Norwegian Multicenter Study Group timolol trial
Purpose
To determine whether long-term therapy with the β-blocker timolol reduces all-cause mortality and reinfarction in patients surviving MI
Reference
The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981; 304: 801–7.
Norwegian Multicenter Study Group timolol trial - TRIAL DESIGN -
Design
Multicenter, randomized, double-blind, placebo-controlled
Patients
1884 patients, mean age 55 years, with acute MI in previous 7–28 days
Follow up and primary end point
Mean 17 months follow up. Primary endpoint all-cause mortality
Treatment
Placebo or timolol 10 mg twice daily
Norwegian Multicenter Study Group timolol trial - RESULTS -
In timolol group, compared with placebo, significant reduction in:
All-cause mortality (10.6 vs. 17.5%, P=0.0005)
Sudden cardiac death (7.7 vs. 13.9%, P=0.0001)
Reinfarction (14.4 vs. 21%, P=0.0006)
Reduction in mortality and sudden death evident early on and difference between groups increased for first 24 months
Difference in withdrawal pattern between timolol and placebo groups was significant (29.1 vs. 23.3%, P<0.01) and due to known side effects of β-adrenergic blockade
Norwegian Multicenter Study Group timolol trial - RESULTS continued -
All-cause mortality and sudden death
Months after randomization
0
18
12
6
24
30
36
0.25
0.20
0.15
0.20
0.05
0.00
Death from all causes
Sudden cardiac death
Placebo
Norwegian Multicenter Study Group. N Engl J Med 1981; 304: 801–7.
*
Death during trial or within
28 days of last dose
Timolol
Norwegian Multicenter Study Group timolol trial - RESULTS continued -
Reinfarction
Months after randomization
0
18
12
6
24
30
36
0.25
0.20
0.15
0.20
0.05
0.00
Cumulative
reinfarction
rate
*
Placebo
Timolol
Norwegian Multicenter Study Group. N Engl J Med 1981; 304: 801–7.
*
Reinfarction during trial
or within 28 days of the last dose
Norwegian Multicenter Study Group timolol trial - RESULTS continued -
Bradycardia
(heart rate <40 beats/min)
Hypotension
Cold hands and feet
Asthenia or fatigue
Pneumonia or bronchitis
Bronchial obstruction
3
15
6
11
27
7
2
11
0
1
0
4
37
26
4
4
0
10
47
29
73
45
45
18
<0.001
<0.05
<0.001
<0.001
<0.05
<0.05
<0.001
<0.05
Significant adverse reactions and reasons for withdrawal from trial
Norwegian Multicenter Study Group. N Engl J Med 1981; 304: 801–7.
Timolol
(n=945)
Timolol
(n=945)
Placebo
(n=939)
Placebo
(n=939)
P
P
Adverse reaction
Withdrawal due to reaction
Norwegian Multicenter Study Group timolol trial - SUMMARY -
After acute MI, long-term timolol reduced:
All-cause mortality
Sudden cardiac death
Reinfarction