Thrombolysis In Myocardial Infarction trial, phase II - TIMI 2


Medical and PTCA management strategies in acute MI.


In an effort to prevent recurrent ischemia and reocclusion, an aggressive, invasive strategy may improve outcome. The strategy includes routine coronary arteriography performed 18 to 48 hours after the administration of rt-PA followed by prophylactic percutaneous transluminal angioplasty (PTCA) if the arteriography demonstrated that the anatomy was suitable.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 3,339
Mean Follow Up: 3 years
Mean Patient Age: 56.8
Female: 18

Patient Populations:

Men and women <76 years of age.
ST-segment elevation (0.1 mV) in at least two electrically contiguous ECG leads.
30 minutes of chest pain suggestive of acute myocardial ischemia.
Treatment with rt-PA could be started within four hours of the onset of the chest pain that precipitated hospital admission.
Patient consent to participate after the study goals, procedures, and risks were explained.


History of a cerebrovascular event
Blood pressure of >180 mmHg systolic or >110 mmHg diastolic
Bleeding disorder
Surgery within the previous two weeks
Recent prolonged cardiopulmonary resuscitation
Percutaneous transluminal coronary angioplasty (PTCA) or severe trauma within six months
Previous coronary artery bypass graft (CABG)
Prosthetic heart valve replacement
Left bundle branch block
Dilated cardiomyopathy
Other serious illness

Primary Endpoints:

Survival that is free of recurrent MI at 42 days

Secondary Endpoints:

Complications of rt-PA therapy and PTCA

Drug/Procedures Used:

rt-PA in all patients, (1) in first 520 patients, 150 mg/6 hours IV (90mg during the first hour, 20mg during the second hour, and 10mg during each of the next 4 hours), (2) because of an unacceptable frequency of intracranial hemorrhage, subsequent pat

Concomitant Medications:

Lidocaine, 1-1.5 mg/kg bolus injection followed by an infusion of 2 to 4 mg/minute for a minimum of 24 hours; heparin given at the start of rt-PA infusion, 5000 U IV bolus followed by a 5-day constant infusion initially at 1000 U/hour, but adjusted to maintain the activated partial thromboplastin time of 1.5-2.0-fold the control; on day 6, 10,000 U of subcutaneous heparin every 12 hours and continued until the predischarge exercise test. In the first 217 patients, aspirin, 80 mg daily for 5 days beginning on the day of rt-PA administration and at a dose of 325 mg per day thereafter; subsequently, aspirin was initiated on day 2 rather than day 1. In patients randomly assigned to the invasive strategy, heparin infusion was decreased by 50% two or three hours before catheterization; at the time of cardiac catheterization, a bolus of 5000 U was administered after the insertion of the arterial sheath. The heparin infusion was resumed at full dose within one hour of the bolus dose in the catheterization laboratory and was continued for a total of five days.

Principal Findings:

In the group assigned to the invasive strategy, PTCA was attempted in 56.7 percent of patients; the procedure was anatomically successful in 93.3 percent.

In the group assigned to the conservative strategy, 13.3 percent of patients underwent clinically indicated PTCA within 14 days of the onset of symptoms. Reinfarction or death within 42 days, the primary end point, occurred in 10.9 percent of the group assigned to the invasive strategy and in 9.7 percent of those assigned to the conservative strategy (P not significant).

There were no significant differences between the two groups in the ejection fraction at rest or during exercise, either at hospital discharge or six weeks after randomization.

1.9 percent of patients who received 150mg of rt-PA and 0.5 percent of patients who received 100mg of rt-PA had intracranial hemorrhage.

In patients on the 100mg rt-PA regimen, major and minor hemorrhagic events were more common among those assigned to the invasive than among those assigned to the conservative strategy (18.5% vs. 12.8%, P less than 0.001). Major or minor hemorrhagic events were associated with the extent of fibrinogen breakdown, peak rt-PA levels, thrombocytopenia, prolongation of the activated partial thromboplastin time (APTT) to more than 90 seconds, weight of 70kg or less, female gender, and physical signs of cardiac decompensation.

Intracranial hemorrhages were more frequent among patients treated with the 150mg rt-PA dose than with the 100mg rt-PA dose (2.1% vs. 0.5%, P less than 0.001). The extent of the plasma-mediated hemostatic defect was also greater in patients receiving the 150mg dose.

The patients assigned to the invasive strategy routinely underwent cardiac catheterization, and when anatomically appropriate, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting 18-48 hours after infarction.

Patients assigned to conservative strategy had these procedures only in response to the occurrence of spontaneous or provoked ischemia.

One-year follow-up data are available in 3,316 patients (99.3%). The primary trial end point, death and nonfatal reinfarction, occurred in 14.7% of invasive strategy patients and in 15.2% of conservative strategy patients (p = NS). When analyzed individually, there was no difference (p = NS) in death (invasive strategy, 6.9%; conservative strategy, 7.4%) or recurrent infarction (invasive strategy, 9.4%; conservative strategy, 9.8%) between the two groups.

Anginal status at 1 year was also similar.

Cardiac catheterization and PTCA were performed more often in invasive strategy patients (98.0% and 61.2%, respectively) compared with conservative strategy patients (45.2% and 20.5%, respectively).

At 1 year, the cumulative number of patients who underwent coronary bypass surgery (invasive strategy, 17.5%; conservative strategy, 17.3%) was similar in the two groups.

Complete 2-year follow-up data are available for 3,187 patients (95.4%). Cumulative life-table rates of death or reinfarction were 17.6% for the invasive strategy group and 17.9% for the conservative strategy group (p = NS) and mortality was 8.9% and 8.7% (p = NS), respectively.

Complete data are available for 1,959 (90.1%) of the 2,174 patients enrolled for 3 years. Rates of death or reinfarction were 21.0% for the invasive strategy group with 20.0% for the conservative strategy group (p = NS), with mortality of 11.5% and 11.0% (p = NS), respectively. In this cohort, the mortality was 1.3% in the 2nd year and 1.7% in the 3rd year from study entry.


In patients with AMI, who were treated with rt-PA and with heparin followed by aspirin, an invasive strategy of coronary arteriography 18 to 48 hours after the onset of symptoms, followed by prophylactic PTCA, offered no advantage in reducing mortality or reinfarction over a more conservative strategy.

Increased morbidity due to hemorrhagic complications is associated with an invasive management strategy in patients with acute myocardial infarction.

The invasive and conservative strategies resulted in similar favorable outcomes at 1 year of follow-up. In particular, the rates of mortality and reinfarction were not different and were impressively low in both groups. One possible advantage of the invasive strategy was detected in subgroup analyses. In patients with a history of myocardial infarction, the data are suggestive that 1-year mortality was lower in invasive strategy patients (10.3%) than in conservative strategy patients (17.0%) (p = 0.03).

TIMI II invasive and conservative strategies resulted in similar favorable outcomes after two and three years. Mortality and reinfarction rates in the two strategies were comparable. Deaths were infrequent in the 2nd and 3rd years from study entry.


1. N Engl J Med 1989;320:618-27. Final results
2. Ann Intern Med 1991;115:256-65. Hemorrhagic events
3. Circulation 1992;85:533-42. 1-year results
4. J Am Coll Cardiol 1993;22:1763-72. 2- and 3-year results
5. J Am Coll Cardiol 1993;22:1773-9. Incidence of VT/VF
6. Circulation. 1995;91(10):2541-8. Non-Q MI follow-up

Clinical Topics: Anticoagulation Management, Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Aortic Surgery, Lipid Metabolism, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Myocardial Infarction, Follow-Up Studies, Cardiac Catheterization, Heparin, Fibrinolytic Agents, Electrocardiography, Angioplasty, Balloon, Coronary, Intracranial Hemorrhages, Coronary Angiography, Chest Pain, Partial Thromboplastin Time, Fibrinogen, Hemostatics, Coronary Artery Bypass, Tissue Plasminogen Activator, Thrombocytopenia

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