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Meta-Analysis
. 2017 Sep 25;9(9):CD011441.
doi: 10.1002/14651858.CD011441.pub2.

Bypassing agent prophylaxis in people with hemophilia A or B with inhibitors

Chatree Chai-Adisaksopha  1 , Sarah J Nevitt, Mindy L Simpson, Maissaa Janbain, Barbara A Konkle
Affiliations
Meta-Analysis

Bypassing agent prophylaxis in people with hemophilia A or B with inhibitors

Chatree Chai-Adisaksopha et al. Cochrane Database Syst Rev. .

Abstract

Background: People with hemophilia A or B with inhibitors are at high risk of bleeding complications. Infusion of bypassing agents, such as recombinant activated FVII (rFVIIa) and plasma-derived activated prothrombin complex concentrate, are suggested as alternative therapies to factor VIII (haemophilia A) or IX (haemophilia B) for individuals who no longer respond to these treatments because they develop inhibitory antibodies. The ultimate goal of treatment is to preserve the individual's joints, otherwise destroyed by recurrent bleeds.

Objectives: To assess the effects of bypassing agent prophylaxis to prevent bleeding in people with hemophilia A or B and inhibitors.

Search methods: We searched for relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries (16 February 2017) and bibliographic references of retrieved studies were reviewed for potential articles to be included in the review.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Coagulopathies Trials Register: 12 December 2016.

Selection criteria: We included randomized and quasi-randomized controlled studies (cross-over or parallel design) evaluating the effect of prophylaxis treatment with bypassing agents compared with on-demand treatment, or studies evaluating the effects of high-dose compared with low-dose prophylaxis in males of any age with hemophilia with inhibitors.

Data collection and analysis: Two authors independently selected studies and extracted data and assessed the risk of bias according to standard Cochrane criteria. They assessed the quality of the evidence using the GRADE criteria.

Main results: We included four randomized studies (duration 7 to 15 months) involving 116 males. Risk of bias was judged to be high in two studies due to the open-label study design and in one study due to attrition bias.Two studies compared on-demand treatment to prophylaxis with bypassing agents. In one study (34 males) prophylaxis significantly reduced mean overall bleeding rates, MD - 7.27 (95% CI -9.92 to -4.62) (low quality evidence), mean number of overall bleeding events per month, MD -1.10 (95% CI -1.54 to -0.66), mean number of hemarthrosis, MD -6.60 (95% CI -9.32 to -3.88) (low quality evidence) and mean number of joints that had hemarthrosis, MD -0.90 (95% CI -1.36 to -0.44). The meta-analysis did not conclusively demonstrate significant benefit of prophylaxis on health-related quality of life as measured by Haem-A-QoL score, EQ-5D total score and utility score, EQ-5D VAS and SF-36 physical summary and mental summary score (low quality evidence for all health-related quality of life analyses).The remaining two studies compared dose regimens. The results from one study (22 males) did not conclusively demonstrate benefit or harm of high-dose versus low-dose recombinant activated factor VIIa (rFVIIa) as a prophylaxis for overall bleeding rate, MD -0.82 (95% CI -2.27 to 0.63) (moderate quality evidence), target joint bleeding rate, MD -3.20 (95% CI -7.23 to 0.83) (moderate quality evidence) and serious adverse events, RR 9.00 (95% CI, 0.54 to 149.50) (moderate quality evidence).The overall quality of evidence was moderate to low due to imprecision from limited information provided by studies with small sample sizes and incomplete outcome data in one study.

Authors' conclusions: The evidence suggests that prophylaxis with bypassing agents may be effective in reducing bleeding in males with hemophilia with inhibitors. However, there is a lack of evidence for the superiority of one agent over the other or for the optimum dosage regimen. Further studies are needed to evaluate the benefits and harms of prophylaxis treatment on health-related quality of life, as well as the effects of dose of bypassing agents on the outcomes.

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Conflict of interest statement

Chatree Chai‐Adisaksopha (lead author): none known.

Sarah Nevitt (co‐author): none known.

Mindy Simpson (co‐author): has been compensated for participation in advisory boards by Baxter Bioscience (now Shire), Biogen Idec (now Bioverativ), CSL Behring, NovoNordisk, Grifols, and Octapharma. Rush University Medical Center receives grant support on behalf of Mindy Simpson from CSL Behring, NovoNordisk, Biogen (now Bioverativ) and Baxter Bioscience (now Shire).

Maissaa Janbain (co‐author): once received consultant fees from CSL Behring and Bayer for attending advisory board meetings.

Barbara Konkle (co‐author): receives research support from Baxter Bioscience, Biogen‐Idec, and Novo‐Nordisk and has consulted for Baxter Bioscience, Bayer, Biogen‐Idec, CSL‐Behring, Novo‐Nordisk and Pfizer.

Clarification statement added from Alan Smyth, Co‐ordinating Editor on 19 March 2020: The published protocol and review was found by the Cochrane Funding Arbiters, post‐publication, to be noncompliant with the Cochrane conflict of interest policy, which includes the relevant parts of the Cochrane Commercial Sponsorship Policy. The review will be updated by March 2021 with the majority of review authors free of conflicts conflicts.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 1 Overall bleeding rates: total number of bleeding events.
1.2
1.2. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 2 Overall bleeding rates: number of monthly bleeding events.
1.3
1.3. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 3 Target joint bleeding rate: number of hemarthroses.
1.4
1.4. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 4 Target joint bleeding rate: number of joint hemorrhages.
1.5
1.5. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 5 Health‐related QoL: change from baseline in total Haem‐A‐QoL score.
1.6
1.6. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 6 Health‐related QoL: change from baseline in total EQ‐5D score.
1.7
1.7. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 7 Health‐related QoL: change from baseline in EQ‐5D VAS score.
1.8
1.8. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 8 Health‐related QoL: change from baseline in EQ‐5D Utility score.
1.9
1.9. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 9 Health‐related QoL: change from baseline in SF 36 Physical Functioning Score.
1.10
1.10. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 10 Health‐related QoL: change from baseline in SF 36 Physical Score.
1.11
1.11. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 11 Health‐related QoL: change from baseline in SF 36 Bodily Pain Score.
1.12
1.12. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 12 Health‐related QoL: change from baseline in SF 36 General Health Score.
1.13
1.13. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 13 Health‐related QoL: change from baseline in SF 36 Vitality / Energy Score.
1.14
1.14. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 14 Health‐related QoL: change from baseline in SF 36 Social Functioning Score.
1.15
1.15. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 15 Health‐related QoL: change from baseline in SF 36 Emotional Score.
1.16
1.16. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 16 Health‐related QoL: change from baseline in SF 36 Mental Health Score.
1.17
1.17. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 17 Health‐related QoL: change from baseline in SF 36 Physcial Summary Score.
1.18
1.18. Analysis
Comparison 1 Prophylaxis compared to on‐demand anti‐inhibitor coagulant complex (AICC) or factor eight inhibitor bypassing activity (FEIBA NF), Outcome 18 Health‐related QoL: change from baseline in SF 36 Mental Summary Score.
2.1
2.1. Analysis
Comparison 2 High‐dose compared to low‐dose recombinant factor VIIIa (rFVIIIa), Outcome 1 Overall bleeding rates: number of bleeds per month.
2.2
2.2. Analysis
Comparison 2 High‐dose compared to low‐dose recombinant factor VIIIa (rFVIIIa), Outcome 2 Target joint bleeding rate: number of joint bleeds over 3 months.
2.3
2.3. Analysis
Comparison 2 High‐dose compared to low‐dose recombinant factor VIIIa (rFVIIIa), Outcome 3 Number of adverse events.
2.4
2.4. Analysis
Comparison 2 High‐dose compared to low‐dose recombinant factor VIIIa (rFVIIIa), Outcome 4 Number of serious adverse events.
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Update of

References

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References to studies excluded from this review

NCT02622321 {published data only}
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NCT02795767 {unpublished data only}
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