1. Biostatistics Core Members Joyce Chang Kirsha Gordon Joseph Goulet
Kathleen McGinnis
Lesley Park
Christopher Rentsch
Kaku So-Armah
Janet Tate, ScD
Director

2. Summary of Activities In support of all VACS projects
Multiple imputation for missing data
Propensity score models
Time-updated and competing risk survival models
Group-based trajectories
Longitudinal Analysis Special Interest Group
Established mid-2015
Meets monthly via web-conference for a methods lesson and to review ongoing analyses and project design
All biostatistics core members
Clinicians interested in these methods
Statistical collaborators at Brown, Vanderbilt and Yale Universities

3. Janet Tate Christopher Rentsch ABC Workgroup
Neurologic Adverse Events With Gabapentin: the Impact of Alcohol-Related Diagnoses, HIV, and HCV
Janet Tate
Christopher Rentsch
ABC Workgroup
177896
VACS Conference
December 2016

4. Confounding by indication!
Gabapentin
Used for
Neuropathic pain (diabetes)
Seizure disorder
Treatment of unhealthy alcohol use
Adverse neurologic effects
Dizziness
Sedation
Seizures
Confounding by indication!

5. Aim To compare outcomes between gabapentin exposed patients and
propensity score matched unexposed patients
Subgroups at increased risk?
Alcohol-related diagnoses (ARD)
HIV
HCV
Need to explain somewhere that we could measure dizziness or sedation directly so looked at altered mental status and falls fractures as a proxy

6. Study sample
Visit to VA clinic likely to prescribe gabapentin
Index date
Exposed: date of first gabapentin
Unexposed random visit date
Exposed
Unexposed
Eligible
n=34,677
n=833,678
Gabapentin exposure before 2002
7,965 (23) -
Outcome in year prior to index date
2,689 (8)
34,965 (4)
Proceed to propensity score
24,741 (71)
660,636 (79)

7. Proxies for dizziness and sedation
Outcomes by ICD-9 code
Proxies for dizziness and sedation
Altered mental status
Delirium (291, 291.1, , 293, 293.1, ),
Confusion (298.2)
Altered mental status (780.97)
Falls or fractures
Falls (E codes 882, 883, 884.9, 885.9, 888, 888.9)
Fractures
Hip: (820.0X, 820.1X, 820.2X, 820.3X, 820.8, 820.9)
Vertebral: (805.2, 805.3, 805.4, 805.5, 805.6, 805.7)
Upper arm: (812.0X, 812.1X, 812.2X, 812.3X, 812.4X, 812.5X)
Seizures
Epilepsy (345.xx) and other convulsions (780.3x)

8. Subgroups HIV HCV ARD Never, lifetime, current (past year)
Positive antibody, detectable HCV RNA, ICD-9 code
ARD
291.X; 303.X; ; 357.5; 425.5; 535.3X; ; ; 980.0/.8/.9; E860.0/.1/.8/.9; V11.3
Never, lifetime, current (past year)

9. Outcomes models
Poisson regression to estimate incidence rates and exposure rate ratios for each adverse neurologic event
Follow-up ends
2 years from index date
Adverse event date
Last follow-up date
Exposed: 90 days after end of last fill

10. Propensity score model
Demographics
Year of index visit
Site prescribing pattern
Inpatient and outpatient utilization
12 labs
48 comorbidities
14 pain diagnoses
5 classes of medications
+ interactions
C-statistic = 0.82
1:5 match

11. Patient flow Visits Exposed Unexposed Eligible n=34,677 n=833,678
Exclusions
Gabapentin exposure before 2002
7,965 (23) -
Outcome in year prior to index date
2,689 (8)
34,965 (4)
Proceed to propensity score
24,741 (71)
660,636 (79)

12. Distribution of propensity scores

13. 1:5 propensity score matched patients
Exposed
Unexposed
Characteristic
n=14,044
n=14,044*
Age
20-44
18.0
18.5
45-54
17.1
17.8
55-59
21.6
21.5
60+
43.2
42.2
Race
Black
47.2
47.5
White
39.9
39.4
Hispanic
8.9
Other
4.0
4.1
Sex
Male
96.9
97.4
Any hospitalization
21.7
21.3
unexposed matches were weighted according to number of matches; 62% of exposed were matched to 5 unexposed, 9% to 4, 10% to 3, 10% to 2, and 9% to 1
* Weighted according to number of matches

14. Characteristics of matched patients
HIV/HCV infection
Uninfected
60.3
58.5
HCV mono-infected
8.4
8.6
HIV mono-infected
3.7
24.7
HIV/HCV dual-infected
7.7
8.2
ARD
Never
61.3
59.7
Lifetime
17.6
17.7
Current
21.1
22.6
Conditions
Seizure
3.6
4.5
Diabetes
23.5
23.3
Neuropathic pain
16.9
16.6
Any chronic pain
93.6
93.9
Other prescription
Opioid
21.3
22.0
Antidepressant
6.3
5.7
NSAID
40.1
40.9
Muscle relaxant
6.8
7.0
Anticonvulsant
1.8

15. Altered mental status Incidence rates per 100 PY Exposed Unexposed
Events IR
Total IR 89
1.32
609
0.74
HIV/HCV infection
Uninfected 45
1.12
284
0.57
HCV only 17
2.94 69
1.10
HIV only 21
1.31
174
0.87
HIV/HCV co-infected 6 82
1.39
ARD
Never 35
0.85
265
0.51
Lifetime 14
1.18
113
0.80
Current 40
2.73
231
1.45

16. Fall or fracture Exposed Unexposed Events IR Total IR 119 1.76 933
Events IR
Total IR
119
1.76
933
1.14
HIV/HCV infection
Uninfected 62
1.54
519
1.04
HCV only 8
1.38 87
1.40
HIV only 36
2.25
219
1.10
HIV/HCV co-infected 13
2.43
108
1.84
ARD
Never 68
1.66
496
0.96
Lifetime 12
1.02
170
1.20
Current 39
2.67
267
1.69

17. Seizure Exposed Unexposed Events IR Total IR 110 1.63 835 1.02
Events IR
Total IR
110
1.63
835
1.02
HIV/HCV infection
Uninfected 55
1.37
465
0.93
HCV only 11
1.90 87
1.40
HIV only 36
2.25
198
0.99
HIV/HCV co-infected 8
1.49 85
1.44
ARD
Never 53
1.29
416
0.80
Lifetime 20
1.70
158
1.12
Current 37
2.53
261
1.65

18. Combined outcome Exposed Unexposed Events IR Total 304 4.55 2141 2.65
Events IR
Total
304
4.55
2141
2.65
HIV/HCV infection
Uninfected
157
3.93
1157
2.35
HCV only 34
5.94
222
3.64
HIV only 87
5.48
520
2.64
HIV/HCV co-infected 26
4.90
242
4.20
ARD
Never
150
3.68
1079
2.10
Lifetime 45
3.85
404
2.90
Current
109
7.57
658
4.26

19. Altered mental status
Relative risks exposed vs not

20. Fall or fracture

21. Seizure

22. Combined outcome

23. Conclusions
Higher risk of neurologic adverse events among gabapentin exposed individuals vs PS matched non-users
Differs based on the presence of an alcohol-related diagnosis, HIV and HCV infection
HIV infection associated with increased rates of falls or fractures, and seizures
Prescribers should consider these risks when prescribing gabapentin for unhealthy alcohol use

24. Next steps Dose Association of gabapentin exposure with
CD4, HIV-1 RNA, and VACS Index
Alcohol consumption

25. Questions? Primary Funding Other Funding NIAAA: R01 AA023733
National Institutes of Health: AHRQ (R01-HS018372), NIAAA (U24-AA020794, U01-AA020790, U01-AA020795, U01-AA020799, U24-AA022001, U24 AA022007, U10 AA completed), NHLBI (R01-HL125032, R01-HL completed, R01-HL completed) , NIAID (U01-A ), NIMH (P30-MH062294), NIDA (R01DA035616), NCI (R01 CA173754)
This is a Jan slide from IWHOD Update where applicable.
On the RSA poster, we listed: RO1 AA023733; U24 AA020794; U01 AA020790