cise stress testing, ambulatory ECG monitoring, metopro-. 101, nifedipine, diltiazem. Introduction. The efficacy of calcium-channel and beta blockers in.
Clin. Cardiol. 15,98-102 (1992)
Paradoxical Effect of Long-Term Treatment of Nifedipine on Total Ischemic Load in Patients with Stable Angina Pectoris MARIARADICE,M.D.,VIITORIO GIUDICI, M.D.,ALBERTO ALBERTMI, M.D., ALBERTO MANNARINI, M.D.
Semeiotica Medica, University of Milan, Milan, Italy
Summary: In 50 patients with stable effort angina the effect of three drugs, metoprolol, nifedipine, and diltiazem was assessed by analyzing exercise stress test response and ambulatory ECG recordings. Both metoprolol and diltiazem caused a significant increase in time to ischemic threshold during exercise and a significant decrease of maximum ST-segment depression (during exercise and ambulatory ECG monitoring) and in the average number of daily ischemic episodes. Only metoprolol significantly reduced heart rate and rate-pressure product at the ischemic threshold during exercise. In the group of patients treated with nifedipine no significant improvement was observed in exercise tolerance or in number of ischemic episodes/24 h. Moreover, the subset of nonresponders in the two methods was larger than in the other two groups. In some of these patients a clearcut worsening of total ischemic load was observed, despite the control of symptoms. This adverse effect might be attributed to the different consequences of the vasodilatory effect of nifedipine on blood flow through stenosed vessels. Key words: stable effort angina, antianginal drugs, exercise stress testing, ambulatory ECG monitoring, metopro101, nifedipine, diltiazem
Introduction The efficacy of calcium-channel and beta blockers in the treatment of patients with stable effort angina is well established.'" Recently, however, several authors have
Address for reprints:
Maria Radice, M.D. via Muratori 29 20135 Milan, Italy Received: February 4,1991 Accepted with revision: September 27, 1991
reported that, in some patients, nifedipine can cause a This paradoxical efworsening of the ischemic ~attern.~-IO fect has been observed after either acute or short-term administration. Thus we performed a study to compare the clinical benefit of long-term treatment with nifedipine and metoprolol in a group of patients with stable angina. In view of the different pharmacologic properties of calciumchannel blockersll, l 2 we also evaluated a third drug, diltiazem. To better quantify the therapeutic benefit, ischemia was assessed not only by exercise stress testing, which might not reflect the total ischemic l0ad,l3-I5but also by monitoring events occurring during daily life.
Methods Subjects
The study group consisted of 50 ambulatory patients (26 men and 24 women) of mean age 53.9+7.1 years (range 37-71 years). Patients were selected if the following criteria were satisfied: (1) stable angina pectoris with chest pain due only or mainly to physical exertion; (2) ischemic heart disease confirmed by angiographic documentation of atherosclerotic obstruction (>75%) of at least one major coronary vessel or by stress thallium-201 imaging and radionuclide angiography; (3) pathologic response to exercise stress testing, defined either as angina (2 patients), or 2 0.1 mV flat or downsloping ST-segmentdepression 0.08 s after the J point (32 patients), or both (16 patients); (4)stability of the ischemic threshold, checked during preliminary exercise tests (changes of exercise time to ischemic threshold among the tests of each patient 5 1 min). Patients were purposely selected on the basis of stability of ischemic threshold during exercise to minimize spontaneous variability of the ischemic picture and to allow a more reliable correlation between ischemic markers and drug effect. Exclusion criteria were: (1) recent myocardial infarction (within the previous 6 months); (2) coronary reperfusion procedures; (3) contraindications to calcium and beta blockers or to repeated exercise tests; (4) need for concomitant therapy with antiarrhythmic or inotropic agents;
M. Radice et al.: Paradoxical effect of nifedipine in angina pectoris ( 5 ) abnormalities on the rest ECG that could interfere with the interpretationof ST-segment changes (i.e., ST-T abnormalities, left ventricular hypertrophy, bundle-branch block, ventricular pre-excitation).
Study Protocol
After a suitable period of withdrawal of any previous antianginal drug (at least 7 days, except for sublingual nitroglycerin) all patients underwent one or more periods of ambulatory ECG monitoring outside the hospital and a bicycle ergometric test. To minimize the spontaneous variability of ST changes during daily life, the period of monitoring was no shorter than 48 h (range 48-88 h). The initial study group, consisting of 38 patients, was in blind fashion randomized to treatment with either metoprolol (n=19) or nifedipine (n =19), both in slow release tablets. Subsequently, 12 additional patients were selected and treated with diltiazem, the same criteria of inclusion and exclusion in the study having been utilized. In each patient the dose of the drug was gradually increased every week to the maximum tolerated dose (for metoprolol: 8 patients with 100 mg and 11 with 200 mg; for nifedipine: 17 patients with 40 mg, l patient with 60 mg, and l with 80 mg; for diltiazem: 9 patients with 180 mg, 2 with 240 mg, and 1 with 360 mg). Baseline characteristics of the three groups of patients are presented in Table I. Distribution of coronary lesions and radionuclide evidence of ischemic heart disease were similar in the three groups. After at least 3 months of therapy, 48 h ambulatory ECG and exercise test were repeated. Exercise Test
Patients performed a multistage bicycle ergometric test in the sitting position, with an initial load of 30 W and increments of 20 W every 2 min. Blood pressure and 12-lead ECG were recorded every minute during the exercise and recovery period. The patients exercised until one of the following end-points was reached: more than 0.2 mV STsegment depression, moderate chest pain, and exhaustion. When ischemic ST depression reached 0.1 mV (ischemic threshold) and at the peak exercise, the rate-pressure product (heart rate X systolic blood pressure, RPP) was calcu-
TABLE I Baseline characteristics of patients in the treatment groups
Metoprolol Nifedipine Diltiazem 53.89 f7.40 53.52f7.62 54.16f 5.7 Age Ejection fraction 0.59+0.11 0.55fO.11 0.53 f0.12 Regional wall motions 9 8 6 Hypokinesis Akinesis
1
1
99
lated. Exercise tests were performed at the same time of day for each patient, 4-6 h after ingestion of the drug. Ambulatory ECG Monitoring
Recordings were obtained using a Del Mar Avionics Recorder Model 447. In each patient the two ECG leads showing the best evidence of ST changes during exercise test were selected. Tapes were analyzed visually at 60 times real-time by a scanner trend Model DCG VII. Calibrations and baseline traces were printed out together with all the episodes of ST-segment depression 20.1 mV present in consecutive beats for at least 60 s. Statistical Analysis
Data are presented as mean f l standard deviation (SD). Paired t-test was used to compare treatment data with the basal data. Comparison among drugs was assessed by unpaired t-test (for qualitative data) or by chi-square test (for quantitative data).
Results Exercise Test
Diltiazem and metoprolol increased exercise time to ischemic threshold and decreased maximal ST-segment depression, the changes being significant in both cases (p c 0.01). With nifedipine the exercise tolerance indexes improved, but not significantly (Table II). Only metoprolol significantly decreased HR and RPP at ischemic threshold and at peak exercise. After treatment the proportion of subjects with a normal ECG response to exercise was higher in the metoprolol group: 8/19 versus 2/19 in the nifedipine group and 2/12 in the diltiazem group. The proportion of patients with improved ischemic threshold time was 9/19 for nifedipine, 7/12 for diltiazem, and 4/19 for metoprolol. In the other cases no improvement of the exercise test results were recorded. No differences in the observed results were related to the dose of the drugs. Ambulatory ECG Monitoring
Before treatment no patient had ST-segment elevation and 38 had 1 or more episodes of ST-segment depression; 165 episodes were recorded (2.48 f2.39/24 h), 813%were asymptomatic and 74.0% preceded by increase in heart rate. Both diltiazem and metoprolol were more effective than nifedipine in reducing the number of ST-segment depression episodes (Table 111); furthermore there were more patients without or with a clearly reduced number of ischemic episodes in these groups compared with the nifedipine group. In the latter group a high proportion of patients
Clin. Cardiol. Vol. 15, February 1992
100
TABLEI1 Effect of metoprolol, nifedipine, and diltiazem on ischemia markers during exercise stress testing
Minutes to ischemic threshold Heart rate at ischemic threshold Rate-pressure product at ischemic threshold Total minutes of exercise Maximum ST depression (nun)
Diltiazem
Nifedipine
Metoprolol Before treatment
After treatment
Before treatment
After treatment
Before treatment
After treatment
4.74f2.81
5.79 f 2 . 17a
4.11 f 2.38
5.03 f2.30
4.83f 1.80
6.79f2.84a
125.89f 16.42
112.58+14.12b
123.42f 15.82
125.32f 17.41
122.92f 16.01
126.08f9.93
21,945f4083
19,380f327Oa
21,846f2809
22,054f3393
20,325+4011
22,089f3453
6.68f2.40
6.87+ 1.76
5.79f2.20
6.39f2.11
6.50f 1.73
7.70f2.66
1.68f0.67
0.95 f 0.93"
1.63f 0.62
1.18f0.56a
1.42f0.70
0.83f0.53"
a=p
