BACKGROUND:Lithium has long been considered to reduce suicidal behaviour in patients with affective disorders, but evidence from large real-world populations remains limited. OBJECTIVE:To estimate the effects of lithium initiation and continuation on suicide deaths and non-lethal suicidal behaviours among adults with bipolar disorder or major depressive disorder. METHODS:We emulated two target trials using electronic health records and administrative claims from US veterans between January 2010 and December 2022. The first trial benchmarked results against the CSP-590 randomised trial by estimating the 1-year risk of suicide-related events (non-fatal suicide attempts, hospitalisations to prevent suicide or suicide deaths) among patients with a recent suicide attempt initiating lithium versus not initiating lithium. The second trial extended follow-up to 10 years to estimate risks of suicide deaths and non-lethal suicidal behaviours separately, including subgroup analyses by age and diagnosis. An additional analysis removed the requirement of a prior suicide attempt. FINDINGS:In the benchmarking analysis, the 1-year risk ratio for suicide-related events comparing lithium initiation with no initiation was 1.06 (95% CI 1.01 to 1.12), consistent with findings from the CSP-590 trial. In the extended analysis, the 10-year per-protocol risk ratio for suicide death was 1.00 (95% CI 0.86 to 1.15) and for non-lethal suicidal behaviours was 0.96 (95% CI 0.90 to 1.02). Results were similar among individuals with and without a prior suicide attempt. CONCLUSION:When added to ongoing pharmacological treatment for patients with affective disorders, lithium may not substantially reduce suicide risk highlighting the need for additional suicide prevention strategies in this population. Limitations include lack of information on adherence, dosage or blood levels of lithium which may have obscured existing differences. CLINICAL IMPLICATIONS:Our findings suggest that adding lithium therapy to the ongoing treatment regimens of patients with affective disorders for the sole purpose of reducing suicide may not be well-tolerated or meaningfully reduce suicide risk.

Objective: Although treat-to-target urate-lowering therapy (ULT) is endorsed as best practice in gout management, limited data exist on its impact on health-related quality of life (HRQoL). We assessed the impact of treat-to-target ULT on HRQoL among participants receiving protocolized gout care, identifying factors associated with HRQoL and HRQoL change. Methods: This was a post hoc analysis of a 72-week randomized trial, pooling data from allopurinol and febuxostat treatment arms. The Veterans RAND-12 Item Health Survey and EuroQol 5-Dimension 3-Level (EQ-5D-3L) were administered at baseline and at 24, 48, and 72 weeks. HRQoL changes over follow-up were examined using paired t-tests. Factors associated with baseline HRQoL were evaluated using multivariable linear regression. General estimating equations were used to identify determinants of HRQoL change over follow-up. Results: Participants (N = 878) in this analysis were 98.9% male, had a mean age of 62.4 years, and 67.4% self-reported White race. HRQoL scores overall, and particularly the domains of physical function, mobility and pain, improved significantly over 72 weeks (P < 0.001) with improvements noted by 24 weeks. Poorer enrollment HRQoL was associated with younger age, non-White race, tophi (for EQ-5D-3L), higher serum urate level, and greater comorbidity. Baseline factors associated with HRQoL improvements over 72 weeks of ULT included lower C-reactive protein level and lower comorbidity scores with similar changes observed by ULT assignment. Conclusion: Treat-to-target ULT in gout is accompanied by HRQoL improvements evident by 24 weeks and sustained through 72 weeks. HRQoL gains with treat-to-target ULT are most prominent in the domains of physical function, mobility, and pain and are greatest in those with lower baseline levels of inflammation and comorbidity.

OBJECTIVE:Though gout guidelines endorse treat-to-target urate-lowering therapy (ULT), its long-term durability following treat-to-target implementation has not been extensively studied. Examining follow-up data from a trial implementing treat-to-target management, we evaluated the frequency and determinants of ULT persistence. METHODS:This analysis examined participants completing the 72-week STOP Gout trial with available follow-up data extending 2-years post-study. Participants were followed passively using administrative and electronic health record data with persistence defined by a ULT dispensing episode overlapping with the 2-year post-study time point. Associations of participant factors with ULT persistence were examined using multivariable logistic regression. RESULTS:Participants in this analysis (n = 638) were predominantly male (99 %) and had a mean age of 62.7 years. At 2-years post-study, 66 % continued ULT. Adjusting for covariates, ≥2 rheumatology visits post-study (vs. none) was associated with greater ULT persistence (aOR 1.75; 95 % CI 1.13-2.72). ULT persistence was lower in individuals reporting Black/African American race (aOR 0.56; 95 % CI 0.36-0.87), Hispanic ethnicity (aOR 0.21; 95 % CI 0.09-0.50), and better quality-of-life at the beginning of post-study follow-up. Though not reaching significance, achievement of serum urate goal at 48-weeks during STOP Gout study demonstrated a borderline association with greater long-term persistence (aOR 1.68; 95 % CI 0.99-2.85). CONCLUSION:Though interventions implementing treat-to-target ULT have demonstrated efficacy in trials, this study suggests that such interventions may have limited durability following transitions back to real-world gout management. The issue of limited treatment durability appears to be compounded among underrepresented patient populations and improved in the context of ongoing rheumatological care.

Background/Objectives: Antihypertensive treatment is crucial for preventing major adverse cardiovascular events, but suboptimal adherence remains a challenge. Methods: This is a secondary analysis of routine care data from a large pragmatic trial comparing two thiazide diuretics: chlorthalidone (CTD) and hydrochlorothiazide (HCTZ). In the trial, 13,523 older hypertensive patients were randomized from 72 Veterans Affairs medical centers. Medication possession ratio (MPR), reflecting adherence to either study medication (CTD or HCTZ), was used and compared across all randomized patients. Results: The overall median MPR was 95% for all randomized patients and 80% for 6656 individuals who reached 2.4 years for the average follow-up. Lower MPR was observed in Black, separated, urban-living, and comorbid patients. About 30% of the participants (n = 4022) were categorized as non-adherent using a definition of MPR < 80%. Those with baseline systolic blood pressure ≥ 136, recent smoking history, and prior heart failure and Black participants had decreased odds of having an MPR ≥ 80%, while increased odds of reaching that threshold were observed in those who had an eGFR ≥ 60, received ≥3 antihypertensive medications, were married, or resided in rural areas. Conclusions: This analysis provided assessment of real-world medication adherence in a sizable older hypertensive cohort. The proportion of non-adherence found in our analysis was comparable to national trends for US older adults taking blood pressure medications. Identifying sociodemographic characteristics and health conditions associated with non-adherence can help clinicians design targeted interventions for improved adherence to clinically prescribed medications. This is important as hypertension and the older adult population are both expected to grow significantly in the future.

OBJECTIVES:We tested the hypotheses that individuals with gout would have distinct circulating inflammatory biomarker patterns compared with non-gout controls and that these differences would be attenuated with highly-effective urate-lowering therapy (ULT). METHODS:This case-control and longitudinal cohort study utilized longitudinal serum samples from a subset of participants from the STOP Gout study and non-gout controls from an institutional biobank at a single time point. Twenty pre-selected inflammatory and cardiometabolic biomarkers were measured and varimax-rotated principal component analysis (PCA) performed. An inflammatory score was generated using standardized biomarker values representing PCs associated with gout and compared between controls and gout patients, and among gout patients over time. A generalized estimating equation was used to assess interactions between clinical factors and change in inflammatory score over time. RESULTS:Five PCs statistically differed in gout (n = 278) at baseline vs. controls (n = 275) after accounting for covariates. Mean inflammatory scores of gout cases at all three time points were increased vs. controls (p < 0.001). There was a decrease in inflammatory scores at both 24- (p = 0.01) and 48-weeks (p < 0.001) vs. baseline among gout cases. Higher baseline score and time were associated with reductions in inflammatory score, whereas hypertension and higher baseline serum urate were associated with an increased inflammatory score. CONCLUSION:Gout is characterized by distinct patterns of circulating inflammatory biomarkers and these appear to change over time with treat-to-target ULT to approximate controls. This study supports the importance of treat-to-target ULT in gout management not only for flare prevention, but also to mitigate systemic inflammation.

Background:Chronic kidney disease (CKD) is prevalent among US Veterans. Identifying patients undergoing dialysis in real-time is crucial for implementing patient safety measures, including stewardship interventions, such as medication dosing adjustments. Limited feasible and accurate tools exist for near-real-time identification. This study aimed to develop a renal replacement therapy (RRT) flag using structured data in the Veterans Health Administration (VHA) electronic health record (EHR). Methods:Data from Veterans who underwent cardiovascular implantable electronic device (CIED) procedures (9/2015-12/2019) were linked to US Renal Data Systems (USRDS) data. Potential identifiers included outpatient hemodialysis procedure records, community care hemodialysis consults, ICD-10 diagnoses, and serum creatinine (SCr) >4 mg/dL. USRDS served as the comparison standard, and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Logistic regression determined the area under the curve (AUC). Results:Among 37,706 CIED procedures on 34,994 Veterans, 967 patients (2.6%) were identified by USRDS as ever receiving RRT (hemodialysis and peritoneal dialysis or transplant), with 520 (1.4%) actively receiving RRT at the time of CIED. The RRT flag, combining ≥4 outpatient procedures in the prior 30 days, ≥1 consult in the prior year, and/or SCr >4 mg/dL, achieved an AUC of 0.976 (95% CI: 0.97-0.98), with high sensitivity (0.96; 95% CI: 0.94-0.97) and specificity (0.99; 95% CI: 0.99-1.00). The PPV was 0.70 (95% CI: 0.67-0.74). Performance was slightly lower when consults were replaced with ICD codes. Conclusions:We developed an accurate electronic flag using structured data to identify active RRT within VHA among Veterans undergoing invasive procedures, supporting patient safety and care adjustments. This flag addresses a crucial patient safety gap and supports expansion of stewardship efforts.

Importance Patients with prior myocardial infarction (MI) or stroke have a greater risk of recurrent cardiovascular (CV) events. Objective To evaluate the association of chlorthalidone (CTD) vs hydrochlorothiazide (HCTZ) with CV outcomes and noncancer deaths in participants with and without prior MI or stroke. Design, Setting, and Participants This was a prespecified secondary analysis of the Diuretic Comparison Project (DCP), a pragmatic randomized clinical trial conducted within 72 participating Veterans Affairs health care systems from June 2016 to June 2021, in which patients aged 65 years or older with hypertension taking HCTZ at baseline were randomized to continue HCTZ or switch to CTD at pharmacologically comparable doses. This secondary analysis was performed from January 3, 2023, to February 29, 2024. Exposures Pharmacologically comparable daily dose of HCTZ or CTD and history of MI or stroke. Main Outcomes and Measures Outcome ascertainment was performed from randomization to the end of the study. The primary outcome consisted of a composite of stroke, MI, urgent coronary revascularization because of unstable angina, acute heart failure hospitalization, or noncancer death. Additional outcomes included achieved blood pressure and hypokalemia (potassium level <3.1 mEq/L; to convert to mmol/L, multiply by 1.0). Results The DCP randomized 13 523 participants to CTD or HCTZ, with a mean (SD) study duration of 2.4 (1.4) years. At baseline, median age was 72 years (IQR, 69-75 years), and 96.8% were male. Treatment effect was evaluated in subgroups of participants with (n = 1455) and without (n = 12 068) prior MI or stroke at baseline. There was a significant adjusted interaction between treatment group and history of MI or stroke. Participants with prior MI or stroke randomized to CTD had a lower risk of the primary outcome than those receiving HCTZ (105 of 733 [14.3%] vs 140 of 722 [19.4%]; hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) compared with participants without prior MI or stroke, among whom incidence of the primary outcome was slightly higher in the CTD arm compared with the HCTZ arm (597 of 6023 [9.9%] vs 535 of 6045 [8.9%]; HR, 1.12; 95% CI, 1.00-1.26; P = .054) (P = .01 for interaction). The incidence of a nadir potassium level less than 3.1 mEq/L and hospitalization for hypokalemia differed among those with and without prior MI or stroke when comparing those randomized to CTD vs HCTZ, with a difference only among those without prior MI or stroke (potassium level <3.1 mEq/L: prior MI or stroke, 43 of 733 [5.9%] vs 37 of 722 [5.1%] [P = .57]; no prior MI or stroke, 292 of 6023 [4.9%] vs 206 of 6045 [3.4%] [P < .001]; hospitalization for hypokalemia: prior MI or stroke, 14 of 733 [1.9%] vs 16 of 722 [2.2%] [P = .72]; no prior MI or stroke: 84 of 6023 [1.4%] vs 57 of 6045 [0.9%] [P = .02]). Conclusions and Relevance Results of this secondary analysis of the DCP trial suggest that CTD may be associated with reduced major adverse CV events and noncancer deaths in patients with prior MI or stroke compared with HCTZ.

Background: Pragmatic trials are gaining popularity as a cost-effective way to examine treatment effectiveness and generate timely comparative evidence. Incorporating supplementary real -world data is recommended for robust outcome monitoring. However, detailed operational guidelines are needed to inform effective use and integration of heterogeneous databases. Objective: Lessons learned from the Veterans Affairs (VA) Diuretic Comparison Project (DCP) are reviewed, providing adaptable recommendations to capture clinical outcomes from real -world data. Methods: Non -cancer deaths and major cardiovascular (CV) outcomes were determined using VA, Medicare, and National Death Index (NDI) data. Multiple ascertainment strategies were applied, including claims -based algorithms, natural language processing, and systematic chart review. Results: During a mean follow-up of 2.4 (SD = 1.4) years, 907 CV events were identified within the VA healthcare system. Slight delays (-1 year) were expected in obtaining Medicare data. An additional 298 patients were found having a CV event outside of the VA in 2016 - 2021, increasing the CV event rate from 3.5 % to 5.7 % (770 of 13,523 randomized). NDI data required -2 years waiting period. Such inclusion did not increase the number of deaths identified (all 894 deaths were captured by VA data) but enhanced the accuracy in determining cause of death. Conclusion: Our experience supports the recommendation of integrating multiple data sources to improve clinical outcome ascertainment. While this approach is promising, hierarchical data aggregation is required when facing different acquisition timelines, information availability/completeness, coding practice, and system configurations. It may not be feasible to implement comparable applications and solutions to studies conducted under different constraints and practice. The recommendations provide guidance and possible action plans for researchers who are interested in applying cross -source data to ascertain all study outcomes.

BACKGROUND:The Diuretic Comparison Project (DCP) was a multi-center, embedded pragmatic trial conducted within the VA healthcare system comparing chlorthalidone and hydrochlorothiazide in preventing major adverse cardiovascular events and non-cancer deaths in hypertensive patients. Study procedures were decentralized, and facility leadership first had to agree and accept study procedures before staff approached participants. Recent evidence suggests facilities that choose and choose not to participate in trials may differ and this study considered such differences within DCP. METHODS:A cross-sectional comparison of facilities participating in DCP was conducted with data from the study start (June 2016) including: 2016 American Community Survey, 2016 Strategic Analytics for Improvement and Learning reports, star ratings, and 2014 hospital complexity. Characteristics of participating and non-participating centers were compared using logistic regression, including county-level socio-economic features and hospital-level performance. RESULTS:Of 144 VA medical centers, leadership at 75 centers (52 %) initiated participation. Facilities in highly-urban and higher median income counties were more likely to participate, as were higher-complexity facilities. Facilities with research experience were 2.18 times as likely to participate. No other hospital performance metrics or county-level demographics were associated with participation. CONCLUSIONS:Overall, this study suggests research exposure and quality care metrics may impact a facility's decision to participate. These results highlight key considerations for recruitment to multi-site, and particularly pragmatic, clinical trials. Consideration of supporting facilities that have not historically participated in research may be fruitful for recruitment. These results emphasize the importance of education about pragmatic study design and its integration with clinical care.

Rationale & Objective We conducted a prespecified examination of the efficacy and safety of allopurinol and febuxostat administered using a treat-to-target strategy in trial participants with chronic kidney disease (CKD). Study Design Prespecified sub cohort analysis of a randomized controlled trial. Setting & Participants: A sub study of the STOP Gout trial in participants with CKD. CKD was defined as an eGFR 30-59 mL/min/1.73 m2 at baseline. Exposure Trial participants with CKD and gout and serum urate (sUA) concentration ≥6.8 mg/dL were randomized 1:1 to receive allopurinol or febuxostat. Urate lowering therapy (ULT) was titrated during weeks 0-24 to achieve a goal sUA of <6.0 mg/dl (<5.0 mg/dl with tophi) (Phase 1) and maintained during weeks 25-48 (Phase 2). Gout flare was assessed between weeks 49-72 (Phase 3). Outcome Gout flare between weeks 49-72 (Phase 3) was the primary outcome. Secondary outcomes included sUA goal achievement and ULT dosing at end of Phase 2, and serious adverse events (SAEs). Analytical Approach Outcomes between treatment groups were compared using logistic regression models for binary outcomes, and Poisson regression for flare rates. Multivariable models were subsequently used, adjusting for factors identified to be imbalanced by treatment arm. Results 351 of 940 participants (37.3%) had CKD; 277 were assessed for the primary outcome. Fewer patients randomized to allopurinol had a flare during phase 3 (32% vs 45%; p=0.02) despite similar attainment of sUA goal (79% vs. 81%; p=0.6) by the end of Phase 2. Acute kidney injury (AKI) was more common in participants with stage 3 CKD randomized to allopurinol compared to febuxostat. Limitations Limited power to assess infrequent safety events, largely male, older population. Conclusions Allopurinol and febuxostat are similarly efficacious and well-tolerated in the treatment of gout in people with CKD when used in a treat-to-target regimen.

OBJECTIVE:Initiating urate-lowering therapy (ULT) in gout can precipitate arthritis flares. There have been limited comparisons of flare risk during the initiation and escalation of allopurinol and febuxostat, administered as a treat-to-target strategy with optimal anti-inflammatory prophylaxis. METHODS:This was a post-hoc analysis of a 72-week randomized, double-blind, placebo-controlled, noninferiority trial comparing the efficacy of allopurinol and febuxostat. For this analysis, the occurrence of flares was examined during weeks 0 to 24 when ULT was initiated and titrated to a serum urate (sUA) goal of less than 6 mg/dl (<5 mg/dl if tophi). Flares were assessed at regular intervals through structured participant interviews. Predictors of flare, including treatment assignment, were examined using multivariable Cox proportional hazards regression. RESULTS:Study participants (n = 940) were predominantly male (98.4%) and had a mean age of 62.1 years with approximately equal proportions receiving allopurinol or febuxostat. Mean baseline sUA was 8.5 mg/dl and all participants received anti-inflammatory prophylaxis (90% colchicine). In a multivariable model, there were no significant associations of ULT treatment (hazard ratio [HR] 1.17; febuxostat vs allopurinol), ULT-dose escalation (HR 1.18 vs no escalation), prophylaxis type, or individual comorbidity with flare and no evidence of ULT-dose escalation interaction. Factors independently associated with flare risk during ULT initiation/escalation included younger age, higher baseline sUA, and absence of tophi. CONCLUSION:These results demonstrate that gout flare risk during the initiation and titration of allopurinol is similar to febuxostat when these agents are administered according to a treat-to-target strategy using gradual ULT-dose titration and best practice gout flare prophylaxis.

Importance Hypertension is a risk factor for the development and progression of chronic kidney diseas (CKD). It is unclear whether different thiazide diuretics have a differential impact on kidney outcomes. Objective To compare kidney outcomes in patients with hypertension taking chlorthalidone and hydrochlorothiazide. Design, Setting, and Participants This prespecified secondary analysis of the Diuretic Comparison Project, a randomized clinical trial comparing chlorthalidone and hydrochlorothiazide for the treatment of hypertension, was conducted between June 1, 2016, and June 1, 2022, through Veterans Affairs facilities nationwide. This analysis extended follow-up to December 31, 2023. Veterans 65 years or older with hypertension who were taking hydrochlorothiazide were included. Intervention The Diuretic Comparison Project randomized 13 523 participants to continue hydrochlorothiazide or switch to chlorthalidone. Main Outcome and Measures The main kidney outcome was CKD progression, defined as doubling of serum creatinine level from baseline, a terminal estimated glomerular filtration rate (eGFR) less than 15 mL/min, or dialysis initiation. Results Analysis included 12 265 participants (90.7%) with a baseline and 1 or more follow-up creatinine measurements (median [IQR] age, 71 [69-75] years; 3.2% female and 96.8% male). The mean (SD) study duration was 3.9 (1.3) years. Chlorthalidone was not superior to hydrochlorothiazide at preventing kidney outcomes (369 of 6118 [6.0%] vs 396 of 6147 [6.4%]; hazard ratio [HR], 0.94; 95% CI, 0.81-1.08; P = .37). Similar results were observed when a 40% or greater reduction of eGFR was substituted for doubling of creatinine in the above outcome, as well as any of the components of the primary composite outcome. There was no difference in the incidence of CKD (961 of 4520 [21.3%] for chlorthalidone vs 939 of 4518 [20.8%] for hydrochlorothiazide; P = .59) or acute kidney injury requiring hospitalization (391 [6.4%] for chlorthalidone vs 379 [6.2%] for hydrochlorothiazide; P = .63) between groups. However, a statistically significant increased incidence of hypokalemia for chlorthalidone vs hydrochlorothiazide was observed (545 [8.9%] vs 426 [6.9%]; P < .001). Conclusions and Relevance Chlorthalidone was not superior to hydrochlorothiazide for kidney outcomes but was associated with an increased risk for hypokalemia. Given these findings, clinicians should feel confident using either agent for the treatment of hypertension and kidney outcomes. Trial RegistrationClinicalTrials.gov Identifier: NCT02185417