Combination Therapy Use and Associated Events in Clinical Practice Following Dissemination of Trial Findings: A De-Implementation Study Using Interrupted Time Series Analysis.

PURPOSE: It takes 17 years, on average, for trial results to be implemented into practice. Using data from the Department of Veterans Affairs (VA), this study assessed the potential impact on clinical practice of the dissemination of findings from a randomized, controlled trial reporting harm with the use of combination therapy. Communication between research and VA Pharmacy Benefits Management Services (PBM)  provided the impetus for communication from the PBM about the findings of the trial in accordance with policy. METHODS: In this de-implementation study, interrupted time series analysis was used for assessing prescribing patterns and adverse clinical events before and after the dissemination of the trial findings. The de-implementation strategy was multicomponent and multilevel. Strategies were aligned with categories outlined in the Expert Recommendations for Implementing Change: train and educate stakeholders, use evaluative and iterative strategies, develop stakeholder inter-relationships, change infrastructure, provide interactive assistance, and engage consumers. VA patients with type 2 diabetes mellitus, chronic kidney disease stages 1 to 3, and a moderate or severe albuminuria who received care between July 2008 and November 2017 were included. Patients were subgrouped according to treatment with an angiotensin-converting enzyme inhibitor + angiotensin receptor blocker. The primary end point was the prevalence of combination therapy use. Secondary end points were the incidences of acute kidney injury and hyperkalemia. FINDINGS: This study followed 712,245 patients, 9297 of whom used combination therapy. Data were available from 428,535 and 283,710 patients pre- and post-intervention, respectively; among these, 8324 and 973 patients used combination therapy, the median ages were 66 and 68 years, and 96.92% and 98.82% were men. One month following communication from the PBM, the reductions in combination therapy users, acute kidney injury events, and hyperkalemia were 331.94 (95% CI, 500.27-163.32), 36.58% (95% CI, 31.90%-41.95%), and 25.49% (95% CI, 14.17%-36.07%) per 100,000 patients per month, respectively (all, P < 0.001), whereas before the communication, these changes were +14.84 (95% CI, 10.27-19.42), -3.46% (95% CI, 3.18-3.74), and -3.27% (95% CI, 2.66%-3.87%) (all, P < 0.001). IMPLICATIONS: The apparent speed and impact of the implementation of changes resulting from the dissemination of trial findings into VA clinical practice are encouraging. The speed of implementation was much faster than average for health care providers in the United States. Established communications between research and clinical practice, as well as established policy and communications between PBM and clinical practice, may be a model for other health care organizations.

Potential for repurposing oral hypertension/diabetes drugs to decrease asthma risk in obesity.

OBJECTIVE: Risk for asthma in the overweight/obese may be mediated by adiponectin and peroxisome proliferator activated receptor pathways and may be reduced by the use of oral drugs impacting these pathways, such as angiotensin converting enzyme inhibitors (ACE-I), thiazolidinediones (TZD), and angiotensin receptor blockers (ARB). Our study objective was to determine whether ACE-I, TZD, and/or ARB use in overweight/obese adults with diabetes mellitus and/or hypertension is associated with a lower risk for incident asthma. METHODS: Using an existing cohort of American veterans, we performed a longitudinal data analysis over 15 years. Exposure was defined by the prescription pickup of ACE-I, TZD, and/or ARB for at least 4 weeks. The outcome, time until new-onset of clinician-diagnosed asthma, was studied using survival analysis. The propensity scoring method controlled for treatment selection bias. RESULTS: 2.83 million eligible veterans, including 77,278 with incident asthma, were studied. As compared to those unexposed, the use of ACE-I alone, TZD alone, or their combinations were each associated with decreased risk for incident asthma (hazard ratios of 0.88, 0.74, and 0.20, respectively; p < 0.001 for all analyses in the fully adjusted statistical models). TZD lowered the risk among racial/ethnic minority subjects more than among White participants (p < 0.001). On the other hand, ARB use alone or in combination with TZD was associated with a higher risk for incident asthma. CONCLUSIONS: Use of ACE-I and/or TZD was associated with a lower risk for incident asthma in overweight/obese patients with diabetes mellitus and/or hypertension.

Effect of vaccination on the case fatality rate for COVID-19 infections 2020-2021: multivariate modelling of data from the US Department of Veterans Affairs.

OBJECTIVES: To evaluate the benefits of vaccination on the case fatality rate (CFR) for COVID-19 infections. DESIGN, SETTING AND PARTICIPANTS: The US Department of Veterans Affairs has 130 medical centres. We created multivariate models from these data-339 772 patients with COVID-19-as of 30 September 2021. OUTCOME MEASURES: The primary outcome for all models was death within 60 days of the diagnosis. Logistic regression was used to derive adjusted ORs for vaccination and infection with Delta versus earlier variants. Models were adjusted for confounding factors, including demographics, comorbidity indices and novel parameters representing prior diagnoses, vital signs/baseline laboratory tests and outpatient treatments. Patients with a Delta infection were divided into eight cohorts based on the time from vaccination to diagnosis. A common model was used to estimate the odds of death associated with vaccination for each cohort relative to that of unvaccinated patients. RESULTS: 9.1% of subjects were vaccinated. 21.5% had the Delta variant. 18 120 patients (5.33%) died within 60 days of their diagnoses. The adjusted OR for a Delta infection was 1.87±0.05, which corresponds to a relative risk (RR) of 1.78. The overall adjusted OR for prior vaccination was 0.280±0.011 corresponding to an RR of 0.291. Raw CFR rose steadily after 10-14 weeks. The OR for vaccination remained stable for 10-34 weeks. CONCLUSIONS: Our CFR model controls for the severity of confounding factors and priority of vaccination, rather than solely using the presence of comorbidities. Our results confirm that Delta was more lethal than earlier variants and that vaccination is an effective means of preventing death. After adjusting for major selection biases, we found no evidence that the benefits of vaccination on CFR declined over 34 weeks. We suggest that this model can be used to evaluate vaccines designed for emerging variants.

A novel method for handling pre-existing conditions in multivariate prediction model development for COVID-19 death in the Department of Veterans Affairs.

Many mathematical models have been proposed to predict death following the Coronavirus Disease 2019 (COVID-19); all started with comorbidity subsets for this still-little understood disease. Thus, we derived a novel predicted probability of death model (PDeathDx) upon all diagnostic codes documented in the Department of Veterans Affairs. We present the conceptual underpinnings and analytic approach in estimating the independent contribution of pre-existing conditions. This is the largest study to-date following patients with COVID-19 to predict mortality. Cases were identified with at least one positive nucleic acid amplification test. Starting in 1997, we use diagnoses from the first time a patient sought care until 14 days before a positive nucleic acid amplification test. We demonstrate the clear advantage of using an unrestricted set of pre-existing conditions to model COVID-19 mortality, as models using conventional comorbidity indices often assign little weight or usually do not include some of the highest risk conditions; the same is true of conditions associated with COVID-19 severity. Our findings suggest that it is risky to pick comorbidities for analysis without a systematic review of all those experienced by the cohort. Unlike conventional approaches, our comprehensive methodology provides the flexibility that has been advocated for comorbidity indices since 1993; such an approach can be readily adapted for other diseases and outcomes. With our comorbidity risk adjustment approach outperforming conventional indices for predicting COVID-19 mortality, it shows promise for predicting outcomes for other conditions of interest.

Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen and relationship with mortality among United States Veterans after testing positive for COVID-19.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are among the most-frequently used medications. Although these medications have different mechanisms of action, they have similar indications and treatment duration has been positively correlated with cardiovascular risk although the degree of risk varies by medication. Our objective was to study treatment effects of chronic use of individual NSAID medications and acetaminophen on all-cause mortality among patients who tested positive for COVID-19 while accounting for adherence. We used the VA national datasets in this retrospective cohort study to differentiate between sporadic and chronic medication use: sporadic users filled an NSAID within the last year, but not recently or regularly. Using established and possible risk factors for severe COVID-19, we used propensity scores analysis to adjust for differences in baseline characteristics between treatment groups. Then, we used multivariate logistic regression incorporating inverse propensity score weighting to assess mortality. The cohort consisted of 28,856 patients. Chronic use of aspirin, ibuprofen, naproxen, meloxicam, celecoxib, diclofenac or acetaminophen was not associated with significant differences in mortality at 30 days (OR = 0.98, 95% CI: 0.95-1.00; OR = 0.99, 95% CI: 0.98-1.00; OR = 1.00, 95% CI: 0.98-1.01; OR = 0.99, 95% CI: 0.98-1.00; OR = 1.00, 95% CI: 0.98-1.01; OR = 0.99, 95% CI: 0.97-1.01; and OR = 1.00, 95% CI: 0.99-1.02, respectively) nor at 60 days (OR = 0.97, 95% CI: 0.95-1.00; OR = 1.00, 95% CI: 0.99-1.01; OR = 0.99, 95% CI: 0.98-1.01; OR = 0.99, 95% CI: 0.97-1.00; OR = 0.99, 95% CI: 0.97-1.01; OR = 0.99, 95% CI: 0.97-1.01; and OR = 1.01, 95% CI: 0.99-1.02, respectively). Although the study design cannot determine causality, the study should assure patients as it finds no association between mortality and chronic use of these medications compared with sporadic NSAID use among those infected with COVID-19.

Development and validation of prediction rules to target care intensification in veteran patients with diabetes.

BACKGROUND: Diabetes affects 30.3 million people in the USA. Among these people, a major risk factor for microvascular complications is having a glycated haemoglobin (HbA1c) value of ≥75 mmol/mol; therefore, it would be helpful to identify patients who will obtain future HbA1c values of <75 mmol/mol. OBJECTIVES: To develop and validate two prediction rules among patients with diabetes having a baseline HbA1c value of ≥75 mmol/mol: (1) HbA1c measurement ever <75 mmol/mol and (2) final HbA1c measurement of <75 mmol/mol. METHODS: Retrospective cohort study using a registry extracting data from the Department of Veterans Affairs's (VA's) electronic health records system. Baseline was 1 Jul 2013-30 June 2014; patients were followed up until 31 July 2016. RESULTS: Our population consisted of 145 659 patients. Across models, predictors were age, sex, minority status, baseline HbA1c value, time, HbA1c≥75 mmol/mol, receiving insulin treatment and consecutive number of HbA1c values of 75 mmol/mol. The overall likelihood of a patient ever having an HbA1c<75 mmol/mol was 73.65%; with the rule, predicted probabilities were 38.94%, 50.75% and 78.88%. The overall likelihood of patients having a final HbA1c measurement of <75 mmol/mol was 55.35%; the rule provided predicted probabilities of 29.93%, 50.17% and 68.58%. CONCLUSIONS: Within each rule, there were similar observed and predicted tertile probabilities; maintaining HbA1c values of <75 mmol/mol resulted in probability shifts in the majority of patients. We recommend psychosocial screening for 15% of patients for whom there is less than one-third chance of maintaining HbA1c<75 mmol/mol. We plan to conduct additional research to see whether this approach helps.

Female Veterans With Diagnoses of Both Chronic Pelvic Pain and Overactive Bladder; How Do They Compare to Women Diagnosed With Interstitial Cystitis?

OBJECTIVE: The objective of this study was to compare women with a known diagnosis of interstitial cystitis (IC) to a population that might be at risk for the diagnosis of IC, women with diagnoses of both chronic pelvic pain (CPP) and overactive bladder (OAB). METHODS: We conducted a retrospective study of data from the Veterans Affairs Corporate Data Warehouse. The cohort included all female veterans who had established care with a primary care provider from 1997 to present. International Classification of Diseases, Ninth Revision codes were used to identify women with a diagnosis of IC, CPP, and OAB. Demographic data and comorbidities were compared between groups. RESULTS: A total of 596,815 women were identified. Two thousand three hundred one women (0.4%) were diagnosed with IC; 4459 women (0.7%) were diagnosed with CPP and OAB. At baseline, women with OAB and CPP were more likely to identify as minority (P < 0.001). Anxiety (57.3% vs 49.5%), depression (39.0% vs 46.0%), and posttraumatic stress disorder (29.7 vs 26.4%) were all more common in the CPP and OAB group than in the IC group. In the multivariable model, women with CPP and OAB were more likely to identify as a minority, use tobacco, and carry a diagnosis of anxiety. CONCLUSIONS: There were more patients diagnosed with CPP and OAB compared with patients diagnosed with IC in this population of female veterans. Given the high rate of comorbid anxiety and depression in both groups, further study is warranted to determine whether these women are misdiagnosed.

A 10-yr Analysis of Chronic Pelvic Pain and Chronic Opioid Therapy in the Women Veteran Population.

Introduction: Chronic pelvic pain (CPP) affects an estimated 30% of women Veterans. Previous research shows high rates of narcotic abuse in the women Veteran population. Narcotics are not recommended for the treatment of CPP. Understanding how CPP impacts narcotic prescribing in the women Veteran population is critical to addressing the public health crisis of opioid abuse. Our objective was to compare chronic opioid therapy (COT) prescribed 5 yr prior to and following CPP diagnosis and to identify predictors of COT as well as adverse events associated with COT. We choose to look at 10 yr of data because we thought this time period would provide unique insight into the longitudinal associations of CPP and COT and was available in the database. Materials and Methods: Women with non-cancer CPP were included for analyses from the Veteran's Affairs Corporate Database Warehouse. COT was defined as 90 d of opiates/calendar year for each of the 5 yr proceeding and following the diagnosis of CPP. Patient characteristics and potential variables influencing COT were collected. We compared baseline demographics between the women who received COT to the women who did not receive COT to find additional demographic predictors of COT in association with CPP. Multivariable analysis identified predictors of COT in this population of women with CPP. We utilized an interrupted time series analysis to understand the impact of the diagnosis of CPP on COT. Results: A total of 49,601 women met inclusion criteria with an average age of 40.1 ± 11.5 yr; 37.3% self-characterized as being a racial minority and 24% had a history of military sexual trauma. Chronic use increased significantly (p < 0.001) in the 5 yr preceding the diagnosis of CPP from 6.3% (n = 3124) of women at time -5 to 13.6% (n = 6746) at time 0. In the first year following the diagnosis of CPP, 16.8% (n = 8,333) of women with CPP met the criteria for COT (p < 0.001) and 15% (n = 7440) of women with CPP remained in the COT group for the remaining 5 yr following the diagnosis. On average women in the COT group had 250-292 d of opioids/year. When comparing women who received chronic narcotics following the diagnosis of CPP versus those who did not receive chronic narcotics, women who received COT were older, more likely to smoke and more frequently diagnosed with other pain conditions such as back pain, headaches, and fibromyalgia. (All p < 0.001). In the multivariable model, predictors of COT following CPP diagnosis included prior COT (OR = 10.0 (95% CI 9.4, 10.6), a positive history of military sexual trauma, smoking, and other chronic pain conditions. Conclusions: The distinct pattern of prescribing shown in this cohort may mean COT is prescribed for CPP and this prescribing pattern contributes to the adverse events associated with COT. As COT is not recommended for CPP, physicians need more education on the therapies available to help CPP patients.

One and the Same? Nocturnal Enuresis and Overactive Bladder in the Female Veteran Population: Evaluation of a Large National Database.

OBJECTIVES: The aims of this study were to describe relationships between women given a diagnosis of nocturnal enuresis (NE) and controls without any urinary complaints and to compare women with NE with those with overactive bladder (OAB). We hypothesized that NE has unique associations with demographics and medical and psychosocial diagnoses. METHODS: This is a secondary analysis of a database that included all female veterans who established care with a primary care provider from 1997 to 2015. International Classification of Diseases, Ninth Revision, codes identified women with a diagnosis of NE or OAB. Patient characteristics, medical diagnoses, and psychosocial factors previously described as relating to NE and/or OAB were compared between the 2 distinct comparative groups, with significance set at P < 0.05. Stepwise logistic regression was used to assess all significant findings. RESULTS: A total of 596,815 women were identified; controls totaled 570,049, the group with OAB totaled 26,446 (4.4%), and the group with NE totaled 301 (0.05%).Multivariable analysis compared the group with NE with controls; all measured psychosocial characteristics remained significantly associated with an NE diagnosis (all Ps < 0.05), as well as obstructive sleep apnea history, stroke, self-identification as "minority," smoking, hypertension, and a body mass index higher than those of the general control population (all Ps < 0.05).When the populations with NE and OAB were compared, a diagnosis of posttraumatic stress disorder, an overdose history, depression, military sexual trauma, increasing body mass index, and younger age remained significantly associated with NE (all Ps < 0.05). CONCLUSIONS: The association of NE with psychosocial characteristics and psychiatric illnesses persisted irrespective of the comparison population. Practitioners should investigate the diagnosis of NE in those female veterans with psychosocial issues.

Military Sexual Trauma in Female Veterans is Associated With Chronic Pain Conditions.

INTRODUCTION: Little is known about the impact of MST on chronic pain conditions among female Veterans. The primary objective of this study was to compare the prevalence of chronic pain conditions among U.S. female veterans with a history of military sexual trauma (MST) to those without a history of MST. We anticipated that female Veterans with a history of MST would have higher associations with chronic pain conditions than the female Veterans without a history of MST. MATERIALS AND METHODS: This was a large-scale, retrospective study using the Veterans' Health Administration Corporate Data Warehouse with institutional approval (15-H175). International Classification of Diseases, 9th Revision codes from the outpatient visits, outpatient problem lists, and inpatient discharge diagnoses were used to identify chronic pain diagnoses. Baseline demographic data including date of birth, self-identified race/ethnicity, and body mass index were obtained. Significant findings in the univariate analysis were then placed into a multivariable logistic regression model to adjust the effect of each predictor for the presence of others. Significance was set at p < 0.01 because of multiple comparisons made. RESULTS: For the entire cohort (516,950 women), 28.9% (149,540) were diagnosed with headaches, 18.3% (94,393) with chronic pelvic pain, 14.4% (74,216) with chronic back pain, 10.5% (54,302) with nonspecific joint pain, 9% (48,509) with fibromyalgia, 6.2% (32,037) with generalized abdominal pain, 4.2% (21,911) with irritable bowel syndrome, and 3.2% (16,309) with dyspareunia. Most women had more than one chronic pain diagnosis. At baseline, women with a history of MST were younger (63.3 ± 15.9 vs. 67.4 ± 17.9 years p < 0.001), heavier (29.5± 6.2 vs. 28.8 ± 6.1 kg/m2 p < 0.001), smokers (49.3 vs. 38.8% p < 0.001), and more likely to be non-Hispanic white (56.3 vs. 52.3% p < 0.001) than women without a history of MST. Women with a history of MST had more pain diagnoses than those without the history of MST (all p < 0.001). The adjusted odds ratio of women with history of MST presenting with any pain condition compared to a women without a history of MST was 1.26 (95% confidence interval 1.24-1.28). In the multivariable model there remained an association between MST and chronic pain conditions including irritable bowel syndrome, chronic pelvic pain, back pain, chronic joint pain, fibromyalgia, dyspareunia, chronic abdominal pain, and headaches after adjusting for baseline differences in age, body mass index, smoking, and ethnicity. Importantly, drug abuse, and overdose were also associated with MST. CONCLUSION: A history of MST is associated with chronic pain diagnoses. Weaknesses of this study are those applicable to analyses of any retrospective database study. Specifically, the data are limited by the accuracy of physician coding and reporting. The strength of this study is that it represents a comprehensive, retrospective evaluation of potential sources for chronic pain within the female veteran population. In summary, we found that female veteran survivors of MST face an increased burden of chronic pain, including a broad range of pain conditions independent of the psychological effects of MST.

Ethnic Disparities in Emergency Severity Index Scores among U.S. Veteran's Affairs Emergency Department Patients.

BACKGROUND: The goal of these analyses was to determine whether there were systematic differences in Emergency Severity Index (ESI) scores, which are intended to determine priority of treatment and anticipate resource needs, across categories of race and ethnicity, after accounting for patient-presenting vital signs and examiner characteristics, and whether these differences varied among male and female Veterans Affairs (VA) ED patients. METHODS AND FINDINGS: We used a large national database of electronic medical records of ED patients from twenty-two U.S. Department of Veterans Affairs ED stations to determine whether ESI assignments differ systematically by race or ethnicity. Multi-level, random effects linear modeling was used to control for demographic characteristics and patient's vital signs (heart rate, respiratory rate, and pain level), as well as age, gender, and experience of triage nurses. The dataset included 129,991 VA patients presenting for emergency care between 2008 and 2012 (91% males; 61% non-Hispanic White, 28% Black, 7% Hispanic, 2% Asian, <1% American Indian/Alaska Native, 1% mixed ethnicity) and 774 nurses for a total of 359,642 patient/examiner encounters. Approximately 13% of the variance in ESI scores was due to patient characteristics and 21% was due to the nurse characteristics. After controlling for characteristics of nurses and patients, Black patients were assigned less urgent ESI scores than White patients, and this effect was more prominent for Black males compared with Black females. A similar interaction was found for Hispanic males. It remains unclear how these results may generalize to EDs and patient populations outside of the U.S. VA Health Care system. CONCLUSIONS: The findings suggest the possibility that subgroups of VA patients receive different ESI ratings in triage, which may have cascading, downstream consequences for patient treatment quality, satisfaction with care, and trust in the health equity of emergency care.