Isosorbide-5-mononitrate (IS-5-MN), the major active metabolite of isosorbide dinitrate, is almost 100% bioavailable after oral administration [30, 31] and exerts prolonged antianginal effects [32, 33]. In December 1991, IS-5-MN was approved in the United States for clinical use in a regimen of two 20-mg doses given 7 hours apart. Continuous therapy three or four times a day with 50 mg of this agent produced tolerance [34]. Twice-daily doses of 20 to 40 mg given at 0800 and 2000 hours did not provide antianginal protection throughout the dose interval and produced partial tolerance [35-37]. We did a multicenter, placebo-controlled, parallel-group study to evaluate the safety, efficacy, and duration of antianginal effects of 0800-hour and 1500-hour doses of 20 mg of IS-5-MN during twice-daily therapy.

Methods

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Men and women attending the referral outpatient cardiology clinics of four university hospitals and the offices of five private cardiologists, with a history of exertional angina pectoris that was stable for at least 3 months, were considered for the trial. Patients were required to have evidence of myocardial ischemia or coronary artery disease. During stress testing, evidence of myocardial ischemia consisted of flat or down-sloping ST-segment depression of at least 1 mm, persisting for 0.08 seconds after the J point. In the absence of exercise-induced myocardial ischemia, patients were eligible for the study provided that at least one of the following criteria was met: 1) documented previous myocardial infarction; 2) obstructive coronary artery disease, with at least 70% cross-sectional obstruction of the right or left anterior descending or left circumflex coronary artery or 50% luminal obstruction of the left main coronary artery; 3) reversible or fixed perfusion defect during thallium stress test; or 4) regional wall motion abnormality during stress radionuclide angiography. Patients were not required to have a minimum number of anginal attacks during daily activity to be included in the study.

Patients with the following medical conditions were excluded: documented myocardial infarction, coronary artery bypass surgery, or coronary angioplasty within the previous 3 months; clinically significant valvular or congenital cardiac disease; peripheral vascular disease; history of uncontrolled hypertension (diastolic blood pressure >105 mm Hg) or hypotension (systolic blood pressure < 90 mm Hg); cardiac arrhythmias; conduction disturbances, left bundle-branch block, or a permanent pacemaker; left ventricular hypertrophy; congestive heart failure; active liver or renal disease; febrile illness; anemia (hemoglobin < 100 g/L); clinically significant metabolic dysfunction; severe pulmonary disease; morbid obesity; inability to undergo repeated exercise tests; contraindication or hypersensitivity to nitrates; psychiatric disturbance requiring drug therapy; or substance abuse.

With the exception of ß-adrenergic blockers, all other antianginal drugs, including calcium channel blockers, long-acting nitrates, or other vasodilator compounds, were withdrawn for at least five half-lives before study entry. Patients who could be safely withdrawn from antianginal medications and remained medically stable were included in the study. Sublingual nitroglycerin was allowed for the relief of an anginal attack but was not allowed for prophylactic use. Cardiac glycosides and -agonists or -antagonists were not allowed.

Study Design

The protocol was approved by the institutional review board of each participating institution. Patients signed a consent form. The screening treadmill test (visit 1) was done using the modified Bruce protocol (starting stage, 1.7 mph; grade, 5%) [38]. Patients who stopped exercise because of angina of moderate severity between 3 minutes 15 seconds to 10 minutes were asked to continue in the study. On the subsequent study days, patients ate a standardized light lunch and a light evening meal, 2 to 2.5 hours before the scheduled exercise tests.

Single-blind Placebo Administration

For the first week, patients took placebo at 0800 hours and 1500 hours under single-blind conditions. In addition, patients who were receiving ß-adrenergic-blocking drugs continued taking them without a dose or schedule change throughout the study. After 5 to 9 days, four stress tests were done (visit 2). The first exercise test was done half an hour before the morning dose of single-blind placebo, and the other three tests were done at 2, 5, and 7 hours after the morning dose. After the hour-7 exercise test, patients took the 1500-hour dose of medication.

Criteria To Continue in the Double-blind Study

To qualify for the double-blind portion of the study, the following criteria had to be met: 1) Patients had to stop exercise because of angina of moderate severity; 2) on at least three of four tests done at visit 2, patients had to reach the end point of moderately severe angina within 3 minutes 15 seconds and 10 minutes; and 3) the time to moderate anginal pain for the stress test done at screening (visit 1) and the test done 2 hours after the dose of single-blind placebo (visit 2) had to be within 25% of each other.

Assignment to Treatment Groups

Patients meeting the eligibility criteria above were randomly assigned to one of two treatment groups: placebo or IS-5-MN, 20 mg, to be taken twice daily at 0800 hours and 1500 hours. The study medications, IS-5-MN and placebo, were supplied as identical tablets. The patients were enrolled sequentially with the exception that nonqualifying patients were replaced within the same treatment group. A blocked randomization schedule (blocked in groups of four) was used to maintain equality of randomized patients within the treatment groups.

Follow-up

Patients received the double-blind medication for the next 2 weeks and returned at the end of each week (visits 3 and 4) for further symptom-limited exercise tests. At these two visits, patients arrived before they had taken the morning dose of medication; after doing their first exercise test of the day (predose exercise test), they took the 0800-hour dose. At visits 3 and 4, patients did exercise tests according to a randomly assigned schedule (schedule 1 or schedule 2). Patients assigned to schedule 1 had stress testing at hours 2, 5, and 7 after the morning dose at visit 3 and at hours 2 and 5 after the 1500-hour dose at visit 4. Patients assigned to schedule 2 did the afternoon stress tests at visit 3 and the morning stress tests at visit 4. Thus, each patient was studied after both the morning and afternoon dose of the double-blind medication.

Measurements

A 12-lead electrocardiogram was recorded, and cuff blood pressure was taken before all treadmill tests throughout the study. During exercise and for a 9-minute recovery period afterward, electrocardiographic monitoring was done. Periodically during exercise, electrocardiograms and blood pressure measurements were obtained. Average heart rate and ST-segment depression were determined. The end point during exercise was angina of moderate severity. During the screening evaluation and single-blind placebo administration, this was the only acceptable reason for premature exercise discontinuation in patients who continued into the double-blind phase. Once patients were in the double-blind portion of the study, other reasons for exercise discontinuation, such as fatigue or excessive dyspnea, were allowed for patients who did not experience angina.

Throughout the study, the patients kept a diary with the time and date for each anginal attack. They rated the severity and recorded duration and cause for the attacks. They also recorded any sublingual nitroglycerin use. At each visit, study medication was retrieved and new medication prescribed. Compliance was assessed by tablet count at each visit.

Statistical Analysis

The data for patients who completed the study were analyzed to compare the efficacy variables of the IS-5-MN treatment group with those of the placebo group after double-blind therapy. The data were rank-transformed and analyzed using an analysis of covariance. Adjustment was made for the corresponding morning pretherapy baseline, which was the exercise test done just before administration of the morning dose of single-blind placebo at visit 2. Statistical significance was judged at the 0.05 level (one-tailed). A two-tailed test was used to evaluate the zero-hour effect and rebound phenomenon.

Patients were randomly assigned to the sequence in which they received the exercise tests. Half of the patients received the morning stress tests after 1 week and the afternoon tests after 2 weeks. The other half of the patients received the tests in the reverse order. This sequence effect and treatment by sequence interaction effect were both examined to evaluate their effect on the treatment.

Efficacy Evaluations

The primary efficacy variable was total exercise duration (the time to moderately severe anginal pain that necessitated discontinuation of walking during the exercise stress test). During double-blind therapy, for patients who did not have moderate angina, total exercise time was substituted. The peak effect (the maximum exercise time at any hour) and the duration of effect were also determined.

Secondary efficacy variables included the magnitude of ST-segment depression, heart rate, systolic and diastolic blood pressure during stress testing, number of anginal attacks, and the number of nitroglycerin tablets consumed.

Assessment of Rebound Phenomenon and Zero-Hour Effect

Rebound was assessed by evaluating the secondary efficacy parameters, such as angina attacks and sublingual nitroglycerin consumption. The zero-hour effect was evaluated by comparing the hour 0 pretherapy stress test result at visit 2 with the hour 0 predose stress test result at visit 3 or 4. The change (visit-4 result minus visit-3 result) was also analyzed.

Safety Evaluations

Safety was assessed by a physical examination, clinical laboratory evaluations, and recordings of study events. Study events were any undesired signs or symptoms associated with the use of the study medications, regardless of whether these events were considered drug related.

Results

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Of 136 patients who met the entry and exclusion criteria, 128 patients stopped exercise because of angina of moderate severity within 3 minutes 15 seconds and 10 minutes and received single-blind placebo. Six of the 128 patients did not stop exercise due to moderately severe angina consistently during subsequent tests and were dropped from the study. The remaining 122 patients entered the randomized, double-blind treatment phase. Of these 122 patients, 6 patients (2 in the placebo group and 4 in the IS-5-MN group) were withdrawn from the study. Data from 116 patients who completed the study (60 in the IS-5-MN group, 56 in the placebo group) are included in the efficacy analysis. Safety results were analyzed for all 122 patients enrolled.

The demographic characteristics of the 116 patients who completed the study are summarized in Table 1. The characteristics of patients assigned to the two treatment groups were similar. Compliance with study drug administration was 90% to 100% in 90% of the patients and was at least 75% in the remaining patients who completed the trial.

Figure 1 shows the mean changes from baseline in total exercise duration for both treatment groups. Compared with placebo, both the 0800-hour and the 1500-hour dose of IS-5-MN produced a greater increase in exercise duration that was statistically significant (P < 0.01) at all time intervals tested. Similarly, the peak effect was greater after both IS-5-MN doses compared with placebo (P < 0.01), occurring 2 hours after drug administration (Table 2).

View larger version (16K): [in this window] [in a new window]   Figure 1. Change in exercise duration among patients receiving placebo and those receiving isosorbide-5-mononitrate therapy. Mean changes in total exercise duration from respective pretherapy baseline values after 0800-hour and 1500-hour doses of isosorbide-5-mononitrate (IS-5-MN) and placebo. Total exercise duration increased significantly (P < 0.01) with IS-5-MN compared with placebo at 2, 5, and 7 hours after the 0800-hour dose and at 2 and 5 hours after the 1500-hour dose (hours 9 and 12 after the 0800-hour dose). Exercise time before the 0800-hour dose did not change significantly. Mean values ±SE are shown by the vertical bars. *P < 0.01.

The exercise duration observed at 2 and 5 hours after the 1500-hour dose did not differ statistically from that after the 0800-hour dose in both treatment groups (Table 4; placebo compared with IS-5-MN, P > 0.2 at 2 hours and at 5 hours).

At baseline, ST-segment depression at termination of exercise was similar in the placebo and IS-5-MN groups (1.2 ±0.2 compared with 1.2 ±0.1 mm, P > 0.2), and these values did not change after 1 to 2 weeks of placebo or IS-5-MN therapy. At comparable work loads, however, ST-segment depression was less in the IS-5-MN group compared with placebo group but achieved statistical significance only at 2 hours after the afternoon dose (0.8 compared with 1.1 mm, P = 0.04). Heart rate and systolic blood pressure during exercise were similar in the placebo and IS-5-MN groups.

The IS-5-MN and placebo groups did not differ in anginal attack rates or nitroglycerin consumption for the whole 24-hour period or for the interval between 0200 and 0800 hours (Table 5). We also observed no difference between the treatment groups for patients without anginal attacks during the study; 13 patients in each group had no episodes of angina.

Assessment of Safety Results

In the IS-5-MN group, treatment was discontinued because of severe headaches, nausea or vomiting, or dizziness in two patients, unstable angina in one patient, and flu-like illness in one patient. In the placebo group, treatment was discontinued because of unstable angina in one patient and nonsustained ventricular tachycardia during the visit-3 exercise test in one patient. Nine (15%) of 62 patients reported headache in the placebo group and 19 (32%) of 60 patients in the IS-5-MN group. No other study-related events were reported. No clinical or statistical increase in the rate of anginal attacks or in nitroglycerin consumption was noted during the 0200- to 0800-hour interval in the IS-5-MN group compared with the placebo group (Table 5).

Discussion

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Our results show that IS-5-MN, 20 mg given once daily in the morning and again 7 hours later, resulted in a significantly improved exercise performance after both doses compared with placebo. We chose the 20-mg dose because it produced a near-maximum effect after a single oral dose [32] and after several doses during twice-daily therapy [33]. Further, it is the only dose approved in the United States. The dose-response relation of isosorbide dinitrate administered in a similar twice-daily schedule and its effect on exercise performance are unknown [28, 29]. When nitroglycerin patches delivering more than 30 mg of nitroglycerin per 24 hours were applied for only 12 hours during the day, exercise duration increased during long-term therapy for at least 8 hours [21]. In our study, comparable or superior results were obtained with twice-daily therapy with 20 mg of IS-5-MN, given in the morning and 7 hours later, which lasted for at least 12 hours as shown by the improvement in exercise performance.

Tolerance, defined as a decrease in magnitude and duration of effects despite constant or increased dose (plasma concentration), is a serious concern during long-term nitrate therapy [1, 2, 10, 11, 13]. A comparison of the effects of IS-5-MN after several doses with those of the first dose has already been done and showed that tolerance does not develop [33, 37]. This study focused on assessing tolerance by comparing efficacy after the morning and afternoon doses during long-term, intermittent nitrate therapy.

Although tolerance was avoided with the twice-daily regimen we used, an apparent diminution of effect occurred after the 1500-hour dose of IS-5-MN compared with the 0800-hour dose. However, a similar phenomenon was observed in the placebo group (highlighting the importance of using a parallel placebo group). Thus, no clinical evidence of loss of efficacy was observed after the 1500-hour dose of IS-5-MN compared with the 0800-hour dose (that is, no evidence of tolerance).

The incorporation of a nitrate-free interval to avoid tolerance has raised concerns that clinical manifestations of nitrate withdrawal may occur, possibly as a rebound increase in anginal attacks during nitrate-free intervals [11, 21]. Another possible manifestation of nitrate withdrawal during intermittent therapy is the zero-hour effect, which is a decreased exercise duration at the end of the nitrate-free interval before the morning dose of medication compared with placebo. Both phenomena have been observed with intermittent nitroglycerin-patch therapy [21]. We found no rebound increase in anginal attacks and no zero-hour effect in the IS-5-MN group compared with the placebo group. The absence of these phenomena may result because plasma concentrations of nitrates should decrease more gradually after the last oral dose of the day than after nitroglycerin-patch removal. However, many patients in our study did not have angina during daily activities even though they all had angina during treadmill exercise. Thus, whether patients who have frequent episodes of angina during daily activity will have a rebound increase in frequency during periods of low plasma nitrate levels at night cannot be assessed from these results. If this is of concern in specific patients, additional therapy with another class of antianginal agent, preferably a long-acting ß-blocker or a long-acting calcium antagonist might be instituted [15].

Our eligibility requirements did not include episodes of angina associated with daily activity during single-blind placebo therapy as long as patients stopped treadmill exercise because of angina of moderate severity. The median values for anginal attacks per week did not change during either double-blind placebo or IS-5-MN treatment (Table 5). Such increases in exercise duration during double-blind placebo administration compared with baseline values during single-blind placebo administration have been well documented in similar parallel-group studies [9].

Unlike many previous investigations [8, 9, 17, 18], in which only nitrate responders were studied, we did not address initial nitrate responsiveness. Thus, our results are applicable to a broader population of patients with stable exercise-induced angina pectoris, without the need of determining responsiveness to sublingual nitroglycerin.

This study shows that pharmacologic tolerance to nitrates can be avoided by using IS-5-MN, 20 mg twice a day, once in the morning and again 7 hours later. The drug can be safely and effectively used either with or without concomitant ß-blocker therapy. Similar studies with isosorbide dinitrate and other long-acting oral nitrates are required to see if tolerance can be avoided with these agents. Further studies are also needed before recommending concomitant use of IS-5-MN and calcium channel blockers.