Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial HemorrhageA Meta-analysis

Chatterjee S, Chakraborty A, Weinberg I et al.,
JAMA. 2014;311(23):2414-2421

Background

Results of studies evaluating the role of thrombolytic therapy in pulmonary embolism (PE) have been conflicting [1-4]. Several studies or meta-analyses were underpowered to assess the association of thrombolytic therapy with mortality [2-4].
There is a clear need for outcomes data of thrombolytics in haemodynamically stable patients with evidence of right ventricular (RV) dysfunction (intermediate-risk PE). Some recent trials studied this, but did not yield definite results, specifically with regard to mortality [6-8]. This meta-analysis evaluated all randomised trials of thrombolytic therapy in PE, with a focus on patients presenting with intermediate-risk PE. 16 RCTs met inclusion criteria. 210 patients (9.93%) patients had low-risk PE, 1499 (70.87%) had intermediate-risk PE, and 31 (1.47%) presented with high-risk PE (385 (18.20%) unclassifiable).

Main results

• Thrombolytic therapy in PE was associated with lower all-cause mortality (OR: 0.53, 95%CI: 0.32-0.88, NNT: 59, 95%CI: 31-380). Mortality was 2.17% in the thrombolytic cohort and 3.89% in the anticoagulant cohort, at a mean duration of follow-up of 81.7 days.
• Thrombolytic therapy was associated with a greater risk of major bleeding than anticoagulant therapy (OR: 2.73, 95%CI: 1.91-3.91, NNH: 18, 95%CI: 13-27) (9.24% major bleeding rate with thrombolytics, vs. 3.42% with anticoagulation).
• Thrombolytic therapy was associated with a higher intracranial haemorrhage (ICH) rate (1.46% vs. 0.19%, OR: 4.63, 95%CI: 1.78-12.04) and a lower risk of recurrent PE (1.17% vs. 3.04%, OR: 0.40, 95%CI: 0.22-0.74).
• A subgroup analysis in patients older than 65 years showed a significantly greater risk of major bleeds with thrombolytic therapy (12.93% vs. 4.10%, OR: 3.10, 95%CI: 2.10-4.56), which was not seen in younger patients.
• In an analysis of trials that exclusively enrolled patients who were haemodynamically stable (RV function objectively assessed), thrombolysis was associated with lower mortality (1.39% vs. 2.92%, OR: 0.48, 95%CI: 0.25-0.92) than anticoagulant therapy, and with greater major bleeding rate (7.74% vs. 2.25%, OR: 3.19, 95%CI: 2.07-4.92).
• In a net clinical benefit analysis that compares mortality benefits with ICH risks (weighted as 0.75 of a mortality event), thrombolytic therapy demonstrated a net clinical benefit of 0.81% (95%CI: 0.65-1.01%). In patients with intermediate-risk PE, the net clinical benefit was 0.62% (95%CI: 0.57-0.67%).

Conclusion

This meta-analysis shows that thrombolytic use is associated with lower all-cause mortality in PE in haemodynamically stable patients with right ventricular dysfunction, as compared with anticoagulant use. This clinical advantage comes with a higher risk of major bleeding and ICH, especially in patients over 65 years old. Risk stratification models for bleeding  are warranted to be able to identify individuals with a high risk of hemorrhagic complications with thrombolytic therapy.

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