TIMI-1

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Chesebro JH, et al. "Thrombolysis in myocardial infarction (TIMI) trial, phase 1: A comparison between intrarvenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge". Circulation. 1987. 76(1):142-154.
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Clinical Question

Among individuals with acute MI, what are the cardiovascular outcomes and adverse effects of tPA compared to streptokinase for acute fibrinolysis?

Bottom Line

tPA opens twice as many occluded infarct-related arteries as SK, regardless of time from onset of symptoms to intervention initiation without increasing bleeding episodes, administration of blood transfusions, or reocclusion of the infarct-related arteries.

Major Points

Streptokinase was explored as a fibrinolytic/thrombolytic for MI in the 1950s. Its use was solidified in the 1980s and 1990s following publication of trials like GISSI (1986) and ISIS-2 (1988). Tissue plasminogen activator (tPA) was developed as a potential alternative agent, though had not been studied in MI.

The original Thrombolysis in Myocardial Infarction (TIMI) trial published in 1987 compared tPA with streptokinase in MI. This trial is noteworthy for demonstrating increased rates of reperfusion with tPA over streptokinase (56% vs. 26%). This publication is noteworthy for defining the TIMI grade flow system, which has become the standard for describing flow through coronary arteries.

tPA was further studied in trials like ISIS-3 (1992), GISSI-2 (1992), and GUSTO (1993).

Design

  • Design: Double-blinded, randomized controlled trial
  • Enrollment: August 20, 1984 until February 5, 1985
  • N=316
    • tPA (n=157)
    • SK (n=159)

Population

Inclusion Criteria

  • 30 minutes of chest pain considered to be caused by an MI
  • ST segment elevation (0.1 mV) in at least two contiguous leads

Exclusion Criteria

  • Lack of informed conset
  • More than seven hours of time elapsed since the onset of chest pain,
  • Age >75 years
  • Uncontrolled hypertension (>200/120 mmHg)
  • Shock (systolic pressure <80 mmHg)
  • Unresponsiveness to volume expansion and IV vasopressors
  • Cerebrovascular event or severe trauma within six months
  • Hemorrhagic diathesis or active hemorrhage
  • Recent treatment with streptokinase or streptococcal infection
  • Left bundle branch block
  • Prior cardiac surgery
  • Prolonged CPR or major surgical procedure within two weeks
  • Dilated cardiomyopathy
  • Oral anticoagulant therapy
  • Psychological or physical inability to participate
  • Childbearing potential
  • Known "advanced illness"

Interventions

  • Patients were randomized to receive either streptokinase 1.5 million units over 1 hour and an infusion of placebo ("tPA") over 3 hours or an infusion of tPA over 3 hours (first hour 40 mg, second hour 20 mg and third hour 20 mg) and an infusion of placebo ("streptokinase") over 1 hour.
  • Patients were given a bolus and were subsequently started on a drip of lidocaine (1 to 1.5 mg/kg bolus, 2 to 4 mg/min infusion), were taken to the cardiac cath lab, had an arterial sheath placed, had baseline coagulation checked, and were given heparin 5,000 units.
  • Coronary arteriography visualized the left and right coronary arteries. Patients were given 200 ug of intracoronary nitroglycerin, those with less than a 50% reduction in the luminal diameter of the infarct-related artery were not given the thrombolytic therapy.
  • The intravenous infusion of the thrombolytic therapy was initiated with repeat opacification of artery at 10, 20, 30, 45, 60, 75, and 90 minutes.
  • Repeat ventriculography and arteriography occurred immediately prior to discharge and at 5 to 25 days after discharge (mean: 10 days).
  • Blinded evaluation of arterial patency was evaluated at each clinical site and at a centralized radiographic laboratory
    • grade 1 or 0 = closed artery
    • grade 2 or 3 = an open artery with complete perfusion within at least three cardiac cycles
  • "usual practice" directed further coronary care, IV infusion of heparin was begun 3 hours after the initial bolus at 1000 u/hrand was adjusted to maintain aPTT between 1.5 - 2x the upper limit of normal; this infusion continued until 8 to 10 days or until serious hemorrhage occurred
  • The arterial sheath was removed 24 to 48 hours after their placement in the setting of a temporary reduction of heparin dosing
  • Prior to cessation of heparin therapy, patients were initiated on dipyridamole 75 mg TID and aspirin 325 mg TID for at least 6 months
  • "Conventional" antianginal therapy was administered as needed
  • Patients were discharged on a beta blocker unless contraindicated or it was "judged unnecessary after a revascularization procedure" to maintain th pulse at less than 60 beats/min
  • Patients were seen in a clinic at 6 weeks, 6 months, and were interviewed by telephone every 6 months thereafter

Outcomes

Data presented as tPA vs. SK

Primary Outcomes

Proportion of patients who went from a grade 0 pre-treatment perfusion to grade 2 or 3 after the intervention
56% vs. 26% (P<0.001)
Proportion of patients who went from grade 0 or 1 pre-treatment perfusion to grade 2 or 3 after the intervention
62% vs. 31% (P not defined)

Secondary Outcomes

Proportion of patients with reperfusion at 30 minutes after the intervention
24% vs. 8% (P<0.001)
Proportion of patients with reperfusion at 60 minutes after the intervention
48% vs. 23% (P<0.001)
Proportion of patients with grade 2 or 3 reperfusion at the predischarge catheterization
42% vs. 21% (P<0.001)
Analysis including no reinfarction in the setting of no predischarge angiogram as "reperfusion": 44% vs. 22% (P<.001)
Proportion of patients with successful reperfusion at 90 min who had reocclusion at the predischarge catheterization
24% vs. 14% (P value?)
Analysis including myocardial deaths as "reocclusions": 29% vs. 30%
The time to reperfusion after the start of thrombolytic therapy
the mean time to reperfusion in grade 0 or 1 was 49 min (median 45 min) in the tPA and 55 min (median 60 min) in the SK (not a significant difference)

Complications

Hypotension not associated with arrhythmia
3% vs. 5%
Fever/chills of unknown etiology
4% vs. 15% (P<0.01)
Urticaria of uncertain cause
1 patient vs. 3 patients (P value not defined)
There was no anaphylaxis in either group
Nausea or vomiting in the first 24 hours
41% vs. 46% (the authors note that it was associated with "injection of the contrast medium")
Transient renal insufficiency occurred in
5% of patients (the authors note that it is "probably related to contrast medium")
Mortality at 21 days
7.0% vs. 6.3% (10/159) for SK (P value not defined), the authors state that this was due to "failure to reperfuse, reinfarction, or recurrent ischemia"
Cardiogenic shock
3% vs. 7% (P value not defined), the authors state that this "occurred primarily in patients in whom reperfusion was not achieved."
Cardiac arrest
13% vs. 10% (P value not defined)
Heart failure
15% vs. 19% (P value not defined)
"Clinical reinfarction"
13% vs. 12% (P value not defined)
Recurrent pain "attributed to ischemia"
46% vs. 44% (P value not defined)
Pericarditis
10% of both tPA and SK, the authors note that it occurred more frequently in "those who did not exhibit recanalization"
Percutaneous transluminal coronary angioplasty prior to discharge
10% vs. 14% (P value not defined)
Coronary artery bypass operations prior to discharge
13% vs. 10% (P value not defined)
Revascularization (presumably revascularization procedures)
35% of both groups with grade 2 or 3 perfusion at baseline
Observed bleeding, echymosis, or hematoma at the site of catheterization
66% vs. 67% (P value not defined)
A "major decrease" in hematocrit
15% vs. 16% (P value not defined)
A "minor decrease" in hematocrit
16% of both tPA and SK groups
Both major and minor bleeding events were at the site of catheterization/site of arterial puncture
78% vs. 80% (P value not defined)
Intracranial bleeding
no events in either groups
Blood loss not from venipuncture or other instrumentation
three patients of tPA and five patients of SK (P value not defined)
Blood administration
Two or more units: 25% vs. 21% (P value not defined)
At least one unit: 29% vs. 27% (P value not defined)

Criticisms

  • Not powered to examine clinical outcome in the two groups