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Thrombolysis in Myocardial Ischemia Trial (TIMI III)

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ClinicalTrials.gov Identifier: NCT00000472
Recruitment Status : Completed
First Posted : October 28, 1999
Last Update Posted : March 16, 2016
Sponsor:
Information provided by:
National Heart, Lung, and Blood Institute (NHLBI)

Tracking Information
First Submitted Date  ICMJE October 27, 1999
First Posted Date  ICMJE October 28, 1999
Last Update Posted Date March 16, 2016
Study Start Date  ICMJE April 1989
Primary Completion Date Not Provided
Current Primary Outcome Measures  ICMJE Not Provided
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00000472 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Thrombolysis in Myocardial Ischemia Trial (TIMI III)
Official Title  ICMJE Not Provided
Brief Summary The Thrombolysis in Myocardial Ischemia Trial (TIMI III) focused on unstable angina and non-Q-wave myocardial infarction. The trial was designed to determine by coronary arteriography the incidence of coronary thrombi in these conditions and the response of these thrombi to tissue-type plasminogen activator (t-PA) in TIMI IIIA and the effects of thrombolytic therapy and of an early invasive strategy on clinical outcome in TIMI IIIB. There was also a registry with two components. A roster enumerated all patients with unstable angina or non-Q-wave myocardial infarction enrolled at cooperating hospitals. From the roster, a study population of 1,893 subjects was selected and followed prospectively for the year to determine incidence of death or myocardial infarction.
Detailed Description

BACKGROUND:

TIMI IIIA and TIMI IIIB follow the contract-supported clinical trial, Thrombolysis in Myocardial Infarction (TIMI I, TIMI IIA, and TIMI II).

Myocardial ischemic syndromes account for a large portion of the annual mortality and morbidity from all causes in industrialized countries and encompass a wide clinical-pathologic spectrum. At one end of this spectrum are patients with chronic stable angina. When studied by coronary arteriography, such patients usually have obstructive atherosclerotic disease with no evidence of fresh thrombosis. At the other end of the spectrum are patients with acute myocardial infarction who present with a discrete episode of prolonged chest pain accompanied by persistent ST-segment elevation. Such patients have a high incidence of thrombotic coronary artery occlusion and the early intravenous administration of thrombolytic agents has been shown to re-establish perfusion, limit the extent of left ventricular dysfunction, and reduce both early or in-hospital and late or one year mortality in this group.

Patients with non-Q-wave myocardial infarction and unstable angina fall between these two extremes. In the days and weeks following the onset of their disorder, their prognosis for survival is better than that of patients with Q-wave myocardial infarction but worse than that of patients with stable angina. Some patients with unstable angina progress to acute myocardial infarction, and some of those with non-Q-wave infarction experience an unstable course with reinfarction. Although others recover from the acute episode without subsequent infarction or reinfarction, they frequently have severe obstructive coronary artery disease and may be left with severe chronic stable angina. National summaries of hospital records indicate that 750,000 patients are hospitalized yearly with unstable angina and 250,000 with non-Q-wave myocardial infarction.

Once the results of creatine kinase measurements and serial electrocardiograms are available, the identification of patients experiencing non-Q-wave myocardial infarction is relatively simple. Identification of patients experiencing unstable angina is more difficult, since numerous definitions of the condition have been offered. There is agreement, however, on two important features of unstable angina. First, ischemia usually develops at rest or is precipitated by minimal exertion; this differs from chronic stable angina, in which most ischemic episodes are precipitated by physical exertion or strong emotion and the resultant increase in myocardial oxygen demand. Second, ischemia is often associated with transient ST-segment depression or elevation, in contrast to the persistent ST-segment elevation characteristic of patients who develop Q-wave infarction.

It has been observed in small numbers of patients that, unlike patients with chronic stable ischemia, patients with unstable angina or non-Q-wave myocardial infarction frequently have a thrombus in a major coronary artery. Initial conventional therapy for unstable angina consists of bed rest, oxygen, nitrates, beta-blockers, calcium antagonists, and aspirin. The use of heparin is widespread but controversial. In many tertiary care hospitals, angiography followed by PTCA is frequently performed, whereas in community hospitals patients are often managed without angiography.

Prior to the TIMI III trial, patients with non-Q-wave myocardial infarction were usually treated in the same way patients with Q-wave myocardial infarction were treated prior to the advent of thrombolytic therapy. Neither heparin therapy nor thrombolytic therapy was routinely employed, although knowledge of the role of thrombosis in some patients with this condition had raised the possibility that one or both approaches might be helpful. Although the early prognosis was favorable, awareness that the longer-term prognosis was as serious as that following Q-wave myocardial infarction had led to increasing use of follow-up coronary angiography to identify patients for whom PTCA or CABG might be useful. Whether or not revascularization improved prognosis in these patients had not been established.

Previous studies of thrombolytic therapy for unstable angina and non-Q-wave myocardial infarction were limited in number and size. The results suggested a benefit, but the significance of this benefit and its relation to the risks and costs of therapy remained to be answered. Also, the value of routine, early coronary angiography followed by PTCA and/or CABG was still unclear in both these conditions.

DESIGN NARRATIVE:

The two clinical trials were initiated simultaneously in different groups of TIMI III clinical centers. All patients enrolled in the study received standard coronary care unit care, including bed rest and oxygen. In TIMI IIIA, patients received baseline angiograms and were randomized in a double-blind manner to t-PA or placebo. All patients then received intravenous heparin. The primary endpoint was the number of patients with a successful result of therapy, defined as an improvement in TIMI perfusion by two grades (from 0 to 2 or 3, or from 1 to 3) or a ten percent reduction in the severity of stenosis. The reduction was based on a comparison between the baseline angiogram and the follow-up angiogram obtained 18 to 48 hours later. Patients in TIMI IIIA were enrolled over a nine month period. The total duration was 24 months, including 12 months of data analysis.

In TIMI IIIB, a total of 1,473 patients seen within 24 hours of ischemic chest pain at rest, considered to represent unstable angina or non-Q-wave myocardial infarction (NQMI), were randomized using a 2 x 2 factorial design to compare t-PA versus placebo as initial therapy and an early invasive strategy consisting of early coronary arteriography followed by revascularization when the anatomy was suitable versus an early conservative strategy consisting of coronary arteriography followed by revascularization if initial medical therapy failed. All patients were treated with bed rest, anti-ischemic medications, aspirin, and heparin. The primary endpoint for the t-PA placebo comparison was death, myocardial infarction, or failure of initial therapy at six weeks. Randomization began in October 1989 and concluded in June 1992. The primary endpoint for the early invasive and early conservative strategies was death, post randomization myocardial infarction or an unsatisfactory exercise tolerance test (ETT) at six weeks.

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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Masking: Double
Primary Purpose: Treatment
Condition  ICMJE
  • Angina Pectoris
  • Cardiovascular Diseases
  • Coronary Disease
  • Heart Diseases
  • Myocardial Infarction
  • Myocardial Ischemia
Intervention  ICMJE
  • Drug: tissue plasminogen activator
  • Drug: heparin
Study Arms  ICMJE Not Provided
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Enrollment  ICMJE Not Provided
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE June 1995
Primary Completion Date Not Provided
Eligibility Criteria  ICMJE Men and women, ages 21 to 76, with unstable angina or non-Q-wave myocardial infarction.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years to 76 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00000472
Other Study ID Numbers  ICMJE 61
R01HL042428 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Not Provided
Study Sponsor  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Investigator: Eugene Braunwald Brigham and Women's Hospital
Investigator: Kenneth Mann University of Vermont
PRS Account National Heart, Lung, and Blood Institute (NHLBI)
Verification Date July 2000

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP