Table 4

Prophylaxis and inhibitor development

Regular prophylaxisIntention to start prophylaxis
DeterminantNo. EDAll inhibitorsHigh-titer inhibitorsAll inhibitorsHigh-titer inhibitors
Crude HR (95% CI)P valueaHR (95% CI)P valueCrude HR (95% CI)P valueaHR (95% CI)P valueN EDCrude HR (95% CI)P valueaHR (95% CI)P valueCrude HR (95% CI)P valueaHR (95% CI)P value
Regular prophylactic infusions 18 846 0.68 (0.47-0.99) .043 0.70 (0.44-1.1)* .14 0.58 (0.36-0.92) .021 0.61 (0.35-1.1)* .093 23 426 0.63 (0.46-0.88) .0060 0.66 (0.46-0.94) .020 0.56 (0.38-0.83) .0039 0.57 (0.36-0.88) .012 
Dose, frequency of prophylaxis 
 1/wk, <30 IU/kg 2422 0.84 (0.46-1.5) .58 0.76 (0.37-1.6)* .46 0.92 (0.46-1.8) .82 0.99 (0.44-2.2)* .98 NA NA NA NA NA NA NA NA NA 
 1/wk, >30 IU/kg 7704 0.58 (0.35-0.94) .027 0.54 (0.29-1.0)* .050 0.48 (0.26-0.89) .020 0.55 (0.26-1.2)* .12 NA NA NA NA NA NA NA NA NA 
 >1/wk, <30 IU/kg 2243 0.39 (0.14-1.1) .075 0.36 (0.11-1.2)* .086 0.42 (0.13-1.4) .16 0.47 (0.13-1.7)* .25 NA NA NA NA NA NA NA NA NA 
 >1/wk, >30 IU/kg 6477 0.86 (0.51-1.5) .58 1.11 (0.48-2.5)* .81 0.57 (0.28-1.2) .13 0.53 (0.23-1.3)* .15 NA NA NA NA NA NA NA NA NA 
Start of prophylaxis before 15 ED 10 527 0.69 (0.47-1.0) .057 NA§ NA 0.64 (0.40-1.0) .059 NA§ NA 19 509 0.64 (0.46-0.88) .0068 NA§ NA 0.57 (0.39-0.85) .0056 NA§ NA 
Start of prophylaxis before 5 ED 3919 0.81 (0.50-1.3) .37 NA§ NA 0.69 (0.38-1.2) .20 NA§ NA 10 981 0.67 (0.47-0.96) .031 NA§ NA 0.60 (0.39-0.94) .024 NA§ NA 
Start of prophylaxis before age 11 mo. 3618 0.68 (0.38-1.2) .19 NA§ NA 0.65 (0.33-1.3) .23 NA§ NA 6929 0.71 (0.47-1.1) .11 NA§ NA 0.69 (0.42-1.1) .14 NA§ NA 
Effect of prophylaxis according to no. ED|| 
 1-10 NA 1.0 (0.48-2.2) NA 0.80 (0.37-1.7) NA 1.2 (0.46-2.9) NA 0.97 (0.39-2.5) NA NA 0.65 (0.36-1.2) NA NA NA 0.75 (0.36-1.56) NA 0.79 (0.37-1.7) NA 
 11-20 NA 0.95 NA 0.93 NA 0.86 NA 0.86 NA NA 0.82 NA NA NA 0.74 NA 0.69 NA 
 21-30 NA 0.22 NA 0.17 NA 0.13 NA 0.15 NA NA 0.34 NA 0.34 NA 0.21 NA 0.20 NA 
 31-40 NA 0.27 NA 0.43 NA 0.084 NA 0.26 NA NA 0.21 NA 0.47 NA 0.066 NA 0.12 NA 
 41-75 NA 0.32 NA 1.3 NA 0.080 NA 0.15 NA NA 0.38 NA 0.97 NA 0.11 NA 0.40 NA 
Effect of prophylaxis in different F8 genotypes N ED         N ED         
 Low-risk genotype 10 153 0.30 (0.11-0.83) .020 0.61 (0.19-2.0) .41 0.14 (0.028-0.72) .018 0.17 (0.028-0.98) .047 10 153 0.47 (0.21-1.1) .069 0.42 (0.16-1.1) .079 0.39 (0.13-1.2) .088 0.32 (0.062-1.6) .17 
 High-risk genotype 16 263 0.94 (0.61-1.4) .77 0.85 (0.51-1.4) .52 0.83 (0.49-1.4) .49 0.83 (0.45-1.6) .57 16 263 0.70 (0.48-1.0) .069 0.78 (0.51-1.2) .25 0.64 (0.40-1.0) .055 0.73 (0.44-1.2) .21 
Regular prophylaxisIntention to start prophylaxis
DeterminantNo. EDAll inhibitorsHigh-titer inhibitorsAll inhibitorsHigh-titer inhibitors
Crude HR (95% CI)P valueaHR (95% CI)P valueCrude HR (95% CI)P valueaHR (95% CI)P valueN EDCrude HR (95% CI)P valueaHR (95% CI)P valueCrude HR (95% CI)P valueaHR (95% CI)P value
Regular prophylactic infusions 18 846 0.68 (0.47-0.99) .043 0.70 (0.44-1.1)* .14 0.58 (0.36-0.92) .021 0.61 (0.35-1.1)* .093 23 426 0.63 (0.46-0.88) .0060 0.66 (0.46-0.94) .020 0.56 (0.38-0.83) .0039 0.57 (0.36-0.88) .012 
Dose, frequency of prophylaxis 
 1/wk, <30 IU/kg 2422 0.84 (0.46-1.5) .58 0.76 (0.37-1.6)* .46 0.92 (0.46-1.8) .82 0.99 (0.44-2.2)* .98 NA NA NA NA NA NA NA NA NA 
 1/wk, >30 IU/kg 7704 0.58 (0.35-0.94) .027 0.54 (0.29-1.0)* .050 0.48 (0.26-0.89) .020 0.55 (0.26-1.2)* .12 NA NA NA NA NA NA NA NA NA 
 >1/wk, <30 IU/kg 2243 0.39 (0.14-1.1) .075 0.36 (0.11-1.2)* .086 0.42 (0.13-1.4) .16 0.47 (0.13-1.7)* .25 NA NA NA NA NA NA NA NA NA 
 >1/wk, >30 IU/kg 6477 0.86 (0.51-1.5) .58 1.11 (0.48-2.5)* .81 0.57 (0.28-1.2) .13 0.53 (0.23-1.3)* .15 NA NA NA NA NA NA NA NA NA 
Start of prophylaxis before 15 ED 10 527 0.69 (0.47-1.0) .057 NA§ NA 0.64 (0.40-1.0) .059 NA§ NA 19 509 0.64 (0.46-0.88) .0068 NA§ NA 0.57 (0.39-0.85) .0056 NA§ NA 
Start of prophylaxis before 5 ED 3919 0.81 (0.50-1.3) .37 NA§ NA 0.69 (0.38-1.2) .20 NA§ NA 10 981 0.67 (0.47-0.96) .031 NA§ NA 0.60 (0.39-0.94) .024 NA§ NA 
Start of prophylaxis before age 11 mo. 3618 0.68 (0.38-1.2) .19 NA§ NA 0.65 (0.33-1.3) .23 NA§ NA 6929 0.71 (0.47-1.1) .11 NA§ NA 0.69 (0.42-1.1) .14 NA§ NA 
Effect of prophylaxis according to no. ED|| 
 1-10 NA 1.0 (0.48-2.2) NA 0.80 (0.37-1.7) NA 1.2 (0.46-2.9) NA 0.97 (0.39-2.5) NA NA 0.65 (0.36-1.2) NA NA NA 0.75 (0.36-1.56) NA 0.79 (0.37-1.7) NA 
 11-20 NA 0.95 NA 0.93 NA 0.86 NA 0.86 NA NA 0.82 NA NA NA 0.74 NA 0.69 NA 
 21-30 NA 0.22 NA 0.17 NA 0.13 NA 0.15 NA NA 0.34 NA 0.34 NA 0.21 NA 0.20 NA 
 31-40 NA 0.27 NA 0.43 NA 0.084 NA 0.26 NA NA 0.21 NA 0.47 NA 0.066 NA 0.12 NA 
 41-75 NA 0.32 NA 1.3 NA 0.080 NA 0.15 NA NA 0.38 NA 0.97 NA 0.11 NA 0.40 NA 
Effect of prophylaxis in different F8 genotypes N ED         N ED         
 Low-risk genotype 10 153 0.30 (0.11-0.83) .020 0.61 (0.19-2.0) .41 0.14 (0.028-0.72) .018 0.17 (0.028-0.98) .047 10 153 0.47 (0.21-1.1) .069 0.42 (0.16-1.1) .079 0.39 (0.13-1.2) .088 0.32 (0.062-1.6) .17 
 High-risk genotype 16 263 0.94 (0.61-1.4) .77 0.85 (0.51-1.4) .52 0.83 (0.49-1.4) .49 0.83 (0.45-1.6) .57 16 263 0.70 (0.48-1.0) .069 0.78 (0.51-1.2) .25 0.64 (0.40-1.0) .055 0.73 (0.44-1.2) .21 

In total, 576 patients were treated on 29 757 EDs to FVIII.

ED, exposure day; N, number; NA, not applicable.

*

Adjusted for ethnicity, F8 gene mutation type, family history of hemophilia and inhibitors, duration between first and current exposure day, duration between exposure days, dose, FVIII product type, peak treatment moments, and surgery. The inverse probability of treatment weights for regular prophylaxis had a mean of 1.0230, median of 0.8503, IQR of 0.5935-1.1043, and a range of 0.11-100.91. The inverse probability of treatment weights for intention to start prophylaxis had a mean of 1.0087, median of 0.9798, IQR of 0.7364-1.1184, and a range of 0.08-11.66.

Patients who started prophylaxis later than 15 or 5 EDs were censored at start of prophylaxis.

Patients who started prophylaxis later than age 11 months were censored at start of prophylaxis.

§

The aHRs for early and late start of prophylaxis were not available as the currently available statistical methods do not allow correct adjustment for confounding and censoring in this specific situation.

||

HRs of prophylaxis compared with on-demand treatment during the number of exposure days, categorized in 10-day periods.

Adjusted for ethnicity, family history of hemophilia and inhibitors, duration between first and current ED, duration between exposure days, dose, FVIII product type, and surgery.

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