INTERVENTION:

Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Eltrombopag Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use

CONDITION:

thrombocytopenic subjects with Chronic Liver Disease Undergoing Elective Invasive Procedures ; MedDRA version: 9.1 Level: HLT Classification code 10043555 Term: Thrombocytopenias ; MedDRA version: 9.1 Level: HLT Classification code 10027681 Term: Hepatic and hepatobiliary disorders

NEC PRIMARY OUTCOME:

Main Objective: · To demonstrate the ability of eltrombopag, compared to placebo to reduce the proportion of subjects with chronic liver disease and thrombocytopenia (platelets <50,000/mL) who receive platelet transfusions administered prior to, during and up to seven days following elective invasive procedures. Primary end point(s): · Proportion of subjects with chronic liver disease and thrombocytopenia (platelets <50,000mL) who do not require a platelet transfusion prior to, during and up to seven days following elective invasive procedures. Secondary Objective: · To evaluate the effect of eltrombopag on the proportion of subjects with bleeding prior to, during and up to seven days following elective invasive procedures.; · To evaluate the safety and tolerability of eltrombopag when administered once daily to thrombocytopenic subjects with chronic liver disease prior to, during and following elective invasive procedures.; · To demonstrate the ability of eltrombopag compared to placebo, to reduce the number of platelet transfusions administered prior to, during and up to 4 weeks (30 days) following elective invasive procedures in subjects with chronic liver disease and a baseline platelet count <50,000/mL.; · To evaluate the effect of eltrombopag on platelet counts in subjects with chronic liver disease and a baseline platelet count <50,000/mL prior to, during and up to 4 weeks (30 days) following elective invasive procedures.; · To describe the pharmacokinetics (PK) of eltrombopag and explore the relationship between the PK and rele

INCLUSION CRITERIA:

1. Male and female subjects, ≥18 years of age with chronic liver disease. 2. Child‐Pugh score of 12 or less (See Appendix 3). 3. Model of End Stage Liver Disease (MELD) score of 24 or less. 4. Subjects who, in the opinion of the investigator, are appropriate candidates to undergo an elective invasive procedure and who require a platelet transfusion to manage the risk of bleeding associated with the procedure. 5. A baseline platelet count <50,000/mL. 6. A baseline serum sodium level >130mEq/L. 7. Haemoglobin concentration >8g/dL stable for at least one month. 9. Subject has no physical limitation to ingest and retain oral medication. 10. Subject is able to understand and comply with protocol requirements and instructions and is likely to complete the study as planned. 11. Subject is able to provide signed and dated written informed consent. 12. In France, a subject will be eligible for inclusion in this study only if either af

Background: There are limited tx options for CIT. Epag, an oral, small molecule, thrombopoietin-receptor agonist that increases platelet (plt) production, is being explored for tx of CIT. Methods: This was the Ph I portion of a Ph I/II, blinded, pbo-controlled multicenter study in adults with solid tumors and baseline plts 300,000μL, who received up to 6 cycles of gem (1000-1250 mg/m2 IV) as monotherapy on Days 1, 8, and 15 Q28 days or Days 1 and 8 Q21 days in combination with cisplatin (50-80 mg/m2 IV Day 1 or divided 1 and 8) or carboplatin (AUC 4-7 IV Day 1). Patients received ctx alone for Cycle 1 and ctx plus epag or matching pbo (randomized 3:1) daily on Days -5 to -1 and 2 to 6 for subsequent cycles. Epag or pbo was interrupted for plts 400,000/μL. Results: 33 patients were randomized; 26 received epag or pbo (Table). Data review with an external, independent physician found no safety concerns, and there were sufficient plt increases with a dose of 100 mg epag vs pbo. No dose-limiting toxicities were reported for epag but 1 for pbo. Most AEs were grade 1 or 2. The most common AE in combined epag- and combined pbo-treated groups was neutropenia. Conclusions: Epag was well-tolerated and improved plt counts. Based on these encouraging Ph I results, Ph II using 100 mg epag in thrombocytopenic patients is planned. (Table Presented).

Core study:

To compare the efficacy of avatrombopag (in addition to standard) of care to eltrombopag (in addition to standard of care) for the treatment of adult participants with chronic immune thrombocytopenia (idiopathic thrombocytopenic purpura \[ITP\]) as measured by durable platelet response.

Open-label Extension Phase:

To evaluate the safety and tolerability of long-term therapy with avatrombopag in participants with chronic ITP (cITP).

Background Eltrombopag is an orally bioavailable small molecule agonist of the thrombopoietin receptor (TPO‐R), stimulating platelet production. Preclinical and early clinical data have shown its anti‐leukemic activity in myeloid malignancies in addition to improved platelet counts, making eltrombopag a suitable candidate treatment following induction therapy for acute myeloid leukemia (AML). Preliminary data suggest that eltrombopag‐mediated iron chelation could be involved in its anti‐tumoral activity rather than apoptosis induction (Roth M, Blood 2012). In a randomized, double blind placebo controlled study conducted in advanced MDS and AML patients (pts) in relapse, refractory or ineligible to receive standard treatments, eltrombopag yielded a trend for improved overall survival (Frey N, ASH, 2012). Methods EPAG 2015 was designed as a randomized phase II multicenter trial aiming at assessing the impact on outcome of eltrombopag administered to elderly AML pts receiving induction chemotherapy (NCT 03603795). Inclusion criteria were: ≥ 60 years of age, newly diagnosed AML (de novo or therapy‐related) except AML3 (APL) and AML7, favorable or intermediate cytogenetic risk (MRC 2010 classification), ECOG performance status < 3; HCT‐CI score < 3, adequate baseline organ function. Exclusion criteria were: AML with adverse cytogenetic risk, or arising from MDS, MPN/CMML, or with BCR‐ABL1, known active central nervous system leukemia, history of thromboembolic event or ongoing use of anticoagulation. The induction chemotherapy regimen consisted of one cycle of daunorubicin 60 mg/m²/day (d), d1 to d3, cytarabine 100 mg/m²/d, CIV d1 to d7, lomustine 200 mg/m², orally d1. Eltrombopag 200 mg orally (100 mg/day for pts with East Asian heritage) or placebo (blinded) was given once daily from day 11 until AML response evaluation or platelet counts > 100 x 109/L (maximum d45). The use of GCS‐F, anti‐fungal, anti‐viral and anti‐pneumocystis jiroveci prophylaxis was recommended. Pts who failed to reach complete remission (CR/CRi) after this cycle of induction were off‐study whereas CR/CRi patients were planned to receive up to 6 courses of mini‐consolidation every 30 to 45 days with daunorubicin 60mg/m², d1, cytarabine 50 mg/m²/12h, subcutaneous, d1 to d5. Pts then received 6 months of maintenance therapy alternating mercaptopurin and methotrexate. The addition of midostaurin in patients with FLT3‐ITD or FLT3‐TKD mutations was not allowed during induction. Allogeneic stem‐cell transplantation (ASCT) was allowed after 2 to 4 cycles in pts with intermediate or adverse risk (European LeukemiaNet 2017). Results From October 2018 to June 2021, 110 pts of a median age of 70 y (range 61‐84). were included (55 per arm). There were 71 males (64.5%). Median complete blood count was 2.7x109/L (0.7‐142). Pts randomized to receive eltrombopag had significantly less previous histories of cancer (3 vs 12; p = 0.01). Most pts had intermediate risk cytogenetics (77.9%). NPM1 and FLT3 mutations (per local analysis) were observed in 26 (23.6%) and 27 pts (15.4%), respectively. High throughput sequencing of a myeloid gene panel, performed centrally will be presented at the meeting. Following induction, 90 pts (81.8%) achieved CR/CRi (45 in each group), including 74 CR (38 in the eltrombopag group and 36 in the placebo group), while 11 failed (5 and 6) and 6 died early (4 and 2). During induction, a similar rate of grade III‐IV adverse events was observed in the two arms (N=29, 52.7% vs 33, 60%, p = 0.4). Severe hemorrhage occurred in 2 pts who received placebo and 1 who received eltrombopag. Central nervous system toxicity was observed only in 2 placebo pts. The number of platelet transfusions was significantly reduced in the eltrombopag group 9.76+ 5.38 vs 12.56 + 9.69, p = 0.063 (10% risk). Of the 90 CR/CRi pts, 85 entered the consolidation phase. Twenty‐eight pts received ASCT in first CR, respectively 13 after eltrombopag and 15 after placebo. The median follow‐up time for alive pts was 20.9 months. Forty‐two pts (77.9%) who received eltrombopag were alive at 12 months vs 46 (85.3%). Event‐free survival at 12 months was 52.7% after eltrombopag vs. 50.5%. These differences are not statistically significant. Conclusion In older AML pts eligible for intensive treatment, adding eltrombopag to induction is feasible and safe, reduces significantly the need of platelet transfusions, yet did not impact survival in this study. [Formula presented] Disclosures: Pigneux: Sanofi: Other: travel;

MSD:

Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizzer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz pharmaceutical: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;

BMS:

Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dumas: Astellas: Honoraria; Daiichi‐Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Abbvie: Honoraria; BMS Celgene: Honoraria; Janssen: Honoraria. Vey: Roche: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria;

BMS:

Honoraria; Amgen: Honoraria. Hunault: abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; clinigen: Honoraria, Membership on an entity's Board of Directors or advisory committees; jazz pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carre:

BMS:

Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Guieze: Abbvie, Beigene, Janssen, Gilead, Roche, AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Desbrosses: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees;

BMS:

Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Simand: amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; jazz pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; astellas: Honoraria. Leguay: clinigen: Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jourdan: Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees;

BMS:

Membership on an entity's Board of Directors or advisory committees. Recher: Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie, Janssen, Jazz Pharmaceuticals, Novartis, BMS‐Celgene, Otsuka, Astellas, Daiichi‐Sankyo, Macrogenics, Roche, Takeda, Servier, Pfizer: Other: Advisory role; AbbVie, Amgen, Novartis, BMS‐Celgene, Jazz Pharmaceuticals, Agios, MaatPharma, Astellas, Roche, Iqvia, Daiichi‐Sankyo: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;

BMS:

Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

INTERVENTION:

Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 25‐ Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐

CONDITION:

Thrombocytopenic subjects with hepatitis C viral infection (HCV) ; MedDRA version: 9.1 Level: LLT Classification code 10019744 Term: Hepatitis

C PRIMARY OUTCOME:

Main Objective: To evaluate the safety and tolerability of open‐label eltrombopag when administered once daily. Primary end point(s): Assessment of safety and tolerability of eltrombopag as measured by the nature and frequency of adverse events, laboratory abnormalities, ocular examinations and clinical monitoring/observation. Secondary Objective: • To evaluate platelet counts before and during antiviral therapy.; • To evaluate maintenance of antiviral therapy.; • To evaluate achievement of antiviral treatment milestones.;

INCLUSION CRITERIA:

1. Male and female subjects, =18 years of age. 2. Evidence of chronic HCV infection (quantifiable HCV RNA, lower limit of detection of 50 IU/ml). 3. Subjects must be previous participants of TPL103922 (ENABLE 1) or TPL108390 (ENABLE 2) and successfully initiated antiviral treatment in those studies. 4. Subjects must have permanently discontinued all investigational products for ENABLE 1 or 2 within 12 weeks from randomisation in ENABLE 1 or 2 due to reasons of thrombocytopenia. Subjects who continued antiviral therapy beyond 6 weeks must have had some degree of thrombocytopenia during this time, defined as having at least a 50% dose reduction of pegylated IFN (for reasons of thrombocytopenia) for a minimum period of 4 weeks. 5. All subjects must have completed the final 6 month (24 week) SVR and ocular follow‐up assessments in ENABLE 1 or ENABLE 2. 6. Subjects who, in th

INTERVENTION:

Product Name: Eltrombopag Product Code: SB497115 Pharmaceutical Form: Tablet INN or Proposed

INN:

eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg/g milligram(s)/gram Concentration type: equal Concentration number: 25‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Product Name: Eltrombopag Product Code: SB497115 Pharmaceutical Form: Tablet INN or Proposed

INN:

eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg/g milligram(s)/gram Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use

CONDITION:

Idiopathic thrombocytopenic purpura (ITP) ; MedDRA version: 8.1 Level: LLT Classification code 10051057 Term: Idiopathic thrombocytopenia

PRIMARY OUTCOME:

Main Objective: To determine the efficacy of oral eltrombopag, when administered once daily, for 6 months duration, to previously treated adult subjects with chronic ITP Primary end point(s): The primary endpoint is the odds of achieving a platelet count at or 50,000/microL and = 400,000/microL during the 6 month treatment period, for subjects receiving eltrombopag relative to placebo Secondary Objective: • To assess ability of eltrombopag to prevent use of rescue treatment ; • To describe pharmacodynamics & durability of eltrombopag response; • To determine efficacy of oral eltrombopag, when administered once daily for 6 weeks ; • To assess safety & tolerability of eltrombopag when administered for 6 months; • To describe effect of eltrombopag on reduction of concomitant ITP medications from baseline; • To assess impact of eltrombopag on incidence & severity of bleeding symptoms of thrombocytopenia when administered once daily for 6 months ; • To assess impact of eltrombopag on health related QoL & patient reported outcomes;

EXPLORATORY OBJECTIVES:

; • To assess effect of administration of eltrombopag on anti‐platelet antibody levels; • To use proteomic analysis to identify proteins that may correlate with safety & tolerability and/or predict response to eltrombopag

INCLUSION CRITERIA:

1. Subject has signed and dated a written informed consent. 2. Adults (?18 years) diagnosed with chronic ITP according to the American Society for Hematology/British Committee for Standards in Hematology (ASH/BCSH) guidelines [George, 1996; BCSH, 2003], and platelet count < 30,000/?L on Day 1 (or within 24 hours prior to dosing on Day 1). In addition, a peripheral blood smear should support the diagnosis of ITP with no evidence of other causes of thrombocytopenia (e.g. pseudothrombocytopenia, myelofibrosis). The physical examination should be normal or at least not show signs suggestive of any disease other than ITP which may cause thrombocytopenia. 3. Subjects who have previously received one or more prior ITP therapies. Previous treatments for ITP include but are not limited to corticosteroids, immunoglobulins, azathioprine, danazol, cyclophosphamide and/or rituximab. 4. Subjects must have either initially responded (platelet count > 100,000/?L) to

Objective. To review the pharmacology, pharmacokinetics, efficacy, and safety of two new thrombopoietic (TPO) receptor agonists, romiplostim and eltrombopag, in the treatment of chronic idiopathic thrombocytopenic purpura (ITP) in adults. Data sources. A MEDLINE search was conducted (1966 to March 2009) using the search terms romiplostim, AMG 531, eltrombopag, SB-497115, idiopathic thrombocytopenic purpura. Articles on phases 1-3 clinical trials in patients with ITP were identified and reviewed. References from manufacturer information, and abstracts from recent hematology meetings, were also evaluated. Study selection and data extraction. Controlled clinical trials evaluating romiplostim and eltrombopag for treatment of chronic ITP in adults were selected from the data sources. All published relevant abstracts were also included. Data synthesis. Limited randomized controlled trials and open-label ongoing long-term extension studies for romiplostim and eltrombopag, have shown that both TPO agonists are effective in improving the platelet count and reducing the bleeding episodes in adult patients with ITP unresponsive to at least one standard treatment. The most common adverse events associated with the drugs are mild to moderate headaches. The use of these agents has also been associated with rare but serious side-effects including bone marrow reticulin fibrosis, thrombotic events, and myeloid malignancies. Conclusions. Until more long-term follow-up data regarding the safety, as well as comparative studies that further define the role of TPO agonists versus other agents in the treatment of chronic ITP are available, these agents should be reserved for patients with ITP refractory or intolerant to standard therapy. © 2010 SAGE Publications.

TECNOLOGÍA EVALUADA:

Eltrombopag.

DESCRIPCION DE LA INTERVENCIÓN:

Eltrombopag (Revolade, GlaxoSmithKline) aumenta la producción de plaquetas activando el receptor de trombopoyetina, estimulando así la producción de plaquetas y reduciendo el sangrado. Eltrombopag tiene una autorización de comercialización de ANMAT para tratamiento de 'púrpura trombocitopénica inmune crónica (idiopática) (PTI) en pacientes de 1 año o más que son refractarios a otros tratamientos (p. ej. corticosteroides, inmunoglobulinas y esplenectomía).

BUSQUEDA BIBLIOGRÁFICA:

Se realizaron búsquedas en MEDLINE (desde 1950 hasta marzo de 2011), EMBASE (desde 1974 hasta marzo de 2019), y en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL) (Cochrane Library 2011, Número 3), para identificar todos los metaanálisis y ensayos con asignación aleatoria sobre la PTI crónica.

RESULTADOS:

Se incluyeron seis ensayos con 808 pacientes. Cinco estudios compararon los agonistas de receptores de TPO con placebo (romiplostim: 100, eltrombopag: 299, placebo: 175); un estudio comparó los agonistas de receptores de TPO con la atención estándar (AE) (romiplostim: 157; AE.: 77). La AE incluyó una variedad de tratamientos, como glucocorticoide, inmunoglobulina anti-D, inmunoglobulina intravenosa, rituximab, azatioprina, etcétera. La supervivencia general, una de nuestras medidas de resultado primarias, no fue estudiada por estos ECAs y no fue posible calcular el número necesario a tratar (NNT). Otra medida de resultado primaria, la mejoría en los eventos de hemorragia significativa, no reveló ninguna diferencia significativa entre el grupo de agonistas de receptores de TPO y el grupo de control (placebo o AE) (versus cociente de riesgos [CR] del placebo 0,48, intervalo de confianza [IC] del 95%: 0,20 a 1,15; versus CR de la AE 0,49, IC del 95%: 0,15 a 1,63). En cuanto a las medidas de resultado secundarias, los agonistas de receptores de TPO mejoraron de forma estadísticamente significativa la respuesta plaquetaria general (versus CR del placebo 4,06, IC del 95%: 2,93 a 5,63; versus CR de la AE 1,81, IC del 95%: 1,37 a 2,37), la respuesta completa (versus CR del placebo 9,29; IC del 95%: 2,32 a 37,15) y la respuesta duradera (versus CR del placebo 14,16; IC del 95%: 2,91 a 69,01). Hubo una reducción significativa en los eventos de hemorragia general (grado 1 a 4 de la OMS) en comparación con el placebo (CR 0,78; IC del 95%: 0,68 a 0,89), pero no en comparación con la AE (CR 0,97; IC del 95%: 0,75 a 1,26).

EXPLICACIONES:

Funded by drug company. There is evidence that industry-sponsored trials may overestimatethetreatmenteffect(Bhandari 2004). Los intervalos de confianza son amplios e incluyen no efecto. Estudio que evaluó intervención con Romiplostin.

Thrombocytopenia is common (40-65%) and potentially serious in myelodysplastic syndromes (MDS). A systematic review was conducted to determine the safety and efficacy of adding a thrombopoietin-receptor (THPO-R) agonist to standard MDS treatment. MEDLINE, EMBASE and CENTRAL databases were searched. We included randomized controlled trials comparing a THPO-R agonist to placebo. A meta-analysis of the effects was performed. Endpoints included bleeding and platelet transfusion rates, risk of progression to acute myeloid leukaemia (AML) and mortality. Three hundred and eighty four patients from five trials were included, four using romiplostim and one using eltrombopag. Overall, the relative risk (RR) of bleeding with romiplostim versus placebo was 0·84 [95% confidence interval (CI): 0·57-1·24]. However, compared to placebo, romiplostim significantly decreased the exposure-adjusted bleeding rate (RR 0·92; 95% CI.: 0·86-0·99), as well as the exposure-adjusted platelet transfusion rate (RR 0·69; 95% CI.: 0·53-0·88). The RR of AML progression with romiplostim was 1·36 (95% CI.: 0·54-3·40), however the outcome data were judged as higher risk of bias. Romiplostim is promising in its ability to decrease patient-important outcomes: bleeding and platelet transfusion need. Although the risk of AML progression was not increased, due to unclear risk of bias in the data, this safety concern is difficult to assess. Therefore, romiplostim cannot yet be routinely recommended. Early eltrombopag data is promising. © 2014 John Wiley & Sons Ltd.

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)