Evaluation of Intracranial Hemorrhage in 49,610 HIV-Infected Veterans and California Medicaid Recipients

Shawn L. Fultz 1, David Zingmond 2, Kirsha S. Gordon 3, Joseph L. Goulet 3, Larry Mole 4, Joseph T King, Jr 3,4, Dawn Bravata 3,4, Hernan Valdez 5, Michael Kraft 6, Amy C Justice 3,4, and VACS Project Team

Office of Public Health and Environmental Hazards, Veterans Health Administration, Department of Veterans Affairs1~University of California Los Angeles, Los Angeles, CA, USA2~VA Connecticut Healthcare System, West Haven, CT, USA3~Yale University School of Medicine, New Haven, CT, USA4~VA Palo Alto Health Care System, Palo Alto, CA, USA5~Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT,

USA6~Boehringer Ingelheim Pharmaceuticals, Inc., Ingelheim, Germany7

OBJECTIVES

• To examine the rate of intracranial hemorrhage in an HIV-infected population not exposed to TPV during the HAART era.

BACKGROUND

• HIV has become a complex chronic disease with extended life expectancy and concomitant long term exposure to antiretroviral (ARV) therapy.

• Common long-term drug toxicities with ARV therapy appear as comorbid conditions.

• In pre-approval trials, 13 of 6840 patients (0.20%) exposed to tipranavir (TPV) have developed intracranial hemorrhage (ICH) at an incident rate of 0.26 per 100 person years of exposure (95% CI 0.09, 0.61). It is unknown whether this rate exceeds that observed with other, non TPV containing HAART regimens.

METHODS

• We identified HIV-infected individuals under care in the U.S. between October 1997 and December 2003 through the US Veterans Healthcare System-derived Virtual Cohort 1 and the California state Medicaid (Medi-Cal) program 2.

• In the Virtual Cohort, patients were identified as being HIV infected by virtue of having at least two outpatient or one inpatient codes for HIV. This algorithm was validated against the VA Immunology Case Registry Data which requires each VA site to confirm the HIV status of patients included in the registry.

• HIV infected Medi-Cal enrollees were identified by the Medical Care Statistical Section of Medi-Cal using case identification from claims and eligibility data developed for ongoing review of HIV-related costs and utilization. AIDS was determined by either two outpatient or one inpatient claims for AIDS or confirmation in the California AIDS Registry.

• ICH was identified using ICD-9 codes (430.xx, 431.xx and 432.xx, except 432.0) 3. Subjects who had ICD-9 codes indicating trauma or ischemic stroke complicated with intracranial hemorrhage were excluded. Other diagnoses were identified using standard, validated, ICD-9 code groupings.

• Prevalence was defined as ICH events occurring from 12 months before to 6 months after date of initial presentation for HIV care.

• Incidence (per 100 person-years) was defined as events occurring after this time frame.

• Poisson regression was used to model incidence rates after adjusting for covariates.

RESULTS

Table 1. Descriptive Statistics Table 2. Prevalence (%) of ICH by Important Covariates*

Funding: National Institute on Alcohol and Alcohol Abuse (2U10 AA 13566); and the Veterans Health Administration; the VHA

Office of Research and Development; and, VHA Public Health Strategic Health Care Group; and the University AIDS

Research Program (ID-05-LA-034). Dr. Zingmond is supported by a NIA Mentored Clinical Scientist Aware

(AG023024-01A1). Conflict of Interest: No financial or in kind support was

provided by any pharmaceutical company for these analyses.

CONCLUSIONS

• VA incidence rates of ICH were lower than those observed in pre marketing trials of Tipranavir, but Medi-Cal rates were similar (Figure 1).

• ICH events may be less completely captured:

•In observational databases using ICD-9 codes than in prospective clinical trials

•in the VA because patients with acute life threatening conditions may go to the nearest hospital rather than a VA facility for emergency care.

• While many risk factors for ICH established outside HIV infection appear to apply, we do not see increased rates of ICH among women compared to men.

• We also see no evidence of increased rates among those on protease inhibitors or on HAART compared to those not on these treatments.

REFERENCES

1. Fultz SL, Skanderson M, Mole LA et al. Development and verification of a ‘virtual’ cohort using the National VA Health Information System. Medical Care 2006; 44(8 Suppl 2): S25-S30.

2. Zingmond, DS,Ettner SL, Cunningham WE. The impact of managed care on access to highly active antiretroviral therapy and on outcomes among HIV-infected Medicaid beneficiaries. Medical Care Research and Review. In press.

3. Rosamond WD, Folsom AR, Chambless LE et al. Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke 1999; 30(4): 736-743.

VA Virtual Cohort

(n=16,573)

Medi-Cal

(n=33,037)

Baseline Demographics

Age, > 40 years 76% 45%

Male 98% 74%

Race/Ethnicity

Black

White

Hispanic

Other

41%

29%

7%

24%

25%

43%

25%

7%

Clinical Characteristics

AIDS Defining Illness 36% 29%

CD4<200 or AIDS Illness 69% 74%

Hypertension (HTN) 23% 12%

Diabetes (DM) 9% 6%

Coronary Artery Dz (CAD) 6% 4%

HTN, DM, or CAD 28% 16%

Alcohol Abuse /Dependence 20% 18%

Liver Disease 2% 4%

Active Protease Inhibitor 20% 26%

Active HAART 21% 29%

Known Dead 20% 20%

Poster # 819Contact Information:Dr. Amy C. JusticeYale University and VA Healthcare SystemBuilding 35A, Rm 212950 Campbell AvenueWest Haven, CT 06511Phone: 203-932-5711 x3541Email: amy.justice2@va.gov

The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs

  VA Virtual Cohort Medi-Cal Cohort

CovariatesCovariate Present %

Covariate Absent %

pCovariate

Present %Covariate

Absent % p

Female Gender 0.00%   0.20%  1 0.50% 0.47% 0 .8

>40 years old 0.00% 0.20% 0.003 0.64% 0.35% <0.001

Black Race 0.20% 0.20%  0.9 0.63% 0.43% 0.02

Hypertension (HTN)

0.34% 0 .09% 0.001  1.80% 0.28% <0.001

Diabetes (DM)

0.27%   0.14%  0.3  1.30% 0.43% <0.001

Coronary Artery Disease (CAD)

0.54% 0.13%  0.01  1.80% 0.42% <0.001

HTN, DM, or CAD

0.28%   0.10% 0.01  1.50% 0.28% <0.001

Alcohol Abuse or Dependence

0.24%   0.13% 0.1 1.10% 3.50%<0.001

Liver Disease

0.00% 0.15%  1 1.90% 4.20% <0.001

AIDS Defining Illness

0.32%   0.08% 0.0004

 0.93% 0.27%

<0.001

CD4<200 or AIDS Illness

0.23%  0.04%  0.01  0.46% 0.53% 0.4

Active Protease Inhibitor

0.04% 0.08%   1.0 0.40% 0.50% 0.2

Active HAART

0.03% 0.18%  0.04  0.38% 0.52% 0.1

Known Dead

0.54% 0.05% <0.001 1.10% 0.33% <0.001

  VA Virtual Cohort Medi-Cal Cohort

CovariatesCovariate Present

Covariate Absent

pCovariate Present

Covariate Absent

p

Female Gender 0.09 0.06 0.7 0.18 0.22 .1

>40 years old 0.07 0.04 0.2 0.27 0.17 <0.001

Black Race 0.10  0 .03 0.01 0.25 0.20 0.1

Hypertension (HTN)

0.16 0.04  0.0001 0.39 0.19 <0.001

Diabetes (DM)

0.17  0.05  0.01 0.43 0.20 <0.001

Coronary Artery Disease (CAD

0.09  0.06  0.6 0.35 0.21 0.04

HTN, DM, or CAD

0.15  0.03  0.0001  0.38 0.18 <0.001

Alcohol Abuse or Dependence

0.10  0.05  0.2 0.32 0.19 0.0007

Liver Disease

0.13  0.06 0.5  0.56 0.21 <0.001

AIDS Defining Illness 0.10 0.05  0.04  0.26 0.12 ,0.0001

CD4<200 or AIDS Illness

0.07  0.06   0.6 0.38 0.16 <0.001

Active Protease Inhibitor

0.04  0.06  0.5 0.22 0.21 0.8

Active HAART

0.07  0.06  0.9  0.20 0.22 0.5

Known Dead

0.24 0.02 <0.001 0.91 0.12 <0.001

Table 3. Incidence (events/100 PY) of ICH by Important Covariates*

*Prevalent intracranial hemorrhage events are identified using ICD-9 codes and were deemed prevalent if they occurred within 12 months prior or 6 months after baseline. Events occurring after this point were considered incident. Active medications are defined as any drug for which the patient has a prescription that would not have run out on or by the baseline date. Neither database captures nonprescription nonsteroidal anti inflammatory agents such as aspirin. Hypertension, diabetes, coronary heart disease, alcohol abuse and dependence, and liver disease are determined based upon the presence of ICD-9 diagnostic codes.

FINDINGS

• Sample included 16,573 veterans and 33,037 California Medicaid recipients for a total of 49,610 individuals with HIV infection

• Veterans were older (>40 years of age); more likely to be male (98% vs. 74%), and less likely to have developed AIDS (36% vs. 74%) compared to Medi-Cal recipients (Table 1, p<0.001).

• Within 12 months before baseline and 6 months after baseline, there were 25 ICH prevalent cases 0.2% (95% CI 0.1-0.2%) within the VA and 173 ICH prevalent cases 0.5% (95% CI 0.4-0.6%) within Medi-Cal.

• The VA Virtual Cohort observed 27 incident cases 0.07 (95% CI: 0.05-0.10) per 100 PY and Medi-Cal observed 274 incident cases 0.23 (0.5 CI: 0.20-0.25) per 100 PY.

• Overall and in every stratified analyses, the prevalence and incidence of ICH was lower among veterans than among those receiving Medi-Cal coverage (Table 2 and 3, p<0.001).

• Stratified analyses showed similar associations in both cohorts.

• Prevalence and incidence of ICH were higher among those

•Over 40 years of age

•With hypertension, diabetes, or coronary artery disease

•With alcohol abuse

•With an AIDS defining illness

• Prevalence and incidence of ICH did not differ by active receipt of protease inhibitors or HAART.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

BI Data

VA Overall

VA Men Only

VA AIDS

VA >40 yrs

Medi -CalOverall

Medi-Cal MenOnly

Medi-Cal AIDS

Medi-Cal >40yrs

ICH Events/100 PY

Figure 1. Boehringer Ingelheim (BI), VA, and Medi-Cal ICH Incidence Rates