Научная статья на тему 'Evaluation of safety, efficacy and pharmacokinetics of Eltrombopag in patients with chronic immune thrombocytopenia: Meta-analysis of randomized controlled trials'

Evaluation of safety, efficacy and pharmacokinetics of Eltrombopag in patients with chronic immune thrombocytopenia: Meta-analysis of randomized controlled trials Текст научной статьи по специальности «Клиническая медицина»

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Ключевые слова
Eltrombopag / immune thrombocytopenia / safety and efficacy / thrombopoietin agonists / meta-analysis / элтромбопаг / иммунная тромбоцитопения / безопасность и эффективность / агонисты тромбопоэтина / метаанализ

Аннотация научной статьи по клинической медицине, автор научной работы — Abdullah Mohammed Al-Dhuraibi, Ahmad Khalaf Alkawaldeh, Wadah Mohammed Al-Dhuraibi, Anna A. Peresypkina

Introduction: Immune thrombocytopenia (ITP) is a complex autoimmune syndrome associated with low platelet count. Eltrombopag is an oral thrombopoietin receptor agonist that used in the treatment of chronic ITP. The aim of the study: The present meta-analysis is to evaluate the safety and efficiency of Eltrombopag in the prevention and therapy of ITP. Materials and Methods: The analysis was performed according to the PRISMA guideline with use of Excerpta Medica Database (EMBASE) as well as Web of Science and the Cochrane (CENTAL) databases. Results: Seven randomized controlled trials (N=766 patients) were included in the final analysis. Overall platelet response was significantly higher in the Eltrombopag group than in placebo (RR=3.90; 95%CI [2.89-5.25]; P<0.00001) showing mild heterogeneity (I2=45%). Incidences of significant bleeding events in Eltrombopag group (World Health Organization [WHO] grades II-IV) (RR=0.63; 95% CI: [0.47-0.85]; P=0.003) showed lower heterogeneity (I2=18%) in comparison to placebo group. Cases of use of rescue medications in Eltrombopag group compared to placebo group (RR=0.40; 95% CI: [0.290.55]; P<0.00001) in all considered studies showed low heterogeneity (I2=41 %; P=0.16). Incidences of any bleeding in Eltrombopag group compared to placebo group (RR=0.77; 95% CI: [0.70-0.86]; P<0.00001; I2=65%) showed substantial heterogeneity. Finally, subgroup analysis of Eltrombopag efficiency revealed significant difference in frequency of bleeding cases between adults (RR=0.84) and children (RR=0.51); (P=0.005). Conclusion: This systematic review presents class one evidence suggesting Eltrombopag as safe and effective drug for therapy of both children and adult patients with ITP.

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Оценка безопасности, эффективности и фармакокинетики элтромбопага у пациентов с хронической иммунной тромбоцитопенией: метаанализ рандомизированных контролируемых исследований

Введение. Иммунная тромбоцитопения (ИТП) представляет собой сложный аутоиммунный синдром, связанный с низким уровнем тромбоцитов. Элтромбопаг является пероральным агонистом рецептора тромбопоэтина, который используется для лечения хронической ИТП. Цель исследования. Настоящий метаанализ заключается в оценке безопасности и эффективности элтромбопага в профилактике и терапии ИТП. Материалы и методы. Анализ проводился в соответствии с руководством PRISMA с использованием базы данных Excerpta Medica (EMBASE), а также баз данных Web of Science и Cochrane (CENTAL). Результаты. В окончательный анализ были включены семь рандомизированных контролируемых испытаний (N=766 пациентов). Общий ответ тромбоцитов был значительно выше в группе элтромбопага, чем в группе плацебо (относительный риск (ОР)=3,90; 95% ДИ [2,89–5,25]; P<0,00001), демонстрируя умеренную гетерогенность (I2=45%). Частота значительных кровотечений в группе элтромбопага (II–IV классы Всемирной организации здравоохранения [ВОЗ]) (ОР=0,63; 95% ДИ: [0,47–0,85]; P=0,003) показала более низкую гетерогенность (I2=18%) по сравнению с к группе плацебо. Случаи применения препаратов экстренной помощи в группе элтромбопага по сравнению с группой плацебо (ОР=0,40; 95% ДИ: [0,29-0,55]; P<0,00001) во всех рассмотренных исследованиях показали низкую гетерогенность (I2=41 %; P=0,16). Частота любого кровотечения в группе элтромбопага по сравнению с группой плацебо (ОР=0,77; 95% ДИ: [0,70-0,86]; P<0,00001; I2=65%) показала существенную гетерогенность. Анализ эффективности элтромбопага в подгруппах выявил достоверную разницу в частоте случаев кровотечений у взрослых (ОР=0,84) и детей (ОР=0,51); (Р=0,005). Заключение. В этом систематическом обзоре представлены доказательства первого класса, свидетельствующие о том, что элтромбопаг является безопасным и эффективным препаратом для лечения как детей, так и взрослых пациентов с ИТП.

Текст научной работы на тему «Evaluation of safety, efficacy and pharmacokinetics of Eltrombopag in patients with chronic immune thrombocytopenia: Meta-analysis of randomized controlled trials»

Research Results in Pharmacology

Research Results in Pharmacology 9(2): 105-113 UDC: 61*5.21/.26:615.01 DOI 10.18413/rrpharmacology.9.10033

Evaluation of safety, efficacy and pharmacokinetics of Eltrombopag in patients with chronic immune thrombocytopenia: Meta-analysis of randomized controlled trials

Abdullah Mohammed Al-Dhuraibi1-2, Ahmad Khalaf Alkhawaldeh3, Wadah Mohammed Al-Dhuraibi4, Anna A. Peresypkina2

1 Aden University, Aden, 6312 Yemen

2Belgorod State National Research University, 85 Pobedy St., Belgorod. 308015 Russia 3 Zarqa University College. Al-Balqa Applied University. Al-Salt 19117 Jordan 4Abian University Abian. Yemen

Corresponding author: Abdullah Mohammed Al-Dhuraibi (aldhuraibi2019(a!gmail.com)

Academic editor: Mikhail Korokin ♦ Received 17 January 2023 ♦ Accepted 05 June 2023 ♦ Published 30 June 2023

Citation: Al-Dhuraibi AM, Alkhawaldeh AK, Al-Dhuraibi WM, Peresypkina AA (2023) Evaluation of safety, efficacy and pharmacokinetics of eltrombopag in patients with chronic immune thrombocytopenia: Meta-analysis of randomized controlled trials. Research Results in Pharmacology 9(2): 105-113. https://10.18413/rrpharmacology.9.10032

Introduction: Immune thrombocytopenia (ITP) is a complex autoimmune syndrome associated with low platelet count. Eltrombopag is an oral thrombopoietin receptor agonist that used in the treatment of chronic ITP. The aim of the study: The present meta-analysis is to evaluate the safety and efficiency of Eltrombopag in the prevention and therapy of ITP.

Materials and Methods: The analysis was performed according to the PRISMA guideline with use of Excerpta Medica Database (EMBASE) as well as Web of Science and the Cochrane (CENTAL) databases.

Results: Seven randomized controlled trials (N=766 patients) were included in the final analysis. Overall platelet response was significantly higher in the Eltrombopag group than in placebo (RR=3.90; 95%CI [2.89-5.25]; P<0.00001) showing mild heterogeneity (I2=45%). Incidences of significant bleeding events in Eltrombopag group (World Health Organization [WHO] grades II-IV) (RR=0.63; 95% CI: [0.47-0.85]; P=0.003) showed lower heterogeneity (I2=18%) in comparison to placebo group. Cases of use of rescue medications in Eltrombopag group compared to placebo group (RR=0.40; 95% CI: [0.29- 0.55]; P<0.00001) in all considered studies showed low heterogeneity (I2=41 %; P=0.16). Incidences of any bleeding in Eltrombopag group compared to placebo group (RR=0.77; 95% CI: [0.70-0.86]; PO.OOOOl; P=65%) showed substantial heterogeneity. Finally, subgroup analysis of Eltrombopag efficiency revealed significant difference in frequency of bleeding cases between adults (RR=0.84) and children (RR=0.51); (P=0.005).

Conclusion: This systematic review presents class one evidence suggesting Eltrombopag as safe and effective drug for therapy of both children and adult patients with ITP.

Abstract

Copyright Al-Dhuraibi AM et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Graphical abstract:

Study or Subgroup

Eltrombopag Control

Events Total Events Total Weight

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

Risk of Bias A B C D E F G

6.1.1 Headache

Bussel et al 2015 0 0 0 0 Not estimable

Yang et al 2016 3 104 0 51 0.8% 3.47 [0.18, 65.87]

Tomiyama et al 2012 1 15 1 8 1.6% 0.53 [0.04, 7.44]

Grainger et al 2015 6 63 3 29 5.0% 0.92 [0.25, 3.43]

Bussel et al 2009 6 76 4 38 6.5% 0.75 [0.23, 2.50]

Bussel et al 2007 13 44 6 21 9.9% 1.03 [0.46, 2.34]

Chenge etal 2011 40 135 20 61 33.7% 0.90 [0.58, 1.41]

Subtotal (95% CI) 437 208 57.6% 0.94 [0.66, 1.33]

Total events 69 34

Heterogeneity: Chi2 = 1.15, df = 5 (P = 0.95); I2 = 0%

Test for overall effect: Z = 0.37 (P = 0.71)

6.1.2 Diarrhea

Tomiyama et al 2012 0 0 0 0 Not estimable

Bussel etal 2015 0 0 0 0 Not estimable

Grainger et al 2015 3 63 0 29 0.8% 3 28 [0.17, 61.53]

Bussel et al 2009 4 76 1 38 1.6% 2.00 [0.23, 17.28]

Bussel et al 2007 1 4 2 7 1.8% 0.88 [0.11, 6.88]

Chenge etal 2011 17 135 6 61 10.1% 1.28 [0.53, 3.09]

Yang etal 2016 11 104 8 51 13.1% 0.67 [0.29, 1.57]

Subtotal (95% CI) 382 186 27.5% 1.07 [0.62, 1.84]

Total events 36 17

Heterogeneity: Chi2 = 2.22, df = 4 (P = 0.70); I2 = 0%

Test for overall effect: Z = 0.24 (P = 0.81)

6.1.3 Upper respiratory tract Infection

Tomiyama et al 2012 0 0 0 0 Not estimable

Bussel et al 2007 0 0 0 0 Not estimable

Bussel etal 2015 0 0 0 0 Not estimable

Grainger et al 2015 1 63 0 29 0.8% 1.41 [0.06, 33.52]

Bussel et al 2009 0 76 1 38 2.4% 0.17 [0.01, 4.05]

Yang etal 2016 7 104 2 51 3.3% 1.72 [0.37, 7.97]

Chenge et al 2011 7 135 5 61 8.4% 0.63 [0.21, 1.91]

Subtotal (95% CI) 378 179 15.0% 0.84 [0.38, 1.85]

Total events 15 8

Heterogeneity: Chi2 = 2.16, df = 3 (P = 0.54); I2 = 0%

Test for overall effect: Z = 0.44 (P = 0.66)

Total (95% CI) 1197 573 100.0% 0.96 [0.72, 1.27]

Total events 120 59

Heterogeneity: Chi2 = 5.69, df = 14 (P = 0.97); I2 = 0% Test for overall effect: Z = 0.30 (P = 0.76)

Test for subgroup differences: Chi2 = 0.28, df = 2 (P = 0.87), I2 = 0% Risk of bias legend

(A) Random sequence generation (selection bias)

(B) Allocation concealment (selection bias)

(C) Blinding of participants and personnel (performance bias)

(D) Blinding of outcome assessment (detection bias)

(E) Incomplete outcome data (attrition bias)

(F) Selective reporting (reporting bias)

(G) Other bias

• f + + *»• ••••••

• •••• + + + + + ♦ ♦ ♦ + • • + + + +

• •••• + + + + + «) + + ♦ ♦ ♦ + + + ttt + ••••••

• •••• • •••

+ + + + + ^

0.01 0.1 1 10 100 Favours [Eltrombopagl] Favours [Placebo]

Keywords

Eltrombopag, immune thrombocytopenia, safety and efficacy, thrombopoietin agonists, meta-analysis

Introduction

Immune thrombocytopenia (ITP) is a complex autoimmune disorder characterized by a dramatic decrease in platelet count. While antibody and/or T cell-mediated platelet destruction are essential processes, ITP's pathogenesis remains uncertain. First-line therapies are mostly oriented to prevent autoantibodies production and subsequent platelet loss, whereas second-line therapies include immunosuppressive medicines. Finally, third-line therapies seek to promote the production of platelets (Blickstein 2019). Prevalence of ITP in all population is estimated to be 2 to 5 per 100,000 people. According to recent guidelines, newly diagnosed ITP patients with a platelet count of less than 30><109/L are recommended for treatment with use of thrombopoietin-

receptor agonist (TPO-RAs) as second-line therapy. Rituximab is reserved as a third-line agent for patients who have failed a TPO-RA (Neunert et al. 2019). ITP therapy aims to avoid bleeding and maintain a platelet count consistent with optimal hemostasis, rather than a regular platelet count (Ahmed et al. 2020). Eltrombopag is oral TPO-RAs that is approved for the treatment of ITP (Agarwal and Mangla 2021). It induces platelet production by binding to the transmembrane domain of the thrombopoietin receptor and causing megakaryocyte proliferation and differentiation (Bhat et al. 2018; Levchenkova et al. 2023). It has recently been used without serious side effects for thrombocytopenia. This offers an interesting opportunity for more studies to evaluate both effectiveness and safety of Eltrombopag (Nampoothiri and Kumar 2020).

Material and Methods

The current meta-analysis was designed to comply with the PRISMA guideline (Page et al. 2021).

Databases

To identify specific randomized controlled trials (RCT) studies of safety and efficacy of Eltrombopag in both adults and children with chronic ITP, we used the following databases: PubMed/Medline, the Web of Science, the Excerpta Medica Database (EMBASE) and the Cochrane Central Registry of Controlled Trials (CENTAL) from September 2019 to March 2021. The following search queries or Medical Topic Headings (Mesh) were used in the PubMed search strategy: (("Eltrombopag" [Mesh]) AND "Thrombocytopenia" [Supplementary Concept]) OR ("Idiopathic, Purpura, Thrombocytopenic,"[Mesh]) AND "Eltrombopag" Some filters were used to restrict PubMed. Finally, a search in Google Scholar was used in manual mode to identify additional trials and relevant studies.

Study selection

Three authors thoroughly checked the title and abstract of the retrieved studies, screening for eligible studies to conduct a meta-analysis based on screening of full text and extraction of data according to the inclusion criteria, prepared review and editing of methodology. Any queries were arbitrated by fully discussing with the third and second senior's reviewers to get final arbitration. The included RCTs were to meet the following inclusion criteria:

1. S t u d i e s w h i c h e x a m i n e d t h e e ffi c a c y o f Eltrombopag in chronic ITP;

2. Studies with adequate data reliable to be pooled in a meta-analysis;

3. The study design was RCT;

4. The studies included adults or children patients suffering from chronic ITP and have platelet count <30x109/L.

Studies were excluded for the following reasons: studies lacking enough detailed information, studies written in a language other than English. Thesis or conference papers were also excluded.

Data extraction

Three authors extracted the data using a standard data extraction form. The extracted study elements from each study included: first author's name, study design, total number of participants, their mean age, exposure's doses, baseline platelet count, duration of follow-up, study outcomes: overall platelet response, incidence of significant bleeding (World Health Organization [WHO] grades II-IV), and incidence of any bleeding, number of cases needed for rescue treatment.

Quality assessment

To protect the study results from bias, we used Cochrane risk of bias assessment scale to assess the quality of methodology of each RCT (Farrah et al. 2019). The quality assessment included the following elements: method for 1) random sequence generation (selection bias), 2) allocation sequence concealment (selection bias), 3) number of patients and personnel (performance bias), 4) blinding of outcome assessment (detection bias),

5) incomplete outcome data (attrition bias), 6) selective outcome reporting (reporting bias) and 7) other bias.

Statistical analysis

Herein, we calculated the hazard ratio (HR) and 95% confidence intervals (CI) as described in the Cochrane Handbook. Dichotomous results were pooled in a fixed-effect model as relative risk (RR) by using Mantel-Haenszel (M-H) method; the fixed-effect model was used on the basis that the RCTs included are similar in terms of study design, quality evaluation and treatment effect calculation (Etminan et al. 2020). Data processing was performed using Check Manager 5.3 for Windows.

Statistical heterogeneity of treatment effect among trials was assessed using the I2 and X2 statistic. The X2 was used to test the existence of significant heterogeneity, I2 represents the variability in effect estimates that is not attributed to chance or random error. I2 test was interpreted according to the recommendations of Cochrane Handbook of Systematic Reviews and metaanalysis, results ranging from 0 to 100% and values of 040%, 30-60%, 50-90%, 75-100% reflecting low, moderate, substantial and considerable levels of heterogeneity, respectively (Koletsi et al. 2018). In case of significant heterogeneity (X2; P<0.1), a random effect model was used to evaluate the reasons. Otherwise, a fixed-effect model was applied and P-value <0.05 was considered statistically significant.

Sensitivity analyses were carried out to assess the effects of selected measures of study designs, to make sure that no single study is affecting the results, and to test whether the total effect size is statistically robust. We performed sensitivity analysis excluding one study in each scenario. All p-values were considered statistically significant when <0.05.

Publication Bias

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Herein, we included fewer than 10-pooled RCTs studies in this meta-analysis; therefore, we could not assess the potential publication bias by Egger test for funnel plot asymmetry (Furuya-Kanamori et al. 2018).

Results

Literature search and study selection

The process of study selection is summarized in the PRISMA flow diagram as shown in Figure 1. After a comprehensive web search, we initially retrieved 937 relevant records, 563 of which were duplicates. After screening the title and abstract on the basis of inclusion/ exclusion criteria, 534 records were excluded. Further screening of 29 full-text articles was assessed for eligibility, 22 articles were excluded: irrelevant (n=10), no outcome of interest (n=1), other language (n=2), not RCT (n=5) or review articles (n=4), and the remaining 7 RCTs with (766 patients in sum) were included in this meta-analysis (Fig. 1).

Study characteristics and quality assessment

According to the Cochrane risk of bias assessment tool, one of include RCTs were judged to have from a moderate to high risk of bias. Sequence generation and allocation concealment were reported adequately in most studies.

Figure 1. The PRISMA flow diagram of studies' screening and selection

Seven RCTs were reported as double-blinded. Summary of quality assessment domains of the included studies is shown in Figure 2 and in Table 1.

Assessment of the efficacy of Eltrombopag

Seven RCTs were included in the meta-analysis for assessment of the pooled effect estimate in terms of platelet response after administration of Eltrombopag, the results showing a statistical significant increase in platelet counts among total (n=766 patients) with chronic ITP compared with placebo (RR=3.90; 95%CI [2.89-5.25]; P<0.00001), moderate heterogeneity (I2=45%) (Fig. 3).

Bussel et al 2007 • • • •

Bussel et al 2009 • • • • • •

Bussel et al 2015 • • • • • •

Chenge et al 2011 * • • « • •

Grainger et al 2015 * • • * • •

Tomiyama et al 2012 • • • • •

Yang et al 2016 • • • • • •

Figure 2. Risk of bias overview and risk of bias graph based on the Cochrane Risk of Bias evaluation tool.

Eltrombopag Control Risk Ratio

Events Total Events Total Weight M-H, Fixed, 95% Cl

48 82 3 27 8.8% 5.27 [1.78, 15.55]

43 74 6 38 15.5% 3.68 [1.72,7.86]

28 45 7 22 18.4% 1.96 [1.02,3.76]

106 135 17 62 45.5% 2.86 [1.89, 4.33]

25 63 1 29 2.7% 11.51 [1.64, 80.87]

9 15 0 8 1.2% 10.69 [0.70, 162.90]

60 104 3 50 7.9% 9.62 [3.17, 29.16]

518 236 100.0% 3.90 [2.89, 5.25]

Risk Ratio M-H, Fixed, 95% CI

Risk of Bias A B C D E F G

Bussel et al 2007 Bussel et al 2009 Bussel et al 2015 Chenge et al 2011 Grainger et al 2015 Tomiyama et al 2012 Yang et al 2016

Total (95% Cl)

Total events 319 37

Heterogeneity: Chi2 = 10.99, df = 6 (P = 0.09); I2 = 45% Test for overall effect: Z = 8.94 (P < 0.00001 )

Risk of bias legend

(A) Random sequence generation (selection bias)

(B) Allocation concealment (selection bias)

(C) Blinding of participants and personnel (performance bias)

(D) Blinding of outcome assessment (detection bias)

(E) Incomplete outcome data (attrition bias)

(F) Selective reporting (reporting bias)

(G) Other bias

• •••

« I i « « «

■■■■■■

I « i I « «

■■■■■■

+ + + + + + + + + + + + + + + +# ••••••

0.01 0.1 1 10 100 Favours [Placebo] Favours [Eltrombopag]

Figure 3. Forest plots (A) of relative risk for effectiveness tests. The overall response of the platelet. CI indicates confidence intervals; M-H, Mantel-Haenszel; RR, relative risk.

Eltrombopag use and the incidence of significant bleeding

For assessment of the association of Eltrombopag administration and improvement of the incidence of bleeding events compared with controls, four RCTs were

included in this meta-analysis, the pooled results show no significant reduction in the incidence of bleeding events among the Eltrombopag users compared with controls (WHO grades II-IV; (RR=0.63; 95% CI: [0.470.85]; P=0.003), reported low heterogeneity I2=18%) (Fig. 4).

Eltrombopag

Control

Risk Ratio

Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

Risk of Bias А В С D E F G

Bussel et al 2015 Chenge et al 2011 Grainger et al 2015 Yang et al 2016

Total (95% CI)

Total events 65

Heterogeneity: Chi2 = 3.67, df = 3 (P = 0.30); I Test for overall effect: Z = 2.99 (P = 0.003)

4 45 7 22 14.4% 0.28 [0.09, 0.85]

44 135 33 62 69.1% 0.61 [0.44, 0.86]

3 63 2 29 4.2% 0.69 [0.12, 3.91]

14 104 6 50 12.4% 1.12 [0.46, 2.75]

347 163 100.0% 0.63 [0.47, 0.85]

48

: 18%

Risk of bias legend

(A) Random sequence generation (selection bias)

(B) Allocation concealment (selection bias)

(C) Blinding of participants and personnel (performance bias)

(D) Blinding of outcome assessment (detection bias)

(E) Incomplete outcome data (attrition bias)

(F) Selective reporting (reporting bias)

(G) Other bias

+ + + + + + + + + + + + + + +

0.01 0.1 1 10 100 Favours [Eltrombopag] Favours [Placebo]

Figure 4. Forest plots (B), Incidence of significant bleeding. CI indicates confidence interval; M-H, Mantel-Haenszel; RR, relative risk.

Number of Eltrombopag users required rescue medications

Herein, we analyzed four studies; the pooled results of which indicated that there was a significant association between Eltrombopag administration and a decreased number of patients requiring rescue medications

compared to placebo group (RR=0.40; 95% CI: [0.29-0.55]; P<0.00001). Pooled studies showed low heterogeneity (I2=41 %; P=0.16) (Fig. 5).

This meta-analysis reports a significant reduction in the incidence of any bleeding among Eltrombopag treated patients in comparison with placebo group (RR=0.77; 95% CI: [0.70-0.86]; P<0.00001; I2=65%) (Fig. 6).

Eltrombopag

Control

Risk Ratio

Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

Risk of Bias А В С D E F G

Bussel et al 2015 Chenge et al 2011 Grainger et al 2015 Yang et al 2016

Total (95% Cl) Total events

6 45 11 22 18.1% 0.27 [0.11,0.63]

24 135 25 62 42.0% 0.44 [0.27, 0.71]

12 63 7 29 11.8% 0.79 [0.35, 1.80]

9 104 17 50 28.1% 0.25 [0.12, 0.53]

347 163 100.0% 0.40 [0.29, 0.55]

51

60

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Heterogeneity: Chi2 = 5.11, df = 3 (P = 0.16); I2 Test for overall effect: Z = 5.56 (P < 0.00001 )

= 41%

+ + + + »<+ ######

0.01 0.1 1 10 100 Favours [Eltrombopag] Favours [Placebo]

Risk of bias legend

(A) Random sequence generation (selection bias)

(B) Allocation concealment (selection bias)

(C) Blinding of participants and personnel (performance bias)

(D) Blinding of outcome assessment (detection bias)

(E) Incomplete outcome data (attrition bias)

(F) Selective reporting (reporting bias)

(G) Other bias

Figure 5. Forest plots (C), Number of cases needed rescue treatment. CI indicates confidence interval; M-H, Mantel-Haenszel; RR, relative risk.

Eltrombopag Control

Risk Ratio

Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

Risk of Bias А В С D E F G

Bussel et al 2007 Bussel et al 2009 Bussel et al 2015 Chenge et al 2011 Grainger et al 2015 Yang et al 2016

Total (95% Cl)

Total events

8 82 4 27 3.1% 0.66 [0.22, 2.02]

46 76 30 38 20.5% 0.77 [0.60, 0.98]

14 45 18 22 Not estimable

106 135 56 62 39.4% 0.87 [0.77, 0.98]

23 63 16 29 11.3% 0.66 [0.42, 1.05]

68 104 37 50 25.7% 0.88 [0.71, 1.10]

460 206 100.0% 0.82 [0.74, 0.91]

251

143

Heterogeneity: Chi2 = 2.57, df = 4 (P = 0.63); I2 = Test for overall effect: Z = 3.64 (P = 0.0003)

0%

+ + + +

•4 + + + +

+ + + + + +

+ + + + + +

0.01 0.1 1 10 100 Favours [Eltrombopag] Favours [Placebo]

Risk of bias legend

(A) Random sequence generation (selection bias)

(B) Allocation concealment (selection bias)

(C) Blinding of participants and personnel (performance bias)

(D) Blinding of outcome assessment (detection bias)

(E) Incomplete outcome data (attrition bias)

(F) Selective reporting (reporting bias)

(G) Other bias

Figure 6. Forest plots (D), incidence of any bleeding. CI indicates confidence interval; M-H, Mantel-Haenszel; RR, relative risk.

Study or Subgroup

Eltrombopag Events Total

Control Events Total

Risk Ratio Weight M-H, Random, 95% CI

Risk Ratio M-H, Random, 95% CI

Risk of Bias A B C D E F G

5.1.1 Adult

Bussel et al 2007 8 82 4 27 3.0%

Bussel et al 2009 46 76 30 38 21.7%

Yang etal 2016 68 104 37 50 23.3%

Chenge et al 2011 106 135 56 62 28.5%

Subtotal (95% CI) 397 177 76.5%

Total events 228 127

Heterogeneity: Tau2 = 0.00; Chi2 = 1.21, df = 3 (P = 0.75); I2 = 0% Test for overall effect: Z = 3.23 (P = 0.001)

5.1.2 Childern

Bussel etal 2015 14 45

Grainger etal 2015 23 63

Subtotal (95% CI) 108

Total events 37

Heterogeneity: Tau2 = 0.10; Chi2 = 2.68, df = 1 (P = 0.10); I2 = 63% Test for overall effect: Z = 2.47 (P = 0.01)

18 16

34

22 11.5% 29 12.0% 51 23.5%

Total (95% CI) 505 228 100.0%

Total events 265 161

Heterogeneity: Tau2 = 0.03; Chi2 = 14.14, df = 5 (P = 0.01); I2 = 65% Test for overall effect: Z = 2.89 (P = 0.004)

Test for subgroup differences: Chi2 = 3.52, df = 1 (P = 0.06), I2 = 71.( Risk of bias legend

(A) Random sequence generation (selection bias)

(B) Allocation concealment (selection bias)

(C) Blinding of participants and personnel (performance bias)

(D) Blinding of outcome assessment (detection bias)

(E) Incomplete outcome data (attrition bias)

(F) Selective reporting (reporting bias)

(G) Other bias

0.66 [0.22, 2.02] 0.77 [0.60, 0.98] 0.88 [0.71, 1.10] 0.87 [0.77, 0.98] 0.85 [0.78, 0.94]

0.38 [0.24, 0.61] 0.66 [0.42, 1.05] 0.50 [0.29, 0.87]

0.74 [0.60, 0.91]

• ••• + + + + + + + + + + + +» + + + + + +

+ + + + + + ••••••

-1-1

0.01 0.1 1 10 100 Favours [Eltrombopag] Favours [Placebo]

Figure 7. Forest plots (F) of subgroup analysis with 95 % confidence intervals for the incidence of any bleeding. Confidence interval is indicated in CI; M-H, Mantel-Haenszel; RR, relative risk.

Heterogeneity was ideally treated by removing Bussel et al. 2015 study that recruited children with chronic ITP (I2=0; P=0.63). Subgroup analysis of Eltrombopag efficacy and incidence of any bleeding were analyzed among children in 2 studies and adult - in 4 studies. Population with chronic ITP

Table 1. Summary of included studies

as shown in Figure 7, the results showed a non-significant difference in Eltrombopag efficacy between the two groups. However, there was a significant difference in the incidence of any bleeding between Eltrombopag adult users (RR=0.84) and children (RR=0.51) users; (I2=87.2% P=0.005).

Design Population Dose Sample FoTUow Results

(Bussel et al. 2007) Multicenter, Double- blind, RCT Adults with relapsed or refractory chronic ITP 30,50 and 75 mg/ day 118 6 weeks In patients with relapsed or refractory ITPP, Eltrombopag showed improved platelet counts in a dose-dependent manner

(Bussel et al. 2009) Multicenter, Double- blind, RCT Adults with previously treated chronic ITP who were naive to thrombopoietic agents 50 mg/day 114 6 weeks Eltrombopag tends to be efficient in chronic ITP control, with good tolerability

(Bussel et al. 2015) Multicenter, Double- blind, RCT Children (1-17 years) old with persistent or chronic ITP 25 to 50 mg/day 67 7 weeks Eltrombopag can be used in children with recurrent or chronic ITP as an effective therapy. The prevalence of increased laboratory liver values was equivalent to that seen in adults.

(Cheng et al. 2011 Multicenter, Double- blind, RCT Adults with chronic ITP 50 mg/day 197 24 weeks In particular, Eltrombopag proved to be effective in treating chronic ITP in patients who do not respond to splenectomy or prior care. Drug toxicity, however, can restrict its use.

(Grainger et al. 2015) Multicenter, Double- blind, RCT Children (1-17 years) old with chronic ITP 25 to 50 mg/day 92 13 weeks Eltrombopag is an effective medication choice with no new safety issues for children with chronic symptomatic ITP.

(Tomiyama et al. 2012) Multicenter, Double- blind, RCT Adults with previously treated chronic ITP 12.5 to 50 mg/day 23 6 weeks Eltrombopag (12.5-50 mg) is effective in the therapy of chronic ITP patients in Japan

(Yang et al. 2017) Multicenter, Double- blind, RCT Chinese adults aged >18 years previously treated for chronic ITP 25-75 mg/ day 155 8 weeks In summary, Eltrombopag 25 mg once daily in Chinese patients with chronic ITP has increased platelet counts to a safe range and decreased bleeding.

Note: ITP - immune thrombocytopenia; RCT - randomized controlled trial.

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Another adverse effects

There was no any major difference in the overall number of adverse effects reported in both groups; the incidence of adverse effects was not higher in the Eltrombopag group compared with placebo group. The pooled RR for adverse events was as follows: severe adverse events (RR=0.96; 95% CI [0.72-1.27]; P=0.76); headache (RR=0.94; 95% CI [0.66, 1.33]; P=0.71), diarrhea (RR=1.07; 95% CI [0.62-1.48]; P=0.81); and abdominal pain (RR=0.84; 95% CI [0.38-1.85]; P=0.66) for all effect estimate of adverse events were not heterogeneous (X2; P>0.1).

Sensitivity analysis

For all efficacy outcomes, the superiority of Eltrombopag remains significant after excluding one study at the time (data not shown).

Discussion

This systematic study, including a direct-comparison meta-analysis, summarizes the effectiveness and safety of Eltrombopag in adults and children with ITP. Our study indicates that Eltrombopag drug can increase the long-lasting and overall response of platelets and decrease the use of rescue drugs without increasing the frequency of adverse effects compared to placebo.

Furthermore, an observational retrospective study involving (n=766 patients) with ITP concluded that the clinical outcomes reported that increase platelet count

with patients used Eltrombopag in comparable with Placebo (RR=3.90; 95%CI [2.89-5.25]; P<0.00001 (Fig. 3).

The pooled results show no significant reduction in the incidence of bleeding events among the Eltrombopag users compared with controls (WHO grades II-IV; (RR=0.63; 95% CI: [0.47- 0.85]; P=0.003), reporting low heterogeneity I2 = 18%) (Fig. 4).

Herein, we analyzed four studies; the pooled results of which indicated that there was a significant association between Eltrombopag administration and a decreased number of patients requiring rescue medications compared to placebo group (RR=0.40; 95% CI: [0.29-0.55]; P<0.00001). Pooled studies showed low heterogeneity (I2=41 %; P=0.16) (Fig. 5).

This meta-analysis reported a significant reduction in the incidence of any bleeding among Eltrombopag treated patients over placebo group (RR=0.77; 95% CI: [0.70-0.86]; P<0.00001; I2=65%), and showed substantial heterogeneity (Fig. 6).

The Eltrombopag efficacy and incidence of any bleeding in subgroup study was evaluated between children (2 studies) and adults (4 studies) with chronic ITP, as shown in Figure 6. The results showed a nonsignificant difference in the efficacy of Eltrombopag between the two groups, but there was a significant difference in the incidence of any bleeding events between adult (RR=0.84) and children (RR=0.51) users, thus pooled studies were homogeneous (I2=87.2 % P=0.005). Subgroup study of the meta-analyzed data referred to in Table 2.

Table 2. Basic characters of the studies included

Study ID/Ref Group Male, N (%) Age, Median (Range) Weight, Median (Range) Prior Therapy 2, N (%) Splenectomy, N (%) Baseline Platelet Count (109 per L), Median (IQR) Platelets 15000/mm3; N (%)

(Bussel et Placebo 13 (45) 42 (18-85) NA 21(72) 14 (48) NA 14 (48)

al. 2007) Eltrombopag 30 mg 14 (47) 51(23-79) NA 26 (87) 15 (50) NA 15 (50)

Eltrombopag 50 mg 9 (30) 45 (23-81) NA 24 (80) 15 (50 NA 12 (40)

Eltrombopag 75 mg 8 (29) 55 (18-85) NA 16 (57) 11 (39) NA 15 (54)

(Cheng et Placebo 19 (30.6) 52.5 (43-63) NA 50 (81) 21 (34) 16000 (9000-24000) 30 (49)

al. 2011) Eltrombopag 42 (31) 47 (34-56) NA 105 (78) 50 (37) 16000 (8000-22000) 67 (50)

(Bussel et Placebo 11 (29) 48 (16)a NA 26 (68) 14 (37) NA 17 (45)

al. 2009) Eltrombopag 33 (43) 51 (17)a NA 56 (74) 31 (41) NA 38 (50)

(Bussel et Placebo 9 (41) 10 (8-12) 43 (33-53) 19 (86) 0 12.4 (8.8)a 11 (50)

al. 2015) Eltrombopag 18(40) 9 (8-10) 39 (34-45) 38 (84) 5 (11) 15.5 (8.0)a 23 (51)

(Tomiya ma et al. 2012) Placebo Eltrombopag 1 (13) 7 (47) 60.5 (38-72) 58.0 (26-72) 57.48+6.613" 61.68+ 10.390a 5 (63) 11 (73) 9500 (7500-19000) 21000 (16000-25000) 6 (75) 3 (20)

(Grainger et al. Placebo 15 (52) 9.8 (8.3-11.3)a 42.7 (33.2-52.3)a 26 (90) 0 NA 19 (66)

2015) Eltrombopag 33 (52) 9.4 (8.2-10.5)a 41 (35.5-46.4)a 46 (73) 4(6) NA 38 (60)

(Yang et Placebo 11 (21.6) 42 (22-66) 62 (42-92) 10 (19.6) 7(13.7) 28 (54.9) 13 (5)

al. 2017) Eltrombopag 27 (26.0) 48 (18-84) 62 (44-96) 19 (18.3) 18 (17.3) 54 (51.9) 14 (0)

The meta-analysis of the RCTs and systematic review concluded that these TPO-RAs had an increased risk of thrombotic events comparable with standard medication or placebo. This review has some limitations. We only included RCTs in this analysis; the findings may not have a strong generalization for strict systematic review and a limited sample size in those trials.

References

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Author Contributions

Conclusion

This systematic review suggests that Eltrombopag is a safe and efficient drug for the treatment of both children and young adult patients with ITP.

Conflict of Interests

No conflict of interests are reported by the authors.

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■ Abdullah Mohammed AL-Dhuraibi, PhD. , Department of Pharmacology and Clinical Pharmacology, Aden University, Aden, Yemen, Department of Pharmacology and Clinical Pharmacology, Medical Institute, Belgorod

National Research University, Russia, aldhuraibi2019@gmail.com, ORCID ID https://orcid.org/ 0000-0002-9044-243X. As the first author, contributed thoroughly checked the title, abstract of retrieved studies, literature search, study selection, data extraction, bias assessment, review writing, editing of methodology and statistical analysis.

■ Ahmad Khalaf Alkawaldeh, Assistant PhD, Department of Medical Allied Sciences, Zarqa University Collage/Al-Balqa Applied University, Jordan, e-mail: Alkawaldeh@gmail.ru, ORCID ID https://orcid.org/ 0000-0003-2847-3427. Literature search, study selection, review writing, data extraction, and bias assessment.

■ Wadah Mohammed AL-Dhuraibi, Researcher, Chemistry Department, Abian University, Abian, Yemen, e-mail: AL-Dhuraibiwadah@gmail.ru, ORCID ID https://orcid.org/0009-0003-8521-3442. Literature search and study selection.

Anna A. Peresypkina, Professor. PhD., Department of Pharmacology and Clinical Pharmacology, Medical Institute, Belgorod National Research University, Russia, e-mail: peresypkina_a@bsu.edu.ru, ORCID ID https:// orcid.org/0000-0003-2829-9860. Resolve disagreement and critical appraisal

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