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(Circulation. 1997;95:2368-2373.)
© 1997 American Heart Association, Inc.

Articles

Short-Acting Nifedipine and Diltiazem Do Not Reduce the Incidence of Cardiac Events in Patients With Healed Myocardial Infarction

Kinji Ishikawa, MD; Shoji Nakai, MD; Toshihiko Takenaka, MD; Ken Kanamasa, MD; Junkichi Hama, MD; Iwao Ogawa, MD; Tadahiko Yamamoto, MD; Miki Oyaizu, MD; Akio Kimura, MD; Kentaro Yamamoto, MD; Hiroshi Yabushita, MD; Ryo Katori, MD; on behalf of the Secondary Prevention Group

From Kinki University, School of Medicine, Osaka, Japan.

Correspondence to Kinji Ishikawa, MD, Professor of Medicine, First Department of Medicine, Kinki University School of Medicine, Osakasayama, Osaka 589, Japan.

	Abstract

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Background The administration of calcium antagonists to patients with healed myocardial infarction is a controversial treatment. This study was conducted to elucidate the effect of short-acting nifedipine and diltiazem on cardiac events in patients with healed myocardial infarction.

Methods and Results A controlled clinical open trial of 1115 patients with healed myocardial infarction was carried out between 1986 and 1994. The patients included 595 who received no calcium antagonist, 341 who received short-acting nifedipine 30 mg/d, and 179 who received short-acting diltiazem 90 mg/d. The primary end points were cardiac events, which were defined as fatal or nonfatal recurrent myocardial infarction; death from congestive heart failure; sudden death; and hospitalization because of worsening angina, congestive heart failure, or premature ventricular contractions. Cardiac events occurred in 51 patients (8.6%) in the no-calcium-antagonist group and 54 (10.4%) in the calcium-antagonist group (odds ratio, 1.24; 95% CI, 0.83 to 1.85), demonstrating that the calcium antagonists did not reduce the incidence of cardiac events. Subgroup analysis revealed no beneficial effects of these drugs for reducing cardiac events in patients with such complications as hypertension or angina pectoris.

Conclusions This study showed that use of short-acting nifedipine and diltiazem in this postmyocardial infarction population was associated with a 24% higher cardiac event rate, but this strong adverse trend did not reach statistical significance.

Key Words: myocardial infarction • angina • death, sudden • prevention

	Introduction

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Calcium antagonists have been widely prescribed in Japan for angina pectoris and hypertension in patients with healed myocardial infarction. Several randomized studies have shown that short-acting nifedipine is not effective in preventing cardiac events.^{1 2} Diltiazem was shown to be effective in reducing reinfarction in patients with non–Q-wave infarctions occurring within 6 months after onset.³ Diltiazem was reported to have no overall beneficial effect on mortality.⁴ However, a great number of patients with healed myocardial infarctions have high blood pressure, angina pectoris, a positive exercise ECG, or variant angina. The effectiveness of nifedipine or diltiazem treatment for patients with healed myocardial infarction and these complications has not yet been demonstrated. The purpose of the present study was to clarify whether treatment with nifedipine or diltiazem in patients with healed myocardial infarction reduces the likelihood of cardiac events.

	Methods

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The present study was a controlled clinical open trial performed on 1115 patients with healed myocardial infarction treated at the First Department of Medicine, Kinki University School of Medicine, Osaka, Japan (Table 1).

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

Recruitment of Patients
Enrollment of patients began in January 1986 and ended in June 1994 (total study period, 102 months). All consecutive patients with myocardial infarction, including inpatients and outpatients treated at our department, were enrolled. The diagnosis of acute myocardial infarction was based on a typical history, ECG changes, and a significant elevation of myocardial serum enzymes. The diagnosis of healed myocardial infarction was made from typical ECG evidence of myocardial infarction with or without a typical history and medical documentation of acute myocardial infarction from the referring hospital. All inpatients with acute myocardial infarction were registered at 8 days after onset. The cardiac events within 7 days of onset were not included in this study. All outpatients with healed myocardial infarction were registered on their first visit to our department.

Drug Assignment and Follow-up
Each patient was assigned an eight-digit hospital identification number on the first visit to our hospital. Drug treatment was assigned according to the last four digits of the hospital identification number: if the first of these four digits was even (99992999), the patient received a calcium antagonist; if odd (99991999), the patient was assigned to the no-calcium-antagonist group. We used the last four digits for this purpose because the other digits have been used for other purposes. Among the calcium antagonists, short-acting nifedipine capsules (10 mg) three times a day (30 mg/d) PO or short-acting diltiazem tablets (30 mg) three times a day (90 mg/d) PO were the most widely used standard medications for cardiac patients in this hospital in the 1980s. These standard doses were applied in the present study for the nifedipine patients and the diltiazem patients. Selection of either nifedipine or diltiazem was left to the choice of the doctor and was based on the patient's tolerance. Compliance with the calcium antagonist treatment regimen was ensured by regular receipt of the prescription. Outpatient visits were scheduled approximately once a month.

Follow-up Examination
Heart rate and blood pressure for inpatients were obtained as a mean value of regular daily checkups. Heart rate for outpatients was measured by ECG recorded in the morning at the laboratory. Blood pressure used for outpatients was obtained from the mean of casual blood pressure readings at the outpatient clinic. Serial blood tests, exercise ECG, and echocardiogram were performed several times during hospitalization for acute myocardial infarction and approximately twice a year on outpatients. Clinical severity in the acute phase was evaluated according to the classifications of Forrester et al⁵ and Killip and Kimball.⁶ Left ventricular wall motion abnormalities were evaluated from the wall motion index with an echocardiogram.⁷ The extent of myocardial infarction was also evaluated by use of the QRS score of the ECG.⁸ Diagnosis of angina pectoris during follow-up was made from typical symptoms and prompt relief with sublingual nitroglycerin, with signs of ischemia on exercise ECG or ²⁰¹Tl scintigram. Diagnosis of variant angina during follow-up was made from typical symptoms with a concomitant ST-segment elevation on the ECG during the attack or with coronary spasm on coronary angiogram accompanied by ST-segment elevation on the ECG elicited by acetylcholine or ergometrine maleate. The exercise test ECG was positive when Master's two-step test and/or the treadmill exercise test was positive. The Master two-step test result was defined as positive if a >0.5-mm (0.05-mV) flat ST-segment displacement was present in a standard ECG after exercise. The treadmill exercise test result was defined as positive if a >1-mm (0.1-mV) flat ST-segment depression was elicited by exercise. A history of hypertension was defined as casual blood pressure of >160 mm Hg systolic or >95 mm Hg diastolic.

Exclusion and Discontinuation
Patients who died within 7 days after onset of acute myocardial infarction were not registered. Those who ceased their visits to our clinic were contacted so that we could determine the reasons for discontinuation and avoid overlooking cardiac events or other medical events.

Primary End Points
The primary end points were cardiac death and nonfatal cardiac complications (Table 2). Cardiac death included fatal recurrent myocardial infarction, death from congestive heart failure, and sudden death. Nonfatal cardiac complications included nonfatal recurrent myocardial infarction, hospitalization due to worsening angina pectoris, congestive heart failure, and premature ventricular contractions. The diagnosis of reinfarction was defined by the same criteria as myocardial infarction for enrollment. The diagnosis of death from congestive heart failure was established when death could be directly attributed to congestive heart failure. Sudden death was defined in accordance with Braunwald's definition.⁹

View this table: [in this window] [in a new window]   Table 2. Effect of Calcium Antagonists on Cardiac Events

Statistical Analysis
The survival rate was estimated by the Kaplan-Meier method and compared between the no-calcium-antagonist and calcium-antagonist groups by means of a two-sided log-rank test. A multivariable analysis of independent predictors of cardiac events was performed with the Cox hazard model of the forward stepwise method. Data are shown as mean±SD. Differences in patient characteristics between any two groups were tested by the ² test. The probability values are two-sided, and a value of P<.05 was considered significant in Tables 1 and 2. We calculated the odds ratio and 95% CIs for all possible risks.¹⁰ To assess the possible modifying effects of patient characteristics, subgroup analyses were made within the strata of the 48 variables listed in Table 1. In a subgroup with a small number of patients (fewer than 100), the result was considered not meaningful. A value of P<.01 was considered significant to qualify the results of subgroup analyses.

	Results

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Study Population
A total of 1115 patients with myocardial infarction (880 men and 235 women, 60.1±11.4 years old) were included in the analysis. The time interval from onset of myocardial infarction to registration was 26.5±32.9 months, and the mean observation period was 18.4±20.5 months. There were 148 inpatients and 967 outpatients. Of these patients, 28.8% had visited our hospital for some reason before onset of myocardial infarction; thus, these patients had hospital identification numbers before registration in this study. Total exposure time from the first hospital visit to the end of follow-up for this study was 59.0±61.8 months.

Baseline Characteristics
Among 1115 patients, 595 patients were treated without and 520 patients with calcium antagonists; 341 patients received short-acting nifedipine 30 mg/d and 179 received short-acting diltiazem 90 mg/d. Forty-eight baseline characteristics of these groups are listed in Table 1. Of these characteristics, there were no differences between the no-calcium-antagonist and calcium-antagonist groups in 35 parameters: sex; age; systolic and diastolic blood pressures; heart rate; inpatient versus outpatient; mean observation period; randomization; infarct sites: anterior, inferior, non–Q-wave infarction, multiple infarcts and others; wall motion index by echocardiogram; ECG QRS score; coronary risk factors (hyperlipidemia, smoking, obesity, and gout); nine blood tests; exercise ECG findings; coronary thrombolysis; percutaneous transluminal coronary angioplasty; coronary artery bypass graft surgery; and the combined medications (antiplatelet agents, cholesterol-lowering agents, warfarin, and antiarrhythmic agents). There were differences in 13 baseline characteristics between the no-calcium-antagonist group and the calcium-antagonist group, as shown in Table 1.

Effect of Calcium Antagonist on Cardiac Events
Among 1115 patients, a total of 105 cardiac events (9.4%) were noted (Table 2). Of 595 patients without calcium antagonists, 51 (8.6%) had cardiac events, whereas of 520 patients with calcium antagonists, 54 (10.4%) had cardiac events (odds ratio, 1.24; 95% CI, 0.83 to 1.85). Of 341 patients with nifedipine, 39 (11.4%) had cardiac events (odds ratio, 1.38; 95% CI, 0.89 to 2.14). Of 179 patients with diltiazem, 15 (8.4%) had cardiac events (odds ratio, 0.98; 95% CI, 0.54 to 1.78). Calcium antagonists had no effect in reducing cardiac events in patients with healed myocardial infarction. There were no differences in noncardiac death and total mortality between the two groups (Table 2). Among noncardiac deaths, 12 patients (2.0%) in the no-calcium-antagonist group and 15 (2.9%) in the calcium-antagonist group died of malignancy (odds ratio, 1.44; 95% CI, 0.67 to 3.11).

Kaplan-Meier Analysis
There was no difference in total mortality between the no-calcium-antagonist group and the calcium-antagonist group (Fig 1). There was also no difference in total mortality among the no-calcium-antagonist, nifedipine, and diltiazem groups.

View larger version (14K): [in this window] [in a new window]   Figure 1. Kaplan-Meier analysis on total mortality between no-calcium-antagonist and calcium-antagonist groups.

Multivariable Analysis
Among the multivariables listed in Table 1, two variables (age >60 years and heart rate >70 bpm) had significant positive correlations (P<.05) in increasing cardiac events. Three variables (patients taking ß-blockers and antiplatelet agents and those who had percutaneous transluminal coronary angioplasty) had significant positive correlations (P<.05) in reducing cardiac events. Multivariable analysis revealed no correlation of calcium antagonists in increasing or reducing cardiac events.

Subgroup Analyses
A total of 96 subgroup analyses were performed on all 48 patient characteristics. For example, patients were divided into those who had or did not have angina pectoris after acute myocardial infarction. These two groups were further divided into two groups: those with and without calcium antagonist; those with calcium antagonist were further divided into those with nifedipine or diltiazem. Cardiac events were compared among those subgroups. Among all subgroup analyses, no subgroup of patients who received nifedipine or diltiazem showed a significant reduction of cardiac events with a value of P<.01.

Among patients who were registered within 6 months after onset of acute myocardial infarction, 14 of 164 of the no-calcium-antagonist subgroup had cardiac events (8.5%), and 11 of the 209 patients with calcium antagonist had cardiac events (5.3%; odds ratio, 0.60; 95% CI, 0.26 to 1.35). A total of 139 patients with nifedipine had 8 cardiac events (5.8%; odds ratio, 0.65; 95% CI, 0.27 to 1.61), and 70 patients with diltiazem had 3 cardiac events (4.3%; odds ratio, 0.54; 95% CI, 0.16 to 1.79).

Of the total patient population, 45.7% had hypertension. Of the hypertensive patients, cardiac events occurred in 17 of 180 patients (9.4%) of the no-calcium-antagonist subgroup and in 27 of 213 patients (12.7%) of the calcium-antagonist subgroup (odds ratio, 1.39; 95% CI, 0.73 to 2.65; Fig 2). The calcium-antagonist subgroup consisted of 19 of 157 patients (12.1%) in the nifedipine and 8 of 56 patients (14.3%) in the diltiazem subgroups. In the patients without hypertension, neither nifedipine nor diltiazem treatment resulted in a significant reduction of cardiac events (no calcium antagonist, 8.8%; calcium antagonist, 11.3%; nifedipine, 12.7%; diltiazem, 9.1%; odds ratio and 95% CI between the no-calcium-antagonist subgroup and the calcium-antagonist subgroup, 1.31 and 0.71 to 2.42, respectively).

View larger version (23K): [in this window] [in a new window]   Figure 2. Effect of calcium antagonist on cardiac events in subgroups of hypertension and angina pectoris.

Angina after infarction was present in 27.8% of the patients. Of the patients with angina, cardiac events occurred in 26 of 110 patients (23.6%) in the no-calcium-antagonist subgroup and in 34 of 151 patients (22.5%) in the calcium-antagonist subgroup (odds ratio, 0.94; 95% CI, 0.52 to 1.68; Fig 2). The calcium-antagonist subgroup consisted of 23 of 106 patients (21.7%) in the nifedipine and 11 of 45 patients (24.4%) in the diltiazem subgroups. In the patients without angina, neither nifedipine nor diltiazem treatment resulted in a significant reduction of cardiac events (no calcium antagonist, 5.9%; calcium antagonist, 5.6%; nifedipine, 6.8%; diltiazem, 3.7%; odds ratio and 95% CI between the no-calcium-antagonist subgroup and the calcium-antagonist subgroup, 0.95 and 0.50 to 1.84). There were 46 patients (4.1% of the total population) with variant angina. Among these, 16 did not receive any calcium antagonist, 20 received nifedipine, and 10 received diltiazem. Cardiac events were seen in 2 patients in the no-calcium-antagonist subgroup (12.5%), 2 in the nifedipine subgroup (10.0%), and none in the diltiazem subgroup (0%). Because of the small number of patients, we were unable to evaluate this result.

The exercise ECG was positive in 103 of the no-calcium-antagonist subgroup and in 116 of the calcium-antagonist subgroup. Cardiac events were not reduced by the calcium antagonists (no calcium antagonist, 4.9%; calcium antagonist, 9.5%; nifedipine, 8.1%; diltiazem, 11.9%); odds ratio and 95% CI between the no-calcium-antagonist and the calcium-antagonist subgroups, 1.95 and 0.68 to 5.59. Negative exercise test results occurred in 207 of the no-calcium-antagonist subgroup and in 171 of the calcium-antagonist subgroup (110 nifedipine patients and 61 diltiazem patients). The incidence of cardiac events was also not reduced by the calcium antagonists (1.4%, 3.5%, 3.6%, and 3.3%, respectively); odds ratio and 95% CI between the no-calcium-antagonist and calcium-antagonist subgroups, 2.30 and 0.62 to 8.55.

Coronary thrombolysis was performed in 33.7% of the patients during the acute phase of myocardial infarction. Calcium antagonists did not reduce cardiac events in the patients with coronary thrombolysis (no calcium antagonist, 20 of 176, 11.4%; calcium antagonist, 17 of 138, 12.3%; nifedipine, 12 of 84, 14.3%; and diltiazem, 5 of 54, 9.3%). Odds ratio and 95% CI between the no-calcium-antagonist subgroup and the calcium-antagonist subgroup were 1.10 and 0.55 to 2.18, respectively.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Calcium antagonists have been prescribed for many patients with healed myocardial infarction, although there has been no study of these drugs that convincingly demonstrates their ability to reduce morbidity or mortality.¹¹ The present study revealed that short-acting nifedipine and diltiazem have no effect on the likelihood of cardiac events when given to patients with healed myocardial infarction.

Held et al¹² did an overview study of calcium antagonists in myocardial infarction and unstable angina and meta-analyzed 28 randomized trials. Their findings suggested a slightly unfavorable effect of calcium antagonists. In the present study, nifedipine 30 mg/d, which is the average daily dose used in Japan, slightly increased the incidence of cardiac events.

Diltiazem exerts a slightly different effect on the incidence of cardiac events. In the Diltiazem Reinfarction Study,¹³ the investigators evaluated the effect of diltiazem on reinfarction within 14 days after onset of non–Q-wave infarction. They found that reinfarction occurred in 9.3% of the placebo group and in 5.2% of the diltiazem group (a 51.2% reduction), although mortality was not reduced. The long-term effect of diltiazem, with a mean follow-up period of 25 months, was reported in the Multicenter Diltiazem Postinfarction Trial (MDPIT).⁴ In patients without pulmonary congestion, diltiazem treatment was associated with a reduced number of cardiac events, whereas in patients with pulmonary congestion, diltiazem was associated with an increased number of cardiac events. The authors concluded that diltiazem exerted no overall effect on mortality or cardiac events in patients with previous infarction. In the present study, there was no overall reduction of cardiac events in the patients who received diltiazem (Table 2).

The time of initiation of treatment after onset shows a distinction between nifedipine and diltiazem. In one study, nifedipine 60 mg/d administered usually within 3 hours after hospital admission resulted in an increase in mortality during the first 6 days.² Another study found that diltiazem treatment initiated 24 to 72 hours after the onset of non–Q-wave infarction resulted in a reduction in the rate of reinfarction during the first 14 days.¹³ This finding does not accord with the finding of the present study that diltiazem had no positive effect, but the two studies cannot be appropriately compared, since cardiac events within 7 days after onset were not included in our study. In SPRINT 1¹ as well as SPRINT 2,² nifedipine had no beneficial effect on long-term prognosis. In the MDPIT examination of diltiazem,³ the incidence of early reinfarction (within 6 months) was reduced in patients with non–Q-wave infarction. Our present study showed no significant reduction of cardiac events in the diltiazem group of patients in whom treatment was initiated within 6 months after onset.

Most of the previous studies in this area were conducted in the prethrombolytic era. Some researchers emphasize the need for reevaluation of these drugs in the thrombolytic era.¹⁴ Early successful thrombolysis salvages myocardium confronted by necrosis, leaving more viable myocardium in the risk area. The risk areas with diseased coronary arteries might be more susceptible to reinfarction. In our present study population, 33.7% of the patients had coronary thrombolysis. Subgroup analysis revealed no benefit in the calcium-antagonist patients.

The Ministry of Health and Welfare in Japan has approved the use of calcium antagonists in patients with hypertension. A recent report showed that heart rate–lowering calcium antagonists in postmyocardial infarction patients significantly reduced cumulative event rates compared with placebos.¹⁵ Our present report did not support their findings.¹⁵ Psaty et al¹⁶ reported that the risk of myocardial infarction increased about 60% among hypertensive patients treated with a short-acting calcium antagonist compared with those treated with diuretics. In our present study population, 45.7% of the patients were hypertensive. Subgroup analysis showed that among hypertensives, the findings are similar (Fig 2) and consistent with those of Psaty et al.

Calcium antagonists are potent antianginal drugs, widely prescribed in Japan for patients with angina after myocardial infarction to relieve angina, increase the quality of life, and possibly prevent reinfarction. In the present study, 27.8% of the patients had angina, including 4.1% with variant angina. However, calcium antagonists failed to reduce cardiac events in the patients with angina pectoris (Fig 2).

The present study has several limitations. Drug assignment was not randomized on a double-blind, placebo-controlled basis, and the study population was relatively small. However, the present study, together with several clinical reports,^{1 2 3 4 12 16} failed to show any ability of nifedipine and diltiazem to prevent cardiac events. It is true that not all calcium antagonists are created equal.¹⁷ Accordingly, the suggested adverse effects of short-acting nifedipine on mortality^{18 19} cannot be extrapolated to those calcium antagonists with a slow onset of action.¹⁹ Some of the newer slower-onset, longer-acting calcium antagonists might still be beneficial.¹⁴ The question of differences between long-acting formulations and short-acting formulations, especially in terms of beneficial effect, can be settled only by conclusive findings from large, long-term randomized clinical trials. Boden et al²⁰ proposed a study of long-acting diltiazem to address some of these issues. Their study may offer important information on how to use calcium antagonists.

In conclusion, use of short-acting nifedipine and diltiazem in this post–myocardial infarction population was associated with a 24% higher cardiac event rate, but this strong adverse trend did not reach statistical significance.

Received July 23, 1996; revision received January 22, 1997; accepted January 23, 1997.

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