Thrombolysis in Myocardial Infarction (TIMI)
Condition: Cardiovascular Diseases; Coronary Disease; Heart Diseases; Myocardial Infarction; Myocardial Ischemia
MeSH terms: Cardiovascular Diseases; Heart Diseases; Myocardial Infarction; Coronary Disease; Myocardial Ischemia; Infarction; Ischemia
Study type: Interventional
Phase: Phase 3

Summary: 
      In TIMI I, to assess the relative thrombolytic activity and side effects of intravenous
      recombinant tissue-type plasminogen activator (rt-PA) versus intravenous streptokinase in
      patients with acute myocardial infarction. In TIMI II, to assess whether intravenous rt-PA
      given in the early hours of acute myocardial infarction should be followed by percutaneous
      transluminal coronary angioplasty (PTCA).
    

Detailed description: 
      BACKGROUND:

      Coronary artery disease is the leading cause of death in the United States, accounting for
      almost 500,000 deaths each year. Studies have confirmed that myocardial infarction is related
      to an occlusive coronary thrombus in up to 80 percent of patients. First and
      second-generation thrombolytic agents (including streptokinase and rt-PA) have been
      successfully used to restore myocardial blood flow where thrombus has occluded an
      infarct-related coronary artery. However, further clinical investigation was necessary to
      determine the most suitable thrombolytic agent dose and method of administration, the risk of
      subsequent reocclusion, restenosis, and/or myocardial infarction, the need for additional
      therapies, and the likelihood of benefit or hemorrhagic complications.

      In 1983 the National Heart, Lung, and Blood Institute established the TIMI Study Group. The
      group consisted of 13 clinical centers (later expanded to 24), a Radiographic Core
      Laboratory, Radionuclide Core Laboratory, and a Data Coordinating Center.

      DESIGN NARRATIVE:

      The TIMI trial was conducted in two stages. In Phase I or TIMI I, eligible patients were
      randomized to receive either 80 mg of recombinant tissue-type plasminogen activator (rt-PA)
      or 1.5 million units of streptokinase intravenously to determine relative safety and
      efficacy. Following randomization, patients found to have angiographically documented
      stenosis greater than 50 percent in the infarct-related artery received thrombolytic therapy
      in a double-blind fashion, full anticoagulation, and conventional care. Patients subsequently
      underwent repeat catheterization, radionuclide ventriculogram, and pre-discharge, six-week
      and six-month cardiovascular examination.

      TIMI I was stopped in February 1985 because of statistically significant differences in
      coronary reperfusion rates in the treatment groups; rt-PA was found to be the superior
      thrombolytic agent. Following TIMI Phase I, the manufacturer of rt-PA changed to a
      large-scale production method for rt-PA, and the new product was found to have thrombolytic
      activity and specificity in vitro and in experimental animals comparable to the product
      manufactured by the old method. However, the TIMI investigators concluded that clinical
      evaluation would be necessary prior to initiation of TIMI Phase II.

      Thus, TIMI Open Label Phase studies were initiated in 1985, with the aim of establishing the
      safety and efficacy of the 'new' intravenous rt-PA. As in Phase I, the endpoint was lysis of
      coronary thrombus within 90 minutes of the initiation of treatment in patients with
      documented total occlusion of the infarct-related coronary artery. Additional goals of the
      study were to determine reocclusion rates of infarct-related arteries at 18-48 hours, as well
      as to determine the efficacy of PTCA to maintain perfusion in infarct-related arteries and
      prevention of recurrent myocardial infarction. The TIMI Open Label Phase studies determined
      that optimal coronary recanalization and maintenance of reperfusion occurred with 150 mg of
      'new' rt-PA infused over six hours. However, subsequent hemorrhagic complications observed
      with 150 mg rt-PA necessitated a change in the dose of rt-PA to 100 mg.

      In TIMI II, patient entry began in April 1986 and ended in June 1988 with enrollment of 3,534
      patients. Patients were treated with intravenous rt-PA within four hours of the onset of
      chest pain thought to be caused by myocardial infarction and randomly assigned to an invasive
      strategy or a conservative strategy. The primary endpoint was survival free of recurrent
      myocardial infarction at six weeks and one year of follow-up. There were 1,681 patients
      assigned to the delayed invasive strategy in which catheterization was performed between 18
      and 48 hours after rt-PA therapy. If catheterization showed a greater than 60 percent
      subtotal stenosis of the infarct-related artery that was considered to be technically
      approachable, angioplasty was attempted. Angioplasty was performed in 60.5 percent of the
      1,500 patients who underwent catheterization in the invasive strategy group. The remaining
      39.5 percent or 593 patients did not have angioplasty performed. There were 1,658 patients
      assigned to a conservative strategy in which cardiac catheterization was reserved for the 587
      patients who had spontaneous or exercise-induced myocardial ischemia within 21 days of
      infarction. A total of 13.5 percent of patients in this arm underwent coronary angioplasty,
      7.6 percent underwent bypass surgery, and 1.1 percent underwent both procedures; 77 percent
      of the patients in the conservative strategy group had no revascularization procedure within
      21 days of infarction.

      TIMI IIA, a subtrial of 586 patients, investigated whether immediate cardiac catheterization
      with percutaneous transluminal coronary angioplasty, when appropriate, would confer an
      advantage over the same procedure performed 18 to 48 hours later. All patients were treated
      with intravenous rt-PA within four hours of the onset of acute myocardial infarction.

      The study completion date listed in this record was obtained from the "End Date" entered in
      the Protocol Registration and Results System (PRS) record.
    

Intervention name(s): tissue plasminogen activator; angioplasty, transluminal, percutaneous coronary
Intervention type(s): Drug; Procedure
Intervention MeSH terms: Plasminogen; Tissue Plasminogen Activator
Allocation: Randomized
Primary purpose: Treatment