Intensive treatment and inhibitor development
| Characteristics . | All inhibitors . | High-titer inhibitors . | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. exposure days . | N inh/N . | % . | Crude HR (95% CI) . | P value . | aHR (95% CI) . | P value . | N inh/N . | % . | Crude HR (95% CI) . | P value . | aHR (95% CI) . | P value . | |
| Treatment characteristics of first exposure | |||||||||||||
| Reason of first exposure to FVIII* | |||||||||||||
| Hemorrhage | 151/488 | 32.6 | 1 | 1 | 98/488 | 21.1 | 1 | 1 | |||||
| Prophylaxis | 19/68 | 28.8 | 0.86 (0.53-1.4) | .55 | 0.91 (0.53-1.6) | .73 | 13/68 | 22.4 | 0.91 (0.51-1.6) | .75 | 0.98 (0.51-1.9) | .95 | |
| Minor and major surgery | 7/20 | 37.1 | 1.1 (0.52-2.4) | .76 | 1.2 (0.54-2.6) | .69 | 5/20 | 27.1 | 1.2 (0.50-3.1) | .65 | 1.2 (0.48-3.1) | .68 | |
| Major surgery at first exposure*† | |||||||||||||
| No major surgery | 169/561 | 31.7 | 1 | 1 | 111/561 | 22.0 | 1 | 1 | |||||
| Venous access surgery | 2/4 | 50.0 | 1.7 (0.41-7.0) | .46 | 1.8 (0.43-7.7) | .42 | 1/4 | 33.3 | 1.3 (0.18-9.3) | .81 | 1.1 (0.14-8.2) | .94 | |
| Surgery for other indications | 6/10 | 60.0 | 2.2 (0.95-5.0) | .066 | 2.1 (0.77-5.8) | .14 | 4/10 | 41.7 | 2.2 (0.79-6.0) | .13 | 1.9 (0.55-6.6) | .31 | |
| Peak treatment moment at first exposure* | |||||||||||||
| None | 107/423 | 26.9 | 1 | 1 | 63/423 | 16.6 | 1 | 1 | |||||
| 3-5 days | 20/55 | 37.0 | 1.5 (0.93-2.4) | .099 | 1.4 (0.87-2.3) | .15 | 14/55 | 26.8 | 1.8 (1.0-3.2) | .052 | 1.7 (0.95-3.1) | .074 | |
| 5-10 days | 29/58 | 50.7 | 2.1 (1.4-3.2) | .00037 | 2.0 (1.3-3.0) | .0026 | 20/58 | 38.2 | 2.5 (1.5-4.1) | .00047 | 2.4 (1.4-4.1) | .0015 | |
| ≥10 days | 21/40 | 52.5 | 2.1 (1.3-3.3) | .0029 | 1.7 (1.0-2.9) | .047 | 19/40 | 49.5 | 3.1 (1.9-5.3) | .000015 | 2.7 (1.5-4.9) | .0014 | |
| Treatment characteristics of subsequent exposure days | |||||||||||||
| Peak treatment moment ≥3 days*† | 18 242 | 1.5 (1.1-2.0) | .015 | 1.5 (1.0-2.2) | .039 | 1.7 (1.2-2.6) | .0066 | 1.6 (1.0-2.6) | .046 | ||||
| Peak treatment moment ≥5 days*† | 12 975 | 1.5 (1.1-2.0) | .0078 | 1.4 (0.97-2.0) | .071 | 1.6 (1.1-2.3) | .012 | 1.3 (0.83-2.1) | .25 | ||||
| Peak treatment moment ≥ 10 days*† | 4282 | 1.7 (1.2-2.5) | .0051 | 1.3 (0.77-2.2) | .32 | 2.1 (1.4-3.3) | .00057 | 1.7 (0.96-3.1) | .068 | ||||
| Surgery*† | 7361 | 0.93 (0.64-1.4) | .73 | 1.0 (0.60-1.8) | .87 | 0.76 (0.46-1.3) | .29 | 0.84 (0.38-1.9) | .68 | ||||
| Type of surgery*† | |||||||||||||
| No or before surgery | 22 396 | 1 | 1 | 1 | 1 | ||||||||
| After surgery for venous access | 5266 | 0.78 (0.48-1.3) | .31 | 0.84 (0.51-1.4) | .50 | 0.61 (0.32-1.2) | .14 | 0.66 (0.34-1.3) | .23 | ||||
| After surgery for other indications | 1660 | 1.5 (0.83-2.6) | .19 | 1.4 (0.74-2.6) | .30 | 1.2 (0.54-2.5) | .69 | 0.95 (0.41-2.2) | .91 | ||||
| Unknown indication | 435 | 0.47 (0.066-3.4) | .46 | 0.40 (0.056-2.9) | .37 | 0.72 (0.099-5.2) | .74 | 0.63 (0.085-4.6) | .65 | ||||
| Duration between exposure days‡,§ | .18|| | .93|| | .030|| | .42|| | |||||||||
| >50 | 1119 | 1 | 1 | 1 | 1 | ||||||||
| 10-50 | 799 | 1.2 (0.68-2.0) | 1.0 (0.64-1.6) | 0.99 (0.50-2.0) | 0.99 (0.49-2.0) | ||||||||
| <10 | 1238 | 1.3 (0.87-2.1) | 1.2 (0.68-2.0) | 1.7 (1.0-2.9) | 1.3 (0.71-2.2) | ||||||||
| Dose of FVIII product (IU/kg) §,¶ | .0019|| | .11|| | .0087|| | .49|| | |||||||||
| <35 | 640 | 1 | 1 | 1 | 1 | ||||||||
| 35-50 | 1093 | 2.4 (1.2-4.9) | 2.4 (1.2-5.2) | 2.4 (1.0-5.7) | 2.4 (0.95-5.8) | ||||||||
| >50 | 1423 | 3.0 (1.5-6.0) | 2.3 (1.0-4.8) | 3.0 (1.3-6.9) | 1.8 (0.72-4.7) | ||||||||
| Characteristics . | All inhibitors . | High-titer inhibitors . | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. exposure days . | N inh/N . | % . | Crude HR (95% CI) . | P value . | aHR (95% CI) . | P value . | N inh/N . | % . | Crude HR (95% CI) . | P value . | aHR (95% CI) . | P value . | |
| Treatment characteristics of first exposure | |||||||||||||
| Reason of first exposure to FVIII* | |||||||||||||
| Hemorrhage | 151/488 | 32.6 | 1 | 1 | 98/488 | 21.1 | 1 | 1 | |||||
| Prophylaxis | 19/68 | 28.8 | 0.86 (0.53-1.4) | .55 | 0.91 (0.53-1.6) | .73 | 13/68 | 22.4 | 0.91 (0.51-1.6) | .75 | 0.98 (0.51-1.9) | .95 | |
| Minor and major surgery | 7/20 | 37.1 | 1.1 (0.52-2.4) | .76 | 1.2 (0.54-2.6) | .69 | 5/20 | 27.1 | 1.2 (0.50-3.1) | .65 | 1.2 (0.48-3.1) | .68 | |
| Major surgery at first exposure*† | |||||||||||||
| No major surgery | 169/561 | 31.7 | 1 | 1 | 111/561 | 22.0 | 1 | 1 | |||||
| Venous access surgery | 2/4 | 50.0 | 1.7 (0.41-7.0) | .46 | 1.8 (0.43-7.7) | .42 | 1/4 | 33.3 | 1.3 (0.18-9.3) | .81 | 1.1 (0.14-8.2) | .94 | |
| Surgery for other indications | 6/10 | 60.0 | 2.2 (0.95-5.0) | .066 | 2.1 (0.77-5.8) | .14 | 4/10 | 41.7 | 2.2 (0.79-6.0) | .13 | 1.9 (0.55-6.6) | .31 | |
| Peak treatment moment at first exposure* | |||||||||||||
| None | 107/423 | 26.9 | 1 | 1 | 63/423 | 16.6 | 1 | 1 | |||||
| 3-5 days | 20/55 | 37.0 | 1.5 (0.93-2.4) | .099 | 1.4 (0.87-2.3) | .15 | 14/55 | 26.8 | 1.8 (1.0-3.2) | .052 | 1.7 (0.95-3.1) | .074 | |
| 5-10 days | 29/58 | 50.7 | 2.1 (1.4-3.2) | .00037 | 2.0 (1.3-3.0) | .0026 | 20/58 | 38.2 | 2.5 (1.5-4.1) | .00047 | 2.4 (1.4-4.1) | .0015 | |
| ≥10 days | 21/40 | 52.5 | 2.1 (1.3-3.3) | .0029 | 1.7 (1.0-2.9) | .047 | 19/40 | 49.5 | 3.1 (1.9-5.3) | .000015 | 2.7 (1.5-4.9) | .0014 | |
| Treatment characteristics of subsequent exposure days | |||||||||||||
| Peak treatment moment ≥3 days*† | 18 242 | 1.5 (1.1-2.0) | .015 | 1.5 (1.0-2.2) | .039 | 1.7 (1.2-2.6) | .0066 | 1.6 (1.0-2.6) | .046 | ||||
| Peak treatment moment ≥5 days*† | 12 975 | 1.5 (1.1-2.0) | .0078 | 1.4 (0.97-2.0) | .071 | 1.6 (1.1-2.3) | .012 | 1.3 (0.83-2.1) | .25 | ||||
| Peak treatment moment ≥ 10 days*† | 4282 | 1.7 (1.2-2.5) | .0051 | 1.3 (0.77-2.2) | .32 | 2.1 (1.4-3.3) | .00057 | 1.7 (0.96-3.1) | .068 | ||||
| Surgery*† | 7361 | 0.93 (0.64-1.4) | .73 | 1.0 (0.60-1.8) | .87 | 0.76 (0.46-1.3) | .29 | 0.84 (0.38-1.9) | .68 | ||||
| Type of surgery*† | |||||||||||||
| No or before surgery | 22 396 | 1 | 1 | 1 | 1 | ||||||||
| After surgery for venous access | 5266 | 0.78 (0.48-1.3) | .31 | 0.84 (0.51-1.4) | .50 | 0.61 (0.32-1.2) | .14 | 0.66 (0.34-1.3) | .23 | ||||
| After surgery for other indications | 1660 | 1.5 (0.83-2.6) | .19 | 1.4 (0.74-2.6) | .30 | 1.2 (0.54-2.5) | .69 | 0.95 (0.41-2.2) | .91 | ||||
| Unknown indication | 435 | 0.47 (0.066-3.4) | .46 | 0.40 (0.056-2.9) | .37 | 0.72 (0.099-5.2) | .74 | 0.63 (0.085-4.6) | .65 | ||||
| Duration between exposure days‡,§ | .18|| | .93|| | .030|| | .42|| | |||||||||
| >50 | 1119 | 1 | 1 | 1 | 1 | ||||||||
| 10-50 | 799 | 1.2 (0.68-2.0) | 1.0 (0.64-1.6) | 0.99 (0.50-2.0) | 0.99 (0.49-2.0) | ||||||||
| <10 | 1238 | 1.3 (0.87-2.1) | 1.2 (0.68-2.0) | 1.7 (1.0-2.9) | 1.3 (0.71-2.2) | ||||||||
| Dose of FVIII product (IU/kg) §,¶ | .0019|| | .11|| | .0087|| | .49|| | |||||||||
| <35 | 640 | 1 | 1 | 1 | 1 | ||||||||
| 35-50 | 1093 | 2.4 (1.2-4.9) | 2.4 (1.2-5.2) | 2.4 (1.0-5.7) | 2.4 (0.95-5.8) | ||||||||
| >50 | 1423 | 3.0 (1.5-6.0) | 2.3 (1.0-4.8) | 3.0 (1.3-6.9) | 1.8 (0.72-4.7) | ||||||||
Associations between inhibitor development and duration, dose, and type of surgery were adjusted with multivariable Cox proportional hazards regression. Associations between inhibitor development and surgery were adjusted with marginal structural models with inverse probability weighting.
Inh/N, number of inhibitor patients per total number of patients.
Adjusted for ethnicity, F8 genotype, family history, product type, and prophylaxis.
In 1 patient, the indication for surgery at first treatment was unknown.
Adjusted for ethnicity, F8 genotype, family history, dose, and product type.
In patients who were never treated with regular prophylaxis.
P for trend.
Adjusted for ethnicity, F8 genotype, family history, duration between ED, product type, and body weight.