Efficacy
of Acebutolol After Acute Myocardial Infarction (The APSI Trial)
Jean-Pierre Boissel, MD, Alain Leizorovicz, MD, Helene Picolet, MD, Thierry Ducruet, MSc, and the APSI Investigators”
A randomized, placebo-controlled trial was carried out to determine the effectiveness of acehutold in preventing late death in high-risk patients surviving an acute myocardial infarction (Ml). The average lyear mortalfty rate in placebo groups of 9 trials of @blockers in post-MI patients was 7.2% compared with 17% in a nonselected cohort of patients who had survived at least 7 days after an MI. The mandate for this trial was based on the fact that highrisk patients whose mortality rate exceeds 20% have not been enrdkrd in significant numbers in previous trials. It remains to be proved whether BMocking therapy in this patient population is beneficial. Selection of high-risk patients for inckrsion in the trial was based on an algorithm set up from the Essai de Prevention Secondaire de I’lnfarctus du Myocarde Registry. At the time of the second interim analysis, the mortality rate in the placebo group was 12%, lower than expected (120%). The trial was stopped; at that time, 309 patients had been allocated to placebo and 298 patients to acebutolol therapy. After 318 days, there were 17 deaths in the acebutolol-treated group and 34 in the placebo group, a reduction in total mortality of 48% (p = 0.019). There were 30 vascular deaths in the placebo group and 12 in the acebutolol group. Thus, cardfovascular mortality with acebutolol was reduced by 58% (p = 0.00s). The incidence of all cardiovascular-related deaths was lower in the acebutdol-treated group. The total reduction in mortality did not appear to be correkrted with secondary risk factors. Although the objective of the
From the APSI Coordinating Center. Unite de Pharmacologic Clinique, Lyon, France. Address for reprints: Jean-Pierre Boisscl, MD, APSI Coordinating Center, Unite de Pharmacologic Clinique, 162 avenue Lacassagne, 69424 Lyon Cedex 3, France. *See Appendix. 24C
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66
study, which was to enroll patients at high risk, was not met, the patients in this trial were at hlgher rfsk than average patients in previous trials. We conclude that moderately high-risk post-MI patients can benefit from treatment with @blockers, and @blockers with mild intrinsic sympathomimetic activity can be effective. (Am JCardioi 1990;6624C-31C)
A
cebutolol et Prevention Secondairede l’lnfarctus (APSI), a double-blind, placebo-controlledtrial of acebutolol following myocardial infarction (Ml), was designed to assessthe efficacy and safety of acebutolol in high-risk patients after acute Ml.’ It has been reported that the average l-year mortality rate in the placebo groups of previous late-intervention trials with @blockers is approximately 7%2;however,the average 1-year mortality rate of an unselectedgroup of 6,900 patients still alive 8 daysafter an acute Ml was 17%in the Essai de Prevention Secondairc de I’Infarctus du Myocarde (EPSIM) Registry kept between 1975and 1979.3 Therefore, the efficacy of p blockers in secondaryprevention after an acute MI has been assessedonly in low- or moderate-risk patients and not in high-risk patients. A post-hoc subgroup analysis of the pooleddata from the first 9 trials showed that all subgroups of patients benefited from treatment. Subgroups with the presence of high-risk prognostic factors that indicated mechanical or electrical failure benefited the most from treatmcnt.4 However, even in those high-risk subgroups,the l-year placebo group mortality rate was 2 and 60 years Female Prior history Angina pectoris Unstable angina Angina pectoris >5 years Nonproven MI Acute pulmonary edema Severe exertional dyspnea Nocturnal dyspnea Intermittent claudication Valvular disease Diabetes mellitus Renal failure Liver cirrhosis Contraindication to oral anticoagulants Present or former smoker Hypertension Onset of symptoms Infarct location other than posterior or inferior Shock Acute pulmonary edema Conduction defect or rhythm disturbance Palpitations Arrhythmia Murmur Cyanosis Cold hands and feet Hepatomegaly Hepatojugular reflux Early stage Breathlessness Choking Relieved in sitting position Smarting Foaming expectoration Auriculoventricular block Heart rate >65 beats/min Major risk factors Prior history of Documented Ml Dyspnea on flat ground Acute stage Atrial fibrillation Ventricular fibrillation or ventricular tachycardia Heart failure Early stage Sinus tachycardia Recurrent angina pectoris Recurrent Ml Number of risk factors (range)
26C
DISEASE
THE AMERICAN JOURNAL OF CARDIOLOGY
548 hours After Admission (n = 719)
Excluded >48 hours After Admission (n = 945)
Included Same Centers (n = 219)
Included Study Total (n = 607)
68.00 29.40
52.00 19.70
52.97 22.83
61.61 27.18
42.10 27.20 21.70 3.80 3.70 22.30 3.40 13.80 3.90 13.40 4.40 2.80 58.50 29.60
35.20 24.10 11.90 1.60 1.50 12.40 1.60 7.10 4.40 10.20 1.30 0.40 3.60 70.30 20.60
41.10 29.22 14.16 2.74 1.37 32.42 0.91 8.68 3.20 15.53 1.83 1.83 4.11 72.15 25.11
43.99 29.00 17.96 2.47 1.65 33.11 1.81 8.90 5.27 14.33 3.13 1.81 5.60 65.07 31 .a0
53.90 6.50 13.90 6.60 3.20 7.30 19.30 4.60 9.60 4.60 9.00
51 .oo 3.30 8.20 8.20 1 .?O 3.90 11.80 1.40 5.00 3.20 5.30
63.01 5.94 15.53 21.00 6.39 9.13 13.24 2.28 11.87 4.57 10.05
69.36 6.10 14.17 16.31 9.06 12.85 14.99 3.79 10.38 2.97 7.58
27.20 20.10 15.20 11.10 4.60 10.70 76.60
16.80 12.10 11.10 5.30 2.80 6.10 86.50
36.99 22.83 20.55 5.02 3.20 10.05 94.9%
41.35 21.42 21.91 6.26 3.13 9.23 93.25
20.30 12.00
11.80 4.20
22.83 13.24
21.58 13.84
8.30 3.00 41.50
5.40 14.60 24.30
10.50 21.92 48.40
15.82 26.36 49.59
10.30 7.00 1.50 5 (O-31)
26.48 13.70 3.65 8 (6-20)
26.85 15.98 3.62 8 (6-20)
6 (l-25)
VOLUME 66
TABLE
III
Reasons
for Exclusion
in 1,664
Patients Excluded During First 48 Hours (n = 719)
domizedpatients is shownin Figure 2. Individual predicted risk wascomputedfrom a logistic function constructed from the EPSIM registry data. The distribution of included and excluded patients in relation to their l-year theoretical risk of mortality is shown in Figure 3. There was no statistically significant difference with respect to predicted risk betweenthe acebutolol group and the placebo group. The baseline characteristics of the 2 groups were assessedthrough comparisonof 266 baselinevariables; only 7 of these 266 characteristics were statistically significantly different (p 75 years Indication for p blockers Other contraindications to p blockers Raynaud’s syndrome Chronic bronchopneumopathy Asthma Nonproven infarction Coma Death Not available
5 5 228 39 31 97 128 131
0.7 0.7 32.0 5.5 4.4 13.6 18.0 18.4 1.4 7.1 2.8 8.0 1.8 7.4 1.3
10 51 20 57 13 53 9
Excluded Between Day 3 and Day 21 (n = 945) Criteria
No.
Complete auriculoventricular block (3rd grade) Cardiac failure requiringtreatment with 22 drugs of different classes Bradycardia (
of Acebutolol After Acute Myocardial Infarction (The APSI Trial)
Jean-Pierre Boissel, MD, Alain Leizorovicz, MD, Helene Picolet, MD, Thierry Ducruet, MSc, and the APSI Investigators”
A randomized, placebo-controlled trial was carried out to determine the effectiveness of acehutold in preventing late death in high-risk patients surviving an acute myocardial infarction (Ml). The average lyear mortalfty rate in placebo groups of 9 trials of @blockers in post-MI patients was 7.2% compared with 17% in a nonselected cohort of patients who had survived at least 7 days after an MI. The mandate for this trial was based on the fact that highrisk patients whose mortality rate exceeds 20% have not been enrdkrd in significant numbers in previous trials. It remains to be proved whether BMocking therapy in this patient population is beneficial. Selection of high-risk patients for inckrsion in the trial was based on an algorithm set up from the Essai de Prevention Secondaire de I’lnfarctus du Myocarde Registry. At the time of the second interim analysis, the mortality rate in the placebo group was 12%, lower than expected (120%). The trial was stopped; at that time, 309 patients had been allocated to placebo and 298 patients to acebutolol therapy. After 318 days, there were 17 deaths in the acebutolol-treated group and 34 in the placebo group, a reduction in total mortality of 48% (p = 0.019). There were 30 vascular deaths in the placebo group and 12 in the acebutolol group. Thus, cardfovascular mortality with acebutolol was reduced by 58% (p = 0.00s). The incidence of all cardiovascular-related deaths was lower in the acebutdol-treated group. The total reduction in mortality did not appear to be correkrted with secondary risk factors. Although the objective of the
From the APSI Coordinating Center. Unite de Pharmacologic Clinique, Lyon, France. Address for reprints: Jean-Pierre Boisscl, MD, APSI Coordinating Center, Unite de Pharmacologic Clinique, 162 avenue Lacassagne, 69424 Lyon Cedex 3, France. *See Appendix. 24C
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66
study, which was to enroll patients at high risk, was not met, the patients in this trial were at hlgher rfsk than average patients in previous trials. We conclude that moderately high-risk post-MI patients can benefit from treatment with @blockers, and @blockers with mild intrinsic sympathomimetic activity can be effective. (Am JCardioi 1990;6624C-31C)
A
cebutolol et Prevention Secondairede l’lnfarctus (APSI), a double-blind, placebo-controlledtrial of acebutolol following myocardial infarction (Ml), was designed to assessthe efficacy and safety of acebutolol in high-risk patients after acute Ml.’ It has been reported that the average l-year mortality rate in the placebo groups of previous late-intervention trials with @blockers is approximately 7%2;however,the average 1-year mortality rate of an unselectedgroup of 6,900 patients still alive 8 daysafter an acute Ml was 17%in the Essai de Prevention Secondairc de I’Infarctus du Myocarde (EPSIM) Registry kept between 1975and 1979.3 Therefore, the efficacy of p blockers in secondaryprevention after an acute MI has been assessedonly in low- or moderate-risk patients and not in high-risk patients. A post-hoc subgroup analysis of the pooleddata from the first 9 trials showed that all subgroups of patients benefited from treatment. Subgroups with the presence of high-risk prognostic factors that indicated mechanical or electrical failure benefited the most from treatmcnt.4 However, even in those high-risk subgroups,the l-year placebo group mortality rate was 2 and 60 years Female Prior history Angina pectoris Unstable angina Angina pectoris >5 years Nonproven MI Acute pulmonary edema Severe exertional dyspnea Nocturnal dyspnea Intermittent claudication Valvular disease Diabetes mellitus Renal failure Liver cirrhosis Contraindication to oral anticoagulants Present or former smoker Hypertension Onset of symptoms Infarct location other than posterior or inferior Shock Acute pulmonary edema Conduction defect or rhythm disturbance Palpitations Arrhythmia Murmur Cyanosis Cold hands and feet Hepatomegaly Hepatojugular reflux Early stage Breathlessness Choking Relieved in sitting position Smarting Foaming expectoration Auriculoventricular block Heart rate >65 beats/min Major risk factors Prior history of Documented Ml Dyspnea on flat ground Acute stage Atrial fibrillation Ventricular fibrillation or ventricular tachycardia Heart failure Early stage Sinus tachycardia Recurrent angina pectoris Recurrent Ml Number of risk factors (range)
26C
DISEASE
THE AMERICAN JOURNAL OF CARDIOLOGY
548 hours After Admission (n = 719)
Excluded >48 hours After Admission (n = 945)
Included Same Centers (n = 219)
Included Study Total (n = 607)
68.00 29.40
52.00 19.70
52.97 22.83
61.61 27.18
42.10 27.20 21.70 3.80 3.70 22.30 3.40 13.80 3.90 13.40 4.40 2.80 58.50 29.60
35.20 24.10 11.90 1.60 1.50 12.40 1.60 7.10 4.40 10.20 1.30 0.40 3.60 70.30 20.60
41.10 29.22 14.16 2.74 1.37 32.42 0.91 8.68 3.20 15.53 1.83 1.83 4.11 72.15 25.11
43.99 29.00 17.96 2.47 1.65 33.11 1.81 8.90 5.27 14.33 3.13 1.81 5.60 65.07 31 .a0
53.90 6.50 13.90 6.60 3.20 7.30 19.30 4.60 9.60 4.60 9.00
51 .oo 3.30 8.20 8.20 1 .?O 3.90 11.80 1.40 5.00 3.20 5.30
63.01 5.94 15.53 21.00 6.39 9.13 13.24 2.28 11.87 4.57 10.05
69.36 6.10 14.17 16.31 9.06 12.85 14.99 3.79 10.38 2.97 7.58
27.20 20.10 15.20 11.10 4.60 10.70 76.60
16.80 12.10 11.10 5.30 2.80 6.10 86.50
36.99 22.83 20.55 5.02 3.20 10.05 94.9%
41.35 21.42 21.91 6.26 3.13 9.23 93.25
20.30 12.00
11.80 4.20
22.83 13.24
21.58 13.84
8.30 3.00 41.50
5.40 14.60 24.30
10.50 21.92 48.40
15.82 26.36 49.59
10.30 7.00 1.50 5 (O-31)
26.48 13.70 3.65 8 (6-20)
26.85 15.98 3.62 8 (6-20)
6 (l-25)
VOLUME 66
TABLE
III
Reasons
for Exclusion
in 1,664
Patients Excluded During First 48 Hours (n = 719)
domizedpatients is shownin Figure 2. Individual predicted risk wascomputedfrom a logistic function constructed from the EPSIM registry data. The distribution of included and excluded patients in relation to their l-year theoretical risk of mortality is shown in Figure 3. There was no statistically significant difference with respect to predicted risk betweenthe acebutolol group and the placebo group. The baseline characteristics of the 2 groups were assessedthrough comparisonof 266 baselinevariables; only 7 of these 266 characteristics were statistically significantly different (p 75 years Indication for p blockers Other contraindications to p blockers Raynaud’s syndrome Chronic bronchopneumopathy Asthma Nonproven infarction Coma Death Not available
5 5 228 39 31 97 128 131
0.7 0.7 32.0 5.5 4.4 13.6 18.0 18.4 1.4 7.1 2.8 8.0 1.8 7.4 1.3
10 51 20 57 13 53 9
Excluded Between Day 3 and Day 21 (n = 945) Criteria
No.
Complete auriculoventricular block (3rd grade) Cardiac failure requiringtreatment with 22 drugs of different classes Bradycardia (
