. 2022 Jan 14;17(1):e0262273. doi: 10.1371/journal.pone.0262273

Table 2. Summary of findings for episodic treatment vs prophylaxis (either low, intermediate, or high dose).

Outcomes (follow-up in months)	№ of participants (studies)	Anticipated absolute effects^* (95% CI)		Relative effect (95% CI)	Certainty of the evidence (GRADE)
Outcomes (follow-up in months)	№ of participants (studies)	Risk with Control	Risk with Intervention	Relative effect (95% CI)	Certainty of the evidence (GRADE)
Episodic treatment (control) vs Low-dose prophylaxis (intervention)
Annualized bleeding rate (12 m)	71 (2 RCTs)	Range of means: 9.4–25.3	Range of means: 2.2–7.7	RM 0.27 (0.17 to 0.43)	⨁◯◯◯ VERY LOW ^a^,^d
Annualized joint bleeding rate (12 m)	71 (2 RCTs)	Range of means: 5.8–10.3	Range of means: 1.0–1.8	RM 0.17 (0.06 to 0.43)	⨁◯◯◯ VERY LOW ^a^,^d
Change in the Hemophilia joint health score-2.1 (HJHS-2.1). Range: 0 to 124. Higher score = worst (12 m)	66 (2 RCTs)	Verma 2016 Low-dose prophylaxis: median change of 0 points. Episodic treatment: median change of 4.5 points (p<0.05). Chozie 2019 Low-dose prophylaxis: median change of -1 points. Episodic treatment: median change of 2 points (p<0.001).			⨁◯◯◯ VERY LOW ^a^,^d
Change in the Petterson score (11.5 m)	21 (1 RCT)	Verma 2016 Low-dose prophylaxis: median change of 0 points. Episodic treatment: median change of 1 point (no p-value provided).			⨁◯◯◯ VERY LOW ^a^,^d^,^e
Episodic treatment (control) vs Intermediate-dose prophylaxis (intervention)
Annualized bleeding rate (12.0 to 82.5 m)	237 (4 RCTs)	Range of means: 13.0–57.7	Range of means: 2.5–6.2	RM 0.15 (0.07 to 0.36)	⨁◯◯◯ VERY LOW ^a^,^b^,^c
Annualized joint bleeding rate (12.0 to 82.5 m)	237 (4 RCTs)	Range of means: 4.9–43.8	Range of means: 0.6–5.2	RM 0.14 (0.07 to 0.27)	⨁◯◯◯ VERY LOW ^a^,^b^,^c
Radiographic findings (49.0 to 82.5 m)	95 (2 RCTs)	413 per 1000	149 per 1000	RR 0.36 (0.18 to 0.71)	⨁◯◯◯ VERY LOW ^a^,^d
Joint structural changes (using eMRI scores). Range: 0 to 45. Higher score = worst (36 m)	83 (1 RCT)	Manco-Johnson 2017: Intermediate-dose prophylaxis: mean change of 0.79 points. Episodic treatment: mean change of 0.96 points (p = 0.66).			⨁◯◯◯ VERY LOW ^a^,^d^,^e
Petterson score at the end of the follow-up (82.5 m)	40 (1 RCT)	Gringeri 2011: Intermediate-dose prophylaxis group (n = 6, median Pettersson score of 5). Episodic treatment group (n = 14, median Pettersson score of 8), p<0.05.			⨁◯◯◯ VERY LOW ^a^,^d^,^e
Quality of life (36.0 to 82.5 m)	123 (2 RCTs)	Gringeri 2011 (82.5 months): Score in the "family" dimension of the Haemo-QoL scale was lower (better) in patients with intermediate-dose prophylaxis (mean: 11.3) than in those with episodic treatment (mean 44.0), p<0.05. Manco-Johnson 2017 (36 months): Mean change in the score of the Haemo-QoL-A: Intermediate-dose prophylaxis group: 3.98 points. Episodic treatment: 6.00 points (p = 0.27). Mean change in the score of the EQ VAS (higher = better): Intermediate-dose prophylaxis: 10.49 points. Episodic treatment: –1.80 points. No p-value provided. Mean change in the EQ-5D utility index score (higher = better): Intermediate-dose prophylaxis: 0.06 points. Episodic treatment: –0.01 points. No p-value provided.			⨁◯◯◯ VERY LOW ^a^,^d
Adverse events (12.0 to 82.5 m)	154 (3 RCTs)	Gringeri 2011: Inhibitors developing: 3/21 patients in the prophylaxis group and 2/19 in the episodic group. CVAD-related infection: 6/20 patient in the prophylaxis group, and 0/19 in the episodic group (no indwelling catheters required). Manco-Johnson 2007 reported that 6/32 patients had CVAD-related infection in the prophylaxis group and 6/33 in the episodic group.			⨁◯◯◯ VERY LOW ^a^,^d
Episodic treatment (control) vs High-dose prophylaxis (intervention)
Annualized bleeding rate (12 m)	52 (1 RCT)	Mean: 57.7	Mean: 4.3	RM 0.07 (0.04 to 0.13)	⨁◯◯◯ VERY LOW ^a^,^d
Annualized joint bleeding rate (12 m)	52 (1 RCT)	Mean: 43.8	Mean: 3.5	RM 0.08 (0.04 to 0.16)	⨁◯◯◯ VERY LOW ^a^,^d

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; yr: years RM: ratio of means; RR: Risk ratio; Haemo-QoL: Hemophilia quality of life questionnaire for children; Haemo-QoL-A: Hemophilia-specific quality of life questionnaire for adults; EQ VAS: EuroQol visual analogue scale; SD: Standard deviation; CVAD: Central venous access device-related infections.

Explanations

^a. We rated down one level for risk of bias.

^b. We rated down one level for imprecision due to the small number of participants that presented the outcome (200–400).

^c. We rated down one level for inconsistency (I² > 70%).

^d. We rated down two levels for imprecision due to the small number of participants that presented the outcome (less than 200)

^e. We rated down one level for publication bias.