title: Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: systematic review and meta-analysis of randomized controlled trials.
abstract: OBJECTIVE
  Thrombopoietin receptor (TPOr) agonists (romiplostim and eltrombopag) are a new approach for the treatment of thrombocytopenia-associated conditions. They promote megakaryocyte differentiation, proliferation and platelet production. In the European Union, both are orphan drugs with an indication restricted to splenectomized immune thrombocytopenic purpura patients who are refractory to other treatments. Due to increasing platelet counts, these drugs may represent a risk for thromboembolic complications. We analyzed whether TPOr agonists affect thromboembolisms occurrence in adult thrombocytopenic patients.
  
  
  METHODS
  We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Searches were carried out in PubMed, SCOPUS, Cochrane Central Register, regulatory agencies websites and publicly available registries of manufacturers. RCTs using romiplostim or eltrombopag in at least one group were included. Absolute risk ratios (ARR), number needed to harm (NNH) and relative risks (RR) were provided. Heterogeneity was analyzed using Cochran's Q test and I(2) statistic.
  
  
  RESULTS
  Of 373 publications identified, 8 studies met the inclusion criteria (n=1180 patients). The quality of reporting amongst studies was variable. Estimated frequency of thromboembolisms was 3.1% (95% CI, 1.8-4.4%) for TPOr agonists and 1.7% (95% CI, 0.3-3.1%) for controls. Summary analyses produced overall meta-ARR for thromboembolisms of 1.8% (95% CI, -0.1-3.6%), and meta-RR of 1.5 (95% CI, 0.7-3.3), meaning a NNH of 55 (1 additional thromboembolism for each 55 patients treated with TPOr agonists). All pooled estimates were homogeneous.
  
  
  CONCLUSIONS
  TPOr agonists show a numerically but non-statistically significant trend to increase the occurrence of thromboembolisms compared to controls, but analyses were underpowered and in some studies information on outcomes was incomplete and of poor quality.
authors.affiliation: Centro Superior de Investigación en Salud Pública (CSISP), Valencia, Spain. ferran_catala@hotmail.com
authors.forename: Ferrán
authors.initials: F
authors.lastname: Catalá-López
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Corrales
authors.forename: Gloria
authors.initials: G
authors.lastname: Martín-Serrano
authors.forename: Aurelio
authors.initials: A
authors.lastname: Tobías
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Calvo
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; D011720:Pyrazoles / Q000009:adverse effects* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D011961:Receptors, Fc / Q000627:therapeutic use; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects* / Q000627:therapeutic use; D012307:Risk Factors; D013921:Thrombocytopenia / Q000150:complications / 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