Verapamil in Acute Myocardial Infarction

DANISH MULTICENTER STUDY GROUP ON VERAPAMIL IN MYOCARDIAL INFARCTION

A double-blind study comparing verapamil with placebo was conducted in 16 Danish departments of internal medicine with coronary care units (CCUs). All patients younger than 75 years admitted to the CCU with suspected acute myocardial in- farction (AMI) were evaluated for inclusion. Of 7,415 patients, 3,917 were excluded on admission be- cause of heart failure, heart block, oth~ severely disabling diseases or treatment with /./-blocking drugs or calcium antagonists. Treatment was started in 3,498 patients with 0.1 mg/kg of verapamil in- travenously and 120 mg perorally on admission followed by 120 mg 3 times daily, or matched pla- cebo. Treatment was continued for 6 months in

patients verified to have had AMI according to all 3 World Health Organization (WHO) criteria. Treat- ment was stopped in patients in whom AMI was ruled out. Of 1,436 patients with AMI, 717 were treated with verapamil and 719 with placebo.

After 6 months, 92 patients (12 .8%) in the verapamil group and 100 (13 .9%) in the placebo group had died. Fifty patients (7 %) in the verapamil group and 60 (8 .3%) in the placebo group had had reinfarction. After 12 months, 109 patients (15.2 % ) in the verapamil group and 118 patients (16 .4%) in the placebo group had died.

(Am J Cardiol 1984;54:24E-28E)

Investigations over the last 15 years demons t ra ted tha t the calcium antagonists protect ischemic myocardium. T h e protect ion is demons t r a t ed by preservat ion of mechanical function, t issue stores of A T P and mito- chondrial function. Calcium antagonists reduce infarct size in exper imenta l coronary occlusion evalua ted by pa thoana tomic , e lect rocardiographic and enzymat ic studies. Coronary vasoconstr ic t ion or vasospasm has been considered a cause in the deve lopmen t of acute myocard ia l infarct ion (AMI). Calcium antagonis ts are effective coronary vasodi la tors and effective in the t r ea tmen t of vasospastic angina. Fur thermore , calcium antagonists prevent reperfusion arrhythmia. These were the major reasons for the decision to under t ake a dou- ble-blind, randomized, placebo-controlled s tudy of the use of verapami l in AMI.

The p r i m a ry objectives of the Danish s tudy were to determine whether regular administrat ion of verapamil to patients with AMI from the t ime of suspicion through the following 6 months would reduce the morta l i ty rate f rom any cause and the reinfarct ion rate. T h e basis for the s tudy and a detai led descr ipt ion were recent ly de- scribed. 1-3

Address for reprints: J. Fischer Hansen, MD, Medical department 2, Kommune hospitalet, DK-1399 Copenhagen K, Denmark.

Methods

In this study patients were considered to have had AMI if they fulfilled all 3 World Health Organization criteria: a typical history, electrocardiographic findings compatible with penetrating or nonpenetrating AMI and an increase in serum enzyme levels to at least 50% above the upper normal limit.

The design of the study is shown in Figure 1. At each step of the study, information was recorded on special files, cards 1 to 5. Patients were evaluated for treatment immediately after admission to the coronary care unit (CCU).

Reasons for exclusion on admission are listed in Table I. If no exclusion criteria were present, treatment was started immediately after admission. If the diagnosis was verified by changes in the electrocardiogram (ECG) and serum enzyme levels, treatment was continued 6 months. If diagnostic cri- teria were not fulfilled, treatment was stopped as soon as the diagnosis was ruled out. Patients still receiving treatment were seen in the outpatient clinic once a month. If treatment was discontinued before the scheduled time, patients were nor- mally examined after 6 months. If a patient was readmitted with suspicion of AMI, the patient was reconsidered for ran- domization and treatment was started again, unless the pa- tient previously had been included in the study because of AMI. If reinfarction was diagnosed in the study period, treatment was continued unless contraindications existed.

Sixteen Danish medical departments with CCUs and a catchment population of about 1 million, corresponding to a fifth of the Danish population, participated in the study. Randomization was performed for each center.

24E

December 21, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54 25E

TABLE I Reasons for Exclusion on Admission in 3,917 Patients

Reason n

Arterial blood pressure 192 <90 mm Hg

Shock 64 Pulmonary edema 217 Pulmonary stasis 704 Heart arrest 249 PQ >0.3 second 36 2 ° and 3 ° AV block 171 Sinoatrial block (including heart 101

rate <45 beats/min) QRS >_0.12 second 264 /3-blocker treatment 984 Calcium-anatagonist treatment 452 Postoperative AMI 28 Valvular heart disease 68 Ventricular tachycardia 47 Other severe invalidating diseases 311 Residence outside the catchment area 198 Previous inclusion in the study 34 Unwillingness to participate 59 Administrative failure 103

AMI = acute myocardial infarction; AV = atrioventricular.

Just after admission to the CCU, patients received 0.1 mg/kg body weight of verapamil intravenously and 120 mg of verapamil orally followed by 120 mg 3 times daily for 6 months, or equivalent placebo.

The study is based on the assumption that the mortality rate of 15% in the placebo group could be reduced to about 9% in the verapamil group. With an ~ of 5% and/3 of 90%, detec- tion of such a difference demands slightly more than 1,400 patients.

The study was begun in June 1979 and recruitment stepped on August 15, 1981, when 1,436 patients with AMI were in- cluded. The last patient stopped treatment in February 1982. One-year survival follow-up based on the Danish central person register was obtained on August 25, 1982.

Results

The total number of patients admitted to the CCU, the number of patients excluded, the number in whom

~ r i v a l to ccu • ulpacted for ~ I

(a l l patlentsl

I . . . . . . . . . . . . . . . . [ I . . . . . . . . . . . . . . . . I

(a l l pat tent l l

Ipat lent l with AMll

~ Cont¢ol, card 4 Ipat lent l w i t h ANI)

¢eXlllnatlon, card 5 (patient| with ~qI)

FIGURE 1. Design of the Danish multicantar study on v~'ap~nll in acute myocardial infarction (AMI). CCU = coronary care unit.

TABLE II Characteristics of 1,436 Patients with Acute Myocardial Infarction (AMI) Before Randomization

Verapamil Placebo

n % n %

Sex Male 565 79 585 81 Female 152 21 134 19

Age (yr) <65 425 59 426 59 >65 292 41 293 41

Previous history AMI 106 15 98 14 Arterial hypertension 72 10 62 9 Angina pectoris 198 28 198 28 Heart failure 34 5 29 4 Diabetes 43 6 49 7 Smoker 423 59 439 61

Location and type of AMI Pentrating total 534 74 548 76

Anterior 255 36 262 36 Inferior 191 27 210 29 Posterior 88 12 76 11

NonpenetraUng total 174 24 162 23 Anterior 109 15 96 13 Inferior 46 6 45 6 Posterior 19 3 21 3

Not determined 9 1 9 1 Duration of symptoms at

treatment start (h) <6 422 58 406 56 7-24 180 25 205 29 >24 107 15 103 14 Not determined 8 1 5 1

Total no. of pts 717 100 719 100

treatment was started and the number finally included are shown in Figure 2. Reasons for exclusion are listed in Table I. The inclusion rate corresponded to 2 patients per day (Fig. 3). Patients in the 2 treatment groups were well matched for sex, age and risk factors on admission, duration of symptoms and type and location of AMI (Table II).

Treatment was stopped for any reason including death before the sixth month in 341 patients in the verapamil group and 295 patients in the placebo group. Of the patients alive after 6 months, 60% in the vera-

Number of patients admitted to CCU

n = 7415

n = 1882 n = 2035 n = 1436 n = 2063

I I n = 968 n = 468

FIGURE 2. Number of patients in the Danish multicenter study treated with verapamil in acute myocardial infarction (AMI). CCU = coronary care unit,

2@E SYMPOSIUM ON EARLY INTERVENTION IN ACUTE MYOCARDIAL INFARCTION

TABLE III Reasons and Time for DlsconUnuation of Study Medications

Verapamil Placebo Discontinuation of

Treatment n % n %

Reasons Death 38 5 49 7 2 ° and 3 ° AV block" 117 16 54 8 Heart failure 55 8 43 6 Sinoatrial block1" 28 4 13 2 Angina pectoris1. 18 3 35 5 Arrhythmias demanding treatment 17 2 29 4

with ~-blocker or verapamil

Unwillingness to continue 54 8 59 8 Other 14 2 13 2

Gastrointestinal complaints (10) (6) Cancer (2) (2) Arterial emboli (2) (5)

Times Week 1" 197 27 144 20 Week 1, day 31. 126 18 97 13 Week 4, day 7" 71 12 47 8 Week 8, day 14 52 10 41 7 Week 8, day >14 92 20 110 20 6 months 1 376 52 424 59

Total no. of pts 717 719

p <0.01 } difference between groups is statistically significant. P <0.05 % = ratio of % of patients who stopped treatment to % of patients

receiving treatment at start of the period. AV = atrioventricular.

pamil group and 69% in the placebo group were still undergoing treatment (p <0.01). Major causes of treatment discontinuation were atrioventricular (AV) block, sinoatrial block, heart failure and angina pectoris (Table III). Within the first week, 27% of the patients in the verapamil group and 20% of those in the placebo group stopped treatment.

The mortality rate after 6 months was 12.8% in the verapamil group and 13.9% in the placebo group; after 12 months it was 15.2% in the verapamil group and 16.4% in the placebo group (difference was not signifi- cant [NS]) (Fig. 4). The mortality rate during the first weeks was highest in the verapamil group; in the last part of the study period the mortality rate was highest in the placebo group (Table IV). Reinfarction was re- corded the first 6 months after the start of treatment.

N~ber of patients

150o

iooo

500

p I ) z/6 ~)z 1/6 z~z 15/8

1979 1980 198o 1981 198]

FIGURE 3. Inclusion rate in the Danish multicenter study on verapamil in acute myocardial infarction (AMI). CCU = coronary care unit.

A first reinfarction was diagnosed in 50 patients in the verapamil group and in 60 patients in the placebo group (NS). Furthermore, a second reinfarction was diagnosed in 6 patients in both groups. The number of reinfarc- tions is slightly higher in the verapamil than in the placebo group for the first week (Table IV).

Complications: Most instances of AV block (Table III) were of short duration and disappeared within 24 hours. In the first week, second- and third-degree AV block developed in 103 patients in the verapamil group and in 47 in the placebo group. Eighteen patients in the verapamil group and 14 in the placebo group died. Thus, AV block in the verapamil group was not associated with a higher mortality rate.

Heart failure necessitating treatment was found significantly more often in the verapamil group (n = 187, 26.1%) than in the placebo group (n = 142, 19.5%) (P <0.01). A blind evaluation of the cause of death based on patient records, autopsy findings and death certifi- cates was performed. In the verapamil group 58% of the deaths among the 66 patients who died during the stay in the hospital were classified as caused by heart failure or shock. In the placebo group 36% of the 64 deaths during the stay in the department were classified as caused by heart failure or shock (p <0.03) (Table V).

Subgroup analyses: Analyses of mortality in relation to sex, history (including AMI, angina pectoris, heart failure, diabetes and hypertension) and infarct type and location did not demonstrate significant differences between the verapamil- and the placebo-treated groups.

Age: Mortality after 6 months was significantly lower (p <0.05) in verapamil-treated patients older than 65 years than in the placebo-treated patients in this age group. In the verapamil group, 14.7% (43 of 292 patients) compared with 21.8% (64 of 293 patients) in the placebo group died. This difference between groups was not seen in patients younger than 65 years of age.

6 ,"ONTHS ) ~

• TREATMENT STOPPED WITHIN SIX MONTHS (180 DAYS) AFTER START

ANn AT LEAST 2q HOURS BEFORE DEATH.

" ° FOR INFORMATION OqN ALL PATIENTS AT ADMISSION: SEE TABLE 1.

FIGURE 4, Number of patients alive and dead after 6 and 12 months in the 2 treatment groups.

December 21, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54 27E

TABLE IV T ime to Death, Number of Deaths and RelnfarcUons, Death Rate and RelnfarcUon Rate In Pat ients at Risk at Start of the Period

Patients at Risk Deaths Reinfarctions

Verapamil Placebo Verapamil Placebo Verapamil Placebo

Period n n n % n % n % n %

Week1 717 719 46 6.4 40 5.6 23 3.2 15 2.1 Week 2 671 679 12 1.8 14 2.1 7 1.0 6 0.9 Week 3 659 665 10 1.5 4 0.6 0 0 5 0.8 22-180days 649 661 24 3.7 42 6.4 26 3.9 40 6.1 181-360 days 625 619 17 2.6 18 2.9 . . . .

Total 717 719 109 15.2 118 16.4 56 7.8 66 9.2

TABLE V Clinical Cause of Death In Patients Who Died Within the FIrM 6 Months after Start of Treatment

Verapamil Placebo

During Stay After During Stay After Clinical Findings in Dept. Discharge in Dept. Discharge

Sudden death* 23 12 31 12 Death between 1 and 24 hours after - - 1 - - 2

start of new symptoms Relnfarction - - 2 1 5 Cardiogenlc shock or pulmonary 38 4 23 13

edema, or both Cerebral thrombosis 2 - - 2 2 Found dead 3 2 5 0 Unknown or noncardiac cause 0 5 2 2

Total 66 26 64 36

• Collapse, death within 1 hour after start of new symptoms or in relation to new arrhythmias, or both.

Duration o[ symptoms: In patients with symptoms for up to 6 hours, the mortality rate was 13.5% in the verapamil group (57 of 422 patients), compared with 12.6% in the placebo group (51 of 406 patients) (NS). In patients with symptoms between 6 and 24 hours in duration, mortality was significantly lower (p <0.05) in the verapamil group, 9.4% (17 of 180 patients) versus 17.1% (35 of 205 patients) in the placebo group.

Time of death: After 3 weeks 649 patients in the verapamil group and 660 in the placebo group were still alive. The number of deaths from day 22 to day 180 was 24 (3.7%) in the verapamil group and 42 (6.4%) in the placebo group (p <0.05) (Table IV).

Time of reinfarction: The number of patients alive after 2 weeks was 659 in the verapamil group and 665 in the placebo group. The number of reinfarctions from day 15 to day 180 was 26 (3.9%) in the verapamil group and 45 (6.8%) in the placebo group (p <0.05) (Table IV).

Discussion

The Danish multicenter trial of verapamil in AMI is the first study in which a calcium antagonist was ad- ministered with the objective of reducing the mortality and reinfarction rates. No late-intervention study using a calcium antagonist has been performed. The findings reported herein, that is, reduced mortality and rein- farction rates of about 10%, do not support the hy- pothesis that the beneficial effect of early intervention is so great that treatment with verapamil should be started in the acute phase of infarction.

The study demonstrates slightly increased mortality and reinfarction rates during the first weeks (Table IV). The number of deaths in patients with AV block was 18 in the verapamil group and 14 in the placebo group. Thus, although the incidence of AV block was more than double in the verapamil group, AV block does not explain the slightly higher mortality rate during the first weeks in the verapamil group.

Patients with the most severe degree of heart failure were excluded on admission (Table I). Nevertheless, heart failure developed in a significantly higher number of patients in the verapamil group and they were clas- sifted as dying from heart failure (Table V). The nega- tive inotropic effect of verapamil 4 may explain the unexpected finding of a higher mortality rate in the verapamil group in the early phase of the study.

Contrary to our expectations, the mortality rate was not reduced by very early intervention. In this regard, Wood et al,5 in their study of arteriographic findings in patients with transmural AMI, found total occlusion in 86.5% of patients with a duration of symptoms of up to 6 hours and in 66.5% of patients with symptom dura- tion of 7 to 24 hours (p <0.001). The reduced mortality rate in the verapamil-treated patients with a dura- tion of symptoms between 6 and 24 hours may be re- lated to a lower proportion of total coronary artery occlusions.

Very early intervention in patients with AMI, that is, within 9 hours after start of symptoms, using nitro- prusside demonstrated a significantly increased mor- tality rate after 3 months compared with that in the

28E SYMPOSIUM ON EARLY INTERVENTION IN ACUTE MYOCARDIAL INFARCTION

matched placebo group. Treatment with nitroprusside 9 to 24 hours after the start of symptoms improved survival compared with that of the placebo group, s These findings agree with ours using verapamil.

S o far, no study has convincingly demonstrated a beneficial effect on survival by early intervention in AMI. 7

Retrospective analyses demonstrated significantly lower mortality and reinfarction rates after 6 months in the verapamil group compared with the placebo group in patients alive 2 to 3 weeks after the start of symptoms (Table V). This finding supports the hy- pothesis that treatment with verapamil after the acute phase of infarction may improve survival and reduce the reinfarction rate.

References

1. Hansen JF, Slgurd B, Mellemgaard K, Lyngby I. Verapamil in acute myo- cardial infarction. Dan Med Bull 1980;27:105-109.

2. Danish Multicenb'e Study Group. Verapamil in myocardial infarction. Clin Exp Pharmacol Physiol 1982;suppl 6:89-96.

3. Danish Multicentre Study Group. Verapamil in acute myocardial infarction. Eur Heart J 1984;5:516-528.

4. Chew CYC, Hecht HS, Collett JT, McAIIIster RG, Slngh BN. Influence of severity of ventricular dysfunction on hemodynamic responses to intrave- nously administered verapamil in ischemic heart disease. Am J Cardiol 1981;47:917-922.

5. deWood MA, Spores J, Nolske R, Mouser LT, Burroughs R, Golden MS, Lang HT. Prevalence of total coronary occlusion during early hours of transmural myocardial infarction. N Engl J Med 1980;303:897-902.

6. Cohn JN, Franclosa JA, Francis GS, Archibald D, Trlslanl F, Fletcher R, Montero A, Clntron G, Clarke J, Hager D, Saunders R, Cobb F, Smith R, Loeb H, Settle H. Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure. N Engl J Med 1982;306:1129-1135.

7. May GS, Furberg CK, Eberleln KA, Geracl BJ. Secondary prevention after myocardial infarction: a review of short-term acute phase trials. Prog Car- diovasc Dis 1963;25:335-359.