Reduced dose bolus alteplase vs conventional alteplase infusion for pulmonary embolism thrombolysis. An international multicenter randomized trial. The Bolus Alteplase Pulmonary Embolism Group.

STUDY OBJECTIVE

To test the hypothesis that a reduced dose of bolus recombinant human tissue-type plasminogen activator (rt-PA) (0.6 mg/kg/15 min, maximum of 50 mg) would result in fewer bleeding complications than standard 100 mg of rt-PA administered as a continuous infusion over 2 h among hemodynamically stable patients with pulmonary embolism (PE). Subsidiary objectives were to compare the two rt-PA regimens with respect to the following: (1) the rate of other adverse clinical events; (2) the magnitude of change from baseline on perfusion lung scans, pulmonary angiograms, or echocardiograms; and (3) the differences in coagulation parameters over time.

DESIGN

A double-blind, double-dummy, randomized, controlled trial.

SETTING

Twenty-eight participating hospitals in the United States, Italy, and Canada.

PATIENTS

Patients could be included if they had symptoms or signs of PE within 14 days of presentation as well as high-probability lung scans and/or pulmonary angiograms demonstrating PE.

INTERVENTIONS

Randomization was undertaken with a 2:1 allocation ratio to rt-PA 0.6 mg/kg/15 min (maximum of 50 mg) or to 100 mg/2 h. Ninety patients were randomized, and 87 patients were treated: 60 with bolus rt-PA and 27 with 2-h rt-PA. All patients underwent baseline and 20- to 28-h follow-up perfusion lung scintigraphy. Patients at angiogram centers underwent baseline and 2-h follow-up angiography, while patients at echocardiogram centers underwent baseline, 3-h, and 20- to 28-h echocardiography. Forty-eight patients also participated in an ancillary study of serial fibrinogen and fibrin degradation product levels.

RESULTS

In the first 14 days after randomization, there were six deaths: five (8.3 percent) in the bolus group vs one death (3.7 percent) in the 2-h group (p = 0.66). There were two clinically suspected nonfatal recurrent PEs during the first 14 days after therapy, one in each treatment group. Overall, 14 patients suffered major or other important bleeding: 8 in the bolus group and 6 in the 2-h group (p = 0.35). Changes in efficacy parameters (scans, angiograms, or echocardiograms) were similar in the two treatment groups. After initiation of therapy, patients who had received bolus rt-PA had less depression of fibrinogen levels (p = 0.007) and smaller increases in fibrinogen degradation products (p = 0.013) than patients who had received 100 mg of rt-PA over 2 h.

CONCLUSIONS

No significant differences were detected between the bolus rt-PA and 2-h rt-PA with respect to bleeding complications, adverse clinical events, or imaging studies. There was less fibrinogenolysis with the bolus dosing regimen.