Patients with human immunodeficiency virus (HIV) infection are at increased risk of cardiovascular disease, but studies on HIV as a risk factor for cardiac arrest in the general population are lacking. We aimed to examine the association of HIV infection with out-of-hospital cardiac arrests (OHCAs). We used the Office of Statewide Health Planning and Development data to evaluate HIV infection as a predictor of OHCA in all California emergency department encounters from 2005 to 2015, adjusting for age, gender, race, income, obesity, smoking, alcohol, substance abuse, hypertension (HTN), diabetes, coronary artery disease, congestive heart failure (CHF), atrial fibrillation, and chronic kidney disease (CKD). We also determined patient characteristics modifying these associations by including interaction terms in multivariable-adjusted models. In 18,542,761 patients (mean age 47 ± 20 years, 53% women, 43,849 with HIV) followed for a median 6.8 years, 133,983 new OHCA events occurred. Incidence rates in patients with HIV were higher than in patients without HIV (1.99 vs 1.16 OHCA events per 1,000-person-years follow-up). After multivariable adjustment, HIV was associated with a 2.5-fold higher risk of OHCA (hazard ratio 2.47, 95% confidence interval 2.29 to 2.66, p <0.001). The risk of OHCA with HIV was disproportionately stronger in younger patients, women, and in those with HTN, CHF, and CKD. In this large prospective study, HIV was associated with a 2.5-fold increased risk of OHCA, with a greater vulnerability to this outcome in patients with HIV who were female or had HTN, CHF, or CKD.
With effective antiretroviral therapy, the life expectancy of patients infected with human immunodeficiency virus (HIV) infection has increased. , However, patients living with HIV infection remain at increased risk of myocardial infarction, atrial fibrillation, heart failure, and cardiovascular mortality. , In patients with heart failure, risks of sudden cardiac death (SCD) and appropriate implantable cardioverter-defibrillator (ICD) therapy are significantly higher in those with HIV than uninfected controls. Furthermore, patients infected with HIV with heart failure are less likely to undergo guideline-directed therapies than uninfected patients. And finally, those with HIV may be more likely to experience drug overdose, an increasingly recognized factor in out-of-hospital cardiac arrest (OHCA). , Hence, there is a need to better understand the relation of HIV infection as an independent risk factor for SCD after accounting for concomitant cardiovascular diseases. Based on the data from a public HIV clinic in San Francisco, the risk of SCD in community-dwelling individuals living with HIV appears to be higher than otherwise expected. However, no previous study has investigated HIV as a risk factor for SCD in the general population where all participants originated from the same cohort, or study base, where longitudinal assessment for sudden death was employed, and where HIV could be assessed as a predictor. We hypothesized that the HIV infection is associated with an increase in the risk of OHCA and sought to study its association in the Office of Statewide Health Planning and Development (OSHPD) databases.
Methods
We used the OSHPD databases to identify all California state residents ≥21 years old who received medical care in a California emergency department, ambulatory surgery, or inpatient hospital unit between January 1, 2005, and June 30, 2015. . To capture repeated visits for a given patient across individual databases specific to the healthcare setting and calendar year, we then merged the individual databases using encrypted unique patient identifiers. To qualify for the present study, patients must have had ≥2 healthcare encounters in OHSPD databases. Patients entered the cohort at their first healthcare encounter and were censored upon incident diagnosis of OHCA, at the time of outpatient or inpatient death, or, in the absence of either, were administratively censored at the end of follow-up (June 30, 2015). Outpatient deaths were ascertained by linking each patient to the Social Security Death Index (available until December 31, 2013), whereas inpatient deaths were identified in the OSHPD inpatient database up until 2015. We excluded patients with missing visit date information or with residence outside of California ( Figure 1 ). We recorded the diagnosis of HIV infection as a time-updated predictor variable. Certification to use de-identified OSHPD data was obtained from the University of California, San Francisco Committee on Human Research. Patients and the public were not involved in the design or conduct of this study.
The following demographic variables were recorded: age, gender, race, ethnicity, and household income. In OSHPD, race and Hispanic ethnicity are reported separately, and race is coded as White or “other” for the vast majority of individuals with Hispanic ethnicity. We, therefore, considered Hispanic ethnicity as a separate mutually exclusive group for the race/ethnicity variable. In OSHPD, up to 25 International Classification of Diseases, Ninth Edition (ICD-9) codes, and 21 Current Procedural Terminology codes were provided for each encounter. The specific codes used for HIV infection, covariates, and each outcome variable (cardiac arrest, ventricular fibrillation, ventricular flutter) are described in Supplementary Table 1 . We recorded dichotomous medical co-morbidity variables (recorded using ICD-9 and Current Procedural Terminology codes) at each healthcare encounter and carried each forward over time.
We defined OHCA by the documentation of 1 of 3 ICD-9 codes documented in the emergency department encounter or an inpatient admission through the emergency room. These ICD-9 codes included 427.41 (ventricular fibrillation), 427.42 (ventricular flutter), 427.5 (cardiac arrest). , To eliminate in-hospital cardiac arrests, cases were excluded if these diagnoses were not coded to have been present on admission. Cases were also excluded if the disposition from the emergency department was unknown or unlikely to represent true cardiac arrests (including disposition was to home, a skilled nursing facility, leaving against medical advice, or after inpatient admission within 24 hours). Furthermore, cases were excluded if there was a diagnosis of sepsis on admission (ICD-9 995.91 to 2), as these cases were likely to represent cardiovascular collapse in the setting of severe systemic illness, and cases with a concomitant primary or secondary diagnosis of trauma were also excluded. ( Supplementary Table 1 ).
Normally distributed continuous variables are presented as means ± SD and were compared using t tests. Continuous variables that were not normally distributed are displayed as medians and interquartile ranges and were compared using the Wilcoxon rank sum test. Categorical variables were compared using the chi-square test. Adjusted person-time incidence rates by HIV for OHCA were estimated and compared using Poisson models with log follow-up time as an offset. We then used Cox proportional hazards models to assess the independent association of HIV infection and OHCA. The proportional hazards assumption was assessed using log-minus-log survival plots. We adjusted the models for potential confounders, identified a priori. These included age, gender, race, income level, obesity, cigarette smoking, alcohol abuse, substance abuse, hypertension, diabetes, coronary artery disease, congestive heart failure, chronic kidney disease, and atrial fibrillation. To identify effect modification of the relation between HIV infection and OHCA, we tested for interactions with these same demographic variables and established OHCA risk factors. Analyses were performed using Stata Statistical Software: Release 14. (StataCorp. 2015. StataCorp LP, College Station, Texas) and SAS 9.4 (SAS Institute Inc., Cary, North Carolina). A 2-tailed p <0.05 was considered statistically significant.
Results
Of the 20,587,307 patients receiving care in California ambulatory surgery centers, emergency departments, and inpatient wards during the study period, 18,542,761 patients were included in our analyses after applying the exclusion criteria ( Figure 1 ). A total of 43,849 patients exhibited an HIV diagnosis. Baseline characteristics of those with and without HIV are shown in Table 1 .
| Variable | HIV infection (N=43,849) | No HIV infection (N=18,498,912) | P value |
|---|---|---|---|
| Mean (95%CI) or count (%) | Mean (95%CI) or count (%) | ||
| Age (at index visit), yrs | 45±12 | 47±20 | <0.0001 |
| Male | 36,949 (84%) | 8,697,988 (47%) | <0.0001 |
| White | 21,866 (50%) | 9,625,243 (52%) | <0.0001 |
| Black | 10,274 (24%) | 1,562,865 (8%) | <0.0001 |
| Hispanic | 9,273 (21%) | 4,912,917 (27%) | <0.0001 |
| Asian/Pacific Islander | 1,246 (3%) | 1,584,756 (9%) | <0.0001 |
| Native American | 141 (0.3%) | 62,979 (0.3%) | <0.0001 |
| Other Race | 1,049 (2%) | 750,152 (4%) | <0.0001 |
| Median household income, $ | 56,967±25,249 | 63,918±24,921 | <0.0001 |
| Obesity | 479 (1%) | 479,178 (3%) | <0.0001 |
| Cigarette smoker | 4,898 (11%) | 1,027,503 (6%) | <0.0001 |
| Alcohol abuser | 793 (2%) | 165,811 (1%) | <0.0001 |
| Substance abuser | 2,945 (7%) | 203,309 (1%) | <0.0001 |
| Hypertension | 6,471 (15%) | 3,634,083 (20%) | <0.0001 |
| Diabetes mellitus | 4,104 (9%) | 1,861,552 (10%) | <0.0001 |
| Coronary artery disease | 1,425 (3%) | 789,697 (4%) | <0.0001 |
| Congestive heart failure | 1,071 (2%) | 505,151 (3%) | <0.0001 |
| Atrial fibrillation | 468 (1%) | 516,258 (3%) | <0.0001 |
| Chronic kidney disease | 1,442 (3%) | 421,277 (2%) | <0.0001 |
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