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.

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.

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.).

Design of a pragmatic clinical trial embedded in the Electronic Health Record: The VA's Diuretic Comparison Project.

BACKGROUND: Recent US guidelines recommend chlorthalidone over other thiazide-type diuretics for the treatment of hypertension based on its long half-life and proven ability to reduce CVD events. Despite recommendations most clinicians prescribe hydrochlorothiazide (HCTZ) over chlorthalidone (CTD). No randomized controlled data exist comparing these two diuretics on cardiovascular outcomes. METHODS: The Diuretic Comparison Project (DCP) is a multicenter, two-arm, parallel, Prospective Randomized Open, Blinded End-point (PROBE) trial testing the primary hypothesis that CTD is superior to HCTZ in the prevention of non-fatal CVD events and non-cancer death. Patients with hypertension taking HCTZ 25 or 50 mg were randomly assigned to either continue their current HCTZ or switch to an equipotent dose of CTD. The primary outcome is time to the first occurrence of a composite outcome consisting of a non-fatal CVD event (stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, or hospitalization for acute heart failure) or non-cancer death. The trial randomized 13,523 patients at 72 VA medical centers. The study is conducted by a centralized research team with site procedures embedded in the electronic health record and all data collected through administrative claims data, with no study related visits for participants. The trial will have 90% power to detect an absolute reduction in the composite event rate of 2.4%. RESULTS: Enrollment ended in November 2021. There are 4128 participting primary care providers and 16,595 patients individually consented to participate, 13,523 of whom were randomized. CONCLUSIONS: DCP should provide much needed evidence as to whether CTD is superior to HCTZ in preventing cardiovascular events in hypertensive patients. CLINICAL TRIAL REGISTRATION: NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417].

Orthostatic changes in systolic blood pressure among SPRINT participants at baseline.

Orthostatic changes in systolic blood pressure (SBP) impact cardiovascular outcomes. In this study, we aimed to determine the pattern of orthostatic systolic pressure changes in participants enrolled in the SBP Intervention Trial (SPRINT) at their baseline visit before randomization and sought to understand clinical factors predictive of these changes. Of the 9323 participants enrolled in SPRINT, 8662 had complete data for these analyses. The SBP after 1 minute of standing was subtracted from the mean value of the three preceding seated SBP values. At the baseline visit, medical history, medications, anthropometric measures, and standard laboratory testing were undertaken. The mean age of SPRINT participants was 68 years, two-thirds were male, with 30% black, 11% Hispanic, and 55% Caucasian. The spectrum of SBP changes on standing demonstrated that increases in SBP were as common as declines, and about 5% of participants had an increase, and 5% had a decrease of >20 mm Hg in SBP upon standing. Female sex, taller height, more advanced kidney disease, current smoking, and several drug classes were associated with larger declines in BP upon standing, while black race, higher blood levels of glucose and sodium, and heavier weight were associated with more positive values of the change in BP upon standing. Our cross-sectional results show a significant spectrum of orthostatic SBP changes, reflecting known (eg, age) and less well-known (eg, kidney function) relationships that may be important considerations in determining the optimal target blood pressure in long-term outcomes of older hypertensive patients.

Distribution of calcification in carotid endarterectomy tissues: comparison of micro-computed tomography imaging with histology.

BACKGROUND: Calcification in atherosclerotic plaques has been viewed as a marker of plaque stability, but whether calcification accumulates in specific anatomic sites in the carotid artery is unknown. We determined the burden and distribution of calcified plaque in carotid endarterectomy (CEA) tissues. METHODS: A total of 22 CEA tissues were imaged with high-resolution micro-computed tomography (micro-CT). Total plaque burden and total calcium score using the Agatston method were quantified. The Agatston score (AS) was also normalized for tissue size. Plaque and calcium distribution were analyzed separately for three CEA regions: common segment (CS), bulb segment (BS), and internal/external segments (IES). RESULTS: The average CEA tissue length was 40.83 (interquartile range [IQR] 33.31-42.41) mm with total plaque burden of 103.45 (IQR: 78.84-156.81) mm(3) and total AS of 38.58 (IQR 11.59-89.97). Total plaque volume was 21.02 (IQR: 14.47-25.42) mm(3) in the CS, 37.89 (22.59-48.32) mm(3) in the BS, and 54.05 (36.87-74.52) mm(3) in the IES. Of the 22 tissues, 15 had no calcium in the CS compared with three in the bulb and two in the IES. Normalized calcified plaque was most prevalent in the BS, the IES and was least prevalent in the CS. The overall correlation of calcification between histology sections and matched micro-CT images was 0.86 (p<0.001). CONCLUSIONS: Calcified plaque is heterogeneously distributed in CEA tissues with most in the bulb and IES regions. The amount of calcification in micro-CT slices shows a high correlation with matched histology sections.

Effects of N-acetylcysteine on glutathione oxidation and fatigue during handgrip exercise.

Fatigue of hand and forearm muscle groups can limit task performance by astronauts wearing space suits. Countermeasures to delay fatigue would therefore be useful to the space program. N-acetylcysteine (NAC) has been shown to inhibit fatigue during other tasks so we tested its effects during handgrip exercise. Volunteers practiced isometric handgrip maneuvers until performance was reproducible over three successive sessions (baseline). Performance then was retested after ingesting NAC (150 mg.kg(-1)) or saline. Drug administration increased NAC and cysteine blood levels (P < 0.001). Performance of sustained maximal efforts was unaffected. During repetitive submaximal efforts, NAC delayed fatigue (130% baseline) and inhibited glutathione oxidation. Saline did not alter glutathione status or performance of sustained maneuvers; repetitive task performance was increased by 15% (P < 0.05), a placebo effect. These data indicate that NAC supports glutathione homeostasis in exercising humans and may delay muscle fatigue during repetitive handgrip exercise. Our findings support oxidative stress as a causal factor in human muscle fatigue and argue for larger translational studies to define NAC effects on human performance.

Isolation, characterization, and functional assessment of oxidatively modified subfractions of circulating low-density lipoproteins.

OBJECTIVE: Current evidence suggests that oxidatively modified human plasma low-density lipoproteins (ox-LDLs) are proatherogenic and cytotoxic to endothelial and vascular smooth muscle cells. The present study describes a method using ion-exchange chromatography that is capable of large-scale subfractionation of LDL for adequate analyses of composition or bioactivities. METHODS AND RESULTS: LDLs from normolipidemic (N-LDL) and homozygous familial hypercholesterolemic (FH-LDL) subjects were separated into 5 subfractions (L1 through L5) by high-capacity ion-exchange chromatography. The most strongly retained fraction from FH subjects, FH-L5, suppressed DNA synthesis in cultured bovine aortic endothelial cells and stimulated mononuclear cell adhesion to cultured endothelial cells under flow conditions in vitro. L5, which represented 1.1+/-0.2% and 3.7+/-1.7% of the LDL from N-LDL and FH-LDL, respectively, was more triglyceride-rich (17% versus 5%) and cholesteryl ester-poor (23% versus 33%) than were L1 through L4. Electrophoretic mobilities on agarose gels increased from L1 to L5. According to SDS-PAGE, apolipoprotein B-100 in N-LDL fractions L1 through L5 appeared as a single approximately 500-kDa band. In contrast, the fractions isolated from FH-LDL showed substantial fragmentation of the apolipoprotein B-100, including bands between 200 and 116 kDa. Competitive ELISA analyses using a malondialdehyde-specific monoclonal antibody against Cu2+ ox-LDL suggest that FH-L5 is malondialdehyde-modified. CONCLUSIONS: Relative to N-LDL, FH-LDL contains higher concentrations of a fraction, L5, that exhibits distinctive physicochemical properties and biological activities that may contribute to initiation and progression of atherogenesis in vivo.

Circulating levels of tumor necrosis factor correlate with indexes of depressed heart rate variability: a study in patients with mild-to-moderate heart failure.

OBJECTIVES: Patients with heart failure have increased circulating levels of tumor necrosis factor (TNF) and TNF receptors. It is not known whether TNF, which is known to blunt beta-adrenergic responsiveness in experimental models, contributes to the loss of heart rate variability in patients with heart failure. Therefore, we examined heart rate variability in relation to circulating levels of TNF, TNF receptors, and norepinephrine in patients with heart failure and in control subjects. METHODS: Heart rate variability was obtained from 24-h ambulatory ECG recordings in age-matched control subjects (n = 10) and patients with mild (n = 15) to moderate (n = 14) heart failure. Plasma levels of TNF and soluble type 1 and 2 TNF receptors were measured by enzyme-linked immunoassay; plasma norepinephrine levels were measured by high-performance liquid chromatography. RESULTS: There was a significant inverse linear correlation between increased circulating levels of TNF, TNF receptors, and norepinephrine for time-domain and frequency-domain indexes of heart rate variability among patients with heart failure and control subjects. Multiple stepwise linear regression analysis showed that TNF was a stronger independent predictor of frequency-domain indexes of heart rate variability than norepinephrine. CONCLUSIONS: TNF is an independent predictor of depressed heart rate variability in patients with heart failure. Insofar as TNF blunts beta-adrenergic signaling, this study suggests the possibility that overexpression of TNF and subsequent loss of beta-adrenergic responsiveness contributes to the decrease in heart rate variability observed in heart failure.