Change In 6-minute Walk Distance Research Articles

Abstract 4127909: Smartphone-enabled, home-based exercise in patients with symptomatic peripheral arterial disease: the Smart Step Grady randomized trial

Introduction: About 10% of peripheral artery disease (PAD) patients develop claudication, with African Americans at higher risk and more severe symptoms. While supervised exercise therapy (SET) is a primary treatment, its uptake is low. We assessed the feasibility and effectiveness of smartphone-delivered home-based exercise therapy (HBET) in improving functional capacity and PAD symptoms in low-resource settings lacking SET. Methods: We conducted an interim analysis of Smart Step, a pilot randomized trial (1:1 ratio) comparing smartphone-enabled HBET to usual care (UC) in symptomatic PAD patients at Grady Memorial Hospital, a public safety net hospital in Atlanta, GA, from August 2018 to March 2024. The HBET group received virtual exercise coaching, app-based education, messaging, and reminders for 12 weeks. The primary outcome was the change in 6-minute walking distance (6MWD) at 12 weeks. Secondary outcomes included changes in the Walking Impairment Questionnaire (WIQ) and Short Form 36 (SF-36) scores. Data were analyzed using intention-to-treat, with mixed model repeated measures regression assessing the association between 6MWD and treatment. Results: We screened 102 patients and enrolled 46. To date, 26 (56%) participants have completed the study, 6 (13%) dropped out, and 14 (30%) are pending completion. The mean [SD] age was 63 [12] years, with 50% female and 90% African American. After 12 weeks, the mean 6MWD increased by 15.7 m from a baseline of 336.0 m in the HBET arm (n=13) and decreased by 6.6 from a baseline of 310.2 m in the UC arm (n=13). The between-group difference was 22.4 [95% CI -11.8 – 56.6] m; p=0.19). The WIQ stair climbing score changed by -10.9 in the UC arm vs. 7.1 in the HBET arm (between group difference 17.9 [95% CI 1.1-34.8]; p=0.04), while the other WIQ sub-scores were more similar between groups. The 12-week changes in SF-36 scores were not different by group. Conclusion: In this preliminary analysis, the HBET arm showed within-group improvements in 6MWD and symptoms after 12 weeks, but most changes were not significantly different when comparing them with the UC arm. Future analyses are pending and will provide the necessary statistical power for a more precise measure of the treatment effects.

417P Comparison of changes in 6-minute walk distance for Colombian patients with Duchenne muscular dystrophy treated with Ataluren with different rates of decline

417P Comparison of changes in 6-minute walk distance for Colombian patients with Duchenne muscular dystrophy treated with Ataluren with different rates of decline

Atrial Fibrillation and Semaglutide Effects in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Program

BackgroundObesity is a key factor in the development and progression of both heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF). In the STEP-HFpEF Program (comprising the STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes] trials), once-weekly semaglutide 2.4 mg improved HF-related symptoms, physical limitations, and exercise function and reduced body weight in patients with obesity-related HFpEF. Whether the effects of semaglutide in this patient group differ in participants with and without AF (and across various AF types) has not been fully examined. ObjectivesThe goals of this study were: 1) to evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF with and without a history of AF; and 2) to determine if the efficacy of semaglutide across all key trial outcomes are influenced by baseline history of AF (and AF types) in the STEP-HFpEF Program. MethodsThis was a secondary analysis of pooled data from the STEP-HFpEF and STEP-HFpEF DM trials. Patients with heart failure, left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to receive once-weekly semaglutide 2.4 mg or matching placebo for 52 weeks. Dual primary endpoints (change in KCCQ-CSS and percent change in body weight), confirmatory secondary endpoints (change in 6-minute walk distance; hierarchical composite endpoint comprising all-cause death, HF events, thresholds of change in KCCQ-CSS, and 6-minute walk distance; and C-reactive protein [CRP]), and exploratory endpoint (change in N-terminal pro–B-type natriuretic peptide [NT-proBNP]) were examined according to investigator-reported history of AF (yes/no). Responder analyses examined the proportions of patients who experienced a ≥5-, ≥10, ≥15, and ≥20-point improvement in KCCQ-CSS per history of AF. ResultsOf the 1,145 participants, 518 (45%) had a history of AF (40% paroxysmal, 24% persistent AF, and 35% permanent AF) and 627 (55%) did not. Participants with (vs without) AF were older, more often male, had higher NT-proBNP levels, included a higher proportion of those with NYHA functional class III symptoms, and used more antithrombotic therapies, beta-blockers, and diuretics. Semaglutide led to larger improvements in KCCQ-CSS (11.5 points [95% CI: 8.3-14.8] vs 4.3 points [95% CI: 1.3-7.2]; P interaction = 0.001) and the hierarchal composite endpoint (win ratio of 2.25 [95% CI: 1.79-2.83] vs 1.30 [95% CI: 1.06-1.59]; P interaction < 0.001) in participants with AF vs without AF, respectively. The proportions of patients receiving semaglutide vs those receiving placebo experiencing ≥5-, ≥10-, ≥15-, and ≥20-point improvement in KCCQ-CSS were also higher in those with (vs without) AF (all P interaction values <0.05). Semaglutide consistently reduced CRP, NT-proBNP, and body weight regardless of AF status (all P interaction values not significant). There were fewer serious adverse events and serious cardiac disorders in participants treated with semaglutide vs placebo irrespective of AF history. ConclusionsIn the STEP-HFpEF Program, AF was observed in nearly one-half of patients with obesity-related HFpEF and was associated with several features of more advanced HF. Treatment with semaglutide led to significant improvements in HF-related symptoms, physical limitations, and exercise function, as well as reductions in weight, CRP, and NT-proBNP in people with and without AF and across AF types. The magnitude of semaglutide-mediated improvements in HF-related symptoms and physical limitations was more pronounced in those with AF vs without AF at baseline. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM; NCT04916470])

Inflammation in Obesity-Related HFpEF: The STEP-HFpEF Program

BackgroundInflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved heart failure–related symptoms, physical limitations, and exercise function, reduced the levels of C-reactive protein (CRP), a biomarker of inflammation, and reduced body weight in participants with obesity-related HFpEF. However, neither the prevalence nor the clinical characteristics of patients who have various magnitudes of inflammation in the context of obesity-related HFpEF have been well described. Furthermore, whether the beneficial effects of semaglutide on the various HF efficacy endpoints in the STEP-HFpEF Program are modified by the baseline levels of inflammation has not been fully established. Finally, the relationship between weight reduction and changes in CRP across the STEP-HFpEF Program have not been fully defined. ObjectivesThis study sought to: 1) evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF that have various levels of inflammation in the STEP-HFpEF Program; 2) determine if the effects of weekly semaglutide 2.4 mg vs placebo across all key outcomes are influenced by baseline levels of inflammation assessed by CRP levels; and 3) determine the relationship between change in CRP and weight loss in the STEP-HFpEF Program. MethodsThis was a secondary analysis of pooled data from 2 international, double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM). The outcomes were change in the dual primary endpoints (health status [measured by the Kansas City Cardiomyopathy Questionnaire—Clinical Summary Score (KCCQ-CSS)] and body weight) from baseline to 52 weeks according to baseline CRP levels. Additional efficacy endpoints included change in 6-minute walk distance (6MWD), a hierarchical composite endpoint that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6MWD, and levels of CRP in semaglutide- vs placebo-treated patients. Patients were stratified into 3 categories based on baseline CRP levels (<2, ≥2 to <10, and ≥10 mg/L). ResultsIn total, 1,145 patients were randomized, of which 71% of patients had evidence of inflammation (CRP ≥2 mg/L). At baseline, those with higher levels of inflammation were younger, were more likely to be female, and had higher body mass index, worse health status (KCCQ-CSS), and shorter 6MWD. Semaglutide vs placebo led to reductions in HF-related symptoms and physical limitations as well as body weight, and to improvements in 6MWD and the hierarchical composite endpoint that were consistent across baseline CRP categories (all P interaction nonsignificant). Semaglutide also reduced CRP to a greater extent than placebo regardless of baseline CRP levels (P interaction = 0.32). Change in CRP from baseline to 52 weeks was similar regardless of the magnitude of weight loss (P interaction = 0.91). ConclusionsInflammation is highly prevalent in obesity-related HFpEF. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced body weight across the categories of baseline CRP. Semaglutide also reduced inflammation, regardless of either baseline CRP or magnitude of weight loss during the trials. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM; NCT04916470])

Predicting Walking Capacity Outcomes After Moderate to High Intensity Locomotor Training in Chronic Stroke.

Moderate-to-high intensity locomotor training (M-HIT) is strongly recommended in stroke rehabilitation but outcomes are variable. This study aimed to identify baseline clinical characteristics that predict change in walking capacity following M-HIT in chronic stroke. This analysis used data from the HIT-Stroke Trial (N=55), which involved up to 36 sessions of either moderate or high intensity locomotor training. A prespecified model assessed how well baseline motor impairment (Fugl-Meyer lower limb motor scale [FM-LL]), comfortable gait speed (CGS), and balance confidence (Activities Balance Confidence scale [ABC]), independently explain changes in 6-minute walk distance (Δ6MWD), while controlling for treatment group. Exploratory analysis tested additional baseline covariates using the all-possible regressions procedure. The prognostic value of each potential covariate was assessed by its average contribution to the explained variance in Δ6MWD (Δ pseudo-R 2 ). With the prespecified model, 8-week Δ6MWD was significantly associated with baseline FM-LL (β=5.0 [95% CI: 1.4, 8.6]) and ABC (β=0.7 [0.0, 1.4]), but not CGS (β=-44.6 [-104.7, 15.6]). The exploratory analysis revealed the top 7 covariates with the highest mean Δ pseudo-R 2 were: FM-LL, pain-limited walking duration, ABC, the use of an assistive device, fatigue, depression, and recent walking exercise history >2 days per week. On average, participants with less motor impairment and higher balance confidence have greater walking capacity improvements after M-HIT in chronic stroke. Additional negative prognostic factors may include pain-limited walking duration, use of an assistive device, fatigue, depression, and recent walking exercise but these exploratory findings need to be confirmed in future studies.

Randomized, Multicenter Study to Assess the Effects of Different Doses of Sildenafil on Mortality in Adults With Pulmonary Arterial Hypertension.

Sildenafil, approved for pulmonary arterial hypertension (PAH), has a recommended adult dose of 20 mg TID, with a previously approved 5-mg TID dose by the US Food and Drug Administration. Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality. To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH. This randomized, double-blind study compared sildenafil at doses of 5, 20, or 80 mg TID in adults with PAH. The primary objective was noninferiority of 80 mg of sildenafil versus 5 mg for all-cause mortality. Secondary end points included time to clinical worsening and change in 6-minute walk distance at 6 months. Interim analyses were planned at 50% and 75% of the anticipated mortality events. Safety and tolerability were assessed in the intention-to-treat population. The study was halted after the first interim analysis, demonstrating noninferiority for 80 mg of sildenafil versus 5 mg. Of 385 patients enrolled across all dose groups, 78 died. The primary analysis showed a hazard ratio of 0.51 (99.7% CI, 0.22-1.21; P<0.001 for noninferiority) for overall survival comparing 80 mg of sildenafil with 5 mg. Time to clinical worsening favored 80 mg of sildenafil compared with 5 mg (hazard ratio, 0.44 [99.7% CI, 0.22-0.89]; P<0.001). Sildenafil at 80 mg improved 6-minute walk distance from baseline at 6 months compared with 5 mg (least square mean change, 18.9 m [95% CI, 2.99-34.86]; P=0.0201). No significant differences were found between 80 mg of sildenafil and 20 mg in mortality, clinical worsening, and 6-minute walk distance. Adverse event-related drug discontinuations were numerically higher with 80 mg of sildenafil. Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of sildenafil over 5 mg. On the basis of these findings, the Food and Drug Administration recently revoked the approval of 5 mg of sildenafil for adults with PAH, reinforced 20 mg TID as the recommended dose, and now allows dose titration up to 80 mg TID, if needed. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487.

Abstract 3027: Home-based, High-pressure Intermittent Limb Compression Following Lower Extremity Revascularization In Patients With Severe Peripheral Artery Disease: A Pilot Trial

Objective: Many patients who undergo lower extremity revascularization (LER) for peripheral artery disease (PAD) continue to experience mobility impairment despite adequate revascularization. High-pressure intermittent limb compression (HPILC) has been shown to augment leg blood flow and improve walking endurance in symptomatic PAD patients. This pilot trial aimed to examine the feasibility of home-based HPILC for 2 hours daily over 3 consecutive months in patients who underwent LER for PAD. The primary outcome was the change in 6-minute walk distance from baseline to 3-month follow-up. Methods: Three months following LER, 9 participants were randomly assigned to either HPILC (n=5) or a sham (n=4) group. Participants were provided with a portable pneumatic air pump and inflatable cuffs that were wrapped around the feet, ankles, and calves (ArtAssist, ACI Medical). The inflation pressures were 120 mmHg and 30 mmHg in the HPILC and sham devices, respectively. A built-in timer, inaccessible to participants, provided one estimate of treatment compliance. Outcomes were assessed before and after the completion of the 3-month interventions. Results: Among the 9 randomized participants, one individual required reintervention and was withdrawn from the study. Adherence to treatment was 74% for HPILC and 92% for sham. As shown in Figure 1, the change in 6-minute walk distance from baseline tended to be higher in the HPILC group compared to the sham-treated group (HPILC: 35.2±38.7 m vs. Sham: -14.7±25 m, p=0.07). There were no group differences in the secondary outcomes, including the changes in the ankle-brachial index, the toe-brachial index, and the Vascular Quality of Life questionnaire scores. Conclusions: Home-based HPILC following LER for PAD is feasible, well-tolerated, and appears to improve walking performance. These preliminary findings indicate that HPILC may be a useful adjunct therapy to enhance lower extremity functioning in patients recovering from LER.

Effect of outpatient cardiac rehabilitation on motor function and health-related quality of life in stroke survivors

BackgroundOutpatient cardiac rehabilitation (CR) is a promising tool for improving functional outcome in stroke survivors, however, evidence for improving emotional health is limited. We aimed to clarify the effects of outpatient CR following in-hospital stroke rehabilitation on health-related quality of life (HRQOL) and motor function. MethodsPatients with acute ischemic stroke or transient ischemic attack discharged directly home were recruited, and 128 patients who fulfilled criteria for insurance coverage of CR were divided into the CR (+) group (n = 46) and CR (-) group (n = 82). All patients underwent in-hospital stroke rehabilitation, and within 2 months after stroke onset, patients in the CR (+) group started a 3-month outpatient CR program of supervised sessions. Changes of motor function and HRQOL assessed by the short form-36 version 2 (SF-36) from discharge to 3 months post-discharge were compared between the two groups. ResultsTwenty-six patients in the CR (+) group completed the program and 66 patients in the CR (-) group were followed up at a 3-month examination. Least-square mean changes in 6-minute walk distance and isometric knee extension muscle strength were significantly higher in the CR (+) group than the CR (-) group (52.6 vs. 16.3 m; 10.1 vs. 3.50 kgf/kg). Improvement of HRQOL at 3 months was not observed in the CR (+) group. ConclusionsOutpatient CR following in-hospital stroke rehabilitation within 2 months after stroke onset improved exercise tolerance and functional strength but not HRQOL assessed by the SF-36 after completion of CR in the present cohort.

Inhaled treprostinil in patients with pulmonary hypertension associated with interstitial lung disease with less severe haemodynamics: a post hoc analysis of the INCREASE study

BackgroundInhaled treprostinil (iTre) is the only treatment approved for pulmonary hypertension due to interstitial lung disease (PH-ILD) to improve exercise capacity. This post hoc analysis evaluated clinical worsening and PH-ILD...

Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial.

Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains. STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [-0.6 to 9.9] points; for body weight, -11 [-13.2 to -8.8], -9.4 [-11.5 to -7.2], and -11.8 [-14.0 to -9.6], respectively; Pinteraction=0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points (Pinteraction>0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7-9.6 points across domains; P≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6-2.9 across domains; P<0.05 for all). In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04788511.

Impact of Left Heart Disease Risk Factors on Outcomes in Pulmonary Arterial Hypertension Therapy

BackgroundCurrent guidelines recommend initial monotherapy for pulmonary arterial hypertension (PAH) with ‘cardiopulmonary comorbidities’, despite limited available evidence to guide management. Research QuestionDo left heart disease (LHD) risk factors have an impact on treatment response and influence applicability of risk assessment in a real-world cohort of PAH patients? Study Design and MethodsThe AMBITION trial criteria was used to define the phenotype of PAH patients with risk factors for LHD. Treatment strategy, functional outcome, long term survival and risk discrimination were compared with a reference PAH cohort using the PHSANZ registry. Results487 incident PAH patients diagnosed between 2011-2020 were included. Of these, 103 (21.1%) fulfilled the definition of PAH with LHD risk factors with 384 (78.9%) remaining as reference group. PAH with LHD risk factors were older (66±13 vs. 58±19years, p<0.001), had lower pulmonary vascular resistance (393±266 vs 708±391dynes/sec/cm-5, p=0.031) and worse 6-minute walk distance (286±130 vs. 327±136m, p=0.005) at diagnosis. PAH with LHD risk factors were less likely to receive less initial combination therapy (27% vs. 44%, p=0.02). Changes in 6-minute walk distance at 12-months were similar in both groups, 43±77 in PAH with LHD risk factors and 50±90m in reference group (p=0.5), including when stratified by initial treatment strategy (monotherapy: 40±81 vs. 38±95m p=0.87 and combination therapy: 53±78 vs. 64±106m, p=0.511; PAH with LHD risk factors vs. reference PAH). Functional class improvements were also similar in both groups. REVEAL 2.0 risk score effectively discriminated risk in both populations (C-statistic=0.756 for PAH with LHD risk factors and C-statistic=0.750 for reference PAH). There was no difference in survival between the two groups (log-rank test p=0.29). InterpretationIn a real-word cohort, PAH patients with LHD risk factors were less likely to be exposed to initial combination therapy. Nevertheless, selected PAH patients with LHD risk factors who were treated with initial combination therapy derived similar functional response compared to reference group. Further studies are needed to phenotype PAH patients with cardiopulmonary comorbidities who may benefit from initial combination therapy.

Group Versus Individual Rehabilitation in Lung Transplantation: A Retrospective Noninferiority Assessment

Purpose: Pulmonary rehabilitation both before and after lung transplant is associated with improved functional exercise capacity and physical quality of life. There is wide variation in rehabilitation program provision. This study's aim was to compare the effects of group versus individual rehabilitation. Methods: Individuals who completed pre- and/or posttransplant outpatient rehabilitation at a single, academic, medical center between March 2019 and March 2021 were included in this study. Noninferiority analysis was used to assess differences in change in 6-minute walk distance (6MWD) between group and individual rehabilitation. Multivariable linear regression models examined 6MWD, Short Physical Performance Battery (SPPB), Ferrans and Powers Quality of Life Index Pulmonary Version (QLI), Center for Epidemiological Studies-Depression Scale (CESD), and San Diego Shortness of Breath Questionnaire (SOBQ). Results: Preoperatively, 93 patients completed group and 81 completed individual rehabilitation. Postoperatively, 110 completed group and 105 completed individual rehabilitation. Individual rehabilitation was noninferior to group rehabilitation (α = 0.05). In addition, there was no significant difference in changes in 6MWD, SPPB, QLI, CESD, or SOBQ, between cohorts pre- and postoperatively (all P &gt; .25). Conclusions: Individual rehabilitation seems to be an acceptable alternative to group rehabilitation for lung transplant candidates and recipients.

Study Design, Rationale, and Methodology for Promote Weight Loss in Patients With Peripheral Artery Disease Who Also Have Obesity: The PROVE Trial.

Background Overweight and obesity are associated with adverse functional outcomes in people with peripheral artery disease (PAD). The effects of weight loss in people with overweight/obesity and PAD are unknown. Methods The PROVE (Promote Weight Loss in Obese PAD Patients to Prevent Mobility Loss) Trial is a multicentered randomized clinical trial with the primary aim of testing whether a behavioral intervention designed to help participants with PAD lose weight and walk for exercise improves 6-minute walk distance at 12-month follow-up, compared with walking exercise alone. A total of 212 participants with PAD and body mass index ≥25 kg/m2 will be randomized. Interventions are delivered using a Group Mediated Cognitive Behavioral intervention model, a smartphone application, and individual telephone coaching. The primary outcome is 12-month change in 6-minute walk distance. Secondary outcomes include total minutes of walking exercise/wk at 12-month follow-up and 12-month change in accelerometer-measured physical activity, the Walking Impairment Questionnaire distance score, and the Patient-Reported Outcomes Measurement Information System mobility questionnaire. Tertiary outcomes include 12-month changes in perceived exertional effort at the end of the 6-minute walk, diet quality, and the Short Physical Performance Battery. Exploratory outcomes include changes in gastrocnemius muscle biopsy measures of mitochondrial cytochrome C oxidase activity, mitochondrial biogenesis, capillary density, and inflammatory markers. Conclusions The PROVE randomized clinical trial will evaluate the effects of exercise with an intervention of coaching and a smartphone application designed to achieve weight loss, compared with exercise alone, on walking performance in people with PAD and overweight/obesity. Results will inform optimal treatment for the growing number of patients with PAD who have overweight/obesity. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04228978.

Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial

In the STEP-HFpEF trial, semaglutide improved symptoms, physical limitations and exercise function and reduced body weight in patients with obesity phenotype of heart failure and preserved ejection fraction (HFpEF). This prespecified analysis examined the effects of semaglutide on dual primary endpoints (change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and body weight) and confirmatory secondary endpoints (change in 6-minute walk distance (6MWD), hierarchical composite (death, HF events, change in KCCQ-CSS and 6MWD) and change in C-reactive protein (CRP)) across obesity classes I–III (body mass index (BMI) 30.0–34.9 kg m−2, 35.0–39.9 kg m−2 and ≥40 kg m−2) and according to body weight reduction with semaglutide after 52 weeks. Semaglutide consistently improved all outcomes across obesity categories (P value for treatment effects × BMI interactions = not significant for all). In semaglutide-treated patients, improvements in KCCQ-CSS, 6MWD and CRP were greater with larger body weight reduction (for example, 6.4-point (95% confidence interval (CI): 4.1, 8.8) and 14.4-m (95% CI: 5.5, 23.3) improvements in KCCQ-CSS and 6MWD for each 10% body weight reduction). In participants with obesity phenotype of HFpEF, semaglutide improved symptoms, physical limitations and exercise function and reduced inflammation and body weight across obesity categories. In semaglutide-treated patients, the magnitude of benefit was directly related to the extent of weight loss. Collectively, these data support semaglutide-mediated weight loss as a key treatment strategy in patients with obesity phenotype of HFpEF. ClinicalTrials.gov identifier: NCT04788511.

The Association Between Mobile App Use and Change in Functional Capacity Among Cardiac Rehabilitation Participants: Cohort Study.

Cardiac rehabilitation (CR) is underused in the United States and globally, with participation disparities across gender, socioeconomic status, race, and ethnicities. The pandemic led to greater adoption of telehealth CR and mobile app use. Our primary objective was to estimate the association between CR mobile app use and change in functional capacity from enrollment to completion in patients participating in a CR program that offered in-person, hybrid, and telehealth CR. Our secondary objectives were to study the association between mobile app use and changes in blood pressure (BP) or program completion. We conducted a retrospective cohort study of participants enrolled in CR at an urban CR program in the United States. Participants were English speaking, at least 18 years of age, participated in the program between May 22, 2020, and May 21, 2022, and downloaded the CR mobile app. Mobile app use was quantified by number of exercise logs, vitals logs, and education material views. The primary outcome was change in functional capacity, measured by change in 6-minute walk distance (6MWD) from enrollment to completion. The secondary outcome was change in BP from enrollment to completion. We estimated associations using multivariable linear or logistic regression models adjusted for age, sex, race, ethnicity, socioeconomic status by ZIP code, insurance, and primary diagnosis for CR referral. A total of 107 participants (mean age 62.9, SD 13.02 years; 90/107, 84.1% male; and 57/105, 53.3% self-declared as White Caucasian) used the mobile app and completed the CR program. Participants had a mean 64.0 (SD 54.1) meter increase in 6MWD between enrollment and completion (P<.001). From enrollment to completion, participants with an elevated BP at baseline (≥130/80 mmHg) experienced a significant decrease in BP (systolic BP -11.5 mmHg; P=.002 and diastolic BP -7.7 mmHg; P=.003). We found no significant association between total app interactions and change in 6MWD (coefficient -0.03, 95% CI -0.1 to 0.07; P=.59) or change in BP (systolic coefficient 0.002, 95% CI -0.03 to 0.03; P=.87 and diastolic coefficient -0.005, 95% CI -0.03 to 0.02; P=.65). There was no significant association between total exercise logs and change in 6MWD (coefficient 0.1, 95% CI -0.3 to 0.4; P=.57) or total BP logs and change in BP (systolic coefficient -0.02, 95% CI -0.1 to 0.06; P=.63 and diastolic coefficient -0.02, 95% CI -0.09 to 0.04; P=.50). There was no significant association between total app interactions and completion of CR (adjusted odds ratio 1.00, 95% CI 0.99-1.01; P=.44). CR mobile app use as part of an in-person, hybrid, or telehealth CR program was not associated with greater improvement in functional capacity or BP or with program completion.

Change in gait speed and adverse outcomes in patients with idiopathic pulmonary fibrosis: A prospective cohort study.

Gait speed is associated with survival in individuals with idiopathic pulmonary fibrosis (IPF). The extent to which four-metre gait speed (4MGS) decline predicts adverse outcome in IPF remains unclear. We aimed to examine longitudinal 4MGS change and identify a cut-point associated with adverse outcome. In a prospective cohort study, we recruited 132 individuals newly diagnosed with IPF and measured 4MGS change over 6 months. Death/first hospitalization at 6 months were composite outcome events. Complete data (paired 4MGS plus index event) were available in 85 participants; missing 4MGS data were addressed using multiple imputation. Receiver-Operating Curve plots identified a 4MGS change cut-point. Cox proportional-hazard regression assessed the relationship between 4MGS change and time to event. 4MGS declined over 6 months (mean [95% CI] change: -0.05 [-0.09 to -0.01] m/s; p= 0.02). A decline of 0.07 m/s or more in 4MGS over 6 months had better discrimination for the index event than change in 6-minute walk distance, forced vital capacity, Composite Physiologic Index or Gender Age Physiology index. Kaplan-Meier curves demonstrated a significant difference in time to event between 4MGS groups (substantial decline: >-0.07 m/s versus minor decline/improvers: ≤-0.07 m/s; p= 0.007). Those with substantial decline had an increased risk of hospitalization/death (adjusted hazard ratio [95% CI] 4.61 [1.23-15.83]). Similar results were observed in multiple imputation analysis. In newly diagnosed IPF, a substantial 4MGS decline over 6 months is associated with shorter time to hospitalization/death at 6 months. 4MGS change has potential as a surrogate endpoint for interventions aimed at modifying hospitalization/death.

Pulmonary vasodilator therapies in pulmonary arterial hypertension associated with CHD: a systematic review and network meta-analysis.

The optimal treatment strategy using pulmonary vasodilators in pulmonary arterial hypertension associated with CHD (PAH-CHD) remains controversial. We aimed to compare the efficacy and safety of pulmonary vasodilators in PAH-CHD. PubMed and EMBASE databases were searched through May 2022 and a network meta-analysis was conducted. The primary outcomes were mean difference of changes in 6-minute walk distance, NYHA functional class, and N-terminal pro-brain natriuretic peptide. The secondary outcomesincluded pulmonary vascular resistance, mean pulmonary arterial pressure, and resting oxygen saturation. We identified 14 studies, yielding 807 patients with PAH-CHD. Bosentan and sildenafil were associated with a significant increase in 6-minute walk distance from baseline compared with placebo (MD 48.92 m, 95% CI 0.32 to 97.55 and MD 59.70 m, 95% CI 0.88 to 118.53, respectively). Bosentan, sildenafil, and combination of bosentan and sildenafil were associated with significant improvement in NYHA functional class compared with placebo (MD -0.33, 95% CI -0.51 to -0.14, MD -0.58, 95% CI -0.75 to -0.22 and MD -0.62, 95% CI -0.92 to -0.31, respectively). Bosentan and sildenafil were also associated with significant improvements in secondary outcomes. These findings were largely confirmed in the subgroup analysis. Various adverse events were reported; however, serious adverse event rates were relatively low (4.8-8.7%), including right heart failure, acute kidney injury, respiratory failure, hypotension, and discontinuation of pulmonary vasodilators. In conclusion, bosentan and sildenafil were the most effective in improving prognostic risk factor such as 6-minute walk distance and NYHA class. Overall, pulmonary vasodilators were well tolerated in PAH-CHD.

Pediatric Population Pharmacokinetic Modeling and Exposure-Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data.

This study aimed to develop a population pharmacokinetic (PK) model of ambrisentan in pediatric patients (8 to <18 years) with pulmonary arterial hypertension (PAH) and compare pediatric ambrisentan systemic exposure with previously reported adult data. Association of ambrisentan exposure with efficacy (6-minute walking distance) and safety (adverse events) were exploratory analyses. A population PK model was developed using pediatric PK data. Steady-state systemic exposure metrics were estimated for the pediatric population and compared with previously reported data in adult patients with PAH and healthy subjects. No covariates had a significant effect on PK parameters; therefore, the final covariate model was the same as the base model. The pediatric population PK model was a 2-compartment model including the effect of body weight (allometric scaling),first-order absorption and elimination, and absorption lag time. Steady-state ambrisentan exposure was similar between the pediatric and adult population when accounting for body weight differences. Geometric mean area under the concentration-time curve at steady state in pediatric patients receiving ambrisentan low dose was 3% lower than in the adult population (and similar in both populations receiving high dose). Geometric mean maximum plasma concentration at steady state in pediatric patients receiving low and high doses was 11% and 18% higher, respectively, than in the adult population. There was no apparent association in the pediatric or adult population between ambrisentan exposure and change in 6-minute walking distance or incidence of ambrisentan-related adverse events in pediatric patients. The similar ambrisentan exposure and exposure-response profiles observed in pediatric and adult populations with PAH suggests appropriateness of body-weight-based dosing in the pediatric population with PAH.

Effect of 5 weeks of oral acetazolamide on patients with pulmonary vascular disease: A randomized, double-blind, cross-over trial

BackgroundThe carbonic anhydrase inhibitor acetazolamide stimulates ventilation through metabolic acidosis mediated by renal bicarbonate excretion. In animal models, acetazolamide attenuates acute hypoxia-induced pulmonary hypertension (PH), but its efficacy in treating patients with PH due to pulmonary vascular disease (PVD) is unknown. Methods28 PVD patients (15 pulmonary arterial hypertension, 13 distal chronic thromboembolic PH), 13 women, mean±SD age 61.6±15.0 years stable on PVD medications, were randomised in a double-blind crossover protocol to 5 weeks acetazolamide (250mg b.i.d) or placebo separated by a ≥2 week washout period. Primary endpoint was the change in 6-minute walk distance (6MWD) at 5 weeks. Additional endpoints included safety, tolerability, WHO functional class, quality of life, arterial blood gases, and hemodynamics (by echocardiography). ResultsAcetazolamide had no effect on 6MWD compared to placebo (treatment effect: mean change [95%CI] -18 [-40 to 4]m, p=0.102) but increased arterial blood oxygenation through hyperventilation induced by metabolic acidosis. Other measures including pulmonary hemodynamics were unchanged. No severe adverse effects occurred, side effects that occurred significantly more frequently with acetazolamide vs. placebo were change in taste (22/0%), paraesthesia (37/4%) and mild dyspnea (26/4%). ConclusionsIn patients with PVD, acetazolamide did not change 6MWD compared to placebo despite improved blood oxygenation. Some patients reported a tolerable increase in dyspnoea during acetazolamide treatment, related to hyperventilation, induced by the mild drug-induced metabolic acidosis. Our findings do not support the use of acetazolamide to improve exercise in patients with PVD at this dosing. ClinicalTrials.gov IdentifierNCT02755298

The relationship between longitudinal change in 6-minute walk distance and physical function in the elderly requiring long-term care.

The relationship between longitudinal change in 6-minute walk distance and physical function in the elderly requiring long-term care.