The 2008 consensus guidelines from the American College of Chest Physicians and the 2008 European Society of Cardiology Task Force guidelines are remarkably similar (Table 1). Both endorse risk stratification and employ similar criteria and recommendations for the use of advanced PE therapy such as thrombolysis, embolectomy, and inferior vena caval filter placement.
Anticoagulation prevents additional thrombus from forming but does not directly dissolve the PE clot that already exists. In contrast, thrombolytic therapy constitutes primary treatment of PE because it dissolves fibrin. When successful, this direct approach results in hemodynamic improvement with reversal of right ventricular hypokinesis, normalization of right ventricular size, and reduction of abnormally high pulmonary arterial pressures. Fibrinolysis may also serve as a medical embolectomy that reduces the source of thrombus in the pelvic, upper extremity, and deep leg veins, thereby lessening the likelihood of recurrent PE. Finally, thrombolytic therapy might decrease long-term elevations of pulmonary vascular resistance by improving pulmonary capillary blood flow, which might theoretically decrease the likelihood of developing chronic thromboembolic pulmonary hypertension.
Thrombolysis of PE mostly utilizes recombinant human tissue plasminogen activator (TPA). The FDA approved dose is 100 mg over 2 h via a continuous peripheral intravenous infusion. In the United States, TPA is administered without concomitant heparin and without a 10 mg bolus-loading dose. In Europe, TPA is usually prescribed with concomitant intravenous unfractionated heparin infusion as a 10 mg bolus dose followed by 90 mg of TPA as a continuous infusion over 2 h. When successful, there is usually clinical improvement by the second hour of therapy. Patients experience a sense of improved well-being, often with resolution of tachypnea as well as lessening or elimination of a requirement for supplemental oxygenation. A side effect is nuisance bleeding, especially gingival oozing and development of ecchymosis at sites where phlebotomy was previously attempted but failed.
Even the most ardent supporters of thrombolysis admit that there exist several major limitations to this strategy. First, it elevates the risk of major, catastrophic bleeding, including gastrointestinal and intracranial hemorrhage. Second, though approved only for treatment of ‘massive PE,’ there is no study demonstrating a survival benefit, other than a single trial of eight patients in which four received streptokinase plus heparin and four received anticoagulation alone . In fact, an observational study from the International Cooperative Pulmonary Embolism Registry suggested that patients with massive PE receiving thrombolysis might not experience any clinical benefit whatsoever with respect to decreasing mortality or major cardiovascular events . While these findings might seem counterintuitive, they mimic observations seen when patients with massive anterior myocardial infarction and cardiogenic shock receive thrombolysis. The physiologic explanation is that in patients with massive PE, an adverse metabolic cascade leading to multisystem organ failure has often advanced so far as to be irreversible.
For patients with submassive PE, defined as right ventricular dysfunction and troponin elevation despite normal systemic arterial pressure, definitive evidence to prove the efficacy of fibrinolysis does not yet exist. MAPPET-3, the largest completed randomized trial of thrombolytic therapy vs. heparin alone, studied patients with submassive PE who had the combination of normal blood pressure and right ventricular dysfunction . TPA, compared with placebo, halved the frequency of escalation of therapy – defined as the need for pressors, mechanical ventilation, cardiopulmonary resuscitation, or open-label thrombolysis – and did not increase major bleeding. Open-label thrombolysis was the major endpoint that drove MAPPET-3 in favor of TPA. Because the decision to use open-label thrombolysis after the initial randomization treatment was subjective, the trial has been criticized, and its findings remain controversial. A meta-analysis of 748 patients in 11 prior randomized thrombolysis trials found that in the subset of trials that included major PE, the mortality rate was halved but the major bleeding rate doubled among thrombolysis-treated subjects .
A large ongoing European randomized controlled trial of tenecteplase in submassive PE (defined as preserved blood pressure but elevated troponin level and right ventricular enlargement) has enrolled about 250 of a required 1100 patients. The principal endpoint is death or cardiovascular collapse.
Thrombolytic therapy is not used often in the United States. Among 15 116 patient discharges with a primary diagnosis of PE, only 2.4% received fibrinolysis. The overall 30-day mortality was 17.4% for those receiving thrombolysis compared with 8.6% for those who did not. Counterintuitively, excess mortality risk was the highest among those PE patients who had a low overall clinical risk but who, nevertheless, received thrombolysis .