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Thrombolysis in Myocardial Infarction (TIMI)

2014-08-27 04:00:09 | BioPortfolio

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).

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.

Study Design

Allocation: Randomized, Primary Purpose: Treatment

Conditions

Cardiovascular Diseases

Intervention

tissue plasminogen activator, angioplasty, transluminal, percutaneous coronary

Status

Completed

Source

National Heart, Lung, and Blood Institute (NHLBI)

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T04:00:09-0400

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The original version of this paper contained an error.

Medical and Biotech [MESH] Definitions

A family of percutaneous techniques that are used to manage CORONARY OCCLUSION, including standard balloon angioplasty (PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY), the placement of intracoronary STENTS, and atheroablative technologies (e.g., ATHERECTOMY; ENDARTERECTOMY; THROMBECTOMY; PERCUTANEOUS TRANSLUMINAL LASER ANGIOPLASTY). PTCA was the dominant form of PCI, before the widespread use of stenting.

Dilatation of an occluded coronary artery (or arteries) by means of a balloon catheter to restore myocardial blood supply.

Use of a balloon catheter for dilatation of an occluded artery. It is used in treatment of arterial occlusive diseases, including renal artery stenosis and arterial occlusions in the leg. For the specific technique of balloon dilatation in coronary arteries, ANGIOPLASTY, TRANSLUMINAL, PERCUTANEOUS CORONARY is available.

An acylated inactive complex of streptokinase and human lysine-plasminogen. After injection, the acyl group is slowly hydrolyzed, producing an activator that converts plasminogen to plasmin, thereby initiating fibrinolysis. Its half-life is about 90 minutes compared to 5 minutes for TPA; (TISSUE PLASMINOGEN ACTIVATOR); 16 minutes for UROKINASE-TYPE PLASMINOGEN ACTIVATOR and 23 minutes for STREPTOKINASE. If treatment is initiated within 3 hours of onset of symptoms for acute myocardial infarction, the drug preserves myocardial tissue and left ventricular function and increases coronary artery patency. Bleeding complications are similar to other thrombolytic agents.

A proteolytic enzyme in the serine protease family found in many tissues which converts PLASMINOGEN to FIBRINOLYSIN. It has fibrin-binding activity and is immunologically different from UROKINASE-TYPE PLASMINOGEN ACTIVATOR. The primary sequence, composed of 527 amino acids, is identical in both the naturally occurring and synthetic proteases.

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