The Norwegian Multicenter Study on Timolol After Myocardial Infarction ‐ Design, Management and Results on Mortality

ABSTRACT A cooperative clinical trial involving 20 hospitals in Norway was carried out to establish the effect of timolol (10 mg twice daily) compared with placebo in patients surviving acute myocardial infarction (AMI). The study was conducted in a randomized double‐blind manner. All patients 20–75 years of age admitted to the centers with suspected AMI were registered and screened for the qualifying diagnosis. If the diagnosis of AMI was confirmed, the patients were evaluated for inclusion into the trial 6–27 days after onset of symptoms when being clinically stable. Of the 3647 patients evaluated, 1763 (48.3 %) had one or more of the criteria for exclusion from entry. These were contraindications to betablockade (18 %), serious disease impeding follow‐up (7 %), need for betablockade (9 %), need for other concomitant treatment not allowed (e.g. anti‐arrhythmics) (4 %) or administrative reasons and unwillingness to participate (10 %). The remaining, 1884 patients (51.7 %) were randomly allocated to treatment with timolol (945) or placebo (939) the morning after the evaluation. Patients were stratified into 3 risk groups. In Risk Group I were patients with more than one infarction, Risk Group II were patients with a first AMI at high risk of late cardiac death and Risk Group III were patients with a first AMI at low risk. Clinical examination was done after 1, 3 and 6 months, thereafter every 6 months. Follow‐up time ranged from 12 to 33 months. The groups were comparable with respect to important baseline characteristics. There were 152 deaths in the placebo group and 98 in the timolol group in the entire series. The life table cumulative probability of total death over 33 months was 21.0 % in the placebo and 13.3 % in the timolol group, corresponding to a reduction of 39.4 % (p=0.0003). The number of patients withdrawn from the trial medication was 219 in the placebo and 275 in the timolol group (p<0.01). The number of deaths during the first 28 days after withdrawal was 19 in the placebo group and 12 in the timolol group. When restricting the analysis to death occurring while the patient was taking the test medication or within 28 days of withdrawal («per protocol») there were 117 deaths in the placebo and 67 in the timolol group. The life table cumulative probability of death analysed per protocol was 17.5 % and 10.6 % in the placebo and timolol groups corresponding to a reduction of 39.3 % (p=0.0005).