EBQ:Thrombolysis in Pulmonary Embolism Metanalysis

incomplete Journal Club Article

Chatterjee S, Chakraborty A, Weinberg I, Kadakia M, Wilensky RL, Sardar P, Kumbhani DJ, Mukherjee D, Jaff MR, Giri J.. "Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial Hemorrhage". JAMA. 2014. 311(23):2414-21.
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Clinical Question

What are the mortality benefits and bleeding risks associated with thrombolytic therapy compared with anticoagulation in acute PE?

Conclusion

Among patients with pulmonary embolism, including those who were hemodynamically stable with right ventricular dysfunction, thrombolytic therapy was associated with lower rates of all-cause mortality and increased risks of major bleeding and ICH

Major Points

Comment from Beckman in editorial (JAMA): "The accrual of 2000 patients over 45 years for a problem associated with 200 000 hospitalizations and 30 000 deaths per year suggests need for a large definitive trial, perhaps stratifying patients by age, using lower doses of thrombolytic agents, or applying a catheter-based strategy to reduce the potentially lethal bleeding risk. In the meantime, thrombolytic therapy should be individualized based on clinical presentation, comorbid conditions, and patient and physician risk tolerance. (...) Additional clinical trials are needed to guide optimal use of thrombolytic therapy in patients with PE."

Study Design

Meta-analysis of all RCTs on thrombolysis in PE, risk of bias was assessed for the domains suggested by the Cochrane Handbook of Systematic Reviews Studies were divided in groups depending on the risk of mortality associated with different presentations of PE: (1) low-risk (hemodynamically stable without objective evidence of RV dysfunction), (2) intermediate-risk (hemodynamically stable with objective evidence of RV dysfunction), high-risk (hemodynamically unstable and/or documented systolic blood pressure <90 mm Hg), or unclassifiable (patient information not adequate to determine risk level)

Population

Patients with PE

Inclusion Criteria

Relevant articles that had a randomized controlled design in "patients with Pulmonary Embolism" that evaluated "thrombolytic therapy" as an intervention with a comparator group that included agents: low-molecular-weight heparin (LMWH), vitamin K antagonist, fondaparinux, or unfractionated heparin; and reporting of "mortality outcome"

Interventions

• Thrombolytic therapy compared to low-molecular-weight heparin (LMWH), vitamin K antagonist, fondaparinux, or unfractionated heparin

Outcomes

Primary: all-cause mortality and major bleeding Secondary: risk of recurrent embolism and intracranial hemorrhage (ICH).

Primary Outcome

• Mortality thrombolysis vs. anticoagulants (OR, 0.53; 95%CI, 0.32-0.88; 2.17% [23/1061] vs 3.89% [41/1054];NNT=59

Secondary Outcomes

• major bleeding (OR, 2.73; 95%CI, 1.91-3.91; 9.24% [98/1061] vs 3.42%[36/1054]; NNH=18
• ICH (OR, 4.63; 95%CI, 1.78-12.04; 1.46%[15/1024] vs 0.19% [2/1019]; NNH=78
• Major bleeding was not significantly increased in pts < 65 years (OR, 1.25; 95%CI, 0.50-3.14)
• Thrombolysis was associated with a lower risk of recurrent PE (OR, 0.40; 95%CI, 0.22-0.74; 1.17%[12/1024] vs 3.04%[31/1019];NNT=54

Subgroup analysis

• Intermediate-risk PE: thrombolysis was associated with lower mortality (OR, 0.48; 95%CI, 0.25-0.92) and more major bleeding events (OR, 3.19; 95%CI, 2.07-4.92).

Criticisms & Further Discussion

• There are still very few patients (n=2115) included in RCT assessing impact of thrombolysis in PE to conclude with assurance about benefit or harm. Need exists for adequately powered study.
• There is only one study (ULTIMA) having analyzed the effect of catheter-delivered thrombolysis via a pulmonary artery catheter and results of this review should only be applied to systemic thrombolysis.

See Also

• Thrombolysis for PE

Thrombolytics for pulmonary embolism

• Clinical Page
  • Thrombolysis for PE
• Research summary page: EBQ:Thrombolysis in Pulmonary Embolism Metanalysis
  • PEITHO Trial
  • TOPCOAT Trial
  • MOPETT Trial