Risk of Intracranial Hemorrhage in Persons with Hemophilia A in the United States: Real-World Retrospective Cohort Study Using the ATHNdataset

Figures & data

Table 1 Demographic, Clinical, and Treatment Characteristics of the Cohort and Incidence of ICH

Characteristic, n (%)	Total Cohort (N=7837)	No ICH, n (%) (n=7702)	ICH, n (%) (n=135)	P-value
Race				0.200
White	5937 (75.8)	5832 (75.7)	105 (77.8)
Black or African American	1156 (14.8)	1132 (14.7)	24 (17.8)
Other	610 (7.8)	604 (7.8)	6 (4.4)
Unknown	134 (1.7)	134 (1.7)	0 (0)
Ethnicity				0.700
Not Hispanic, Latinx, or Spanish origin	6482 (82.7)	6370 (82.7)	112 (83.0)
Hispanic, Latinx, or Spanish origin	1314 (16.8)	1292 (16.8)	22 (16.3)
Unknown	41 (0.5)	40 (0.5)	1 (0.7)
Age, years				<0.001
2–12	1003 (12.8)	956 (12.4)	47 (34.8)
13–18	1336 (17.0)	1317 (17.1)	19 (14.1)
19–29	2221 (28.3)	2205 (28.6)	16 (11.9)
30–49	2322 (29.6)	2293 (29.8)	29 (21.5)
50–74	955 (12.2)	931 (12.1)	24 (17.8)
Mortality				0.011
Alive	7588 (96.8)	7463 (97.3)	125 (92.6)
Deceased	249 (3.2)	239 (3.1)	10 (7.4)
Current or prior Medicaid				0.018
No	4778 (61.0)	4709 (61.1)	69 (51.1)
Yes	3059 (39.0)	2993 (38.8)	66 (48.9)
Current or prior HCV				0.011
Yes with known start date	463 (5.9)	447 (5.8)	16 (11.9)
Yes with unknown start date	803 (10.2)	792 (10.2)	11 (8.1)
No	6571 (83.8)	6463 (83.9)	108 (80.0)
Current or prior HIV				<0.001
Yes with known start date	384 (4.9)	367 (4.8)	17 (12.6)
Yes with unknown start date	335 (4.3)	328 (4.3)	7 (5.2)
No	7118 (90.8)	7007 (91.0)	111 (82.2)
Current or prior HTN				0.001
Yes with known start date	56 (0.7)	53 (0.7)	3 (2.2)
Yes with unknown start date	143 (1.8)	135 (1.8)	8 (5.9)
No	7638 (97.5)	7514 (97.6)	124 (91.9)
Current or prior rFVIII				<0.001
Yes with known start date	6334 (80.8)	6235 (81.0)	99 (73.3)
Yes with unknown start date	785 (10.0)	777 (10.1)	8 (5.9)
No	718 (9.2)	690 (9.0)	28 (20.7)
Current or prior pdFVIII				0.034
Yes with known start date	883 (11.3)	859 (11.2)	24 (17.8)
Yes with unknown start date	126 (1.6)	123 (1.6)	3 (2.2)
No	6828 (87.1)	6720 (87.3)	108 (80.0)
Current or prior FVIII (rFVIII and/or pdFVIII)				0.001
Yes with known start date	6612 (84.4)	6504 (84.4)	108 (80.0)
Yes with unknown start date	793 (10.1)	782 (10.2)	11 (8.1)
No	433 (5.5)	416 (5.4)	17 (12.6)
Current or prior bypassing agent				0.007
Yes with known start date	601 (7.7)	581 (7.5)	20 (14.8)
Yes with unknown start date	77 (1.0)	75 (1.0)	2 (1.5)
No	7159 (91.3)	7046 (91.5)	113 (83.7)
Current or prior non-factor treatment				<0.001
Yes with known start date	1878 (24.0)	1872 (24.3)	6 (4.4)
Yes with unknown start date	145 (1.9)	144 (1.9)	1 (0.7)
No	5814 (74.2)	5686 (73.8)	128 (94.8)
Current or prior prophylaxis				0.120
Yes	5647 (72.1)	5559 (72.2)	88 (65.2)
No	1550 (19.8)	1514 (19.7)	36 (26.7)
Yes with unknown start date	640 (8.2)	629 (8.2)	11 (8.1)
Current or prior inhibitor				0.200
Yes	434 (5.5)	422 (5.5)	12 (8.9)
No	6665 (85.0)	6557 (85.1)	108 (80.0)
Yes with unknown start date	738 (9.4)	723 (9.4)	15 (11.1)

Abbreviations: FVIII, factor VIII; HCV, hepatitis C virus; HTN, hypertension; ICH, intracranial hemorrhage; pdFVIII, plasma-derived FVIII; rFVIII, recombinant FVIII.

Figure 1 ICH incidence rate during the study period (2010–2020).

Abbreviation: ICH, intracranial hemorrhage.

Figure 2 Risk of ICH in univariate analysis.

Abbreviations: CI, confidence interval; FVIII, factor VIII; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HR, hazard ratio; HTN, hypertension; ICH, intracranial hemorrhage.

Figure 3 Kaplan–Meier curves of key characteristics. (A) Race; (B) Age; (C) Mortality; (D) Medicaid; (E) Hepatitis C; (F) HIV; (G) Any FVIII treatment (pdFVIII and rFVIII); (H) Prophylaxis.

Abbreviations: FVIII, factor VIII; HCV, hepatitis C virus; HIV, human immunodeficiency virus; pdFVIII, plasma-derived factor VIII; rFVIII, recombinant factor VIII.

Figure 4 Risk of ICH in multivariable analysis with significant covariates (univariate analysis) and prophylaxis:inhibitor interaction.

Abbreviations: CI, confidence interval; FVIII, factor VIII; HCV, hepatitis C virus; HR, hazard ratio; HIV, human immunodeficiency virus; HTN, hypertension; ICH, intracranial hemorrhage.

Table 2 Multivariable CoxPH Model with Interaction and Bootstrap Sensitivity Analyses

Characteristic	Population		Bootstrap Sensitivity
	HR	95% CI	HR	95% CI
Age, years (reference: 2–12)
13–18	0.25	0.14–0.42	0.38	0.23–0.50
19–29	0.11	0.065–0.20	0.24	0.12–0.27
30–49	0.14	0.077–0.24	0.25	0.12–0.28
50–74	0.14	0.066–0.29	0.22	0.10–0.34
Mortality (reference: alive)
Deceased	1.41	0.67–2.97	2.03	0.87–3.53
Current or prior Medicaid (reference: no)
Yes	1.51	1.06–2.14	1.15	0.99–1.67
Current or prior HCV (reference: yes)
Yes with unknown start date	0.54	0.23–1.27	0.33	0.21–0.89
No	0.56	0.28–1.11	0.44	0.29–0.92
Current or prior HIV (reference: yes)
Yes with unknown start date	0.68	0.26–1.81	0.90	0.34–1.99
No	0.32	0.17–0.64	0.39	0.24–0.79
Current or prior HTN (reference: yes)
Yes with unknown start date	1.26	0.33–4.83	0.81	0.22–2.69
No	0.29	0.088–0.96	0.47	0.11–1.05
FVIII (rFVIII and/or pdFVIII; reference: yes)
Yes with unknown start date	0.86	0.38–1.92	2.01	0.00–3.63
No	2.66	1.41–4.99	2.12	1.03–3.06
Current or prior prophylaxis (reference: yes)
Yes with unknown start date	2.96	0.34–25.84	0.74	0.00–3.63
No	7.67	2.24–26.30	2.03	1.30–9.12
Current or prior inhibitor (reference: yes)
Yes with unknown start date	2.12	0.72–6.26	1.08	0.64–3.39
No	1.90	0.75–4.80	1.04	0.73–3.03
Current or prior prophylaxis, inhibitor interaction (reference: yes [with unknown start date], yes [with unknown start date])
Prophylaxis (no) Inhibitor (no)	0.16	0.044–0.58	0.59	0.12–0.92
Prophylaxis (yes with unknown start date) Inhibitor (no)	0.53	0.053–5.37	1.08	0.33–2.6e6
Prophylaxis (no) Inhibitor (yes with unknown start date)	0.32	0.061–1.72	0.59	0.15–2.83
Prophylaxis (yes with unknown start date) Inhibitor (yes with unknown start date)	0.36	0.018–7.10	1.27	0.00–1.7e6

Abbreviations: CI, confidence interval; CoxPH, Cox proportional hazards; FVIII, factor VIII; HCV, hepatitis C virus; HR, hazard ratio; HTN, hypertension; pdFVIII, plasma-derived FVIII; rFVIII, recombinant FVIII.

Table 3 Multivariable CoxPH Model with Interaction and Penalty-Based Ridge-Regression Analyses

Characteristic	Population		RR1		RR2		RR3
	HR	P-value	HR	P-value	HR	P-value	HR	P-value
Age, years (reference: 2–12)
13–18	0.25	<0.001	0.26	<0.001	0.30	<0.001	0.34	<0.001
19–29	0.12	<0.001	0.12	<0.001	0.15	<0.001	0.18	<0.001
30–49	0.14	<0.001	0.15	<0.001	0.18	<0.001	0.23	<0.001
50–74	0.14	<0.001	0.15	<0.001	0.20	<0.001	0.26	<0.001
Mortality (reference: alive)
Deceased	1.41	0.370	1.41	0.365	1.42	0.351	1.42	0.337
Current or prior Medicaid (reference: no)
Yes	1.51	0.022	1.51	0.022	1.51	0.019	1.50	0.018
Current or prior HCV (reference: yes)
Yes with unknown start date	0.54	0.160	0.54	0.155	0.55	0.151	0.57	0.150
No	0.56	0.098	0.58	0.108	0.63	0.157	0.68	0.219
Current or prior HIV (reference: yes)
Yes with unknown start date	0.68	0.441	0.69	0.448	0.70	0.462	0.72	0.477
No	0.33	0.001	0.34	0.001	0.37	0.002	0.40	0.004
Current or prior HTN (reference: ever)
Ever with unknown start date	1.26	0.731	1.27	0.727	1.28	0.716	1.29	0.698
Never	0.29	0.042	0.30	0.046	0.33	0.059	0.35	0.073
Current or prior FVIII (rFVIII and/or pdFVIII; reference: yes)
Yes with unknown start date	0.86	0.712	0.86	0.713	0.88	0.739	0.89	0.758
No	2.65	0.002	2.66	0.002	2.62	0.002	2.55	0.002
Current or prior prophylaxis (reference: yes)
No	7.67	0.001	5.99	0.002	4.11	0.007	3.09	0.018
Yes with unknown start date	2.96	0.327	2.32	0.420	1.67	0.578	1.40	0.679
Current or prior inhibitor (reference: yes)
No	1.90	0.177	1.64	0.246	1.33	0.436	1.17	0.645
Yes with unknown start date	2.12	0.173	1.82	0.238	1.46	0.402	1.27	0.565
Current or prior prophylaxis, inhibitor interaction (reference: yes [with unknown start date], yes [with unknown start date])
Prophylaxis (no) Inhibitor (no)	0.16	0.005	0.21	0.009	0.30	0.028	0.39	0.068
Prophylaxis (yes with unknown start date) Inhibitor (no)	0.53	0.592	0.68	0.729	0.92	0.934	1.08	0.935
Prophylaxis (no) Inhibitor (yes with unknown start date)	0.32	0.186	0.41	0.273	0.57	0.467	0.72	0.666
Prophylaxis (yes with unknown start date) Inhibitor (yes with unknown start date)	0.36	0.498	0.46	0.596	0.63	0.743	0.75	0.830

Abbreviations: CoxPH, Cox proportional hazards; FVIII, factor VIII; HCV, hepatitis C virus; HR, hazard ratio; HTN, hypertension; pdFVIII, plasma-derived FVIII; rFVIII, recombinant FVIII; RR1, ridge regression penalty 1; RR2, ridge regression penalty 2; RR3, ridge regression penalty 3.