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Effect of Sacubitril/Valsartan vs Standard Medical Therapies on Plasma NT-proBNP Concentration and Submaximal Exercise Capacity in Patients With Heart Failure and Preserved Ejection Fraction: The PARALLAX Randomized Clinical Trial.
Pieske, B, Wachter, R, Shah, SJ, Baldridge, A, Szeczoedy, P, Ibram, G, Shi, V, Zhao, Z, Cowie, MR, ,
JAMA. 2021;(19):1919-1929
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Abstract
IMPORTANCE There is limited evidence on the benefits of sacubitril/valsartan vs broader renin angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute walk distance, and quality of life in patients with heart failure and mildly reduced or preserved left ventricular ejection fraction (LVEF >40%). OBJECTIVE To evaluate the effect of sacubitril/valsartan on N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, 6-minute walk distance, and quality of life vs background medication-based individualized comparators in patients with chronic heart failure and LVEF of more than 40%. DESIGN, SETTING, AND PARTICIPANTS A 24-week, randomized, double-blind, parallel group clinical trial (August 2017-October 2019). Of 4632 patients screened at 396 centers in 32 countries, 2572 patients with heart failure, LVEF of more than 40%, elevated NT-proBNP levels, structural heart disease, and reduced quality of life were enrolled (last follow-up, October 28, 2019). INTERVENTIONS Patients were randomized 1:1 either to sacubitril/valsartan (n = 1286) or to background medication-based individualized comparator (n = 1286), ie, enalapril, valsartan, or placebo stratified by prior use of a renin angiotensin system inhibitor. MAIN OUTCOMES AND MEASURES Primary end points were change from baseline in plasma NT-proBNP level at week 12 and in the 6-minute walk distance at week 24. Secondary end points were change from baseline in quality of life measures and New York Heart Association (NYHA) class at 24 weeks. RESULTS Among 2572 randomized patients (mean age, 72.6 years [SD, 8.5 years]; 1301 women [50.7%]), 2240 (87.1%) completed the trial. At baseline, the median NT-proBNP levels were 786 pg/mL in the sacubitril/valsartan group and 760 pg/mL in the comparator group. After 12 weeks, patients in the sacubitril/valsartan group (adjusted geometric mean ratio to baseline, 0.82 pg/mL) had a significantly greater reduction in NT-proBNP levels than did those in the comparator group (adjusted geometric mean ratio to baseline, 0.98 pg/mL) with an adjusted geometric mean ratio of 0.84 (95% CI, 0.80 to 0.88; P < .001). At week 24, there was no significant between-group difference in median change from baseline in the 6-minute walk distance with an increase of 9.7 m vs 12.2 m (adjusted mean difference, -2.5 m; 95% CI, -8.5 to 3.5; P = .42). There was no significant between-group difference in the mean change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (12.3 vs 11.8; mean difference, 0.52; 95% CI, -0.93 to 1.97) or improvement in NYHA class (23.6% vs 24.0% of patients; adjusted odds ratio, 0.98; 95% CI, 0.81 to 1.18). The most frequent adverse events in the sacubitril/valsartan group vs the comparator group were hypotension (14.1% vs 5.5%), albuminuria (12.3% vs 7.6%), and hyperkalemia (11.6% vs 10.9%). CONCLUSIONS AND RELEVANCE Among patients with heart failure and left ventricular ejection factor of higher than 40%, sacubitril/valsartan treatment compared with standard renin angiotensin system inhibitor treatment or placebo resulted in a significantly greater decrease in plasma N-terminal pro-brain natriuretic peptide levels at 12 weeks but did not significantly improve 6-minute walk distance at 24 weeks. Further research is warranted to evaluate potential clinical benefits of sacubitril/valsartan in these patients. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03066804.
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Cardiac rehabilitation of elderly patients in eight rehabilitation units in western Europe: Outcome data from the EU-CaRE multi-centre observational study.
Prescott, E, Eser, P, Mikkelsen, N, Holdgaard, A, Marcin, T, Wilhelm, M, Gil, CP, González-Juanatey, JR, Moatemri, F, Iliou, MC, et al
European journal of preventive cardiology. 2020;(16):1716-1729
Abstract
AIMS: The European Cardiac Rehabilitation in the Elderly (EU-CaRE) HORIZON 2020 project compares the sustainable effects of cardiac rehabilitation (CR) in elderly patients. METHODS AND RESULTS A total of 1633 patients with coronary artery disease (CAD) or heart valve replacement (HVR), with or without revascularization, aged 65 or above, who participated in CR were included. Peak oxygen uptake (VO2peak), smoking, body mass index, diet, physical activity, serum lipids, psychological distress and medication were assessed before and after CR (T0 and T1) and after 12 months (T2). Patients undergoing coronary artery bypass surgery or surgical HVR had lower VO2peak at T0 and a greater increase to T1 and T2 (2.8 and 4.4 ml/kg/min, respectively) than CAD patients undergoing percutaneous or no revascularization (1.6 and 1.4 ml/kg/min, respectively). After multivariable adjustment, earlier CR uptake was associated with greater improvements in VO2peak. The proportion of CAD patients with three or more uncontrolled risk factors declined from 58.4% at T0 to 40.1% at T2 (p < 0.0001). Psychological distress scores all improved and adherence to medication was overall good at all sites. There were significant differences in risk factor burden across sites, but no CR program was superior to others. CONCLUSIONS The outcomes of VO2peak in CR programs across Europe seemed mainly determined by timing of uptake and were maintained or even further improved at 1-year follow-up. Despite significant improvements, 40.1% of CAD patients still had three or more risk factors not at target after 1 year. Differences across sites could not be ascribed to characteristics of the CR programs offered.
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Comparative effectiveness of torasemide versus furosemide in symptomatic therapy in heart failure patients: Preliminary results from the randomized TORNADO trial.
Balsam, P, Ozierański, K, Marchel, M, Gawałko, M, Niedziela, Ł, Tymińska, A, Sieradzki, B, Sieradzki, M, Fojt, A, Bakuła, E, et al
Cardiology journal. 2019;(6):661-668
Abstract
BACKGROUND Recent reports suggest that torasemide might be more beneficial than furosemide in patients with symptomatic heart failure (HF). The aim was to compare the effects of torasemide and furosemide on clinical outcomes in HF patients. METHODS This study pilot consisted of data from the ongoing multicenter, randomized, unblinded endpoint phase IV TORNADO (NCT01942109) study. HF patients in New York Heart Association (NYHA) II-IV class with a stable dose of furosemide were randomized to treatment with equipotential dose of torasemide (4:1) or continuation of unchanged dose of furosemide. On enrollment and control visit (3 months after enrollment) clinical examination, 6-minute walk test (6MWT) and assessment of fluid retention by ZOE Fluid Status Monitor were performed. The primary endpoint was a composite of improvement of NYHA class, improvement of at least 50 m during 6MWT and decrease in fluid retention of at least 0.5 W after 3-months follow-up. RESULTS The study group included 40 patients (median age 66 years; 77.5% male). During follow-up 7 patients were hospitalized for HF worsening (3 in torasemide and 4 in furosemide-treated patients). The primary endpoint reached 15 (94%) and 14 (58%) patients on torasemide and furosemide, respectively (p = 0.03). CONCLUSIONS In HF patients treated with torasemide fluid overload and symptoms improved more than in the furosemide group. This positive effect occurred already within 3-month observation.
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Iron deficiency in patients with heart failure with preserved ejection fraction and its association with reduced exercise capacity, muscle strength and quality of life.
Bekfani, T, Pellicori, P, Morris, D, Ebner, N, Valentova, M, Sandek, A, Doehner, W, Cleland, JG, Lainscak, M, Schulze, PC, et al
Clinical research in cardiology : official journal of the German Cardiac Society. 2019;(2):203-211
Abstract
BACKGROUND The prevalence of iron deficiency (ID) in outpatients with heart failure with preserved ejection fraction (HFpEF) and its relation to exercise capacity and quality of life (QoL) is unknown. METHODS 190 symptomatic outpatients with HFpEF (LVEF 58 ± 7%; age 71 ± 9 years; NYHA 2.4 ± 0.5; BMI 31 ± 6 kg/m2) were enrolled as part of SICA-HF in Germany, England and Slovenia. ID was defined as ferritin < 100 or 100-299 µg/L with transferrin saturation (TSAT) < 20%. Anemia was defined as Hb < 13 g/dL in men, < 12 g/dL in women. Low ferritin-ID was defined as ferritin < 100 µg/L. Patients were divided into 3 groups according to E/e' at echocardiography: E/e' ≤ 8; E/e' 9-14; E/e' ≥ 15. All patients underwent echocardiography, cardiopulmonary exercise test (CPX), 6-min walk test (6-MWT), and QoL assessment using the EQ5D questionnaire. RESULTS Overall, 111 patients (58.4%) showed ID with 89 having low ferritin-ID (46.84%). 78 (41.1%) patients had isolated ID without anemia and 54 patients showed anemia (28.4%). ID was more prevalent in patients with more severe diastolic dysfunction: E/e' ≤ 8: 44.8% vs. E/e': 9-14: 53.2% vs. E/e' ≥ 15: 86.5% (p = 0.0004). Patients with ID performed worse during the 6MWT (420 ± 137 vs. 344 ± 124 m; p = 0.008) and had worse exercise time in CPX (645 ± 168 vs. 538 ± 178 s, p = 0.03). Patients with low ferritin-ID had lower QoL compared to those without ID (p = 0.03). CONCLUSION ID is a frequent co-morbidity in HFpEF and is associated with reduced exercise capacity and QoL. Its prevalence increases with increasing severity of diastolic dysfunction.
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SYNERGIC TRIAL (SYNchronizing Exercises, Remedies in Gait and Cognition) a multi-Centre randomized controlled double blind trial to improve gait and cognition in mild cognitive impairment.
Montero-Odasso, M, Almeida, QJ, Burhan, AM, Camicioli, R, Doyon, J, Fraser, S, Li, K, Liu-Ambrose, T, Middleton, L, Muir-Hunter, S, et al
BMC geriatrics. 2018;(1):93
Abstract
BACKGROUND Physical exercise, cognitive training, and vitamin D are low cost interventions that have the potential to enhance cognitive function and mobility in older adults, especially in pre-dementia states such as Mild Cognitive Impairment (MCI). Aerobic and progressive resistance exercises have benefits to cognitive performance, though evidence is somewhat inconsistent. We postulate that combined aerobic exercise (AE) and progressive resistance training (RT) (combined exercise) will have a better effect on cognition than a balance and toning control (BAT) intervention in older adults with MCI. We also expect that adding cognitive training and vitamin D supplementation to the combined exercise, as a multimodal intervention, will have synergistic efficacy. METHODS The SYNERGIC trial (SYNchronizing Exercises, Remedies in GaIt and Cognition) is a multi-site, double-blinded, five-arm, controlled trial that assesses the potential synergic effect of combined AE and RT on cognition and mobility, with and without cognitive training and vitamin D supplementation in older adults with MCI. Two-hundred participants with MCI aged 60 to 85 years old will be randomized to one of five arms, four of which include combined exercise plus combinations of dual-task cognitive training (real vs. sham) and vitamin D supplementation (3 × 10,000 IU/wk. vs. placebo) in a quasi-factorial design, and one arm which receives all control interventions. The primary outcome measure is the ADAS-Cog (13 and plus modalities) measured at baseline and at 6 months of follow-up. Secondary outcomes include neuroimaging, neuro-cognitive performance, gait and mobility performance, and serum biomarkers of inflammation (C reactive protein and interleukin 6), neuroplasticity (brain-derived neurotropic factor), endothelial markers (vascular endothelial growth factor 1), and vitamin D serum levels. DISCUSSION The SYNERGIC Trial will establish the efficacy and feasibility of a multimodal intervention to improve cognitive performance and mobility outcomes in MCI. These interventions may contribute to new approaches to stabilize and reverse cognitive-mobility decline in older individuals with MCI. TRIAL REGISTRATION Identifier: NCT02808676. https://www.clinicaltrials.gov/ct2/show/NCT02808676 .
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Efficacy of patients' preferred exercise modalities in chronic obstructive pulmonary disease: A parallel-group, randomized, clinical trial.
Wu, M, Zhou, LQ, Li, S, Zhao, S, Fan, HJ, Sun, JM, Li, XN, Luo, J, Wang, AQ, Wu, JP, et al
The clinical respiratory journal. 2018;(4):1581-1590
Abstract
INTRODUCTION Physical exercise effectively improves health-related quality of life in patients with chronic obstructive pulmonary disease (COPD). However, application of this medical intervention is problematic, due to poor adherence to the exercise program or unawareness of the significance of this intervention. OBJECTIVE To determine whether COPD patients who adopted personal-preferred exercise modalities (PPEMs) for daily training would demonstrate sustained benefits due to improved adherence. METHODS Stable COPD patients were randomly assigned to the daily PPEMs group or the control group (without extra exercise apart from daily life activities). All other treatments were similar. The primary outcome was the health-related quality of life (HRQoL), measured with St. George's Respiratory Questionnaire (SGRQ) score at 12 months. Other measures included the Borg dyspnea score, 6-min walking distance (6MWD) and lung function variables. RESULTS The intention-to-treat (ITT) population included 94 patients, 68 of them completed the study protocol over 12 months (the PP-population). A greater decline of SGRQ score (improvement of HRQoL) in the PPEMs group than that in the controls was demonstrated over 12 months (-19.1 vs -9.0 in the ITT population and -19.1 vs -8.7 in the PP population, P ≤ .001 for all comparisons), the reduction exceeded the minimal clinically important difference of ≥ 4 points. The PPEMs group also showed a greater reduction than the control group in Borg score at 12 months in the ITT and the PP population as well (P < .01). No significant improvement was found in 6MWD or in lung function variables. CONCLUSIONS COPD patients could benefit from extra daily PPEMs, and the gain may sustain at least for 1 year.
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Loop diuretic adjustments in patients with chronic heart failure: Insights from HF-ACTION.
Fudim, M, O'Connor, CM, Mulder, H, Coles, A, Bhatt, AS, Ambrosy, AP, Kraus, WE, Piña, IL, Whellan, DJ, Mentz, RJ
American heart journal. 2018;:133-141
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BACKGROUND The relationship between diuretic use or change in diuretic use and outcomes in chronic heart failure (HF) remains poorly defined. We evaluated the association between diuretic use and changes in health status, exercise capacity, and clinical events in a large randomized trial of subjects with HF. METHODS HF-ACTION randomized 2,331 outpatients with HF and ejection fraction ≤35% to aerobic exercise training versus usual care. We grouped patients according to loop diuretic use from baseline through 6 months: continued use, never use, initiated, and discontinued. The association between diuretic use and changes in health status, exercise capacity, and clinical outcomes (all-cause mortality/hospitalization, cardiovascular mortality, and HF hospitalization) through 12 months was assessed using Cox proportional hazards models and generalized linear regression models, respectively. RESULTS A total of 2,004 (86%) patients had complete data on diuretic use. There was no association between diuretic status and Kansas City Cardiomyopathy Questionnaire, 6-minute walk distance, or peak Vo2 in adjusted analyses (all P > .05). A dose increase was associated with decrease in 6-minute walk distance (-4.25 m, SE 1.12 m, P < .001) and change in Kansas City Cardiomyopathy Questionnaire overall score (-0.56 m, SE 0.24 m, P = .02). There were no between-group differences for all-cause death or hospitalization comparing continuous use versus never use (adjusted HR 0.91; 95% CI 0.72-1.15; P = .432). CONCLUSIONS The initiation or discontinuation of diuretics over a 6-month time frame was not associated with a difference in mortality, hospitalizations, exercise, or health status outcomes, but a dose increase in HF patients was associated with worse exercise and health status outcomes.
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Effects of combined exercise training and electromyostimulation treatments in chronic heart failure: A prospective multicentre study.
Iliou, MC, Vergès-Patois, B, Pavy, B, Charles-Nelson, A, Monpère, C, Richard, R, Verdier, JC, ,
European journal of preventive cardiology. 2017;(12):1274-1282
Abstract
Background Exercise training as part of a comprehensive cardiac rehabilitation is recommended for patients with cardiac heart failure. It is a valuable method for the improvement of exercise tolerance. Some studies reported a similar improvement with quadricipital electrical myostimulation, but the effect of combined exercise training and electrical myostimulation in cardiac heart failure has not been yet evaluated in a large prospective multicentre study. Purpose The aim of this study was to determine whether the addition of low frequency electrical myostimulation to exercise training may improve exercise capacity and/or muscular strength in cardiac heart failure patients. Methods Ninety-one patients were included (mean age: 58 ± 9 years; New York Heart Association II/III: 52/48%, left ventricular ejection fraction: 30 ± 7%) in a prospective French study. The patients were randomised into two groups: 41 patients in exercise training and 50 in exercise training + electrical myostimulation. All patients underwent 20 exercise training sessions. In addition, in the exercise training + electrical myostimulation group, patients underwent 20 low frequency (10 Hz) quadricipital electrical myostimulation sessions. Each patient underwent a cardiopulmonary exercise test, a six-minute walk test, a muscular function evaluation and a quality of life questionnaire, before and at the end of the study. Results A significant improvement of exercise capacity (Δ peak oxygen uptake+15% in exercise training group and +14% in exercise training + electrical myostimulation group) and of quality of life was observed in both groups without statistically significant differences between the two groups. Mean creatine kinase level increased in the exercise training group whereas it remained stable in the combined group. Conclusions This prospective multicentre study shows that electrical myostimulation on top of exercise training does not demonstrate any significant additional improvement in exercise capacity in cardiac heart failure patients.
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Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency.
van Veldhuisen, DJ, Ponikowski, P, van der Meer, P, Metra, M, Böhm, M, Doletsky, A, Voors, AA, Macdougall, IC, Anker, SD, Roubert, B, et al
Circulation. 2017;(15):1374-1383
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BACKGROUND Iron deficiency is common in patients with heart failure (HF) and is associated with reduced exercise capacity and poor outcomes. Whether correction of iron deficiency with (intravenous) ferric carboxymaltose (FCM) affects peak oxygen consumption [peak VO2], an objective measure of exercise intolerance in HF, has not been examined. METHODS We studied patients with systolic HF (left ventricular ejection fraction ≤45%) and mild to moderate symptoms despite optimal HF medication. Patients were randomized 1:1 to treatment with FCM for 24 weeks or standard of care. The primary end point was the change in peak VO2 from baseline to 24 weeks. Secondary end points included the effect on hematinic and cardiac biomarkers, quality of life, and safety. For the primary analysis, patients who died had a value of 0 imputed for 24-week peak VO2. Additional sensitivity analyses were performed to determine the impact of imputation of missing peak VO2 data. RESULTS A total of 172 patients with HF were studied and received FCM (n=86) or standard of care (control group, n=86). At baseline, the groups were well matched; mean age was 64 years, 75% were male, mean left ventricular ejection fraction was 32%, and peak VO2 was 13.5 mL/min/kg. FCM significantly increased serum ferritin and transferrin saturation. At 24 weeks, peak VO2 had decreased in the control group (least square means -1.19±0.389 mL/min/kg) but was maintained on FCM (-0.16±0.387 mL/min/kg; P=0.020 between groups). In a sensitivity analysis, in which missing data were not imputed, peak VO2 at 24 weeks decreased by -0.63±0.375 mL/min/kg in the control group and by -0.16±0.373 mL/min/kg in the FCM group; P=0.23 between groups). Patients' global assessment and functional class as assessed by the New York Heart Association improved on FCM versus standard of care. CONCLUSIONS Treatment with intravenous FCM in patients with HF and iron deficiency improves iron stores. Although a favorable effect on peak VO2 was observed on FCM, compared with standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak VO2 among patients who died. Whether FCM is associated with an improved outcome in these high-risk patients needs further study. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01394562.
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Novel Approach Targeting the Complex Pathophysiology of Hypertrophic Cardiomyopathy: The Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) Trial.
Olivotto, I, Hellawell, JL, Farzaneh-Far, R, Blair, C, Coppini, R, Myers, J, Belardinelli, L, Maron, MS
Circulation. Heart failure. 2016;(3):e002764
Abstract
UNLABELLED Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, with an overall prevalence of at least 1:500 in the adult population although only a fraction of affected patients come to clinical recognition. It is also the most common cause of sudden cardiac death in young adults and a major cause of morbidity caused by chronic heart failure symptoms. However, more than half a century since the original description of the disease, there is no currently approved therapy for the treatment of patients with HCM, and to date there have been only 5 randomized studies of medical therapies in HCM. As such, unmet medical need in HCM has been highlighted by the National Heart, Lung, and Blood Institute (NHLBI) as a research priority. Encouragingly, the infrastructure needed to conduct rigorous clinical trials in HCM has recently emerged because of the heightened awareness and understanding of the disease, development of clinical centers of excellence, and advances in diagnostic imaging. In this article, we will discuss the complex pathophysiology of HCM, review the current therapeutic landscape, describe new mechanistic insights into the central role of the late sodium current in HCM, and introduce the scientific rationale and execution of the Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) trial, the largest randomized, double-blind, placebo controlled clinical trial, now underway, designed to evaluate the effect of a novel pharmacological approach in patients with symptomatic HCM. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT02291237.