Calcium channel blockers, a heterogeneous class of cardiovascular drugs, are widely used for the treatment of hypertension and symptomatic coronary artery disease (CAD; 1,2). Despite the proven antihypertensive efficacy of dihydropyridines, their antiischemic properties are still controversial (3,4). Long-acting dihydropyridines like felodipine (5) and amlodipine (6) may overcome problems associated with short-acting drugs of this class (e.g., nifedipine-like variable plasma levels that induce neurohumoral activity) (7). Furthermore, unlike nifedipine (8), they have been found to be well tolerated in patients with heart failure (9,10). Felodipine and amlodipine have shown their antiischemic efficacy in various trials (11-16), but so far no direct comparison using ambulatory ST-segment monitoring has been published. Because different compounds, even from the same drug class, may differ with regard to antiischemic efficacy and tolerability in the same group of patients, we carried out a comparative trial between these two drugs by using ambulatory 24-h electrocardiographic monitoring.
MATERIAL AND METHODS
This study was a prospective, randomized, double-blind, crossover trial to compare the antiischemic and antianginal efficacy of felodipine extended release and amlodipine in patients with stable exercise-induced angina pectoris (Fig. 1) During a run-in phase of 9 days, patients were taking one tablet of felodipine placebo and one capsule of amlodipine placebo. Additionally, they were given long-acting nitrates [2.5 mg glyceryl trinitrate (GTN)] t.i.d. from days 1 to 7 of the run-in phase.
Patients were randomized to treatment with either felodipine extended-release tablets, 5 mg once daily, or amlodipine capsules, 5 mg once daily, and their corresponding placebos. After 1 week of treatment, doses were increased to 10 mg once daily each. After another 3 weeks, the treatment regimens were switched, and both drugs were given in the same manner for another 4 weeks. Felodipine and its placebo were identical in size, shape, and color, as were amlodipine and its placebo. The double-dummy technique was applied because the formulation of both active drugs was not identical. No other antianginal drug was allowed (except GTN tablets to be taken for short-term pain relief). At each visit, patients were asked about possible adverse events, and returned their diary in which they had recorded the frequency and intensity of chest pain, GTN consumption, and their activities. Blood pressure (BP) and heart rate were measured at rest at all visits. Compliance was checked by pill count. The protocol was approved by the ethics committee of Freiburg, Germany, and was conducted in accordance with the Declaration of Helsinki. All patients gave informed, written consent before the study.
Patients were included in the study if they fulfilled the following entry criteria: (a) age between 30 and 80 years; (b) a history of angina and a positive exercise-stress test (ST-segment depression >1 mm), or a positive 24-h ambulatory electrocardiogram during the 3 months preceding the study; (c) ≥6 ischemic episodes (ST-segment depression of ≥1 mm lasting for ≥1 min) during 24-h ambulatory electrocardiographic monitoring at the end of the run-in period (no nitrate was given at the day of registration and the morning before).
Patients with any of the following criteria were excluded from the study: concomitant antianginal therapy other than nitroglycerine during the run-in period (β-blockers, angiotensin-converting enzyme (ACE) inhibitors, long-acting nitrates, molsidomine) or any other drug known to influence the ST segment, unstable angina, myocardial infarction, coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA) or stroke within the last 3 months, congestive heart failure, hypotension (systolic BP <100 mm Hg in the standing position), left ventricular hypertrophy [end-diastolic left ventricular posterior or septal wall >11.5 mm recorded by B-scan guided M-mode echocardiography in the parasternal longaxis view by using the PENN criteria (17)], bundle branch block, severe liver disease, renal insufficiency, pregnancy, or documented hypersensitivity to felodipine or amlodipine.
Fifty-two patients were recruited for the study (25 men and 27 women; mean age, 63 years). The mean duration of angina was 59 months (range, 3-223 months). Forty-nine patients had a positive exercise-stress test (ST-segment depression >1 mm), and 41 patients showed ischemic episodes during 24-h ambulatory electrocardiographic monitoring. Angiographically proven CAD was present in nine patients. PTCA had been carried out in six patients, and one patient had a bypass operation. Ten patients had had a myocardial infarction, four had a minor stroke, and eight complained about intermittent claudication. None had congestive heart failure. Eighteen were diabetics, of whom 13 were taking oral hypoglycemic drugs, and three were insulin dependent. Obstructive pulmonary disease was present in six, and 14 of the patients were smokers.
Ambulatory electrocardiographic monitoring
Ambulatory electrocardiographic monitoring was performed by using a Marquette Laser-Holter-system 8000, software version 5.5, with a frequency response of 0.05-100 Hz, thereby meeting the American Heart Association specifications for heart rate and ST-segment changes. The two leads used were CM2 and CM5, corresponding to Wilson chest leads V2 and V5. The system was calibrated before and after each placement. Recordings were done at the end of the run-in period and after each 4-week treatment phase, starting after drug intake in the morning. Tapes were analyzed at 60 times the real time under continuous visual inspection, and an episode of transient ischemia was defined as a horizontal or descending ST-segment depression 1 mm (80 ms after the J-point) lasting for 1 min and separated from other episodes by 1 min. Duration and maximal ST-segment depression of each episode were analyzed, and the channel showing the most pronounced changes was used for interpretation. Episodes of significant ST-segment depression were recorded on paper at a speed of 25 mm/s.
The primary efficacy parameter of the study was the number of ST-segment depressions (1 mm) during 24-h ambulatory electrocardiographic monitoring at the end of the two active treatment periods. Assuming a normal distribution of the logarithm of the number of ST-segment depressions, it was calculated that ≥35 patients had to complete the two treatment sequences to detect a reduction of the number of ST-segment depressions by 50% with a power of 80% and an alpha error of 5%. This calculation was based on a standard deviation of the logarithmic transformation of ST-segment depressions of 0.62 (18).
Following the study protocol for the primary variable of interest, number of ST-segment depressions, the usual crossover hypothesis tests were carried out by adopting the traditional univariate repeated-measurements model (19, p. 30). For the analysis of the logarithmic transformation of the variable, the value zero, indicating no ST-segment depression, was replaced by a uniformly distributed random value between zero and 1. The Wilcoxon matched-pairs signed-rank test was used to test the differences between baseline and treatment with felodipine and amlodipine. The other variables were analyzed by using the Wilcoxon test.
Of the 52 patients enrolled, 47 completed the protocol. Four patients withdrew because of adverse events, two taking felodipine (palpitations) and two taking amlodipine (palpitations in one patient and worsened angina in the other). One patient taking amlodipine refused further cooperation without any specific reason. The following results are based on the 47 patients with complete data sets.
Table 1 summarizes the results of 24-h ambulatory electrocardiographic monitoring at the end of the two active treatment periods. A similar pronounced reduction of the number of ST-segment depressions, normalized for 24 h, from 19.9 at baseline to 2.3 with amlodipine and to 2.4 with felodipine was seen (p = 0.83 between treatments and p < 0.001 compared with baseline). Nineteen (40%) patients taking felodipine and 18 (38%) patients taking amlodipine were free of ST-segment depressions after the active treatment phases; however, only 10 patients showed no ST-segment depression during either drug treatment.
Total and mean duration of episodes of ST-segment depression, maximal ST depression, and longest ischemic episodes were also substantially reduced by both treatments (all p values <0.001 for the comparison with baseline). There was no evidence for a difference in the treatment effects between the two regimens.
Number of anginal attacks and nitrate consumption
The mean number of anginal attacks per week decreased from 16.4 ± 10.0 (mean ± SD) during run-in to 4.7 ± 4.3 with amlodipine and 4.3 ± 4.6 with felodipine (difference between both treatments, p = 0.26; differences from baseline, p < 0.001). Acccordingly, the mean consumption of nitroglycerine capsules per week decreased from 14.7 ± 9.1 during run-in to 4.0 ± 4.0 with amlodipine and to 3.8 ± 4.1 with felodipine (difference between treatments, p = 0.40; differences from baseline, p < 0.001).
Heart rate and blood pressure
During the study, mean heart rate (beats/min) at rest remained constant (76.9 ± 8.7 during run-in, 77.3 ± 8.0 beats/min during felodipine treatment, and 77.9 ± 8.3 beats/min during amlodipine treatment; p = 0.39 between treatments and p = 0.21 and p = 0.87 vs. baseline). So did mean heart rate during 24-h electrocardiographic monitoring (80.4 ± 10.9 beats/min during run-in, 80.9 ± 9.4 beats/min during amlodipine, and 80.0 ± 9.2 beats/min during felodipine treatment (p = 0.14 between treatments and p = 0.58 and p = 0.52 vs. baseline, respectively). Mean sitting systolic and diastolic BP decreased from 143.7 ± 18.9/89.0 ± 11.4 mm Hg during placebo run-in to 137.6 ± 16.3/85.1 ± 9.9 mm Hg and 137.8 ± 17.1/84.5 ± 9.8 mm Hg with amlodipine and felodipine, respectively (difference between treatments p = 0.91 and p = 0.35 for systolic and diastolic BP and p < 0.001 for systolic and diastolic BP with both treatments compared with baseline).
Table 2 shows that there were no relevant differences in the frequencies and types of reported adverse events between the two treatments. Two patients in each treatment group withdrew because of adverse reactions.
In this randomized, double-blind, crossover trial in 47 patients with stable angina pectoris, felodipine extendedrelease, 5-10 mg, and amlodipine, 5-10 mg, both given once daily, significantly reduced the number and duration of ischemic episodes as well as the mean maximal ST-segment depression compared with baseline. No differences between the two treatment regimens were seen in these variables. Furthermore, clinical parameters like number of anginal attacks per week and nitroglycerine consumption per week also were significantly reduced to a similar extent by both treatments. Five patients withdrew from the study. In three of them, one receiving amlodipine and two receiving felodipine, drug-related palpitations were the reason. One patient taking amlodipine reported an increase in the frequency of anginal attacks, and another patient withdrew without specific reasons. Thus both drugs were well tolerated.
Several recent trials studied the antiischemic efficacy of various antianginal drugs by using ambulatory electrocardiographic monitoring (11,12,20-23). It seems difficult to compare these trials in detail, because patients (symptomatic vs. asymptomatic) and study protocols varied considerably. In studies with calcium channel blockers, amlodipine (11,12) or slow-release nifedipine (20,22,23) or diltiazem (21,22) were investigated and compared with either placebo (11,12), β-blocker (12,20,21,23), or various combinations (22). Furthermore, the combined effect of the calcium channel blocker and the β-blocker was analyzed (12), or the calcium channel blocker was studied in patients in whom the majority were receiving baseline therapy with a β-blocker (11). In all studies testing a β-blocker (12,20,21,23), this drug was superior to the calcium channel blocker, but in all but one (20), the latter proved to be effective in reducing ischemia as detected by ambulatory electrocardiographic monitoring.
In our study, ischemic episodes were more frequent, as was their total duration compared with most of the previously mentioned trials. Anginal attacks were also more frequent. This may be explained by differences in patient characteristics, as well as by definition of ischemia end points. The efficacy in reducing various parameters of ischemia appeared substantially higher, with similar or fewer adverse events as compared with the results with calcium channel blockers reported in the various trials mentioned. The more severe ischemia at baseline in our study might be the reason for this finding. Mean resting heart rate and mean heart rate on 24-h electrocardiographic monitoring during therapy with felodipine or amlodipine were comparable between both drugs and not different from baseline. This is consistent with the results of other studies (11,13).
An interesting observation in this study was that not all patients who had responded to the first drug also showed an antiischemic effect after they were given the second drug. This may result either from different antiischemic responses to the drugs or from intraindividual changes over time.
In conclusion, felodipine extended release and amlodipine, 10 mg o.d., given over four weeks each, have been shown to be effective antiischemic and antianginal drugs. No relevant differences in their antiischemic and antianginal properties in patients with stable angina pectoris could be demonstrated, and both were tolerated well. Besides the symptomatic improvement and the reduction of ischemic events on 24-h electrocardiographic monitoring, it might be interesting to see their effects on cardiovascular end points in this patient group, because the evidence of prognostic implications for ischemic events on ambulatory electrocardiographic monitoring is still equivocal (24-26). Only a few studies with antianginal drugs have addressed this issue (25-27). Against the background of the ongoing controversy about calcium channel blockers in the treatment of CAD (28-32) and in hypertension (33-36), data are urgently required from clinical trials to solve this issue.
Acknowledgment: This study was supported by Astra GmbH, Wedel, Germany.
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