A systematic review for the role of systemic thrombolysis in intermediate-risk (submassive) pulmonary embolism

Background: Pulmonary emboli (PE) represents an extended spectrum of diseases. 10% of submassive PE progress to massive PE, and while overall mortality is around 5%, it can reach 30%,(1) highlighting the potential severity of submassive PE. Treatment of low and high-risk PE is rather straightforward. However, treating intermediate risk PE is challenging due to the potential risks associated with aggressive therapy. We assessed the effect of adding thrombolytic therapy to standard treatment with heparin on short-term mortality, clinical deterioration, and bleeding in intermediate-risk PE cases. Intermediate-risk PE in this systematic review is objectively confirmed PE either by computer tomography (CT) or ventilation/perfusion (V/Q) scan in normotensive patients (systolic blood pressure ≥ 90 mmHg) with evidence of right ventricular strain by echocardiography or CT with or without evidence of myocardial injury by raised cardiac biomarkers.(2) Methods: A literature search was conducted using PubMed, OvidSP Platform, Google Scholar, BestBETs, The Cochrane Library - Databases, American College of Chest Physicians (ACCP), American Heart Association (AHA), European Society of Cardiology (ESC), American College of Emergency Physicians (ACEP), and NICE guidelines from 1946 to the 21(st) March 2018. References of retrieved articles were reviewed for other possibly related citations. The randomized controlled trials (RCTs) were studied and appraised using the Cochrane risk-of-bias tool (Table 1). Results: From 66 potentially relevant studies, six RCTs were published between 2002 and 2017 and included in this systematic review (Table 2). A total of 1568 patients were enrolled: 747 received thrombolytic therapy with alteplase (two trials, 155 patients) or tenecteplase (four trials, 592 patients), and 821 were treated with heparin only. None of these RCTs proved that adding thrombolytic therapy to standard anticoagulant treatment statistically decreased early mortality. The five studies looking at clinical deterioration proved that thrombolysis was beneficial. Five out of six RCTs resulted in a non-significant difference in major bleeding prevalence. Only the PEITHO(3) trial proved the opposite. The incidence of minor bleeding was significantly higher in the four studies in which it was measured (Table 3). Conclusions: Currently, there is inadequate evidence to support the use of systematic thrombolysis for patients with acute intermediate-risk PE. Although it may prevent clinical deterioration which necessitates escalation of treatment in the short term, it comes with increased risk of bleeding. Individual risk-benefit patient assessment and shared decision making may be wise until better evidence to proceed otherwise is demonstrated. Larger clinical trials concerning reduced thrombolytic doses and prolonged infusion rate is essential.