Robustness and fragility of evidence supporting systemic thrombolysis in acute pulmonary embolism.

Abstract

Systemic thrombolysis is recommended for high-risk PE and select intermediate-risk patients. We assessed the robustness of RCT evidence comparing systemic thrombolytic therapy with standard anticoagulation. We systematically reviewed RCTs of intravenously administered alteplase or tenecteplase versus heparin. The primary endpoint was all-cause mortality; secondary endpoints included recurrent PE, clinical deterioration in intermediate-risk patients, and major bleeding. Fragility index (FI) or reverse FI (RFI) and fragility quotient (FQ) or reverse FQ (RFQ) were calculated to assess outcome stability. Absolute and relative risk reductions, number needed to treat (NNT), and number needed to harm (NNH) were also derived. Nine RCTs enrolling 1,682 patients met inclusion criteria. Overall, systemic thrombolysis was associated with a nonsignificant reduction in mortality (1.7% vs. 3.8%; RR 0.73; 95% CI 0.39-1.38; p = 0.33) with moderate robustness (RFI = 8; RFQ = 0.004; NNT 91; RRR 27%; ARR 2.1%). Mortality was highly fragile in high-risk PE (RFI = 0) and fragile in intermediate-risk patients (RFI = 4). Systemic thrombolysis moderately reduced recurrent PE (RR 0.42; 95% CI 0.18-0.97; FI = 5; RFQ = 0.002) and prevented clinical deterioration in intermediate-risk patients (RR 0.31; 95% CI 0.15-0.65; FI = 8; RFQ = 0.006; NNT 29; RRR 71%; ARR 3.5%). Major bleeding was robustly increased (FI = 30; RFQ = 0.001; NNH 17), mainly driven by tenecteplase (FI = 9; RFQ = 0.007; NNH 11), whereas alteplase showed no significant increase (RFI = 3). Mortality benefit of systemic thrombolysis is fragile, while major bleeding risk is robust, underscoring the limitations of current guidelines and the need for adequately powered RCTs to inform individualized treatment in high- and intermediate-risk PE.