Thrombolysis In Myocardial Infarction trial, phase I - TIMI 1

Description:

Streptokinase vs. alteplase for mortality in acute MI.

Hypothesis:

rt-PA or SK is more effective in the treatment of evolving acute MI.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 290
Mean Follow Up: 21 days
Female: 20
Mean Ejection Fraction: The baseline ejection fraction was more often below 35% in patients treated with SK (p <. 05)

Patient Populations:

At least 30 minutes of chest pain considered to be caused by myocardial ischemia
ST-segment elevation (0.1 mV) in at least two contiguous ECG leads

Exclusions:

Lack of informed consent
>7 hours time elapsed since the onset of chest pain
>75 years old
Uncontrolled hypertension (>200/120 mmHg)
Shock (systolic pressure <80 mmHg)
Unresponsiveness to volume expansion and IV vasopressors
Cerebrovascular event or severe trauma within 6 months
Hemorrhagic diathesis or active hemorrhage
Recent treatment with SK or streptococcal infection
Left bundle branch block
Previous cardiac surgery
Prolonged cardiopulmonary resuscitation or major surgical procedure within 2 weeks
Dilated cardiomyopathy
Oral anticoagulant therapy
Psychological or physical inability to participate
Childbearing potential
Known advanced illness

Primary Endpoints:

Proportion of patients who had TIMI Perfusion grade 2 or 3 reperfusion at 90 minutes among those who had grade 0 perfusion before treatment. Since grade 1 perfusion reflects ineffective myocardial perfusion, the same endpoint was sought among patients with grade 0 or 1 pretreatment perfusion

Secondary Endpoints:

Proportion of patients with reperfusion at 30 and 60 minutes after initiation of thrombolytic therapy, the proportion of patients with TIMI Perfusion grade 2 or 3 reperfusion at the predischarge catheterization, the proportion of patients with successful reperfusion at 90 minutes who had reocclusion at the predischarge catheterization, the time to reperfusion after the start of thrombolytic therapy, complications of therapy including hemorrhage, allergy, and arrhythmia. Other clinical events were tabulated through hospital discharge or 21 days (whichever occurred first), global and regional left ventricular ejection fraction

Drug/Procedures Used:

rt-PA in successive hourly doses of 40, 20 and 20 mg IV; or SK, 1.5 x 106 U IV infused over 1 hour.

Concomitant Medications:

Premedication: lidocaine, 1-1.5 mg/kg bolus followed by infusion of 2-4 mg/minute for >24 hours; heparin, 5000 U; and intracoronary glyceryl trinitrate, 200 æg. Coronary care: heparin, 1000 U/hour; dipyridamole, 75 mg tid; aspirin, 325 mg tid. Conventional antianginal therapy as required. Discharge on beta-blocker (unless contraindicated)

Principal Findings:

Ninety minutes after the start of thrombolytic therapy, occluded infarct-related arteries had opened in 62% of 113 patients in the rt-PA and 31% of 119 patients in the SK group (p less than .001).

Twice as many occluded infarct-related arteries opened after rt-PA compared with SK at the time of each of seven angiograms obtained during the first 90 min after commencing thrombolytic therapy.

Regardless of the time from onset of symptoms to treatment, more arteries were opened after rt-PA than SK.

The reduction in circulating fibrinogen and plasminogen and the increase in circulating fibrin split products at 3 and 24 hr were significantly less in patients treated with rt-PA than in those treated with SK (p less than .001).

The occurrence of bleeding events, administration of blood transfusions, and reocclusion of the infarct-related artery was comparable in the two groups.

The mortality rate at 6 and 12 months was not significantly different in patients treated with rt-PA compared with SK (7.7% and 10.5% rt-PA vs. 9.5% and 11.6% for SK). There was no significant difference in 6- and 12-month mortality or in the rate of recurrent AMI in patients who received thrombolytic therapy before compared with after 4 hours of the onset of AMI symptoms.

The frequency of recurrent AMI, coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) was similar in the two treatment groups. When the results were analyzed on the basis of the patency of the infarct-related artery, irrespective of thrombolytic agent used, for those patients with patent arteries 90 minutes after the initiation of therapy, there was a trend toward a lower 6-month (5.6% vs. 12.5%) and 12-month mortality (8.1% vs. 14.8%) (p = 0.07).

For patients with sustained patency (reperfusion without reocclusion by hospital discharge), there was an extremely low, although insignificant, decrease in mortality at 6 and 12 months (3.7% and 5.6%) compared with patients without early reperfusion who survived to hospital discharge (5.9% and 8.4%). This extremely low mortality was not associated with an altered risk of recurrent AMI or rate of CABG, PTCA, or both, which was comparable in the two groups.

The frequency of major and minor hemorrhagic events (33% rt-PA, 31% streptokinase) and associated transfusions (22% rt-PA, 20% streptokinase) were comparable in both groups. More than 70% of bleeding episodes in each group occurred at catheterization or vascular puncture sites.

Precipitable fibrinogen levels, measured in plasma samples collected in the presence of a protease inhibitor (aprotinin), declined in rt-PA and streptokinase groups by averages of 26 and 57% at 3 h and by 33 and 58% at 5 h, respectively (rt-PA vs. streptokinase, p less than 0.001). At 5 h the plasma plasminogen declined by 57% (rt-PA) and 82% (streptokinase) (p less than 0.001); plasma fibrin(ogen) degradation products were higher in streptokinase-treated patients (244 ±12 micrograms/ml, mean ±SE) than in rt-PA-treated patients (97 ±9 micrograms/ml, p less than 0.001). At 27 h, plasma fibrinogen and plasminogen levels were lower and fibrin(ogen) degradation products higher than pretreatment levels in both groups. The frequency of hemorrhagic events was higher in patients with greater changes in plasma factors at 5 h; within treatment groups the levels of fibrin(ogen) degradation products correlated with bleeding complications (p less than 0.005).

229 patients had radionuclide ventriculograms at discharge for assessment of global and regional left ventricular ejection fraction. Among these 229 patients 185 had totally occluded infarct-related arteries, and angiographic reperfusion of the infarct-related artery occurred in 69% of patients treated with rt-PA and 28% of patients treated with streptokinase (p less than 0.001). Mean global left ventricular ejection fraction was not different for rt-PA-treated patients compared with streptokinase-treated patients (0.46 vs. 0.45). However, the average regional ejection fraction of the regions subtended by the infarct-related artery showed a trend toward better average infarct region ejection fraction in patients treated with rt-PA than in patients treated with streptokinase (0.40 vs. 0.36; 0.05 less than p less than 0.06). Analysis of data according to perfusion status of the infarct-related artery showed no difference in mean global left ventricular ejection fraction between patients with sustained vs. nonsustained reperfusion (0.47 vs. 0.44). However, there was better average regional ejection fraction of the region subtended by the infarct-related artery in patients with sustained reperfusion (0.40 vs. 0.36; p less than 0.01).

In 65 of the 125 patients who failed to reperfuse, left ventricular ejection fraction (LVEF) was assessed by contrast ventriculography both at initial cardiac catheterization (before thrombolytic therapy) and at hospital discharge. Among the patients who had both studies, global LVEF tended to increase from pretreatment to hospital discharge in group A (from 50.6 ±1.8% to 53.4 ±1.8%, p = 0.10) but decreased in group B patients (from 50.3 ±1.8% to 47.8 ±1.7%, p = 0.02). At hospital discharge, global LVEF was greater in patients with coronary collaterals (53.5 ±1.7% vs. 49.6 ±1.7%, p = 0.01).

Quantitation of regional left ventricular function by radionuclide techniques provides a noninvasive means for evaluating the effects of thrombolysis. This study suggests a direct relation between improvement of regional left ventricular function and the greater infarct-related artery patency rate achieved by rt-PA compared with streptokinase.

The mortality rate significantly increased with age and was 3.5%, 11.5% and 12% in patients less than 65, 65 to 69 and 70 to 76 years of age, respectively (p less than 0.001). Logistic regression analyses selected female gender, diabetes mellitus, extensive coronary artery disease, history of congestive heart failure, continuing chest pain immediately after recombinant tissue-type plasminogen activator (rt-PA) administration, low systolic blood pressure at the time of admission and advanced age as variables predictive of in-hospital death. The incidence of major hemorrhagic events among patients not undergoing cardiac surgery during hospitalization was 8.7%, 14.5% and 24.7% in patients aged less than 65, 65 to 69 and greater than or equal to 70 years, respectively (p less than 0.001). The majority of hemorrhages were secondary to cardiac catheterization or puncture wounds. Variables related to a major hemorrhagic event included protocol, age, rt-PA dose/kg body weight and elevated diastolic blood pressure on admission. Of five intracranial bleeding events, three occurred in patients greater than 65 years. Transfusion requirements significantly increased with age (p less than 0.001). Reperfusion status at 90 min in the TIMI Phase I and open label studies A to C was similar in the three age groups studied and ranged from 60% to 71%.

125 patients failed to recanalize at 90 minutes after administration of tissue plasminogen activator or streptokinase. Patients with angiographically documented collaterals (group A, n = 51) had significantly lower values of peak serum CK than patients without collaterals (group B, n = 74) (1,877 ±216 vs. 2,661 ±212 IU/l, respectively [mean ±SEM], p = 0.004). Similarly, CK-derived infarct size estimates were significantly lower in group A than in group B (20.6 ±2.5 vs. 31.4 ±2.8 CK gram equivalents, p = 0.001). The infarct size observed in patients with collaterals was less for anterior infarctions as well as for infarctions of other locations; thus, the beneficial effects of collaterals were independent of the site of the infarct.

Interpretation:

In patients with acute myocardial infarction, rt-PA elicited reperfusion in twice as many occluded infarct-related arteries as compared with SK at each of seven serial observations during the first 90 min after onset of treatment.

The observed differences in mortality support the hypothesis that successful thrombolytic therapy decreases infarct size and thereby decreases the mortality of AMI.

In the doses administered, rt-PA induces systemic fibrinogenolysis that is substantially less intense than that induced by streptokinase. The high frequency of bleeding encountered is related to the protocol used, including vigorous anticoagulation, arterial punctures and thrombolytic therapy. These findings emphasize the need for avoidance of invasive procedures and for meticulous care in the selection and management of patients subjected to thrombolytic therapy.

The results demonstrate that, in patients in whom thrombolytic therapy fails to induce reperfusion, the presence of coronary collateral vessels at the onset of myocardial infarction is associated with limitation of infarct size as assessed enzymatically and with improved ventricular function on discharge as assessed by LVEF.

References:

1. N Engl J Med 1985;312:932-6. Study design and baseline results
2. Circulation 1987;76:142-54. Final results (hospital discharge)
3. Am J Cardiol 1988;62:179-85 [published erratum appears in Am J Cardiol 1988;62:1151]. 6- and 12-month follow-up
4. J Am Coll Cardiol 1988;11:1-11. Hemorrhagic manifestations
5. J Am Coll Cardiol 1989;13:998-1005. Regional ventricular function
6. J Am Coll Cardiol 1989; 14:1159-65. Elderly subgroup
7. Circulation 1991; 83:739-46. Collateral circulation

Clinical Topics: Cardiac Surgery, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and Heart Failure, Lipid Metabolism, Acute Heart Failure, Interventions and Coronary Artery Disease

Keywords: Thrombolytic Therapy, Coronary Artery Disease, Follow-Up Studies, Contraceptive Agents, Blood Pressure, Protease Inhibitors, Fibrinolytic Agents, Aprotinin, Angioplasty, Balloon, Coronary, Blood Transfusion, Streptokinase, Plasminogen, Stroke Volume, Fibrinogen, Tissue Plasminogen Activator, Myocardial Infarction, Radioisotopes, Ventricular Function, Left, Cardiac Catheterization, Body Weight, Estrone, Chest Pain, Heart Failure, Fibrin, Coronary Artery Bypass, Diabetes Mellitus, Logistic Models


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