Unstable angina or non Q-wave MI: few benefited from early angioplasty and none from giving tPA.

Clinical bottom line (level 1b)

  1. tPA given to patients with unstable angina or non-Q-wave MI did not prevent deaths, non-fatal MI, episodes of ischaemia or revascularisation procedures at six weeks or one year. Intracranial haemorrhage may be increased.
  2. Early angioplasty followed by CABG if required compared with PTCA only after failure of medical therapy leds to fewer patients on more than one antianginal drug (NNT = 14 at 6 weeks) , and fewer readmissions (NNT = 16 at 6 weeks)
  3. However, more patients had a revascularisation procedure at one year (NNT = 16 at 12 months) , and there was no clear effect on death, non-fatal MI or episodes of ischaemia.
TIMI III-B Investigators : Circulation 1994; 89: 1545-1556
Anderson et al: Journal of the American College of Cardiology 1995; 26: 1643-1650
Expires July 2003

The study

Unblinded concealed randomised trial with intention-to-treat
Setting: 31 hospitals, USA and Canada

1473 patients (aged range 21 to 79 years; mean 58, 66% male) unstable angina or non Q-wave MI defined as chest pain at rest lasting between 5 minutes and 6 hours occurring within 24 hours of enrollment and objective evidence of ischaemia, one of:
  • ECG changes- ST elevation 1 mm or more in two contiguous leads for less than 30 minutes, or persistent ST depression 1 mm or more, or T wave inversion durina an episode of rest pain within the last seven days
  • history of MI
  • 70% or more luminal diameter stenosis on previous coronary angiogram
  • positive exercise thallium scintigraphy

Excluded if

  • treatable cause of unstable angina
  • MI in previous 21 days
  • coronary arteriography within last 30 days
  • PTCA <36 monthd
  • prior CABG
  • pulmonary oedema, systolic blood pressure >180 mmHg, diastolic BP >100 mmHg
  • contraindication to thrombolysis or heparin
  • left bundle branch block
  • co-existing severe illness
  • women of childbearing age
  • anticoagulants
Control Group: (n = 744, 744 analysed): placebo
Experimental Group: (n = 729, 729 analysed): tPA 0.8 mg/kg within 25 hours of pain (max 80 mg, one third, but no more than 20 mg given as a bolus, remainder over 90 minutes)
Experimental Group: (n = 740, 740 analysed): early invasive therapy. Patients had coronary angiography and PTCA if required within 18 to 48 hours. CABG performed within 6 weeks if: 50% or more left main coronary artery obstruction; three vessel disease and ejection fraction <40%; recurrent unstable angina despite medical therapy in patients who had PTCA or were not suitable for PTCA
Comparison Group: (n = 733, 733 analysed): early conservative therapy. Patients had cardiac catheterisation and angiography only after failure of initial therapy, defined as: single episode of ischaemic discomfort at rest, lasting 5 minutes or more with 2 mm ore more ST elevation or depression in two contiguous leads; single episode of ischaemic discomfort at rest, lasting 20 minutes or more, or two or more separate episodes of ischaemic pain at rest, each lasting five minutes or more with ECG changes sufficient to satisfy inclusion criteria; >20 minutes of ischaemic ST deviation on 24 hour Holter monitoring; unsatisfactory result on predischarge stress thallium exercise test before completion of modified Bruce protocol stage II- ischaemic discomfort, 2 mm or more ST segment deviation, or fall in systolic blood pressure >10 mmHg; significant abnormalities on thallium scan in two or more regions; after hospital discharge, recurrence of unstable angina with rest pain; moderate to severe angina after hospital discharge despite maximal anti-ischaemic therapy
All patients had conventional medical therapy for unstable angina: beta-blocker (metoprolol 50 mg po every 12 hours); calcium antagonist (diltiazem 30 mg po every 6 hours); long-acting nitrate (isosorbide dinitrate 10 mg po every 8 hours) or larger doses and supplemented by nitroglycerin; heparin 500 units iv bolus and a maintenance infusion so aPTT 1.5 to 2.0; aspirin 325 mg po od started on the second day and continued for a year
97% followed for 12 months

The evidence

tPa vs placebo
Outcome Time to outcome CEREERRRR
(95% CI)		ARR
(95% CI)		NNT
(95% CI)
death 6 weeks 19
(2.55%)		 17
(2.33%)		 9%
(-74% to 52%)		 0.22%
(-1.35% to 1.80%)		 451
(NNT = 56 to infinity;
NNH = 74 to infinity)
non fatal MI 6 weeks 32
(4.30%)		 48
(6.58%)		 -53%
(-137% to 1%)		 -2.28%
(-4.60% to 0.03%)		 -44
(NNT = 3000 to infinity;
NNH = 22 to infinity)
spontaneous ischaemia 6 weeks 166
(22.3%)		 136
(18.7%)		 16%
(-2% to 32%)		 3.66%
(-0.46% to 7.77%)		 27
(NNT = 13 to infinity;
NNH = 220 to infinity)
any unfavourable outcome 6 weeks 217
(29.2%)		 201
(27.6%)		 5%
(-11% to 20%)		 1.59%
(-3.01% to 6.20%)		 63
(NNT = 16 to infinity;
NNH = 33 to infinity)
death or MI 12 months 76
(10.6%)		 9
(12.4%)		 -16%
(-55% to 13%)		 -1.73%
(-4.98% to 1.53%)		 -58
(NNT = 65 to infinity;
NNH = 20 to infinity)
revascularisation 12 months 469
(63.0%)		 430
(59.0%)		 6%
(-2% to 14%)		 4.05%
(-0.93% to 9.03%)		 25
(NNT = 11 to infinity;
NNH = 110 to infinity)

early invasive vs early conservative therapy
Outcome Time to outcome CEREERRRR
(95% CI)		ARR
(95% CI)		NNT
(95% CI)
death 6 weeks 18
(2.46%)		 18
(2.43%)		 1%
(-89% to 48%)		 0.02%
(-1.55% to 1.60%)		 4300
(NNT = 64 to infinity;
NNH = 64 to infinity)
non fatal MI 6 weeks 42
(5.73%)		 38
(5.14%)		 10%
(-37% to 42%)		 0.59%
(-1.72% to 2.91%)		 170
(NNT = 34 to infinity;
NNH = 58 to infinity)
any unfavourable outcome 6 weeks 133
(18.1%)		 120
(16.2%)		 11%
(-12% to 29%)		 1.93%
(-1.92% to 5.78%)		 52
(NNT = 17 to infinity;
NNH = 52 to infinity)
using one or less antianginal drugs 6 weeks 339
(46.3%)		 394
(53.2%)		 -15%
(-28% to -4%)		 -6.99%
(-12.1% to -1.90%)		 14
(8 to 53)
readmission to hospital 6 weeks 100
(13.6%)		 55
(7.43%)		 46%
(26% to 60%)		 6.21%
(3.09% to 9.33%)		 16
(11 to 32)
death or MI 12 months 89
(12.2%)		 80
(10.8%)		 11%
(-18% to 33%)		 1.33%
(-1.92% to 4.59%)		 75
(NNT = 22 to infinity;
NNH = 52 to infinity)
revascularisation 12 months 425
(58.0%)		 474
(64.1%)		 -10%
(-20% to -2%)		 -6.07%
(-11.1% to -1.10%)		 -16
(-91 to -9)
  • Four patients given tPA had intracranial haemorrhage compared with none given placebo.

Comments

  1. tPA given late following onset of chest pain. Studies have shown benefit in patients with MI decreases over time.
  2. Results applicable to the group of patients with 'non ST elevation infarction
  3. PTCA techniques have advanced, and new methods may no longer be a less successfu option, although no study has directly compaed this.

Citation

  1. TIMI III-B Investigators , : Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI III-B Trial. Circulation 1994; 89: 1545-1556
  2. Anderson HV, et al: One-year results of the thrombolysis in myocardial infarction (TIMI) IIIb trial: a randomised comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non-Q-wave myocardial infarction. Journal of the American College of Cardiology 1995; 26: 1643-1650
Contributor: Nick Shenker and Chris Ball, July 2000
Reviewer: Christian Torp-Pedersen

Clinical Question.
Patient unstable angina or suspected non-Q wave MI
Intervention or Exposure tPA, thrombolysis, PTCA, CABG
Comparison PTCA, placebo
Outcome death, revascularisation procedures