Thrombolysis In Myocardial Ischemia trial, phase IV - TIMI 4

Description:

Alteplase, anistreplase, or both for clinical outcomes in acute MI.

Hypothesis:

Aggressive thrombolytic-antithrombotic regimens could improve the outcome achieved with standard regimens.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 382
Mean Follow Up: 1 year
Mean Patient Age: 58
Female: 26.5

Patient Populations:

Ischemic pain > 30 minutes
ST-segment elevation (>0.1 mV) in at least two contiguous ECG leads
New left bundle branch block
Onset of pain within six hours of the planned initiation of treatment

Exclusions:

> 80 years of age
Administration of rt-PA for AMI within the previous two weeks
Administration of anistreplase or streptokinase at any time
Oral anticoagulation
Women of childbearing potential
Previously documented left bundle branch block
Other serious illness
Inability to comply with the protocol or to give informed consent
Previous participation in TIMI 4
Contraindications to thrombolytic therapy

Primary Endpoints:

Combined endpoint of "unsatisfactory outcome" defined as the occurrence of any of the following through hospital discharge: death (all-cause mortality), severe congestive heart failure or cardiogenic shock, low ejection fraction (measured by radionuclide ventriculogram as < 40% [or as < 30% for patients with previous MI]), reinfarction, TIMI Perfusion grade flow < 2 at 90 minutes or 18 to 36 hours, reocclusion assessed by sestamibi imaging, major spontaneous hemorrhaging, or severe anaphylaxis

Drug/Procedures Used:

Front-loaded rt-PA, 15mg bolus then 0.75 mg/kg (up to 50mg) infusion over 30 minutes followed by a 0.50 mg/kg (up to 35mg) infusion over 60 minutes; or APSAC, 30 U bolus over 2-5 minutes; or rt-PA, 15mg bolus then 0.75 mg/kg (up to 50mg) infusion over 2-5 minutes; or rt-PA, 15 mg bolus then 0.75 mg/kg (up to 50 mg) infusion over 30 minutes and APSAC, 20 U bolus

Concomitant Medications:

Heparin, 5000 U IV bolus then 1000 U/hour infusion; aspirin, 325 mg once daily; metoprolol, IV then oral. Further treatment at the discretion of the physician.

Principal Findings:

Patency of the infarct-related artery (TIMI Perfusion grade 2 or 3 flow) at 60 min after the start of thrombolysis was significantly higher in rt-PA-treated patients (77.8% vs. 59.5% for APSAC-treated patients and 59.3% for combination-treated patients [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.03]).

At 90 min, the incidence of both infarct-related artery patency and TIMI grade 3 flow was significantly higher in rt-PA-treated patients (60.2% had TIMI Perfusion grade 3 flow vs. 42.9% and 44.8% of APSAC- and combination-treated patients, respectively [rt-PA vs. APSAC, p < 0.01; rt-PA vs. combination, p = 0.02]).

The incidence of unsatisfactory outcome was 41.3% for rt-PA compared with 49% for APSAC and 53.6% for the combination (rt-PA vs. APSAC, p = 0.19; rt-PA vs. combination, p = 0.06).

The mortality rate at 6 weeks was lowest in the rt-PA-treated patients (2.2% vs. 8.8% for APSAC and 7.2% for combination thrombolytic therapy [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.06]).

Use of a standardized heparin nomogram to achieve therapeutic anticoagulation after thrombolysis:
Subtherapeutic activated partial thromboplastin time values were noted in 4%, 14%, 29%, 46%, 37%, and 34% of patients 8, 12, 24, 48, 72, and 96 hours, respectively, after heparin treatment was begun.
Patients with subtherapeutic values at 24 hours were younger (mean ±SD, 55.2 ±10.6 vs. 59.6 ±10.6 years, P = .02) and weighed more (86.4 ±13.5 vs. 78.9 ±15.7 kg, P = .007) than patients with therapeutic values.
Centers that used the nomogram had significantly fewer subtherapeutic values at 48 and 96 hours. In addition, heparin therapy was interrupted less frequently at centers that used the nomogram (38.1% vs. 68.7%, P <. 001).
Major spontaneous hemorrhage, reinfarction, and reocclusion rates were low and were about the same in the two groups.

Reocclusion was observed more frequently in arteries with TIMI 2 vs. TIMI 3 flow (10.4% vs. 2.2%, p = 0.003), in ulcerated lesions (10.7% vs. 3.0%, p = 0.009) and in the presence of collateral vessels (18.2% vs. 5.6%, p = 0.03). Similar trends were observed for eccentric (7.3% vs. 2.3%, p = 0.06) and thrombotic (8.4% vs. 3.3%, p = 0.06) lesions. Reocclusion was associated with more severe mean percent stenosis (77.9% vs. 73.9%, p = 0.04). Lesion length, reference segment diameter and Fourier measures of lesion irregularity were not associated with reocclusion.

Patients with any previous history of angina were less likely than with those without angina to experience in-hospital death (3% vs. 8%) (P = .03), severe congestive heart failure (CHF) or shock (1% vs. 7%, P = .006), or the combined end point of in-hospital death, severe CHF, or shock (4% vs. 12%, P = .004). Moreover, patients with any history of angina were more likely to have a smaller creatine kinase (CK)-determined infarct size (119 vs. 154 CK integrated units; P = .01) and were less likely to have Q waves on their ECG (57% vs. 69%; P = .01).

In the subset of patients who experienced angina within the 48 hours before infarction (compared with those who did not), there was a trend toward less likely in-hospital death (3% vs. 6%; P = .09), a lower incidence of severe CHF or shock (1% vs. 6% P = .008), a lower combined end point of death, CHF, or shock (3% vs. 10%; P = .006), smaller infarct size assessed by CK (115 vs. 151 CK units; P = .03), and a trend toward fewer Q-wave infarcts.

However, patients with a history of previous angina did have a trend toward more recurrent ischemic pain. Of importance is that the beneficial in-hospital effects of previous angina were not dependent on angiographically visible coronary collaterals.

Interpretation:

Front-loaded rt-PA achieved significantly higher rates of early reperfusion and was associated with trends toward better overall clinical benefit and survival than those achieved with APSAC or their combination.

The use of a heparin nomogram provided improved anticoagulation in patients treated with thrombolytic therapy for myocardial infarction. Weight- and age-adjusted heparin dosing may provide further improvement in anticoagulation with heparin therapy. Several simply assessed angiographic variables, such as the presence of TIMI grade 2 flow, ulceration, collateral vessels and greater percent diameter stenosis at 90 min after thrombolytic therapy, are associated with significantly higher rates of infarct-related artery reocclusion by 18 to 36 hours and may aid in identifying that subset of patients who are at significantly higher risk of early reocclusion and who potentially warrant further early pharmacologic or mechanical intervention.

Previous angina confers a beneficial effect on in-hospital outcome after acute myocardial infarction. The reasons for this benefit are uncertain, but one potential mechanism for this observation may be ischemic preconditioning.

References:

1. J Am Coll Cardiol 1994;24:1602-10. Final results
2. Arch Intern Med 1994;154:1492-96. Long-term follow-up
3. J Am Coll Cardiol 1995;25:582-9. Angiographic predictors of reocclusion
4. Circulation 1995;91:37-45. Previous angina alters outcome

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, EP Basic Science, Lipid Metabolism, Novel Agents, Acute Heart Failure, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Thrombolytic Therapy, Myocardial Infarction, Creatine Kinase, Heparin, Pain, Constriction, Pathologic, Fibrinolytic Agents, Electrocardiography, Nomograms, Ischemic Preconditioning, Coronary Angiography, Heart Failure, Partial Thromboplastin Time, Bundle-Branch Block, Anistreplase, Tissue Plasminogen Activator


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