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Felodipine and Amlodipine in Stable Angina Pectoris: Results of a Randomized Double-Blind Crossover Trial

Koenig, Wolfgang; Höher, Martin

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Journal of Cardiovascular Pharmacology: April 1997 - Volume 29 - Issue 4 - p 520-524
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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.


Study design

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.

FIG. 1
FIG. 1:
Study design. o.d., once daily; 24h ECG, 24-h ambulatory electrocardiographic monitoring; ECHO, echocardiographic examination; AE, reporting of potential adverse events.

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.

ST-segment depression

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.

Results of 24-h ambulatory electrocardiographic monitoring

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).

Adverse events

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.

Frequency of adverse events


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.


1. Manolio TA, Cutler JA, Furberg CD, Psaty BM, Whelton PK, Applegate WB. Trends in pharmacologic management of hypertension in the United States. Arch Intern Med 1995;155:829-37.
2. Ferrari R, Visioli O. Calcium channel blockers and ischemic heart disease: theoretical expectations and clinical experience. Eur Heart J 1991;12:18-24.
3. Waters D. Proischemic complications of dihydropyridine calcium channel blockers [Editorial]. Circulation 1991;84:2598-600.
4. Thadani U, Zellner SR, Glasser S, et al. Double-blind, dose-response, placebo-controlled multicenter study of nisoldipine: a new second-generation calcium channel blocker in angina pectoris. Circulation 1991;84:2398-408.
5. Todd PA, Faulds D. Felodipine: a review of the pharmacology and therapeutic use of the extended release formulation in cardiovascular diseases. Drugs 1992;44(2):251-77.
6. Murdoch D, Heel RC. Amlodipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs 1991;41(3):478-505.
7. Ruzicka M, Leenen FHH. Relevance of intermittent increases in sympathetic activity for adverse outcome on short-acting calcium antagonists. In: Laragh JH, Brenner BM, eds. Hypertension: pathophysiology, diagnosis and management. New York: Raven Press, 1995:2815-25.
8. Elkayam U, Amin J, Mehra A, Vasquez J, Weber L, Rahimtoola SH. A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combibation in the treatment of chronic congestive heart failure. Circulation 1990;82:1954-61.
9. Packer M, O'Connor CM, Ghali JK, et al., for the Prospective Randomized Amlodipine Survival Evaluation study group. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996;335:1107-14.
10. Cohn JN, Ziesche SM, Loss LE, Anderson GF, and the V-HeFT study group. Effect of felodipine on short-term exercise and neurohormone and long-term mortality in heart failure: results of V-HeFT III [Abstract]. Circulation 1995;92:I-143.
11. Deanfield JE, Detry JMRG, Lichtlen PR, Magnani B, Sellier Ph, Thaulow E, for the CAPE-Study group. Amlodipine reduces transient myocardial ischemia in patients with coronary artery disease: double-blind circadian anti-ischemia program in Europe (CAPE-trial) J Am Coll Cardiol 1994;6:1460-7.
12. Davies RF, Habibi H, Klinke P, et al. for the Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS) investigators. Effect of amlodipine, atenolol and their combination on myocardial ischemia during treadmil exercise and ambulatory monitoring. J Am Coll Cardiol 1995;25:619-25.
13. De Vries RJM, Dunselmann PHJM, van Veldhuisen DJ, ven den Heuvel AFM, Wielenga RP, Lie KI. Comparison between felodipine and isosorbide mononitrate as adjunct to beta blockade in patients >65 years of age with angina pectoris. Am J Cardiol 1994;74:1201-6.
14. Ezekowitz MD, Hossack K, Mehta JL, et al. Amlodipine in chronic stable angina: results of a multicenter double-blind crossover trial. Am Heart J 1995;129:527-35.
15. Ekelund LG, Ulvenstamm G, Walldius G, Aberg A. Effects of felodipine versus nifedipine on exercise tolerance in stable angina pectoris. Am J Cardiol 1994;73:658-60.
16. Schulte KL. 24-H anti-anginal and anti-ischemic effects with once daily felodipine: a double-blind comparison with nifedipine, twice daily, and placebo in patients with stable exercise induced angina pectoris. Eur Heart J 1995;16:171-6.
17. Devereux R, Casale PN, Eisenberg RR, Miller DH, Kligfield P. Electrocardiographic detection of left ventricular hypertrophy using echocardiographic determination of left ventricular mass as the reference standard, computer diagnosis and physician interpretation. J Am Coll Cardiol 1984;3:82-7.
18. Scheler S, Motz W, Strauer BE. Transiente Myokardischämien bei Hypertonikem. Z Kardiol 1989;78:197-203.
19. Jones B, Kenward MG. Design and analysis of crossover trials. London: Chapman & Hall, 1989.
20. Ardissino D, Savonitto S, Egstrup K, et al. Transient myocardial ischemia during daily life in rest and exertional angina pectoris and comparison of effectiveness of metoprolol versus nifedipine. Am J Cardiol 1991;67:946-52.
21. Portegies MCM, Sijbring P, Göbel EJAM, Viersma JW, Kong IL. Efficacy of metoprolol and diltiazem in treating silent myocardial ischemia. Am J Cardiol 1994;74:1095-8.
22. Knatterud GL, Bourassa MG, Pepine CJ, et al. Effects of treatment strategies to suppress ischemia in patients with coronary artery disease: 12-week results of the asymptomatic cardiac ischemia pilot (ACIP) study. J Am Coll Cardiol 1994;24:11-20.
23. von Arnim T for the TIBBS investigators. Medical treatment to reduce total ischemic burden: Total Ischemic Burden Bisoprolol Study (TIBBS), a multicenter trial comparing bisoprolol and nifedipine. J Am Coll Cardiol 1995;25:231-8.
24. Quyyumi AA, Panza JA, Diodati JG, Callahan TS, Bonow RO, Epstein SE. Prognostic implications of myocardial ischemia during daily life in low risk patients with coronary artery disease. J Am Coll Cardiol 1993;21:700-8.
25. Pepine CJ, Cohn PF, Deedwania PC, et al., for the ASIST study group. Effects of treatment on outcome in mildly symptomatic patients with ischemia during daily life: the Atenolol Silent Ischemia Study (ASIST). Circulation 1994;90:762-8.
26. Dargie HJ, Ford I, Fox KM, on behalf of the TIBET study group. Total Ischaemic Burden European Trial (TIBET): effects of ischaemia and treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina. Eur Heart J 1996;17:104-12.
27. Rehnqvist N, Hjemdahl P, Billing E, et al. Effects of metoprolol vs verapamil in patients with stable angina pectoris: The Angina Prognosis Study in Stockholm (APSIS). Eur Heart J 1996;17:76-81.
28. Furberg CD, Psaty BM, Myers JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326-31.
29. Opie LH, Messerli FH. Nifedipine and mortality: grave defects in the dossier. Circulation 1995;92:1068-73.
30. Kloner RA. Nifedipine in ischemic heart disease. Circulation 1995;92:1074-8.
31. Yusuf S. Calcium antagonists in coronary artery disease and hypertension. Circulation 1995;92:1079-82.
32. Furberg CD, Psaty BM. Corrections to the nifedipine meta-analysis [Letter to the Editor]. Circulation 1996;93:1472-7.
33. Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995;274:620-5.
34. Buring JE, Glynn RJ, Hennekens CH. Calcium channel blockers and myocardial infarction: a hypothesis formulated but not yet tested. [Editorial]. JAMA 1995;274:654-5.
35. Pahor M, Guralnik JM, Corti MC, Foley DJ, Carbonin P, Havlik RJ. Long-term survival and use of antihypertensive medications in older persons. J Am Geriatr Soc 1995;43:1191-7.
36. Borhani NO, Mercuri M, Borhani PA, et al. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). JAMA 1996;276(10):785-91.

Calcium channel blocker; Felodipine; Amlodipine; Ischemia; 24-h Ambulatory electrocardiographic monitoring

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