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We compared the efficacy of once-daily administration of nifedipine CR 40 mg (N) with that of twice-daily diltiazem R 100 mg (D) in patients with vasospastic angina (VSA) registered in 8 cardiovascular institutes in Aomori Prefecture.
Methods and results
VSA was diagnosed by the ischemic ST segment changes during chest pain attacks at rest and/or acetylcholine induction test done during coronary angiography. Thirty-seven patients were randomly allocated to either the N (n = 20) or D group (n = 17). The number of symptomatic attacks and amount of short-acting nitrate use were examined based on data in diaries written by the patients. There were no significant differences in the baseline characteristics between the two groups. The mean number (median number) of attacks per week was significantly decreased in the N group from 2.56 (2.0) at baseline to 0.41 (0.0) after 4 weeks of treatment, to 0.24 (0.0) after 8 weeks, and to 0.36 (0.0) after 12 weeks (all p < 0.05 vs. baseline). It was also decreased in D group from 2.71 (2.0) at baseline to 0.55 (0.0) after 4 weeks, to 0.32 (0.0) after 8 weeks, and to 0.27 (0.0) after 12 weeks (all p < 0.05 vs. baseline). The numbers of attacks before and after treatment were comparable between N and D groups. In one patient in each of the N and D groups, the allocated drug was crossed over to the other due to recurrence of the attacks. One patient in each group experienced adverse effects and the drug was changed to the other.
Conclusion
Once-daily administration of nifedipine CR was as effective as twice-daily diltiazem R in the prevention of VSA attacks.
]. In addition to its central mechanism for variant angina, coronary spasm has also been revealed to play important roles in some cases of exertional angina, acute myocardial infarction (AMI), and sudden cardiac death [
]. According to the “Guideline on the Diagnosis and Treatment of Coronary Spastic Angina” published by the Japanese Circulation Society in 2008, calcium antagonists are recommended as the class I drug [
Prognostic effects of calcium channel blockers on cardiac events, stroke and end-stage renal disease in patients with angina pectoris. Retrospective comparative study of benidipine, diltiazem and nifedipine.
]. Furthermore, benzothiazepin agents can cause bradycardia, whereas dihydropyridine agents can induce an excessive decrease in blood pressure and tachycardia. There have been few studies to date on clinical trials comparing the therapeutic effects of calcium antagonists to one another. From a standpoint of the patient's adherence for taking medicine, such a drug that is effective even if administered once-daily is preferable when it is used as a long-term treatment medicine. In this study, we compared the effects of once-daily administration of nifedipine CR tablet (40 mg) taken before going to bed with those of twice-daily administration of diltiazem R capsule (100 mg) in relation to the prevention of coronary spasm. We also examined the types and frequencies of adverse effects as well as measures against them.
Methods
Study patients
With the approval of the ethics committee of our institution, this study was conducted in 37 patients who had been diagnosed with VSA in 8 institutions in Aomori Prefecture between January 2007 and December 2008. Written informed consent was obtained from each patient before entry to the study. In addition to the symptoms of angina pectoris either in the early morning or at rest, the criteria for diagnosing VSA were defined as follows: (1) induction of a coronary spasm by acetylcholine test during coronary arteriography being associated with ischemic electrocardiogram (ECG) changes [
] and/or (2) no significant stenosis by coronary arteriography and the recording of ischemic ST segment changes by ambulatory ECG coinciding with chest pain at rest. We excluded the patients who had fixed stenosis >50% of the lumen diameter in the coronary artery, those who had allergic history for dihydropyridine or benzothiazepin calcium antagonist, and those with pregnancy or possibility of pregnancy, as well as those who were judged by their attending physicians as not suitable for the trial due to heart failure, arrhythmia, and so on. There were 38 patients who met these criteria. Since one patient did not visit the out-patient clinic after the entry, the study was performed in the other 37.
Drugs used in the study
Nifedipine CR, a long-acting once-daily formulation of nifedipine, has a polymer matrix delivery system composed of a slow-release coat and a fast-release core and is available in Japan. The dissolution rates for the two layers are different, with the outer layer dissolving at a slower rate than the internal layer. Drug concentrations after administration of the nifedipine CR formulation peak within 4 h after administration, and are sustained at that level for at least 24 h after administration [
A sustained-release formulation of diltiazem (diltiazem R) is available in Japan for the treatment of VSA. This formulation has a more prolonged plasma half-life, and results in effective blood levels and antianginal effect than the conventional tablet form. The half-life of diltiazem R is approximately 7 h and it does not always suppress the myocardial ischemic episode in the early morning if administered before going to bed [
Clinical effect of Herbesser (CRD-401) and its sustained release preparation (TA-2006) on variant angina and rest angina—evaluation by 24-h Holter recordings.
The registered patients were randomized to either the diltiazem R group (100 mg dose, twice-daily, administration in the morning and before going to bed) or the nifedipine CR group (40 mg dose, once-daily, administration before going to bed) in accordance with the sealed envelope method. During the 12-week period after the initiation of treatment, we followed up the occurrence of angina episodes at 4, 8, and 12 weeks. The angina episode frequency and the amount of fast-acting nitroglycerin (NTG) consumption were examined based on the patients’ symptom diaries. The concomitant use of coronary vasodilators other than the study drug was not allowed during the follow-up period. We measured the blood pressures and heart rates at the initiation of treatment as well as 4, 8, and 12 weeks after the treatment. We also performed ambulatory 24-h ECG at the initiation of treatment and after 12 weeks. Furthermore, in each patient, the attending physicians evaluated the therapeutic effects on a five-point scale: (1) prominent improvement, (2) improvement, (3) slight improvement, (4) no effect, and (5) deterioration.
With regard to safety evaluation, adverse effects were defined as the occurrences of new symptoms and complications whose causal relationships with the study drug could not be ruled out during the treatment period. The administration of each study drug was discontinued if the attending physician judged it to have insufficient effect or the continuation to be impossible due to adverse effects, at which point we evaluated the efficacy and safety. We also evaluated the efficacy and safety in withdrawn cases based on data by that point. Meanwhile, the observation was continued after switching to the other study drug at the discretion of the attending physician.
We observed the effects of the drug for a 12-week period. Anginal attack due to coronary spasm usually responds to calcium antagonist within a few days [
] and therefore this study period was considered enough to see the efficacy. Also, this period was considered necessary to see the development of any adverse effects and to see the changes in the blood pressure and heart rate.
Statistical analysis
The measured values are expressed as mean value ± one standard deviation or median value and 25th and 75th percentiles. We used Fisher's exact test for the comparison of the patients’ backgrounds. For the sequential changes of the spasm frequency and the amount of NTG consumption, we used Friedman's rank test and then Dunnett's multiple test. We also used the Mann–Whitney U test to compare between the two groups. For the sequential changes of the blood pressure and heart rate, we used the analysis of variance followed by Bonferroni's test. We used a t-test to compare the values between the groups. To compare the treatment efficacy between the groups, we conducted a chi-square test with “slight improvement” or above as valid. p < 0.05 was considered to be statistically significant.
Results
Patients’ backgrounds
Of the 37 registered patients, 17 were allocated to diltiazem R and 20 to nifedipine CR groups (Fig. 1). In two cases in the diltiazem R group, the absence or insufficiency of efficacy after the treatment forced one patient to discontinue the allocated drug and switch to the other drug, and the other patient to concomitantly use the other drug while maintaining the allocated drug. Despite the confirmation of efficacy after 4 weeks, one patient was withdrawn as he stopped visiting the hospital thereafter. Meanwhile, one patient in the nifedipine CR group discontinued the administration after 4 days due to the lack of efficacy and switched to the other drug. Although an evident prophylactic effect was observed after 4 weeks in one patient, a side effect (palpitation) forced the discontinuation of the allocated drug. Two other patients were withdrawn despite the efficacy, being observed until the 8th week since they stopped visiting the hospital thereafter.
Figure 1Flow chart of the number of the patients in each group during the study period.
Table 1 shows the patients’ profiles at baseline. There was no significant difference between the groups in any of the backgrounds as well as the types of angina pectoris and diagnostic methods. Table 2 shows the frequencies of angina episodes immediately before the administration of the study drugs, amounts of NTG consumption, blood pressures, and heart rates. There were no significant differences between the two groups.
Table 1Comparison of clinical profiles.
Nifedipine CR group (n = 20)
Diltiazem R group (n = 17)
p-Value
Male gender (%)
12 (60.0)
8 (47.1)
0.648
Age
65.6 ± 9.6
60.9 ± 11.9
0.202
BMI
23.4 ± 3.1
23.1 ± 2.3
0.729
Type of angina (rest/effort/variant)
13/0/7
12/0/5
0.992
Diagnosis (ACh provocation test/other)
18/2
16/1
1.000
ACh provocation test
ECG change (ST elevation/depression)
4/14
4/12
1.000
Spasm site
LAD
18 (100.0)
15 (93.8)
0.471
LCx
8 (44.4)
9 (56.3)
0.732
RCA
6 (33.3)
2 (12.5)
0.233
Provocation dose of ACh (Low/High)
10/8
13/3
0.152
Previous myocardial infarction
0
0
1.000
Hypertension (%)
7 (35.0)
6 (35.3)
0.744
Diabetes mellitus (%)
2 (10.0)
0 (0.0)
0.489
Dyslipidemia (%)
8 (40.0)
3 (17.6)
0.262
Liver disease (%)
0 (0.0)
0 (0.0)
1.000
Renal disease (%)
1 (5.0)
0 (0.0)
1.000
Smoking (%)
8 (40.0)
8 (47.1)
0.874
BMI, body mass index; ACh, acetylcholine; ECG, electrocardiogram; LAD, left anterior descending artery; LCx, left circumflex artery, RCA, right coronary artery; Low, 20 μg for RCA and/or 50 μg for left coronary artery (LCA); High, 50 μg for RCA and/or 100 μg for LCA.
Frequency of angina and amount of NTG consumption during follow-up
After initiation of the treatment, the frequency of angina attacks was markedly reduced in both treatment groups. Fig. 2a shows the frequency of angina during the study period for the two groups. In comparison with the frequency at baseline, that in the diltiazem R group decreased significantly by the 4th week of treatment and the suppressive effect was maintained until the 12th week. In the nifedipine CR group, it also decreased significantly during the 4th week of treatment with the suppressive effect maintained until the 12th week. No significant difference was observed in the frequency at each time point after the initiation of treatment between both the groups. As shown in Fig. 2b, the amount of fast-acting NTG consumption at each time point after the initiation of treatment exhibited no significant difference compared to immediately before the administration in both groups. Due to the small number of cases in which ischemic ST changes had been detected prior to the initiation of treatment in both drug groups, we could not compare the ambulatory ECG findings before and after the initiation of treatment.
Figure 2Changes in the numbers of angina attacks (a) and nitroglycerin consumption (b) per week in nifedipine CR and diltiazem R groups during the study period. In both groups, the frequency of angina decreased significantly by the 4th week and the suppressive effect was maintained until the 12th week. The nitroglycerin consumption exhibited no significant change in each group. *p < 0.05 vs. 0 weeks.
Fig. 3 shows the changes in the blood pressure during the study period. In both groups, no significant change was observed in both the systolic and diastolic pressures.
Figure 3Changes in systolic and diastolic blood pressures in each group during the study period. No significant change was observed in either group.
Fig. 4 exhibits the changes in the heart rate. In the diltiazem R group, the heart rate decreased slightly after the treatment, which did not reach a significant difference from the baseline value. In the nifedipine CR group, the heart rate was unchanged until 4 weeks after the treatment, but increased significantly by 7.2 ± 8.9 beats/min after 8 weeks (p < 0.05). The heart rate after 12 weeks was not different from the baseline value.
Figure 4Changes in heart rate in each group. The heart rate remained unchanged until 4 weeks after the start of treatment, but was increased significantly after 8 weeks in the nifedipine CR group. *p < 0.05 vs. week 0.
Fig. 5 shows the results of the five-point scale efficacy evaluation by the attending physicians, taking into account the circumstances of angina episodes, amount of fast-acting NTG consumption, and subjective symptoms of the patients in a comprehensive manner. The efficacy rates above “slight improvement” were 94% in the diltiazem R group and 95% in the nifedipine CR group with no difference observed between the two groups.
Figure 5Comparison of the five-point scale efficacy of each drug evaluated by the attending physicians. The efficacy rates above “slight improvement” were similar between the two groups (p = 0.859 by chi-square test).
As shown in Fig. 1, there were 3 cases of withdrawal among the 17 patients: one patient discontinued the drug and switched to the other drug due to recurrences of angina episodes within 4 weeks of starting the treatment. Another patient experienced recurrence at 8 weeks but continued diltiazem concomitantly with another antianginal drug (nicorandil), which resulted in the elimination of the symptoms. The remaining one patient stopped visiting the hospital after 4 weeks until which no angina episode had been reported. Ambulatory 24-h ECG done after 12 weeks showed no ischemic ST segment changes in any of the 14 patients, but detected asymptomatic advanced atrioventricular block, which was not present in the baseline 24-h ECG, in one patient, leading to the discontinuation of the drug and switching to nifedipine CR.
Nifedipine CR group
Four of the 20 patients either discontinued the drug or were withdrawn: one patient experienced recurrence of angina at 4 days after the treatment and switched to diltiazem. In this patient, the time of angina shifted from the early morning before treatment to night after treatment. The anginal episode disappeared after diltiazem treatment. One patient started being aware of palpitation after 4 weeks and switched to diltiazem. The remaining 2 patients stopped visiting the hospital after 8 weeks until which no angina episode had been reported. Ambulatory 24-h ECG done after 12 weeks detected neither ischemic ST segment changes nor side effects in any of the 16 patients.
Discussion
In this study, we conducted a prospective study on the prophylactic effects on the anginal episodes due to coronary spasm and safety of the once-daily administration of long-acting nifedipine CR before going to bed in comparison with those of the twice-daily administration of diltiazem R in the morning and before going to bed in patients with VSA. Consequently, the once-daily administration of nifedipine CR had the same efficacy as the twice-daily administration of diltiazem R in terms of prophylactic effects on angina. The attending physicians recognized no difference between the two groups in their comprehensive evaluation of the treatment efficacy.
VSA has been reported to show a relatively favorable long-term prognosis. However, in even asymptomatic cases, it can induce disruption of coronary atherosclerotic plaques and thrombus formation, which can possibly cause AMI and sudden cardiac death. Therefore, its prevention is indispensable. Despite their effectiveness in spasm prevention, long-acting nitrates are graded as Class IIa treatment in the “Guidelines on the Diagnosis and Treatment of Coronary Spastic Angina” [
]. Accordingly, the guideline recommended calcium antagonists as the Class I treatment. It should be pointed out that some calcium antagonists are not covered by the national health insurance for use against angina pectoris and VSA. Furthermore, the effects of calcium antagonists on the prognosis may vary depending on their types [
Prognostic effects of calcium channel blockers on cardiac events, stroke and end-stage renal disease in patients with angina pectoris. Retrospective comparative study of benidipine, diltiazem and nifedipine.
Nifedipine, diltiazem, and verapamil are first-generation calcium antagonists. Nifedipine is a dihydropyridine calcium antagonist that possesses strong vasodilatory and antihypertensive effects with little influence on myocardial contraction. Diltiazem, by contrast, is a benzothiazepin calcium antagonist that has less vasodilatory and antihypertensive effects than the dihydropyridine derivatives, and possesses depressant effects on the sinus node and atrioventricular conduction [
]. Although clinical trials have reported the efficacy of these drugs against variant angina and VSA, the characteristics of each drug should be taken into consideration when it is used. Kimura et al. reviewed the effects of these three types of first-generation calcium antagonists on variant angina [
]. They all displayed similar efficacy with the proportion of prominent improvement being 94.0% by nifedipine, 90.8% by diltiazem, and 85.7% by verapamil. However, the first-generation nifedipine and diltiazem had difficulty in complete suppression of coronary spasm occurring in the early morning due to the relatively short duration of the efficacy. Morikami et al. examined the efficacy of twice-daily administration of slow-release nifedipine (nifedipine L) on variant angina pectoris [
]. Twice-daily nifedipine L was proven to be highly effective against not only symptomatic but also asymptomatic ischemic episodes in patients with variant angina [
]. In recent years, drugs effective for 24 h after once-daily administration have been called for in order to improve medication adherence especially in the diseases that require long-term pharmacotherapy. Nifedipine CR tablet is a sustained-release preparation of nifedipine, which may hold promise for efficacy against variant angina with only once-daily administration. In this study, we administered diltiazem R twice-daily in the morning and before going to bed and nifedipine CR once-daily before going to bed, in the light of the fact that angina attacks in VSA are characteristically apt to occur during the night-time and in the early morning and sometimes occur during the daytime [
]. The dose was set at 200 mg/day (the maximum permissible amount in Japan) for diltiazem R, and 40 mg/day by referring to the report by Morikami et al. [
] for nifedipine CR. The once-daily administration of nifedipine CR was proven to be as effective as diltiazem R, thus corroborating the efficacy of nifedipine CR in terms of medication adherence. Recently, Oikawa et al. compared the efficacy of once-daily treatment with nifedipine CR 40 mg and twice-daily treatment with benidipine 4 mg in patients with VSA. Once-daily treatment with nifedipine CR 40 mg was more effective than twice-daily treatment with benidipine in the prevention of VSA attacks [
Effects of treatment with once-daily nifedipine CR and twice-daily benidipine on prevention of symptomatic attacks in patients with coronary spastic angina pectoris—Adalat Trial vs. Coniel in Tokyo against Coronary Spastic Angina (ATTACK CSA).
There was no significant change in the systolic and diastolic blood pressures in both drug groups. Both drugs show a relaxation effect on the vascular smooth muscle, and nifedipine especially seems to cause an excessive reduction in the blood pressure due to its strong vasodilator effect. Landmark reported that this effect does not appear in patients with normal blood pressure [
]. Thus, there would be little risk of nifedipine CR inducing hypotension in patients with VSA and normal blood pressure.
The heart rate decreased slightly, albeit not significantly, in the diltiazem R group. This can be explained by its depressant effect on the sinus node [
]. In the nifedipine CR group, the heart rate increased slightly and significantly at 8 weeks after administration. This increase was not likely to be attributable to a reflex accompanying the blood pressure decrease since it was not observed at 4 and 12 weeks. In patients with hypertension, it was reported that the once-daily administration of nifedipine CR tablet induces a similar antihypertensive effect to the twice-daily administration of nifedipine retard tablet, while exerting a smaller influence on the autonomic nervous system and heart rate [
]. Even though the increase in the heart rate may be small, however, it might induce palpitations, a side effect of nifedipine, in some patients.
Conclusion
In this study, we evaluated the efficacy and safety of once-daily administration of nifedipine CR in patients with VSA in direct comparison with diltiazem R. The efficacy of nifedipine CR was the same as that of diltiazem R, and there was no particular problem with safety. Understanding the characteristics of both drugs may lead to their appropriate usage such as administration of nifedipine CR for patients with a bradycardia tendency or hypertension and diltiazem R for patients with a tachycardia tendency or normal blood pressure. Thus, once-daily administration of nifedipine CR can be an alternative as the first-line drug for the treatment of VSA along with diltiazem R.
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Prognostic effects of calcium channel blockers on cardiac events, stroke and end-stage renal disease in patients with angina pectoris. Retrospective comparative study of benidipine, diltiazem and nifedipine.
Clinical effect of Herbesser (CRD-401) and its sustained release preparation (TA-2006) on variant angina and rest angina—evaluation by 24-h Holter recordings.
Effects of treatment with once-daily nifedipine CR and twice-daily benidipine on prevention of symptomatic attacks in patients with coronary spastic angina pectoris—Adalat Trial vs. Coniel in Tokyo against Coronary Spastic Angina (ATTACK CSA).
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