Abstract: 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. 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.

Plain-language summary: We searched the scientific databases for clinical studies evaluating the effects of bypassing agents in men with hemophilia A or B with inhibitors. We included four studies (duration 7 to 15 months), involving 116 individuals. Two studies compared the prophylactic infusion with bypassing agent to on-demand treatment (treatment given only after the bleeding occurred) and two studies compared high-dose to low-dose preventative therapies. Limited evidence showed that prophylactic use of bypassing agents reduced bleeding events, joint bleeding events and number of affected joints. There was no evidence for improved quality of life amongst those who received prophylaxis as compared to those who received on-demand therapy. There was no evidence for a difference in benefits or harms between high- and low-dose rFVIIa for prophylaxis. The overall quality of evidence of these studies was moderate to low as the included studies were small and provided limited information. Also, in one of the studies, up to 24% of the men recruited were not included in the analysis of the results, which further increases imprecision of results.