- Email: [email protected]
Secondary prevention with verapamil after myocardial infarction
Secondary Prevention with Verapamil After Myocardial Infarction The Danish Study Group on Verapamil in Myocardial Infarction*
The effect of verapamil on death and major events (i.e., death or reinfarction) after an acute myocardial infarction was studied in a double-blind, randommdtkenter trial, the Dani=hm-, ish Verapamil IdamUon Trial II (DAVIT II). Eight hundred seventy-eight pathts started tmatmed with verapamU 360 mg/day and 897 patknts with placeho. Treatment eonunued for up to 18 months (mean 16 months). Ninety-five deaths and 149 major events occurred in the verapamil grojdp and 119 deathsad19Omajoreventsintheplacebogroup. Eighteen-month mortalityrates wereli.land 13*% (hazard ratio 0.90,95% codWnce limits 0.63 to 1.03, p = 0.109), and major event rates 18.0 and 21.6% (0.80,0.64 to 0.99,p =O.O27)in the verapamil and placeho groups respecuvely. Whencombiningtheresuttsofthistrialwiththeresuits of the fh-st Danish study on verapamil in myocardal infarction, the meta-analyds demonsbated that tmatment with verapamil from the second week after an acute myocardial infarction resulted inaraductlonofpooledoddsratiosof022(9S% conhhce interval 0.01 to 0.37, p = 0.04) for death, Oal(O.03 to 0.35, p = 0.02) for major events, and 0.27 (0.06 to 0.43, p = 0.02) far first rehbfarctlons. It is cendded that brig-term treatment with verapamU after an acute myocardial infarction is assodated with a significant reduction in overall modality as well as major event and reinfarction rates. (AmJCadii 1990;66:331401)
erapamil has been proved in in vitro and in vivo studies to reduce ischemic injury and infarct size.1-4Basedon this evidenceand a pilot study,5 the Danish Study Group on Verapamil in Myocardial Infarction conducted an early intervention, randomized, double-blind, placebo-controlled trial, the Danish Verapamil Infarction Trial I (DAVIT I), with the purposeof examining whether administration of verapamil 120 mg t.i.d. from the time of admissionand over the following 6 months might decrease total death and reinfarction rates.4,6DAVIT I included 7 17 patients in the verapamil group and 719 patients in the placebo group. After 6 months, nonsignificant differences in mortality rates, 12.8%in verapamil versus 13.8%in placebo-treatedpatients, and in reinfarction rates, 7% versus 8.3% respectively, were found. A retrospective analysis of the data from DAVIT I demonstrateda lower mortality rate between day 22 and day 180 in the verapamil group, 3.7% comparedwith 6.4%in the placebogroup (p = 0.05). The reinfarction rate from day 15 to day 180 was 3.9%in the verapamil group compared with 7.0% in the placebo group (p = 0.03).4*6,7Furthermore, the analysis demonstrated that verapamil in patients with a history of angina pectoris reduced the number of patients who developed acute myocardial infarction 39.4%,comparedwith 46.7% of placebo-treatedpatients (p = O-05).* Among other findings, these were the major reasons for the decision to conduct a late intervention study, the Danish Verapamil Infarction Trial II (DAVIT II), to examinewhether treatment with verapamil from the second week after an acute myocardial infarction and continued for 12 to 18 months might reduce total mortality and major events,i.e., death and reinfarction, compared with placebo.9The purposesof this paper are to give an overview of the results of DAVIT II and to present the results of a combined analysis of the results of DAVIT I and II.
V
ORGANIZATION,
PATIENTS,
METHODS
A detailed description of the design of the DAVIT I and II studieshaspreviously beenpublished.4y9 DAVIT II wasa multicenter, double-blind, placebo-controlledstudy of verapamill20 mg t.i.d. Patientswereincluded between days 7 and 15. Treatment was continued for at least 12 months and was terminated when the patients had been From the Department of Internal Medicine B, Hillerqd County Hospitreated for 18 months. tal, Hillerqd, Denmark. Patients <76 years of age with an acute myocardial Address for reprints: Jprgen Fiiher Hansen, MD, Department of Cardiology, Hvidovre Hospital, Kettegaards All&, DK-2650 Hvidovre, infarction verified by a typical history, electrocardioDenmark. graphic changescompatible with myocardial infarction, and significant elevation of myocardial serum enzymes *For members of the Study Group, see Eur Heart J 1984;5:516- were eligible for the study. Exclusion criteria included 528 and Am J Cardiol 1990;66:779-785. heart failure not controlled with furosemideI 160mg per THE AMERICAN JOURNAL OF CARDIOLOGY DECEMBER 18, 1990
33 1
TABLE
I Baseline
Characteristics
of 1,775
Randomized
TABLE
Ill
Status
After
12 Months
Patients
Placebo
Total number of patients Sex: Male Female Age: <65 years 265 years History: AMI Hypertension Angina pectoris Diabetes Cigarette smoking
Placebo N %
Verapamil N %
897 714 183 577 320 148 125 234 50 552
100 79.6 20.4 64.3 35.7 16.5 13.9 26.1 5.6 61.5
878 702 176 589 289 124 125 237 48 557
100 80.0 20.0 67.1 32.9 14.1 14.2 27.0 5.5 63.4
Complications in CCU:
Shock Heart failure Cardiac arrest
35 323 41
3.9 36.0 4.5
32 291 36
3.6 33.1 4.0
Status at randomization:
CT-index <50 CT-index 250 Not measurable Congestion, chest x-ray Atrial fibrillation Bundle branch block Diuretics Digoxin Antiarrhythmics Nitrates other than sublingual
483 273 141 58
53.8 30.4 15.7 6.5
459 284 135 59
52.3 32.3 15.4 5.7
27 64 375 111 21 75
3.0 7.2 41.8 12.4 2.3 8.4
23 50 349 98 22 69
2.6 6.7 39.7 11.2 2.5 7.9
329 315 161 92
36.7 35.1 17.9 10.3
318 325 141 94
36.2 37.0 16.1 10.7
461 113
51.4 12.6
482 105
54.9 12.0
253 70
28.2 7.8
220 71
25.1 8.1
Anterolateral Q-wave lnferoposterior Q-wave Non-Q-wave Other
AMI type/ location:
No heart failure: Male Female Heart failure: Male Female
Sex and heart failure:
AMI = acute myocardial N - number.
TABLE
II Reasons
infarction;
CCU = coronary
for Permanent
care unit; CT = cardiothoracic;
Withdrawal
from
Treatment
Number of patients Death* Second- or third-degree AV block** Did not want to continue Heart failure Angina pectoris Antiarrhythmic treatment Antihypertensive treatment** Constipation, abdominal pain* * Sinus bradycardia, SA block* Could not take oral medication Hypotension, diiness Administrative reasons Other reasons At end of the study period
Placebo N %
Verapamil N %
897 72 7
100 8.0 0.8
878 48 23
100 5.5 2.6
61 43 95 14 10 11 2 11 14 25 16 516
6.8 4.8 10.6 1.6 1.1 1.2 0.2 1.2 1.6 2.8 1.8 57.5
68 50 74 13 0 27 9 7 17 37 19 486
7.7 5.7 8.4 1.5 3.1 1.0 0.8 1.9 4.2 2.2 55.4
q=?$l. Overall dli-square = 43.3, p
34
1
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
66
Number of patients Treatment Digoxin Diuretics* Nitroglycerin Other nitrates Cliniwl findings Angina pectoris Dyspnea Peripheral edema Pulmonary congestion Smoker* NYHA group I II III-IV Medication Three tablets/day Heart rate (mean f SD) beats/min** Mean follow-up, days (h SD) Systolic blood pressure (mean f SD) mm Hg** Diastolic blood pressure (mean f SD) mm Hg** l p <0.05. ** p co.01. N = number:
N
%
N
566
100
528
Verapamil % 100
58 194 164 106
10.2 34.3 29.0 18.7
43 144 130 76
8.1 27.3 24.6 14.4
191 83 19 8 200 425 131 10
33.7 14.7 3.4 1.4 35.3 75.1 23.1 1.8
151 81 24 3 221 404 117 7
28.6 15.3 4.5 0.6 41.9 76.5 22.2 1.3
97.2
490
92.8 70flO
550 76f
11
367f
15
368 f 16
141 f 20
136 f 18
86fll
NYHA = New York Heart Association;
82flO
SD = standard
deviation.
day; second-and third-degree atrioventricular block after the third day of admission;sinoatrial block within 3 days of randomization; treatment of angina pectoris, arrhythmias, or hypertensionwith @blockersand calcium antagonists; patient’s unwillingness to participate; patient’s residenceoutside the catchment area; other severedisabling diseaseinfluencing the prognosisor making outpatient control difficult or impossible;postoperativeor posttraumatic infarctions and congenital or valvular heart disease. The primary end points of interest were total death and first major event, i.e., death or reinfarction. To explain the possibleeffect of verapamil, analysesof sudden death, cardiac death and cardiac events (cardiac death and reinfarction) werealsoplanned.A reinfarction had to fulfill the same criteria as the qualifying infarction, whereasautopsyexamination had to demonstratea myocardial infarction. Suddendeath was defined as instantaneousdeath, death within 1 hour of onset of new symptoms, or the patient who was found dead unexpectedly. Cardiac death meant that no other cause of death was diagnosedbased on all available information. Statistical analysis was performed using the BMDP statistical program package 1987 version programs lD, 3D, 4F, 1L and 2L. Comparison of the 2 treatment groups with respect to baseline and other variables was done with such standard tests as the chi-square test and the Wilcoxon Mann-Whitney test. Comparisonof survival and other event curves was done using the TaroneWare test, a life-table method which takes into account variations in follow-up duration and which givesapproximately the same weight to early and late events. The
r- TABLE
IV Number
of End-Point
Intention-to-treat Total death First major event (1) Cardiac death Sudden death First reinfarction First cardiac event (2) Treatment stop + 7 days Total death First major event (1) Cardiac death Sudden death First reinfarction First cardiac event (2)
Events
and l&Month
Event
Rates According
to Treatment
Group
119 180 107 63 107 170
13.8 21.6 12.3 7.4 13.2 20.2
95 146 84 46 84 137
11.1 18.0 9.9 5.6 11.0 17.0
0.108 0.027 0.101 0.101 0.044 0.027
0.80 0.80 0.79 0.74 0.77 0.80
0.61J.05 oLqo.99 0.59.1.05 0.50.1.07 0.58,1.03 0.64.1.00
80 144 79 52 93 143
10.7 19.0 10.5 7.0 13.0 18.8
55 102 53 31 65 101
8.2 15.3 7.8 4.7 10.4 15.1
0.081 0.014 0.064 0.042 0.036 0.014
0.74 0.75 0.72 0.64 0.74 0.75
0.52.1.04 0.58,0.96 0.51.1.02 0.41,l.cC 0.54.1.01 0.58,0.96
(1) First major event = first remfarction or death. (2) First cardiac event = first reinfarction or cardiac death.
comparisonswere made on an intention-to-treat basis as well as on an as-treated basis. The as-treated analysis included all eventsup to 7 days after treatment cessation for patients who stopped prior to the scheduled time. Statistical testswere 2-sidedwith an (Ylevel of 0.05. Event curveswere constructed according to the methodsof Kaplan-Meier. Hazard ratios and confidencelimits for hazard ratios were calculated using the BMDP program for Cox-regression,2L. Minor discrepanciesbetweenthe resulting confidence limits and the p values from the Tarone-Ware tests are due to the fact that the hazard ratios are basedon the proportional hazards assumption,which is not the case for the TaroneWare test. RESULTS
In the study period, 11,447patients were hospitalized 13,771 times. Six thousand nine hundred sixty-six never had acute myocardial infarction. Of 4,481 patients with at least 1 infarction, 2,706 were excluded, 490 died prior to randomization, and 2,216 patients were alive at exclusion. Major reasonsfor exclusion of the 2,216 patients were congestiveheart failure (13%), sinoatrial or atrioventricular block (1 l%), treatment with j3blockers(18%) or calcium antagonists (19%), other severedisabling diseases (120/o),and patients not wanting to participate (16%) or living outside the catchment area (8%). One thousand sevenhundred seventy-five were consecutively included in the study: 878 patients were randomized to treatment with verapamil, and 897 to treatment with placebo. The 2 groups of patients were well-matched in relation to previoushistory, complicationsduring hospital stay, and status at the day of randomization. No statistically significant differences were found in any of the recorded parameters between the 2 groups (Table I). Patients were randomized 9 f 2.7 days (mean f 1 SD) after admission.At randomization, heart rate was75 f 11 beats/mm, systolic blood pressure was 120 f 16 mm Hg, and diastolic blood pressurewas 76 f 10 mm Hg, with no differencesbetweenthe 2 groups. Mean age was 59.5 f 9.2 years in the placebogroup and 58.5 f 9.4
years in the verapamil group for males, and 62.4 f 9.5 years and 62.3 f 8.7 years for females.Femaleswere a mean of 3.2 yearsolder than males(p
THE AMERICAN
JOURNAL
OF CARDIOLOGY
DECEMBER
18. 1990
35
1
Fewer patients in the verapamil group than in the placebogroup weretreated with diuretics in the follow-up period (p <0.05) (Table III), and congestiveheart failure wasnot significantly more often the reasonfor permanent treatment stop in the verapamil group (Table II). hd points: Intention-to-treat analyses (Table IV) demonstrated after 18 months a nonstatistically significant reduction in overall mortality (Fig. 1) in the verapamil group compared with the placebo group. Major events, i.e., reinfarction or death (Fig. 2), were significantly reduced in the verapamil group. The total number of reinfarctions (including secondand third reinfarctions) was 91 in the verapamil group and 129 in the placebo group. There was a reduction of 29% in all recorded reinfarctions. Eighteen-month first reinfarction (Fig. 3) and cardiac event rates were statistically significantly reducedin the verapamil group comparedwith the placebo group. Analyses of the results as-treated,by recording of all eventsto the day of treatment stop plus 7 days in patients who stoppedtoo early, and up to the last day of treatment stop in patients who stoppedtreatment according to the protocol, are presented in Table IV. Subgroup analyses: Prior to breaking the code,it was decided to perform a number of subgroup analyses(Table V). The variables were sex, age above and below 65 years, previous myocardial infarction, cardiac arrest in the coronary care unit, atria1fibrillation, angina pectoris, type and location of the myocardial infarction, and heart failure at any time prior to randomization during stay in the coronary care unit. As only 2.8% of the patients had atria1fibrillation and 4.3%had had cardiac arrest, these2 groups were considered too small for further analysis. The results are presentedasoverall mortality and cardiac
I 1 24
- - - - -
Placebo Verapamil
180 897 878
760 760
D8ys
360 674 703
491 518
FtGURE 2. cunulrtivhma)oreventrate,accodngtotreatmemt(p=0.02).Numbewofpathtsatridabdmmetthe with pemksh from Am J CadioLe) bottom. (R-
Placebo - - - - - Verapamil
15.0
0
180
897 878
822 818
Da,,s
360 778 784
FtGUREl.Chddhfemortd&rate,d~to(p=O.11).Nwnberofpdontsatriskbrhormatl:thabottom. Plaoobo, N = 897; Vorapemil, N = 878. (Reproduced missionfromAmJCudiol.~
36 1
event rates on an intention-to-treat basis.Theseanalyses demonstrateda statistically significant lower eventrate in the verapamil group comparedwith the placebogroup in males and in patients without congestiveheart failure. Further interaction analysesdemonstratedthat the differencebetweenmalesand femalescould be explained by a higher prevalenceof congestiveheart failure in females
540 598 614
with per-
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66
897 878
760 760
674 703
491 518
FtGURE3.6mddhfeftrstfeinWctbnrateaccodngto r-(p = 0.04). Number of patients at risk is shown at .
TABLE
V Number
of End-Point
Sex:
male female Age: <65 years 865 years Previous AMI: no yes History of angina pectoris: no
yes Heart failure no in the coronary yes care unit: AMI type/location: Anterolateral Q-wave lnferoposterior Q-wave Non-Q-wave Other AMI = acute myocardial
infarction;
Events
and 18-month
Event
Rates According
to Baseline
p Value
138 32 92 78 117 48
20.7 18.4 16.8 26.3 17.2 33.9
108 29 77 60 105 25
16.7 18.1 14.2 22.7 15.2 26.5
0.025 0.664 0.066 0.317 0.205 0.066
0.142 0.368 0.024 0.791
104 66 97 73
16.7 29.9 18.0 24.0
79 58 74 63
13.3 26.5 13.9 23.1
0.039 0.292 0.012 0.805
0.839 0.100 0.526 0.342
61 49 35 25
19.6 16.2 24.2 29.6
59 36 24 18
20.3 12.0 18.5 21.8
0.900 0.070 0.124 0.192
pValue
100 19 59 60 78 41
14.6 11.0 10.6 19.6 11.2 25.6
73 22 51 44 68 27
10.6 13.1 9.0 15.3 9.4 20.2
0.035 0.496 0.304 0.322 0.385 0.173
641 237 587 291
70 49 64 55
11.0 21.8 11.8 17.5
52 43 43 52
8.3 18.4 7.7 17.9
318 325 141 94
43 38 18 20
13.4 12.5 12.2 22.4
40 26 13 16
13.2 8.1 9.8 16.3
702 176 589 289 740 138
663 234 574 323
329 315 161 92
Group
N
N
714 183 577 320 736 161
Placebo
and Treatment
Cardiac events Verapamil Event Event Rate(%) N Rate (%)
Deaths Verapamil Event Event Rate(%) Rate(%) N
Patients Verapamil Placebo N N
Variables Placebo
N = number.
significant reduction of mortality and reinfarction rate from the secondto third week.4,7We know that verapamil is effective in prevention of ischemic episodesin patients with stable angina pectoris,13unstable angina,14J5vasospasticangina16and silent ischemia.15J7DAVIT I demonstrateda prevalenceof ventricular ectopic beatsafter 6 months of treatment in the verapamil-treated patients of 3.2% compared with 6.1% in the placebo-treatedgroup (p = 0.05).7 These findings support the hypothesis that verapamil may reduce myocardial ischemia after a myocardial infarction and may prevent ventricular arrhythmias as well. Thus, DAVIT II was conductedto investigate whether treatment with verapamil reduced total death and major events.If an effect were found, further analysisshould be performed to seehow verapamil influencedcardiac death, suddendeath, reinfarctions and cardiac events. Mechanism of aeM That the reduction in major eventsin DAVIT II is related to treatment with verapamil is supported by the finding that death significantly more often was the reasonfor permanent treatment stop in the placebo than in the verapamil group (Table II). The effect of verapamil might be related to a reduction in myocardial ischemiaasdemonstratedby the lower prevalence of angina pectoris and the reduced consumptionof DISCUSSION nitroglycerin in the verapamil group comparedwith the Animal experiments have demonstrated that treat- placebo group. The effect of verapamil might also be ment with verapamil prior to an ischemic injury reduces related to the demonstratedsignificantly lower heart rate infarct size.1-3J0Continuation of treatment after coro- and blood pressure during verapamil treatment comnary artery occlusion maintains the beneficial effect of pared with placebo treatment. This was found also in verapamil. l l Pretreatment also prevents postischemic DAVIT I.19 The decreasein sudden death (Table IV) stunning.12 Extrapolating from these animal experi- may have beendue to a reduction of ventricular arrhythments, the best chance of preventing or limiting infarct mias. In animal experiments,verapamil has beenproven size should be prophylactic treatment with verapamillJO to prevent reperfusion arrhythmias20s21 and the conducThese experimental findings are also in accordancewith tion delay found in ischemicmyocardium.22In onestudy, the retrospectiveanalysisof the results of DAVIT L4 with verapamil significantly reduced ventricular arrhythmias no effect of verapamil on mortality or reinfarction during and fibrillation during myocardial infarction.23 Verapathe acute phase of a myocardial infarction, but with a mil may also prevent exercise-inducedventricular tachy(39.2%) than in males (33.4%) (p = 0.04), and a higher mean age in femalescomparedwith males (p
THE AMERICAN
JOURNAL
OF CARDIOLOGY
DECEMBER
18, 1990
37 1
A SVRlPD!HUM:
ATRERDSCLERDSlS
AND VASGULAR
PRDlECllDN
cardia24during myocardial ischemia25and reduce ventricular ectopic beats.7Whether reduction in prevalence of ventricular arrhythmias also might be of importance in DAVIT II is under investigation basedon 296 patients who were on 24-hour Holter monitoring before, one month after and 12- 18 months after inclusion in the trial. Subgroup analyses: Theseanalysesare basedon the results of DAVIT I and are important due to the claim of the Multicenter Diltiazem Postinfarction Trial (MDPIT) study group that calcium antagonists may havea detrimental effect in patients with congestiveheart failure.26 The analyses(Table V, Figs. 4 and 5) demonstrated that patients without congestiveheart failure during their stay in the coronary care unit had a significantly better prognosisthan patients with congestiveheart failure. Verapamil causeda significant reduction of mortality and cardiac eventsin patients without congestiveheart failure. No difference betweenthe 2 groups was found in patients with congestiveheart failure. Reanalysisof cardiac events in DAVIT I, in relation to congestiveheart failure while in the coronary care unit basedon patients alive at day 3, demonstratedin patients without congestive heart failure a 6-month major event rate in the verapamil group of 9.3% and in the placebo group of 11.6%
(not significant). The correspondingfigures for patients with congestiveheart failure were 28.3% and 30% (not significant). Thus, neither in DAVIT I nor II wasa detrimental effect of verapamil in patients with congestive heart failure demonstrated.But the overall effect of verapamil was found in patients without a history of congestive heart failure in the coronary care unit. The beneficial effect of verapamil in patients without congestiveheart failure is in accordancewith the findings of MDPIT26 that diltiazem reducedcardiac eventsin patients without congestiveheart failure. In patients with congestiveheart failure, verapamil did not increase cardiac event rate, contrary to the results of MDPIT, which demonstrated an increasedcardiac eventrate in patients with congestive heart failure in the coronary care unit treated with diltiazem compared with patients treated with placebo. other studies: Two other large-scalepostinfarction, double-blind, placebo-controlled trials have been conducted with calcium antagonists:the SecondaryPrevention Reinfarction Israeli Nifedipine Trial (SPRINT)27 and MDPIT.26 The protocols of these 2 trials are very similar to the DAVIT II protocol, although we excluded patients in need of Badrenoreceptor blocker treatment. Twenty percent of the patients in SPRINT and about
1
24
20
180
Days
360
540
360
180
5iO
Days
~~,~ - - - -- Verapamil No Heart Failure
PlGURE4.CmdaUVe~eventr~~t0baamsnthpatidswRhandwitheuthsartfaiiwe.Nmbsrefpe uentsatlisitbdlewnatthsbettm.~,no~f~, n=574;vempmnl,nohedfdhm,n=~~,~ verapmii, hem-l f&me, n = 291. faihe,n=323;
38 1
-.
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66
PIGURE 5. Cuddive mortmlity Me, mccodw to hpdiWltSWRhdWRhOUthavttaiiUrS.NumbarOf~ mttisshownmtthebott~.(Ra(woduoed with pennisdon hm Am J Cardiol..s)
TABLE VI Meta-Analyse@ of Total Mortality, and Reinfarctions Based on DAVIT I and l14,g Number of Randomized Allocated Allocated Placebo Verapamil Deaths 60/679 DAVIT I * 46/671 119/897 DAVIT II 95/878 Pooled odds ratio 0.78; 95% confidence Major events 87/679 DAVIT I * 68/67 1 146/878 180/897 DAVIT II Pooled odds ratio 0.79; 95% confidence Reinfarctions 32/671 50/679 DAVIT I* DAVIT II 84/878 107/897 Pooled odds ratio 0.73; 95% confidence
to the effect of ,f3blockers. Thus, verapamil may be considered as an alternative to P-blocker treatment after an acute myocardial infarction.
Major Events
Statistical Calculations Obs. Minus Variance of O-E Expect. (O-E) -6.6 -10.9 interval 0.634.99;
24.6 47.1 p = 0.04
-9.0 -15.3 interval 0.654.95;
34.3
-8.7 -10.5 interval 0.57-0.94;
CONCLUSIONS
The overall effect of long-term verapamil treatment in patients after an acute myocardial infarction, as demonstrated in DAVIT I and II, is a 20 to 27% reduction in oddsratio of death, reinfarction and major events,which correspondsto the findings in trials with 0 adrenoreceptor-blocking drugs. The effect is first of all related to a beneficial effect in patients without congestiveheart failure during the acute myocardial infarction. Basedon the results of DAVIT I and II, the reduced prevalence of angina pectoris in the verapamil-treated patients, compared with the placebo-treated patients, and the documented effect of verapamil in all types of angina, verapamil may be recommendedfor treatment of patients after an acute myocardial infarction.
66.6 p = 0.02 19.2
42.6 p = 0.02
alive day 8. expect. = expected; obs. = observed. ’ Patents
55% of the patients in MDPIT were on @blockers at randomization. The inclusion rate was 48% in SPRINT and 18% in MDPIT compared with 40% in DAVIT II. The l-year mortality rate of about 6 to 7% in SPRINT and MDPIT should be comparedwith 10.8%in the DAVIT II placebo group. It is also of interest to note that 25% of the 333 deaths in MDPIT were classified as noncardiac compared with 18% of 132 deaths in SPRINT and 15%of 214 deaths in DAVIT II. SPRINT, using 30 mg nifedipine/day, found a lo-month mortality and nonfatal reinfarction rate of 5.7% and 4.8% respectively in the placebo group, and of 5.8% and 4.4% respectivelyin the nifedipine group (not significant). The patients in MDPIT received 240 mg of diltiazem a day. After a mean observation period of 25 months, the mortality rates in the placebo and diltiazem groups were equal (about 16%) and the cardiac event rates (cardiac death and nonfatal reinfarction) about 20% and 18%. Thus, neither nifedipine nor diltiazem demonstratedan overall beneficial effect on survival or reinfarction rate after an acute myocardial infarction. The lack of effect of nifedipine might be explained by the pronounced vasodilator properties of nifedipine often associatedwith an increase in heart rate.27The lack of effect of diltiazem might be related to simultaneousp-blocker treatment in about 55% of the patients. If the 2 drugs are influencing the same factors, no further effect could be expected by adding diltiazem to @blockers.28 Yusuf et a129recently gave an extensive review of early and late intervention trials in patients after an acute myocardial infarction based on meta-analyses. In 25 long-term, late-intervention P-blocker trials, the reduction in pooled odds ratio of mortality was calculated at 22% (95% confidence interval [CI] 16 to 30%) and of reinfarctions, 27% (CI 17 to 37%). In 10 antiplatelet trials, the respectivefigures were 11%(CI 2 to 19%)and 31%(CI 21 to 41%). This meansthat both /I blockersand antiplatelet drugs have a beneficial effect, and that the beneficial effect of verapamil evaluated from the 2 verapamil studies, DAVIT I and II (Table VI), corresponds
1. Nayler WG. Calcium antagonists and the ischemic myocardium. Int J Cardiol 1987:15:267-285. 2. Kloner RA, Braunwald E. Effects of calcium antagonists on infarcting myocardium. Am J Cardiol 1987;59:84B-94B. 3. Skolnick AE, Frishman WH. Calcium-channel blockers in myocardial infarction. Arch Intern Med 1989;149:1669~1677. 4. The Danish Study Group on Verapamil in Myocardial Infarction. Verapamil in acute myocardial infarction. Eur Heart J 1984;5:516-558. 5. Hansen JF, Sigurd B, Mellemgaard K, Lyngbye J. Verapamil in acute myocardial infarction. Dan Med Bull 1980;27:105~109. 6. The Danish Study Group on Verapamil in Myocardial Infarction. Verapamil in acute myocardial infarction. Am J Cardiol 1984;54:24E-28E. 7. The Danish Study Group on Verapamil in Myocardial Infarction. The Danish studies on verapamil in myocardial infarction. Br J C/in Pharmacol 1986;21:1973-204s. 8. Hansen JF. The Danish Study Group on Verapamil in Myocardial Infarction. Letter to the editor. Eur Heart J 1986;7:910-911. 9. The 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 11 (DAVIT II). Am / Cardiol 1990;66:779-785. 10. Reimer KA, Jennings RB. Verapamil in two reperfusion models of myocardial infarction. Lob Invest 1984;51:655-666. 11. Yellon DM, Hearse DJ. Maxwell MP, Chambers DE, Downey JM. Sustained limitation of myocardial necrosis 24 hours after coronary artery occlusion: Verapamil infusion in dogs with small myocardial infarcts. Am J Cardiol 1983;51:1409-1413. 12. Przyklenk K, Kloner RA. Effect of verapamil on postischemic “stunned” myocardium. Importance of the timing of treatment. J Am Coil Cardiol 1988;11:614-623. 13. Subramanian VB, Bowles ML, Lahiri A, Davies AB, Raftery EB. Long-term antianginal action of verapamil assessed with quantitated serial treadmill stress testing. Am J Cardiol 1981;48:529-535. 14. Mauritson DR, Johnson SM, Winniford MD, Gary JR, Willerson JT, Hillis LD. Verapamil for unstable angina at rest. A short-termed, randomized, doubleblind study. Am Heart J 1983;106:652-658. 15. Mauri F, Mafrici A, Biraghi M, Cerri P, De Biase AM. Effectiveness of calcium antagonist drugs in patients with unstable angina and proven coronary artery disease. Eur Heart J 1988;9(suppl N):158-163. 16. Johnson SM, Mauritson DR, WilIerson JT, Hillis LD. A controlled trial of verapamil for Prinzmetal’s variant angina. N Engl J Med 1981;304:862-866. 17. Parodi 0, Simonetti I, Michelassi C, Carpeggiani C, Biagini A, L’Abbate A, Maseri A. Comparison of verapamil and propranolol therapy for angina at rest: A randomized, multiple crossover, controlled trial in the coronary care unit. Am J Cardiol 1986;57:899-906. 16. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockadeduring and after mywardial infarction: An overview of the randomized trials. Prog Cardiooasc Dis 1985;27:335-371. 19. The Danish Study Group on Verapamil in Myocardial Infarction. Abrupt withdrawal of verapamil in ischemic heart disease. Eur Heart J 1984,5:529-532. 20. Kauman JA, Aramendia P. Prevention of ventricular fibrillation induced by
THE AMERICAN
JOURNAL
OF CARDIOLOGY
DECEMBER
18, 1990
39 1
A SYMPOSIUM:
ATNENOSCLENOSIS
AND VASCULAR
PROTECTION
coronary ligation. J Pharmocol Exp Ther 1968;164:326-340. 21. Sugiyama S, Ozawa T, Suzuki K, Kate T. Effects of verapamil and propranolol on ventricular vulnerability after coronary reperfusion. J Electrocardiol 1980;13:49-54. 22. Peter T, Fujimoto T, Hamamoto H, Mandel WJ. Comparative study of the effect of slow channel-inhibiting agents on ischemla-induced conduction delay as relevant to the genesis of ventricular fibrillation. Am Heart J 1983;106:10231028. 23. Rolli A, Favaro L, Finardi A, Aurier E, Bonatti V, Botti G. Efflcacite du verapamil dans la pr6vention de la fibrillation ventriculaire B la phase aigue de l’infarctus du myocarde. Arch Mul Coeur 1988;81:907-911. 24. Woelfel A, Foster JR, McAllister RG, Simpson RJ, Gettes LS. Efficacy of verapamil in exercise-induced ventricular tachycardia. Am J Cardiol 1985;56:292-297.
40 I
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66
25. Giilker H, Godejohann U, Dorsel T, Behrenbeck T, Heuer H, Bender F. Prophylaxe belastungsinduzierter ventrikuliirer Arrhythmien durch Verapamil. Z Kardiol 1987;76:404-410, 26. The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Eng/ J Med 1988;319:385-392. 27. The Israeli SPRINT Study Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT). A randomized intervention trial of nifedipine in patients with acute myocardial infarction. Eur Heart J 1988;9:354-364. 28. Packer M. Combined beta-adrenergic and calcium-entry blockade in angina pectoris. N Engl J Med 1989;320:709-718. 29. Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinical trials in heart disease. I. Treatments following myocardial infarction. JAMA 1988;2088-2093.
The effect of verapamil on death and major events (i.e., death or reinfarction) after an acute myocardial infarction was studied in a double-blind, randommdtkenter trial, the Dani=hm-, ish Verapamil IdamUon Trial II (DAVIT II). Eight hundred seventy-eight pathts started tmatmed with verapamU 360 mg/day and 897 patknts with placeho. Treatment eonunued for up to 18 months (mean 16 months). Ninety-five deaths and 149 major events occurred in the verapamil grojdp and 119 deathsad19Omajoreventsintheplacebogroup. Eighteen-month mortalityrates wereli.land 13*% (hazard ratio 0.90,95% codWnce limits 0.63 to 1.03, p = 0.109), and major event rates 18.0 and 21.6% (0.80,0.64 to 0.99,p =O.O27)in the verapamil and placeho groups respecuvely. Whencombiningtheresuttsofthistrialwiththeresuits of the fh-st Danish study on verapamil in myocardal infarction, the meta-analyds demonsbated that tmatment with verapamil from the second week after an acute myocardial infarction resulted inaraductlonofpooledoddsratiosof022(9S% conhhce interval 0.01 to 0.37, p = 0.04) for death, Oal(O.03 to 0.35, p = 0.02) for major events, and 0.27 (0.06 to 0.43, p = 0.02) far first rehbfarctlons. It is cendded that brig-term treatment with verapamU after an acute myocardial infarction is assodated with a significant reduction in overall modality as well as major event and reinfarction rates. (AmJCadii 1990;66:331401)
erapamil has been proved in in vitro and in vivo studies to reduce ischemic injury and infarct size.1-4Basedon this evidenceand a pilot study,5 the Danish Study Group on Verapamil in Myocardial Infarction conducted an early intervention, randomized, double-blind, placebo-controlled trial, the Danish Verapamil Infarction Trial I (DAVIT I), with the purposeof examining whether administration of verapamil 120 mg t.i.d. from the time of admissionand over the following 6 months might decrease total death and reinfarction rates.4,6DAVIT I included 7 17 patients in the verapamil group and 719 patients in the placebo group. After 6 months, nonsignificant differences in mortality rates, 12.8%in verapamil versus 13.8%in placebo-treatedpatients, and in reinfarction rates, 7% versus 8.3% respectively, were found. A retrospective analysis of the data from DAVIT I demonstrateda lower mortality rate between day 22 and day 180 in the verapamil group, 3.7% comparedwith 6.4%in the placebogroup (p = 0.05). The reinfarction rate from day 15 to day 180 was 3.9%in the verapamil group compared with 7.0% in the placebo group (p = 0.03).4*6,7Furthermore, the analysis demonstrated that verapamil in patients with a history of angina pectoris reduced the number of patients who developed acute myocardial infarction 39.4%,comparedwith 46.7% of placebo-treatedpatients (p = O-05).* Among other findings, these were the major reasons for the decision to conduct a late intervention study, the Danish Verapamil Infarction Trial II (DAVIT II), to examinewhether treatment with verapamil from the second week after an acute myocardial infarction and continued for 12 to 18 months might reduce total mortality and major events,i.e., death and reinfarction, compared with placebo.9The purposesof this paper are to give an overview of the results of DAVIT II and to present the results of a combined analysis of the results of DAVIT I and II.
V
ORGANIZATION,
PATIENTS,
METHODS
A detailed description of the design of the DAVIT I and II studieshaspreviously beenpublished.4y9 DAVIT II wasa multicenter, double-blind, placebo-controlledstudy of verapamill20 mg t.i.d. Patientswereincluded between days 7 and 15. Treatment was continued for at least 12 months and was terminated when the patients had been From the Department of Internal Medicine B, Hillerqd County Hospitreated for 18 months. tal, Hillerqd, Denmark. Patients <76 years of age with an acute myocardial Address for reprints: Jprgen Fiiher Hansen, MD, Department of Cardiology, Hvidovre Hospital, Kettegaards All&, DK-2650 Hvidovre, infarction verified by a typical history, electrocardioDenmark. graphic changescompatible with myocardial infarction, and significant elevation of myocardial serum enzymes *For members of the Study Group, see Eur Heart J 1984;5:516- were eligible for the study. Exclusion criteria included 528 and Am J Cardiol 1990;66:779-785. heart failure not controlled with furosemideI 160mg per THE AMERICAN JOURNAL OF CARDIOLOGY DECEMBER 18, 1990
33 1
TABLE
I Baseline
Characteristics
of 1,775
Randomized
TABLE
Ill
Status
After
12 Months
Patients
Placebo
Total number of patients Sex: Male Female Age: <65 years 265 years History: AMI Hypertension Angina pectoris Diabetes Cigarette smoking
Placebo N %
Verapamil N %
897 714 183 577 320 148 125 234 50 552
100 79.6 20.4 64.3 35.7 16.5 13.9 26.1 5.6 61.5
878 702 176 589 289 124 125 237 48 557
100 80.0 20.0 67.1 32.9 14.1 14.2 27.0 5.5 63.4
Complications in CCU:
Shock Heart failure Cardiac arrest
35 323 41
3.9 36.0 4.5
32 291 36
3.6 33.1 4.0
Status at randomization:
CT-index <50 CT-index 250 Not measurable Congestion, chest x-ray Atrial fibrillation Bundle branch block Diuretics Digoxin Antiarrhythmics Nitrates other than sublingual
483 273 141 58
53.8 30.4 15.7 6.5
459 284 135 59
52.3 32.3 15.4 5.7
27 64 375 111 21 75
3.0 7.2 41.8 12.4 2.3 8.4
23 50 349 98 22 69
2.6 6.7 39.7 11.2 2.5 7.9
329 315 161 92
36.7 35.1 17.9 10.3
318 325 141 94
36.2 37.0 16.1 10.7
461 113
51.4 12.6
482 105
54.9 12.0
253 70
28.2 7.8
220 71
25.1 8.1
Anterolateral Q-wave lnferoposterior Q-wave Non-Q-wave Other
AMI type/ location:
No heart failure: Male Female Heart failure: Male Female
Sex and heart failure:
AMI = acute myocardial N - number.
TABLE
II Reasons
infarction;
CCU = coronary
for Permanent
care unit; CT = cardiothoracic;
Withdrawal
from
Treatment
Number of patients Death* Second- or third-degree AV block** Did not want to continue Heart failure Angina pectoris Antiarrhythmic treatment Antihypertensive treatment** Constipation, abdominal pain* * Sinus bradycardia, SA block* Could not take oral medication Hypotension, diiness Administrative reasons Other reasons At end of the study period
Placebo N %
Verapamil N %
897 72 7
100 8.0 0.8
878 48 23
100 5.5 2.6
61 43 95 14 10 11 2 11 14 25 16 516
6.8 4.8 10.6 1.6 1.1 1.2 0.2 1.2 1.6 2.8 1.8 57.5
68 50 74 13 0 27 9 7 17 37 19 486
7.7 5.7 8.4 1.5 3.1 1.0 0.8 1.9 4.2 2.2 55.4
q=?$l. Overall dli-square = 43.3, p
34
1
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
66
Number of patients Treatment Digoxin Diuretics* Nitroglycerin Other nitrates Cliniwl findings Angina pectoris Dyspnea Peripheral edema Pulmonary congestion Smoker* NYHA group I II III-IV Medication Three tablets/day Heart rate (mean f SD) beats/min** Mean follow-up, days (h SD) Systolic blood pressure (mean f SD) mm Hg** Diastolic blood pressure (mean f SD) mm Hg** l p <0.05. ** p co.01. N = number:
N
%
N
566
100
528
Verapamil % 100
58 194 164 106
10.2 34.3 29.0 18.7
43 144 130 76
8.1 27.3 24.6 14.4
191 83 19 8 200 425 131 10
33.7 14.7 3.4 1.4 35.3 75.1 23.1 1.8
151 81 24 3 221 404 117 7
28.6 15.3 4.5 0.6 41.9 76.5 22.2 1.3
97.2
490
92.8 70flO
550 76f
11
367f
15
368 f 16
141 f 20
136 f 18
86fll
NYHA = New York Heart Association;
82flO
SD = standard
deviation.
day; second-and third-degree atrioventricular block after the third day of admission;sinoatrial block within 3 days of randomization; treatment of angina pectoris, arrhythmias, or hypertensionwith @blockersand calcium antagonists; patient’s unwillingness to participate; patient’s residenceoutside the catchment area; other severedisabling diseaseinfluencing the prognosisor making outpatient control difficult or impossible;postoperativeor posttraumatic infarctions and congenital or valvular heart disease. The primary end points of interest were total death and first major event, i.e., death or reinfarction. To explain the possibleeffect of verapamil, analysesof sudden death, cardiac death and cardiac events (cardiac death and reinfarction) werealsoplanned.A reinfarction had to fulfill the same criteria as the qualifying infarction, whereasautopsyexamination had to demonstratea myocardial infarction. Suddendeath was defined as instantaneousdeath, death within 1 hour of onset of new symptoms, or the patient who was found dead unexpectedly. Cardiac death meant that no other cause of death was diagnosedbased on all available information. Statistical analysis was performed using the BMDP statistical program package 1987 version programs lD, 3D, 4F, 1L and 2L. Comparison of the 2 treatment groups with respect to baseline and other variables was done with such standard tests as the chi-square test and the Wilcoxon Mann-Whitney test. Comparisonof survival and other event curves was done using the TaroneWare test, a life-table method which takes into account variations in follow-up duration and which givesapproximately the same weight to early and late events. The
r- TABLE
IV Number
of End-Point
Intention-to-treat Total death First major event (1) Cardiac death Sudden death First reinfarction First cardiac event (2) Treatment stop + 7 days Total death First major event (1) Cardiac death Sudden death First reinfarction First cardiac event (2)
Events
and l&Month
Event
Rates According
to Treatment
Group
119 180 107 63 107 170
13.8 21.6 12.3 7.4 13.2 20.2
95 146 84 46 84 137
11.1 18.0 9.9 5.6 11.0 17.0
0.108 0.027 0.101 0.101 0.044 0.027
0.80 0.80 0.79 0.74 0.77 0.80
0.61J.05 oLqo.99 0.59.1.05 0.50.1.07 0.58,1.03 0.64.1.00
80 144 79 52 93 143
10.7 19.0 10.5 7.0 13.0 18.8
55 102 53 31 65 101
8.2 15.3 7.8 4.7 10.4 15.1
0.081 0.014 0.064 0.042 0.036 0.014
0.74 0.75 0.72 0.64 0.74 0.75
0.52.1.04 0.58,0.96 0.51.1.02 0.41,l.cC 0.54.1.01 0.58,0.96
(1) First major event = first remfarction or death. (2) First cardiac event = first reinfarction or cardiac death.
comparisonswere made on an intention-to-treat basis as well as on an as-treated basis. The as-treated analysis included all eventsup to 7 days after treatment cessation for patients who stopped prior to the scheduled time. Statistical testswere 2-sidedwith an (Ylevel of 0.05. Event curveswere constructed according to the methodsof Kaplan-Meier. Hazard ratios and confidencelimits for hazard ratios were calculated using the BMDP program for Cox-regression,2L. Minor discrepanciesbetweenthe resulting confidence limits and the p values from the Tarone-Ware tests are due to the fact that the hazard ratios are basedon the proportional hazards assumption,which is not the case for the TaroneWare test. RESULTS
In the study period, 11,447patients were hospitalized 13,771 times. Six thousand nine hundred sixty-six never had acute myocardial infarction. Of 4,481 patients with at least 1 infarction, 2,706 were excluded, 490 died prior to randomization, and 2,216 patients were alive at exclusion. Major reasonsfor exclusion of the 2,216 patients were congestiveheart failure (13%), sinoatrial or atrioventricular block (1 l%), treatment with j3blockers(18%) or calcium antagonists (19%), other severedisabling diseases (120/o),and patients not wanting to participate (16%) or living outside the catchment area (8%). One thousand sevenhundred seventy-five were consecutively included in the study: 878 patients were randomized to treatment with verapamil, and 897 to treatment with placebo. The 2 groups of patients were well-matched in relation to previoushistory, complicationsduring hospital stay, and status at the day of randomization. No statistically significant differences were found in any of the recorded parameters between the 2 groups (Table I). Patients were randomized 9 f 2.7 days (mean f 1 SD) after admission.At randomization, heart rate was75 f 11 beats/mm, systolic blood pressure was 120 f 16 mm Hg, and diastolic blood pressurewas 76 f 10 mm Hg, with no differencesbetweenthe 2 groups. Mean age was 59.5 f 9.2 years in the placebogroup and 58.5 f 9.4
years in the verapamil group for males, and 62.4 f 9.5 years and 62.3 f 8.7 years for females.Femaleswere a mean of 3.2 yearsolder than males(p
THE AMERICAN
JOURNAL
OF CARDIOLOGY
DECEMBER
18. 1990
35
1
Fewer patients in the verapamil group than in the placebogroup weretreated with diuretics in the follow-up period (p <0.05) (Table III), and congestiveheart failure wasnot significantly more often the reasonfor permanent treatment stop in the verapamil group (Table II). hd points: Intention-to-treat analyses (Table IV) demonstrated after 18 months a nonstatistically significant reduction in overall mortality (Fig. 1) in the verapamil group compared with the placebo group. Major events, i.e., reinfarction or death (Fig. 2), were significantly reduced in the verapamil group. The total number of reinfarctions (including secondand third reinfarctions) was 91 in the verapamil group and 129 in the placebo group. There was a reduction of 29% in all recorded reinfarctions. Eighteen-month first reinfarction (Fig. 3) and cardiac event rates were statistically significantly reducedin the verapamil group comparedwith the placebo group. Analyses of the results as-treated,by recording of all eventsto the day of treatment stop plus 7 days in patients who stoppedtoo early, and up to the last day of treatment stop in patients who stoppedtreatment according to the protocol, are presented in Table IV. Subgroup analyses: Prior to breaking the code,it was decided to perform a number of subgroup analyses(Table V). The variables were sex, age above and below 65 years, previous myocardial infarction, cardiac arrest in the coronary care unit, atria1fibrillation, angina pectoris, type and location of the myocardial infarction, and heart failure at any time prior to randomization during stay in the coronary care unit. As only 2.8% of the patients had atria1fibrillation and 4.3%had had cardiac arrest, these2 groups were considered too small for further analysis. The results are presentedasoverall mortality and cardiac
I 1 24
- - - - -
Placebo Verapamil
180 897 878
760 760
D8ys
360 674 703
491 518
FtGURE 2. cunulrtivhma)oreventrate,accodngtotreatmemt(p=0.02).Numbewofpathtsatridabdmmetthe with pemksh from Am J CadioLe) bottom. (R-
Placebo - - - - - Verapamil
15.0
0
180
897 878
822 818
Da,,s
360 778 784
FtGUREl.Chddhfemortd&rate,d~to(p=O.11).Nwnberofpdontsatriskbrhormatl:thabottom. Plaoobo, N = 897; Vorapemil, N = 878. (Reproduced missionfromAmJCudiol.~
36 1
event rates on an intention-to-treat basis.Theseanalyses demonstrateda statistically significant lower eventrate in the verapamil group comparedwith the placebogroup in males and in patients without congestiveheart failure. Further interaction analysesdemonstratedthat the differencebetweenmalesand femalescould be explained by a higher prevalenceof congestiveheart failure in females
540 598 614
with per-
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66
897 878
760 760
674 703
491 518
FtGURE3.6mddhfeftrstfeinWctbnrateaccodngto r-(p = 0.04). Number of patients at risk is shown at .
TABLE
V Number
of End-Point
Sex:
male female Age: <65 years 865 years Previous AMI: no yes History of angina pectoris: no
yes Heart failure no in the coronary yes care unit: AMI type/location: Anterolateral Q-wave lnferoposterior Q-wave Non-Q-wave Other AMI = acute myocardial
infarction;
Events
and 18-month
Event
Rates According
to Baseline
p Value
138 32 92 78 117 48
20.7 18.4 16.8 26.3 17.2 33.9
108 29 77 60 105 25
16.7 18.1 14.2 22.7 15.2 26.5
0.025 0.664 0.066 0.317 0.205 0.066
0.142 0.368 0.024 0.791
104 66 97 73
16.7 29.9 18.0 24.0
79 58 74 63
13.3 26.5 13.9 23.1
0.039 0.292 0.012 0.805
0.839 0.100 0.526 0.342
61 49 35 25
19.6 16.2 24.2 29.6
59 36 24 18
20.3 12.0 18.5 21.8
0.900 0.070 0.124 0.192
pValue
100 19 59 60 78 41
14.6 11.0 10.6 19.6 11.2 25.6
73 22 51 44 68 27
10.6 13.1 9.0 15.3 9.4 20.2
0.035 0.496 0.304 0.322 0.385 0.173
641 237 587 291
70 49 64 55
11.0 21.8 11.8 17.5
52 43 43 52
8.3 18.4 7.7 17.9
318 325 141 94
43 38 18 20
13.4 12.5 12.2 22.4
40 26 13 16
13.2 8.1 9.8 16.3
702 176 589 289 740 138
663 234 574 323
329 315 161 92
Group
N
N
714 183 577 320 736 161
Placebo
and Treatment
Cardiac events Verapamil Event Event Rate(%) N Rate (%)
Deaths Verapamil Event Event Rate(%) Rate(%) N
Patients Verapamil Placebo N N
Variables Placebo
N = number.
significant reduction of mortality and reinfarction rate from the secondto third week.4,7We know that verapamil is effective in prevention of ischemic episodesin patients with stable angina pectoris,13unstable angina,14J5vasospasticangina16and silent ischemia.15J7DAVIT I demonstrateda prevalenceof ventricular ectopic beatsafter 6 months of treatment in the verapamil-treated patients of 3.2% compared with 6.1% in the placebo-treatedgroup (p = 0.05).7 These findings support the hypothesis that verapamil may reduce myocardial ischemia after a myocardial infarction and may prevent ventricular arrhythmias as well. Thus, DAVIT II was conductedto investigate whether treatment with verapamil reduced total death and major events.If an effect were found, further analysisshould be performed to seehow verapamil influencedcardiac death, suddendeath, reinfarctions and cardiac events. Mechanism of aeM That the reduction in major eventsin DAVIT II is related to treatment with verapamil is supported by the finding that death significantly more often was the reasonfor permanent treatment stop in the placebo than in the verapamil group (Table II). The effect of verapamil might be related to a reduction in myocardial ischemiaasdemonstratedby the lower prevalence of angina pectoris and the reduced consumptionof DISCUSSION nitroglycerin in the verapamil group comparedwith the Animal experiments have demonstrated that treat- placebo group. The effect of verapamil might also be ment with verapamil prior to an ischemic injury reduces related to the demonstratedsignificantly lower heart rate infarct size.1-3J0Continuation of treatment after coro- and blood pressure during verapamil treatment comnary artery occlusion maintains the beneficial effect of pared with placebo treatment. This was found also in verapamil. l l Pretreatment also prevents postischemic DAVIT I.19 The decreasein sudden death (Table IV) stunning.12 Extrapolating from these animal experi- may have beendue to a reduction of ventricular arrhythments, the best chance of preventing or limiting infarct mias. In animal experiments,verapamil has beenproven size should be prophylactic treatment with verapamillJO to prevent reperfusion arrhythmias20s21 and the conducThese experimental findings are also in accordancewith tion delay found in ischemicmyocardium.22In onestudy, the retrospectiveanalysisof the results of DAVIT L4 with verapamil significantly reduced ventricular arrhythmias no effect of verapamil on mortality or reinfarction during and fibrillation during myocardial infarction.23 Verapathe acute phase of a myocardial infarction, but with a mil may also prevent exercise-inducedventricular tachy(39.2%) than in males (33.4%) (p = 0.04), and a higher mean age in femalescomparedwith males (p
THE AMERICAN
JOURNAL
OF CARDIOLOGY
DECEMBER
18, 1990
37 1
A SVRlPD!HUM:
ATRERDSCLERDSlS
AND VASGULAR
PRDlECllDN
cardia24during myocardial ischemia25and reduce ventricular ectopic beats.7Whether reduction in prevalence of ventricular arrhythmias also might be of importance in DAVIT II is under investigation basedon 296 patients who were on 24-hour Holter monitoring before, one month after and 12- 18 months after inclusion in the trial. Subgroup analyses: Theseanalysesare basedon the results of DAVIT I and are important due to the claim of the Multicenter Diltiazem Postinfarction Trial (MDPIT) study group that calcium antagonists may havea detrimental effect in patients with congestiveheart failure.26 The analyses(Table V, Figs. 4 and 5) demonstrated that patients without congestiveheart failure during their stay in the coronary care unit had a significantly better prognosisthan patients with congestiveheart failure. Verapamil causeda significant reduction of mortality and cardiac eventsin patients without congestiveheart failure. No difference betweenthe 2 groups was found in patients with congestiveheart failure. Reanalysisof cardiac events in DAVIT I, in relation to congestiveheart failure while in the coronary care unit basedon patients alive at day 3, demonstratedin patients without congestive heart failure a 6-month major event rate in the verapamil group of 9.3% and in the placebo group of 11.6%
(not significant). The correspondingfigures for patients with congestiveheart failure were 28.3% and 30% (not significant). Thus, neither in DAVIT I nor II wasa detrimental effect of verapamil in patients with congestive heart failure demonstrated.But the overall effect of verapamil was found in patients without a history of congestive heart failure in the coronary care unit. The beneficial effect of verapamil in patients without congestiveheart failure is in accordancewith the findings of MDPIT26 that diltiazem reducedcardiac eventsin patients without congestiveheart failure. In patients with congestiveheart failure, verapamil did not increase cardiac event rate, contrary to the results of MDPIT, which demonstrated an increasedcardiac eventrate in patients with congestive heart failure in the coronary care unit treated with diltiazem compared with patients treated with placebo. other studies: Two other large-scalepostinfarction, double-blind, placebo-controlled trials have been conducted with calcium antagonists:the SecondaryPrevention Reinfarction Israeli Nifedipine Trial (SPRINT)27 and MDPIT.26 The protocols of these 2 trials are very similar to the DAVIT II protocol, although we excluded patients in need of Badrenoreceptor blocker treatment. Twenty percent of the patients in SPRINT and about
1
24
20
180
Days
360
540
360
180
5iO
Days
~~,~ - - - -- Verapamil No Heart Failure
PlGURE4.CmdaUVe~eventr~~t0baamsnthpatidswRhandwitheuthsartfaiiwe.Nmbsrefpe uentsatlisitbdlewnatthsbettm.~,no~f~, n=574;vempmnl,nohedfdhm,n=~~,~ verapmii, hem-l f&me, n = 291. faihe,n=323;
38 1
-.
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66
PIGURE 5. Cuddive mortmlity Me, mccodw to hpdiWltSWRhdWRhOUthavttaiiUrS.NumbarOf~ mttisshownmtthebott~.(Ra(woduoed with pennisdon hm Am J Cardiol..s)
TABLE VI Meta-Analyse@ of Total Mortality, and Reinfarctions Based on DAVIT I and l14,g Number of Randomized Allocated Allocated Placebo Verapamil Deaths 60/679 DAVIT I * 46/671 119/897 DAVIT II 95/878 Pooled odds ratio 0.78; 95% confidence Major events 87/679 DAVIT I * 68/67 1 146/878 180/897 DAVIT II Pooled odds ratio 0.79; 95% confidence Reinfarctions 32/671 50/679 DAVIT I* DAVIT II 84/878 107/897 Pooled odds ratio 0.73; 95% confidence
to the effect of ,f3blockers. Thus, verapamil may be considered as an alternative to P-blocker treatment after an acute myocardial infarction.
Major Events
Statistical Calculations Obs. Minus Variance of O-E Expect. (O-E) -6.6 -10.9 interval 0.634.99;
24.6 47.1 p = 0.04
-9.0 -15.3 interval 0.654.95;
34.3
-8.7 -10.5 interval 0.57-0.94;
CONCLUSIONS
The overall effect of long-term verapamil treatment in patients after an acute myocardial infarction, as demonstrated in DAVIT I and II, is a 20 to 27% reduction in oddsratio of death, reinfarction and major events,which correspondsto the findings in trials with 0 adrenoreceptor-blocking drugs. The effect is first of all related to a beneficial effect in patients without congestiveheart failure during the acute myocardial infarction. Basedon the results of DAVIT I and II, the reduced prevalence of angina pectoris in the verapamil-treated patients, compared with the placebo-treated patients, and the documented effect of verapamil in all types of angina, verapamil may be recommendedfor treatment of patients after an acute myocardial infarction.
66.6 p = 0.02 19.2
42.6 p = 0.02
alive day 8. expect. = expected; obs. = observed. ’ Patents
55% of the patients in MDPIT were on @blockers at randomization. The inclusion rate was 48% in SPRINT and 18% in MDPIT compared with 40% in DAVIT II. The l-year mortality rate of about 6 to 7% in SPRINT and MDPIT should be comparedwith 10.8%in the DAVIT II placebo group. It is also of interest to note that 25% of the 333 deaths in MDPIT were classified as noncardiac compared with 18% of 132 deaths in SPRINT and 15%of 214 deaths in DAVIT II. SPRINT, using 30 mg nifedipine/day, found a lo-month mortality and nonfatal reinfarction rate of 5.7% and 4.8% respectively in the placebo group, and of 5.8% and 4.4% respectivelyin the nifedipine group (not significant). The patients in MDPIT received 240 mg of diltiazem a day. After a mean observation period of 25 months, the mortality rates in the placebo and diltiazem groups were equal (about 16%) and the cardiac event rates (cardiac death and nonfatal reinfarction) about 20% and 18%. Thus, neither nifedipine nor diltiazem demonstratedan overall beneficial effect on survival or reinfarction rate after an acute myocardial infarction. The lack of effect of nifedipine might be explained by the pronounced vasodilator properties of nifedipine often associatedwith an increase in heart rate.27The lack of effect of diltiazem might be related to simultaneousp-blocker treatment in about 55% of the patients. If the 2 drugs are influencing the same factors, no further effect could be expected by adding diltiazem to @blockers.28 Yusuf et a129recently gave an extensive review of early and late intervention trials in patients after an acute myocardial infarction based on meta-analyses. In 25 long-term, late-intervention P-blocker trials, the reduction in pooled odds ratio of mortality was calculated at 22% (95% confidence interval [CI] 16 to 30%) and of reinfarctions, 27% (CI 17 to 37%). In 10 antiplatelet trials, the respectivefigures were 11%(CI 2 to 19%)and 31%(CI 21 to 41%). This meansthat both /I blockersand antiplatelet drugs have a beneficial effect, and that the beneficial effect of verapamil evaluated from the 2 verapamil studies, DAVIT I and II (Table VI), corresponds
1. Nayler WG. Calcium antagonists and the ischemic myocardium. Int J Cardiol 1987:15:267-285. 2. Kloner RA, Braunwald E. Effects of calcium antagonists on infarcting myocardium. Am J Cardiol 1987;59:84B-94B. 3. Skolnick AE, Frishman WH. Calcium-channel blockers in myocardial infarction. Arch Intern Med 1989;149:1669~1677. 4. The Danish Study Group on Verapamil in Myocardial Infarction. Verapamil in acute myocardial infarction. Eur Heart J 1984;5:516-558. 5. Hansen JF, Sigurd B, Mellemgaard K, Lyngbye J. Verapamil in acute myocardial infarction. Dan Med Bull 1980;27:105~109. 6. The Danish Study Group on Verapamil in Myocardial Infarction. Verapamil in acute myocardial infarction. Am J Cardiol 1984;54:24E-28E. 7. The Danish Study Group on Verapamil in Myocardial Infarction. The Danish studies on verapamil in myocardial infarction. Br J C/in Pharmacol 1986;21:1973-204s. 8. Hansen JF. The Danish Study Group on Verapamil in Myocardial Infarction. Letter to the editor. Eur Heart J 1986;7:910-911. 9. The 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 11 (DAVIT II). Am / Cardiol 1990;66:779-785. 10. Reimer KA, Jennings RB. Verapamil in two reperfusion models of myocardial infarction. Lob Invest 1984;51:655-666. 11. Yellon DM, Hearse DJ. Maxwell MP, Chambers DE, Downey JM. Sustained limitation of myocardial necrosis 24 hours after coronary artery occlusion: Verapamil infusion in dogs with small myocardial infarcts. Am J Cardiol 1983;51:1409-1413. 12. Przyklenk K, Kloner RA. Effect of verapamil on postischemic “stunned” myocardium. Importance of the timing of treatment. J Am Coil Cardiol 1988;11:614-623. 13. Subramanian VB, Bowles ML, Lahiri A, Davies AB, Raftery EB. Long-term antianginal action of verapamil assessed with quantitated serial treadmill stress testing. Am J Cardiol 1981;48:529-535. 14. Mauritson DR, Johnson SM, Winniford MD, Gary JR, Willerson JT, Hillis LD. Verapamil for unstable angina at rest. A short-termed, randomized, doubleblind study. Am Heart J 1983;106:652-658. 15. Mauri F, Mafrici A, Biraghi M, Cerri P, De Biase AM. Effectiveness of calcium antagonist drugs in patients with unstable angina and proven coronary artery disease. Eur Heart J 1988;9(suppl N):158-163. 16. Johnson SM, Mauritson DR, WilIerson JT, Hillis LD. A controlled trial of verapamil for Prinzmetal’s variant angina. N Engl J Med 1981;304:862-866. 17. Parodi 0, Simonetti I, Michelassi C, Carpeggiani C, Biagini A, L’Abbate A, Maseri A. Comparison of verapamil and propranolol therapy for angina at rest: A randomized, multiple crossover, controlled trial in the coronary care unit. Am J Cardiol 1986;57:899-906. 16. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockadeduring and after mywardial infarction: An overview of the randomized trials. Prog Cardiooasc Dis 1985;27:335-371. 19. The Danish Study Group on Verapamil in Myocardial Infarction. Abrupt withdrawal of verapamil in ischemic heart disease. Eur Heart J 1984,5:529-532. 20. Kauman JA, Aramendia P. Prevention of ventricular fibrillation induced by
THE AMERICAN
JOURNAL
OF CARDIOLOGY
DECEMBER
18, 1990
39 1
A SYMPOSIUM:
ATNENOSCLENOSIS
AND VASCULAR
PROTECTION
coronary ligation. J Pharmocol Exp Ther 1968;164:326-340. 21. Sugiyama S, Ozawa T, Suzuki K, Kate T. Effects of verapamil and propranolol on ventricular vulnerability after coronary reperfusion. J Electrocardiol 1980;13:49-54. 22. Peter T, Fujimoto T, Hamamoto H, Mandel WJ. Comparative study of the effect of slow channel-inhibiting agents on ischemla-induced conduction delay as relevant to the genesis of ventricular fibrillation. Am Heart J 1983;106:10231028. 23. Rolli A, Favaro L, Finardi A, Aurier E, Bonatti V, Botti G. Efflcacite du verapamil dans la pr6vention de la fibrillation ventriculaire B la phase aigue de l’infarctus du myocarde. Arch Mul Coeur 1988;81:907-911. 24. Woelfel A, Foster JR, McAllister RG, Simpson RJ, Gettes LS. Efficacy of verapamil in exercise-induced ventricular tachycardia. Am J Cardiol 1985;56:292-297.
40 I
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66
25. Giilker H, Godejohann U, Dorsel T, Behrenbeck T, Heuer H, Bender F. Prophylaxe belastungsinduzierter ventrikuliirer Arrhythmien durch Verapamil. Z Kardiol 1987;76:404-410, 26. The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Eng/ J Med 1988;319:385-392. 27. The Israeli SPRINT Study Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT). A randomized intervention trial of nifedipine in patients with acute myocardial infarction. Eur Heart J 1988;9:354-364. 28. Packer M. Combined beta-adrenergic and calcium-entry blockade in angina pectoris. N Engl J Med 1989;320:709-718. 29. Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinical trials in heart disease. I. Treatments following myocardial infarction. JAMA 1988;2088-2093.