Thrombolysis In Myocardial Ischemia trial, phase 11B - TIMI 11B

Description:

Enoxaparin vs. heparin for death/ reinfarction/ ischemia in acute MI.

Hypothesis:

To compare enoxaparin with unfractionated heparin for patients with acute coronary syndromes.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 3,910

Patient Populations:

Unstable angina or non-Q wave MI
Ischemic discomfort of ≥5 minutes duration at rest within 24 hours of randomization
History of CAD
ST segment changes or positive cardiac markers

Primary Endpoints:

A composite of all cause mortality, recurrent MI, or severe recurrent ischemia requiring urgent revascularization.
Primary safety endpoint: Major bleeding resulting either in death or a retroperitoneal, intracranial, or intraocular bleed associated with a hemoglobin drop of 3 gm/dL.

Drug/Procedures Used:

Acute: Unfractionated IV heparin 70 U/kg bolus with infusion of 15 U/kg/hr (adjusted to a target aPTT of 1.5 to 2.5 times control) or enoxaparin 30mg IV, followed 1 mg/kg subcutaneously q 12 hours. Chronic: Enoxaparin (40mg for patients <65kg, 60mg.

Concomitant Medications:

Aspirin

Principal Findings:

In the acute phase of TIMI 11B, patients randomized to IV unfractionated heparin for at least 3 days or enoxaparin given as a 30 mg IV, followed by subcutaneous injections of 1 mg/kg every 12 hours. Blinding was maintained through a double-dummy placebo design. Double-blind subcutaneous injections were administered for 8 days or until hospital discharge, whichever came first. Overall, median duration of therapy with unfractionated heparin or its matched placebo was 3 days; the median duration of therapy with enoxaparin or its matched placebo was 4.6 days.

Both groups were well-matched at baseline. Approximately 60% of the overall population was diagnosed ultimately as having had unstable angina and 35% with non-Q wave myocardial infarction. Study drug treatment was initiated in 99% of patients.

Kaplan-Meier curves for the composite primary endpoint began to diverge after only 8 hours, showing a 24% relative risk reduction at 48 hours (7.3% vs. 5.5%, p=0.026). At days 8 and 14, the enoxaparin group showed a stable 15% reduction in relative risk, both of which were statistically significant. This risk reduction was achieved without an increase in the rate of either spontaneous or instrumented major hemorrhage.

During the chronic phase of the trial, investigators sought to determine whether any further benefit was achieved with an additional 30 days of enoxaparin therapy following discharge. The initial observed benefit with enoxaparin was sustained through day 43, although no further relative decrease in events was observed. By day 43, the event rate was 17.3% in the enoxaparin group and 19.7% in the unfractionated heparin group, for a relative risk reduction of 12% (p=0.048). There was an increase in the rate of major hemorrhage with chronic enoxaparin therapy compared to placebo (2.9% vs. 1.5%, p=0.02).

Interpretation:

Enoxaparin appears to be effective anticoagulant therapy in the setting of non-ST elevation acute coronary syndromes, without the need for continuous infusions or therapeutic monitoring. When the TIMI 11B results were pooled with the ESSENCE trial data, forming a collective database of more than 7000 patients, a consistent and significant 20% relative reduction in the primary endpoint was seen across all time periods studied.

References:

1. Circulation 1998;98(Suppl I):I-504. Preliminary results

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Anticoagulation Management and ACS

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Enoxaparin, Risk Reduction Behavior, Research Personnel, Partial Thromboplastin Time, Heparin


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