(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
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.
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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
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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).
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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
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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.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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.
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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).
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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.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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 mortality18 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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