Strategies for secondary use of real-world clinical and administrative data for outcome ascertainment in pragmatic clinical trials.

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 âˆ¼2 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.

Chlorthalidone vs Hydrochlorothiazide for Hypertension Treatment After Myocardial Infarction or Stroke: A Secondary Analysis of a Randomized Clinical Trial.

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. Trial Registration: ClinicalTrials.gov Identifier: NCT02185417.

Role of Diuretics in Cardiovascular Events and Mortality in Systolic Blood Pressure Intervention Trial: A Post Hoc Analysis.

BACKGROUND: In a post hoc analysis, we examined whether postrandomization diuretics use can explain and/or mediate the beneficial effects of intensive systolic BP lowering on cardiovascular disease and all-cause mortality in the Systolic Blood Pressure Intervention Trial (SPRINT). METHODS: SPRINT was a randomized, controlled trial of 9361 participants comparing the effects of intensive (systolic BP target <120 mm Hg) versus standard (systolic BP target <140 mm Hg) BP control on a primary composite cardiovascular end point in participants aged 50 years or older with systolic BP of 130-180 mm Hg. In time-varying multivariable Cox analyses, we assessed hazard ratios (HRs) of cardiovascular end points and all-cause mortality in participants on thiazide type, loop and/or potassium (K) sparing, or no diuretics. We also conducted mediation analysis to formally assess the role of diuretics in the effects of intensive systolic BP lowering. RESULTS: At baseline, diuretics were prescribed in 46% and 48% of participants in standard and intensive systolic BP-lowering groups, respectively, and in 46% and 74% in the corresponding groups during the trial. The lower risk of cardiovascular end points in the intensive group (HR, 0.75; 95% confidence interval [CI], 0.64 to 0.89) persisted after adjustment for postrandomization time-varying diuretics use (HR, 0.74; 95% CI, 0.62 to 0.89). Across the entire study population, time-varying diuretics use was not associated with cardiovascular end points (compared with no diuretics, HR for thiazide type, 0.89; 95% CI, 0.73 to 1.10, and loop/K sparing, 1.29; 95% CI, 0.97 to 1.73). However, thiazide-type diuretics were associated with lower risk of cardiovascular end points in the intensive (HR, 0.62; 95% CI, 0.46 to 0.85) but not in the standard (HR, 1.07; 95% CI, 0.82 to 1.39) group. In mediation analysis, HRs for total effect, direct effect (not mediated through diuretics use), and indirect effect (mediated through diuretics) of the intervention on cardiovascular end points were 0.66 (95% CI, 0.54 to 0.79), 0.67 (95% CI, 0.54 to 0.81), and 0.98 (95% CI, 0.88 to 1.10), respectively. The results were largely similar for all-cause mortality. CONCLUSIONS: The favorable effects of intensive systolic BP lowering on cardiovascular end points and all-cause mortality in SPRINT were independent of and not mediated by time-varying diuretics use. However, thiazide-type diuretics use associated with benefit if intensive systolic BP lowering was targeted.

Similar cardiovascular outcomes in patients with diabetes and established or high risk for coronary vascular disease treated with dulaglutide with and without baseline metformin / Desfechos cardiovasculares semelhantes em pacientes com diabetes e risco estabelecido ou alto para doença vascular coronariana tratada com dulaglutida com e sem linha de base metformina

Objective Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. Research design and methods Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular or unknown causes. Key secondary outcomes included a microvascular composite endpoint, all-cause death, and heart failure. The effect of dulaglutide in patients with and without baseline metformin was evaluated by a Cox regression hazard model with baseline metformin, dulaglutide assignment, and their interaction as independent variables. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox regression model with adjustments for factors differing at baseline between people with vs. without metformin, identified using the backward selection. Results Compared to patients with metformin at baseline (n = 8037; 81%), those without metformin (n = 1864; 19%) were older and slightly less obese and had higher proportions of women, prior CV events, heart failure, and renal disease. The primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without. There was no significant difference in the effect of dulaglutide on the primary outcome in patients with vs. without metformin at baseline [HR 0.92 (CI 0.81­1.05) vs. 0.78 (CI 0.61­0.99); interaction P = 0.18]. Findings for key secondary outcomes were similar in patients with and without baseline metformin. Conclusion This analysis suggests that the cardioprotective effect of dulaglutide is unaffected by the baseline use of metformin therapy.

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial

Background Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. Methods REWIND was a multicenter, randomized, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m² (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1­5·9) comprising 51 820 person years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77­0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68­0·87; p<0·0001), with HRs of 0·89 (0·78­1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39­1·44; p=0·39) for chronic renal replacement therapy. (AU)

Synopsis of the 2020 U.S. Department of Veterans Affairs/U.S. Department of Defense Clinical Practice Guideline: The Diagnosis and Management of Hypertension in the Primary Care Setting

This guideline represents an important step toward clarifying the evidence regarding the management of patients with hypertension within the VA/DoD primary care settings. As with other clinical practice guidelines, challenges remain, such as evidence gaps, the need to develop effective strategies for guideline implementation, and the need for strategies to evaluate the effect of guideline adherence on clinical outcomes. This guideline is primarily intended for health care practitioners in primary care, including physicians, nurse practitioners, physician assistants, pharmacists, nurses, and others involved in the care of patients with hypertension, although it may also be informative for specialty care practitioners.