title: Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: Systematic review and meta-analysis of randomized controlled trials.
abstract: OBJECTIVE
  Romiplostim and eltrombopag are thrombopoietin receptor (TPOr) agonists that promote megakaryocyte differentiation, proliferation and platelet production. In 2012, a systematic review and meta-analysis reported a non-statistically significant increased risk of thromboembolic events for these drugs, but analyses were limited by lack of statistical power. Our objective was to update the 2012 meta-analysis examining whether TPOr agonists affect thromboembolism occurrence in adult thrombocytopenic patients.
  
  
  METHODS
  We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Updated searches were conduced on PubMed, Cochrane Central, and publicly available registries (up to December 2014). RCTs using romiplostim or eltrombopag in at least one group were included. Relative risks (RR), absolute risk ratios (ARR) and number needed to harm (NNH) were estimated. Heterogeneity was analyzed using Cochran's Q test and I(2) statistic.
  
  
  RESULTS
  Fifteen studies with 3026 adult thrombocytopenic patients were included. Estimated frequency of thromboembolism was 3.69% (95% CI: 2.95-4.61%) for TPOr agonists and 1.46% (95% CI: 0.89-2.40%) for controls. TPOr agonists were associated with a RR of thromboembolism of 1.81 (95% CI: 1.04-3.14) and an ARR of 2.10% (95% CI: 0.03-3.90%) meaning a NNH of 48. Overall, we did not find evidence of statistical heterogeneity (p=0.43; I(2)=1.60%).
  
  
  CONCLUSIONS
  Our updated meta-analysis suggested that TPOr agonists are associated with a higher risk of thromboemboembolic events compared with controls, and supports the current recommendations included in the European product information on this respect.
authors.affiliation: Division of Pharmacoepidemiology and Pharmacovigilance, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain; Fundación Instituto de Investigación en Servicios de Salud, Valencia, Spain. Electronic address: ferran_catala@hotmail.com.
authors.forename: Ferrán
authors.initials: F
authors.lastname: Catalá-López
authors.affiliation: Division of Pharmacoepidemiology and Pharmacovigilance, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Corrales
authors.affiliation: Division of Pharmacoepidemiology and Pharmacovigilance, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain.
authors.forename: César
authors.initials: C
authors.lastname: de la Fuente-Honrubia
authors.affiliation: Division of Pharmacoepidemiology and Pharmacovigilance, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: González-Bermejo
authors.affiliation: Division of Pharmacoepidemiology and Pharmacovigilance, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Martín-Serrano
authors.affiliation: Division of Pharmacoepidemiology and Pharmacovigilance, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Montero
authors.affiliation: Division of Pharmacoepidemiology and Pharmacovigilance, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain.
authors.forename: Diego Macías
authors.initials: DM
authors.lastname: Saint-Gerons
mesh_terms: D000328:Adult; D001565:Benzoates / Q000009:adverse effects* / Q000627:therapeutic use; D006401:Hematologic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D006834:Hydrazines / Q000009:adverse effects* / Q000627:therapeutic use; D015233:Models, Statistical; D011720:Pyrazoles / Q000009:adverse effects* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D011961:Receptors, Fc / Q000627:therapeutic use; D053628:Receptors, Thrombopoietin / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects* / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000188:drug therapy*; D013923:Thromboembolism / Q000139:chemically induced*; D013926:Thrombopoietin / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D001565:Benzoates; D006401:Hematologic Agents; D006834:Hydrazines; D011720:Pyrazoles; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; C488777:romiplostim; C520809:eltrombopag
keywords: Eltrombopag; Ensayo clínico aleatorizado controlado; Meta-analysis; Randomized controlled trials; Romiplostim; Thrombocytopenia; Thromboembolism; Thrombosis; Trombocitopenia; Tromboembolismo; Trombopoyetina; Trombosis