Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: Systematic review and meta-analysis of randomized controlled trials / Riesgo de tromboembolismo con agonistas del receptor de la trombopoyetina en pacientes adultos con trombocitopenia: revisión sistemática y metaanálisis de ensayos clínicos aleatorizados y controlados

Background and 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. Materials and 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 I2 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; I2 = 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 (AU)

Fundamento y objetivo: Los agonistas del receptor de la trombopoyetina (TPOr) (romiplostim y eltrombopag) promueven la diferenciación megacariocítica, la proliferación y la producción de plaquetas. En 2012, una revisión sistemática y metaanálisis informó de un aumento no estadísticamente significativo del riesgo tromboembólico para estos medicamentos, pero los análisis presentaban limitaciones por la falta de potencia estadística. El objetivo es actualizar el metaanálisis de 2012 examinando si los agonistas del TPOr afectan a la incidencia de tromboembolismos en los pacientes adultos con trombocitopenia. Material y métodos: Se llevó a cabo una revisión sistemática y metaanálisis de ensayos clínicos aleatorizados y controlados (ECA). Se actualizaron búsquedas llevadas a cabo en PubMed, Cochrane Central, y registros públicos (hasta Diciembre de 2014). Se incluyeron ECA en los que se administrara romiplostim o eltrombopag en al menos uno de los grupos de pacientes tratados. Se calcularon los riesgos relativos (RR), la diferencia absoluta de riesgo (ARR, por sus siglas en inglés) y el número necesario de pacientes para dañar (NNH). Se examinó la heterogeneidad estadística mediante la Q de Cochran y el estadístico I2. Resultados: Se incluyeron 15 estudios con 3026 pacientes adultos diagnosticados de trombocitopenia. Las frecuencias de acontecimientos tromboembólicos fueron de 3.69% ([intervalo de confianza] IC del 95%: 2,95–4,61%) para los agonistas del TPOr y de 1,46% (IC95%: 0,89–2,40%) para los controles. Los agonistas del TPOr se asociaron con un riesgo relativo de tromboembolismo de 1,81 (IC95%: 1,04–3,14) y una ARR del 2,10% (IC95%: 0,03–3,90%), que significa un NNH de 48. En general, no se encontró evidencia de heterogeneidad estadística (p = 0,43; I2 = 1,60%). Conclusiones: El metaanálisis actualizado sugiere que los agonistas del TPOr están asociados con un mayor riesgo de eventos thromboembólicos en comparación con los controles. Estos resultados apoyan las precauciones incluidas en la información del medicamento en la Unión Europea en relación con el riesgo tromboembólico (AU)

Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: Systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND 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. MATERIALS AND 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.

Riesgo tromboembólico con agonistas del receptor de la trombopoyetina en pacientes adultos con trombocitopenia: revisión sistemática y metaanálisis de ensayos clínicos aleatorizados y controlados / Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: systematic review and meta-analysis of randomized controlled trials

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 diferenciación megacariocítica, la proliferación y la producción de plaquetas. En la Unión Europea, han sido autorizados como medicamentos huérfanos, con una indicación restringida a los pacientes esplenectomizados con púrpura trombocitopénica inmune que son refractarios a otros tratamientos. Debido al incremento de los recuentos de plaquetas, estos fármacos pueden representar un riesgo de tromboembolias. Se analiza si los agonistas del TPOr afectan a la incidencia de acontecimientos tromboembólicos en pacientes adultos con trombocitopenia. Material y métodos: Revisión sistemática y meta-análisis de ensayos clínicos aleatorizados y controlados (ECA). Se realizó una búsqueda en PubMed, SCOPUS, Cochrane Central Register, web de las agencias reguladoras y registros de acceso público (p.ej, gubernamentales y de los fabricantes). Se incluyeron ECA en los que se administrara romiplostim o eltrombopag en al menos uno de los grupos de pacientes tratados. Se calcularon la reducción absoluta de riesgo (RAR), el número necesario de pacientes a dañar (NNH) y el riesgo relativo (RR). Se examinó la heterogenidad mediante la Q de Cochrane y el estadístico I2. Resultados: De las 373 publicaciones identificadas, 8 estudios cumplieron los criterios de inclusión (n=1.180 pacientes). Se encontraron variaciones en la calidad de la información entre estudios. Las frecuencias de acontecimientos tromboembólicos fueron de 3,1% [intervalo de confianza (IC) del 95% = 1,8-4,4%] para los agonistas del TPOr y de 1,7% (IC95% = 0,3-3,1%) para el grupo control (AU)

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 I2 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 (AU)

Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: systematic review and meta-analysis of randomized controlled trials.

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.