Effects of Levosimendan on Quality of Life and Emotional Stress in Advanced Heart Failure Patients

AIM: Levosimendan improves central hemodynamics and symptoms in acutely decompensated chronic heart failure (CHF) patients. However, its effects on quality of life, emotional stress and functional capacity of patients with advanced CHF have not been properly investigated. METHODS AND RESULTS: Sixty-three advanced CHF patients (NYHA III-IV, LVEF<30%) were randomized (2:1) to receive either a 24-h levosimendan infusion of 0.1 mug/kg/min or placebo. Questionnaires addressing quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ), functional and overall, Duke's Activity Status Index (DASI)] and emotional stress [Zung self-rating depression scale (SDS), Beck Depression Inventory (BDI)], as well as plasma BNP and 6-min walking distance (6MWT as a marker of exercise capacity) were assessed before treatment and at hospital discharge. A significant improvement in NYHA class (2.1 +/- 0.7 from 3.3 +/- 0.7, p < 0.01), 6 MWT (305 +/- 152 from 215 +/- 142 m, p < 0.01) and plasma BNP (598 +/- 398 from 1,078 +/- 756 pg/ml, p < 0.01) was observed post-treatment only in levosimendan-treated group. KCCQ functional (45 +/- 19 from 35 +/- 17%, p < 0.05) and overall (34 +/- 13 from 28 +/- 11%, p < 0.05), DASI (26 +/- 13 from 22 +/- 12, p < 0.05), Zung SDS (38 +/- 12 from 42 +/- 13, p < 0.01) and BDI (11 +/- 6 from 14 +/- 8, p < 0.05) scores also improved in levosimendan-treated patients, while remained unchanged in the placebo group. The hospital length stay was shorter in levosimendan group compared to placebo (3.2 +/- 1.7 versus 5.8 +/- 2.1 days, p < 0.01). Levosimendan-induced BNP reduction was significantly correlated with concomitant increase in 6MWT (r = 0.643, p < 0.001) as well as with the decrease of BDI (r = 0.30, p < 0.05) and Zung SDS (r = 0.25, p = 0.05). CONCLUSION: Levosimendan seems to have a beneficial effect on quality of life, physical activity and emotional stress in advanced CHF patients, reducing concurrently hospitalization length.     

Effects of Repeated Co-Injections of Corticosteroids and Hyaluronic Acid on Knee Osteoarthritis: A Prospective,Double-Blind Randomized Controlled Trial

BackgroundWe compared the effects of repeated co-injections of corticosteroids plus hyaluronic acid (HA) with the effects of HA injections alone in patients with knee osteoarthritis.MethodsA double-blind randomized controlled trial was conducted between October 2016 and July 2017 at a medical center. Patients (n = 57) who fulfilled the clinical and radiographic criteria for knee osteoarthritis established by the American College of Rheumatology with a Kellgren-Lawrence score of 2 or 3 were included. They were assigned to either the HA group (n = 29) or corticosteroids plus HA group (n = 28), and injections were administered under ultrasound guidance once a week for 3 consecutive weeks. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were the primary outcomes. Physical functional performance (10-m fast walking and chair-rising time) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) were secondary outcomes. The assessment was performed prior to injections, 1 week, and 1, 3, and 6 months after injections. Data were analyzed through repeated-measures analysis of covariance.ResultsBoth groups experienced decreased pain and improved physical function and physical functional performance over time. We found significant group × time interaction effects favoring the corticosteroids plus HA group in WOMAC-pain (P = .005) and physical function (P = .005), chair-rising time (P = .032), and KOOS-pain (P = .001).ConclusionsRepeated co-injections of corticosteroids plus HA more effectively decreased pain and improved physical function and physical functional performance than injections of HA alone from 1 week through 6 months posttreatment.     

Efficacy and Safety of 1-Hour Infusion of Recombinant Human Atrial Natriuretic Peptide in Patients With Acute Decompensated Heart Failure: A Phase III,Randomized, Double-Blind,Placebo-Controlled,Multicenter Trial

The aim of the study was to evaluate the efficacy and safety of 1-h infusion of recombinant human atrial natriuretic peptide (rhANP) in combination with standard therapy in patients with acute decompensated heart failure (ADHF).This was a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients with ADHF were randomized to receive a 1-h infusion of either rhANP or placebo at a ratio of 3:1 in combination with standard therapy. The primary endpoint was dyspnea improvement (a decrease of at least 2 grades of dyspnea severity at 12 h from baseline). Reduction in pulmonary capillary wedge pressure (PCWP) 1 h after infusion was the co-primary endpoint for catheterized patients. Overall, 477 patients were randomized: 358 (93 catheterized) patients received rhANP and 118 (28 catheterized) received placebo. The percentage of patients with dyspnea improvement at 12 h was higher, although not statistically significant, in the rhANP group than in the placebo group (32.0% vs 25.4%, odds ratio=1.382, 95% confidence interval [CI]: 0.863–2.212, P = 0.17). Reduction in PCWP at 1 h was significantly greater in patients treated with rhANP than in patients treated with placebo (−7.74 ± 5.95 vs −1.82 ± 4.47 mm Hg, P < 0.001). The frequencies of adverse events and renal impairment within 3 days of treatment were similar between the 2 groups. Mortality at 1 month was 3.1% in the rhANP group vs 2.5% in the placebo group (hazard ratio = 1.21, 95% CI: 0.34–4.26; P > 0.99).1-h rhANP infusion appears to result in prompt, transient hemodynamic improvement with a small, nonsignificant, effect on dyspnea in ADHF patients receiving standard therapy. The safety of 1-h infusion of rhANP seems to be acceptable. (WHO International Clinical Trials Registry Platform [ICTRP] number, ChiCTR-IPR-14005719.)     

Beneficial Effects of Listening to Classical Music in Patients With Heart Failure: A Randomized Controlled Trial

BackgroundPractical recommendations on nonpharmacologic non-device/surgical interventions in patients with heart failure (HF) are well known. Although complementary treatments may have beneficial effects, there is no evidence that these on their own improve mortality, morbidity, or quality of life. We examined the effects of listening to recorded classical music on HF-specific quality of life (QOL), generic QOL, sleep quality, anxiety, depression, and cognitive state in patients with HF in the home-care setting.Methods and ResultsMulticenter randomized controlled trial. One hundred fifty-nine patients with HF were randomized on a 1:1 basis in 2 groups: experimental (music) and control. Patients were evaluated after 30, 60, 90 days (experimental period) and at 6 months. Patients randomized to the music group listened to music from a large preselected playlist, at least 30 minutes per day, for 3 months on an MP3 player. Patients in the control group received standard care. HF-specific QOL, generic QOL, self-care, somatic perception of HF symptoms, sleep quality, anxiety and depression, and cognitive abilities were assessed throughout the use of specific scales. On average, patients in the music group showed greater improvements in terms of HF-specific QOL (P < .001), generic-QOL (P = .005), quality of sleep (P = .007), anxiety and depression levels (P < .001 for both), and cognitive performances (P = .003).ConclusionsListening to recorded classical music is a feasible, noninvasive, safe, and inexpensive intervention, able to improve QOL in patients with HF in the home-care setting.     

A Randomized Controlled Trial of Mobile Health Intervention in Patients With Heart Failure and Diabetes

BackgroundMobile health (mHealth) platforms can affect health behaviors but have not been rigorously tested in randomized trials.ObjectivesWe sought to evaluate the effectiveness of a pragmatic mHealth intervention in patients with heart failure (HF) and diabetes (DM).MethodsWe conducted a multicenter randomized trial in 187 patients with both HF and DM to assess an mHealth intervention to improve physical activity and medication adherence compared to usual care. The primary endpoint was change in mean daily step count from baseline through 3 months. Other outcomes included medication adherence, health-related quality of life and metabolomic profiling.ResultsThe mHealth group had an increase in daily step count of 151 steps/day at 3 months, whereas the usual-care group had a decline of 162 steps/day (least squares mean between-group difference = 313 steps/day; 95% CI: 8 619; P = 0.044). Medication adherence, measured using the Voils Adherence Questionnaire, did not change from baseline to 3 months (LS-mean change –0.08 in mHealth vs –0.15 in usual care; P = 0.47). The mHealth group had an improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score compared to the usual-care group (LS-mean difference = 5.5 points, 95% CI: 1.4, 9.6; P = 0.009). Thirteen metabolites, primarily medium- and long-chain acylcarnitines, changed differently between treatment groups from baseline to 3 months (P < 0.05).ConclusionsIn patients with HF and DM, a 3-month mHealth intervention significantly improved daily physical activity, health-related quality of life and metabolomic markers of cardiovascular health but not medication adherence.Condensed AbstractHeart failure (HF) and diabetes (DM) have overlapping biological and behavioral risk factors. We conducted a multicenter randomized, clinical trial in 187 patients with both HF (regardless of ejection fraction) and DM to assess whether an mHealth intervention could improve physical activity and medication adherence. The mHealth group had an increase in mean daily step count and quality of life but not in medication adherence. Medium- and long-chain acylcarnitines changed differently in treatment groups from baseline to 3 months (P < 0.05). These data have important implications for designing effective lifestyle interventions in HF and DM.     

Protective Effect of Folic Acid on Oxidative DNA Damage: A Randomized,Double-Blind,and Placebo Controlled Clinical Trial

Although previous reports have linked DNA damage with both transmissions across generations as well as our own survival, it is unknown how to reverse the lesion. Based on the data from a Randomized, Double-blind, Placebo Controlled Clinical Trial, this study aimed to assess the efficacy of folic acid supplementation (FAS) on DNA oxidative damage reversal.In this randomized clinical trial (RCT), a total of 450 participants were enrolled and randomly assigned to 3 groups to receive folic acid (FA) 0.4 mg/day (low-FA), 0.8 mg/day (high-FA), or placebo (control) for 8 weeks. The urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG) and creatinine (Cr) concentration at pre- and post-FAS were measured with modified enzyme-linked immunosorbent assay (ELISA) and high-performance liquid chromatography (HPLC), respectively. A multivariate general linear model was applied to assess the individual effects of FAS and the joint effects between FAS and hypercholesterolemia on oxidative DNA damage improvement. This clinical trial was registered with ClinicalTrials.gov, number {"type":"clinical-trial","attrs":{"text":"NCT02235948","term_id":"NCT02235948"}}NCT02235948.Of the 438 subjects that received FA fortification or placebo, the median (first quartile, third quartile) of urinary 8-OHdG/Cr for placebo, low-FA, and high-FA groups were 58.19 (43.90, 82.26), 53.51 (38.97, 72.74), 54.73 (39.58, 76.63) ng/mg at baseline and 57.77 (44.35, 81.33), 51.73 (38.20, 71.30), and 50.65 (37.64, 76.17) ng/mg at the 56th day, respectively. A significant decrease of urinary 8-OHdG was observed after 56 days FA fortification (P < 0.001). Compared with the placebo, after adjusting for some potential confounding factors, including the baseline urinary 8-OHdG/Cr, the urinary 8-OHdG/Cr concentration significantly decreased after 56 days FAS [β (95% confidence interval) = −0.88 (−1.62, −0.14) and P = 0.020 for low-FA; and β (95% confidence interval) = −2.68 (−3.42, −1.94) and P < 0.001 for high-FA] in a dose-response fashion (P_trend < 0.001). Test of interaction between hypercholesterolemia and FA supplementation on urinary 8-OHdG reduction was significant (P = 0.001).The present study demonstrates that FA fortification is independently linked to the reduction of urinary 8-OHdG/Cr in a dose-related pattern, which suggests that FA is beneficial to protect against oxidative damage to DNA. This effect is apparently stronger in those with hypercholesterolemia. The authors provide a new insight into the prevention and reversal of oxidative DNA damage.     

The Effects of METhotrexate Therapy on the Physical Capacity of Patients With ISchemic Heart Failure: A Randomized Double-Blind,Placebo-Controlled Trial (METIS Trial)

BackgroundThe cytokine hypothesis suggests that there is an association between chronic heart failure (CHF) and inflammation. Methotrexate could improve CHF patients' clinical status, especially those with ischemic etiology.Methods and ResultsMETIS is a randomized, double-blinded trial studying 50 patients with ischemic CHF given methotrexate (7.5 mg) or placebo, plus folic acid (5 mg), for 12 weeks. The primary end point was the difference in 6-minute walk test (6MWT) distance before and after treatment. We also evaluated functional class (NYHA), Short-Form 36 protocol quality of life, C-reactive protein (CRP), incidence of adverse effects, and the combined incidence of death, myocardial infarction, stroke, hospitalization, and need for myocardial revascularization. There was no significant difference between groups in distance covered in the 6MWT: the methotrexate group improved by 24.5 ± 39.5 m, the placebo group by 21.3 ± 43.7 m (P = .80). The NYHA scores improved in 66.7% of the methotrexate group patients and in 50.0% of the placebo group (P = .2). SF-36 scores indicated improved mental health in the placebo group. There were no significant differences in CRP levels, the combined outcome, or adverse events.ConclusionsThese results show that the methotrexate group tended toward improved NYHA scores and that there were no significant changes in 6MWT results or secondary assessments.     

Endurance Exercise Training in Older Patients with Heart Failure: Results from a Randomized, Controlled, Single-Blind Trial

OBJECTIVES: To test the hypothesis that exercise training (ET) improves exercise capacity and other clinical outcomes in older persons with heart failure with reduced ejection fraction (HfrEF). DESIGN: Randomized, controlled, single‐blind trial. SETTING: Outpatient cardiac rehabilitation program. PARTICIPANTS: Fifty‐nine patients aged 60 and older with HFrEF recruited from hospital records and referring physicians were randomly assigned to a 16‐week supervised ET program (n=30) or an attention‐control, nonexercise, usual care control group (n=29). INTERVENTION: Sixteen‐week supervised ET program of endurance exercise (walking and stationary cycling) three times per week for 30 to 40 minutes at moderate intensity regulated according to heart rate and perceived exertion. MEASUREMENTS: Individuals blinded to group assignment assessed four domains pivotal to HFrEF pathophysiology: exercise performance, left ventricular (LV) function, neuroendocrine activation, and health‐related quality of life (QOL). RESULTS: At follow‐up, the ET group had significantly greater exercise time and workload than the control group, but there were no significant differences between the groups for the primary outcomes: peak exercise oxygen consumption (VO₂ peak), ventilatory anaerobic threshold (VAT), 6‐minute walk distance, QOL, LV volumes, EF, or diastolic filling. Other than serum aldosterone, there were no significant differences after ET in other neuroendocrine measurements. Despite a lack of a group “training” effect, a subset (26%) of individuals increased VO₂ peak by 10% or more and improved other clinical variables as well. CONCLUSION: In older patients with HFrEF, ET failed to produce consistent benefits in any of the four pivotal domains of HF that were examined, although the heterogeneous response of older patients with HFrEF to ET requires further investigation to better determine which patients with HFrEF will respond favorably to ET.     

地高辛联合倍他乐克治疗心力衰竭并发心房纤颤的疗效观察

目的观察地高辛联合倍他乐克治疗慢性心力衰竭合并心房纤颤的效果。方法选择慢性心力衰竭合并快速心房纤颤患者70例,随机分成2组。治疗组35例采用地高辛+倍他乐克治疗;对照组35例,采用地高辛治疗。12周后观察心室率和左心室射血分数(LVEF)变化的情况。结果地高辛+倍他乐克治疗组改善心室率和LVEF的疗效明显强于地高辛,差异有统计学意义(P0.01)。结论地高辛与倍他乐克联用治疗慢性心力心房纤颤伴快速心房纤颤取得了较好的疗效。     

A Multicenter Randomized Controlled Evaluation of Automated Home Monitoring and Telephonic Disease Management in Patients Recently Hospitalized for Congestive Heart Failure: The SPAN-CHF II Trial

BackgroundWe performed a prospective, randomized investigation assessing the incremental effect of automated health monitoring (AHM) technology over and above that of a previously described nurse directed heart failure (HF) disease management program. The AHM system measured and transmitted body weight, blood pressure, and heart rate data as well as subjective patient self-assessments via a standard telephone line to a central server.Methods and ResultsA total of 188 consented and eligible patients were randomized between intervention and control groups in 1:1 ratio. Subjects randomized to the control arm received the Specialized Primary and Networked Care in Heart Failure (SPAN-CHF) heart failure disease management program. Subjects randomized to the intervention arm received the SPAN-CHF disease management program in conjunction with the AHM system. The primary end point was prespecified as the relative event rate of HF hospitalization between intervention and control groups at 90 days. The relative event rate of HF hospitalization for the intervention group compared with controls was 0.50 (95%CI [0.25–0.99], P = .05).ConclusionsShort-term reductions in the heart failure hospitalization rate were associated with the use of automated home monitoring equipment. Long-term benefits in this model remain to be studied.     

Inspiratory Muscle Training and Functional Electrical Stimulation for Treatment of Heart Failure With Preserved Ejection Fraction: Rationale and Study Design of a Prospective Randomized Controlled Trial

Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent form of heart failure in developed countries. Regrettably, there is no evidence‐based effective therapy for HFpEF. We seek to evaluate whether inspiratory muscle training, functional electrical stimulation, or a combination of both can improve exercise capacity as well as left ventricular diastolic function, biomarker profile, quality of life (QoL), and prognosis in patients with HFpEF. A total of 60 stable symptomatic patients with HFpEF (New York Heart Association class II–III/IV) will be randomized (1:1:1:1) to receive a 12‐week program of inspiratory muscle training, functional electrical stimulation, a combination of both, or standard care alone. The primary endpoint of the study is change in peak exercise oxygen uptake; secondary endpoints are changes in QoL, echocardiogram parameters, and prognostic biomarkers. As of March 21, 2016, thirty patients have been enrolled. Searching for novel therapies that improve QoL and autonomy in the elderly with HFpEF has become a health care priority. We believe that this study will add important knowledge about the potential utility of 2 simple and feasible physical interventions for the treatment of advanced HFpEF.     

Evaluating the Efficacy,Safety, and Tolerability of Serelaxin When Added to Standard Therapy in Asian Patients With Acute Heart Failure: Design and Rationale of RELAX-AHF-ASIA Trial

Background

Acute heart failure (AHF), a common and growing health concern worldwide, is associated with high risk of post-discharge rehospitalization and mortality. Existing evidence indicates potential therapeutic benefits of serelaxin in Caucasian AHF patients, but corresponding data in Asians remain scarce. RELAX-AHF-ASIA, a multinational, randomized, double-blind, placebo-controlled, phase III trial, will evaluate the effects of serelaxin on symptom relief and clinical outcomes in Asian AHF patients, with the use of novel assessments.

Recruitment Strategies of a Decentralized Randomized Placebo Controlled Clinical Trial: The Canagliflozin Impact on Health Status,Quality of Life and Functional Status in Heart Failure (CHIEF-HF) Trial

BackgroundThere has been growing Interest in patient-centered clinical trials using mobile technologies to reduce the need for in-person visits. The CHIEF-HF (Canagliflozin Impact on Health Status, Quality of Life and Functional Status in Heart Failure) trial was designed as a double-blind, randomized, fully decentralized clinical trial (DCT) that identified, consented, treated, and followed participants without any in-person visits. Patient-reported questionnaires were the primary outcome, which were collected by a mobile application. To inform future DCTs, we sought to describe the strategies used in successful trial recruitment.MethodsThis article describes the operational structure and novel strategies employed in a completely DCT by summarizing the recruitment, enrollment, engagement, retention, and follow-up processes used in the execution of the trial at 18 centers.ResultsA total of 18 sites contacted 130,832 potential participants, of which 2572 (2.0%) opened a hyperlink to the study website, completed a brief survey, and agreed to be contacted for potential inclusion. Of these, 1333 were eligible, and 658 consented; there were 182 screen failures, due primarily to baseline Kansas City Cardiomyopathy Questionnaire scores’ not meeting inclusion criteria, resulting in 476 participants’ being enrolled (18.5%). There was significant site-level variation in the number of patients invited (median = 2976; range 73–46,920) and in those agreeing to be contacted (median = 2.4%; range 0.05%–16.4%). At the site with the highest enrollment, patients contacted by electronic medical record portal messaging were more likely to opt into the study successfully than those contacted by e-mail alone (7.8% vs 4.4%).ConclusionsCHIEF-HF used a novel design and operational structure to test the efficacy of a therapeutic treatment, but marked variability across sites and strategies for recruiting participants was observed. This approach may be advantageous for clinical research across a broader range of therapeutic areas, but further optimization of recruitment efforts is warranted.RegistrationNCT04252287 https://clinicaltrials.gov/ct2/show/NCT04252287