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

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.
    

Intervention name(s): tissue plasminogen activator; heparin
Intervention type(s): Drug; Drug
Intervention MeSH terms: Heparin; Plasminogen; Tissue Plasminogen Activator
Allocation: Randomized
Masking: Double
Primary purpose: Treatment