HEPARIN PLUS ALTEPLASE COMPARED WITH HEPARIN ALONE IN PATIENTS WITH SUBMASSIVE PULMONARY EMBOLISM.

Konstantinides S, et al. N Engl J Med 2002 Oct 10;347(15):1143-50.

BACKGROUND: The use of thrombolytic agents in the treatment of hemodynamically stable patients with acute submassive pulmonary embolism remains controversial.

METHODS: We conducted a study of patients with acute pulmonary embolism and pulmonary hypertension or right ventricular dysfunction but without arterial hypotension or shock. The patients were randomly assigned in double-blind fashion to receive heparin plus 100 mg of alteplase or heparin plus placebo over a period of two hours. The primary end point was in-hospital death or clinical deterioration requiring an escalation of treatment, which was defined as catecholamine infusion, secondary thrombolysis, endotracheal intubation, cardiopulmonary resuscitation, or emergency surgical embolectomy or thrombus fragmentation by catheter.

RESULTS: Of 256 patients enrolled, 118 were randomly assigned to receive heparin plus alteplase and 138 to receive heparin plus placebo. The incidence of the primary end point was significantly higher in the heparin-plus-placebo group than in the heparin-plus-alteplase group (P=0.006), and the probability of 30-day event-free survival (according to Kaplan-Meier analysis) was higher in the heparin-plus-alteplase group (P=0.005). This difference was due to the higher incidence of treatment escalation in the heparin-plus-placebo group (24.6 percent vs. 10.2 percent, P=0.004), since mortality was low in both groups (3.4 percent in the heparin-plus-alteplase group and 2.2 percent in the heparin-plus-placebo group, P=0.71). Treatment with heparin plus placebo was associated with almost three times the risk of death or treatment escalation that was associated with heparin plus alteplase (P=0.006). No fatal bleeding or cerebral bleeding occurred in patients receiving heparin plus alteplase.

CONCLUSIONS: When given in conjunction with heparin, alteplase can improve the clinical course of stable patients who have acute submassive pulmonary embolism and can prevent clinical deterioration requiring the escalation of treatment during the hospital stay.

COMMENTS: This study appeared to demonstrate significant improvement when treating submassive PE with alteplase. However, there was no difference in either death or recurrent PE. The only difference is that there were more patients in the placebo group who required “rescue thrombolysis.” The trial protocol allowed for breaking of the randomization code if additional therapy had to be provided, which means that the investigator were no longer blinded to the alteplase or placebo. Therefore, if the patient decompensated and the investigator found out that the patient got placebo, he would more likely be willing to give alteplase. On the other hand, if the patient had already been given alteplase, additional thrombolysis is less likely. Thus, the only difference that was demonstrated was achieved only after breaking the randomization code. This by itself could explain “rescue thrombolysis” in the placebo group.