WHAT ARE THE TIMI TRIALS?

Robert M. Greene, M.D., FACC

In 1984 Brigham and Women’s Hospital launched a series of national clinical studies, under the leadership of Dr. Eugene Braunwald, known as the TIMI (Thrombolysis In Myocardial Infarction) trials. These trials initially examined different thrombolytic or "clot-busting” drugs in patients with acute myocardial infarction (AMI). Latter these trials studied other aspects of the diagnosis and treatment of patients with acute coronary syndromes. Over the past three decades the TIMI trials have revolutionized cardiac care.
The TIMI trials could be divided into three categories - the TIMI classic, TIMI contemporary and TIMI future.

TIMI classic

In 1985 the TIMI 1 trial was one of the first studies to perform coronary angiography in patients with AMI prior to either intravenous streptokinase to the newly developed agent, t-PA. This study suggested that t-PA would be a superior agent in improving patient outcome, and the findings were later substantiated in the larger GUSTO-I trial and the TIMI 4 trial.
In order to evaluate more carefully the perfusion a grading system was developed for use in the TIMI 1 trial.

• TIMI grade 0 flow indicates complete occlusion of the coronary artery,
• TIMI grade 1 and 2 successively better flow,
• TIMI grade 3 flow denotes full coronary perfusion with normal flow.

Another major finding in this trial was the establishment of the importance of the patency of the infarct-related artery (IRA) on early and late mortality in acute MI. This observation is referred to as the open artery hypothesis.

In 1991 Alta Bates Medical Center participated its first TIMI trial. The TIMI 4 trial showed that intravenous front-loaded t-PA achieved significantly higher rates of reperfusion and improved clinical benefit and survival of AMI patients. The strategy of "rescue" PTCA was also shown to be able be done acutely with high technical success rate, and later trials confirmed PCI improved clinical outcomes.

In 1995 a new anti-thrombotic agent derived from leech saliva, called hirudin, was used for the first time at Alta Bates Hospital in the TIMI 9 trial. The TIMI 10 trial examined the safety of a new thrombolytic, discovered by Genentech called TNK-tPA, which Alta Bates Hospital used exclusively as our primary thrombolytic agent in patients with AMI.

TIMI contemporary

The TIMI investigators have also extended our understanding of anti-thrombin agents in patients with acute coronary syndromes. The TIMI 11 trial studied the safety and efficacy of enoxaparin (a low molecular weight heparin) and the TIMI 14 and TIMI 20-Intregriti trials showed how to use combinations of reduced dose thrombolytic with abciximab or eptifibatide in the treatment of acute MI patients.

Today, of course, all AMI patients undergo primary PCI at ABSMC in less than 90 minutes of arrival. For more stable patients TIMI 18-TACTICS showed the importance of risk stratifying patients with the TIMI risk score, adopting an early invasive strategy and measuring clinical outcomes in the National Registry of Myocardial Infarction.

The REPLACE-2 trial, as the name suggests, studied bivalirudin, which is now the standard anticoagulant, administered to patient underlying emergency and elective PCI procedures.

TIMI Future

In the next few years we will be starting other trials using combination of novel antithrombin and antiplatelet agents. Whatever the strategy these TIMI trials will continue to provide insight into the pathophysiology of patients with the entire range of acute coronary syndromes. The impetus over the next few years will be to deliver therapy-drug -device- more effectively, more timely and to a larger number of patients with acute coronary syndromes.