Original article Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: systematic review and meta-analysis of randomized controlled trials Ferra ´n Catala ´ -Lo ´ pez a,b,c, *, Inmaculada Corrales c,d , Gloria Martı ´n-Serrano c , Aurelio Tobı ´as e , Gonzalo Calvo f a Centro Superior de Investigacio ´n en Salud Pu ´blica (CSISP), Valencia, Spain b Fundacio ´n Instituto de Investigacio ´n en Servicios de Salud, Valencia, Spain c Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Medicines and Healthcare Products Agency (AEMPS), Madrid, Spain d Quality Agency of the Spanish National Health System, Madrid, Spain e Institute of Environmental Assessment and Water Research (IDAEA), Spanish Council for Scientific Research (CSIC), Barcelona, Spain f Service of Clinical Pharmacology, Hospital Clı´nic, Barcelona, Spain Med Clin (Barc). 2012;139(10):421–429 A R T I C L E I N F O Article history: Received 23 August 2011 Accepted 15 November 2011 Available online 23 January 2012 Keywords: Eltrombopag Meta-analysis Randomized controlled trials Romiplostim Thromboembolism Thrombosis Thrombocytopenia A B S T R A C T Background and 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. Materials and 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. ß 2011 Elsevier Espan ˜a, S.L. All rights reserved. Riesgo tromboembo ´ lico con agonistas del receptor de la trombopoyetina en pacientes adultos con trombocitopenia: revisio ´n sistema ´ tica y metaana ´ lisis de ensayos clı´nicos aleatorizados y controlados Palabras clave: Eltrombopag Metaana ´ lisis R E S U M E N Fundamento y objetivo: Los agonistas del receptor de trombopoyetina (TPOr) (romiplostim y eltrombopag) son un nuevo enfoque para el tratamiento de la trombocitopenia asociada a algunas enfermedades. Los agonistas del TPOr promueven la diferenciacio ´n megacariocı ´tica, la proliferacio ´n y la * Corresponding author. E-mail address: ferran_catala@hotmail.com (F. Catala ´ -Lo ´ pez). ww w.els evier.es /med ic in ac lin ic a 0025-7753/$ – see front matter ß 2011 Elsevier Espan ˜a, S.L. All rights reserved. doi:10.1016/j.medcli.2011.11.023 Document downloaded from http://www.elsevier.es, day 23/10/2012. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.