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.

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.

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.

Orthostatic Hypotension, Hypertension Treatment, and Cardiovascular Disease: An Individual Participant Meta-Analysis.

Importance: There are ongoing concerns about the benefits of intensive vs standard blood pressure (BP) treatment among adults with orthostatic hypotension or standing hypotension. Objective: To determine the effect of a lower BP treatment goal or active therapy vs a standard BP treatment goal or placebo on cardiovascular disease (CVD) or all-cause mortality in strata of baseline orthostatic hypotension or baseline standing hypotension. Data Sources: Individual participant data meta-analysis based on a systematic review of MEDLINE, EMBASE, and CENTRAL databases through May 13, 2022. Study Selection: Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) with orthostatic hypotension assessments. Data Extraction and Synthesis: Individual participant data meta-analysis extracted following PRISMA guidelines. Effects were determined using Cox proportional hazard models using a single-stage approach. Main Outcomes and Measures: Main outcomes were CVD or all-cause mortality. Orthostatic hypotension was defined as a decrease in systolic BP of at least 20 mm Hg and/or diastolic BP of at least 10 mm Hg after changing position from sitting to standing. Standing hypotension was defined as a standing systolic BP of 110 mm Hg or less or standing diastolic BP of 60 mm Hg or less. Results: The 9 trials included 29 235 participants followed up for a median of 4 years (mean age, 69.0 [SD, 10.9] years; 48% women). There were 9% with orthostatic hypotension and 5% with standing hypotension at baseline. More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline orthostatic hypotension (hazard ratio [HR], 0.81; 95% CI, 0.76-0.86) similarly to those with baseline orthostatic hypotension (HR, 0.83; 95% CI, 0.70-1.00; P = .68 for interaction of treatment with baseline orthostatic hypotension). More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline standing hypotension (HR, 0.80; 95% CI, 0.75-0.85), and nonsignificantly among those with baseline standing hypotension (HR, 0.94; 95% CI, 0.75-1.18). Effects did not differ by baseline standing hypotension (P = .16 for interaction of treatment with baseline standing hypotension). Conclusions and Relevance: In this population of hypertension trial participants, intensive therapy reduced risk of CVD or all-cause mortality regardless of orthostatic hypotension without evidence for different effects among those with standing hypotension.

A Centralized EHR-Based Model for the Recruitment of Rural and Lower Socioeconomic Participants in Pragmatic Trials: A Secondary Analysis of the Diuretic Comparison Project.

Importance: Participant diversity is important for reducing study bias and increasing generalizability of comparative effectiveness research. Objective: Demonstrate the operational efficiency of a centralized electronic health record (EHR)-based model for recruiting difficult-to-reach participants in a pragmatic trial. Design, Setting, and Participants: This comparative effectiveness study was a secondary analysis of Diuretic Comparison Project, a randomized clinical trial conducted between 2016 and 2022 (mean [SD] follow-up, 2.4 [1.4] years) comparing 2 commonly prescribed antihypertensives, which used an EHR-based recruitment model. Electronic study workflows, in tandem with routine clinical practice, were adapted by 72 Veteran Affairs (VA) primary care networks. Data were analyzed from August to December 2022. Main Outcomes and Measures: Measures reflecting recruitment capacity (monthly rate), operational efficiency (median time for completion of electronic procedures), and geographic reach (percentage of patients recruited from rural areas) were examined. Results: A total of 13 523 patients with hypertension (mean [SD] age, 72 [5.4] years; 13 092 male [96.8%]) were recruited from 537 outpatient clinics. Approximately 205 patients were randomized per month and a median of 35 days (Q1-Q3, 23-80 days) was needed to complete electronic recruitment. The annual income was below the national median for 69% of the cohort. Patients from all 50 states, Puerto Rico, and the District of Columbia were included and 45% resided in rural areas. Conclusions and Relevance: In this secondary analysis of a multicenter pragmatic trial, a centralized EHR-based recruitment model was associated with improved participation from underrepresented groups. These participants often are difficult to reach, with their exclusion potentially biasing trial results; eliminating in-person study visits and local site involvement can minimize barriers for the recruitment of patients from rural and lower socioeconomic areas. Trial Registration: The Diuretic Comparison Project (DCP) was registered on ClinicalTrials.gov Identifier: NCT02185417.

Sex-Specific Effects of Blood Pressure Lowering Pharmacotherapy for the Prevention of Cardiovascular Disease: An Individual Participant-Level Data Meta-Analysis.

BACKGROUND: Whether the relative effects of blood pressure (BP)-lowering treatment on cardiovascular outcomes differ by sex, particularly when BP is not substantially elevated, has been uncertain. METHODS: We conducted an individual participant-level data meta-analysis of randomized controlled trials of pharmacological BP lowering. We pooled the data and categorized participants by sex, systolic BP categories in 10-mm Hg increments from <120 to ≥170 mm Hg, and age categories spanning from <55 to ≥85 years. We used fixed-effect one-stage individual participant-level data meta-analyses and applied Cox proportional hazard models, stratified by trial, to analyze the data. RESULTS: We included data from 51 randomized controlled trials involving 358 636 (42% women) participants. Over 4.2 years of median follow-up, a 5-mm Hg reduction in systolic BP decreased the risk of major cardiovascular events both in women and men (hazard ratio [95% CI], 0.92 [0.89-0.95] for women and 0.90 [0.88-0.93] for men; P for interaction, 1). There was no evidence for heterogeneity of relative treatment effects by sex for the major cardiovascular disease, its components, or across the different baseline BP categories (all P for interaction, ≥0.57). The effects in women and men were consistent across age categories and the types of antihypertensive medications (all P for interaction, ≥0.14). CONCLUSIONS: The effects of BP reduction were similar in women and men across all BP and age categories at randomization and with no evidence to suggest that drug classes had differing effects by sex. This study does not substantiate sex-based differences in BP-lowering treatment.

Single-Pill Combination Product Availability of the Antihypertensive Regimens Used for Intensive Systolic Blood Pressure Treatment in the Systolic Blood Pressure Intervention Trial.

BACKGROUND: Single-pill combination (SPC) antihypertensive products improve blood pressure control and medication adherence among patients with hypertension. It is unknown to what degree commercially available SPC products could be used to target an intensive systolic blood pressure goal of <120 mm Hg. METHODS: This cross-sectional analysis included participants randomized to the intensive treatment arm (goal systolic blood pressure <120 mm Hg) of the Systolic Blood Pressure Intervention Trial (SPRINT) using ≥2 antihypertensive medication classes at the 12-month postrandomization visit. Antihypertensive medication data were collected using pill bottle review by research coordinators, and regimens were categorized by the unique combinations of antihypertensive classes. We calculated the proportion of regimens used, which are commercially available as one of the 7 SPC class combinations in the United States as of January 2023. RESULTS: Among the 3833 SPRINT intensive arm participants included (median age, 67.0 years; 35.5% female), participants were using 219 unique antihypertensive regimens. The 7 regimens for which there are class-equivalent SPC products were used by 40.3% of participants. Only 3.2% of all medication class regimens used are available as a class-equivalent SPC product (7/219). There are no SPC products available with 4 or more medication classes, which were used by 1060 participants (27.7%). CONCLUSIONS: Most SPRINT participants in the intensive arm used an antihypertensive medication regimen, which is not commercially available as a class equivalent SPC product. To achieve the SPRINT results in real-world settings, maximize the potential benefit of SPCs, and reduce pill burden, improvements in the product landscape are needed. REGISTRATION: URL: https://www. CLINICALTRIALS: gov/ct2/show/NCT01206062; Unique identifier: NCT01206062.

Racial and ethnic disparities in the enrolment of medicare medication therapy management programs.

Objectives: Racial/ethnic disparities have been found in prior literature examining enrolment in Medicare medication therapy management programs. However, those studies were based on various eligibility scenarios because enrolment data were unavailable. This study tested for potential disparities in enrolment using actual MTM enrolment data. Methods: Medicare Parts A&B claims, Medication Therapy Management Data Files, and the Area Health Resources File from 2013 to 2014 and 2016 to 2017 were analysed in this retrospective analysis. An adjusted logistic regression compared odds of enrolment between racial/ethnic minorities and non-Hispanic Whites (Whites) in the total sample and subpopulations with diabetes, hypertension, or hyperlipidaemia. Trends in disparities were analysed by including interaction terms in regressions between dummy variables for race/ethnic minority groups and period 2016-2017. Key Findings: Disparities in MTM enrolment were detected between Blacks and Whites with diabetes in 2013-2014 (Odds Ratio = 0.78, 95% Confidence Interval = 0.75-0.81). This disparity improved from 2013-2014 to 2016-2017 for Blacks (Odds Ratio=1.08, 95% Confidence Interval = 1.04-1.11) but persisted in 2016-2017 (Odds Ratio = 0.84, 95% Confidence Interval = 0.81-0.87). A disparity was identified between Blacks and Whites with hypertension in 2013-2014 (Odds Ratio = 0.92, 95% Confidence Interval = 0.89-0.95) but not in 2016-2017. Enrolment for all groups, however, declined between periods. For example, in the total sample, the odds of enrolment declined from 2013-2014 to 2016-2017 by 22% (Odds Ratio=0.78, 95% Confidence Interval=0.75-0.81). Conclusions: Racial disparities in MTM enrolment were found between Blacks and Whites among Medicare beneficiaries with diabetes in both periods and among individuals with hypertension in 2013-2014. As overall enrolment fell between periods, concerns about program enrolment remain.

Antihypertensive Medication Regimens Used by US Adults With Hypertension and the Potential for Fixed-Dose Combination Products: The National Health and Nutrition Examination Surveys 2015 to 2020.

Background Fixed-dose combination (FDC) antihypertensive products improve blood pressure control and adherence among patients with hypertension. It is unknown to what degree commercially available FDC products meet the current hypertension management prescription patterns in the United States. Methods and Results This cross-sectional analysis of the National Health and Nutrition Examination Surveys 2015 to March 2020 included participants with hypertension taking ≥2 antihypertensive medications (N=2451). After constructing each participant's regimen according to antihypertensive classes used, we estimated the extent to which the 7 class-level FDC regimens available in the United States as of January 2023 would match the regimens used. Among a weighted population of 34.1 million US adults (mean age, 66.0 years; 52.8% women; 69.1% non-Hispanic White race and ethnicity), the proportions using 2, 3, 4, and ≥5 antihypertensive classes were 60.6%, 28.2%, 9.1%, and 1.6%, respectively. The 7 FDC regimens were among 189 total regimens used (3.7%), and 39.2% of the population used one of the FDC regimens (95% CI, 35.5%-43.0%; 13.4 million US adults); 60.8% of the population (95% CI, 57.0%-64.5%; 20.7 million US adults) were using a regimen not available as a class-equivalent FDC product. Conclusions Three in 5 US adults with hypertension taking ≥2 antihypertensive classes are using a regimen that is not commercially available as a class-equivalent FDC product as of January 2023. To maximize the potential benefit of FDCs to improve medication adherence (and thus blood pressure control) among patients taking multiple antihypertensive medications, use of FDC-compatible regimens and improvements in the product landscape are needed.

Telephone informed consent in a pragmatic point-of-care clinical trial embedded in primary care.

BACKGROUND: One benefit of pragmatic clinical trials is reduction of the burden on patients and clinical staff while facilitating a learning healthcare system. One way to decrease the work of clinical staff is through decentralized telephone consent. METHODS: The Diuretic Comparison Project (DCP) was a nationwide Point of Care pragmatic clinical trial conducted by the VA Cooperative Studies Program. The purpose of the trial was to compare the clinical effectiveness on major CV outcomes of two commonly used diuretics, hydrochlorothiazide and chlorthalidone, in an elderly patient population. Telephone consent was allowed for this study because of its minimal risk designation. Telephone consent was more difficult than initially anticipated and the study team constantly adjusted methods to find timely solutions. RESULTS: The major challenges can be categorized as call center-related, telecommunications, operational, and study population based. In particular, the possible technical and operational pitfalls are rarely discussed. By presenting hurdles here, future studies may avoid these challenges and start studies with a more effective system in place. CONCLUSIONS: DCP is a novel study designed to answer an important clinical question. The lessons learned from implementing a centralized call center for the Diuretic Comparison Project helped the study reach enrollment goals and develop a centralized telephone consent system that can be utilized for future pragmatic and explanatory clinical trials. CLINICAL TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov; NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417]. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Solving racial/ethnic disparities associated with Medicare Part D Star Ratings.

OBJECTIVE: Medicare Part D Star Ratings are instrumental in shaping healthcare quality improvement efforts. However, the calculation metrics for medication performance measures for this program have been associated with racial/ethnic disparities. In this study, we aimed to explore whether an alternative program, named Star Plus by us that included all medication performance measures developed by Pharmacy Quality Alliance and applicable to our study population, would reduce such disparities among Medicare beneficiaries with diabetes, hypertension, and/or hyperlipidemia. METHOD: We conducted an analysis of a 10% random sample of Medicare A/B/D claims linked to the Area Health Resources File. Multivariate logistic regressions with minority dummy variables were used to examine racial/ethnic disparities in measure calculations of Star Ratings and Star Plus, respectively. RESULTS: Adjusted results indicated that relative to non-Hispanic Whites (Whites), racial/ethnic minorities had significantly lower odds of being included in the Star Ratings measure calculations: the odds ratios (ORs) for Blacks, Hispanics, Asians, and Others were 0.68 (95% confidence interval [CI] = 0.66-0.71), 0.73 (CI = 0.69-0.78), 0.88 (CI = 0.82-0.93), and 0.92 (CI = 0.88-0.97), respectively. In contrast, every beneficiary in the sample was included in Star Plus. Further, racial/ethnic minorities had significantly higher increase in the odds of being included in measure calculation in Star Plus than Star Ratings. The ORs for Blacks, Hispanics, Asians, and Others were 1.47 (CI = 1.41-1.52), 1.37 (CI = 1.29-1.45), 1.14 (CI = 1.07-1.22), and 1.09 (CI = 1.03-1.14), respectively. CONCLUSIONS: Our study demonstrated that racial/ethnic disparities may be eliminated by including additional medication performance measures to Star Ratings.

The impact of COVID-19 on a large pragmatic clinical trial embedded in primary care.

INTRODUCTION: The COVID-19 pandemic had significant impact on clinical care and clinical trial operations, but the impact on decentralized pragmatic trials is unclear. The Diuretic Comparison Project (DCP) is a Point-of Care (POC) pragmatic trial testing whether chlorthalidone is superior to hydrochlorothiazide in preventing major cardiovascular (CV) events and non-cancer death. DCP utilized telephone consent, data collection from the electronic health record and Medicare, forwent study visits, and limited provider commitment beyond usual care. We assessed the impact of COVID-19 on recruitment, follow-up, data collection, and outcome ascertainment in DCP. METHODS: We compared data from two 8-month periods: Pre-Pandemic (July 2019-February 2020) and Mid-Pandemic (July 2020-February 2021). Consent and randomization rates, diuretic adherence, blood pressure (BP) and electrolyte follow-up rates, records of CV events, hospitalization, and death rates were compared. RESULTS: Providers participated at a lower rate mid-pandemic (65%) than pre-pandemic (71%), but more patients were contacted (7622 vs. 5363) and consented (3718 vs. 3048) mid-pandemic than pre-pandemic. Patients refilled medications and remained on their randomized diuretic equally (90%) in both periods. Overall, rates of BP, electrolyte measurements, and hospitalizations decreased mid-pandemic while deaths increased. CONCLUSIONS: While recruitment, enrollment, and adherence did not suffer during the pandemic, documented blood pressure checks and laboratory evaluations decreased, likely due to fewer in-person visits. VA hospitalizations decreased, despite a considerable number of COVID-related hospitalizations. This suggests changes in clinical care during the pandemic, but the limited impact on DCP's operations during a global pandemic is an important strength of POC trials. CLINICAL TRIAL REGISTRATION: NCT02185417.

Practical issues in pragmatic trials: the implementation of the Diuretic Comparison Project.

BACKGROUND/AIMS: The US Department of Veterans Affairs Point of Care Clinical Trial Program conducts studies that utilize informatics infrastructure to integrate clinical trial protocols into routine care delivery. The Diuretic Comparison Project compared hydrochlorothiazide to chlorthalidone in reduction of major cardiovascular events in subjects with hypertension. Here we describe the cultural, technical, regulatory, and logistical challenges and solutions that enabled successful implementation of this large pragmatic comparative effectiveness Point of Care clinical trial. METHODS: Patients were recruited from 72 Veterans Affairs Healthcare Systems using centralized processes for subject identification, obtaining informed consent, data collection, safety monitoring, site communication, and endpoint identification with minimal perturbation of the local clinical care ecosystem. Patients continued to be managed exclusively by their clinical care providers without protocol specified study visits, treatment recommendations, or data collection extraneous to routine care. Centralized study processes were operationalized through the application layer of the electronic health record via a data coordinating center staffed by clinical nurses, data scientists, and statisticians without site-based research coordinators. Study data was collected from the Veterans Affairs electronic health record supplemented by Medicare and National Death Index data. RESULTS: The study exceeded its enrolled goal (13,523 subjects) and followed subjects for the 5-year study duration. The key determinant of program success was collaboration between researchers, regulators, clinicians, and administrative staff at the site level to customize study procedures to align with local clinical practice. This flexibility was enabled by designation of the study as minimal risk and determination that clinical care providers were not engaged in research by the Veterans Affairs Central Institutional Review Board. Cultural, regulatory, technical, and logistical problems were identified and solved through iterative collaboration between clinical and research entities. Paramount among these problems was customization of the Veterans Affairs electronic health record and data systems to accommodate study procedures. CONCLUSIONS: Leveraging clinical care for large-scale clinical trials is feasible but requires a rethinking of traditional clinical trial design (and regulation) to better meet requirements of clinical care ecosystems. Study designs must accommodate site-specific practice variation to reduce the impact on clinical care. A tradeoff thus exists between designing trial processes tailored to expedite local study implementation versus those to produce a more refined response to the research question. The availability of a uniform and flexible electronic health record in the Department of Veterans Affairs played a major role in the success of the trial. Conducting Point of Care research in other healthcare systems without such research-friendly infrastructure presents a more formidable challenge.

Racial and ethnic disparities in Medicare Part D medication therapy management services utilization.

Background: The Medicare Part D medication therapy management (MTM) program has positive effects on medication and health service utilization. However, little is known about its utilization, much less so about the use among racial and ethnic minorities. Objective: To examine MTM service utilization among older Medicare beneficiaries and to identify any racial and ethnic disparity patterns. Methods: A retrospective cross-sectional analysis of 2017 Medicare administrative data, linked to the Area Health Resources Files. Fourteen outcomes related to MTM service nature, initiation, quantity, and delivery were examined using logistic, negative binomial, and Cox proportional hazards regression models. Results: Racial and ethnic disparities were found with varying patterns across outcomes. For example, compared with White patients, the odds of opting out of MTM were 8% higher for Black patients (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.03-1.14), 57% higher for Hispanic patients (OR = 1.57, 95% CI = 1.42-1.72), and 57% higher for Asian patients (OR = 1.57, 95% CI = 1.33-1.85). The odds of continuing MTM from the previous years were 12% lower for Black patients (OR = 0.88, 95% CI = 0.86-0.90) and 3% lower for other patients (OR = 0.97, 95% CI = 0.95-0.99). In addition, the probability of being offered a comprehensive medication review (CMR) after MTM enrollment was 9% lower for Hispanic patients (hazard ratio [HR] = 0.91, 95% CI = 0.85-0.97), 9% lower for Asian patients (HR = 0.91, 95% CI = 0.87-0.94), and 3% lower for other patients (HR = 0.97, 95% CI = 0.95-0.99). Hispanic and Asian patients were more likely to have someone other than themselves receive a CMR. Conclusions: Racial and ethnic disparities in MTM service utilization were identified. Although the disparities in specific utilization outcomes vary across racial/ethnic groups, it is evident that these disparities exist and may result in vulnerable communities not fully benefiting from the MTM services. Causes of the disparities should be explored to inform future reform of the Medicare Part D MTM program.

Antihypertensive Medication Regimens Used in the Systolic Blood Pressure Intervention Trial.

BACKGROUND: Describing the antihypertensive medication regimens used in the SPRINT (Systolic Blood Pressure Intervention Trial) would contextualize the standard and intensive systolic blood pressure (SBP) interventions and may inform future implementation efforts to achieve population-wide intensive SBP goals. METHODS: We included SPRINT participants with complete medication data at the prerandomization and 12-month visits. Regimens were categorized by antihypertensive medication class. Analyses were stratified by treatment group (standard goal SBP <140 mm Hg versus intensive goal SBP <120 mm Hg). RESULTS: Among 7860 participants (83.7% of 9361 randomized), the median number of classes used at the prerandomization visit was 2.0 and 2.0 in the standard and intensive groups (P=0.559). At 12-months, the median number of classes used was 3.0 and 2.0 in the intensive and standard groups (P<0.001). Prerandomization, angiotensin-converting enzyme inhibitor (ACE), or angiotensin-II receptor blocker (ARB) monotherapy was the most common regimen in the intensive and standard groups (12.6% versus 12.2%). At 12-months, ACE/ARB monotherapy was still the most common regimen among standard group participants (14.7%) and was used by 5.3% of intensive group participants. Multidrug regimens used by the intensive and standard participants at 12 months were as follows: an ACE/ARB with thiazide (12.2% and 7.9%); an ACE/ARB with calcium channel blocker (6.2% and 6.8%); an ACE/ARB, thiazide, and calcium channel blocker (11.4% and 4.3%); and an ACE/ARB, thiazide, calcium channel blocker, and beta-blocker (6.5% and 1.2%). CONCLUSIONS: SPRINT investigators favored combining ACEs or ARBs, thiazide diuretics, and calcium channel blockers to target SBP <120 mm Hg, compared to ACE/ARB monotherapy to target SBP <140 mm Hg. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT01206062.

Cost-Effectiveness of Medication Therapy Management Program Across Racial and Ethnic Groups Among Medicare Beneficiaries.

OBJECTIVES: Equity and effectiveness of the medication therapy management (MTM) program in Medicare has been a policy focus since its inception. The objective of this study was to evaluate the cost-effectiveness of the Medicare MTM program in improving medication utilization quality across racial and ethnic groups. METHODS: This study analyzed 2017 Medicare data linked to the Area Health Recourses File. A propensity score was used to match MTM enrollees and nonenrollees, and an incremental cost-effectiveness ratio between the 2 groups was calculated. Effectiveness was measured as the proportion of appropriate medication utilization based on medication utilization measures developed by Pharmacy Quality Alliance. Net monetary benefits were compared across racial and ethnic groups at various societal willingness-to-pay (WTP) thresholds. The 95% confidence intervals were obtained by nonparametric bootstrapping. RESULTS: MTM dominated non-MTM among the total sample (N = 699 992), as MTM enrollees had lower healthcare costs ($31 135.89 vs $32 696.69) and higher proportions of appropriate medication utilization (87.47% vs 85.31%) than nonenrollees. MTM enrollees had both lower medication costs ($10 681.21 vs $11 003.08) and medical costs ($20 454.68 vs $21 693.61) compared with nonenrollees. The cost-effectiveness of MTM was higher among Black patients than White patients across the WTP thresholds. For instance, at a WTP of $3006 per percentage point increase in effectiveness, the net monetary benefit for Black patients was greater than White patients by $2334.57 (95% confidence interval $1606.53-$3028.85). CONCLUSIONS: MTM is cost-effective in improving medication utilization quality among Medicare beneficiaries and can potentially reduce disparities between Black and White patients. Expansion of the current MTM program could maximize these benefits.

Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events.

BACKGROUND: Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear. METHODS: In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed. RESULTS: A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001). CONCLUSIONS: In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT02185417.).

Longer-Term All-Cause and Cardiovascular Mortality With Intensive Blood Pressure Control: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive blood pressure control reduced cardiovascular morbidity and mortality. However, the legacy effect of intensive treatment is unknown. Objective: To evaluate the long-term effects of randomization to intensive treatment with the incidence of cardiovascular and all-cause mortality approximately 4.5 years after the trial ended. Design, Setting, and Participants: In this secondary analysis of a multicenter randomized clinical trial, randomization began on November 8, 2010, the trial intervention ended on August 20, 2015, and trial close-out visits occurred through July 2016. Patients 50 years and older with hypertension and increased cardiovascular risk but without diabetes or history of stroke were included from 102 clinic sites in the US and Puerto Rico. Analyses were conducted between October 2021 and February 2022. Interventions: Randomization to systolic blood pressure (SBP) goal of less than 120 mm Hg (intensive treatment group; n = 4678) vs less than 140 mm Hg (standard treatment group; n = 4683). Main Outcomes and Measures: Extended observational follow-up for mortality via the US National Death Index from 2016 through 2020. In a subset of 2944 trial participants, outpatient SBP from electronic health records during and after the trial were examined. Results: Among 9361 randomized participants, the mean (SD) age was 67.9 (9.4) years, and 3332 (35.6%) were women. Over a median (IQR) intervention period of 3.3 (2.9-3.9) years, intensive treatment was beneficial for both cardiovascular mortality (hazard ratio [HR], 0.66; 95% CI, 0.49-0.89) and all-cause mortality (HR, 0.83; 95% CI, 0.68-1.01). However, at the median (IQR) total follow-up of 8.8 (8.3-9.3) years, there was no longer evidence of benefit for cardiovascular mortality (HR, 1.02; 95% CI, 0.84-1.24) or all-cause mortality (HR, 1.08; 95% CI, 0.94-1.23). In a subgroup of participants, the estimated mean outpatient SBP among participants randomized to intensive treatment increased from 132.8 mm Hg (95% CI, 132.0-133.7) at 5 years to 140.4 mm Hg (95% CI, 137.8-143.0) at 10 years following randomization. Conclusions and Relevance: The beneficial effect of intensive treatment on cardiovascular and all-cause mortality did not persist after the trial. Given increasing outpatient SBP levels in participants randomized to intensive treatment following the trial, these results highlight the importance of consistent long-term management of hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Dulaglutide and cardiovascular and heart failure outcomes in patients with and without heart failure: a post-hoc analysis from the REWIND randomized trial.

AIMS: People with diabetes are at high risk for cardiovascular events including heart failure (HF). We examined the effect of the glucagon-like peptide 1 agonist dulaglutide on incident HF events and other cardiovascular outcomes in those with or without prior HF in the randomized placebo-controlled Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. METHODS AND RESULTS: The REWIND major adverse cardiovascular event (MACE) outcome was the first occurrence of a composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes). In this post-hoc analysis, a HF event was defined as an adjudication-confirmed hospitalization or urgent evaluation for HF. Of the 9901 participants studied over a median follow-up of 5.4 years, 213/4949 (4.3%) randomly assigned to dulaglutide and 226/4952 (4.6%) participants assigned to placebo experienced a HF event (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.77-1.12; p = 0.456). In the 853 (8.6%) participants with HF at baseline, there was no change in either MACE or HF events with dulaglutide as compared to participants without HF (p = 0.44 and 0.19 for interaction, respectively). Combined cardiovascular death and HF events were marginally reduced with dulaglutide compared to placebo (HR 0.88, 95% CI 0.78-1.00; p = 0.050) but unchanged in patients with and without HF at baseline (p = 0.31). CONCLUSIONS: Dulaglutide was not associated with a reduction in HF events in patients with type 2 diabetes regardless of baseline HF status over 5.4 years of follow-up.