Two trials have specifically assessed the effect of thrombolysis in patients with submassive PE: Management Strategies and Prognosis of Pulmonary Embolism Trial-3 (MAPPET-3)12 and Tenecteplase Italian Pulmonary Embolism Study (TIPES)13 (Table 1). In the MAPPET-3 multicenter, randomized, double-blind, placebo-controlled study, Konstantinides and colleagues12 evaluated the effect of alteplase on the clinical outcome of patients with submassive PE. The study randomized 256 hemodynamically stable patients with acute PE and either pulmonary hypertension (defined as a tricuspid regurgitant jet velocity >2.8 m/s, present in 68.8% of the enrolled patients) or RV dysfunction (defined as RV enlargement combined with loss of inspiratory collapse of the inferior vena cava, present in 31.2% of the enrolled patients) to receive IV recombinant tissue plasminogen activator, 100 mg over 2 h, followed by unfractionated heparin infusion, or placebo tissue plasminogen activator plus heparin anticoagulation. The study used in-hospital death or clinical deterioration requiring escalation of therapy (defined as catecholamine infusion, rescue fibrinolysis, mechanical ventilation, cardiopulmonary resuscitation, or emergency surgical embolectomy) as the primary end point. Compared with heparin anticoagulation alone, fibrinolysis resulted in a significant reduction in the primary end point (10.2% vs 24.6%, P = .004). Mortality did not differ between the randomized treatment groups. The study attributed the difference to a higher frequency of escalation of therapy in patients randomized to anticoagulation with heparin alone compared with those treated with fibrinolysis. Both randomized treatment groups had low rates of major bleeding, although the heparin treatment group, surprisingly, had a trend toward more major bleeding compared with the thrombolysis treatment group (3.6% vs 0.8%, P = .29).