Author + information
- Received August 5, 1996
- Revision received December 11, 1996
- Accepted December 16, 1996
- Published online April 1, 1997.
- Diego Ardissino, MDA,*,
- Piera Angelica Merlini, MDB,
- Stefano Savonitto, MDB,
- Gloria Demicheli, MDA,
- Paola Zanini, MDA,
- Federico Bertocchi, MDA,
- Colomba Falcone, MDA,
- Stefano Ghio, MDA,
- Giampiero Marinoni, MDA,
- Carlo Montemartini, MDA and
- Antonio Mussini, MDA ()
- ↵*Dr. Diego Ardissino, Division of Cardiology, IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
Objectives. This study was designed to evaluate whether the addition of transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical therapy improves the natural history of unstable angina pectoris.
Background. Transdermal nitroglycerin is widely used to treat angina pectoris, but the development of tolerance is a major problem that may reduce its clinical efficacy. It has been suggested that the addition of N-acetylcysteine to nitroglycerin reverses the development of tolerance, potentiates the hemodynamic response to nitroglycerin and may improve in-hospital prognosis in unstable angina.
Methods. We assessed the efficacy of adding transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical therapy in a randomized, double-blind, placebo-controlled trial involving 200 patients with unstable angina who were followed up for 4 months.
Results. Outcome events—death, myocardial infarction or refractory angina requiring revascularization—occurred in 31% of patients receiving nitroglycerin, 42% of those receiving N-acetylcysteine, 13% of those receiving nitroglycerin plus N-acetylcysteine and 39% of those receiving placebo (p = 0.0052). Kaplan-Meier curves showed a higher probability (p < 0.01) of no failure of medical treatment in the group receiving both nitroglycerin and N-acetylcysteine than in those receiving placebo, N-acetylcysteine or nitroglycerin alone. The combination of nitroglycerin and N-acetylcysteine was associated with a high incidence of side effects (35%), mainly intolerable headache, which was almost twice as frequent as in patients receiving nitroglycerin alone.
Conclusions. The combination of nitroglycerin and N-acetylcysteine, associated with conventional medical therapy in the long-term treatment of patients with unstable angina, reduces the occurrence of outcome events. However, the high incidence of side effects limits the clinical applicability of this therapeutic strategy at least at the dosage used in the present study.
(J Am Coll Cardiol 1997;29:941–7)
© 1997 by the American College of Cardiology
Although nitroglycerin and other organic nitrates are among the oldest and most efficacious remedies used to treat anginal attacks, their clinical efficacy in the long-term management of angina pectoris is still controversial ([1, 2]). A major problem with long-term prophylactic nitrate therapy is the development of tolerance, which may reduce clinical efficacy. The basis for nitrate tolerance is not completely understood, but the most widely espoused theory is that continuous nitrate administration leads to the depletion of the reduced sulfhydryl groups, which are essential for the pharmacologic effect of nitrates ([3–5]).
The sulfhydryl donor N-acetylcysteine has been shown to enhance nitroglycerin-induced dilation of the smaller coronary vessels (), potentiate the hemodynamic response to nitrates ([7–9]) and reverse the development of nitrate tolerance ([10–12]). In patients with unstable angina receiving intravenous nitroglycerin, an infusion of high doses of N-acetylcysteine augmented the efficacy of nitrates and improved short-term prognosis by preventing the development of acute myocardial infarction (). However, it is not known whether long-term treatment with transdermal nitroglycerin and oral N-acetylcysteine is effective in improving long-term prognosis in patients with unstable angina pectoris. This report describes a 4-month, double-blind, randomized, placebo-controlled trial designed to examine whether the addition of transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical management improves the natural history of unstable angina pectoris.
1.1 Patient selection.
Patients with unstable angina who were consecutively admitted to our institution and were deemed not to require emergency coronary revascularization were considered eligible to enter the study. A log of all hospital admissions was kept during the recruitment phase. Unstable angina was defined as 1) chest pain of recent onset, 2) a sudden worsening of preexisting stable angina, or 3) postinfarction angina developing after an asymptomatic period of >12 weeks. The prerequisite for inclusion in the study was the occurrence of chest pain at rest associated with transient ischemic repolarization changes: that is, the electrocardiographic (ECG) demonstration of ≥1-mm ST segment depression or elevation 80 ms after the J point, T wave inversion or the pseudonormalization of previously negative T waves. All patients fulfilled the criteria for class IIB or IIIB of the Braunwald’s classification of unstable angina.
Patients with the following conditions were excluded from the study: 1) age >75 years; 2) previous coronary artery bypass surgery or coronary angioplasty; 3) valvular heart disease; 4) systolic blood pressure <100 mm Hg; 5) congenital heart disease; 6) symptomatic cerebrovascular disease; 7) extracardiac conditions that may interfere with 4-month prognosis; and 8) extracardiac conditions that intensify myocardial ischemia, such as anemia, fever, infections, uncontrolled hypertension, tachyarrythmias, unusual emotional stress, thyrotoxicosis and hypoxemia secondary to respiratory failure.
1.2 Study protocol.
All patients included in the study were followed up by three cardiologists (G.D., P.Z., A.M.), who adopted a uniform approach to the management of unstable angina for investigational purposes. Patients were screened for the study as soon as the results of coronary arteriography were available and it was determined that they did not require emergency coronary revascularization. Emergency coronary revascularization was performed in patients with left main coronary artery disease (>50% stenosis) or persistent angina at rest despite maximal medical therapy. Of a total of 346 screened patients, 146 underwent emergency coronary revascularization, and 200 were considered eligible to enter the study. After the determination of eligibility, the study protocol was explained to each patient and their written informed consent was obtained. The patients were then randomly assigned on a double-blind basis to one of the following treatments: 1) nitroglycerin plus N-acetylcysteine placebo; 2) nitroglycerin placebo plus N-acetylcysteine; 3) nitroglycerin plus N-acetylcysteine; and 4) nitroglycerin placebo plus N-acetylcysteine placebo. Throughout the study, the patients were instructed to record the number and severity of anginal attacks and their use of nitroglycerin on diary cards, and to refer to the investigators in charge in the case of any problem. Ambulatory ECG (Holter) monitoring was used to help the investigators assess the need for emergency revascularization; it was performed four times: 1) on the day before randomization, 2) on the 1st day of trial drug administration, 3) during the 2nd week of randomized treatment, and 4) after 4 months. Follow-up visits, consisting of an ECG and a complete physical examination, were scheduled 1, 2, 3 and 4 months after enrollment.
1.3 Conventional treatment.
On enrollment, patients received a standardized conventional medical treatment: a combination of aspirin (300 to 325 mg daily), metoprolol (100 to 200 mg daily) and nifedipine (40 to 80 mg daily). If aspirin was contraindicated, it was replaced by ticlopidine (250 to 500 mg daily); if metoprolol was contraindicated, it was replaced by diltiazem (180 to 360 mg daily). The protocol required that the use of these agents be maintained throughout the study period. Administration of all nitrate medications (except nitroglycerin to treat anginal attacks) was required to be stopped >4 days before the start of the study. Other concomitant medications that were considered necessary for the patients’ welfare and that did not interfere with the study medications were given at the discretion of the investigators. The administration of such drugs had to be recorded in the case report form.
1.4 Study drug.
The nitroglycerin 10-mg and nitroglycerin placebo patches were identical, as were the N-acetylcysteine 600-mg and N-acetylcysteine placebo tablets. Because of the different ways of administering nitroglycerin and N-acetylcysteine, the double-dummy technique was used. One nitroglycerin patch (active or placebo) and three N-acetylcysteine tablets (active or placebo) were given per day. The trial medications were prepackaged, and four boxes (one for each month of treatment) of each of the two study drugs were available. The eight boxes were collected in a patient medication pack bearing a sequential patient number. To ensure random allocation to the treatments, each patient was to be given the patient medication pack bearing the lowest available patient number. Patient compliance to the trial treatments was measured by means of residual patch and tablet counts at each visit. Good compliance was defined as 80% to 120% of scheduled patch or tablet consumption.
1.5 Study end points.
The primary end point was the 4-month composite incidence of cardiac death, Q wave and non-Q wave myocardial infarction, or persistent angina requiring coronary bypass surgery or angioplasty. In the case of more than one event, the most serious was counted. Cardiac death was defined as death due to cardiac causes. Q wave myocardial infarction was defined as 1) prolonged chest pain; 2) an increase in creatine kinase levels to more than twice normal values; 3) the development of new Q waves on the 12-lead ECG. Non-Q wave myocardial infarction required only the first two characteristics. Persistent angina requiring coronary revascularization was defined as the presence of recurrent anginal chest pain leading to hospital admission. Occasional angina or angina controlled by medical therapy that did not require a repeat hospital admission, was not considered an end point.
Adverse drug reactions were closely monitored at each visit during the study and were to be recorded on the case report form. The following data were to be collected: the nature of the adverse drug reaction, date of onset and resolution, severity of the reaction, relation to the trial drug, action taken, therapy required and outcome. Severe headache was defined as headache that required analgesic therapy and led to temporary or permanent discontinuation of the study drugs.
1.6 Holter monitoring.
Continuous two-channel Holter monitoring was performed by using Delmar Avionics Electrocardiocorders (model 445), which have a frequency response of 0.05 to 100 Hz and meet the specifications of the American Heart Association. The leads showing the most evident ECG changes during spontaneous anginal attacks were monitored. The leads with abnormal waves or significant ST segment shifts were avoided, and control recordings were made in each patient in the supine, prone, standing and sitting positions. The system was calibrated before and after each placement. The tapes were analyzed by a cardiologist (P.Z.) at 60 times real time under continuous visual inspection, and an episode of transient ischemia was defined as ≥1-mm ST segment elevation or depression occurring 80 ms after the J point, lasting for ≥1 min and separated from other episodes by ≥1 min. When a significant ST segment change was noted on the monitor, the episode was recorded on ECG paper at 25 mm/s. The number and duration of ischemic episodes were recorded.
1.7 Coronary arteriography.
Selective coronary arteriography was performed in multiple views by the Sones or Judkins technique, after premedication with 10 mg of diazepam. Patients were classified as having one-, two- or three-vessel disease according to the number of vessels showing significant coronary stenosis, defined as a >50% narrowing in the diameter of the coronary arteries.
1.8 Statistical analysis.
The end point status of all of the patients withdrawn over the 4-month period was established, and the outcomes were recorded and included in the analysis. The difference between the four treatment arms was therefore diluted, because the analysis included patients who had not received the drug for the entire study period. Although this type of analysis reduces the probability of demonstrating a difference between the four arms, we considered this conservative approach more appropriate than alternative ways of handling withdrawals.
The results are expressed as odds ratios (OR) and 95% confidence limits (CL). Event rates were tested by means of two-tailed chi-square statistics. In addition to performing contingency table analysis, we considered the time-dependent nature of treatment failure by applying the Kaplan-Meier actuarial method to examine failure rates over time. The Kaplan-Meier actuarial curves were then compared by using a log-rank test according to the intention to treat principle.
Holter monitoring was performed only in patients actually receiving the study drug; therefore, the statistical analysis was performed on a “per protocol” basis. The prevalence of patients showing at least one ischemic episode at the different time points was compared within each treatment group by means of the chi-square test.
Baseline characteristics were compared by using the chi-square test for discrete variables and the analysis of variance for continuous variables. All of the presented tests are two-tailed. A p value <0.05 was considered statistically significant.
2.1 Composition of the study group.
A total of 200 patients were randomized. Protocol deviations were noted in two patients. In one, the decision to perform emergency coronary revascularization was taken before administration of the study medication; the other patient, who was randomized before giving informed consent, refused to adhere to the protocol. These patients were followed up for the occurrence of outcome events and both were analyzed with the others according to the intention to treat principle. Compliance with the drug regimen was considered good in 91% of the patients and did not differ among treatment groups.
The clinical, ECG and angiographic characteristics of the four study groups are shown in Table 1. No intergroup differences were observed for any of the baseline variables.
2.2 Study end points.
The distribution of outcome events is shown in Table 2. Outcome events occurred in 17 patients (31%) receiving nitroglycerin, in 19 (42%) receiving N-acetylcysteine, in 7 (13%) receiving nitroglycerin plus N-acetylcysteine and in 18 (39%) receiving placebo (p = 0.0052). The risk of developing an outcome event was significantly lower in the group receiving nitroglycerin plus N-acetylcysteine than in the groups receiving placebo (OR 0.25; 95% CL 0.07, 0.7; p = 0.0022), nitroglycerin alone (OR 0.31; 95% CL 0.098, 0.90; p = 0.018) or N-acetylcysteine alone (OR 0.19; 95% CL 0.06, 0.57; p = 0.0008). No significant differences were observed among the groups receiving placebo, nitroglycerin alone or N-acetylcysteine alone.
Kaplan-Meier curves showing the 4-month probability of no failure of medical treatment are shown in Fig. 1. The probability of no failure of medical treatment was significantly higher in the group receiving nitroglycerin plus N-acetylcysteine than in each of the other three groups (p < 0.01). No significant differences were observed among the groups receiving placebo, nitroglycerin alone or N-acetylcysteine alone.
Complications, side effects and their time of occurrence by treatment group during the 4-month study period are shown in Table 3and Table 4. Severe headache occurred in 17 patients receiving nitroglycerin and N-acetylcysteine, an incidence almost twice that of patients receiving nitroglycerin alone; it occurred in only 2 patients receiving N-acetylcysteine alone (1 patient) or placebo (1 patient). Among other complications, gastrointestinal disorders (epigastralgia and diarrhea) were the most frequent, occurring mainly in the group receiving N-acetylcysteine alone. Drug discontinuation because of side effects was more frequent in the group receiving nitroglycerin plus N-acetylcysteine than in the other treatment groups (p = 0.028). Except in the placebo group, most complications or side effects occurred within the 1st month of treatment.
2.4 Holter monitoring.
Table 5shows the results of Holter monitoring by treatment group. At baseline, the prevalence of patients showing the presence of at least one ischemic episode was similar in the four groups. The prevalence of patients who had ischemic episodes on Holter monitoring did not differ at the various time points in the groups receiving placebo, N-acetylcysteine alone or nitroglycerin alone; in the group receiving nitroglycerin plus N-acetylcysteine, there was a significant reduction in the prevalence of those showing ischemia on the 1st day of treatment, at the 2nd week and at the 4th month of treatment (p = 0.033).
3.1 Nitrates and the prevention of myocardial ischemia.
Nitrates relieve or prevent myocardial ischemia by multiple mechanisms (). They cause dilation of the venous bed with peripheral pooling of blood, so that there is a reduced venous return to the heart with a corresponding reduction in heart size. They also reduce arterial and arteriolar tone, reductions that lower systemic pressure and left ventricular volume. The reduced blood pressure and smaller heart size lead to reduced myocardial oxygen consumption. In addition, nitrates increase myocardial oxygen supply by dilating epicardial coronary arteries and enhancing collateral blood flow.
The vasodilating effects of nitrates are currently attributed ([4, 5]) to stimulation of the production of cyclic guanosine monophosphate in vascular smooth muscle. It has been suggested () that the organic nitrates are converted to nitric acid, leading to the production of nitric oxide and nitrosothiols by means of reactions with sulfhydryl-containing compounds. The nitric oxide and nitrosothiols stimulate guanylate cyclase, thus producing the vasodilating cyclic guanosine monophosphate. Continued nitrate exposure leads to the depletion of reduced sulfhydryl groups with a consequent decrease in the formation of nitric oxide and nitrosothiols, and diminished activation of guanylate cyclase, which blunts the pharmacologic effect of nitrates ().
3.2 Effect of N-acetylcysteine.
N-acetylcysteine, a source of sulfhydryl groups, has been shown ([10–12]) to potentiate the peripheral and coronary vasodilator effects of nitroglycerin in vivo, and to prevent the development of tolerance. In patients with unstable angina, the addition of intravenous N-acetylcysteine to intravenous nitroglycerin has also been shown () to potentiate the effect of nitrates and improve short-term, in-hospital prognosis by reducing the occurrence of myocardial infarction. In this study we evaluated the long-term clinical effect of adding transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical treatment in patients with unstable angina pectoris deemed not to require emergency coronary revascularization. In comparison with placebo, no significant differences in outcome were observed with the addition of transdermal nitroglycerin or oral N-acetylcysteine alone, whereas the combination of nitroglycerin and N-acetylcysteine significantly reduced the occurrence of combined end point events over the 4-month study period. However, the more pronounced effect of combining nitroglycerin and N-acetylcysteine was associated with a higher incidence of side effects or premature discontinuation, mainly related to the occurrence of severe headache (thus confirming the more potent vasodilating effect of the drug combination). The high incidence of severe headache in those receiving the drug combination limits the clinical applicability of this therapeutic strategy, at least at the doses used in the present study.
3.3 Possible mechanisms of beneficial effect of combination therapy.
We performed Holter monitoring only in the patients who actually received the study medications (thus excluding those who had already reached an end point or who had stopped taking the study drug because of side effects). Although our data must be viewed in light of this limitation, it is interesting that the number of patients showing more than one ischemic episode was significantly reduced only in the group treated with nitroglycerin plus N-acetylcysteine. These results reinforce the finding of a more pronounced effect of the combination therapy. As we did not observe an early effect that was lost during follow-up in the group treated with nitroglycerin alone (i.e., the development of tolerance), we cannot ascribe the beneficial effect of the combination therapy to the prevention of tolerance.
Another possible explanation for the beneficial effect of the combination of nitroglycerin and N-acetylcysteine on prognosis may be related to the antiplatelet effect of nitroglycerin ([15–17]), which is greatly potentiated by N-acetylcysteine at pharmacologic concentrations achievable in vivo ([18–21]). In unstable angina, a condition for which antiplatelet therapy has been shown ([22–25]) to improve acute, subacute and long-term prognosis, this effect may be of particular interest, although its relevance in patients receiving aspirin, as were those in our study group, remains to be determined.
The combination of nitroglycerin and N-acetylcysteine, associated with conventional medical therapy in the long-term treatment of patients with unstable angina deemed not to require emergency coronary revascularization, reduces the occurrence of outcome events. However, the high incidence of side effects may limit the clinical applicability of this therapeutic strategy, at least at the doses used in our study. Further studies are needed to titrate dose regimens at which the efficacy/tolerability profile may be favorable and clinically acceptable.
☆ Drs. Zanini and Demicheli were supported in part by a grant from Ciba-Geigy, Origgio, Italy and Zambon, Cormano, Italy.
- confidence limits
- electrocardiogram, electrocardiographic
- odds ratio
- Received August 5, 1996.
- Revision received December 11, 1996.
- Accepted December 16, 1996.
- The American College of Cardiology
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