Angelique Zeringue

Rate of Kidney Function Decline Associates with Mortality

The effect of rate of decline of kidney function on risk for death is not well understood. Using the Department of Veterans Affairs national databases, we retrospectively studied a cohort of 4171 patients who had rheumatoid arthritis and early stage 3 chronic kidney disease (CKD; estimated GFR 45 to 60 ml/min) and followed them longitudinally to characterize predictors of disease progression and the effect of rate of kidney function decline on mortality. After a median of 2.6 years, 1604 (38%) maintained stable kidney function; 426 (10%), 1147 (28%), and 994 (24%) experienced mild, moderate, and severe progression of CKD, respectively (defined as estimated GFR decline of 0 to 1, 1 to 4, and >4 ml/min per yr). Peripheral artery disease predicted moderate progression of CKD progression. Black race, hypertension, diabetes, cardiovascular disease, and peripheral artery disease predicted severe progression of CKD. After a median of 5.7 years, patients with severe progression had a significantly increased risk for mortality (hazard ratio 1.54; 95% confidence interval 1.30 to 1.82) compared with those with mild progression; patients with moderate progression exhibited a similar trend (hazard ratio 1.10; 95% confidence interval 0.98 to 1.30). Our results demonstrate an independent and graded association between the rate of kidney function decline and mortality. Incorporating the rate of decline into the definition of CKD may transform a static definition into a dynamic one that more accurately describes the potential consequences of the disease for an individual.

Anxiety disorders increase risk for incident myocardial infarction in depressed and nondepressed Veterans Administration patients.

BACKGROUND Depression is a risk factor for incident myocardial infarction (MI), but little is known about the independent or additive risk from anxiety disorders. METHODS In a 7-year retrospective cohort design, we identified a cohort free of cardiovascular disease in fiscal years 1999 and 2000 that contained 96,612 patients between 25 and 80 years of age who had an International Classification of Diseases, Ninth Revision, Clinical Modification code indicating a diagnosis of depression in 2000 (baseline) and 259,387 patients without depression. Cox proportional hazards models stratified by depression were computed to test for a main effect of anxiety disorder unspecified, generalized anxiety disorder, panic disorder, social phobia, obsessive-compulsive disorder, and posttraumatic stress disorder (PTSD) on risk of incident MI. The models were adjusted for multiple MI risk factors and sociodemographics. RESULTS Depressed as compared to nondepressed Veterans Administration patients were at increased risk for incident MI (HR 1.39; 95% CI 1.34-1.45). In nondepressed patients those with anxiety disorder unspecified (HR 1.34; 95% CI 1.21-1.47), panic disorder (HR 1.43; 95% CI 1.11-1.83), and PTSD (HR 1.25; 95% CI 1.16-1.36) were at increased risk for incident MI. The independent risk associated with anxiety disorders was reduced in patients comorbid for depression. CONCLUSIONS In Veterans Administration patients free of heart disease in 1999 and 2000, those with depression, anxiety disorder unspecified, panic disorder, and PTSD were at increased risk of incident MI. Anxiety disorders are independent risk factors for MI. Depression partially accounts for the effect of anxiety disorders on risk of MI in patients with both conditions.

TNF-α Antagonist Use and Risk of Hospitalization for Infection in a National Cohort of Veterans With Rheumatoid Arthritis

Medications used to treat rheumatoid arthritis (RA) may confer an increased risk of infection. We conducted a retrospective cohort study of veterans with RA followed in the United States Department of Veterans Affairs health care system from October 1998 through September 2005. Risk of hospitalization for infection associated with tumor necrosis factor (TNF)-&agr; antagonists therapy was measured using an extension of Cox proportional hazards regression, adjusting for demographic characteristics, comorbid illnesses, and other medications used to treat RA.A total of 20,814 patients met inclusion criteria, including 3796 patients who received infliximab, etanercept, or adalimumab. Among the study cohort, 1465 patients (7.0%) were hospitalized at least once for infection. There were 1889 hospitalizations for infection. The most common hospitalized infections were pneumonia, bronchitis, and cellulitis. Age and several comorbid medical conditions were associated with hospitalization for infection. Prednisone (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.88-2.43) and TNF-&agr; antagonist use (HR, 1.24; 95% CI, 1.02-1.50) were associated with hospitalization for infection, while the use of disease-modifying antirheumatic drugs (DMARDs) other than TNF-&agr; antagonists was not. Compared to etanercept, infliximab was associated with risk for hospitalization for infection (HR, 1.51; 95% CI, 1.14-2.00), while adalimumab use was not (HR, 0.95; 95% CI, 0.68-1.33). In all treatment groups, rate of hospitalization for infection was highest in the first 8 months of therapy.We conclude that patients with RA who are treated with TNF-&agr; antagonists are at higher risk for hospitalization for infection than those treated with other DMARDs. Prednisone use is also a risk factor for hospitalization for infection.Abbreviations: CI = confidence interval, DMARD = disease-modifying antirheumatic drug, HFI = hospitalization for infection, HR = hazard ratio, ICD-9-CM = International Classification of Diseases, Version 9, Clinical Modification, NHDS = National Hospital Discharge Survey, RA = rheumatoid arthritis, TNF-&agr; = tumor necrosis factor-&agr;, VA = Veterans Affairs.

Depression increases risk of incident myocardial infarction among Veterans Administration patients with rheumatoid arthritis

OBJECTIVE This study evaluates whether depression is a risk factor for incident myocardial infarction (MI) in Department of Veterans Affairs (VA) patients with rheumatoid arthritis (RA) between 30 and 79 years of age. METHODS We used a retrospective cohort study of 15,634 patients with RA. Diagnoses and sociodemographic data were obtained from VA administrative and pharmacy databases between fiscal years 1999 and 2006. Entry into the cohort required 2 years of patient time with no evidence of cardiovascular disease. Cox proportional hazard models with time-dependent covariates were computed to determine whether RA patients with depression as compared to RA patients without depression were at increased risk for MI during the maximum 6-year follow-up period. RESULTS Unadjusted analyses indicated depressed RA patients were 1.4 times more likely than nondepressed RA patients to have an MI during follow-up. These results remained significant (HR=1.4; 95% CI: 1.1-1.8) in the adjusted Cox proportional hazards model which included the effects of sociodemographics and known physical risks (e.g., diabetes) for MI. CONCLUSIONS Depressed RA patients, without a history of cardiovascular disease, are 40% more likely to have a heart attack as compared to those without depression. These data demonstrate a rapid (within 6 years) transition to MI following onset of depression in RA patients. Increased monitoring of depression and heart disease status in this patient population may be warranted which in turn may result in longer duration of life.

Increased Body Mass Index Is Associated With Improved Survival in United States Veterans With Diffuse Large B-Cell Lymphoma

PURPOSE Obesity increases the risk of death from many malignancies, including non-Hodgkins lymphoma (NHL). In diffuse large B-cell lymphoma (DLBCL), the most common form of NHL, the association between body mass index (BMI) at diagnosis and survival is unclear. PATIENTS AND METHODS We evaluated the association between BMI at diagnosis and overall survival in a retrospective cohort of 2,534 United States veterans diagnosed with DLBCL between October 1, 1998 and December 31, 2008. Cox modeling was used to control for patient- and disease-related prognostic variables. RESULTS Mean age at diagnosis was 68 years (range, 20 to 100 years); 64% of patients were overweight (BMI, 25 to < 30) or obese (BMI, ≥ 30). Obese patients were significantly younger, had significantly fewer B symptoms, and trended toward lower-stage disease, compared with other BMI groups. Cox analysis showed reduced mortality in overweight and obese patients (overweight: hazard ratio [HR], 0.73; 95% CI, 0.65 to 0.83; obese: HR, 0.68; 95% CI, 0.58 to 0.80), compared with normal-weight patients (BMI, 18.5 to < 25). Treatment during the rituximab era reduced the risk of death without affecting the association between BMI and survival. Disease-related weight loss occurred in 29% of patients with weight data 1 year before diagnosis. Cox analysis based on BMI 1 year before diagnosis continued to demonstrate reduced risk of death in overweight and obese patients. CONCLUSION Being overweight or obese at the time of DLBCL diagnosis is associated with improved overall survival. Understanding the mechanisms responsible for this association will require further study.

Tumor necrosis factor-α blockade, cardiovascular outcomes, and survival in rheumatoid arthritis

The effect of TNF-α blockade on the risk of cardiovascular outcomes and long-term survival in patients with rheumatoid arthritis (RA) is not known. We assembled a cohort of 20,811 (75,329 person-years) U.S. veterans who were diagnosed with RA between October 1998 and September 2005, and who were treated with a disease-modifying anti-rheumatic drug (DMARD). Cox survival models were built to examine the effect of TNF-α antagonists on the risk of a composite endpoint of cardiovascular outcomes defined as the occurrence of atherosclerotic heart disease, congestive heart failure, peripheral artery disease, or cerebrovascular disease, and on the risk of death. Treatment with TNF-α antagonists was not associated with a significant effect on the composite endpoint of cardiovascular outcomes. When each outcome was examined separately, the use TNF-α antagonists was not associated with an increased risk of atherosclerotic heart disease, congestive heart failure, or peripheral artery disease, but it was associated with decreased risk of cerebrovascular disease (hazard ratio [HR] = 0.83; confidence interval [CI] = 0.70-0.98). The use of TNF-α antagonists did not affect the risk of death (HR = 0.99; CI = 0.87-1.14). In subgroup analyses, the use TNF-α antagonists was associated with a reduced risk of cardiovascular outcomes (HR = 0.90, CI = 0.83-0.98) in patients younger than the median age of our cohort (63 years). The use TNF-α antagonists was not associated with a change in the risk of death in any other subgroup. These results show that the risk of cardiovascular events and survival in patients who receive TNF-α antagonists is not different than those who receive other DMARDs.

Mental health disorders and the risk of AIDS-defining illness and death in HIV-infected veterans.

Objective:Mental health comorbidities are common in HIV-infected veterans and can impact clinical outcomes for HIV. We examined the impact of mental health diagnoses on progression to AIDS-defining illness (ADI) and death in a large cohort of HIV-infected veterans who accessed care between 2001 and 2006. Design:Retrospective cohort study using the national Veterans Health Administration (VHA) HIV Clinical Case Registry. Methods:We identified HIV-infected veterans initiating combination antiretroviral therapy (cART) within the VHA between 2000 and 2006. The prevalences of the following mental health diagnoses were examined: schizophrenia, bipolar disorder, depression, anxiety, and substance use disorder. Cox proportional hazards models were constructed to examine the relationship between mental health conditions and two outcomes, all-cause mortality and ADI. Models were computed before and after adjusting for confounding factors including age, race, baseline CD4 cell count, comorbidities and cART adherence. Results:Among 9003 veterans receiving cART, 31% had no mental health diagnosis. Age, race, baseline comorbidity score, CD4, and cART adherence were associated with shorter time to ADI or death. All-cause mortality was more likely among veterans with schizophrenia, bipolar disorder and substance use, and ADI was more likely to occur among veterans with substance use disorder. Conclusions:Our results demonstrate the high prevalence of mental health diagnoses among HIV-infected veterans. In the era of highly active antiretroviral therapy, presence of psychiatric diagnoses impacted survival and development of ADI. More aggressive measures addressing substance abuse and severe mental illness in HIV-infected veterans are necessary.

An observational study of musculoskeletal pain among patients receiving bisphosphonate therapy.

OBJECTIVE To seek evidence for the association of bisphosphonate use with diffuse musculoskeletal pain (MSKP) in a large national cohort, controlling for conditions associated with MSKP. PATIENTS AND METHODS This retrospective cohort study enrolled all US veterans aged 65 years or older with a vertebral or hip fracture who were treated for at least 1 year between October 1, 1998, and September 30, 2006 (N=26,545). All International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes, demographics, and pharmaceutical data were obtained from national databases. A composite end point, based on ICD-9-CM codes compatible with diffuse MSKP, was constructed. The primary outcome was time until MSKP. We performed regression analysis using the Cox proportional hazards model, controlling for age, sex, race, alcoholism, depression, anxiety, smoking, recent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) use, rheumatic disease, and comorbidity score. RESULTS The univariate regression identified an association of bisphosphonate exposure and MSKP (hazard ratio, 1.22; 95% confidence interval, 1.04-1.44). In the multivariate regression, however, patients prescribed a bisphosphonate were not more likely to be assigned an ICD-9-CM code compatible with diffuse MSKP (hazard ratio, 1.10; 95% confidence interval, 0.93-1.30). Consistent with prior studies, we found that female sex, depression, anxiety, comorbidity score, and the presence of a rheumatic disease were all associated with a greater risk of a diagnosis of diffuse MSKP. There was no demonstrable association with statin exposure. CONCLUSION Bisphosphonate use was not associated with a statistically higher rate of MSKP in this cohort. Individual patients may rarely report MSKP while taking bisphosphonates; however, for our studied cohort, incident MSKP does not appear to explain bisphosphonate discontinuation rates.

Serious Bleeding Events due to Warfarin and Antibiotic Co-prescription in a Cohort of Veterans

BACKGROUND Antibiotics may interact with warfarin, increasing the risk for significant bleeding events. METHODS This is a retrospective cohort study of veterans who were prescribed warfarin for 30 days without interruption through the US Department of Veterans Affairs between October 1, 2002 and September 1, 2008. Antibiotics considered to be high risk for interaction with warfarin include: trimethoprim/sulfamethoxazole (TMP/SMX), ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin. Low-risk antibiotics include clindamycin and cephalexin. Risk of bleeding event within 30 days of antibiotic exposure was measured using Cox proportional hazards regression, adjusted for demographic characteristics, comorbid conditions, and receipt of other medications interacting with warfarin. RESULTS A total of 22,272 patients met inclusion criteria, with 14,078 and 8194 receiving high- and low-risk antibiotics, respectively. There were 93 and 36 bleeding events in the high- and low-risk groups, respectively. Receipt of a high-risk antibiotic (hazard ratio [HR] 1.48; 95% confidence interval [CI], 1.00-2.19) and azithromycin (HR 1.93; 95% CI, 1.13-3.30) were associated with increased risk of bleeding as a primary diagnosis. TMP/SMX (HR 2.09; 95% CI, 1.45-3.02), ciprofloxacin (HR 1.87; 95% CI, 1.42-2.50), levofloxacin (HR 1.77; 95% CI, 1.22-2.50), azithromycin (HR 1.64; 95% CI, 1.16-2.33), and clarithromycin (HR 2.40; 95% CI, 1.16-4.94) were associated with serious bleeding as a primary or secondary diagnosis. International normalized ratio (INR) alterations were common; 9.7% of patients prescribed fluconazole had INR value >6. Patients who had INR performed within 3-14 days of co-prescription were at a decreased risk of serious bleeding (HR 0.61; 95% CI, 0.42-0.88). CONCLUSIONS Warfarin users who are prescribed high-risk antibiotics are at higher risk for serious bleeding events. Early INR evaluation may mitigate this risk.

Using Job-Title-Based Physical Exposures From O*NET in an Epidemiological Study of Carpal Tunnel Syndrome

Objective: We studied associations between job-title-based measures of force and repetition and incident carpal tunnel syndrome (CTS). Background: Job exposure matrices (JEMs) are not commonly used in studies of work-related upper-extremity disorders. Method: We enrolled newly hired workers in a prospective cohort study. We assigned a Standard Occupational Classification (SOC) code to each job held and extracted physical work exposure variables from the Occupational Information Network (O*NET). CTS case definition required both characteristic symptoms and abnormal median nerve conduction. Results: Of 1,107 workers, 751 (67.8%) completed follow-up evaluations. A total of 31 respondents (4.4%) developed CTS during an average of 3.3 years of follow-up. Repetitive motion, static strength, and dynamic strength from the most recent job held were all significant predictors of CTS when included individually as physical exposures in models adjusting for age, gender, and BMI. Similar results were found using time-weighted exposure across all jobs held during the study. Repetitive motion, static strength, and dynamic strength were correlated, precluding meaningful analysis of their independent effects. Conclusion: This study found strong relationships between workplace physical exposures assessed via a JEM and CTS, after adjusting for age, gender, and BMI. Though job-title-based exposures are likely to result in significant exposure misclassification, they can be useful for large population studies where more precise exposure data are not available. Application: JEMs can be used as a measure of workplace physical exposures for some studies of musculoskeletal disorders.