Chest
Volume 106, Issue 3, September 1994, Pages 718-724
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Clinical Investigations: Pulmonary Embolism
Reduced Dose Bolus Alteplase vs Conventional Alteplase Infusion for Pulmonary Embolism Thrombolysis: An International Multicenter Randomized Trial

https://doi.org/10.1378/chest.106.3.718Get rights and content

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.

Section snippets

Methods

The protocol was approved by the human subjects committees of the 28 participating hospitals in the United States, Italy, and Canada, and by the FDA. Participating institutions were predesignated as angiography or echocardiography centers. Written informed consent was obtained from all patients. The trial ran between August 29, 1991, and December 14, 1992. Nineteen centers enrolled 48 patients in a coagulation laboratory ancillary study that began on February 10, 1992.

Patients 18 years of age

Results

The 90 patients who were enrolled, 61 to bolus rt-PA and 29 to 2-h rt-PA, had similar clinical baseline characteristics (Table 1). One patient randomized to bolus rt-PA at an echocardiogram center had an increasingly large pericardial effusion on echocardiogram, and the treating physicians decided not to proceed with thrombolytic therapy. Two patients at angiogram centers assigned to 2-h rt-PA had their randomization kits opened before completion of pulmonary angiography. The angiogram of one

Discussion

The principal hypothesis in our trial was that 0.6 mg/kg of bolus rt-PA (maximum of 50 mg) would be associated with fewer major and other important bleeding events than a fixed dose of 100 mg of 2-h rt-PA. However, we did not detect a significant difference between the two treatment groups with respect to bleeding complications. If a difference does exist in favor of bolus rt-PA, it is much smaller than we would have anticipated from previous bolus rt-PA studies5 and would have required

ACKNOWLEDGMENTS

The Bolus Alteplase Pulmonary Embolism (BAPE) Group is an international research group consisting of the following individuals, committees, and institutions represented as follows: Principal Investigator: Samuel Z. Goldhaber, MD, FCCP; National Coordinators: Samuel Z. Goldhaber, MD, FCCP, (United States), Giancarlo Agnelli, MD (Italy), Mark N. Levine, MD (Canada); Data Monitoring and Safety Committee: Eugene Braunwald, MD, FCCP, (Chairman) (Boston), Yiannis Bassiakos, PhD (Brookline), Michael

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    Supported in part by grants from Genentech, Inc and Boehringer Ingelheim Italia.

    Dr. Samuel Z. Goldhaber receives support from the National Heart, Lung, and Blood Institute Academic Award in Systemic and Pulmonary Vascular Medicine (HL 02663).

    A list of the BAPE Group members appears in the Acknowledgment.

    Revision accepted April 25.

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