Lower mortality rate but more major bleedings with thrombolytics in pulmonary embolismChatterjee S et al., JAMA. 2014 - JAMA. 2014;311(23):2414-2421
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.,
BackgroundResults 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).
- 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%).
ConclusionThis 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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References1. Goldhaber SZ, Haire WD, Feldstein ML, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet. 1993;341(8844):507-511.
2. Konstantinides S, Geibel A, Heusel G, et al; Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347(15):1143-1150.
3. Wan S, Quinlan DJ, Agnelli G et al. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. 2004;110(6):744-749.
4. Thabut G, Thabut D, Myers RP, et al. Thrombolytic therapy of pulmonary embolism: ameta-analysis. J AmColl Cardiol. 2002;40(9): 1660-1667.
5. Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost. 2014;12(4):459-468.
6. SharifiM, Bay C, Skrocki L, et al; “MOPETT” Investigators. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-277.
7. Fasullo S, Scalzo S, Maringhini G, et al. Six-month echocardiographic study in patients with submassive pulmonary embolism and right ventricle dysfunction: comparison of thrombolysis with heparin. Am J Med Sci. 2011;341(1):33-39.