Emicizumab prophylaxis in people with hemophilia A and inhibitors: a systematic review and meta-analysis

Prudente, Tiago Paiva; Camelo, Ricardo Mesquita; Guimarães, Rafael Alves; Roberti, Maria do Rosário Ferraz

doi:10.1590/1516-3180.2023.0102.R1.20022024

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Sao Paulo Medical Journal

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ORIGINAL ARTICLE • Sao Paulo Med. J. 142 (5) • 2024 • https://doi.org/10.1590/1516-3180.2023.0102.R1.20022024 copy

Emicizumab prophylaxis in people with hemophilia A and inhibitors: a systematic review and meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

BACKGROUND:

Until recently, the treatment of people with hemophilia A and inhibitors (PwHAi) was based on the use of bypassing agents (BPA). However, the advent of emicizumab as prophylaxis has demonstrated promising results.

OBJECTIVES:

We aimed to compare the bleeding endpoints between PwHAi on BPA and those on emicizumab prophylaxis.

DESIGN AND SETTING:

Systematic review of interventions and meta-analysis conducted at the Universidade Federal de Goiás, Goiânia, Goiás, Brazil.

METHODS:

The CENTRAL, MEDLINE, Scopus, and LILACS databases were searched on February 21, 2023. Two authors conducted the literature search, publication selection, and data extraction. The selected publications evaluated the bleeding endpoints between PwHAi on emicizumab prophylaxis and those on BPA prophylaxis. The risk of bias was evaluated according to the Joanna Briggs Institute criteria. A meta-analysis was performed to determine the annualized bleeding rate (ABR) for treated bleeds.

RESULTS:

Five publications (56 PwHAi) were selected from the 543 retrieved records. Overall, bleeding endpoints were lower during emicizumab prophylaxis than during BPA prophylaxis. All the publications had at least one risk of bias. The only common parameter for the meta-analysis was the ABR for treated bleeds. During emicizumab prophylaxis, the ABR for treated bleeds was lower than during BPA prophylaxis (standard mean difference: −1.58; 95% confidence interval −2.50, −0.66, P = 0.0008; I² = 68.4%, P = 0.0031).

CONCLUSION:

Emicizumab was superior to BPA in bleeding prophylaxis in PwHAi. However, both the small population size and potential risk of bias should be considered when evaluating these results.

SYSTEMATIC REVIEW REGISTRATION:

CRD42021278726, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=278726.

KEY WORDS (MeSH terms):
Hemophilia A; Antibodies, monoclonal, humanized; Blood coagulation factors; Emicizumab

AUTHORS’ KEYWORDS:
Hemophilia A; Inhibitors; Prophylaxis; Annualized bleeding rate; Bypassing agents

Platform	Search strategy	Number of publications
CENTRAL	(((((hemophilia) OR (haemophilia)) OR (factor VIII)) OR (FVIII)) AND (((inhibitor) OR (anti-factor VIII)) OR (anti-FVIII))) AND (((emicizumab) OR (ACE910)) OR (hemlibra))	30
MEDLINE	(“hemophilia A”) OR (“haemophilia A”) AND (emicizumab OR hemlibra OR ACE910) AND (inhibitor OR anti-FVIII OR anti-factor VIII)	318
LILACS	“hemophilia A” OR “haemophilia A” [Words] and emicizumab OR hemlibra OR ACE910 [Words] and inhibitor OR anti-FVIII OR anti-factor VIII [Words]	01
Scopus	( ( hemophilia OR haemophilia OR factor AND viii OR fviii ) AND ( inhibitor OR “anti-factor viii” OR “anti-fviii” ) AND ( emicizumab OR ace910 OR hemlibra ) ) AND ( LIMIT-TO ( DOCTYPE , “ar” ) )	194

First author, year	Study design	Sponsor	Country (ies)	N	Age	Sex	HA severity	Inhibitor titer (BU/mL)	BPA prophylaxis regimen	Emicizumab prophylaxis regimen: loading dose	Emicizumab prophylaxis regimen: maintenance dose	ABR for treated bleeds during BPA prophylaxis	ABR for treated bleeds during emicizumab prophylaxis	Adverse events^* *Related to emicizumab only;
Oldenburg, 2017¹²12. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017;377(9):809-18. PMID: 28691557; https://doi.org/10.1056/nejmoa1703068. https://doi.org/10.1056/nejmoa1703068...	Controlled RCT	Roche and Chugai Pharmaceutical	Spain, Costa Rica, USA, Italy, United Kingdom, Germany, Japan, Poland, Australia, Republic of Korea, France, South Africa, New Zealand, Taiwan	24	17^# # People with hemophilia A without and with inhibitors; ABR = annualized bleeding rate; ADA = anti-drug antibodies; BPA = bypassing agents; BU = Bethesda units; HA = hemophilia A; QW = weekly; M = male; Med = median; NR = not reported/not possible to be inferred; NRCT = non-randomized controlled trial; RCT = randomized controlled trial; SD = standard deviation; USA = United States of America.	M	NR	NR	NR	3.0 mg/kg QW × 4	1.5 mg/kg QW	Med: 11.5 Mean: 17.1 SD: 13.2	Med: 0 Mean: 9.7 SD: 11.1	Yes^# # People with hemophilia A without and with inhibitors; ABR = annualized bleeding rate; ADA = anti-drug antibodies; BPA = bypassing agents; BU = Bethesda units; HA = hemophilia A; QW = weekly; M = male; Med = median; NR = not reported/not possible to be inferred; NRCT = non-randomized controlled trial; RCT = randomized controlled trial; SD = standard deviation; USA = United States of America.
Young, 2019¹³13. Young G, Liesner R, Chang T, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019;134(24):2127-38. PMID: 31697801; https://doi.org/10.1182/blood.2019001869. https://doi.org/10.1182/blood.2019001869...	Controlled NRCT	Roche and Chugai Pharmaceutical	United Kingdom, USA, Spain, Germany, Italy, South Africa, Japan, Turkey, France, Costa Rica	15	<12	M	NR	>5	NR	3.0 mg/kg QW × 4	1.5 mg/kg QW	Med: 17.9 Mean: 20.4 SD: 13.3	Med: 0 Mean: 0.3 SD: 0.4	No 2 neutralizing ADA
Shima, 2021²⁴24. Shima M, Nagao A, Taki M, et al. Long-term safety and efficacy of emicizumab for up to 5.8 years and patients’ perceptions of symptoms and daily life: A phase 1/2 study in patients with severe haemophilia A. Haemophilia. 2021;27(1):81-9. PMID: 33236410; https://doi.org/10.1111/hae.14205. https://doi.org/10.1111/hae.14205...	Controlled NRCT	Chugai Pharmaceutical	Japan	3	>12	M	Severe	NR	NR	3.0 mg/kg QW × 4	3.0 mg/kg QW	Med: 24.3 Mean: 25.4 SD: 3.5	Med: 0 Mean: 0.6 SD: 0.6	No
Misgav, 2021²⁵25. Misgav M, Brutman-Barazani T, Budnik I, et al. Emicizumab prophylaxis in haemophilia patients older than 50 years with cardiovascular risk factors: real-world data. Haemophilia. 2021;27(2):253-60. PMID: 33595174; https://doi.org/10.1111/hae.14261. https://doi.org/10.1111/hae.14261...	Cohort	None	Israel	2	62.9 (mean)	NR	Severe	35.6	>2 times/week	3.0 mg/kg QW × 4	1.5 mg/kg QW	Med: 15.5, Mean: 15.5 SD: 6.1	Med: 2.2 Mean: 2.2 SD: 0.6	No
McCary, 2020²⁶26. McCary I, Guelcher C, Kuhn J, et al. Real-world use of emicizumab in patients with haemophilia A: Bleeding outcomes and surgical procedures. Haemophilia. 2020;26(4):631-6. PMID: 32311809; https://doi.org/10.1111/hae.14005. https://doi.org/10.1111/hae.14005...	Cohort	None	USA	12	8.05 (median)	M	Severe	NR	4 times/week	3.0 mg/kg QW × 4	Not informed	Med: 2 Mean: 7.3 SD: 7.3	Med: 0 Mean: 0 SD: 0.2	No

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[1] Address for correspondence: Tiago Paiva Prudente, Faculdade de Medicina, Universidade Federal de Goiás (UFG), R. 235, s/n - Setor Leste Universitário, Goiânia (GO), Brazil, CEP: 74605-050 Tel.: (64) 99931-3089, E-mail:tiagopaiva@discente.ufg.br