Helicobacter pylori Burden in the United States According to Individual Demographics and Geography: A Nationwide Analysis of the Veterans Healthcare System.

BACKGROUND & AIMS: There are no contemporary large-scale studies evaluating the burden of Helicobacter pylori in the United States according to detailed demographics. The primary objective was to evaluate H pylori positivity in a large national healthcare system according to individual demographics and geography. METHODS: We conducted a nationwide retrospective analysis of adults in the Veterans Health Administration who completed H pylori testing between 1999 and 2018. The primary outcome was H pylori positivity overall, as well as according to zip code-level geography, race, ethnicity, age, sex, and time period. RESULTS: Among 913,328 individuals (mean, 58.1 years; 90.2% male) included between 1999 and 2018, H pylori was diagnosed in 25.8%. Positivity was highest in non-Hispanic black (median, 40.2%; 95% confidence interval [CI], 40.0%-40.5%) and Hispanic (36.7%; 95% CI, 36.4%-37.1%) individuals and lowest in non-Hispanic white individuals (20.1%; 95% CI, 20.0%-20.2%). Although H pylori positivity declined in all racial and ethnic groups over the timeframe, the disproportionate burden of H pylori in non-Hispanic black and Hispanic compared with non-Hispanic white individuals persisted. Approximately 4.7% of the variation in H pylori positivity was explained by demographics, with race and ethnicity accounting for the vast majority. CONCLUSIONS: The burden of H pylori is substantial in the United States among veterans. These data should (1) motivate research aimed at better understanding why marked demographic differences in H pylori burden persist so that mitigating interventions may be implemented and (2) guide resource allocation to optimize H pylori testing and eradication in high-risk groups.

Heart failure subtype after acute kidney injury.

INTRODUCTION: Acute kidney injury (AKI) is associated with increased risk of heart failure (HF). Determining the type of HF experienced by AKI survivors (heart failure with preserved or reduced ejection fraction, HFpEF or HFrEF) could suggest potential mechanisms underlying the association and opportunities for improving post-AKI care. METHODS: In this retrospective study of adults within the Vanderbilt University health system with a diagnosis of HF, we tested whether AKI events in the two years preceding incident HF associated more with HFpEF or HFrEF while controlling for known predictors. HF outcomes were defined by administrative codes and classified as HFpEF or HFrEF by echocardiogram data. We used multivariable logistic regression models to estimate the effects of AKI on the odds of incident HFpEF versus HFrEF. RESULTS: AKI (all stages) trended towards a preferential association with HFpEF in adjusted analyses (adjusted OR 0.80, 95% CI 0.63 - 1.01). Stage 1 AKI was associated with higher odds of HFpEF that was statistically significant (adjusted OR 0.62, 95% CI 0.43 - 0.88), whereas stages 2-3 AKI showed a trend toward HFrEF that did not reach statistical significance (adjusted OR 1.11, 95% CI 0.76 - 1.63). CONCLUSIONS: AKI as a binary outcome trended towards a preferential association with HFpEF. Stage 1 AKI was associated with higher odds of HFpEF, whereas stage 2-3 trended towards an association with HFrEF that did not meet statistical significance. Different mechanisms may predominate in incident HF following mild versus more severe AKI. Close follow-up with particular attention to volume status and cardiac function after discharge is warranted after even mild AKI.

Primary Occurrence of Cardiovascular Events After Adding Sodium-Glucose Cotransporter-2 Inhibitors or Glucagon-like Peptide-1 Receptor Agonists Compared With Dipeptidyl Peptidase-4 Inhibitors: A Cohort Study in Veterans With Diabetes.

BACKGROUND: The effectiveness of glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in preventing major adverse cardiac events (MACE) is uncertain for those without preexisting cardiovascular disease. OBJECTIVE: To test the hypothesis that MACE incidence was lower with the addition of GLP1RA or SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) for primary cardiovascular prevention. DESIGN: Retrospective cohort study of U.S. veterans from 2001 to 2019. SETTING: Veterans aged 18 years or older receiving care from the Veterans Health Administration, with data linkage to Medicare, Medicaid, and the National Death Index. PATIENTS: Veterans adding GLP1RA, SGLT2i, or DPP4i onto metformin, sulfonylurea, or insulin treatment alone or in combination. Episodes were stratified by history of cardiovascular disease. MEASUREMENTS: Study outcomes were MACE (acute myocardial infarction, stroke, or cardiovascular death) and heart failure (HF) hospitalization. Cox models compared the outcome between medication groups using pairwise comparisons in a weighted cohort adjusted for covariates. RESULTS: The cohort included 28 759 GLP1RA versus 28 628 DPP4i weighted pairs and 21 200 SGLT2i versus 21 170 DPP4i weighted pairs. Median age was 67 years, and diabetes duration was 8.5 years. Glucagon-like peptide-1 receptor agonists were associated with lower MACE and HF versus DPP4i (adjusted hazard ratio [aHR], 0.82 [95% CI, 0.72 to 0.94]), yielding an adjusted risk difference (aRD) of 3.2 events (CI, 1.1 to 5.0) per 1000 person-years. Sodium-glucose cotransporter-2 inhibitors were not associated with MACE and HF (aHR, 0.91 [CI, 0.78 to 1.08]; aRD, 1.28 [-1.12 to 3.32]) compared with DPP4i. LIMITATION: Residual confounding; use of DPP4i, GLP1RA, and SGLT2i as first-line therapies were not examined. CONCLUSION: The addition of GLP1RA was associated with primary reductions of MACE and HF hospitalization compared with DPP4i use; SGLT2i addition was not associated with primary MACE prevention. PRIMARY FUNDING SOURCE: VA Clinical Science Research and Development and supported in part by the Centers for Diabetes Translation Research.

Rematching on-the-fly: Sequential matched randomization and a case for covariate-adjusted randomization.

Covariate-adjusted randomization (CAR) can reduce the risk of covariate imbalance and, when accounted for in analysis, increase the power of a trial. Despite CAR advances, stratified randomization remains the most common CAR method. Matched randomization (MR) randomizes treatment assignment within optimally identified matched pairs based on covariates and a distance matrix. When participants enroll sequentially, sequentially matched randomization (SMR) randomizes within matches found "on-the-fly" to meet a pre-specified matching threshold. However, pre-specifying the ideal threshold can be challenging and SMR yields less-optimal matches than MR. We extend SMR to allow multiple participants to be randomized simultaneously, to use a dynamic threshold, and to allow matches to break and rematch if a better match later enrolls (sequential rematched randomization; SRR). In simplified settings and a real-world application, we assess whether these extensions improve covariate balance, estimator/study efficiency, and optimality of matches. We investigate whether adjusting for more covariates can be detrimental upon covariate balance and efficiency as is the case of traditional stratified randomization. As secondary objectives, we use the case study to assess how SMR schemes compare side-by-side with common and related CAR schemes and whether adjusting for covariates in the design can be as powerful as adjusting for covariates in a parametric model. We find each SMR extension, individually and collectively, to improve covariate balance, estimator efficiency, study power, and quality of matches. We provide a case-study where CAR schemes with randomization-based inference can be as and more powerful than non-CAR schemes with parametric adjustment for covariates.

Validation of an algorithm to identify fractures among patients within the Veterans Health Administration.

OBJECTIVE: To validate an algorithm that identifies fractures using billing codes from the International Classification of Diseases Ninth Revision (ICD-9) and Tenth Revision (ICD-10) for inpatient, outpatient, and emergency department visits in a population of patients. METHODS: We identified and reviewed a random sample of 543 encounters for adults receiving care within a single Veterans Health Administration healthcare system and had a first fracture episode between 2010 and 2019. To determine if an encounter represented a true incident fracture, we performed chart abstraction and assessed the type of fracture and mechanism. We calculated the positive predictive value (PPV) for the overall algorithm and each component diagnosis code along with 95% confidence intervals. Inverse probabilities of selection sampling weights were used to reflect the underlying study population. RESULTS: The algorithm had an initial PPV of 73.5% (confidence interval [CI] 69.5, 77.1), with low performance when weighted to reflect the full population (PPV 66.3% [CI 58.8, 73.1]). The modified algorithm was restricted to diagnosis codes with PPVs > 50% and outpatient codes were restricted to the first outpatient position, with the exception of one high performing code. The resulting unweighted PPV improved to 90.1% (CI 86.2, 93.0) and weighted PPV of 91.3% (CI 86.8, 94.4). A confirmation sample demonstrated verified performance with PPV of 87.3% (76.0, 93.7). PPVs by location of care (inpatient, emergency department and outpatient) remained greater than 85% in the modified algorithm. CONCLUSIONS: The modified algorithm, which included primary billing codes for inpatient, outpatient, and emergency department visits, demonstrated excellent PPV for identification of fractures among a cohort of patients within the Veterans Health Administration system.

Changes in family involvement occasioned by FAMS mobile health intervention mediate changes in glycemic control over 12 months.

Mobile phone-delivered interventions have proven effective in improving glycemic control (HbA1c) in the short term among adults with type 2 diabetes (T2D). Family systems theory suggests engaging family/friend in adults' diabetes self-care may enhance or sustain improvements. In secondary analysis from a randomized controlled trial (N = 506), we examined intervention effects on HbA1c via change in diabetes-specific helpful and harmful family/friend involvement. We compared a text messaging intervention that did not target family/friend involvement (REACH), REACH plus family-focused intervention components targeting helpful and harmful family/friend involvement (REACH + FAMS), and a control condition. Over 6 months, both intervention groups experienced improvement in HbA1c relative to control, but at 12 months neither did. However, REACH + FAMS showed an indirect effect on HbA1c via change in helpful family/friend involvement at both 6 and 12 months while REACH effects were not mediated by family/friend involvement. Consistent with family systems theory, improvements in HbA1c mediated by improved family/friend involvement were sustained.

Comparison of COVID-19 versus influenza on the incidence, features, and recovery from acute kidney injury in hospitalized United States Veterans.

Acute kidney injury is a common complication in patients hospitalized with SARSCoV-2 (COVID-19), with prior studies implicating multiple potential mechanisms of injury. Although COVID-19 is often compared to other respiratory viral illnesses, few formal comparisons of these viruses on kidney health exist. In this retrospective cohort study, we compared the incidence, features, and outcomes of acute kidney injury among Veterans hospitalized with COVID-19 or influenza and adjusted for baseline conditions using weighted comparisons. A total of 3402 hospitalizations for COVID-19 and 3680 hospitalizations for influenza admitted between October 1, 2019 and May 31, 2020 across 127 Veterans Administration hospitals nationally were studied using the electronic medical record. Acute kidney injury occurred more frequently among those with COVID-19 compared to those with influenza (40.9% versus 29.4%, weighted analysis) and was more severe. Patients with COVID-19 were more likely to require mechanical ventilation and vasopressors and experienced higher mortality. Proteinuria and hematuria were frequent in both groups but more common in COVID-19. Recovery of kidney function was less common in patients with COVID-19 and acute kidney injury but was similar among survivors. Thus, findings from this study confirm that acute kidney injury is more common and severe among patients hospitalized with COVID-19 compared to influenza, a finding that may be driven largely by illness severity. Hence, the combined impact of these two illnesses on kidney health may be significant and have important implications for resource allocation.

Renin-angiotensin aldosterone inhibitor use at hospital discharge among patients with moderate to severe acute kidney injury and its association with recurrent acute kidney injury and mortality.

Recurrent episodes of acute kidney injury (AKI) are common among AKI survivors. Renin-angiotensin aldosterone inhibitors (RAASi) are often indicated for these patients but may increase the risk for recurrent AKI. Here, we examined whether RAASi associates with a higher risk for recurrent AKI and mortality among survivors of moderate to severe AKI in a retrospective cohort of Veterans who survived Stage II or III AKI. The primary exposure was RAASi at hospital discharge and the primary endpoint was recurrent AKI within 12 months. Cox proportional hazards models were fit on a propensity score-weighted cohort to compare time to recurrent AKI and mortality by RAASi exposure. Among 96,983 patients, 40% were on RAASi at discharge. Compared to patients who continued RAASi use, those discontinuing use experienced no difference in risk for recurrent AKI but had a significantly higher risk of mortality [hazard ratio 1.33 (95% confidence interval1.26-1.41)]. No differences in recurrent AKI risk was observed for non-users started or not on RAASi compared to prevalent users who continued RAASi. Subgroup analyses among those with diabetes, chronic kidney disease, heart failure, and malignancy were similar with exception of a modest reduction in recurrent AKI risk among RAASi discontinuers with chronic kidney disease. Thus, RAASi use among survivors of moderate to severe AKI was associated with little to no difference in risk for recurrent AKI but was associated with improved survival. Reinitiating or starting RAASi among patients with strong indications is warranted but should be balanced with individual overall risk for recurrent AKI and with adequate monitoring.

Development of a Typology of Diabetes-Specific Family Functioning Among Adults With Type 2.

BACKGROUND: Family members' responses to adults' diabetes and efforts to manage it vary widely. Multiple aspects of diabetes-specific family functioning have been identified as important for self-management and psychosocial well-being in theoretical (i.e., theories of social support and collaborative coping) and observational literature. PURPOSE: Develop a typological framework of diabetes-specific family functioning and examine cross-sectional associations between type and diabetes outcomes. METHODS: We used electronic health record (EHR) data to identify a cohort of 5,545 adults receiving outpatient care for type 2 diabetes and invited them to complete a survey assessing 10 dimensions of diabetes-specific family functioning. We used k-means cluster analysis to identify types. After type assignment, we used EHR data for the full cohort to generate sampling weights to correct for imbalance between participants and non-participants. We used weighted data to examine unadjusted associations between participant characteristics and type, and in regression models to examine associations between type and diabetes outcomes. Regression models were adjusted for sociodemographics, diabetes duration, and insulin status. RESULTS: We identified and named four types: Collaborative and Helpful (33.8%), Satisfied with Low Involvement (22.2%), Want More Involvement (29.6%), and Critically Involved (14.5%; reflecting the highest levels of criticism and harmful involvement). Across these types, hemoglobin A1c, diabetes distress, depressive symptoms, diabetes medication adherence, and diabetes self-efficacy worsened. After covariate adjustment, type remained independently associated with each diabetes outcome (all p's < .05). CONCLUSIONS: The typology extends theories of family support in diabetes and applications of the typology may lead to breakthroughs in intervention design, tailoring, and evaluation.

Mixed-Methods Randomized Evaluation of FAMS: A Mobile Phone-Delivered Intervention to Improve Family/Friend Involvement in Adults' Type 2 Diabetes Self-Care.

BACKGROUND: Family and friends have both helpful and harmful effects on adults' diabetes self-management. Family-focused Add-on to Motivate Self-care (FAMS) is a mobile phone-delivered intervention designed to improve family/friend involvement, self-efficacy, and self-care via monthly phone coaching, texts tailored to goals, and the option to invite a support person to receive texts. PURPOSE: We sought to evaluate how FAMS was received by a diverse group of adults with Type 2 diabetes and if FAMS improved diabetes-specific family/friend involvement (increased helpful and reduced harmful), diabetes self-efficacy, and self-care (diet and physical activity). We also assessed if improvements in family/friend involvement mediated improvements in self-efficacy and self-care. METHODS: Participants were prospectively assigned to enhanced treatment as usual (control), an individualized text messaging intervention alone, or the individualized text messaging intervention plus FAMS for 6 months. Participants completed surveys at baseline, 3 and 6 months, and postintervention interviews. Between-group and multiple mediator analyses followed intention-to-treat principles. RESULTS: Retention, engagement, and fidelity were high. FAMS was well received and helped participants realize the value of involving family/friends in their care. Relative to control, FAMS participants had improved family/friend involvement, self-efficacy, and diet (but not physical activity) at 3 and 6 months (all ps < .05). Improvements in family/friend involvement mediated effects on self-efficacy and diet for FAMS participants but not for the individualized intervention group. CONCLUSIONS: The promise of effectively engaging patients' family and friends lies in sustained long-term behavior change. This work represents a first step toward this goal by demonstrating how content targeting helpful and harmful family/friend involvement can drive short-term effects. TRIAL REGISTRATION NUMBER: NCT02481596.

Timing of Recovery From Moderate to Severe AKI and the Risk for Future Loss of Kidney Function.

RATIONALE & OBJECTIVE: The extent of recovery of kidney function following acute kidney injury (AKI) is known to be associated with future chronic kidney disease. Less is known about how the timing of recovery affects the rate of future loss of kidney function. STUDY DESIGN: We performed a retrospective cohort study examining the independent association between the timing of recovery from moderate to severe AKI and future loss of kidney function. SETTING & PARTICIPANTS: 47,903 adult US veterans with stage 2 or 3 AKI who recovered to within 120% of baseline creatinine level within 90 days of peak injury. EXPOSURE: The timing of recovery of kidney function from peak inpatient serum creatinine level grouped into 1 to 4, 5 to 10, 11 to 30, and 31 to 90 days. OUTCOME: A sustained 40% decline in estimated glomerular filtration rate below that calculated from the last serum creatinine level available during the 90-day recovery period or kidney failure (2 outpatient estimated glomerular filtration rates<15mL/min/1.73m2, dialysis procedures > 90 days apart, kidney transplantation, or registry within the US Renal Data System). ANALYTICAL APPROACH: Time to the primary outcome was examined using multivariable Cox proportional hazards regression. RESULTS: Among 47,903 patients, 29,316 (61%), 10,360 (22%), 4,520 (9%), and 3,707 (8%) recovered within 1 to 4, 5 to 10, 11 to 30, and 31 to 90 days, respectively. With a median follow-up of 42 months, unadjusted incidence rates for the kidney outcome were 2.01, 3.55, 3.86, and 3.68 events/100 person-years, respectively. Compared with 1 to 4 days, recovery within 5 to 10, 11 to 30, and 31 to 90 days was associated with increased rates of the primary outcome: adjusted HRs were 1.33 (95% CI, 1.24-1.43), 1.41 (95% CI, 1.28-1.54), and 1.58 (95% CI, 1.43-1.75), respectively. LIMITATIONS: Predominately male population, residual confounding, and inability to make causal inferences because of the retrospective observational study design. CONCLUSIONS: The timing of recovery provides an added dimension to AKI phenotyping and prognostic information regarding the future occurrence of loss of kidney function. Studies to identify effective interventions on the timing of recovery from AKI are warranted.

Detection of calibration drift in clinical prediction models to inform model updating.

Model calibration, critical to the success and safety of clinical prediction models, deteriorates over time in response to the dynamic nature of clinical environments. To support informed, data-driven model updating strategies, we present and evaluate a calibration drift detection system. Methods are developed for maintaining dynamic calibration curves with optimized online stochastic gradient descent and for detecting increasing miscalibration with adaptive sliding windows. These methods are generalizable to support diverse prediction models developed using a variety of learning algorithms and customizable to address the unique needs of clinical use cases. In both simulation and case studies, our system accurately detected calibration drift. When drift is detected, our system further provides actionable alerts by including information on a window of recent data that may be appropriate for model updating. Simulations showed these windows were primarily composed of data accruing after drift onset, supporting the potential utility of the windows for model updating. By promoting model updating as calibration deteriorates rather than on pre-determined schedules, implementations of our drift detection system may minimize interim periods of insufficient model accuracy and focus analytic resources on those models most in need of attention.

Long-acting Opioid Use and the Risk of Serious Infections: A Retrospective Cohort Study.

BACKGROUND: Although evidence from animal and human studies indicates opioid analgesics increase susceptibility to infections, it is unclear whether the risk varies by specific opioid. We compared the risk of serious infection among patients initiating long-acting opioid analgesics with and without previously reported immunosuppressive properties. METHODS: We conducted a retrospective cohort study of Tennessee Medicaid enrollees age ≥18 years initiating long-acting opioids (1995-2015). Hospitalizations for serious infection were identified using validated coding algorithms. We used multivariable Poisson regression models to calculate adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) to compare the infection risk among patients using long-acting opioids with known immunosuppressive properties (morphine, fentanyl, methadone) to the infection risk among patients using long-acting opioids without known immunosuppressive properties (oxycodone, oxymorphone, tramadol) accounting for demographics, opioid dose, comorbidities and pain conditions, medication use, frailty indicators, and healthcare encounter history using exposure propensity scores. We further compared users of individual long-acting opioids to long-acting morphine users (considered the prototypical immunosuppressive opioid). RESULTS: Among the 61 240 patients initiating opioids with immunosuppressive properties and 22 811 patients initiating opioids without immunosuppressive properties, we identified 1906 serious infections. Nonimmunosuppressive opioid users had a lower rate of infections than immunosuppressive opioid users (aIRR:0.78 [CI: 0.66-0.91]). Among individual opioids, oxycodone users had a lower rate of infection than morphine users (aIRR:0.73 [CI: 0.60-0.89]). There were no significant differences in the infection risk between other opioids and morphine. CONCLUSION: The risk of serious infections among long-acting opioid users varies by opioid type. Providers should carefully consider the risk of serious infections when making pain management decisions.

Evaluation of weight change and hypoglycaemia as mediators in the association between insulin use and death.

AIM: To evaluate whether weight change or hypoglycaemia mediates the association between insulin use and death. MATERIALS AND METHODS: In a retrospective cohort of veterans who filled a new prescription for metformin and added insulin or sulphonylurea (2001-2012), we assessed change in body mass index (BMI) and hypoglycaemia during the first 12 months of treatment intensification. Cox proportional hazards models compared the risk of death between treatment groups. Using the difference method, we estimated the indirect effect and proportion mediated through each mediator. A sensitivity analysis assessed mediators in the first 6 months of intensified therapy. RESULTS: Among 28 892 patients surviving 12 months, deaths per 1000 person-years were 15.4 for insulin users and 12.9 for sulphonylurea users (HR 1.20, 95% CI 0.87, 1.64). Change in BMI and hypoglycaemia mediated 13% (-98, 98) and -1% (-37, 71) of this association, respectively. Among 30 214 patients surviving 6 months, deaths per 1000 person-years were 34.8 for insulin users and 21.3 for sulphonylurea users (HR 1.66, 95% CI 1.28, 2.15). Change in BMI and hypoglycaemia mediated 9% (1, 23) and 0% (-9, 4) of this association, respectively. CONCLUSIONS: We observed an increased risk of death among metformin users intensifying treatment with insulin versus sulphonylurea and surviving 6 months of intensified therapy, but not among those surviving 12 months. This association was mediated in part by weight change.

Accuracy of a composite event definition for hypoglycemia.

PURPOSE: To evaluate the accuracy of a composite definition for the identification of hypoglycemia events that used both administrative claims and laboratory data in a cohort of patients. METHODS: We reviewed medical records in a sample of presumed hypoglycemia events among patients who received care at the Veterans Health Administration Tennessee Valley Healthcare System in 2001 to 2012. A hypoglycemia event was defined as a hospitalization or emergency department visit judged by the treating clinician to be due to hypoglycemia, or an outpatient laboratory or point-of-care blood glucose measurement <60 mg/dL. Based on medical record review, each event was classified as true positive (severe, documented symptomatic, documented asymptomatic) or false positive (probable symptomatic, not hypoglycemia). The positive predictive values (PPV) of the individual event types (hospitalization, emergency department, and outpatient) were estimated. RESULTS: Of 2250 events identified through the composite definition, 321 events (15 hospitalizations, 103 emergency department visits, and 203 outpatient events) were reviewed. The PPVs were 80% for hospitalization events, 48% for emergency department events, and 96% for outpatient events. The emergency department definition included a nonspecific diagnosis code for diabetic complications which captured many false positive events. Excluding this code from the definition improved the PPV for emergency department events to 70% and missed one true event. CONCLUSIONS: Our composite definition for hypoglycemia performed moderately well in a cohort of Veterans. Further evaluation of the emergency department events may be needed.

Opioid Analgesic Use and Risk for Invasive Pneumococcal Diseases: A Nested Case-Control Study.

Background: Although certain opioid analgesics have immunosuppressive properties and increase the risk for infections in animals, the clinical effects of prescription opioid use on infection risk among humans are unknown. Objective: To test the hypothesis that prescription opioid use is an independent risk factor for invasive pneumococcal disease (IPD). Design: Nested case-control study. Setting: Tennessee Medicaid database linked to Medicare and Active Bacterial Core surveillance system databases (1995 to 2014). Patients: 1233 case patients with IPD aged 5 years and older matched to 24 399 control participants by diagnosis date, age, and county of residence. Measurements: Opioid use was measured on the basis of pharmacy prescription fills. Invasive pneumococcal disease was defined by the isolation of Streptococcus pneumoniae from a normally sterile site. The odds of current opioid use were compared between the case and control groups, accounting for known IPD risk factors. Secondary analyses categorized opioid use by opioid characteristics, applied an IPD risk score to assure comparability between exposure groups, and analyzed pneumonia and nonpneumonia IPD cases separately. Results: Persons in the case group had greater odds than control participants of being current opioid users (adjusted odds ratio [aOR], 1.62 [95% CI, 1.36 to 1.92]). Associations were strongest for opioids that were long acting (aOR, 1.87 [CI, 1.24 to 2.82]), of high potency (aOR, 1.72 [CI, 1.32 to 2.25]), or were used at high dosages (50 to 90 morphine milligram equivalents [MME]/d: aOR, 1.71 [CI, 1.22 to 2.39]; ≥90 MME/d: aOR, 1.75 [CI, 1.33 to 2.29]). Results were consistent when the IPD risk score was taken into account and pneumonia and nonpneumonia IPD were analyzed separately. Limitations: Unmeasured confounding and measurement error, although sensitivity analyses suggested that neither was likely to affect results. Actual opioid use and other nonprescription use (such as illicit opioid use) were not measured. Conclusion: Opioid use is associated with an increased risk for IPD and represents a novel risk factor for these diseases. Primary Funding Source: National Institutes of Health.

Association of Smoking Cessation With Subsequent Risk of Cardiovascular Disease.

Importance: The time course of cardiovascular disease (CVD) risk after smoking cessation is unclear. Risk calculators consider former smokers to be at risk for only 5 years. Objective: To evaluate the association between years since quitting smoking and incident CVD. Design, Setting, and Participants: Retrospective analysis of prospectively collected data from Framingham Heart Study participants without baseline CVD (original cohort: attending their fourth examination in 1954-1958; offspring cohort: attending their first examination in 1971-1975) who were followed up through December 2015. Exposures: Time-updated self-reported smoking status, years since quitting, and cumulative pack-years. Main Outcomes and Measures: Incident CVD (myocardial infarction, stroke, heart failure, or cardiovascular death). Primary analyses included both cohorts (pooled) and were restricted to heavy ever smokers (≥20 pack-years). Results: The study population included 8770 individuals (original cohort: n = 3805; offspring cohort: n = 4965) with a mean age of 42.2 (SD, 11.8) years and 45% male. There were 5308 ever smokers with a median 17.2 (interquartile range, 7-30) baseline pack-years, including 2371 heavy ever smokers (406 [17%] former and 1965 [83%] current). Over 26.4 median follow-up years, 2435 first CVD events occurred (original cohort: n = 1612 [n = 665 among heavy smokers]; offspring cohort: n = 823 [n = 430 among heavy smokers]). In the pooled cohort, compared with current smoking, quitting within 5 years was associated with significantly lower rates of incident CVD (incidence rates per 1000 person-years: current smoking, 11.56 [95% CI, 10.30-12.98]; quitting within 5 years, 6.94 [95% CI, 5.61-8.59]; difference, -4.51 [95% CI, -5.90 to -2.77]) and lower risk of incident CVD (hazard ratio, 0.61; 95% CI, 0.49-0.76). Compared with never smoking, quitting smoking ceased to be significantly associated with greater CVD risk between 10 and 15 years after cessation in the pooled cohort (incidence rates per 1000 person-years: never smoking, 5.09 [95% CI, 4.52-5.74]; quitting within 10 to <15 years, 6.31 [95% CI, 4.93-8.09]; difference, 1.27 [95% CI, -0.10 to 3.05]; hazard ratio, 1.25 [95% CI, 0.98-1.60]). Conclusions and Relevance: Among heavy smokers, smoking cessation was associated with significantly lower risk of CVD within 5 years relative to current smokers. However, relative to never smokers, former smokers' CVD risk remained significantly elevated beyond 5 years after smoking cessation.

Association of Treatment With Metformin vs Sulfonylurea With Major Adverse Cardiovascular Events Among Patients With Diabetes and Reduced Kidney Function.

IMPORTANCE: Before 2016, safety concerns limited metformin use in patients with kidney disease; however, the effectiveness of metformin on clinical outcomes in patients with reduced kidney function remains unknown. OBJECTIVE: To compare major adverse cardiovascular events (MACE) among patients with diabetes and reduced kidney function who continued treatment with metformin or a sulfonylurea. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of US veterans receiving care within the national Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016. There were 174 882 persistent new users of metformin and sulfonylureas who reached a reduced kidney function threshold (estimated glomerular filtration rate <60 mL/min/1.73 m2 or creatinine ≥1.4 mg/dL for women or ≥1.5 mg/dL for men). Patients were followed up from reduced kidney function threshold until MACE, treatment change, loss to follow-up, death, or study end (December 2016). EXPOSURES: New users of metformin or sulfonylurea monotherapy who continued treatment with their glucose-lowering medication after reaching reduced kidney function. MAIN OUTCOMES AND MEASURES: MACE included hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death. The analyses used propensity score weighting to compare the cause-specific hazard of MACE between treatments and estimate cumulative risk accounting for the competing risks of changing therapy or noncardiovascular death. RESULTS: There were 67 749 metformin and 28 976 sulfonylurea persistent monotherapy users; the weighted cohort included 24 679 metformin and 24 799 sulfonylurea users (median age, 70 years [interquartile range {IQR}, 62.8-77.8]; 48 497 men [98%]; and 40 476 white individuals [82%], with median estimated glomerular filtration rate of 55.8 mL/min/1.73 m2 [IQR, 51.6-58.2] and hemoglobin A1c level of 6.6% [IQR, 6.1%-7.2%] at cohort entry). During follow-up (median, 1.0 year for metformin vs 1.2 years for sulfonylurea), there were 1048 MACE outcomes (23.0 per 1000 person-years) among metformin users and 1394 events (29.2 per 1000 person-years) among sulfonylurea users. The cause-specific adjusted hazard ratio of MACE for metformin was 0.80 (95% CI, 0.75-0.86) compared with sulfonylureas, yielding an adjusted rate difference of 5.8 (95% CI, 4.1-7.3) fewer events per 1000 person-years of metformin use compared with sulfonylurea use. CONCLUSIONS AND RELEVANCE: Among patients with diabetes and reduced kidney function persisting with monotherapy, treatment with metformin, compared with a sulfonylurea, was associated with a lower risk of MACE.

Acute kidney injury is a risk factor for subsequent proteinuria.

Acute kidney injury (AKI) is associated with subsequent chronic kidney disease (CKD), but the mechanism is unclear. To clarify this, we examined the association of AKI and new-onset or worsening proteinuria during the 12 months following hospitalization in a national retrospective cohort of United States Veterans hospitalized between 2004-2012. Patients with and without AKI were matched using baseline demographics, comorbidities, proteinuria, estimated glomerular filtration rate, blood pressure, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (ACEI/ARB) use, and inpatient exposures linked to AKI. The distribution of proteinuria over one year post-discharge in the matched cohort was compared using inverse probability sampling weights. Subgroup analyses were based on diabetes, pre-admission ACEI/ARB use, and AKI severity. Among the 90,614 matched AKI and non-AKI pairs, the median estimated glomerular filtration rate was 62 mL/min/1.73m2. The prevalence of diabetes and hypertension were 48% and 78%, respectively. The odds of having one plus or greater dipstick proteinuria was significantly higher during each month of follow-up in patients with AKI than in patients without AKI (odds ratio range 1.20-1.39). Odds were higher in patients with Stage II or III AKI (odds ratios 1.32-1.81) than in Stage I AKI (odds ratios 1.18-1.32), using non-AKI as the reference group. Results were consistent regardless of diabetes status or baseline ACEI/ARB use. Thus, AKI is a risk factor for incident or worsening proteinuria, suggesting a possible mechanism linking AKI and future CKD. The type of proteinuria, physiology, and clinical significance warrant further study as a potentially modifiable risk factor in the pathway from AKI to CKD.

Metformin use and incidence cancer risk: evidence for a selective protective effect against liver cancer.

PURPOSE: Several observational studies suggest that metformin reduces incidence cancer risk; however, many of these studies suffer from time-related biases and several cancer outcomes have not been investigated due to small sample sizes. METHODS: We constructed a propensity score-matched retrospective cohort of 84,434 veterans newly prescribed metformin or a sulfonylurea as monotherapy. We used Cox proportional hazard regression to assess the association between metformin use compared to sulfonylurea use and incidence cancer risk for 10 solid tumors. We adjusted for clinical covariates including hemoglobin A1C, antihypertensive and lipid-lowering medications, and body mass index. Incidence cancers were defined by ICD-9-CM codes. RESULTS: Among 42,217 new metformin users and 42,217 matched-new sulfonylurea users, we identified 2,575 incidence cancers. Metformin was inversely associated with liver cancer (adjusted hazard ratio [aHR] = 0.44, 95% CI 0.31, 0.64) compared to sulfonylurea. We found no association between metformin use and risk of incidence bladder, breast, colorectal, esophageal, gastric, lung, pancreatic, prostate, or renal cancer when compared to sulfonylurea use. CONCLUSIONS: In this large cohort study that accounted for time-related biases, we observed no association between the use of metformin and most cancers; however, we found a strong inverse association between metformin and liver cancer. Randomized trials of metformin for prevention of liver cancer would be useful to verify these observations.