Traumatic Brain Injury and Long-Term Risk of Stroke Among US Military Veterans

Andrea L.C. Schneider, MD, PhD; Carrie B. Peltz, PhD; Yixia Li, MPH; Amber Bahorik, PhD; Raquel C. Gardner, MD; Kristine Yaffe, MD

Disclosures

Stroke. 2023;54(8):2059-2068.

Abstract and Introduction

Abstract

Background: Traumatic brain injury (TBI) is associated with significant morbidity, but the association of TBI with long-term stroke risk in diverse populations remains less clear. Our objective was to examine the long-term associations of TBI with stroke and to investigate potential differences by age, sex, race and ethnicity, and time since TBI diagnosis.

Methods: Retrospective cohort study of US military veterans aged 18+ years receiving healthcare in the Veterans Health Administration system between October 1, 2002 and September 30, 2019. Veterans with TBI were matched 1:1 to veterans without TBI on age, sex, race and ethnicity, and index date, yielding 306 796 veterans with TBI and 306 796 veterans without TBI included in the study. In primary analyses, Fine-Gray proportional hazards models adjusted for sociodemographics and medical/psychiatric comorbidities were used to estimate the association between TBI and stroke risk, accounting for the competing risk of mortality.

Results: Participants were a mean age of 50 years, 9% were female, and 25% were of non-White race and ethnicity. Overall, 4.7% of veterans developed a stroke over a median follow-up of 5.2 years. Veterans with TBI had 1.69 times (95% CI, 1.64–1.73) increased risk of any stroke (ischemic or hemorrhagic) compared to veterans without TBI. This increased risk was highest in the first-year post-TBI diagnosis (hazard ratio [HR], 2.16 [95% CI, 2.03–2.29]) but remained elevated for 10+ years. Similar patterns were observed for secondary outcomes, with associations of TBI with hemorrhagic stroke (HR, 3.92 [95% CI, 3.59–4.29]) being stronger than with ischemic stroke (HR, 1.56 [95% CI, 1.52–1.61]). Veterans with both mild (HR, 1.47 [95% CI, 1.43–1.52]) and moderate/severe/penetrating injury (HR, 2.02 [95% CI, 1.96–2.09]) had increased risk of stroke compared to veterans without TBI. Associations of TBI with stroke were stronger among older compared to younger individuals (P interaction-by-age<0.001) and were weaker among Black veterans compared to other race and ethnicities (P interaction-by-race<0.001).

Conclusions: Veterans with prior TBI are at increased long-term risk for stroke, suggesting they may be an important population to target for primary stroke prevention measures.

Graphic Abstract: A graphic abstract is available for this article.

Introduction

Traumatic brain injury (TBI) is common and is associated with significant morbidity among survivors.^[1,2] Military veterans have a higher prevalence of lifetime history of TBI (up to 56%) compared with civilians and, therefore, represent an enriched population in which to study the long-term sequelae of TBI.^[3] Much of the prior research on TBI has focused on shorter-term injury recovery-related outcomes (ie, functional outcomes occurring within 1 year of injury),^[4,5] with fewer studies focused on associations with longer-term neurological consequences.

Traumatic cerebral microvascular injury is an increasingly recognized endophenotype of TBI, and there is emerging evidence that resulting persistent microvascular dysfunction after TBI may lead to later neurological disease, including dementia and stroke.^[6] Indeed, there have been several prior studies investigating associations of TBI with stroke risk.^[7–16] The majority of these prior studies are limited by racial and ethnic homogeneity.^[9–13] Many of these prior studies also did not investigate associations of TBI with both ischemic and hemorrhagic stroke risk.^[7–16] The long-term risk of stroke after TBI remains unclear, particularly in populations comprised of diverse race and ethnicity groups. Information on these outcomes is important to better understand risk, burden, and possible mechanisms.

The overall objective of the present study was to examine the long-term associations of TBI and TBI severity with stroke risk (overall, and separately for ischemic and hemorrhagic stroke types) in a sample of US military veterans receiving healthcare in the Veterans Health Administration (VHA) system. We additionally sought to investigate potential differences in associations of TBI with stroke risk by age, sex, race and ethnicity, and time since TBI diagnosis.

1 2 3 4

Next Section

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Baseline Characteristics of US Veterans With and Without TBI
	Veterans without TBI (n=306 796)	Veterans with TBI (n=306 796)	SMD
Demographics
Age, y, mean (SD)	50.4 (17.6)	50.2 (17.6)	−0.012
Age category, y, n (%)			−0.010
18–44	129 887 (42.3)	130 909 (42.6)
45–64	111 583 (36.3)	111 742 (36.4)
65+	65 326 (21.2)	64 145 (20.9)
Female, n (%)	27 866 (9.0)	27 866 (9.0)	−0.001
Race and ethnicity, n (%)			<0.001
Non-Hispanic White	230 179 (75.0)	230 179 (75.0)
Non-Hispanic Black	56 609 (18.4)	56 609 (18.4)
Hispanic	9925 (3.2)	9925 (3.2)
Other*	10 083 (3.2)	10 083 (3.2)
Median annual income in zip code <$25 930, n (%)	97 708 (31.8)	98 026 (31.9)	0.004
>25% of residents in zip code college educated, n (%)	153 638 (50.0)	155 741 (50.7)	0.020
Current smoking, n (%)	38 456 (12.5)	57 087 (18.6)	0.168
Index year, median (25th–75th percentile)	2012 (2008–2015)	2012 (2009–2015)	0.006
Follow-up time, median (25th–75th percentile)	5.23 (2.35–8.78)	5.18 (2.35–8.71)	−0.021
Medical comorbidities
Hypertension, n (%)	94 700 (30.8)	115 945 (37.7)	0.145
Hyperlipidemia, n (%)	89 413 (29.1)	105 547 (34.4)	0.112
Diabetes, n (%)	36 557 (11.9)	46 088 (15.0)	0.090
Atrial fibrillation, n (%)	6789 (2.2)	13 256 (4.3)	0.118
Coronary artery disease, n (%)	19 055 (6.2)	24 836 (8.1)	0.072
Psychiatric comorbidities
Posttraumatic stress disorder, n (%)	32 479 (10.5)	111 178 (36.2)	0.635
Depression, n (%)	48 040 (15.6)	111 669 (36.4)	0.486

An SMD of >0.1 or <−0.1 was considered a meaningful difference. SMD indicates standardized mean difference; and TBI, traumatic brain injury.
*Other race and ethnicities includes: American Indian or Alaska Native, Asian, and Native Hawaiian

Table 2. Risk of Stroke by TBI Status
	Veterans without TBI	Veterans with TBI
Any stroke
No. of events/no. of PYs	10 297/1 811 490	18 435/1 787 238
Unadjusted incidence rate per 1000 PYs (95% CI)	5.7 (5.4–6.0)	10.3 (10.0–10.7)
Adjusted* Cox proportional hazards model, HR (95% CI)	1 (Reference)	1.80 (1.76–1.85)
Adjusted* Fine-Gray proportional hazards model, HR (95% CI)	1 (Reference)	1.69 (1.64–1.73)†‡
Ischemic stroke
No. of events/no. of PYs	9924/1 812 455	16 645/1 795 283
Unadjusted incidence rate per 1000 PYs (95% CI)	5.5 (5.2–5.7)	9.3 (8.9–9.6)
Adjusted* Cox proportional hazards model, HR (95% CI)	1 (Reference)	1.68 (1.63–1.72)
Adjusted* Fine-Gray proportional hazards model, HR (95% CI)	1 (Reference)	1.56 (1.52–1.61)†‡
Hemorrhagic stroke
No. of events/no. of PYs	660/1 848 365	2603/1 851 144
Unadjusted incidence rate per 1000 PYs (95% CI)	0.4 (0.3–0.4)	1.4 (1.3–1.5)
Adjusted* Cox proportional hazards model, HR (95% CI)	1 (Reference)	3.92 (3.59–4.29)
Adjusted* Fine-Gray proportional hazards model, HR (95% CI)	1 (Reference)	3.73 (3.40–4.08)†‡

HR indicates hazard ratio; PY, person-years; and TBI, traumatic brain injury.
*Model adjusted for demographics (age, sex, race and ethnicity, income, education, and current smoking), medical comorbidities
(hypertension, hyperlipidemia, diabetes, coronary artery disease, and atrial fibrillation), and psychiatric comorbidities
(posttraumatic stress disorder and depression).
†P interaction by race and ethnicity <0.001.
‡P interaction by age <0.001.

Table 3. Adjusted* Risk of Stroke by TBI Status Stratified by Age and Race and Ethnicity
	Veterans without TBI		Veterans with TBI
	No. of events/no. of PYs	HR (95% CI)	No. of events/no. of PYs	HR (95% CI)
Any stroke
Stratified by age, y
Age 18–44	1002/733 018	1 (Reference)	1687/778 267	1.68 (1.54–1.83)
Age 45–64	5495/763 288	1 (Reference)	9043/744 928	1.54 (1.49–1.60)
Age 65+	3795/315 183	1 (Reference)	7696/264 044	1.94 (1.86–2.03)
Stratified by race and ethnicity
Non-Hispanic White	7289/1 350 767	1 (Reference)	13 760/1 324 665	1.74 (1.69–1.79)
Non-Hispanic Black	2518/352 689	1 (Reference)	3756/351 792	1.42 (1.35–1.50)
Hispanic	309/55 856	1 (Reference)	598/57 000	1.84 (1.58–2.14)
Other	176/52 177	1 (Reference)	312/53 781	1.73 (1.40–2.13)
Ischemic stroke
Stratified by age, y
Age 18–44	930/733 201	1 (Reference)	1461/779 535	1.55 (1.42–1.70)
Age 45–64	5289/763 895	1 (Reference)	8221/749 174	1.45 (1.40–1.50)
Age 65+	3700/315 339	1 (Reference)	6957/266 574	1.78 (1.71–1.86)
Stratified by race and ethnicity
Non-Hispanic White	7037/1 351 405	1 (Reference)	12 344/1 330 957	1.60 (1.55–1.65)
Non-Hispanic Black	2420/352 959	1 (Reference)	3481/353 191	1.36 (1.29–1.44)
Hispanic	296/55 890	1 (Reference)	538/57 188	1.70 (1.45–1.98)
Other	166/52 201	1 (Reference)	276/53 947	1.55 (1.25–1.94)
Hemorrhagic stroke
Stratified by age, y
Age 18–44	110/736 533	1 (Reference)	292/784 821	2.70 (2.12–3.44)
Age 45–64	385/784 829	1 (Reference)	1245/781 098	3.00 (2.65–3.38)
Age 65+	165/328 003	1 (Reference)	1063/285 224	6.21 (5.21–7.40)
Stratified by race and ethnicity
Non-Hispanic White	420/1 376 949	1 (Reference)	1976/1 371 638	4.32 (3.86–4.83)
Non-Hispanic Black	193/361 855	1 (Reference)	476/365 711	2.37 (1.98–2.82)
Hispanic	28/56 801	1 (Reference)	99/58 978	3.27 (2.10–5.08)
Other	19/52 760	1 (Reference)	49/54 816	2.59 (1.45–4.63)

HR indicates hazard ratio; PY, person-years; and TBI, traumatic brain injury.
*Fine-Gray proportional hazards model adjusted for demographics (age, gender, race, income, education, and current smoking), medical comorbidities (hypertension, hyperlipidemia, diabetes, and atrial fibrillation), and psychiatric comorbidities (posttraumatic stress disorder and depression).

Table 4. Risk of Stroke by TBI Severity
	Veterans without TBI	Veterans with mild TBI	Veterans with moderate or severe or penetrating TBI
Any stroke
No. of events/no. of PYs	10 297/1 811 490	6744/791 250	8767/607 738
Unadjusted incidence rate per 1000 PYs (95% CI)	5.7 (5.4–6.0)	8.5 (8.1–9.0)	14.4 (13.7–15.2)
Adjusted* Cox proportional hazards model, HR (95% CI)	1 (Reference)	1.59 (1.54–1.64)	2.18 (2.11–2.24)
Adjusted* Fine-Gray proportional hazards model, HR (95% CI)	1 (Reference)	1.47 (1.43–1.52)	2.02 (1.96–2.09)
Ischemic stroke
No. of events/no. of PYs	9924/1 812 455	6323/792 827	7585/613 534
Unadjusted incidence rate per 1000 PYs (95% CI)	5.5 (5.2–5.7)	8.0 (7.5–8.4)	12.4 (11.7–13.1)
Adjusted* Cox proportional hazards model, HR (95% CI)	1 (Reference)	1.55 (1.50–1.60)	1.92 (1.7–1.99)
Adjusted* Fine-Gray proportional hazards model, HR (95% CI)	1 (Reference)	1.43 (1.38–1.48)	1.78 (1.73–1.84)
Hemorrhagic stroke
No. of events/no. of PYs	660/1 848 365	637/814 134	1671/638 374
Unadjusted incidence rate per 1000 PYs (95% CI)	0.4 (0.3–0.4)	0.8 (0.6–0.9)	2.6 (2.3–2.9)
Adjusted* Cox proportional hazards model, HR (95% CI)	1 (Reference)	2.23 (1.99–2.50)	6.45 (5.87–7.09)
Adjusted* Fine-Gray proportional hazards model, HR (95% CI)	1 (Reference)	2.11 (1.88–2.36)	6.14 (5.58–6.76)

HR indicates hazard ratio; PY, person-years; and TBI, traumatic brain injury.
*Model adjusted for demographics (age, sex, race and ethnicity, income, education, and current smoking), medical comorbidities (hypertension, hyperlipidemia, diabetes, coronary artery disease, and atrial fibrillation), and psychiatric comorbidities (posttraumatic stress disorder and depression).