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Original Investigation |

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

Saurav Chatterjee, MD1; Anasua Chakraborty, MD2; Ido Weinberg, MD3; Mitul Kadakia, MD4; Robert L. Wilensky, MD4; Partha Sardar, MD5; Dharam J. Kumbhani, MD, SM, MRCP6; Debabrata Mukherjee, MD, MS5; Michael R. Jaff, DO3; Jay Giri, MD, MPH4
[+] Author Affiliations
1Division of Cardiology, St Luke’s-Roosevelt Hospital Center of the Mount Sinai Health System, New York, New York
2Division of Pulmonology and Critical Care, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
3Institute for Heart, Vascular, and Stroke Care, Massachusetts General Hospital, Boston
4Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia
5Division of Cardiology, Texas Tech University, El Paso
6Division of Cardiology, University of Texas Southwestern Medical Center, Dallas
JAMA. 2014;311(23):2414-2421. doi:10.1001/jama.2014.5990.
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Importance  Thrombolytic therapy may be beneficial in the treatment of some patients with pulmonary embolism. To date, no analysis has had adequate statistical power to determine whether thrombolytic therapy is associated with improved survival, compared with conventional anticoagulation.

Objective  To determine mortality benefits and bleeding risks associated with thrombolytic therapy compared with anticoagulation in acute pulmonary embolism, including the subset of hemodynamically stable patients with right ventricular dysfunction (intermediate-risk pulmonary embolism).

Data Sources  PubMed, the Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from inception through April 10, 2014.

Study Selection  Eligible studies were randomized clinical trials comparing thrombolytic therapy vs anticoagulant therapy in pulmonary embolism patients. Sixteen trials comprising 2115 individuals were identified. Eight trials comprising 1775 patients specified inclusion of patients with intermediate-risk pulmonary embolism.

Data Extraction and Synthesis  Two reviewers independently extracted trial-level data including number of patients, patient characteristics, duration of follow-up, and outcomes.

Main Outcomes and Measures  The primary outcomes were all-cause mortality and major bleeding. Secondary outcomes were risk of recurrent embolism and intracranial hemorrhage (ICH). Peto odds ratio (OR) estimates and associated 95% CIs were calculated using a fixed-effects model.

Results  Use of thrombolytics was associated with lower all-cause mortality (OR, 0.53; 95% CI, 0.32-0.88; 2.17% [23/1061] vs 3.89% [41/1054] with anticoagulants; number needed to treat [NNT] = 59) and greater risks of major bleeding (OR, 2.73; 95% CI, 1.91-3.91; 9.24% [98/1061] vs 3.42% [36/1054]; number needed to harm [NNH] = 18) and 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 patients 65 years and younger (OR, 1.25; 95% CI, 0.50-3.14). Thrombolysis was associated with a lower risk of recurrent pulmonary embolism (OR, 0.40; 95% CI, 0.22-0.74; 1.17% [12/1024] vs 3.04% [31/1019]; NNT = 54). In intermediate-risk pulmonary embolism trials, 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).

Conclusions and Relevance  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. However, findings may not apply to patients with pulmonary embolism who are hemodynamically stable without right ventricular dysfunction.

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Figure 1.
Search Strategy and Study Selection
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Figure 2.
Odds of Mortality in Patients With Pulmonary Embolism Treated With Thrombolytic Therapy vs Anticoagulation

Evaluated using the Peto method of meta-analysis. The standard practice in meta-analysis of odds ratios (ORs) and risk ratios is to exclude studies from the meta-analysis where there are no events in either group.13 A 0-cell or continuity correction was not used based on recommendations regarding calculation of a Peto OR for studies with 0 events in only 1 group.13 MOPETT indicates Moderate Pulmonary Embolism Treated with Thrombolysis trial; PEITHO, Pulmonary Embolism Thrombolysis trial; PIOPED, Prospective Investigation of Pulmonary Embolism Diagnosis; TIPES, Tenecteplase Italian Pulmonary Embolism Study; TOPCOAT, Tenecteplase or Placebo: Cardiopulmonary Outcomes At Three Months; ULTIMA, Ultrasound Accelerated Thrombolysis of Pulmonary Embolism trial; UPETSG, Urokinase Pulmonary Embolism Trial Stage 1.

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Figure 3.
Odds of Mortality in Patients With Intermediate-Risk Pulmonary Embolism Treated With Thrombolytic Therapy vs Anticoagulation

Evaluated using the Peto method of meta-analysis. The standard practice in meta-analysis of odds ratios (ORs) and risk ratios is to exclude studies from the meta-analysis where there are no events in either group.13 A 0-cell or continuity correction was not used based on recommendations regarding calculation of a Peto OR for studies with 0 events in only 1 group.13 MOPETT indicates Moderate Pulmonary Embolism Treated with Thrombolysis trial; PEITHO, Pulmonary Embolism Thrombolysis trial; TIPES, Tenecteplase Italian Pulmonary Embolism Study; TOPCOAT, Tenecteplase or Placebo: Cardiopulmonary Outcomes At Three Months; ULTIMA, Ultrasound Accelerated Thrombolysis of Pulmonary Embolism trial.

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