Norwegian Multicenter Study Group timolol trial

1
Norwegian Multicenter Study Group timolol trial

• Purpose
• To determine whether long-term therapy with the
  ß-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
  8017.

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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 728 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

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Norwegian Multicenter Study Group timolol trial
- RESULTS -

• In timolol group, compared with placebo,
  significant reduction in
• All-cause mortality (10.6 vs. 17.5, P0.0005)
• Sudden cardiac death (7.7 vs. 13.9, P0.0001)
• Reinfarction (14.4 vs. 21, P0.0006)
• 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, Plt0.01) and due to known side effects of
  ß-adrenergic blockade

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Norwegian Multicenter Study Group timolol trial
- RESULTS continued -

All-cause mortality and sudden death
0.25
Death from all causes
Sudden cardiac death
0.20
Placebo
0.15
0.20
Timolol
0.05
0.00
0
18
12
6
24
30
36
Months after randomization

Death during trial or within
28 days of last dose
Norwegian Multicenter Study Group. N Engl J Med
1981 304 8017.

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Norwegian Multicenter Study Group timolol trial
- RESULTS continued -

Reinfarction
Cumulative
0.25
reinfarction

rate
0.20
0.15
0.20
Placebo
0.05
Timolol
0.00
0
18
12
6
24
30
36
Months after randomization

Reinfarction during trial
Norwegian Multicenter Study Group. N Engl J Med
1981 304 8017.
or within 28 days of the last dose
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Norwegian Multicenter Study Group timolol trial
- RESULTS continued -

Significant adverse reactions and reasons for
withdrawal from trial
Adverse reaction
Withdrawal due to reaction
Timolol
Timolol
Placebo
Placebo
P
P
(n945)
(n945)
(n939)
(n939)
Bradycardia
3
2
37
47
lt0.001
lt0.001
(heart rate lt40 beats/min)






Hypotension
15
11
26
29
lt0.05
lt0.05
Cold hands and feet
6
0
4
73
lt0.001
Asthenia or fatigue
11
1
4
45
lt0.001
Pneumonia or bronchitis
27
0
0
45
lt0.05
Bronchial obstruction
7
4
10
18
lt0.05
Norwegian Multicenter Study Group. N Engl J Med
1981 304 8017.
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Norwegian Multicenter Study Group timolol trial
- SUMMARY -

• After acute MI, long-term timolol reduced
• All-cause mortality
• Sudden cardiac death
• Reinfarction