BACKGROUND:The DCP (Diuretic Comparison Project), a pragmatic trial, evaluated whether chlorthalidone compared with hydrochlorothiazide would reduce the risk of nonfatal cardiovascular disease or noncancer-related death. The intent-to-treat analysis found no difference in such comparison (hazard ratio, 1.04 [95% CI, 0.94-1.16]). The objective of the current study is to estimate the per-protocol effect of chlorthalidone (12.5/25 mg daily) compared with hydrochlorothiazide (25/50 mg daily) in preventing major adverse cardiovascular events among older patients with hypertension. METHODS:The effect of adhering to treatment strategies was assessed by censoring at first instance of nonadherence, defined as a gap (>90-day gap in drug coverage), switch (switching between study medications), and discontinuation (stop taking chlorthalidone/hydrochlorothiazide altogether for >90 days before the end of the study). The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and noncancer-related death. Using inverse probability weighting, we evaluated the per-protocol effect of chlorthalidone and hydrochlorothiazide using DCP trial data. RESULTS:Nonadherence was found in 5476 (40%) participants; among 8047 (60%) adherents, 3905 (49%) were randomized to chlorthalidone and 4142 (51%) to hydrochlorothiazide. After censoring time when participants deviated from the assigned treatments, the estimated 5-year risk ratio of the composite primary outcome of nonfatal cardiovascular disease and noncancer-related death was 1.36 (95% CI, 0.96-2.12) in chlorthalidone compared with hydrochlorothiazide. CONCLUSIONS:The per-protocol analysis indicated a lower risk with hydrochlorothiazide compared with chlorthalidone in preventing nonfatal cardiovascular disease and noncancer-related death; however, this difference was not statistically significant using dispensation data to identify adherence. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02185417.

We developed an automatic self-enhancement-based perfusion mapping (SEPM) method to relatively map the microvascular perfusion level in contrast-enhanced magnetic resonance imaging (CE-MRI) into four categories: hyper-enhanced, isoenhanced, hypo-enhanced, and non-enhanced. These regions are identified based on the relative enhancement from the local pre-contrast arrival frame. We hypothesized that the signal intensity and change in signal intensity of skeletal calf muscles over a course of approximately 10 min of dynamic CE-MRI are measures of perfusion abnormalities that are of importance in patients with peripheral artery disease (PAD). Impairments of the microvascular circulation of the skeletal calf muscles in PAD patients can be quantified by analyzing signal enhancement patterns in CE-MRI. We assessed hypoperfusion in 52 study participants including 35 PAD patients and 17 matched controls. We also investigated PAD subgroups with a known higher risk of adverse outcomes including those with concomitant diabetes mellitus and those who did not complete a graded 6-min treadmill walking test. Our findings show that PAD patients demonstrate a consistently higher rate of hypoperfusion percentages compared to matched controls. Our findings further indicate that each calf muscle group exhibits varying levels of heterogeneity, reflecting non-uniform perfusion dynamics. In five distinct calf muscle groups and averaged over all calf muscle compartments, the average percentage of the hypoperfused regions was lowest in the control group and highest in the more severe PAD groups including treadmill non-completers and those with concomitant diabetes. The quantification of the microcirculation is of importance to assess PAD patients.

Peripheral artery disease (PAD) remains underdiagnosed and undertreated and is associated with an increased risk for adverse cardiovascular outcomes. Imaging provides an approach to identifying patients with PAD. However, the role of integrating imaging with machine learning to identify PAD patients and potentially assess disease severity remains understudied. A total of 56 participants, including 36 PAD patients with intermittent claudication and 20 matched controls, underwent contrast-enhanced magnetic resonance imaging (CE-MRI) calf muscle perfusion scanning. CE-MRI-derived dynamic muscle perfusion maps were developed to quantify alterations of the microvascular circulation in the calf muscles based on voxel contrast enhancement. These dynamic muscle perfusion maps categorized voxels as hyper-, iso-, or hypo-enhanced and were generated for the anterior (AM), lateral (LM), and deep posterior (DM) muscle groups, and the soleus (SM) and gastrocnemius muscles (GM). An unsupervised block-search algorithm was developed to identify heterogeneous regions of interest based on homogeneity. Machine learning methods were utilized to classify PAD patients from controls, with subgroup analyses performed based on lower extremity function and diabetes. The hypo-enhanced and hyper-enhanced voxel percentages obtained from the dynamic muscle perfusion maps were used to train a decision tree classifier to distinguish PAD patients from controls. The two-group classifier obtained a leave-one-out cross-validation (LOOCV) F1-score of 87.6 and 76.7% with hyper-enhanced and hypo-enhanced perfusion features averaged over all muscle groups, respectively. Hypo-enhanced perfusion features, a marker of microvascular perfusion abnormalities, classified PAD patients who completed a 6-minute treadmill walking test compared to those who did not, with an LOOCV F1-score of 67.6%. Using the same method, hypo-enhanced perfusion features differentiated PAD patients with diabetes versus those without with an LOOCV F1-score of 70.3%. In conclusion, CE-MRI derived measures of skeletal calf muscle perfusion can be used with a decision tree classifier to differentiate PAD patients from matched controls. Machine learning can also identify PAD patients with lower exercise capacity and those with concomitant diabetes. Machine learning and CE-MRI derived measures of the calf microcirculation could be of interest in the study of PAD and disease severity.

OBJECTIVE:To determine the effects of intensive blood pressure treatment on orthostatic hypertension. DESIGN:Systematic review and individual participant data meta-analysis. DATA SOURCES:MEDLINE, Embase, and Cochrane CENTRAL databases through 13 November 2023. INCLUSION CRITERIA:Population: ≥500 adults, age ≥18 years with hypertension or elevated blood pressure; intervention: randomized trials of more intensive antihypertensive drug treatment (lower blood pressure goal or active agent) with duration ≥6 months; control: less intensive antihypertensive drug treatment (higher blood pressure goal or placebo); outcome: measured standing blood pressure. MAIN OUTCOMES:Orthostatic hypertension, defined as an increase in systolic blood pressure ≥20 mm Hg or diastolic blood pressure ≥10 mm Hg after changing from sitting to standing. DATA SYNTHESIS:Two investigators independently abstracted articles. Individual participant data from nine trials identified during the systematic review were appended together as a single dataset. RESULTS:Of 31 124 participants with 315 497 standing blood pressure assessments, 9% had orthostatic hypotension (that is, a drop in blood pressure after standing of systolic ≥20 mm Hg or diastolic ≥10 mm Hg), 17% had orthostatic hypertension, and 3.2% had both a rise in systolic blood pressure and standing blood pressure ≥140 mm Hg at baseline. The effects of more intensive treatment were similar across trials with odds ratios for orthostatic hypertension ranging from 0.85 to 1.08 (I2=38.0%). During follow-up, 17% of patients assigned to more intensive treatment had orthostatic hypertension, whereas 19% of those assigned less intensive treatment had orthostatic hypertension. Compared with less intensive treatment, the risk of orthostatic hypertension was lower with more intensive blood pressure treatment (odds ratio 0.93, 95% confidence interval 0.90 to 0.96). Effects were greater among non-black versus black adults (odds ratio 0.86 v 0.97; P for interaction=0.003) and adults without diabetes versus those with diabetes (0.88 v 0.96; P for interaction=0.05) but did not differ by age ≥75 years, sex, baseline seated blood pressure ≥130/≥80 mm Hg, obesity, stage 3 kidney disease, stroke, cardiovascular disease, standing systolic blood pressure ≥140 mm Hg, or pre-randomization orthostatic hypertension (P for interactions ≥0.05). CONCLUSIONS:In this pooled cohort of adults with elevated blood pressure or hypertension, orthostatic hypertension was common and more intensive blood pressure treatment modestly reduced the occurrence of orthostatic hypertension. These findings suggest that approaches generally used for seated hypertension may also prevent hypertension on standing. STUDY REGISTRATION:Prospero CRD42020153753 (original proposal).

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.

ImportanceHypertension is a risk factor for the development and progression of chronic kidney disease (CKD). It is unclear whether different thiazide diuretics have a differential impact on kidney outcomes.ObjectiveTo compare kidney outcomes in patients with hypertension taking chlorthalidone and hydrochlorothiazide.Design, Setting, and ParticipantsThis 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.InterventionThe Diuretic Comparison Project randomized 13 523 participants to continue hydrochlorothiazide or switch to chlorthalidone.Main Outcome and MeasuresThe 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.ResultsAnalysis 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 RelevanceChlorthalidone 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

Peripheral artery disease (PAD) is associated with impaired blood flow in the lower extremities and histopathologic changes of the skeletal calf muscles, resulting in abnormal microvascular perfusion. We studied the use of convolution neural networks (CNNs) to differentiate patients with PAD from matched controls using perfusion pattern features from contrast-enhanced magnetic resonance imaging (CE-MRI) of the skeletal calf muscles. We acquired CE-MRI based skeletal calf muscle perfusion in 56 patients (36 patients with PAD and 20 matched controls). Microvascular perfusion imaging was performed after reactive hyperemia at the midcalf level, with a temporal resolution of 409 ms. We analyzed perfusion scans up to 2 minutes indexed from the local precontrast arrival time frame. Skeletal calf muscles, including the anterior muscle, lateral muscle, deep posterior muscle group, and the soleus and gastrocnemius muscles, were segmented semiautomatically. Segmented muscles were represented as 3-dimensional Digital Imaging and Communications in Medicine stacks of CE-MRI perfusion scans for deep learning (DL) analysis. We tested several CNN models for the 3-dimensional CE-MRI perfusion stacks to classify patients with PAD from matched controls. A total of 2 of the best performing CNNs (resNet and divNet) were selected to develop the final classification model. A peak accuracy of 75% was obtained for resNet and divNet. Specificity was 80% and 94% for resNet and divNet, respectively. In conclusion, DL using CNNs and CE-MRI skeletal calf muscle perfusion can discriminate patients with PAD from matched controls. DL methods may be of interest for the study of PAD.

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: Extracellular volume fraction (ECV), measured with contrast-enhanced magnetic resonance imaging (CE-MRI), has been utilized to study myocardial fibrosis, but its role in peripheral artery disease (PAD) remains unknown. We hypothesized that T1 mapping and ECV differ between PAD patients and matched controls. Methods and Results: A total of 37 individuals (18 PAD patients and 19 matched controls) underwent 3.0T CE-MRI. Skeletal calf muscle T1 mapping was performed before and after gadolinium contrast with a motion-corrected modified look–locker inversion recovery (MOLLI) pulse sequence. T1 values were calculated with a three-parameter Levenberg–Marquardt curve fitting algorithm. ECV and T1 maps were quantified in five calf muscle compartments (anterior [AM], lateral [LM], and deep posterior [DM] muscle groups; soleus [SM] and gastrocnemius [GM] muscles). Averaged peak blood pool T1 values were obtained from the posterior and anterior tibialis and peroneal arteries. T1 values and ECV are heterogeneous across calf muscle compartments. Native peak T1 values of the AM, LM, and DM were significantly higher in PAD patients compared to controls (all p < 0.028). ECVs of the AM and SM were significantly higher in PAD patients compared to controls (AM: 26.4% (21.2, 31.6) vs. 17.3% (10.2, 25.1), p = 0.046; SM: 22.7% (19.5, 27.8) vs. 13.8% (10.2, 19.1), p = 0.020). Conclusions: Native peak T1 values across all five calf muscle compartments, and ECV fractions of the anterior muscle group and the soleus muscle were significantly elevated in PAD patients compared with matched controls. Non-invasive T1 mapping and ECV quantification may be of interest for the study of PAD.

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

Importance:Hypertension is a risk factor for the development and progression of chronic kidney disease (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 Registration:ClinicalTrials.gov Identifier: NCT02185417.

BACKGROUND:Hepatocellular carcinoma (HCC) is a common cancer worldwide. Extrahepatic spread is not unusual during HCC disease, but bone metastases at initial presentation are rare.CASE DESCRIPTION:We describe a case of HCC presenting with a clavicular head mass and spinal metastases with normal α-fetoprotein (AFP) level and hepatitis C virus infection without cirrhosis. After undergoing bone and liver biopsies, the patient started a 12-week course of sofosbuvir/velpatasvir and bevacizumab/atezolizumab for lifelong therapy with palliative intent. Since 2021, the patient has been receiving a combination of bevacizumab and atezolizumab every 21 days. On this regimen as of March 2023, his osseous metastases were stable and his liver lesions had not enlarged.CONCLUSIONS:This case demonstrates a very unusual HCC presentation, the importance of a thorough workup of bone metastasis, and the limited value of AFP for HCC screening, even in disseminated disease.

Background: Antihypertensive treatment (AHT) is crucial for preventing major adverse cardiovascular events and other negative health outcomes, but poor adherence remains a challenge. We assessed the associations between patient characteristics and adherence to two thiazide-type diuretics in a large sample of hypertensive patients from the Diuretic Comparison Project (DCP), a nationwide randomized pragmatic trial conducted in the Veterans Affairs Healthcare System. Methods: Study data, collected electronically during routine clinical care, were used to determine adherence to chlorthalidone and hydrochlorothiazide. Participants were classified as adherent (70.3%; 9,501 of 13,523) or non-adherent (29.7%; 4,022 of 13,523) based on a medication possession ratio threshold of 80%, irrespective of randomized drug assignment. Logistic regression was used to measure the associations. Results: Non-adherent participants were more likely to be older, Black, not married, residing in urban areas, current smokers, and had a higher level of baseline systolic blood pressure (Table 1). History of cardiovascular disease and diabetes were associated with lower adherence. However, participants with higher BMI and those who received more antihypertensive drugs showed better adherence than those with lower levels. Conclusion: These findings contribute to the identification of several patient characteristics as predictors of lower medication adherence. DCP’s pragmatic nature allowed for real-world data capture and may be useful to inform clinicians of patient groups who may not adhere to their medication and who might benefit from targeted interventions.

Background Computational fluid dynamics has shown good agreement with contrast‐enhanced magnetic resonance imaging measurements in cardiovascular disease applications. We have developed a biomechanical model of microvascular perfusion using contrast‐enhanced magnetic resonance imaging signal intensities derived from skeletal calf muscles to study peripheral artery disease (PAD). Methods and Results The computational microvascular model was used to study skeletal calf muscle perfusion in 56 individuals (36 patients with PAD, 20 matched controls). The recruited participants underwent contrast‐enhanced magnetic resonance imaging and ankle‐brachial index testing at rest and after 6‐minute treadmill walking. We have determined associations of microvascular model parameters including the transfer rate constant, a measure of vascular leakiness; the interstitial permeability to fluid flow which reflects the permeability of the microvasculature; porosity, a measure of the fraction of the extracellular space; the outflow filtration coefficient; and the microvascular pressure with known markers of patients with PAD. Transfer rate constant, interstitial permeability to fluid flow, and microvascular pressure were higher, whereas porosity and outflow filtration coefficient were lower in patients with PAD than those in matched controls (all P values ≤0.014). In pooled analyses of all participants, the model parameters (transfer rate constant, interstitial permeability to fluid flow, porosity, outflow filtration coefficient, microvascular pressure) were significantly associated with the resting and exercise ankle‐brachial indexes, claudication onset time, and peak walking time (all P values ≤0.013). Among patients with PAD, interstitial permeability to fluid flow, and microvascular pressure were higher, while porosity and outflow filtration coefficient were lower in treadmill noncompleters compared with treadmill completers (all P values ≤0.001). Conclusions Computational microvascular model parameters differed significantly between patients with PAD and matched controls. Thus, computational microvascular modeling could be of interest in studying lower extremity ischemia.

Background: Orthostatic hypertension (OHTN) is associated with cardiovascular disease (CVD). We previously demonstrated how more intensive blood pressure (BP) treatment reduced orthostatic hypotension (OH) via a net increase in BP upon standing. Whether this effect also increased OHTN was not examined. Methods: We used pooled data from an individual participant data meta-analysis of 9 randomized BP pharmacologic treatment trials with seated and standing BP (search conducted through May 13, 2022). OHTN was defined as an increase in SBP ≥20 or DBP ≥10 mm Hg after changing from sitting to standing. Effects were examined overall and by baseline characteristics. Results: Of 31,124 participants with 315,497 standing BP assessments, 9% had OH, and 20% had OHTN at baseline. Trial effects were similar ( I 2 = 38.0%). During follow-up, 17% of those assigned more intensive treatment had OHTN, while 19% of those assigned less intensive treatment had OHTN. Intensive BP treatment significantly lowered OHTN risk (OR 0.93; 95% CI: 0.90, 0.96) ( Figure ). Effects were significantly greater among non-Black adults (OR 0.86 vs 0.97, P -interaction =0.003) and adults without diabetes (OR 0.88 vs 0.96; P -interaction =0.047). Effects did not differ by age≥75 years, sex, baseline seated BP≥130/≥80 mm Hg, obesity, stage 3 kidney disease, stroke, cardiovascular disease, standing SBP ≥140 mm Hg, or pre-randomization OHTN ( P -interactions ≥0.05). Conclusion: In this pooled cohort of adults with hypertension or higher CVD risk, OHTN was more common than OH and more intensive BP treatment reduced OHTN risk. The relationship between this effect with respect to CVD should be a focus of subsequent research.

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.