Source: Hao Q, Dong BG, Yue J, Wu T, Liu GJ. Thrombolytic therapy for pulmonary embolism (Review). Cochrane Database Syst Rev 2015;12:CD004437.
Study Population: 2167 patients with pulmonary embolism from 17 randomized controlled trials
Efficacy Endpoints: Mortality, recurrent PE
Harm Endpoints: Major or minor hemorrhage
Narrative: Pulmonary embolism (PE) is a potentially life-threatening condition caused by occlusion in the pulmonary arterial circulation. PE can be categorized as low-risk, submassive (associated with evidence of right heart strain), or massive (associated with hemodynamic instability).1, 2, 3 The latter two subtypes are associated with increased morbidity and mortality.1, 2, 3 Traditionally, anticoagulation has been the mainstay of treatment. In massive PE, however, it is important to restore pulmonary blood flow rapidly, which is often accomplished by the use of thrombolytic agents or surgical embolectomy.1, 3 The medical literature has reported improvement in clot lysis, restoration of normal pulmonary circulation, a decrease in right heart strain, and improvement in long-term cardiac output and exercise tolerance with the use of thrombolytics.4, 5, 6 However, not all studies have demonstrated improvement in survival or other patient outcomes with thrombolytics, and thrombolytics carry an increased risk of bleeding.4, 7, 8, 9, 10, 11 The Cochrane review discussed here evaluates the efficacy of thrombolytics versus heparin alone for acute PE.12
This Cochrane review is the third update of an original review published in 2006.13 The authors have included 17 randomized controlled trials (RCT), which included a total of 2167 patients who were diagnosed with acute PE confirmed by imaging or other validated assessment tool. The intervention group received thrombolytic therapy followed by heparin; the control group received heparin alone in 11 studies and heparin plus placebo in the remaining 6 studies. The primary outcomes included overall mortality, recurrent PE, major hemorrhagic events (defined as intracranial or retroperitoneal hemorrhage, decreased hemoglobin by more than 2 g/dL, or transfusion of 2 or more units of blood), and minor hemorrhagic events (defined as bleeding not meeting criteria for major bleeding). The included studies used several different types of thombolytics: alteplase (5 trials), streptokinase (5 trials), rt-PA (3 trials), urokinase (2 trials), tenecteplase (3 trials), and catheter-directed thrombolysis (1 trial). Eleven of the trials included patients with submassive PE, one trial evaluated massive PE, and 6 trials did not report the type of PE. Four trials included both massive PE and PE of unknown type. The sample sizes of the included trials ranged from 8 to 1006 patients, with the majority of RCTs including less than 100 patients. Mean age of included patients approximated 60 years.
This updated review found that thrombolytics plus heparin reduced the risk of death compared to heparin alone (odds ratio [OR]: 0.57; 95% confidence interval [CI] 0.37-0.87; absolute risk difference [ARD]: 2.9%; Number-needed-to-treat [NNT]: 34; low quality evidence). However, this effect was not significant when the four studies at high risk of bias were excluded (OR: 0.66; 95% CI 0.42-1.06). Thrombolytics also reduced the risk of recurrent PE (OR: 0.51; 95% CI 0.29-0.89; ARD: 2%; NNT: 50). Patients who received thrombolytics had a higher risk of major hemorrhagic events (OR: 2.90; 95% CI 1.95-4.31; ARD: 10.3%, Number-needed-to harm [NNH]: 10; low quality evidence) as well as minor hemorrhagic events (OR: 3.09; 95% CI 1.58-6.06; ARD: 25%; NNH: 4; low quality evidence).
Caveats: The meta-analysis discussed here has several important limitations. First, the overall evidence quality was low to very low due to limitations in trial design, influence of pharmaceutical companies, and small sample sizes. The mortality benefit was not present in the sensitivity analysis after exclusion of the four trials with unclear or high risk of bias. Studies used a variety of follow-up periods and thrombolytic agents, thus introducing significant heterogeneity. Sample sizes varied significantly as well, and most studies included less than 100 patients. No studies evaluated surgical embolectomy compared to thrombolytics. Randomization and blinding varied significantly among included trials. Four trials received funding from pharmaceutical companies.
Identifying hemodynamically stable patients and unstable patients (massive PE) is imperative in PE. Among the trials included in the Cochrane analysis, however, only one trial, with a sample size of 8, specifically enrolled patients with massive PE.14 The impact of thrombolytics in patients with massive PE could not be determined in this review; however, the American College of Chest Physicians provides a grade 2C recommendation to administer thrombolytics in patients with acute PE and hypotension.15
A prior meta-analysis by Chatterjee et al. found decreased mortality with thrombolytic therapy.4 However, that review included several studies at high risk of bias and did not conduct sensitivity analyses.
Finally, the trials included in the Cochrane meta-analysis used a variety of thrombolytic agents, some of which (e.g. streptokinase) are no longer used because of the higher risk of hemorrhage.
In summary, low-quality evidence indicates that thrombolytics may reduce mortality and recurrent PE in patients with acute PE. However, thrombolytics significantly increase the risk of major and minor hemorrhagic events. Therefore, we assign a color rating of Yellow (unknown benefit) to thrombolytic therapy for undifferentiated PE. Further high-quality studies are needed to determine whether specific patient groups, particularly those with submassive or massive PE, may benefit from thrombolytic therapy or suffer harm from these agents.
Author: Brit Long, MD; Alex Koyfman, MD; Michael Gottlieb, MD, RDMSSupervising editors: Shahriar Zehtabchi, MD; Allan Wolfson, MD
Published/Updated: February 1, 2019
The title bar is color-coded with our overall recommendation.