Anticoagulation has been the principal therapy used to treat pulmonary embolism (PE) since not long after Dr. D.W. Barritt and Dr. S.C. Jordan published the results a small randomized, controlled trial in 1960. In that trial, one of the 16 patients who were treated with intravenous heparin died; among the 15 untreated patients, five died and five experienced a nonfatal thrombotic event.1 Although subsequent clinical experiments confirm that most patients treated promptly with an effective anticoagulant regimen survive a PE, there is widespread agreement that patients who present in (or develop) significant PE-associated hypotension should receive fibrinolytic therapy.
The recently published Pulmonary Embolism Thrombosis Study (PEITHO) was designed to determine whether hemodynamically stable patients with echocardiographic and laboratory markers of increased mortality risk would benefit from adding intravenous (systemic) tenecteplase, a fibrinolytic agent, to anticoagulation. To be included in the trial, a patient had to have right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury (defined by an elevated serum concentration of cardiac troponin I or troponin T). The primary outcome measure was death or hemodynamic decompensation within seven days after randomization. Patients in the experimental arm received heparin and tenecteplase, while patients in the control arm received heparin and a placebo. Both the patient and the treating investigator were blinded to treatment assignment unless rescue thrombolysis was contemplated. If a patient experienced a persistent drop in systolic blood pressure, the primary efficacy endpoint was met, and open-label fibrinolytic therapy could be given. The composite of death or hemodynamic collapse occurred in 13 (2.6%) of the 506 patients who received tenecteplase, and in 28 (5.6%) of 499 who were given placebo (p=0.02). Between randomization and day seven, a total of six patients (1.2%) in the tenecteplase group and nine (1.8%) in the placebo group died (p=0.42). By day 30, the all-cause mortality rates were 2.4 percent in the tenecteplase group, and 3.2 percent in the placebo group (p=0.42). Both extracranial bleeding (6.3% vs. 1.2%; p<0.001) and hemorrhagic stroke (2.0% vs. 0.2%; p=0.003) were more common in the tenecteplase group. A pre-specified subgroup analysis suggested that the increased risk of major bleeding with tenecteplase (vs. placebo) was greater in patients over 75 years of age (odds ratio [OR] = 20.38 if age > 75 years vs. OR = 2.80 if age ≤ 75 years; p-value for interaction = 0.09).
In Brief
There are several important messages that come from this study of more than 1,000 patients with intermediate-risk PE. First, the addition of tenecteplase to anticoagulation did not effect a statistically significant reduction in overall mortality. Much like another study of hemodynamically stable, intermediate-risk patients with pulmonary embolism published 12 years earlier,2 the present PEITHO study suggests that anticoagulation, plus rescue thrombolysis in case of hemodynamic deterioration, is a strategy associated with low (1.8%) mortality, even in patients with evidence of right heart strain. Second, the PEITHO study adds to the previously published evidence that systemic administration of fibrinolytic agents causes a non-trivial number of extra- and intracranial bleeds. And third, the subgroup analysis from PEITHO suggests that the risk of major thrombolysis-associated bleeding is likely more pronounced in older patients.
The stakes are high when a clinician decides whether to administer thrombolytic therapy to a hemodynamically stable PE patient who has biochemical or echocardiographic evidence of right heart strain. Although PEITHO was not powered to detect a mortality benefit, the absence of statistically significant difference in overall survival at 30 days in this large, randomized trial suggests that high-quality anticoagulation, along with close monitoring for deterioration, is still an acceptable approach to intermediate-risk PE patients. However, the data also suggest that younger PE patients with high-risk features may benefit more from thrombolysis and, if an anticoagulation-alone strategy is used, the healthcare team must be prepared to provide rescue thrombolysis quickly (in PEITHO, 5% of the patients who did not receive up-front fibrinolysis subsequently experienced hemodynamic collapse). A recent meta-analysis of data pooled from PEITHO and similar (smaller) studies of thrombolytic therapy for intermediate-risk PE suggests that one death might be prevented for every 65 patients treated with fibrinolysis plus anticoagulation (rather than anticoagulation alone).3 Considering that this benefit would come at a cost of at least three additional major bleeds, the clinical equipoise surrounding thrombolytic therapy for intermediate-risk PE is likely to persist.
References
Competing Interests
Dr. Garcia indicated no relevant conflicts of interest.
