Pro-Urokinase for Myocardial Infarction - PRIMI

Description:

PRIMI was an open-label, prospective pilot trial to determine the effect of simultaneous infusions of low-dose recombinant tissue-type plasminogen activator (t-PA) and single-chain urokinase-type plasminogen activator (scu-PA, pro-urokinase) on coronary arterial thrombolysis in patients with acute myocardial infarction.

Hypothesis:

t-PA and scu-PA will have a synergistic effect on thrombolysis. Using the drugs together may allow lower total doses and therefore lower bleeding risk.

Study Design

Study Design:

Patients Enrolled: 23
Mean Follow Up: Hosptial discharge
Mean Patient Age: 18-76
Female: 43

Patient Populations:

Men and women aged 18 to 76 years with suspected acute MI characterized by chest pain lasting more than 30 minutes, ST segment elevation of 0.1mV in at least two contiguous precordial or limb lead, symptoms lasting less than 6 hours.

Exclusions:

Standard contraindications to thrombolytic therapy, cardiogenic shock, PTCA within past 6 months, prior CABG.

Primary Endpoints:

Infarct artery patency at 90 minutes.

Secondary Endpoints:

Hematologic levels of clotting factors. Bleeding rates. Adverse events.

Drug/Procedures Used:

Patients with acute MI received a 5000IU heparin bolus. Thrombolysis was initiated with 20% of the customary dose of t-PA (20mg) given IV as a 10mg bolus followed by 10mg infusion over 60 minutes. Immediately after commencing t-PA infusion, a 724,000 IU bolus (4mg) of scu-PA was administered followed by a 2,226,000 IU infusion (12.3mg) over 60 minutes. Angiography was performed at 90 minutes in all patents.

Concomitant Medications:

All patients received aspirin and heparin.

Principal Findings:

PRIMI enrolled 23 patients (13 men and 10 women). Mean age was 61 years and mean time from symptom onset to thrombolytic therapy was 2.6 hours. Infarct related arteries included LAD (39%), RCA (52%), and LCX (9%).

A patent infarct related vessel (TIMI 2 or 3 flow) occurred in 70% of patients (23 patients) at 90 minute angiogram. Two additional patients achieved TIMI grade 3 flow at 113 and 150 minutes.

Hematologic analysis showed an increase in fibrinogen degradation products to >20 fold by 90 minutes. Plasminogen and alpha-2-antiplasmin levels dropped significantly.

No bleeding episodes requiring termination of treatment occurred. Mean hemoglobin levels decreased from 14.7 to 12.2 with treatment. A single hospital death occurred in a 66 year old man from cerebral hemorrhage. Post mortem exam confirmed cerebral microvascular amyloidosis.

Interpretation:

Among patients with acute MI, combination thrombolytic therapy with t-PA and scu-PA was associated with infarct vessel patency rates comparable to other monotherapy thrombolysis trials at lower total thrombolytic dosages. This pilot study provides the basis for further trials with larger numbers of patients, although scu-PA in combination with tPA was not adopted as a treatment strategy for MI.

References:

Kirshenbaum JM, Bahr RD, Flaherty JT, Gurewich V, Levine HJ, Loscalzo J, Schumacher RR, Topol EJ, Wahr DW, Braunwald E. Clot-selective coronary thrombolysis with low-dose synergistic combinations of single-chain urokinase-type plasminogen activator and recombinant tissue-type plasminogen activator. The Pro-Urokinase for Myocardial Infarction Study Group. Am J Cardiol. 1991 Dec 15;68(17):1564-9.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Lipid Metabolism, Novel Agents

Keywords: Thrombolytic Therapy, Myocardial Infarction, Urokinase-Type Plasminogen Activator, Heparin, Fibrinolytic Agents, Hemoglobins, Chest Pain, Plasminogen Activators, Recombinant Proteins, Fibrinogen, Tissue Plasminogen Activator, Cerebral Hemorrhage


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