Drugs 44 (Suppl. I): 33-43, 1992 00 12-6667/92/0100-0033/$5.50/0 © Adis International Limited. All rights reserved. DRSUP3343
Secondary Prevention with Calcium Antagonists after Acute Myocardial Infarction J I?J1'gen Fischer Hansen
Department of Cardiology, Hvidovre University Hospital, Hvidovre, Denmark
Summary
Experimental studies have demonstrated that the 3 calcium antagonists nifedipine, diltiazem, and verapamil have a comparable effect in the prevention of myocardial damage during ischaemia. Secondary prevention trials after acute myocardial infarction, which aimed at improving survival and preventing reinfarction, nevertheless demonstrated pronounced differences between the 3 drugs. Nifedipine had no effect on reinfarction or death. Diltiazem had no overall effect but prevented first reinfarction or cardiac death (cardiac events) in patients without heart failure, and increased cardiac events in patients with heart failure before randomisation. Verapamil prevented first reinfarction or death (major events); the most pronounced effect was found in patients without heart failure before randomisation. Verapamil did not have detrimental effects in patients treated for heart failure before randomisation. Differences between trials and between drugs explaining the different clinical findings are evaluated.
On the basis of experiments in isolated heart muscle preparations and in intact animals, calcium antagonists could be expected to reduce infarct size in myocardial infarction (Kloner & Braunwald 1987; Nayler 1991). Furthermore, during long term treatment calcium antagonists may be expected to prevent reinfarction and death, by prevention of myocardial ischaemia and protection of the myocardium during ischaemia (Nayler 1987). Although experimental studies demonstrate similar results with different calcium antagonists, results of clinical trials in patients after myocardial infarction (MI) show evident differences (Persson 1991). The purpose of this paper is to compare the results of 3 late secondary intervention trials - the Multicenter Diltiazem Postinfarction Trial (MDPIT) [Multicenter Diltiazem Postinfarction Trial Research Group 1988], The Secondary Prevention Reinfarction Israeli Nifedipine Trial
(SPRINT) [Israeli SPRINT Study Group 1988], and The Danish Verapamil Infarction Trial II (DAVIT II) [Danish Study Group on Verapamil in Myocardial Infarction 1990a] - and to determine whether differences in patient population and treatment other than trial medication might explain the divergent results of the 3 studies.
1. Comparison 0/ Trials 1.1 Protocols Tables I and II describe the inclusion criteria, study duration, eligible patients, end-points, trial medication, inclusion rate of eligible patients and exclusions. The inclusion rate is highest in SPRINT (56%) compared with DAVIT II (40%) and MDPIT (19%). This high inclusion rate in SPRINT might be explained by differences in criteria for diagnosis
Drugs 44 (Suppl. 1) 1992
34
Table I. Comparison of the 3 late secondary intervention trials with calcium antagonists in patients after acute myocardial infarction (AMI) MDPIT
DAVIT II
SPRINT
Chest discomfort. ECG changes and elevation of cardiac enzymes 25-75
Chest discomfort. ECG changes and elevation of cardiac enzymes .;; 75
2 of the 3 criteria as outlined in MDPIT and DAVIT II 30-74
3-15
7-15
7-21
12-52 25
12-18 16
6-12 10
Eligible patients Total a Included (%) Excluded (%)
13148 2466 (19) 10682 (81)
3991 1775 (40) 2216 (60)
4045 2276 (56) 1769 (44)
Medication Daily dose (mg)
Diltiazem 60 qid
Verapamil 120 tid
Nifedipine 10 tid
End-points
Death First reinfarction or cardiac death (cardiac event)
Death First reinfarction or death (major event)
Death First nonfatal reinfarction
Inclusion criteria Diagnosis of AMI
Patient age (years) Study period Start of treatment (days after AMI) Duration of treatment (months) Range Mean
a Death before randomisation omitted. Abbreviations: tid = 3 times daily; qid = 4 times daily; MDPIT = Multicenter Diltiazem Postinfarction Trial Research Group 1988; Danish Study Group on Verapamil in Myocardial Infarction 1990a; SPRINT Israeli SPRINT Study Group 1988. DAVIT II
=
of acute MI. In addition to chest pain and electrocardiographic changes compatible with acute MI, all patients in MDPIT and DAVIT II required a significant elevation of serum cardiac enzymes for inclusion. This was not necessary in SPRINT. Furthermore, patients with sinoatrial block, bradycardia, and second and third degree atrioventricular block were not excluded in SPRINT. Major differences between trials are related to the use of !3-blockers, which was a reason for exclusion in DAVIT II, but not in MDPIT and SPRINT. Treatment with a calcium antagonist was the reason for more than 30% of the exclusions in MDPIT compared with 15% in the other 2 trials. The SPRINT study group states that 'the major causes of exclusion were inability to cooperate or refusal to sign the consent form'. This group, which represents
=
41.7% of excluded patients, probably contains some of the patients placed in other exclusion groups in MDPIT and DAVIT II. 1.2 End-Points Results of the 3 trials are presented in figure I and tables III and IV. Mortality rates calculated in SPRINT according to Kaplan-Meier methods were 5.7% in the placebo group and 5.8% in the nifedipine group at 1 year (not statistically significant). In MDPIT mortality rates were 16% in both diltiazem- and placebo-treated patients (not statistically significant) after nearly 3 years of observation. Mortality rates after 1.5 years in DAVIT II were 13.8% in placebo recipients and 11.2% in verapamil-treated patients (not statistically significant).
Secondary Prevention with Calcium Antagonists
No difference in cardiac death was found between drug- and placebo-treated patients in SPRINT or MDPIT; in DAVIT II cardiac death rates were 12.3% in the placebo group and 9.9% in verapamil-treated patients (hazard ratio 0.79, 95% confidence limits 0.59 to 1.05; p = 0.10). Sudden death was not reported in MDPIT, and in SPRINT no difference was found between the 2 groups; in DAVIT II sudden death rates were 7.4% in placebo recipients and 5.6% in verapamil-treated patients (hazard ratio 0.74, 95% confidence limits 0.50 to 1.07; p = 0.10). Noncardiac causes of death were reported for 24% of 333 deaths in MDPIT, 18% of 130 deaths in SPRINT and in 11 % of 214 deaths in DAVIT II. These pronounced differences between the studies may be explained by the longer observation period in MDPIT and a difference in patient selection, e.g. significantly more patients were excluded as a result of other severe diseases in DAVIT II than in MDPIT (p < 0.001), and the cardiac mortality rates in the placebo groups after 12 months were 10% in DAVIT II, 4.6% in SPRINT, and
35
around 7% (i.e. three-quarters of the 9% total mortality) in MDPIT (table III). A first nonfatal reinfarction (table III) was recorded in SPRINT in 4.8% of patients in the placebo group and in 4.4% of nifedipine-treated patients (not statistically significant). In MDPIT 15% fewer nonfatal reinfarctions were recorded in the diltiazem-treated group than in the placebo group (not statistically significant). In DAVIT II all reinfarctions, fatal or nonfatal, were reported. The definition of nonfatal reinfarction is not stated in MDPIT or SPRINT. If a nonfatal reinfarction means that the patient is alive 21 days after the reinfarction, then first nonfatal reinfarctions were recorded in 76 placebo recipients and in 54 verapamil recipients in DAVIT II (hazard ratio 0.70, 95% confidence limits 0.50 to 0.99; p = 0.03) [table III]. Cardiac event is the other major end-point in MDPIT and is defined as first reinfarction or cardiac death. The cardiac event rate was reduced by 10% in diltiazem recipients compared with placebo recipients (not statistically significant) [table IV].
Tabla II. Reasons for exclusion from the 3 late secondary intervention trials with calcium antagonists in patients after acute myocardial infarction
No. of reasons for exclusion Reason for exclusion (%) Heart failure Pulmonary hypertension with right heart failure Cardiogenic shock/hypotension Sinoatrial block/bradycardia Second and third degree atrioventricular block Other severe diseases Nonconsensus Cardiac surgery Calcium antagonist treatment II-Blocker treatment Died before randomisation Other reasons
MDPIT
DAVIT II
SPRINT-
11152b
2881 c
1769b
0.4 2.6 0.4 1.7 5.3 25.2 10.2 31.4 0 4.2 8.8
} 10.9 2.6 2.7 6.2 9.7 13.5 0 15.5 15.1 17.0 12.8
+ + + + 41.7
+ 14.2 0
+
a Number of deaths before randomisation not reported. b 1 reason per patient. c More than 1 reason in 377 admissions. Abbreviations and symbol: MDPIT = Multicenter Diltiazem Postinfarction Trial Research Group 1988; DAVIT II = Danish Study Group on Verapamil in Myocardial Infarction 1990a; SPRINT = Israeli SPRINT Study Group 1988; + = reason for exclusion but number of patients not available.
Drugs 44 (Suppl. 1) 1992
36
FOllOw-up
NO. 01 patients
Placebo mortality (%)
Nifedipine Pooled short term
5632
1 day-6 weeks
SPRINT II
1358
6 months
SPRINT I
2276
1 year
6.2 13.3 5.7
Oiltiazem
685
4.1
2466
13.6
congestive heart failure 1909
5.3
Pooled short term
MDPIT ~No
Verapamil DAVIT I
1436
13.9
DAVIT II
1775
13.8
- No congestive heart failure 1161
11.8
o
0.5
1.0
1.5
2.0
Odds ratio
Mortality data from postinfarction studies with nifedipine, diltiazem and verapamil, given as odds ratios with 95% confidence intervals. Pooled data from the overview by Held et al. (1989). SPRINT II = SPRINT Study Group 1988; SPRINT I = Israeli SPRINT Study Group 1988; MDPIT = Multicenter Diltiazem Postinfarction Trial Research Group 1988; DA VIT I = Danish Study Group on Verapamil in Myocardial Infarction 1984; DAVIT II = Danish Study Group on Verapamil in Myocardial Infarction I 990a.
Fig. 1.
Cardiac event rates were calculated in order to compare the results of DAVIT II and MDPIT. A 20% reduction in the hazard ratio was found in the verapamil group compared with the placebo group (p = 0.03) [table IV). In MDPIT the hazard ratio of the cardiac event rate in diltiazem-treated patients without congestion on any chest x-ray obtained before randomisation was significantly reduced by 23% compared with placebo recipients. In the 20% of patients with congestion on chest x-ray, the cardiac event rate was significantly increased in diltiazem-treated patients. In DA VIT II cardiac events were significantly reduced by 29% in patients without heart failure who were treated with verapamil compared with placebo recipients (p = 0.01). In the 35% of patients
treated for heart failure before randomisation, no difference was found between the 2 groups of patients (table IV). Major event, defined as first reinfarction or death, was a preselected end-point in DAVIT II and corresponds with reinfarction-free survival (fig. 2). 18-month first major event rate was 21.6% in the placebo group and 18% in the verapamil group (hazard ratio 0.80, 95% confidence limits 0.64 to 0.99; p = 0.03). In patients without heart failure before randomisation, the 18-month first major event rates were 19.7% and 14.6%, respectively (hazard ratio 0.70, 95% confidence limits 0.52 to 0.93; p = 0.01); in patients with heart failure the values were 24.9% and 24.9% (hazard ratio 1.00, 95% confidence limits 0.72 to 1.39; p = 0.98) in the placebo and verapamil groups, respectively.
37
Secondary Prevention with Calcium Antagonists
Table III. Comparison of number of patients and events, and 12-month mortality rates from the 3 late secondary intervention trials with calcium antagonists in patients after acute myocardial infarction
DAVIT II
MDPIT
Patients Death
placebo
diltiazem
placebo
verapamil
placebo
nifedipine
1234
1232
897
878
1146
1130
167
166
119
95
65
65
107
84
76
54
55
50
63
46
28
23
107
84
53
53
12
12
6
6
First reinfarction First nonfatal reinfarction
116
99
Sudden death Cardiac death
SPRINT
127
124
Noncardiac death
43
38
12
11
First cardiac event
226
202
170
137
180
146
9
9
11
9
First major event 12-month mortality rate (%) Abbreviations: MDPIT
= Multicenter Diltiazem Postinfarction Trial Research Group 1988; DAVIT II = Danish Study Group on Verapamil
in Myocardial Infarction 1990a; SPRINT
= Israeli SPRINT Study Group 1988.
Table IV. Comparison of mortality and cardiac event rates in MDPIT and DAVIT II (intention-to-treat)
DAVIT II
MDPIT placebo
diltiazem
placebo
verapamil
Mortality
Mortality rate (%)8
16
16
Hazard ratio 95% confidence limits
14
11
1.02
0.80
(0.82-1.27)
(0.61-1.05)
Cardiac event All patients
First cardiac event rate (%)8
20
Hazard ratio 95% confidence limits
18
20
17
0.90
0.80
(0.74-1.08)
(0.64-0.99)
Patients without heart failure
No. of patients 12-month event rate (%)
959
950
574
11
8
16
Hazard ratio 95% confidence limits
587 9
0.77
0.71
(0.61-0.98)
(0.52-0.96)
Patients with heart failure
No. of patients 12-month event rate (%) Hazard ratio 95% confidence limit a
MDPIT: 33 months; DAVIT II: 18 months.
Abbreviations: MDPIT
248
242
323
18
26
21
291 19
1.41
0.97
(1.01-1.96)
(0.69-1.35)
= Multicenter Diltiazem Postinfarction Trial Research Group 1988; DAVIT II = Danish Study Group on Verapamil
in Myocardial Infarction 1990a.
Drugs 44 (Suppl. 1) 1992
38
49% in MDPIT and 47% in SPRINT, and significantly more patients had diabetes in SPRINT (19%) compared with DAVIT II (6%) and MDPIT (9%). No information is available regarding the number of patients with angina pectoris before admission to MDPIT, and the significantly higher prevalence of angina pectoris in SPRINT (34%) compared with DAVIT II (26%) is most probably explained by inclusion of patients with unstable angina in SPRINT. Mean age is about 2 years higher in DAVIT II than in the other 2 studies; this might partly explain the higher mortality rate in the placebo group of DAVIT II.
1.00
iii
.~
::>
III
~c
0.96 0.92
" 0.88
"-'-__
Verapamil " ......_-
.. _-....-..- .... -
~
0.84 J! c .a; a:
-.
0.80 0.76 0
180
360
540
Days
1.4 Findings at Randomisation
Fig. 2. Ratio of reinfarction-free survival to allocated treatment with verapamil (n =878) or placebo (n =897) in DAVIT II (hazard ratio 0.80; 95% confidence limits 0.64 to 0.99; p = 0.03) [From Danish Study Group on Verapamil in Myocardial Infarction I 990a).
1.3 History of Included Patients Analyses of available information (table V) demonstrated that significantly more patients were treated for systemic hypertension in MDPIT (38%) than in SPRINT (24%) and DAVIT II (14%). 62% of DA VIT II patients were smokers compared with
Table V. Comparison of history prior to admission in the after acute myocardial infarction
No. of patients Mean age (years ± SO) Female ("!o) Previous myocardial infarction ("!o) Systemic hypertension ("!o) Diabetes ("!o) Smokers ("!o) Angina pectoris ("!o)
3 late
There were pronounced differences between the 3 studies in medical treatment at randomisation (table VI). These differences may reflect different attitudes to the use of drugs in patients with acute MI. For example, 32% of patients in SPRINT were treated with antiarrhythmic drugs compared with 9% in MDPIT and 2% in DAVIT II, and only 8% were treated with nitrates other than nitroglycerin in DAVIT II compared with 43% in SPRINT and 60% in MDPIT. The fact that more patients were treated with diuretics in DAVIT II (40%) compared with MDPIT (23%) and SPRINT (25%) may
secondary intervention trials with calcium antagonists in patients
MDPIT
DAVIT II
SPRINT
2466 58 ± 10 20
1775 60 ± 9 20 17 14* 6 62* 26·
21498 58 ± 9
21* 38t 9t 49t
17 24 19 47
34
a Information on 127 patients missing. Abbreviations and symbols: MDPIT = Multicenter Diltiazem Postinfarction Trial Research Group 1988; DAVIT II = Danish Study Group on Verapamil in Myocardial Infarction 1990a; SPRINT = Israeli SPRINT Study Group 1988; t = statistically different compared with DAVIT II and SPRINT (p < 0.001);:1: = statistically different compared with DAVIT II and SPRINT (p < 0.01); • statistically different compared with SPRINT (p < 0:001).
=
39
Secondary Prevention with Calcium Antagonists
Table VI. Comparison of medical status at randomisation in the 3 late secondary intervention trials with calcium antagonists in patients after acute myocardial infarction MDPIT (n = 2466) Medication (%) /3-Blockers Diuretics Digoxin Antiarrhythmics Nitrates (other than sublingual)
55 23 14
9 60
Clinical findings (mean value) Heart rate (beats/min) SBP (mm Hg) DBP (mm Hg) Infarct type location (%) Anterolateral a-wave Inferoposterior a-wave Non-a-wave Other 24-Hour electrocardiographic monitoring No. of patients Mean heart rate (beats/min) ~ 10 ventricular ectopic beats/hour ("!o) ~ 3 ventricular ectopic beats in a row ("!o)
DAVIT II (n = 1755)
SPRINT (n = 2149)8
0 40 12 2 8
18 25 10 32 43
75 120 76
78 137 85
31 39 26 4
37 36 17 10
1677 72 17 10
247 79 17 11
a Information on 127 patients missing. Abbreviations: MDPIT = Multicenter Diltiazem Postinfarction Trial Research Group 1988; DAVIT II = Danish Study Group on Verapamil in Myocardial Infarction 1990a; SPRINT = Israeli SPRINT Study Group 1988; SBP = systolic blood pressure; DBP = diastolic blood pressure.
reflect different patient selection (e.g. exclusion of patients with heart failure in MDPIT and exclusion of patients with unstable angina in SPRINT). Secondary prevention is considered an indication for ~-blocker treatment in the United States. Thi,s is reflected in the large number (55%) of patients in the MDPIT study treated with ~-block ers. The indications for ~-blockers in the SPRINT trial (18%) were not stated. In Denmark during the study period for DAVIT II, ~-blockers were indicated for hypertension, angina pectoris and arrhythmias. Patients in need of ~-blockers were excluded from DAVIT II. Systolic and diastolic blood pressures were significantly higher in patients included in SPRINT compared with DAVIT II. Blood pressure information is not available for MDPIT. Subgroups in
MDPIT (Bigger et al. 1990) and DAVIT II (data on file, DAVIT II Study Group) underwent 24-hour electrocardiographic monitoring. Mean heart rate was 72 beats/min in MDPIT and 79 beats/min in DAVIT II. This difference may be due to ~-blocker treatment in MDPIT. The prevalence of more than 10 ventricular ectopic beats/hour or 3 or more ventricular ectopic beats in a row was the same in the 2 studies (table VI).
2. Discussion 2.1 Differences between Trials Analyses of the 3 late secondary prevention trials with the 3 prototypes of calcium antagonists demonstrate major differences in inclusion rate and cri-
40
teria, exclusion criteria, concomitant treatment and previous history. These differences between included patients are probably reflected in the different event rates in the placebo groups of the 3 studies, such as the 12-month mortality rates of6% in SPRINT, 9% in MDPIT, and 11% in DAVIT II. The consequences of these differences with regard to evaluation of the overall effect of calcium antagonist treatment after acute MI are difficult to determine but support the view recently expressed by Persson (1991) that 'the use of pooled data from the calcium antagonist studies regarding secondary prevention after MI is not reliable'. Nifedipine has been tested in a large number of trials with intervention starting both early and late after an acute MI (see review by Raffienbeul & Ebner 1991). Nifedipine had no overall effect on mortality (fig. 1) or reinfarction rate in either early or late intervention trials (Yusuf et al. 1991). Studies with diltiazem also demonstrate no overall effect on mortality (fig. 1) or reinfarction, although the early intervention non-Q-wave diltiazem study (Gibson et al. 1986) demonstrated a 50% reduction in reinfarction rate (p = 0.03, 1sided) in diltiazem-treated patients compared with placebo recipients. These findings were further supported by analyses of a subset of 634 patients with non-Q-wave infarction in MDPIT demonstrating a 12-month cardiac event rate of 9% with diltiazem compared with 15% in the placebo recipients (hazard ratio 0.65, 95% confidence limits 0.43 to 0.96) [Gibson 1991]. Whether this effect of diltiazem is related to non-Q-wave infarctions is debatable. Recently, Boden et al. (1991) analysed infarct type and location and found that an effect of diltiazem was demonstrated in inferoposterior Q-wave and in non-Q-wave infarctions. When this is combined with the information that diltiazem prevented cardiac events in patients without heart failure, it looks more probable that diltiazem might be effective in patients with small infarcts. The overall lack of effect of diltiazem on mortality and cardiac events is puzzling. One possible explanation is that a large number of patients were already receiving treatment with j3-blockers (55% in MDPIT and 62% in the non-Q-wave infarction
Drugs 44 (Suppl. 1) 1992
study) and with vasodilators (60% in MDPIT). Thus, no further effect may be obtained by adding diltiazem (Packer 1989). The increased event rate in patients with heart failure treated with diltiazem in MDPIT might be explained by the addition of a negative inotropic agent to patients already treated with j3-blockers and/or the addition of a vasodilator and negative inotropic agent to patients already receiving vasodilator therapy. From a theoretical point of view, it is very likely that diltiazem has an effect on mortality and reinfarction after acute MI, at least in patients with good left ventricular function (Multicenter Diltiazem Postinfarction Trial Research Group 1988). Further studies are needed to evaluate the effect of diltiazem without concomitant j3-blocker and vasodilator therapy. DAVIT II differs from MDPIT in several aspects. In DAVIT II no patient received treatment with j3-blockers, and only a minority (8 vs 60%) with vasodilators. Probably more patients had clinical heart failure before randomisation (40 vs 20%). These differences might explain the fact that verapamil improved reinfarction-free survival, and that no harmful effect was demonstrated in patients with heart failure. The decision to perform DAVIT II was, to a large extent, based on a retrospective analysis of DAVIT I (Danish Study Group on Verapamil in Myocardial Infarction 1984), which demonstrated a statistically significant reduction in mortality for patients alive 22 days after admission in the verapamil group (6.4%) compared with the placebo group (3.7%) [p < 0.05], and a statistically significant reduction in reinfarctions in patients alive on day 15 (3.9% vs 7.0%, respectively) [p < 0.03]. In DAVIT I treatment commenced at admission and was continued for 6 months. On the eighth day, 671 patients who received verapamil and 679 placebo-treated patients were alive. When the results of the 2 DAVIT studies were combined using the method advocated by Yusufet al. (1985) [fig. 3] which included patients alive 8 days after starting treatment from DAVIT I and all patients from DAVIT II, the pooled odds ratio of DAVIT I and II for mortality was 0.78 (95% confidence limits 0.63 to 0.99; p = 0.04) and that for first rein-
Secondary Prevention with Calcium Antagonists
41
Results from an overview of trials with under 50 deaths (10 trials)
I I I I I
I
Individual late-entry trials with over 50 deaths (10 trials)
I I I
I
----+-~--I
r---- -------~---------------
I
I I
Late mortality in early-entry trials (3 trials)
I
I
I I
I I
• I
All trials
..
"iii
:s
I I I
DAVIT II [
I
DAVIT I late mortality
I I
Both DAVIT trials
o
0.2
• 0.4
~
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Odds ratio (active: control)
Fig. 3. Mortality data from postinfarction studies with fj-blockers and verapamil given as odds ratios with 95 or 99% confidence limits. Late mortality in early entry trials is based on all deaths in patients alive on day 8 after randomisation. Solid lines represent confidence limits for trials that ran to the scheduled finish; dotted lines represent 99% confidence limits for trials stopped early because of observed trend;-= 95% confidence limits from an overview of all fj-blocker trials; DAVIT I = Danish Study Group on Verapamil in Myocardial Infarction 1984; DAVIT II = Danish Study Group on Verapamil in Myocardial Infarction 1990a (after Yusuf et al. 1985).
farction was 0.73 (95% confidence limits 0.57 to 0.94; p = 0.02) [Danish Study Group on Verapamil in Myocardial Infarction 1990b]. These analyses support the theory that verapamil is effective in preventing death and reinfarction as a secondary preventive agent. Furthermore, the overall effect corresponds to the effect demonstrated for {:I-blockers (Yusuf et al. 1988). 2.2 Differences between Drugs The different results of treatment with nifedipine, verapamil, and diltiazem in secondary prevention trials, as outlined in tables III and IV, may
also be explained by the different pharmacological effects of the drugs (Opie 1990). It may be of importance that verapamil and diltiazem have a negative chronotropic effect, while nifedipine often increases heart rate. All 3 drugs have negative inotropic and vasodilator properties but the balance between these 2 effects is different. The ratio, evaluated from portal vein and papillary muscle, of vascular inhibition: the negative inotropic effect has been estimated at 1.4 for verapamil, 7 for diltiazem, and 14 for nifedipine (Opie 1990). The pronounced vasodilator effect of nifedipine explains the description of the paradox of angina and ar-
Drugs 44 (Suppl. 1) 1992
42
terial hypotension in nifedipine-treated patients. In post-MI patients this may cause a deterioration of blood supply to the myocardium by a reduction in perfusion pressure and diastolic perfusion time. The effects are of special importance in patients with severe coronary artery stenosis or occluded coronary arteries and collateral vessels. Attenuation of the blood flow may result in ischaemic heart failure due to myocardial stunning, myocardial necrosis due to hypoperfusion, and ventricular arrhythmias due to ischaemia (Opie 1991). The vasodilator effect of verapamil is pronounced enough to prevent vasospastic angina (Beller 1989) but seldom causes hypotension (Danish Study Group on Verapamil in Myocardial Infarction 1990a). Verapamil improves left ventricular diastolic function in patients with coronary artery disease (Betocchi et al. 1990; Serato et al. 1990), an effect found to a lesser extent or not at all with nifedipine (Lahiri et al. 1990). The negative inotropic and vasodilator properties of diltiazem seem to be between that of nifedipine and verapamil. Recently, Richardt et al. (1991) demonstrated that verapamil and nifedipine inhibited the release of norepinephrine (noradrenaline) in isolated rat hearts during ischaemia, an effect that was absent or demonstrated to a lesser degree with diltiazem. This finding may be of interest because it may explain why verapamil prevented sudden death (Hansen 1991) and reduced overall mortality (Danish Study Group on Verapamil in Myocardial Infarction 1990b) while diltiazem had no effect in MDPIT. The finding of Richardt and colleagues (1991) may also add to our understanding of the surprising finding of MDPIT that heart failure increased in patients with reduced ejection fraction « 40%) treated with diltiazem compared with those administered placebo (Goldstein et al. 1991). In this group of patients with impaired left ventricular systolic function, the cardiac event rate was significantly increased in diltiazem-treated patients compared with placebo recipients. It has been agreed that 'diltiazem may enhance neuroendocrine activation in these patients thereby accelerating left ventricular decompensation and augmenting the likelihood of lethal arrhythmias'
(Goldstein et al. 1991). Although systemic neuroendocrine activation by nifedipine has been demonstrated in normal and hypertensive patients (Opie 1990), it remains speculative whether this is of importance in patients with heart failure (Packer 1989). Further differences exist between calcium antagonists, as verapamil does not increase plasma catecholamine levels in patients with hypertension (Opie 1990). From the clinical point of view, it is of importance that verapamil, contrary to diltiazem, did not increase the cardiac event rate in patients treated for heart failure before randomisation. It is also remarkable that after 12 months significantly fewer patients in the verapamil group (27.3%) compared with the placebo group (34.3%) received treatment with diuretics (p < 0.05). Of patients treated with diuretics at randomisation, 31.2% of those who received verapamil and 17.9% of placebo recipients terminated treatment with diuretics within 12 months. Thus, the deleterious effect in heart failure patients described for diltiazem was not found with verapamil.
3. Conclusion Although laboratory studies have demonstrated a comparable effect of calcium antagonists on ischaemic myocardium, important clinical differences exist between the 3 types of calcium antagonists. Treatment with nifedipine has been demonstrated to have no or a deleterious effect, diltiazem to have no overall effect, and verapamil to have a beneficial effect on reinfarction-free survival after acute MI. The beneficial effect of verapamil is primarily found in patients with good left ventricular function. The consequences of this demonstrated effect of verapamil may be 2-fold. Firstly, verapamil can be used for secondary prevention in patients with contraindications to (jblocker treatment, including those with pulmonary diseases, and those with side effects attributed to (j-blockers (Yusuf et al. 1991). Secondly, when comparing the effect of verapamil with that of (jblockers in secondary prevention, the major effect of (j-blockers is found in patients with impaired left
Secondary Prevention with Calcium Antagonists
ventricular function (Boissel et al. 1991; Goldstein et a1. 1991; Lichstein et a1. 1990) and that of verapamil in patients with normal left ventricular function. Thus, in patients without heart failure during the acute event, verapamil may be used as the first drug of choice, and in patients with heart failure, a (j-blocker may be used as the first drug of choice.
References Beller GA. Calcium antagonists in the treatment of Prinzmetal's angina and unstable angina pectoris. Circulation 81 (Suppl. IV): IV-78-IV87, 1989 Betocchi S, Piscione F, Perrone-Filardi P, Pace L, Cappilli-Bigazzi M, et al. Effects of intravenous verapamil on left ventricular relaxation and filling in stable angina pectoris. American Journal of Cardiology 66: 818-825. 1990 Bigger JT, Coromilas J, Rolnitzky LM, Heiss JL, K1eiger RE, the Multicenter Diltiazem Postinfarction Trial Investigators. Effect of diltiazem on cardiac rate and rhythm after myocardial infarction. American Journal of Cardiology 65: 539-546, 1990 Boden WE, Krone RJ. K1eiger RE, Oakes D, Greenberg H, et ai, the Multicenter Diltiazem Post-Infarction Trial Research Group. Electrocardiographic subset analysis of diltiazem administration on long-term outcome after acute myocardial infarction. American Journal of Cardiology 67: 335-342,1991 Boissel JP, Leizorovicz A, Picolet H, Peyrieux JC, the APSI Investigators. Secondary prevention after high risk acute myocardial infarction with low-dose acebutolol. American Journal of Cardiology 67: 251-260, 1991 Danish Study Group on Verapamil in Myocardial Infarction. Verapamil in acute myocardial infarction. European Heart Journal 5: 516-528. 1984 Danish Study Group on Verapamil in Myocardial Infarction. The effect of verapamil on mortality and major events after myocardial infarction. The Danish Verapamil Infarction Trial II (DAVIT II). American Journal of Cardiology 66: 779-785, 1990a Danish Study Group on Verapamil in Myocardial Infarction. Secondary prevention with verapamil after myocardial infarction. American Journal of Cardiology 66: 331-401, 1990b Gibson RS. Management of acute non-Q-wave myocardial infarction. The role of prophylactic diltiazem therapy and indications for predischarge coronary arteriography. Drugs 42 (Suppl. 2): 28-37, 1991 Gibson RS. Boden WE, Theroux p. Strauss HD, Pratt CM, et al. Diltiazem and reinfarction in patients with non-Q-wave myocardial infarction. Results of a double-blind, randomised multicenter trial. New England Journal of Medicine 315: 423-429, 1986 Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S, the Adverse Experience Committee, and the Multicenter Diltiazem Postinfarction Research Group. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. Circulation 83: 52-60, 1991 Hansen JF. Calcium antagonists and myocardial infarction. Cardiovascular Drugs and Therapy 5: 665-670. 1991 Israeli SPRINT Study Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT). A randomized intervention trial of nifedipine in patients with acute myocardial infarction. European Heart Journal 9: 354-364, 1988
43
K10ner RA, Braunwald E. Effect of calcium antagonists on infarcting myocardium. American Journal of Cardiology 59: 84894B, 1987 Lahiri A, Rodrigues AE, Caboni PR, Raftery ER. Effect of longterm treatment with calcium antagonist on left ventricular diastolic function in stable angina and heart failure. Circulation 81 (Suppl. III): 111-130-111-138, 1990 Lichstein E, Hager WD, Gregory JJ, Heiss JL, Rolnitzky LM, et aI., the Multicenter Diltiazem Postinfarction Research Group. Relation between beta-adrenergic blocker use, various correlates of left ventricular function and the chance of developing congestive heart failure. Journal of the American College of Cardiology 16: 1327-1332, 1990 Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. New England Journal of Medicine 319: 385392, 1988 Nayler WG. Calcium antagonists and the ischemic myocardium. International Journal of Cardiology 15: 267-285, 1987 Nayler WG. Basic mechanisms involved in the protection of the ischaemic myocardium: the role of calcium antagonists. Drugs 42 (Suppl. 2): 21-27, 1991 Opie LH. Clinical use of calcium channel antagonist drugs, 2nd ed., K1uwer Academic Publishers, Boston, 1990 Opie LH. Calcium antagonists post infarction: the significance of experimental studies on potentially lethal early ischemic ventricular arrhythmias. Cardiovascular Drugs and Therapy 5: 671676, 1991 Packer M. Combined beta-adrenergic and calcium-entry blockade in angina pectoris. New England Journal of Medicine 320: 709718, 1989 Persson S. Calcium antagonists in secondary prevention after myocardial infarction. Drugs 42 (Suppl. 2): 54-60, 1991 Raffienbeul W, Ebner F. Myocardial infarction: secondary prevention with nifedipine. Drugs 42 (Suppl 2): 38-42, 1991 Richardt G, Haass M, SchOmig A. Calcium antagonists and cardiac noradrenaline release in ischemia. Journal of Molecular and Cellular Cardiology 23: 269-277, 1991 Serato JF, Zaret BL, Schulman DS, Black HR, Soufer R. Usefulness of verapamil on congestive heart failure associated with abnormal left ventricular filling and normal left ventricular systolic performance. American Journal of Cardiology 66: 981986, 1990 SPRINT Study Group. The secondary prevention re-infarction Israeli nifedipine trial (SPRINT II): design and methods, results. European Heart Journal 9 (Suppl. I): 350A, 1988 Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in mycoardial infarction or angina in light of the secondary Danish Verapamillnfitrction Trial (DAVIT II) and other recent studies. American Journal of Cardiology 67: 1295-1297, 1991 YusufS, Peto R, Lewis J, Collins R, Sleight P. Betablockade during and after myocardial infarction. An overview of the randomized trials. Progress in Cardiovascular Diseases 27: 335371, 1985 Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinical trials in heart disease. I. Treatment following myocardial infarction. Journal of the American Medical Association 260: 2088-2093, 1988
Correspondence and reprints: Dr Jergen Fischer Hansen. Department of Cardiology, Hvidovre Hospital. DK-2650 Hvidovre. Denmark.
Secondary Prevention with Calcium Antagonists after Acute Myocardial Infarction J I?J1'gen Fischer Hansen
Department of Cardiology, Hvidovre University Hospital, Hvidovre, Denmark
Summary
Experimental studies have demonstrated that the 3 calcium antagonists nifedipine, diltiazem, and verapamil have a comparable effect in the prevention of myocardial damage during ischaemia. Secondary prevention trials after acute myocardial infarction, which aimed at improving survival and preventing reinfarction, nevertheless demonstrated pronounced differences between the 3 drugs. Nifedipine had no effect on reinfarction or death. Diltiazem had no overall effect but prevented first reinfarction or cardiac death (cardiac events) in patients without heart failure, and increased cardiac events in patients with heart failure before randomisation. Verapamil prevented first reinfarction or death (major events); the most pronounced effect was found in patients without heart failure before randomisation. Verapamil did not have detrimental effects in patients treated for heart failure before randomisation. Differences between trials and between drugs explaining the different clinical findings are evaluated.
On the basis of experiments in isolated heart muscle preparations and in intact animals, calcium antagonists could be expected to reduce infarct size in myocardial infarction (Kloner & Braunwald 1987; Nayler 1991). Furthermore, during long term treatment calcium antagonists may be expected to prevent reinfarction and death, by prevention of myocardial ischaemia and protection of the myocardium during ischaemia (Nayler 1987). Although experimental studies demonstrate similar results with different calcium antagonists, results of clinical trials in patients after myocardial infarction (MI) show evident differences (Persson 1991). The purpose of this paper is to compare the results of 3 late secondary intervention trials - the Multicenter Diltiazem Postinfarction Trial (MDPIT) [Multicenter Diltiazem Postinfarction Trial Research Group 1988], The Secondary Prevention Reinfarction Israeli Nifedipine Trial
(SPRINT) [Israeli SPRINT Study Group 1988], and The Danish Verapamil Infarction Trial II (DAVIT II) [Danish Study Group on Verapamil in Myocardial Infarction 1990a] - and to determine whether differences in patient population and treatment other than trial medication might explain the divergent results of the 3 studies.
1. Comparison 0/ Trials 1.1 Protocols Tables I and II describe the inclusion criteria, study duration, eligible patients, end-points, trial medication, inclusion rate of eligible patients and exclusions. The inclusion rate is highest in SPRINT (56%) compared with DAVIT II (40%) and MDPIT (19%). This high inclusion rate in SPRINT might be explained by differences in criteria for diagnosis
Drugs 44 (Suppl. 1) 1992
34
Table I. Comparison of the 3 late secondary intervention trials with calcium antagonists in patients after acute myocardial infarction (AMI) MDPIT
DAVIT II
SPRINT
Chest discomfort. ECG changes and elevation of cardiac enzymes 25-75
Chest discomfort. ECG changes and elevation of cardiac enzymes .;; 75
2 of the 3 criteria as outlined in MDPIT and DAVIT II 30-74
3-15
7-15
7-21
12-52 25
12-18 16
6-12 10
Eligible patients Total a Included (%) Excluded (%)
13148 2466 (19) 10682 (81)
3991 1775 (40) 2216 (60)
4045 2276 (56) 1769 (44)
Medication Daily dose (mg)
Diltiazem 60 qid
Verapamil 120 tid
Nifedipine 10 tid
End-points
Death First reinfarction or cardiac death (cardiac event)
Death First reinfarction or death (major event)
Death First nonfatal reinfarction
Inclusion criteria Diagnosis of AMI
Patient age (years) Study period Start of treatment (days after AMI) Duration of treatment (months) Range Mean
a Death before randomisation omitted. Abbreviations: tid = 3 times daily; qid = 4 times daily; MDPIT = Multicenter Diltiazem Postinfarction Trial Research Group 1988; Danish Study Group on Verapamil in Myocardial Infarction 1990a; SPRINT Israeli SPRINT Study Group 1988. DAVIT II
=
of acute MI. In addition to chest pain and electrocardiographic changes compatible with acute MI, all patients in MDPIT and DAVIT II required a significant elevation of serum cardiac enzymes for inclusion. This was not necessary in SPRINT. Furthermore, patients with sinoatrial block, bradycardia, and second and third degree atrioventricular block were not excluded in SPRINT. Major differences between trials are related to the use of !3-blockers, which was a reason for exclusion in DAVIT II, but not in MDPIT and SPRINT. Treatment with a calcium antagonist was the reason for more than 30% of the exclusions in MDPIT compared with 15% in the other 2 trials. The SPRINT study group states that 'the major causes of exclusion were inability to cooperate or refusal to sign the consent form'. This group, which represents
=
41.7% of excluded patients, probably contains some of the patients placed in other exclusion groups in MDPIT and DAVIT II. 1.2 End-Points Results of the 3 trials are presented in figure I and tables III and IV. Mortality rates calculated in SPRINT according to Kaplan-Meier methods were 5.7% in the placebo group and 5.8% in the nifedipine group at 1 year (not statistically significant). In MDPIT mortality rates were 16% in both diltiazem- and placebo-treated patients (not statistically significant) after nearly 3 years of observation. Mortality rates after 1.5 years in DAVIT II were 13.8% in placebo recipients and 11.2% in verapamil-treated patients (not statistically significant).
Secondary Prevention with Calcium Antagonists
No difference in cardiac death was found between drug- and placebo-treated patients in SPRINT or MDPIT; in DAVIT II cardiac death rates were 12.3% in the placebo group and 9.9% in verapamil-treated patients (hazard ratio 0.79, 95% confidence limits 0.59 to 1.05; p = 0.10). Sudden death was not reported in MDPIT, and in SPRINT no difference was found between the 2 groups; in DAVIT II sudden death rates were 7.4% in placebo recipients and 5.6% in verapamil-treated patients (hazard ratio 0.74, 95% confidence limits 0.50 to 1.07; p = 0.10). Noncardiac causes of death were reported for 24% of 333 deaths in MDPIT, 18% of 130 deaths in SPRINT and in 11 % of 214 deaths in DAVIT II. These pronounced differences between the studies may be explained by the longer observation period in MDPIT and a difference in patient selection, e.g. significantly more patients were excluded as a result of other severe diseases in DAVIT II than in MDPIT (p < 0.001), and the cardiac mortality rates in the placebo groups after 12 months were 10% in DAVIT II, 4.6% in SPRINT, and
35
around 7% (i.e. three-quarters of the 9% total mortality) in MDPIT (table III). A first nonfatal reinfarction (table III) was recorded in SPRINT in 4.8% of patients in the placebo group and in 4.4% of nifedipine-treated patients (not statistically significant). In MDPIT 15% fewer nonfatal reinfarctions were recorded in the diltiazem-treated group than in the placebo group (not statistically significant). In DAVIT II all reinfarctions, fatal or nonfatal, were reported. The definition of nonfatal reinfarction is not stated in MDPIT or SPRINT. If a nonfatal reinfarction means that the patient is alive 21 days after the reinfarction, then first nonfatal reinfarctions were recorded in 76 placebo recipients and in 54 verapamil recipients in DAVIT II (hazard ratio 0.70, 95% confidence limits 0.50 to 0.99; p = 0.03) [table III]. Cardiac event is the other major end-point in MDPIT and is defined as first reinfarction or cardiac death. The cardiac event rate was reduced by 10% in diltiazem recipients compared with placebo recipients (not statistically significant) [table IV].
Tabla II. Reasons for exclusion from the 3 late secondary intervention trials with calcium antagonists in patients after acute myocardial infarction
No. of reasons for exclusion Reason for exclusion (%) Heart failure Pulmonary hypertension with right heart failure Cardiogenic shock/hypotension Sinoatrial block/bradycardia Second and third degree atrioventricular block Other severe diseases Nonconsensus Cardiac surgery Calcium antagonist treatment II-Blocker treatment Died before randomisation Other reasons
MDPIT
DAVIT II
SPRINT-
11152b
2881 c
1769b
0.4 2.6 0.4 1.7 5.3 25.2 10.2 31.4 0 4.2 8.8
} 10.9 2.6 2.7 6.2 9.7 13.5 0 15.5 15.1 17.0 12.8
+ + + + 41.7
+ 14.2 0
+
a Number of deaths before randomisation not reported. b 1 reason per patient. c More than 1 reason in 377 admissions. Abbreviations and symbol: MDPIT = Multicenter Diltiazem Postinfarction Trial Research Group 1988; DAVIT II = Danish Study Group on Verapamil in Myocardial Infarction 1990a; SPRINT = Israeli SPRINT Study Group 1988; + = reason for exclusion but number of patients not available.
Drugs 44 (Suppl. 1) 1992
36
FOllOw-up
NO. 01 patients
Placebo mortality (%)
Nifedipine Pooled short term
5632
1 day-6 weeks
SPRINT II
1358
6 months
SPRINT I
2276
1 year
6.2 13.3 5.7
Oiltiazem
685
4.1
2466
13.6
congestive heart failure 1909
5.3
Pooled short term
MDPIT ~No
Verapamil DAVIT I
1436
13.9
DAVIT II
1775
13.8
- No congestive heart failure 1161
11.8
o
0.5
1.0
1.5
2.0
Odds ratio
Mortality data from postinfarction studies with nifedipine, diltiazem and verapamil, given as odds ratios with 95% confidence intervals. Pooled data from the overview by Held et al. (1989). SPRINT II = SPRINT Study Group 1988; SPRINT I = Israeli SPRINT Study Group 1988; MDPIT = Multicenter Diltiazem Postinfarction Trial Research Group 1988; DA VIT I = Danish Study Group on Verapamil in Myocardial Infarction 1984; DAVIT II = Danish Study Group on Verapamil in Myocardial Infarction I 990a.
Fig. 1.
Cardiac event rates were calculated in order to compare the results of DAVIT II and MDPIT. A 20% reduction in the hazard ratio was found in the verapamil group compared with the placebo group (p = 0.03) [table IV). In MDPIT the hazard ratio of the cardiac event rate in diltiazem-treated patients without congestion on any chest x-ray obtained before randomisation was significantly reduced by 23% compared with placebo recipients. In the 20% of patients with congestion on chest x-ray, the cardiac event rate was significantly increased in diltiazem-treated patients. In DA VIT II cardiac events were significantly reduced by 29% in patients without heart failure who were treated with verapamil compared with placebo recipients (p = 0.01). In the 35% of patients
treated for heart failure before randomisation, no difference was found between the 2 groups of patients (table IV). Major event, defined as first reinfarction or death, was a preselected end-point in DAVIT II and corresponds with reinfarction-free survival (fig. 2). 18-month first major event rate was 21.6% in the placebo group and 18% in the verapamil group (hazard ratio 0.80, 95% confidence limits 0.64 to 0.99; p = 0.03). In patients without heart failure before randomisation, the 18-month first major event rates were 19.7% and 14.6%, respectively (hazard ratio 0.70, 95% confidence limits 0.52 to 0.93; p = 0.01); in patients with heart failure the values were 24.9% and 24.9% (hazard ratio 1.00, 95% confidence limits 0.72 to 1.39; p = 0.98) in the placebo and verapamil groups, respectively.
37
Secondary Prevention with Calcium Antagonists
Table III. Comparison of number of patients and events, and 12-month mortality rates from the 3 late secondary intervention trials with calcium antagonists in patients after acute myocardial infarction
DAVIT II
MDPIT
Patients Death
placebo
diltiazem
placebo
verapamil
placebo
nifedipine
1234
1232
897
878
1146
1130
167
166
119
95
65
65
107
84
76
54
55
50
63
46
28
23
107
84
53
53
12
12
6
6
First reinfarction First nonfatal reinfarction
116
99
Sudden death Cardiac death
SPRINT
127
124
Noncardiac death
43
38
12
11
First cardiac event
226
202
170
137
180
146
9
9
11
9
First major event 12-month mortality rate (%) Abbreviations: MDPIT
= Multicenter Diltiazem Postinfarction Trial Research Group 1988; DAVIT II = Danish Study Group on Verapamil
in Myocardial Infarction 1990a; SPRINT
= Israeli SPRINT Study Group 1988.
Table IV. Comparison of mortality and cardiac event rates in MDPIT and DAVIT II (intention-to-treat)
DAVIT II
MDPIT placebo
diltiazem
placebo
verapamil
Mortality
Mortality rate (%)8
16
16
Hazard ratio 95% confidence limits
14
11
1.02
0.80
(0.82-1.27)
(0.61-1.05)
Cardiac event All patients
First cardiac event rate (%)8
20
Hazard ratio 95% confidence limits
18
20
17
0.90
0.80
(0.74-1.08)
(0.64-0.99)
Patients without heart failure
No. of patients 12-month event rate (%)
959
950
574
11
8
16
Hazard ratio 95% confidence limits
587 9
0.77
0.71
(0.61-0.98)
(0.52-0.96)
Patients with heart failure
No. of patients 12-month event rate (%) Hazard ratio 95% confidence limit a
MDPIT: 33 months; DAVIT II: 18 months.
Abbreviations: MDPIT
248
242
323
18
26
21
291 19
1.41
0.97
(1.01-1.96)
(0.69-1.35)
= Multicenter Diltiazem Postinfarction Trial Research Group 1988; DAVIT II = Danish Study Group on Verapamil
in Myocardial Infarction 1990a.
Drugs 44 (Suppl. 1) 1992
38
49% in MDPIT and 47% in SPRINT, and significantly more patients had diabetes in SPRINT (19%) compared with DAVIT II (6%) and MDPIT (9%). No information is available regarding the number of patients with angina pectoris before admission to MDPIT, and the significantly higher prevalence of angina pectoris in SPRINT (34%) compared with DAVIT II (26%) is most probably explained by inclusion of patients with unstable angina in SPRINT. Mean age is about 2 years higher in DAVIT II than in the other 2 studies; this might partly explain the higher mortality rate in the placebo group of DAVIT II.
1.00
iii
.~
::>
III
~c
0.96 0.92
" 0.88
"-'-__
Verapamil " ......_-
.. _-....-..- .... -
~
0.84 J! c .a; a:
-.
0.80 0.76 0
180
360
540
Days
1.4 Findings at Randomisation
Fig. 2. Ratio of reinfarction-free survival to allocated treatment with verapamil (n =878) or placebo (n =897) in DAVIT II (hazard ratio 0.80; 95% confidence limits 0.64 to 0.99; p = 0.03) [From Danish Study Group on Verapamil in Myocardial Infarction I 990a).
1.3 History of Included Patients Analyses of available information (table V) demonstrated that significantly more patients were treated for systemic hypertension in MDPIT (38%) than in SPRINT (24%) and DAVIT II (14%). 62% of DA VIT II patients were smokers compared with
Table V. Comparison of history prior to admission in the after acute myocardial infarction
No. of patients Mean age (years ± SO) Female ("!o) Previous myocardial infarction ("!o) Systemic hypertension ("!o) Diabetes ("!o) Smokers ("!o) Angina pectoris ("!o)
3 late
There were pronounced differences between the 3 studies in medical treatment at randomisation (table VI). These differences may reflect different attitudes to the use of drugs in patients with acute MI. For example, 32% of patients in SPRINT were treated with antiarrhythmic drugs compared with 9% in MDPIT and 2% in DAVIT II, and only 8% were treated with nitrates other than nitroglycerin in DAVIT II compared with 43% in SPRINT and 60% in MDPIT. The fact that more patients were treated with diuretics in DAVIT II (40%) compared with MDPIT (23%) and SPRINT (25%) may
secondary intervention trials with calcium antagonists in patients
MDPIT
DAVIT II
SPRINT
2466 58 ± 10 20
1775 60 ± 9 20 17 14* 6 62* 26·
21498 58 ± 9
21* 38t 9t 49t
17 24 19 47
34
a Information on 127 patients missing. Abbreviations and symbols: MDPIT = Multicenter Diltiazem Postinfarction Trial Research Group 1988; DAVIT II = Danish Study Group on Verapamil in Myocardial Infarction 1990a; SPRINT = Israeli SPRINT Study Group 1988; t = statistically different compared with DAVIT II and SPRINT (p < 0.001);:1: = statistically different compared with DAVIT II and SPRINT (p < 0.01); • statistically different compared with SPRINT (p < 0:001).
=
39
Secondary Prevention with Calcium Antagonists
Table VI. Comparison of medical status at randomisation in the 3 late secondary intervention trials with calcium antagonists in patients after acute myocardial infarction MDPIT (n = 2466) Medication (%) /3-Blockers Diuretics Digoxin Antiarrhythmics Nitrates (other than sublingual)
55 23 14
9 60
Clinical findings (mean value) Heart rate (beats/min) SBP (mm Hg) DBP (mm Hg) Infarct type location (%) Anterolateral a-wave Inferoposterior a-wave Non-a-wave Other 24-Hour electrocardiographic monitoring No. of patients Mean heart rate (beats/min) ~ 10 ventricular ectopic beats/hour ("!o) ~ 3 ventricular ectopic beats in a row ("!o)
DAVIT II (n = 1755)
SPRINT (n = 2149)8
0 40 12 2 8
18 25 10 32 43
75 120 76
78 137 85
31 39 26 4
37 36 17 10
1677 72 17 10
247 79 17 11
a Information on 127 patients missing. Abbreviations: MDPIT = Multicenter Diltiazem Postinfarction Trial Research Group 1988; DAVIT II = Danish Study Group on Verapamil in Myocardial Infarction 1990a; SPRINT = Israeli SPRINT Study Group 1988; SBP = systolic blood pressure; DBP = diastolic blood pressure.
reflect different patient selection (e.g. exclusion of patients with heart failure in MDPIT and exclusion of patients with unstable angina in SPRINT). Secondary prevention is considered an indication for ~-blocker treatment in the United States. Thi,s is reflected in the large number (55%) of patients in the MDPIT study treated with ~-block ers. The indications for ~-blockers in the SPRINT trial (18%) were not stated. In Denmark during the study period for DAVIT II, ~-blockers were indicated for hypertension, angina pectoris and arrhythmias. Patients in need of ~-blockers were excluded from DAVIT II. Systolic and diastolic blood pressures were significantly higher in patients included in SPRINT compared with DAVIT II. Blood pressure information is not available for MDPIT. Subgroups in
MDPIT (Bigger et al. 1990) and DAVIT II (data on file, DAVIT II Study Group) underwent 24-hour electrocardiographic monitoring. Mean heart rate was 72 beats/min in MDPIT and 79 beats/min in DAVIT II. This difference may be due to ~-blocker treatment in MDPIT. The prevalence of more than 10 ventricular ectopic beats/hour or 3 or more ventricular ectopic beats in a row was the same in the 2 studies (table VI).
2. Discussion 2.1 Differences between Trials Analyses of the 3 late secondary prevention trials with the 3 prototypes of calcium antagonists demonstrate major differences in inclusion rate and cri-
40
teria, exclusion criteria, concomitant treatment and previous history. These differences between included patients are probably reflected in the different event rates in the placebo groups of the 3 studies, such as the 12-month mortality rates of6% in SPRINT, 9% in MDPIT, and 11% in DAVIT II. The consequences of these differences with regard to evaluation of the overall effect of calcium antagonist treatment after acute MI are difficult to determine but support the view recently expressed by Persson (1991) that 'the use of pooled data from the calcium antagonist studies regarding secondary prevention after MI is not reliable'. Nifedipine has been tested in a large number of trials with intervention starting both early and late after an acute MI (see review by Raffienbeul & Ebner 1991). Nifedipine had no overall effect on mortality (fig. 1) or reinfarction rate in either early or late intervention trials (Yusuf et al. 1991). Studies with diltiazem also demonstrate no overall effect on mortality (fig. 1) or reinfarction, although the early intervention non-Q-wave diltiazem study (Gibson et al. 1986) demonstrated a 50% reduction in reinfarction rate (p = 0.03, 1sided) in diltiazem-treated patients compared with placebo recipients. These findings were further supported by analyses of a subset of 634 patients with non-Q-wave infarction in MDPIT demonstrating a 12-month cardiac event rate of 9% with diltiazem compared with 15% in the placebo recipients (hazard ratio 0.65, 95% confidence limits 0.43 to 0.96) [Gibson 1991]. Whether this effect of diltiazem is related to non-Q-wave infarctions is debatable. Recently, Boden et al. (1991) analysed infarct type and location and found that an effect of diltiazem was demonstrated in inferoposterior Q-wave and in non-Q-wave infarctions. When this is combined with the information that diltiazem prevented cardiac events in patients without heart failure, it looks more probable that diltiazem might be effective in patients with small infarcts. The overall lack of effect of diltiazem on mortality and cardiac events is puzzling. One possible explanation is that a large number of patients were already receiving treatment with j3-blockers (55% in MDPIT and 62% in the non-Q-wave infarction
Drugs 44 (Suppl. 1) 1992
study) and with vasodilators (60% in MDPIT). Thus, no further effect may be obtained by adding diltiazem (Packer 1989). The increased event rate in patients with heart failure treated with diltiazem in MDPIT might be explained by the addition of a negative inotropic agent to patients already treated with j3-blockers and/or the addition of a vasodilator and negative inotropic agent to patients already receiving vasodilator therapy. From a theoretical point of view, it is very likely that diltiazem has an effect on mortality and reinfarction after acute MI, at least in patients with good left ventricular function (Multicenter Diltiazem Postinfarction Trial Research Group 1988). Further studies are needed to evaluate the effect of diltiazem without concomitant j3-blocker and vasodilator therapy. DAVIT II differs from MDPIT in several aspects. In DAVIT II no patient received treatment with j3-blockers, and only a minority (8 vs 60%) with vasodilators. Probably more patients had clinical heart failure before randomisation (40 vs 20%). These differences might explain the fact that verapamil improved reinfarction-free survival, and that no harmful effect was demonstrated in patients with heart failure. The decision to perform DAVIT II was, to a large extent, based on a retrospective analysis of DAVIT I (Danish Study Group on Verapamil in Myocardial Infarction 1984), which demonstrated a statistically significant reduction in mortality for patients alive 22 days after admission in the verapamil group (6.4%) compared with the placebo group (3.7%) [p < 0.05], and a statistically significant reduction in reinfarctions in patients alive on day 15 (3.9% vs 7.0%, respectively) [p < 0.03]. In DAVIT I treatment commenced at admission and was continued for 6 months. On the eighth day, 671 patients who received verapamil and 679 placebo-treated patients were alive. When the results of the 2 DAVIT studies were combined using the method advocated by Yusufet al. (1985) [fig. 3] which included patients alive 8 days after starting treatment from DAVIT I and all patients from DAVIT II, the pooled odds ratio of DAVIT I and II for mortality was 0.78 (95% confidence limits 0.63 to 0.99; p = 0.04) and that for first rein-
Secondary Prevention with Calcium Antagonists
41
Results from an overview of trials with under 50 deaths (10 trials)
I I I I I
I
Individual late-entry trials with over 50 deaths (10 trials)
I I I
I
----+-~--I
r---- -------~---------------
I
I I
Late mortality in early-entry trials (3 trials)
I
I
I I
I I
• I
All trials
..
"iii
:s
I I I
DAVIT II [
I
DAVIT I late mortality
I I
Both DAVIT trials
o
0.2
• 0.4
~
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Odds ratio (active: control)
Fig. 3. Mortality data from postinfarction studies with fj-blockers and verapamil given as odds ratios with 95 or 99% confidence limits. Late mortality in early entry trials is based on all deaths in patients alive on day 8 after randomisation. Solid lines represent confidence limits for trials that ran to the scheduled finish; dotted lines represent 99% confidence limits for trials stopped early because of observed trend;-= 95% confidence limits from an overview of all fj-blocker trials; DAVIT I = Danish Study Group on Verapamil in Myocardial Infarction 1984; DAVIT II = Danish Study Group on Verapamil in Myocardial Infarction 1990a (after Yusuf et al. 1985).
farction was 0.73 (95% confidence limits 0.57 to 0.94; p = 0.02) [Danish Study Group on Verapamil in Myocardial Infarction 1990b]. These analyses support the theory that verapamil is effective in preventing death and reinfarction as a secondary preventive agent. Furthermore, the overall effect corresponds to the effect demonstrated for {:I-blockers (Yusuf et al. 1988). 2.2 Differences between Drugs The different results of treatment with nifedipine, verapamil, and diltiazem in secondary prevention trials, as outlined in tables III and IV, may
also be explained by the different pharmacological effects of the drugs (Opie 1990). It may be of importance that verapamil and diltiazem have a negative chronotropic effect, while nifedipine often increases heart rate. All 3 drugs have negative inotropic and vasodilator properties but the balance between these 2 effects is different. The ratio, evaluated from portal vein and papillary muscle, of vascular inhibition: the negative inotropic effect has been estimated at 1.4 for verapamil, 7 for diltiazem, and 14 for nifedipine (Opie 1990). The pronounced vasodilator effect of nifedipine explains the description of the paradox of angina and ar-
Drugs 44 (Suppl. 1) 1992
42
terial hypotension in nifedipine-treated patients. In post-MI patients this may cause a deterioration of blood supply to the myocardium by a reduction in perfusion pressure and diastolic perfusion time. The effects are of special importance in patients with severe coronary artery stenosis or occluded coronary arteries and collateral vessels. Attenuation of the blood flow may result in ischaemic heart failure due to myocardial stunning, myocardial necrosis due to hypoperfusion, and ventricular arrhythmias due to ischaemia (Opie 1991). The vasodilator effect of verapamil is pronounced enough to prevent vasospastic angina (Beller 1989) but seldom causes hypotension (Danish Study Group on Verapamil in Myocardial Infarction 1990a). Verapamil improves left ventricular diastolic function in patients with coronary artery disease (Betocchi et al. 1990; Serato et al. 1990), an effect found to a lesser extent or not at all with nifedipine (Lahiri et al. 1990). The negative inotropic and vasodilator properties of diltiazem seem to be between that of nifedipine and verapamil. Recently, Richardt et al. (1991) demonstrated that verapamil and nifedipine inhibited the release of norepinephrine (noradrenaline) in isolated rat hearts during ischaemia, an effect that was absent or demonstrated to a lesser degree with diltiazem. This finding may be of interest because it may explain why verapamil prevented sudden death (Hansen 1991) and reduced overall mortality (Danish Study Group on Verapamil in Myocardial Infarction 1990b) while diltiazem had no effect in MDPIT. The finding of Richardt and colleagues (1991) may also add to our understanding of the surprising finding of MDPIT that heart failure increased in patients with reduced ejection fraction « 40%) treated with diltiazem compared with those administered placebo (Goldstein et al. 1991). In this group of patients with impaired left ventricular systolic function, the cardiac event rate was significantly increased in diltiazem-treated patients compared with placebo recipients. It has been agreed that 'diltiazem may enhance neuroendocrine activation in these patients thereby accelerating left ventricular decompensation and augmenting the likelihood of lethal arrhythmias'
(Goldstein et al. 1991). Although systemic neuroendocrine activation by nifedipine has been demonstrated in normal and hypertensive patients (Opie 1990), it remains speculative whether this is of importance in patients with heart failure (Packer 1989). Further differences exist between calcium antagonists, as verapamil does not increase plasma catecholamine levels in patients with hypertension (Opie 1990). From the clinical point of view, it is of importance that verapamil, contrary to diltiazem, did not increase the cardiac event rate in patients treated for heart failure before randomisation. It is also remarkable that after 12 months significantly fewer patients in the verapamil group (27.3%) compared with the placebo group (34.3%) received treatment with diuretics (p < 0.05). Of patients treated with diuretics at randomisation, 31.2% of those who received verapamil and 17.9% of placebo recipients terminated treatment with diuretics within 12 months. Thus, the deleterious effect in heart failure patients described for diltiazem was not found with verapamil.
3. Conclusion Although laboratory studies have demonstrated a comparable effect of calcium antagonists on ischaemic myocardium, important clinical differences exist between the 3 types of calcium antagonists. Treatment with nifedipine has been demonstrated to have no or a deleterious effect, diltiazem to have no overall effect, and verapamil to have a beneficial effect on reinfarction-free survival after acute MI. The beneficial effect of verapamil is primarily found in patients with good left ventricular function. The consequences of this demonstrated effect of verapamil may be 2-fold. Firstly, verapamil can be used for secondary prevention in patients with contraindications to (jblocker treatment, including those with pulmonary diseases, and those with side effects attributed to (j-blockers (Yusuf et al. 1991). Secondly, when comparing the effect of verapamil with that of (jblockers in secondary prevention, the major effect of (j-blockers is found in patients with impaired left
Secondary Prevention with Calcium Antagonists
ventricular function (Boissel et al. 1991; Goldstein et a1. 1991; Lichstein et a1. 1990) and that of verapamil in patients with normal left ventricular function. Thus, in patients without heart failure during the acute event, verapamil may be used as the first drug of choice, and in patients with heart failure, a (j-blocker may be used as the first drug of choice.
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Correspondence and reprints: Dr Jergen Fischer Hansen. Department of Cardiology, Hvidovre Hospital. DK-2650 Hvidovre. Denmark.
