THE NORWEGIAN MULTICENTER STUDY ON TIMOLOL AFTER MYOCARDIAL INFARCTION
Authors: Johansen PerLund‐ 
Published: August 2010

The reduction in mortality induced by timolol was seen in all three risk groups. Thus the cumulative probability of death at 33 months (analyzed «per protocol») was reduced by 25 % in risk group I (p<0.05), 50 % in risk group II (p<0.01) and by 19 % in risk group III (ns). When number of deaths was analyzed «as randomized», a statistically significant reduction in mortality was seen also in risk group III.

93 % of all deaths on treatment or within 28 days after withdrawal were cardiac deaths, 113 in the placebo group versus 58 in the timolol group (p<0.001). The number of sudden deaths (death < 24 hrs after onset of symptoms) was 95 in the placebo group versus 47 in the timolol group (p<0.001). Only 13 deaths were non‐cardiac (cerebrovascular disease (5), malignancies (4), other (4)).

When the cause of death (in the per protocol period) was classified as instant, primary arrhythmia, cardiac failure, found dead, new MI or non‐cardiac, statistically significant fewer deaths in the timolol group were found in the following categories: instant death (38 versus 11, p<0.001), primary arrhythmia (7 versus 0, p<0.05), found dead (26 versus 9, p<0.01).

Among patients withdrawn from the study there was no difference in deaths occurring later than 28 days after withdrawal. In the first 28 days after withdrawal a tendency to reduction in mortality in the timolol‐treated patients was still seen.

In «the per protocol period» there were 52 episodes of witnessed heart arrest in the placebo group versus 19 in the timolol group (p<0.001). The total number of all probable heart arrests and instant deaths (witnessed and non‐witnessed) was 77 in the placebo group versus 26 in the timolol group (p<0.001).

The number of initial re‐infarctions in «the per protocol period» was lower in the timolol‐ than in the placebo‐treated patients in all risk groups, the difference being statistically significant in risk group II and in all risk groups combined. The cumulative re‐infarction rate at 33 months was 20.1 % in the placebo group and 14.4 % in the timolol group ‐ a reduction of 28.4 % (p<0.001). The difference in cumulative reinfarction rate between placebo and timolol was almost unchanged after 6 months of follow‐up. Relatively few severe adverse experiences were seen. Heart failure was reported in 63 patients in the placebo group versus 73 in the timolol group. The difference between placebo‐ and timolol‐treated patients reached levels of statistical significance for the following adverse experiences: bradycardia, hypotension, asthenia, cold hands and feet, bronchial obstruction ‐ all appearing more frequently in the timolol group.

Arrhythmias requiring treatment were seen more frequently in the placebo group, 38 versus 13 (p<0.001). Need for beta‐blocker was also seen more frequently in the placebo group, 68 versus 32 (p<0.001).

In conclusion, the study has shown that when conventional contraindications to beta‐blockade are respected, a large proportion of patients surviving a MI can be given timolol 7–28 days after onset of symptoms and that timolol reduces mortality and re‐infarction rates substantially in these patients.