Thrombolysis in Myocardial Infarction (TIMI)

March 15, 2016 updated by: National Heart, Lung, and Blood Institute (NHLBI)
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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Phase

  • Phase 3

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Men and women under age 76. Patients had acute myocardial infarction.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Joseph Babb, Bridgeport Hospital
  • Jeffery Borer, Weill Medical College of Cornell University
  • Bernard Chaitman, St. Louis University Medical Center
  • James Chesebro, Mayo Foundation
  • Richard Davison, Northwestern University
  • Harold Dodge, University of Washington
  • Frederick Feit, NYU Langone Health
  • Charles Francis, Yale University
  • Joel Gore, University of Massachusetts, Worcester
  • Michael Herman, New York Medical College
  • Morrison Hodges, University of Minnesota
  • Harvey Kemp, St. Luke's-Roosevelt Institute for Health Sciences
  • Genell Knatterud, Maryland Medical Research Institute
  • Costas Lambrew, MaineHealth
  • Philip Ludbrook, Washington University School of Medicine
  • Kenneth Mann, University of Vermont
  • John Markis, Beth Israel Hospital
  • John Morrison, North Shore University Hospital
  • Hiltrud Mueller, Montefiore Medical Center
  • Eric Powers, Columbia University
  • Robert Roberts, Baylor College of Medicine
  • Williams Rogers, University of Alabama at Birmingham
  • Allan Ross, George Washington University
  • Thomas Ryan, University Hospital Inc.
  • Marc Schweiger, Baystate Medical Center
  • Gerald Timmis, William Beaumont Hospitals
  • James Willerson, University of Texas
  • David Williams, Rhode Island Hospital
  • Barry Zaret, Yale University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 1983

Study Completion (Actual)

December 1, 1990

Study Registration Dates

First Submitted

October 27, 1999

First Submitted That Met QC Criteria

October 27, 1999

First Posted (Estimate)

October 28, 1999

Study Record Updates

Last Update Posted (Estimate)

March 16, 2016

Last Update Submitted That Met QC Criteria

March 15, 2016

Last Verified

July 1, 2000

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 24
  • R01HL042311 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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