Prophylaxis and inhibitor development
. | Regular prophylaxis . | Intention to start prophylaxis . | ||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Determinant . | No. ED . | All inhibitors . | High-titer inhibitors . | . | All inhibitors . | High-titer inhibitors . | ||||||||||||
Crude HR (95% CI) . | P value . | aHR (95% CI) . | P value . | Crude HR (95% CI) . | P value . | aHR (95% CI) . | P value . | N ED . | Crude HR (95% CI) . | P value . | aHR (95% CI) . | P value . | Crude HR (95% CI) . | P value . | aHR (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 prophylaxis . | Intention to start prophylaxis . | ||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Determinant . | No. ED . | All inhibitors . | High-titer inhibitors . | . | All inhibitors . | High-titer inhibitors . | ||||||||||||
Crude HR (95% CI) . | P value . | aHR (95% CI) . | P value . | Crude HR (95% CI) . | P value . | aHR (95% CI) . | P value . | N ED . | Crude HR (95% CI) . | P value . | aHR (95% CI) . | P value . | Crude HR (95% CI) . | P value . | aHR (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.