COMMENTARY

The Best in Pulmonary Medicine

Nicholas J. Gross, MD, PhD

Disclosures

January 19, 2011

In This Article

Efficacy and Safety of Low Dose Recombinant Tissue-Type Plasminogen Activator for the Treatment of Acute Pulmonary Thromboembolism: A Randomized, Multicenter, Controlled Trial

Wang C, Zhai Z, Yang Y, et al.
Chest. 2010;137:254-262

Study Summary

Recombinant tissue-type plasminogen activator (rt-PA) has been in clinical use since 1996, during which time several dosing regimens have been explored and tested. The currently recommended dose for massive pulmonary embolism is 100 mg administered over 2 hours.[48] However, the therapeutic margin of rt-PA is not large, and the danger of hemorrhage, particularly intracranial hemorrhage, is ever-present. The present study aimed to determine whether a smaller dose than recommended (50 mg) would be as effective as, and possibly safer than, the currently recommended dose. In a prospective, randomized, multicenter trial in Beijing, China, 118 patients with massive pulmonary thromboembolism (PTE) received either 100 mg or 50 mg of rt-PA over 2 hours. Efficacy outcomes were echocardiographic evidence of improvement in right ventricular function, improvement in perfusion defects on lung V/Q scans, or improvements in pulmonary artery obstruction by CT angiograms. Safety endpoints were monitored for 14 days and included mortality, hemorrhage, and recurrence of PTE.

The results were that improvements in each of the efficacy outcomes were indistinguishable. The number of deaths were 3 and 1 in the higher-dosage vs lower-dosage groups, and were related to either the initial PTE or hemorrhage. Major bleeding tended to be less in the 50-mg rt-PA group; overall 3% of patients in the 50-mg group had major bleeding vs 10% in the 100-mg group. Subgroup analysis by body mass index (BMI) revealed no difference between rt-PA dosages with respect to efficacy outcomes. However, bleeding events in patients with body weight > 65 kg or BMI > 25 were significantly less frequent in the 50-mg rt-PA group (8.7% vs 42.9%, P < .014). The investigators concluded that the lower dose of rt-PA, 50 mg, is appropriate for the management of PTE.

Viewpoint

Pulmonary thromboembolism is a serious problem that confronts pulmonologists as well as other internists and primary caregivers.[49] The National Heart, Lung, and Blood Institute estimates that in 1998 there were 650,000 cases and 9000 fatalities from PTE.[50] The currently approved dose was arrived at in 1988 from a very small study, only 44 patients, that compared rt-PA with an alternative agent, urokinase, and that showed their equivalence.[51] Since then, various dosage regimens, different total dosages, and different administration rates have been explored. The present trial represents the first head-to-head trial of a lower dose. The findings support the suggestion of Wang and colleagues that a half-dose of rt-PA is as effective as the recommended 100-mg dose and may be safer, particularly in the heavier patient. Before that conclusion is accepted, however, several aspects need to be considered.

The study was relatively small and needs to be replicated in a larger group. Two thirds of the enrollees only had anatomic imaging evidence of PTE and may not have actually needed any rt-PA. Perhaps the most important consideration is that the trial was conducted entirely with Chinese patients. Given the known genetic, metabolic, morphologic, and even dietary differences between Asian and non-Asian populations, the present results may not be generalizable to other patients. However, the apparent reduction in bleeding problems with a smaller dose, particularly in heavier patients, is most interesting and a consideration that will resonate with many caregivers. It may change clinical practice with further experience.

Abstract

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