stress scan or an echo stress test was performed in the event that the results of the stress test were not conclusive for ischemia.

The participants were followed up at the cardiology outpatient clinic for at least 3 months after the initiation of this study for prompt recognition of the appearance of any anginal complaints or symptoms of heart failure. Each of the patients was provided with a short-acting nitrate spray and instructed to use it immediately on the resumption of anginal symptoms. They were instructed to inform the attending physician as early as possible of any occurrence of chest pain. Participation in the study was terminated before the given time of closure either on the patient’s request, in the event of clinical or hemodynamic deterioration, when there was any change in the type or dosage of concomitant medications, if the patient were hospitalized due to cardiac-associated symptoms, or if nitrates were again used in any form.

Statistical Analysis
All variables are expressed as mean ± 1 SD. Differences between variables were compared using the Student t test for two groups. Univariate analysis for selected epidemiologic, clinical, angiographic, and therapeutic parameters was performed using the Mann-Whitney nonparametric test for continuous variables and the Fisher exact test for categorical variables. Multivariate logistic regression analysis was applied to the data including explanatory variables whose parameters were found to be significant in the univariate analysis; p < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
One-hundred twenty angina-free and hemodynamically stable patients, 88% of them being in functional class I and the rest in early class II (Canadian Cardiothoracic Society functional classes) comprised the final study population: 80 patients in the study group and 40 control subjects. The members of the two groups showed no significant differences in mean age, the occurrence of coronary risk factors, the presence of congestive heart failure, or a history of prior myocardial infarction and revascularization procedures (Table 1 ). There were also no significant differences between them with regard to the use of medications (Table 2 ). At the time of recruitment, the patients whose nitrates were withdrawn and the control subjects were similar in weight and exercise test parameters (Table 3 ). The incidence of recurrent angina that was benign in its consequences after nitrate withdrawal was 10% (8 of 80 patients) compared with 2% (1 of 40 subjects) in the control group (p = 0.141). The mean interval until the recurrence of anginal symptoms was 2 weeks.


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  		Table 1.. Clinical Characteristics of the Patients Randomized to the Control or Nitrate Withdrawal Group*

 

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  		Table 2.. Medications Used by All Study Patients*

 

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  		Table 3.. Physical Findings of All Study Patients*

 
Of the 8 patients who experienced recurrent anginal symptoms after the withdrawal of their nitrates, 6 of 12 patients (50%) were receiving isosorbide dinitrate (IDSN) three times daily, 1 of 36 patients (0.03%) was receiving slow-release (SR) mononitrate twice daily, and 1 of 32 patients (0.03%) was receiving an SR mononitrate once daily (p < 0.001) [Table 2 ]. Selected baseline characteristics of these patients are presented in Table 4 ; their conditions improved promptly and without exception after reinstitution of the medication. Given the relatively low-risk cohort, it is not surprising that apart from one patient (one of eight patients) with recurrent angina who was catheterized and underwent coronary angioplasty, there were no reports of death or hospitalizations for any other cardiovascular events in patients with nitrates withdrawn. According to multivariate logistic regression analysis, a lower EF was a borderline independent predictor of recurrence of angina pectoris after withdrawal of nitrate therapy (p = 0.06).


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  		Table 4.. Baseline Characteristics of the Eight Patients With Relapsing Anginal Symptoms Following Nitrate Withdrawal

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Ischemic heart disease is nearly always caused by atheroma in one or more of the coronary arteries. When the obstruction caused by an uncomplicated atheromatous plaque exceeds a critical value, myocardial oxygen demand exceeds the ability of the stenosed vessel to supply oxygenated blood, and patients complain of intermittent chest pain that is probably caused by products of anaerobic metabolism in the working myocardium, formed as a result of the temporary imbalance between oxygen supply and demand.

In addition, spasm of smooth muscle in the vascular media can contribute to ischemia. The mechanism of such spasm also probably varies. Possible mediators include vasoconstrictors released from formed elements of blood (eg, platelets or WBCs) in relation to atheroma, or from nerve terminals. 5- Hydroxytryptamine (serotonin), thromboxane A2, and various neuropeptides and endothelium-derived peptides (eg, angiotensin II and endothelin) may each contribute alone or in combination in different circumstances. A relative deficiency of endothelium-derived vasodilators, including nitric oxide and prostacyclin, may be as important as release of vasoconstrictors. Nitrates that are metabolized by smooth-muscle cells with generation of nitric oxide relieve angina by relaxing vascular smooth muscle.

The aim of the present study was to evaluate the safety of abrupt nitrate cessation in angina-free and hemodynamically stable patients with coronary artery disease. Because we considered that it would be unethical or dangerous, at least theoretically, to withdraw nitrates in patients who had experienced significant angina in the past, they were not included in the study. We found that withdrawal of nitrates in these patients was not associated with a significantly increased likelihood of relapsing anginal symptoms nor with hemodynamic deterioration compared to matched patients who continued received nitrates. The patients who were apparently predisposed to relapse were more likely to have been receiving nitrates three times daily, and all the patients with recurrent angina experienced prompt and complete resolution of their symptoms once nitrates were reinstituted, thus supporting the diagnosis of recurrent angina.

Nitrates are administered regularly to patients with acute presentation of angina pectoris and acute myocardial infarction, and constitute an important medication in these patients despite the controversy regarding their effect on mortality.17 18 19 The question of if and when to discontinue nitrates remains unresolved because of the lack of controlled studies and the frequent prehospital use of nitroglycerin in ostensible "control groups." Several important problems may arise from chronic treatment with nitrates in patients with coronary artery disease: due to their development of tolerance to the medication,7 8 20 21 the drug may be ineffective should these patients require acute nitrate treatment on rehospitalization for acute coronary syndromes. Moreover, there are reports suggesting that long-term therapy with nitrates may result in abnormal coronary vasomotion and dysfunction,22 23 and may even raise concern about the potential adverse effects of long-acting nitrate therapy in chronic coronary disease.24

In addition, many patients with coronary artery disease have primary or secondary sexual dysfunction that can be resolved with sildenafil16 ; however, the use of this agent (and its congeners) is contraindicated in those receiving nitrates because of the potentially serious and possibly life-threatening interaction that can result. Use of nitrates in patients receiving sildenafil can result in profound and dangerous decrease in BP.16 The popularity and success of sildenafil lend greater importance to the combined use of both agents. The anticipated appearance of other phosphodiesterase-5 inhibitors on the market adds to the potential relevance of our findings since these agents will share the nitrate contraindication associated with sildenafil.

Indirect evidence suggests that nitrate withdrawal can have deleterious effects. One example is the occurrence of acute myocardial infarction that had been documented in workers of the munitions industry after they no longer underwent occupational exposure to nitrates.11 12 Despite the relative additive efficacy ascribed to intermittent nitrate therapy compared to continuous regimens, the former can also be associated with recurrent myocardial ischemia during the nitrate-free period.13 14 This led to the suggestion that use of intermittent nitrate therapy could be accompanied by an increase in rest angina and myocardial infarction,14 but the results from a large study15 that addressed this issue contradicted these observations. Further supporting that study are the results showing a "zero-hour effect" in which the withdrawal of nitroglycerin (transdermal or oral) had no effect on exercise performance.25 26 27

Our study provides evidence that nitrate withdrawal in patients resembling our study population causes a 10% chances of recurrent angina that is benign and easily treatable. Five of seven patients who experienced recurrent angina pectoris tended to have a relatively lower EF (range, 36 to 42%) compared to the entire group in whom nitrates were withdrawn (Table 4) . Perhaps physicians would be well advised not to overlook this trend whenever they consider withdrawing the long-acting nitrates from their patients who have a relatively low EF.

Moreover, because ß-blockers are well known to be the best cardioprotective agents, their dosage should be optimized before nitrates are withdrawn. One may speculate that in order to further minimize the chances for recurrence of angina, a longer period of nitrate treatment should be allowed before withdrawal to allow the possible development of collaterals or for other local potential adaptation mechanisms to have been set into motion. However, the time of treatment before withdrawal was not different for those in whom angina recurred in comparison with those in whom it did not, and this may indicate that the length of time to withdrawal does not play a major role in angina recurrence. We believe that this is the first work to demonstrate the consequences of abrupt withdrawal of nitrates in coronary patients who had been receiving oral nitrates on a regular basis for at least 3 months.

A few words of caution and study limitations: because it is possible that the agents may be providing some degree of myocardial protection even if the patients were not experiencing symptoms, and since our study lacks a placebo control component in the withdrawal arm, together with the small number of studied patients (ie, a larger study size might have produced a statistically significant difference in the incidence of angina between the withdrawal group and the continued therapy group), additional larger-scale, longer-term, and placebo-controlled prospective studies for establishing clear-cut guidelines for recommending the discontinuation of nitrates in patients such as these are warranted.


   Acknowledgements
 
We thank Esther Eshkol for editorial assistance.


   Footnotes
 
Abbreviations: EF = ejection fraction; ISDN = isosorbide dinitrate; SR = slow release

Received for publication August 14, 2002. Accepted for publication March 19, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Parker, JD, Parker, JO (1998) Nitrate therapy for stable angina pectoris. N Engl J Med 338,520-531[Free Full Text]
  2. Murad, F Drugs used for the treatment of angina: organic nitrates, calcium-channel blockers, and (beta)-adrenergic antagonists. Gilman, AG Rall, TW Nies, ASet al eds. Goodman and Gilman’s the pharmacological basis of therapeutics 8th ed. 1990,764-783 Pergamon Press. New York, NY:
  3. Moncada, S, Higgs, A The L-arginine-nitric oxide pathway. N Engl J Med 1993;329,2002-2012[Free Full Text]
  4. Loscalzo, J N-acetylcysteine potentiates inhibition of platelet aggregation by nitroglycerin. J Clin Invest 1985;76,703-708[ISI][Medline]
  5. Kelly, RA, Balligand, JL, Smith, TW Nitric oxide and cardiac function. Circ Res 1996;79,363-380[Free Full Text]
  6. Katsuki, S, Murad, F Regulation of adenosine cyclic 3', 5'-monophosphate and guanosine cyclic 3', 5'-monophosphate levels and contractility in bovine tracheal smooth muscle. Mol Pharmacol 1977;13,330-341[Abstract/Free Full Text]
  7. Abrams, J Clinical aspects of nitrate tolerance. Eur Heart J 1991;12(Suppl E),42-52
  8. Elkayam, U Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention. Ann Intern Med 1991;114,667-677[ISI][Medline]
  9. DeMots, H, Glasser, SP Intermittent transdermal nitroglycerin therapy in the treatment of chronic stable angina. J Am Coll Cardiol 1989;13,786-795[Abstract]
  10. Parker, JD, Parker, AB, Farrell, B, et al Intermittent transdermal nitroglycerin therapy: decreased anginal threshold during the nitrate-free interval. Circulation 1995;91,973-978[Abstract/Free Full Text]
  11. Lange, RL, Reid, MS, Tresch, DD, et al Nonatheromatous ischemic heart disease following withdrawal from chronic industrial nitroglycerin exposure. Circulation 1995;91,973-978
  12. Morton, WE Occupational habituation to aliphatic nitrates and the withdrawal hazards of coronary disease and hypertension. J Occup Med 1977;19,197-200[ISI][Medline]
  13. Ferratini, M, Pirelli, S, Merlini, P, et al Intermittent transdermal nitroglycerin monotherapy in stable exercise-induced angina: a comparison with a continuous schedule. Eur Heart J 1989;10,998-1002[Abstract/Free Full Text]
  14. Waters, DD, Juneau, M, Gossard, D, et al Limited usefulness of intermittent nitroglycerin patches in stable angina. J Am Coll Cardiol 1989;13,421-425[Abstract]
  15. Parker, JO, Farrell, B, Lahey, KA, et al Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. N Engl J Med 1987;316,1440-1444[Abstract]
  16. Cheitlin, MD, Hutter, AMJ, Brindis, RG, et al ACC/AHA expert consensus document: use of sildenafil (Viagra) in patients with cardiovascular disease: American College of Cardiology/American Heart Association. J Am Coll Cardiol 1999;33,273-282[Free Full Text]
  17. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58050 patients with suspected acute myocardial infarction. Lancet 1995;345,669-685[CrossRef][ISI][Medline]
  18. . GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction; Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico. Lancet 1994;343,1115-1122[ISI][Medline]
  19. Yusuf, S, Collins, R, MacMahon, S, et al Effect of intravenous nitrates on mortality in acute myocardial infarction. Lancet 1988;1,1088-1092[ISI][Medline]
  20. Roth, A, Kulick, D, Friedenberger, L, et al Early tolerance to the hemodynamic effects of high dose transdermal nitroglycerin in responders with severe chronic heart failure. J Am Coll Cardiol 1987;9,858-864[Abstract]
  21. Elkayam, U, Roth, A, Mehra, A, et al Randomized study to evaluate the relation between oral isosorbide dinitrate dosing interval and the development of early tolerance to its effect on left ventricular filling pressure in patients with chronic heart failure. Circulation 1991;84,2040-2048[Abstract/Free Full Text]
  22. Caramori, PRA, Adelman, AG, Azevedo, ER, et al Therapy with nitroglycerin increases coronary vasoconstriction in response to acetylcholine. J Am Coll Cardiol 1998;32,1969-1974[Abstract/Free Full Text]
  23. Heitzer, H, Just, H, Brockhoff, C, et al Long-term nitroglycerin treatment is associated with supersensitivity to vasoconstrictors in men with stable coronary artery disease: prevention by concomitant treatment with captopril. J Am Coll Cardiol 1998;31,83-88[Abstract/Free Full Text]
  24. Nakamura, Y, Moss, AJ, Brown, MW, et al Long-term nitrate use may be deleterious in ischemic heart disease: a study using the databases from two-large scale postinfarction studies; Multicenter Myocardial Ischemia Research Group. Am Heart J 1999;138,577-585[CrossRef][ISI][Medline]
  25. Parker, JO Eccentric dosing with isosorbide-5-mononitrate in angina pectoris. Am J Cardiol 1993;72,871-876[CrossRef][ISI][Medline]
  26. Parker, JO, Amies, MH, Hawkinson, RW, et al Intermittent transdermal nitroglycerin therapy in angina pectoris: clinically effective without tolerance or rebound; Minitran Efficacy Study Group. Circulation 1995;91,1368-1374[Abstract/Free Full Text]
  27. Olsson, G, Allgen, J, Amtorp, O, et al Absence of pre-dose rebound phenomena with once daily 5-ISMN in a controlled-release formulation. Eur Heart J 1992;13,814-817[Abstract/Free Full Text]




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