Epidemiology of Diabetic Kidney Disease among US Veterans.

Rationale: With a large number of patients and high mortality, diabetic kidney disease (DKD) imposes a significant burden on US health care. Although diabetes is the leading cause of chronic kidney disease and complications, the epidemiology of DKD in the contemporary US veteran population is generally unknown. Objective: We aimed to estimate the rate of DKD progression and to measure the general epidemiology of DKD in the United States veteran population. Study Design: We performed a retrospective observational research using electronic health-care records and administrative databases. Setting: The DKD patient cohort was abstracted from the Veterans Health Administration health-record data from January 2016 to March 2022. Participants: We defined DKD patients using the laboratory test data based on Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines. Analytic Approach: Summary statistics include the five-year cumulative incidence of progression to an advanced stage from the DKD stage at the cohort entry date and prevalence at a series of single time points. Results: A total of 685,288 patients (male [96%], mean age 62 years, Caucasian [64%], non-Hispanic [87%]) met our eligibility criteria. The 5-year cumulative incidence of progression to an advanced DKD stage or all-cause death from DKD stages G1 A2/A3, G2 A2/A3, G3a, and G3b were 52.0%, 47.4%, 50.5%, and 60.9%, respectively. In sum, 594,082 patients were classified as moderate or high risk as per KDIGO guidelines in 2021, and stages G3a and G3b accounted for 51.2% and 25.3%, respectively, of cases. Conclusion: More than half of DKD patients underwent a stage progression or death within 5 years. A substantial number of DKD patients at an earlier stage might be left undetermined. The study findings warrant a revision of DKD patient identification and management in US veterans.

Precision of Medication Therapy Problem Identification and Classification amongst Primary Care Clinic Pharmacists.

This study assesses the level of agreement on medication therapy problem (MTP) identification and classification between primary care, ambulatory care pharmacists within a health-system that recently implemented system-wide pharmacist provision of comprehensive medication management (CMM) services. Twenty standardized case vignettes were created and distributed to pharmacists who reviewed each case and identified and categorized MTPs. Outcomes include the number of MTPs identified, identification (yes/no) of specific MTPs within each case (e.g., need for a statin), and Pharmacy Quality Alliance (PQA) category used when classifying MTPs. The level of agreement on MTP identification/categorization was measured using intraclass correlation coefficient (ICC) and interpreted using the Landis and Koch interpretation scale. "Moderate agreement" was observed for the number of MTPs identified by pharmacists (ICC equal to 0.45; 95% confidence interval [CI]: 0.31 to 0.65). In approximately one-half of opportunities, the pharmacists agreed perfectly on the number of MTPs; in approximately one-third of opportunities, the number of MTPs identified varied by 1; and approximately one-tenth of the time, the number of MTPs varied by 2. In regard to the MTP identification (yes/no) and categorization, percent agreement was ≥73% across all MTPs. The results support the need for further training and education and provide the information necessary to target specific disease states.

Quality of systematic reviews in HIV: The case of clinical outcomes associated with patient medication adherence.

AIM: Use of systematic reviews (SRs) as first-level evidence for guideline recommendations hinges on review quality. In particular, US guidelines for adherence-related recommendations in the treatment of human immunodeficiency virus (HIV) are not based on available SRs of adherence-outcome relationships; it is unclear why. No published studies report on the quality of SRs on HIV adherence and outcomes, which may be driving the lack of use. We describe the quality of this body of literature. METHODS: Literature searches were conducted in Ovid MEDLINE, EMBASE, CINAHL, PubMed Central, the Cochrane Library, Science Citation Index, Web of Science, ScIELO Citation Index, and Ovid Emcare. Screening and quality assessments were performed in duplicate using AMSTAR 2. Funding sources and impact factors of publishing journals were also extracted, and correlations between quality rankings and numbers of critical weaknesses versus impact factors were assessed using Spearman's rank correlation coefficient. RESULTS: Nine SRs of 1141 records met eligibility criteria. Overall confidence in the results was critically low for most (78%) SRs. Underperformance was found across all AMSTAR 2 domains. Impact factor (a surrogate or journal reputation) did not correlate with quality. CONCLUSIONS: SRs do not necessarily comprise top-level evidence despite the availability of quality appraisal tools and reporting guidance, which could explain the lack of SR evidence in US HIV medication adherence-related guideline recommendations. All parties to evidence synthesis publication should require quality assessment of studies.

Characteristics and Healthcare Utilization Among Veterans Treated for Heart Failure With Reduced Ejection Fraction Who Switched to Sacubitril/Valsartan.

BACKGROUND: US guidelines recommend that patients with heart failure with reduced ejection fraction (HFrEF), who tolerate an ACEI (angiotensin-converting enzyme inhibitor) or ARB (angiotensin II receptor blocker), be switched to sacubitril/valsartan to reduce morbidity and mortality. We compared characteristics and healthcare utilization between Veterans with HFrEF who were switched to sacubitril/valsartan versus maintained on an ACEI or ARB. METHODS: retrospective cohort study of treated HFrEF (July 2015-June 2017) using Veterans Affairs data. The index date was the first fill for sacubitril/valsartan and if none, for an ACEI or ARB. Treated HFrEF was defined by (1) left ventricular ejection fraction ≤40%, (2) ≥1 in/outpatient HF encounter, and (3) ≥1 ACEI or ARB fill, all within 1-year preindex. Poisson regression models were used to compare baseline characteristics and 1:1 propensity score-matched adjusted 4-month follow-up healthcare utilization between sacubitril/valsartan switchers and ACEI or ARB maintainers. RESULTS: Switchers (1612; 4.2%) were less likely than maintainers (37 065; 95.8%) to have a history of myocardial infarction or hypertension, and more likely to be black, have a lower left ventricular ejection fraction, and higher preindex healthcare utilization. Switchers were less likely to experience follow-up all-cause hospitalizations (11.2% versus 14.0%; risk ratio 0.80 [95% CI, 0.65-0.98], P value 0.035). CONCLUSIONS: Few Veterans with treated HFrEF were switched to sacubitril/valsartan within the first 2 years of Food and Drug Administration approval. Sacubitril/valsartan use was associated with a lower risk for all-cause hospitalizations at 4 months follow-up. Reasons for lack of guideline-recommended sacubitril/valsartan initiation warrant investigation and may reveal opportunities for HFrEF care optimization.

Angina Severity, Mortality, and Healthcare Utilization Among Veterans With Stable Angina.

Background Canadian Cardiovascular Society (CCS) angina severity classification is associated with mortality, myocardial infarction, and coronary revascularization in clinical trial and registry data. The objective of this study was to determine associations between CCS class and all-cause mortality and healthcare utilization, using natural language processing to extract CCS classifications from clinical notes. Methods and Results In this retrospective cohort study of veterans in the United States with stable angina from January 1, 2006, to December 31, 2013, natural language processing extracted CCS classifications. Veterans with a prior diagnosis of coronary artery disease were excluded. Outcomes included all-cause mortality (primary), all-cause and cardiovascular-specific hospitalizations, coronary revascularization, and 1-year healthcare costs. Of 299 577 veterans identified, 14 216 (4.7%) had ≥1 CCS classification extracted by natural language processing. The mean age was 66.6±9.8 years, 99% of participants were male, and 81% were white. During a median follow-up of 3.4 years, all-cause mortality rates were 4.58, 4.60, 6.22, and 6.83 per 100 person-years for CCS classes I, II, III, and IV, respectively. Multivariable adjusted hazard ratios for all-cause mortality comparing CCS II, III, and IV with those in class I were 1.05 (95% CI, 0.95-1.15), 1.33 (95% CI, 1.20-1.47), and 1.48 (95% CI, 1.25-1.76), respectively. The multivariable hazard ratio comparing CCS IV with CCS I was 1.20 (95% CI, 1.09-1.33) for all-cause hospitalization, 1.25 (95% CI, 0.96-1.64) for acute coronary syndrome hospitalizations, 1.00 (95% CI, 0.80-1.26) for heart failure hospitalizations, 1.05 (95% CI, 0.88-1.25) for atrial fibrillation hospitalizations, 1.92 (95% CI, 1.40-2.64) for percutaneous coronary intervention, and 2.51 (95% CI, 1.99-3.16) for coronary artery bypass grafting surgery. Conclusions Natural language processing-extracted CCS classification was positively associated with all-cause mortality and healthcare utilization, demonstrating the prognostic importance of anginal symptom assessment and documentation.

Glycemic Control and Insulin Treatment Alter Fracture Risk in Older Men With Type 2 Diabetes Mellitus.

Diabetes mellitus among older men has been associated with increased bone mineral density but paradoxically increased fracture risk. Given the interactions among medication treatment, glycemic control, and diabetes-associated comorbidities, the relative effects of each factor remains unclear. This retrospective study includes 652,901 male veterans aged ≥65 years with diabetes and baseline hemoglobin A1c (HbA1c) value. All subjects received primary care in the Veterans Health Administration (VHA) from 2000 to 2010. Administrative data included ICD9 diagnoses and pharmacy records and was linked to Medicare fee-for-service data. Hazard ratios (HR) for any clinical fracture and hip fracture were calculated using competing risk hazards models, adjusted for fracture risk factors including age, race/ethnicity, body mass index (BMI), alcohol and tobacco use, rheumatoid arthritis, corticosteroid use, as well as diabetes-related comorbidities including cardiovascular disease, chronic kidney disease, and peripheral neuropathy. HbA1c <6.5% was associated with a higher risk of any clinical fracture (HR = 1.08, 95% confidence interval [CI] 1.06-1.11) compared with the reference HbA1c of 7.5% to 8.5%. Fracture risk was not increased among those with A1c ≥8.5%, nor among those with A1c 6.5% to 7.5%. Use of insulin was independently associated with greater risk of fracture (HR = 1.10, 95% CI 1.07-1.12). There was a significant interaction between insulin use and HbA1c level, (p < 0.001), such that those using insulin with HbA1c <6.5% had HR = 1.23 and those with HbA1c 6.5% to 7.5% had HR = 1.15. Metformin use was associated with decreased fracture risk (HR = 0.88, 95% CI 0.87-0.90). We conclude that among older men with diabetes, those with HbA1c lower than 6.5% are at increased risk for any clinical and hip fracture. Insulin use is associated with higher fracture risk, especially among those with tight glycemic control. Our findings demonstrate the importance of the treatment regimen and avoiding hypoglycemia for fracture prevention in older men with diabetes. © 2019 American Society for Bone and Mineral Research.

The impact of a musculoskeletal training program on residents' recognition and treatment of osteoporosis.

BACKGROUND: Osteoporosis is inadequately treated in primary care settings. Under-recognition of the condition among male Veterans may contribute to this problem. In order to improve understanding of bone health in older male patients, we developed the "Musculoskeletal (MSK) Education Week", a multidisciplinary clinical training initiative within a primary care ambulatory rotation for internal medicine (IM) residents at the Salt Lake City VA Medical Center. The objective of this study was to evaluate the impact of this program on trainees' recognition of osteoporosis or treatment of this condition following the training experience. METHODS: We examined several clinical behaviors of post-graduate year 1 (PGY-1) IM trainees following their participation in the MSK Education Week between July 1-April 30, 2014. To determine the prevalence of these clinical behaviors, we conducted an observational study of patients age 50 and older enrolled at the Salt Lake City VA Healthcare System from July 1, 2013 to May 31, 2014. We used time-dependent multivariable Cox proportional hazard models to evaluate the impact of the training program on 4 osteoporosis-related outcomes: (1) completion of dual energy X-ray absorptiometry (DXA) scan, (2) diagnosis of osteopenia, (3) diagnosis of osteoporosis, and (4) initiation of osteoporosis medications. RESULTS: Twenty-six PGY-1 IM residents participated in the MSK Education Week, and 43,678 Veterans were identified over these periods of observation. In the Veterans cohort, 1154 had an encounter with a provider who had completed the training (and were therefore "exposed" to the training) and 42,524 Veterans did not. After adjusting for confounders, the effect of the provider training program was significant for DXA (HR = 1.78, 95% CI: 1.11, 2.87), osteoporosis diagnosis (HR = 3.90, 95% CI: 2.09, 7.29), and initiation of medications (HR = 2.87, 95% CI: 2.02, 4.09) outcomes. CONCLUSIONS: We have shown that IM residents' participation in the MSK Education Week was associated with significantly improvements in their completion of DXA scans, diagnosis of osteoporosis, and initiation of fracture-reducing medications in a population of US Veterans. Long-term follow up is needed to determine whether these initial results are followed by actual reductions in osteoporotic fractures.

Limited Osteoporosis Screening Effectiveness Due to Low Treatment Rates in a National Sample of Older Men.

OBJECTIVE: To determine the association between dual-energy x-ray absorptiometry (DXA) testing for osteoporosis and subsequent fractures in US male veterans without a previous fracture. PATIENTS AND METHODS: This is a propensity score-matched observational study using Centers for Medicare and Medicaid Services and Veterans Affairs (VA) data from January 1, 2000, through December 31, 2010, with a mean follow-up time of 4.7 years (range, 0-10 years). Men receiving VA primary care aged 65 to 99 years without a previous fracture (N=2,539,812) were included. Men undergoing DXA testing were propensity score matched with untested controls in a 1:3 ratio, indicating the probability of DXA testing within the next year. Time to first clinical fracture was the primary outcome. Comorbidities, demographic characteristics, medications, DXA results, and osteoporosis treatment were defined using administrative data and natural language processing. A landmark analysis contingent on surviving to 12 months after screening was completed, accounting for competing risk of mortality. RESULTS: During follow-up of 153,311 men tested by DXA and 390,158 controls, 56,083 (10.3%) had sustained a fracture and 111,774 (20.6%) died. Overall, DXA testing was not associated with a decrease in fractures; conclusions are limited by unmeasured confounders and low medication initiation and adherence in those meeting treatment thresholds (12% of follow-up time). In contrast, DXA testing in prespecified subgroups was associated with a lower risk of fracture in comparison to the overall population who underwent DXA testing: androgen deprivation therapy (hazard ratio [HR], 0.77; 95% CI, 0.66-0.89), glucocorticoids (HR, 0.77; 95% CI, 0.72-0.84), age 80 years and older (HR, 0.85; 0.81-0.90), 1 or more VA guideline risk factors (HR, 0.91; 95% CI, 0.87-0.95), and high Fracture Risk Assessment Tool using body mass index score (HR, 0.90; 95% CI, 0.86-0.95). CONCLUSION: Current VA DXA testing practices are ineffective overall; interventions to improve treatment adherence are needed. Targeted DXA testing in higher-risk men was associated with a lower fracture risk.

Clinical and Economic Outcomes of Ranolazine Versus Conventional Antianginals Users Among Veterans With Chronic Stable Angina Pectoris.

Real-world outcomes in patients with chronic stable angina treated with ranolazine and other antianginal medications as second- or third-line therapy are limited. In a historical cohort study of veterans with chronic stable angina, we compared time with coronary revascularization procedures, hospitalizations, and 1-year healthcare costs between new-users of ranolazine versus conventional antianginals (i.e., calcium channel blockers, ß blockers, or long-acting nitrates) as second- or third-line. Weighted regression models calculated adjusted hazard ratios (HR) at up to 8-year follow-up, and adjusted incremental costs in the first year. Weighted groups comprised 4,699 ranolazine users and 31,815 conventional antianginal users. Percutaneous coronary intervention (PCI) occurred more often in ranolazine users compared with conventional antianginal users (HR 1.16; 95% confidence intervals [CI] 1.08 to 1.25, p <0.001), and coronary artery bypass grafting occurred less often (HR 0.82; 95% CI 0.68 to 1.00, p <0.046). All-cause and atrial fibrillation (AF) hospitalizations were less common with ranolazine users compared with conventional users (all-cause: HR 0.94; 95% CI 0.90 to 0.99, p <0.010; AF:HR 0.74; 95% CI 0.67 to 0.82, p <0.001), and acute coronary syndrome was more common (HR 1.13; 95% CI 1.00 to 1.27, p <0.042). Adjusted 1-year costs were $24,517 in ranolazine users and $24,798 in conventional users (difference, $-280; 95% CI $-1,742 to $1,181, p = 0.71). In conclusion, ranolazine users had lower rates of coronary artery bypass grafting and all-cause and AF hospitalizations, but higher rates of percutaneous coronary intervention and hospitalizations due to acute coronary syndrome compared with conventional antianginal users. Healthcare costs were similar between ranolazine and conventional antianginal users.

Benzodiazepines, Health Care Utilization, and Suicidal Behavior in Veterans With Posttraumatic Stress Disorder.

OBJECTIVE: To evaluate the relationships between benzodiazepine use and (1) health care utilization and (2) suicide risk in veterans diagnosed with posttraumatic stress disorder (PTSD). METHODS: This propensity-matched retrospective cohort study included veterans diagnosed with 1 ICD-9 code for PTSD who were active users of the Veterans Affairs health care system between January 1, 2001, and December 31, 2014. Exposure included at least 1 thirty-day prescription of a benzodiazepine within 1 year following PTSD diagnosis among patients with no recent history of benzodiazepine use. The primary outcomes were health care utilization and suicidal behavior. RESULTS: A total of 242,493 of 1,134,201 eligible veterans were included in the propensity-matched cohort, 80,831 (7.13%) of whom were prescribed benzodiazepines. Veterans with PTSD who received benzodiazepines had significantly more hospitalizations (incident rate ratio [IRR] = 1.27; 95% CI, 1.10-1.47) and emergency department (IRR = 1.16; 95% CI, 1.13-1.20), general outpatient (IRR = 1.19; 95% CI, 1.16-1.21), outpatient mental health (IRR = 1.49; 95% CI, 1.41-1.57), and total mental health (IRR = 1.37; 95% CI, 1.34-1.40) visits. Benzodiazepine users had a significantly greater risk of death due to suicide (hazard ratio [HR] = 2.74; 95% CI, 2.40-3.13) and were significantly more likely to have medically documented suicide attempts (HR = 1.85; 95% CI, 1.65-2.08) and suicidal ideation (HR = 1.57; 95% CI, 1.48-1.67). CONCLUSIONS: Benzodiazepine users had higher rates of health care utilization and were more likely to attempt and complete suicide than patients without benzodiazepine exposure. This study strengthens the empirical evidence against the use of benzodiazepines in veterans with PTSD. Prescribers should weigh the benefits and risks-especially the almost 3-fold increase in suicide risk-when prescribing benzodiazepines in these patients.

Health Care Costs in a Cohort of HIV-Infected U.S. Veterans Receiving Regimens Containing Tenofovir Disoproxil Fumarate/Emtricitabine.

BACKGROUND: Tenofovir disoproxil fumarate (TDF), a key component in many human immunodeficiency virus (HIV) treatment regimens, is associated with increased renal and bone toxicities. The contributions of such toxicities to treatment costs, as well as the relative differences in treatment costs for various TDF/emtricitabine (FTC) regimens, remains unexplored. OBJECTIVE: To estimate and compare mean overall and renal- and bone-specific costs, including total, inpatient, outpatient, and pharmacy costs in patients treated with TDF/FTC+efavirenz (EFV) compared with several non-EFV-containing TDF/FTC regimens. METHODS: We conducted a national cohort study of treatment-naive HIV-infected U.S. veterans who initiated treatment from 2003 to 2015 with TDF/FTC in combination with EFV, elvitegravir/cobicistat, rilpivirine, or ritonavir-boosted protease inhibitors (atazanavir, darunavir, or lopinavir). Outcomes of interest were quarterly total, inpatient, outpatient, and pharmacy costs using data from the Veterans Health Administration (VHA) electronic medical record and Managerial Cost Accounting System (an activity-based accounting system that allocates VHA expenditures to patient encounters). We controlled for measured confounders using inverse probability of treatment (IPT) weights and assessed differences using standardized mean differences (SMDs). For comparisons where SMDs exceeded 0.1 after IPT weighting, we used the more conservative matching weights in sensitivity analyses. For hypothesis testing, we compared IPT-adjusted differences in quarterly costs between treatment groups using Mann-Whitney U-tests and generalized estimating equation (GEE) regression models. RESULTS: Of 33,048 HIV-positive veterans, 7,222 met eligibility criteria, including 4,172 TDF/FTC + EFV recipients; mean (SD) age of the cohort was 50.0 (10.0) years; 96.7% were male; 60.1% were black; and 30.1% were white. Quarterly periods of exposure to EFV-containing regimens were 22,499 and of exposure to non-EFV-containing regimens were 11,633. After IPT weighting, absolute SMDs were < 0.1 except for a few covariates in the rilpivirine comparison. The per-patient adjusted mean total quarterly costs were $7,145 for EFV versus $8,726 for non-EFV (P < 0.001; Mann-Whitney U-test) and the per-patient adjusted mean difference in total quarterly costs was $1,419 lower for EFV versus all non-EFV combined (P < 0.001; GEE model). Corresponding values for outpatient costs ($2,656 vs. $2,942; P < 0.001; difference, -$254; P = 0.001), inpatient costs ($2,009 vs. $2,614; P < 0.001), radiology costs ($213 vs. $276; P < 0.001), and pharmacy costs ($2,480 vs. $3,170; P < 0.001; difference, -$600; P < 0.001) were all lower for EFV versus all non-EFV combined. Findings based on matching weights were qualitatively similar. Contributions of renal and bone costs to the total costs of treatment were very small, ranging between $52 and $94 per patient per quarter for renal outcomes and between $6 and $114 for bone outcomes. CONCLUSIONS: Among 7,222 HIV-treated veterans over an average follow-up of 1.2 years per patient, those patients receiving TDF/FTC + EFV had lower overall health care costs compared with those receiving non-EFV regimens. DISCLOSURES: This study was funded by Bristol-Myers Squibb. Nelson, Ma, Crook, Knippenberg, Nyman, and LaFleur are employees of the University of Utah, which received a grant from Bristol-Myers Squibb to conduct this study. Nyman also discloses honoraria for consulting from Otsuka and for writing a book chapter from Fresenius. La Fleur reports advisory board and consulting fees from Bristol-Myers Squibb outside of this study. Paul and Esker are employees of, and own stock in, Bristol-Myers Squibb.

Tenofovir-Associated Bone Adverse Outcomes among a US National Historical Cohort of HIV-Infected Veterans: Risk Modification by Concomitant Antiretrovirals.

INTRODUCTION: Tenofovir disoproxil fumarate (TDF) has been associated with greater incidences of bone complications, which might be modified by some concomitantly administered antiretrovirals, possibly by their effect on tenofovir concentrations. We compared bone adverse outcomes among treatment-naïve HIV-infected US veterans initiating efavirenz (EFV)-containing TDF/emtricitabine (FTC) regimens versus those initiating non-EFV-containing TDF/FTC regimens. METHODS: Using national Veterans Health Administration clinical and administrative data sets, we identified a cohort of treatment-naïve HIV-infected veterans without bone disease who initiated therapy with TDF/FTC plus EFV, rilpivirine, elvitegravir/cobicistat, or ritonavir-boosted protease inhibitors in 2003-2015. The primary composite adverse bone outcome was the unadjusted incidence rate (IR) of osteoporosis, osteopenia, or fragility fracture (any hip, wrist, or spine fracture). To account for selection bias and confounding, we used inverse probability of treatment-weighted Cox proportional hazards regression models to calculate adjusted hazard ratios (HRs) for each outcome associated with EFV + TDF/FTC versus each non-EFV-containing TDF/FTC regimen. RESULTS: Of 33,048 HIV-positive veterans, 7161 initiated a TDF/FTC-containing regimen (mean age, 50 years; baseline CD4 < 200 cells/mm3, 33.3%; HIV-1 RNA > 100,000 copies/ml, 22.3%; mean follow-up, 13.0 months). Of these, 4137 initiated EFV- and 3024 non-EFV-containing regimens. Veterans initiating EFV- versus non-EFV-containing TDF/FTC regimens had a lower IR of the composite bone outcome (29.3 vs. 41.4 per 1000 patient-years), with significant risk reductions for this outcome [HR, 0.69; 95% confidence interval (CI), 0.58-0.83] and fragility fracture (HR, 0.59; 95% CI, 0.44-0.78). CONCLUSION: EFV + TDF/FTC is associated with a lower risk of adverse bone outcomes compared with other TDF-containing regimens in the VHA. FUNDING: Bristol-Myers Squibb.

Adherence and virologic outcomes among treatment-naïve veteran patients with human immunodeficiency virus type 1 infection.

Many studies have estimated the association between the adherence to antiretroviral therapies and human immunodeficiency virus (HIV) patients' virologic/immunologic outcomes. However, evidence is lacking on the causal effect of adherence on the outcomes. The goal of this study is to understand whether near perfect adherence is necessary to achieve optimal virologic outcome and also to investigate the effect of initial adherence to antiretroviral therapies on initial viral suppression by different regimens. A cohort study was conducted on HIV veterans initiating antiretroviral therapies in 1999 to 2015. The primary outcome was the first viral suppression occurred within 30 to 60 days since the index date. Multiple imputation was used to impute the missing value of virologic outcomes. The inverse probability of treatment weighting (IPTW) method was applied to estimate the viral suppression rate at each specific adherence category for each regimen category. Marginal structural models with IPTW were used to estimate the risk of viral suppression in lower-adherence categories in comparison to near-perfect adherence level ≥95%. Data showed that lower adherence caused lower viral suppression rate, with the association differentiated by the regimen. Patients on integrase strand transfer had the highest viral suppression rate, with patients on protease inhibitors having the lowest rate. Regardless of regimens, the viral suppression rate among patients at initial adherence of 75 to <95% was not statistically different from patients at adherence of ≥95%; however, the differences might be clinically significant.

Predicting poor adherence to antiretroviral therapy among treatment-naïve veterans infected with human immunodeficiency virus.

Previous studies suggested that human immunodeficiency virus (HIV) infected patients at risk of poor adherence were not distinguishable only based on the baseline characteristics. This study is to identify patient characteristics that would be consistently associated with poor adherence across regimens and to understand the associations between initial and long-term adherence. HIV treatment-naïve patients initiated on protease inhibitors, nonnucleoside reverse transcriptase inhibitors, or integrase strand transfer inhibitors were identified from the Veteran Health Administration system. Initial adherence measured as initial coverage ratio (ICR) and long-term adherence measured as thereafter 1-year proportion days covered (PDC) of base agent and complete regimen were estimated for each patient. The patients most likely to exhibit poor adherence were African-American, with lower socioeconomic status, and healthier. The initial coverage ratio of base agent and complete regimen were highly correlated, but the correlations between ICR and thereafter 1-year PDC were low. However, including initial adherence as a predictor in predictive model would substantially increase predictive accuracy of future adherence.

Competing Risks of Fracture and Death in Older Adults with Chronic Kidney Disease.

OBJECTIVES: To examine whether chronic kidney disease (CKD) at any stage is associated with fracture risk after adjusting for competing mortality and to determine whether age or race modify the relationship between CKD and fracture risk. DESIGN: Prospective cohort study. SETTING: Department of Veterans Affairs (VA) national healthcare system. PARTICIPANTS: Men receiving VA primary care aged 65 and older with no history of fracture or osteoporosis therapy (N = 712, 918). MEASUREMENTS: We determined CKD stage from baseline estimated glomerular filtration rate (eGFR). Participants were followed for up to 10 years for occurrence of any fracture or death. We ascertained fractures and covariates from VA medical records and Medicare claims. RESULTS: Of the 356,459 older veterans with CKD (defined as eGFR <60 mL/min per 1.73 m2 ), 15.7% (n = 56,032) experienced a fracture, and 43.0% (n = 153,438) died over a median time at risk of 5.2 years. Veterans with CKD Stages 3 to 5 had a greater risk of death than those without CKD, which biased estimates from traditional survival models. Competing risk models showed that Stage 3 CKD was associated with greater hazard (adjusted subdistribution hazard ratio (sdHR) = 1.07, 95% confidence interval (CI) = 1.02-1.11) of fracture (than those without CKD) and a trend toward greater hazard for Stage 4 (sdHR = 1.07, 95% CI = 0.94-1.22) and Stage 5 (sdHR = 1.31, 95% CI = 0.97-1.77) CKD. Age, race, and bone mineral density did not modify the relationship between CKD and fracture risk. CONCLUSIONS: In older male veterans, CKD, including Stage 3, is associated with a moderately greater fracture risk irrespective of age, race, or bone mineral density.

Brief Report: Tenofovir-Associated Nephrotoxicity Among a US National Historical Cohort of HIV-Infected Veterans: Risk Modification by Concomitant Antiretrovirals.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) has been associated with renal complications. The third agent in TDF-containing antiretroviral regimens may modify that risk. We compared renal adverse outcomes among treatment-naive HIV-infected patients initiating TDF-containing regimens including efavirenz (EFV) or other agents. SETTING: This population-based historical cohort study used national Veterans Health Administration (VHA) clinical and administrative data sets to identify treatment-naive HIV-infected veterans initiating antiretroviral therapy with TDF/emtricitabine (FTC) + EFV, rilpivirine (RPV), elvitegravir/cobicistat (EVG/c), or ritonavir (RTV)-boosted protease inhibitors (PIs) from 2003 to 2015. METHODS: Unadjusted incidence rates (IRs) for each regimen and covariate-adjusted hazard ratios [ using Cox proportional hazards models and inverse probability of treatment weighting] for between-regimen comparisons were calculated for renal outcomes including confirmed proteinuria, defined as 2 consecutive protein-to-creatinine ratios >150 mg/g or albumin-to-creatinine ratios >30 mg/g occurring ≥90 days apart; chronic kidney disease (CKD), defined as 2 consecutive estimated glomerular filtration rate measurements <60 mL·min·1.73 m occurring ≥90 days apart; and kidney dialysis. RESULTS: Of 33,048 HIV-positive veterans, 4172 received EFV + TDF/FTC, 234 EVG/c/TDF/FTC, 173 RPV/TDF/FTC, and 2651 RTV-boosted PIs + TDF/FTC. Confirmed proteinuria and CKD IRs were numerically lower with EFV + TDF/FTC versus non-EFV + TDF/FTC (dialysis IRs were rare and comparable). After inverse probability of treatment weighting adjustment, EFV + TDF/FTC was associated with lower CKD risk versus non-EFV + TDF/FTC (hazard ratio, 0.62; 95% confidence interval, 0.53 to 0.72), EVG/c/TDF/FTC (0.75; 0.59 to 0.95), RPV/TDF/FTC (0.20; 0.17 to 0.24), and RTV-boosted PIs + TDF/FTC (0.62; 0.53 to 0.72). CONCLUSIONS: EFV + TDF/FTC was associated with significantly lower risk of CKD versus other TDF-containing regimens in the Veterans Health Administration.

Clinical Fractures Among Older Men With Diabetes Are Mediated by Diabetic Complications.

Introduction: Type 2 diabetes mellitus among older women has been associated with increased bone mineral density, but paradoxically with increased fracture risk. Findings among older men have varied, and potential mechanisms have not been fully elucidated. Methods: A retrospective study of male veterans 65 to 99 years of age who received primary care in the Veterans Health Administration from 2000 to 2010, using administrative data from all 146 Veterans Health Administration medical centers linked to Centers for Medicare and Medicaid Services Medicare fee-for-service data. Potential mediating factors of the diabetes-associated risk were evaluated using negative binomial regression models with the outcomes of any clinical fracture and hip fracture. Results: Of 2,798,309 Veterans included in the cohort, 900,402 (32.3%) had a diagnosis of diabetes. After adjusting for age, race, ethnicity, body mass index, alcohol and tobacco use, rheumatoid arthritis, and corticosteroid use, the risk of any clinical fracture associated with diabetes was 1.22 (95% confidence interval, 1.21 to 1.23) and that of hip fracture was 1.21 (95% confidence interval, 1.19 to 1.23). Significant mediating factors included peripheral neuropathy, cardiovascular disease, and congestive heart failure, with 45.5% of the diabetes-associated fracture risk explained by these diagnoses. Conclusions: Older male Veterans with diabetes have a 22% increased risk of incident clinical fracture compared with those without. A significant portion of this risk is explained by diabetes-related comorbidities, specifically peripheral neuropathy and congestive heart failure. Identification of these mediating factors suggests possible mechanisms, as well as potential interventions.

Cardiovascular outcomes among HIV-infected veterans receiving atazanavir.

OBJECTIVE: Patients with HIV infection have an increased risk of cardiovascular disease compared with uninfected individuals. Antiretroviral therapy with atazanavir (ATV) delays progression of atherosclerosis markers; whether this reduces cardiovascular disease event risk compared with other antiretroviral regimens is currently unknown. DESIGN: Population-based, noninterventional, historical cohort study conducted from 1 July 2003 through 31 December 2015. SETTING: Veterans Health Administration hospitals and clinics throughout the United States. PARTICIPANTS: Treatment-naive patients with HIV infection (N = 9500). ANTIRETROVIRAL EXPOSURES: Initiating antiretroviral regimens containing ATV, other protease inhibitors, nonnucleoside reverse transcriptase inhibitors (NNRTIs), or integrase strand transfer inhibitors (INSTIs). MAIN OUTCOME/EFFECT SIZE MEASURES: Incidence rates of myocardial infarction (MI), stroke, and all-cause mortality within each regimen. ATV versus other protease inhibitor, NNRTI, or INSTI covariate-adjusted hazard ratios by using Cox proportional hazards models and inverse probability of treatment weighting. RESULTS: Incidence rates for MI, stroke, and all-cause mortality with ATV-containing regimens (5.2, 10.4, and 16.0 per 1000 patient-years, respectively) were lower than with regimens containing other protease inhibitors (10.2, 21.9, and 23.3 per 1000 patient-years), NNRTIs (7.5, 15.9, and 17.5 per 1000 patient-years), or INSTIs (13.0, 33.1, and 21.5 per 1000 patient-years). After inverse probability of treatment weighting, adjusted hazard ratios (95% confidence intervals) for MI, stroke, and all-cause mortality with ATV-containing regimens versus all non-ATV-containing regimens were 0.59 (0.41-0.84), 0.64 (0.50-0.81), and 0.90 (0.73-1.11), respectively. CONCLUSION: Among treatment-naive HIV-infected patients in the Veterans Health Administration initiating ATV-containing regimens, risk of both MI and stroke were significantly lower than in those initiating regimens containing other protease inhibitors, NNRTIs, or INSTIs.

The Bone Health Team: A Team-Based Approach to Improving Osteoporosis Care for Primary Care Patients.

BACKGROUND: Significant improvements in secondary prevention of osteoporotic fractures have been noted with fracture liaison services. However, similar models for the primary prevention of such fractures have not been reported. OBJECTIVE: To determine the impact of a Bone Health Team (BHT) on osteoporosis screening and treatment rates in U.S. veterans in primary care practices. DESIGN: Historical cohort study of a primary care-based intervention of a BHT from February 2013 to February 2015. SETTING: Community-based outpatient clinics of the Salt Lake City Veterans Affairs Health Care System. PARTICIPANTS: Men aged 70 years and older and women aged 65 years and older. INTERVENTION: Enrollment in the BHT. MEASUREMENTS: Rates of dual energy x-ray absorptiometry (DXA) completion, chart diagnosis of osteoporosis or osteopenia, completion of vitamin D measurement, and initiation of fracture reducing medication. RESULTS: Our cohort consisted of 7644 individuals, 975 of whom were exposed to the BHT and 6669 of whom were not. Comparison of patients exposed to the BHT versus non-exposed subjects demonstrated a substantial increase in all outcome measures studied. Hazard ratios (HRs) from multivariable cox proportional hazard models were: measurement of vitamin D, HR = 1.619 ( P < .001); chart diagnosis of osteopenia, HR = 37.00 ( P < .001); chart diagnosis of osteoporosis, HR = 16.38 ( P < .001); osteoporosis medication, HR = 17.03 ( P < .001); and completion of DXA, HR = 139.9 ( P < .001). CONCLUSIONS AND RELEVANCE: The implementation of a dedicated BHT produced significantly increased rates of intermediate osteoporosis outcome measures in US veterans in primary care practices. Additional research describing medication adherence rates and cost-effectiveness is forthcoming.

Determining Multiple Sclerosis Phenotype from Electronic Medical Records.

BACKGROUND: Multiple sclerosis (MS), a central nervous system disease in which nerve signals are disrupted by scarring and demyelination, is classified into phenotypes depending on the patterns of cognitive or physical impairment progression: relapsing-remitting MS (RRMS), primary-progressive MS (PPMS), secondary-progressive MS (SPMS), or progressive-relapsing MS (PRMS). The phenotype is important in managing the disease and determining appropriate treatment. The ICD-9-CM code 340.0 is uninformative about MS phenotype, which increases the difficulty of studying the effects of phenotype on disease. OBJECTIVE: To identify MS phenotype using natural language processing (NLP) techniques on progress notes and other clinical text in the electronic medical record (EMR). METHODS: Patients with at least 2 ICD-9-CM codes for MS (340.0) from 1999 through 2010 were identified from nationwide EMR data in the Department of Veterans Affairs. Clinical experts were interviewed for possible keywords and phrases denoting MS phenotype in order to develop a data dictionary for NLP. For each patient, NLP was used to search EMR clinical notes, since the first MS diagnosis date for these keywords and phrases. Presence of phenotype-related keywords and phrases were analyzed in context to remove mentions that were negated (e.g., "not relapsing-remitting") or unrelated to MS (e.g., "RR" meaning "respiratory rate"). One thousand mentions of MS phenotype were validated, and all records of 150 patients were reviewed for missed mentions. RESULTS: There were 7,756 MS patients identified by ICD-9-CM code 340.0. MS phenotype was identified for 2,854 (36.8%) patients, with 1,836 (64.3%) of those having just 1 phenotype mentioned in their EMR clinical notes: 1,118 (39.2%) RRMS, 325 (11.4%) PPMS, 374 (13.1%) SPMS, and 19 (0.7%) PRMS. A total of 747 patients (26.2%) had 2 phenotypes, the most common being 459 patients (16.1%) with RRMS and SPMS. A total of 213 patients (7.5%) had 3 phenotypes, and 58 patients (2.0%) had 4 phenotypes mentioned in their EMR clinical notes. Positive predictive value of phenotype identification was 93.8% with sensitivity of 94.0%. CONCLUSIONS: Phenotype was documented for slightly more than one third of MS patients, an important but disappointing finding that sets a limit on studying the effects of phenotype on MS in general. However, for cases where the phenotype was documented, NLP accurately identified the phenotypes. Having multiple phenotypes documented is consistent with disease progression. The most common misidentification was because of ambiguity while clinicians were trying to determine phenotype. This study brings attention to the need for care providers to document MS phenotype more consistently and provides a solution for capturing phenotype from clinical text. DISCLOSURES: This study was funded by Anolinx and F. Hoffman-La Roche. Nelson serves as a consultant for Anolinx. Kamauu is owner of Anolinx, which has received multiple research grants from pharmaceutical and biotechnology companies. LaFleur has received a Novartis grant for ongoing work. 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 or the U.S. government. Study concept and design were contributed by Butler, LaFleur, Kamauu, DuVall, and Nelson. DuVall collected the data, and interpretation was performed by Nelson, DuVall, and Kamauu, along with Butler, LaFleur, and Knippenberg. The manuscript was written primarily by Nelson, along with Knippenberg and assisted by the other authors, and revised by Knippenberg, Nelson, and DuVall, along with the other authors.