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

Chatterjee. 2014 JAMA:311(23);2414-2421.

Clinical Question

  • In patients with PE, does the addition of thrombolysis to anticoagulation, compared with anticoagulation alone, affect mortality and bleeding complications?


  • Meta-analysis
  • Followed PRISMA statement
  • Systematic search using MeSH and keywords in the following databases:
    • PubMed, Cochrane, EMBASE, EBSCO, Web of Science, CINAHL
    • No language restriction


  • Trial Inclusion: Randomised trials comparing thrombolysis vs. anticoagulant therapy in patients with PE
  • Trial Exclusion: Comparisons of different thrombolytic agents against one another or different doses of the same thrombolytic drug
  • Trial Populations: Adult patients; stratified into high-, intermediate-, low- and unknown-risk according to haemodynamic stability and RV dysfunction (by echogardiogram or biomarkers).
    • 16 trials comprising 2115 patients were identified, 4 of these trials accounted for 74% of the total patients
    • 8 trials comprising 1775 patients with intermediate-risk PE for sub-group analysis
      • Haemodynamically stable (BP>90mmHg) with objective evidence of right ventricular dysfunction on echocardiogram, and/or Troponin/brain natriuretic peptide
        • PEITHO: 1005 patients
        • MAPPETT 3: 256 patients
        • MOPETT: 121 patients
        • Goldhaber: 101 patients
        • TOPCOAT: 83 patients
        • FASULLO: 72 patients
        • ULTIMA: 59 patients (catheter directed thrombolysis)
        • TIPES: 58 patient


  • Thrombolysis and anticoagulation
    • various types and doses used


  • Anticoagulation alone
    • Heparin, low molecular weight heparin or fondaparinux



Measure Thrombolytic Anticoagulants OR ARR NNT/NNH p
Primary Outcome
All-cause mortality 2.17% 3.89% 0.53
(95% CI 0.32–0.88)
1.72% 59 0.01
Major bleeding 9.24% 3.42% 2.73
(95% CI 1.91–3.91)
-5.82% 18 <0.001
Secondary Outcomes
Recurrent PE 1.17% 3.04% 0.40
(95% CI 0.22–0.74)
1.87% 53 0.03
ICH 1.46% 0.19% 4.63
(95% CI 1.78–12.04)
-1.27% 79 0.002
Pre-specified sub-group analyses
Major bleeding
age >65 years
12.93% 4.1% 3.10
(95% CI 2.10–4.56)
-8.83% 11 0.001
Major bleeding
age ≤65 years
2.84% 2.27% 1.25
(95% CI 0.50–3.14)
-0.57% 175 0.89
All-cause mortality
Intermediate-risk PE
1.39% 2.92% 0.48
(95% CI 0.25–0.92)
1.53% 65 0.03
Major bleeding
Intermediate-risk PE
7.74% 2.25% 3.19
(95% CI 2.07–4.92)
-5.49% 18 0.001
OR = Odds Ratio; ARR = Absolute Rate Reduction; NNT/NNH = Number needed-to-treat/harm; ICH = Intra-cerebral haemorrhage

Authors’ Conclusions

  • Among patients with PE, including those who are haemodynamically stable, thrombolysis was associated with lower mortality and more major bleeding


  • Clear inclusion criteria for studies included
  • Results of individual studies presented clearly
  • Trial registered with PROSPERO


  • Definitions for haemodynamic isntability, major and minor bleeding and RV dysfunction were not standardised between studies
  • Varying doses and types of thrombolysis used in different studies.
  • One study utilised catheter directed thrombolysis which may not be possible in most centres. However with this study excluded the results for the primary outcome were still statistically significant
  • The authors report that study methods were assessed for risk of bias, but this is not reported in the results. MAPPETT-3 and PEITHO provide 1/3 of patients for this meta-analysis, and both have weaknessness of concern.

The Bottom Line

  • Thrombolysis for PE is associated with a lower all cause mortality when compared to anticoagulation. This improvement is maintained in the subgroup of ‘intermediate risk’ PE with a NNT of 65. This is despite a significant increase in major bleeding in the thrombolysis group, with a NNH of 18. Of note, patients who were ≤65 years had no increase in major bleeding with thrombolysis.
  • With the MOPETT and TOPCOAT studies finding improved longterm outcomes with regards to pulmonary hypertension, and self assessment of overall health in the thrombolysis groups, this meta-analysis provides a convincing argument for the use of thrombolysis in submassive PE.
  • If I have a submassive PE, I want thrombolysis. (I am under 65 years). I would want half-standard dose as per the MOPETT trial. If my dad (he is over 65 years) had a sub-massive PE I would not recommend thrombolysis as the 12.9% chance of major bleeding means that the risks may outweigh the benefits.


abstract / doi: 10.1001/jama.2014.5990

Editorial, Commentaries or Blogs


Summary author: @DavidSlessor and @DuncanChambler
Summary date: 29 June 2014
Peer-review editor: @stevemathieu75

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