Long term safety and outcomes after atrial shunting for heart failure with preserved or mildly reduced ejection fraction: 5-year and 3-year follow-up in the REDUCE LAP-HF I and II trials.

BACKGROUND: There is a little evidence regarding long-term safety and efficacy for atrial shunt devices in heart failure (HF). METHODS: The REDUCE LAP-HF I (n=44) and II (n=621) trials (RCT-I and -II) were multicenter, randomized, sham-controlled trials of patients with HF and ejection fraction >40%. Outcome data were analyzed from RCT-I, a mechanistic trial with 5-year follow-up, and RCT-II, a pivotal trial identifying a responder group (n=313) defined by exercise PVR <1.74 WU and no cardiac rhythm management device with 3-year follow-up. RESULTS: At 5 years in RCT I, there were no differences in cardiovascular (CV) mortality, HF events, embolic stroke, or new-onset atrial fibrillation between groups. After 3 years in RCT II, there was no difference in the primary outcome (hierarchical composite of CV mortality, stroke, HF events, and KCCQ) between shunt and sham in the overall trial. Compared to sham, those with responder characteristics in RCT-II had a better outcome with shunt (win ratio 1.6 [95% CI 1.2-2.2], P=0.006; 44% reduction in HF events [shunt 9 vs. control 16 per 100 patient-years], P=0.005; and greater improvement in KCCQ overall summary score [+17.9±20.0 vs. +7.6±20.4], P<0.001), while non-responders had significantly more HF events. Shunt treatment at 3 years was associated with a higher rate of ischemic stroke (3.2% vs. 0%, 95% CI 2% - 6.1%, p=0.032) and lower incidence of worsening kidney dysfunction (10.7% vs. 19.3%, p=0.041). CONCLUSIONS: With up to 5 years of follow up, adverse events were low in patients receiving atrial shunts. In the responder group, atrial shunt treatment was associated with a significantly lower HF event rate and improved KCCQ compared to sham through 3 years of follow-up. CLINICALTRIALS: gov registration: NCT02600234, NCT03088033.

Impact of telemedical management on hospitalization and mortality in heart failure patients with diabetes: a post-hoc subgroup analysis of the TIM-HF2 trial.

BACKGROUND: The TIM-HF2 study demonstrated that remote patient management (RPM) in a well-defined heart failure (HF) population reduced the percentage of days lost due to unplanned cardiovascular hospital admissions or all-cause death during 1-year follow-up (hazard ratio 0.80) and all-cause mortality alone (HR 0.70). Higher rates of hospital admissions and mortality have been reported in HF patients with diabetes compared with HF patients without diabetes. Therefore, in a post-hoc analysis of the TIM-HF2 study, we investigated the efficacy of RPM in HF patients with diabetes. METHODS: TIM-HF2 study was a randomized, controlled, unmasked (concealed randomization), multicentre trial, performed in Germany between August 2013 and May 2018. HF-Patients in NYHA class II/III who had a HF-related hospital admission within the previous 12 months, irrespective of left ventricular ejection fraction, and were randomized to usual care with or without added RPM and followed for 1 year. The primary endpoint was days lost due to unplanned cardiovascular hospitalization or due to death of any cause. This post-hoc analysis included 707 HF patients with diabetes. RESULTS: In HF patients with diabetes, RPM reduced the percentage of days lost due to cardiovascular hospitalization or death compared with usual care (HR 0.66, 95% CI 0.48-0.90), and the rate of all-cause mortality alone (HR 0.52, 95% CI 0.32-0.85). RPM was also associated with an improvement in quality of life (mean difference in change in global score of Minnesota Living with Heart Failure Questionnaire score (MLHFQ): - 3.4, 95% CI - 6.2 to - 0.6). CONCLUSION: These results support the use of RPM in HF patients with diabetes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01878630.

Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomised, multicentre, blinded, sham-controlled trial.

BACKGROUND: Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients. METHODS: In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged ≥40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov, NCT03088033. FINDINGS: Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1·0 [95% CI 0·8-1·2]; p=0·85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (pinteraction=0·002 [>70 mm Hg associated with worse outcomes]), right atrial volume index (pinteraction=0·012 [≥29·7 mL/m2, worse outcomes]), and sex (pinteraction=0·02 [men, worse outcomes]). There were no differences in the composite safety endpoint between the two groups (n=116 [38%] for shunt device vs n=97 [31%] for sham procedure; p=0·11). INTERPRETATION: Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%. FUNDING: Corvia Medical.

Identification of Pparγ-modulated miRNA hubs that target the fibrotic tumor microenvironment.

Liver fibrosis interferes with normal liver function and facilitates hepatocellular carcinoma (HCC) development, representing a major threat to human health. Here, we present a comprehensive perspective of microRNA (miRNA) function on targeting the fibrotic microenvironment. Starting from a murine HCC model, we identify a miRNA network composed of 8 miRNA hubs and 54 target genes. We show that let-7, miR-30, miR-29c, miR-335, and miR-338 (collectively termed antifibrotic microRNAs [AF-miRNAs]) down-regulate key structural, signaling, and remodeling components of the extracellular matrix. During fibrogenic transition, these miRNAs are transcriptionally regulated by the transcription factor Pparγ and thus we identify a role of Pparγ as regulator of a functionally related class of AF-miRNAs. The miRNA network is active in human HCC, breast, and lung carcinomas, as well as in 2 independent mouse liver fibrosis models. Therefore, we identify a miRNA:mRNA network that contributes to formation of fibrosis in tumorous and nontumorous organs of mice and humans.

De novo identification of maximally deregulated subnetworks based on multi-omics data with DeRegNet.

BACKGROUND: With a growing amount of (multi-)omics data being available, the extraction of knowledge from these datasets is still a difficult problem. Classical enrichment-style analyses require predefined pathways or gene sets that are tested for significant deregulation to assess whether the pathway is functionally involved in the biological process under study. De novo identification of these pathways can reduce the bias inherent in predefined pathways or gene sets. At the same time, the definition and efficient identification of these pathways de novo from large biological networks is a challenging problem. RESULTS: We present a novel algorithm, DeRegNet, for the identification of maximally deregulated subnetworks on directed graphs based on deregulation scores derived from (multi-)omics data. DeRegNet can be interpreted as maximum likelihood estimation given a certain probabilistic model for de-novo subgraph identification. We use fractional integer programming to solve the resulting combinatorial optimization problem. We can show that the approach outperforms related algorithms on simulated data with known ground truths. On a publicly available liver cancer dataset we can show that DeRegNet can identify biologically meaningful subgraphs suitable for patient stratification. DeRegNet can also be used to find explicitly multi-omics subgraphs which we demonstrate by presenting subgraphs with consistent methylation-transcription patterns. DeRegNet is freely available as open-source software. CONCLUSION: The proposed algorithmic framework and its available implementation can serve as a valuable heuristic hypothesis generation tool contextualizing omics data within biomolecular networks.

Efficacy of telemedical interventional management in patients with heart failure (TIM-HF2): a randomised, controlled, parallel-group, unmasked trial.

BACKGROUND: Remote patient management in patients with heart failure might help to detect early signs and symptoms of cardiac decompensation, thus enabling a prompt initiation of the appropriate treatment and care before a full manifestation of a heart failure decompensation. We aimed to investigate the efficacy of our remote patient management intervention on mortality and morbidity in a well defined heart failure population. METHODS: The Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial was a prospective, randomised, controlled, parallel-group, unmasked (with randomisation concealment), multicentre trial with pragmatic elements introduced for data collection. The trial was done in Germany, and patients were recruited from hospitals and cardiology practices. Eligible patients had heart failure, were in New York Heart Association class II or III, had been admitted to hospital for heart failure within 12 months before randomisation, and had a left ventricular ejection fraction (LVEF) of 45% or lower (or if higher than 45%, oral diuretics were being prescribed). Patients with major depression were excluded. Patients were randomly assigned (1:1) using a secure web-based system to either remote patient management plus usual care or to usual care only and were followed up for a maximum of 393 days. The primary outcome was percentage of days lost due to unplanned cardiovascular hospital admissions or all-cause death, analysed in the full analysis set. Key secondary outcomes were all-cause and cardiovascular mortality. This study is registered with ClinicalTrials.gov, number NCT01878630, and has now been completed. FINDINGS: Between Aug 13, 2013, and May 12, 2017, 1571 patients were randomly assigned to remote patient management (n=796) or usual care (n=775). Of these 1571 patients, 765 in the remote patient management group and 773 in the usual care group started their assigned care, and were included in the full analysis set. The percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause death was 4·88% (95% CI 4·55-5·23) in the remote patient management group and 6·64% (6·19-7·13) in the usual care group (ratio 0·80, 95% CI 0·65-1·00; p=0·0460). Patients assigned to remote patient management lost a mean of 17·8 days (95% CI 16·6-19·1) per year compared with 24·2 days (22·6-26·0) per year for patients assigned to usual care. The all-cause death rate was 7·86 (95% CI 6·14-10·10) per 100 person-years of follow-up in the remote patient management group compared with 11·34 (9·21-13·95) per 100 person-years of follow-up in the usual care group (hazard ratio [HR] 0·70, 95% CI 0·50-0·96; p=0·0280). Cardiovascular mortality was not significantly different between the two groups (HR 0·671, 95% CI 0·45-1·01; p=0·0560). INTERPRETATION: The TIM-HF2 trial suggests that a structured remote patient management intervention, when used in a well defined heart failure population, could reduce the percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause mortality. FUNDING: German Federal Ministry of Education and Research.

Comparative clinical study of the prophylaxis of heterotopic ossifications after total hip arthroplasty using etoricoxib or diclofenac.

PURPOSE: This study investigated whether etoricoxib (COX-II blocker) has a superior efficacy of preventing heterotopic ossification (HO) after total hip arthroplasty (THA) compared to diclofenac (non-selective NSAID). METHODS: One hundred patients were included (50 in each group) in this single centre, prospective, double-blinded, randomized, controlled trial. Etoricoxib (90 mg) was administered once and diclofenac (75 mg) twice per day for a perioperative period of nine days. The incidence of HO was evaluated on radiographs of the pelvis six months after surgery. RESULTS: Eighty nine of 100 (89 %) patients could be analysed. The overall HO incidence was 37.8 %. There was no significant difference between both study groups. Twelve patients (27.3 %) of the DIC group and 13 patients (28.9 %) of the ETO group showed Brooker grade I ossifications. Five patients (11.4 %) of the DIC and four patients of the ETO (8.9 %) group showed grade II HO formations. No class III or IV HO formations occured in both groups. Ad hoc analysis detected a negative correlation between HO incidence and limited abduction and internal rotation of the hip. CONCLUSIONS: Etoricoxib and diclofenac are equally effective for oral HO prophylaxis after primary cementless THA when given for nine peri-operative days to ensure a full recovery and high patient satisfaction.

Decreased femoral periprosthetic bone mineral density: a comparative study using DXA in patients after cementless total hip arthroplasty with osteonecrosis of the femoral head versus primary osteoarthritis.

INTRODUCTION: Trabecular properties in osteonecrosis of the femoral head (ONFH) are altered for bone volume and structure in the femoral head and proximal femoral canal. We analysed the periprosthetic bone mineral density (BMD) as a correlate to bony ingrowth in patients with ONFH who received a cementless THA. MATERIALS AND METHODS: We performed a matched-pair analysis of 100 patients with ONFH (n = 50) and primary osteoarthritis (n = 50) who received the same, unilateral cementless THA. We compared the periprosthetic BMD 5 years after surgery by means of dual energy X-ray absorptiometry (DXA) analysing the seven femoral regions of interest (ROIs) according to Gruen. RESULTS: Within the ONFH group, significantly lower BMD values were found in the ROI 1 and 7 (p < 0.05). No statistically significant difference was found for ROIs 2-6. CONCLUSIONS: An altered periprosthetic bone stock in the proximal femur in patients with prior ONFH might be a possible risk factor for premature loosening of the femoral stem in THA. Surgeons need to consider coating and fixation philosophy of cementless implants when choosing the right stem for patients with ONFH.

Current therapeutic strategies of heterotopic ossification--a survey amongst orthopaedic and trauma departments in Germany.

BACKGROUND: Heterotopic ossification (HO) is a complication after tissue trauma, fracture and surgery (i.e. total hip arthroplasty). Prophylaxis is the most effective therapy. If HO formations become symptomatic and limit patients' quality of life, revision surgery is indicated and is usually combined with a perioperative oral prophylaxis (NSAIDs) and/or irradiation. However, a long-term use of NSAIDs can induce gastro-intestinal or cardiac side-effects and possible bony non-unions during fracture healing. Subject of this study was to assess the current status of HO prophylaxis after injuries or fractures and to evaluate current indications and strategies for excision of symptomatic HO. METHODS: Between 2013 and 2014, a questionnaire was sent to 119 orthopaedic and trauma surgery departments in Germany. Participation was voluntary and all acquired data was given anonymously. RESULTS: The cumulative feedback rate was 71 %. Trauma and orthopaedic surgery departments in Germany recommend oral HO prophylaxis after acetabulum and femoral neck fractures, elbow dislocation, and fracture or dislocation of the radial head. Pain upon movement and an increasing loss of range of motion in the affected joint are considered to be clear indications for HO surgery. A partial removal of ROM-limiting HO formations was also considered important. The vast majority of all departments include perioperative oral HO prophylaxis and/or irradiation if surgical HO removal is planned. The choice and duration of NSAIDs is highly variable. CONCLUSION: HO is of clinical significance in current traumatology and orthopaedics. Certain fractures and injuries are prone to HO, and prophylactic measures should be taken. The respondents in this survey assessed current therapeutic strategies for HO formations similarly. These concepts are in line with the literature. However, the duration of perioperative oral HO prophylaxis varied greatly among the specialist centres. This is significant as a long-term use of NSAIDs fosters a potential risk for the patients' safety and could influence the clinical outcome. National and international guidelines need to be developed to further reduce HO rates and improve patients' safety in trauma and orthopaedic surgery.

The impact of hypoxia on mesenchymal progenitor cells of human skeletal tissue in the pathogenesis of heterotopic ossification.

PURPOSE: Mesenchymal progenitor cells (MPCs) are capable of differentiating into osteo/chondrogenic cells to contribute substantially to heterotopic ossification (HO). This study aimed to examine the impact of hypoxia on MPCs in the aetiology of HO. METHODS: MPCs from human normal and HO skeletal tissue were cultivated under normoxia and hypoxia. Gene expression of factors which have a key role in HO aetiology (BMPs, COX-1 and COX-2, etc.) were examined by real-time PCR. Tissue of both groups was analysed by immunohistochemistry. RESULTS: Under hypoxia, COX-1, -2 and SOX-9 gene expression was elevated in HO MPCs, whereas in normal muscle tissue only COX-2 was upregulated. MPCs from HO had a significantly elevated gene expression of BMP-4 and decreased expression of BMP-1 and HIF-1 under hypoxia compared to normal MPCs. Immunohistochemistry detected no significant differences between normal and HO tissue. CONCLUSIONS: Hypoxia causes an enhanced gene expression of factors, which have a key role in HO pathophysiology. A better understanding of this entity will possibly allow reducing HO rates in orthopaedic and trauma surgery.

The impact of standard combined anteversion definitions on gait and clinical outcome within one year after total hip arthroplasty.

PURPOSE: Different target areas within the concept of combined cup and stem anteversion have been published for total hip arthroplasty (THA). We asked whether component positioning according to eight standard combined anteversion rules is associated with (1) more physiological gait patterns, (2) higher improvement of gait variables and (3) better clinical outcome after THA. METHODS: In a prospective clinical study, 60 patients received cementless THA through an anterolateral MIS approach in a lateral decubitus position. Six weeks postoperatively, implant position was analysed using 3D-CT by an independent external institute. Preoperatively, six and 12 months postoperatively range of motion, normalized walking speed and hip flexion symmetry index were measured using 3D motion-capture gait analysis. Patient-related outcome measures (HHS, HOOS, EQ-5D) were obtained by an observer blinded to 3D-CT results. Eight combined anteversion definitions and Lewinnek's "safe zone" were evaluated regarding their impact on gait patterns and clinical outcome. RESULTS: Combined cup and stem anteversion according to standard combined anteversion definitions as well as cup placement within Lewinnek's "safe zone" did not influence range of motion, normalized walking speed and/or hip flexion symmetry index six and 12 months after THA. Similarly, increase of gait parameters within the first year after THA was comparable between all eight combined anteversion rules. Clinical outcome measures like HHS, HOOS and EQ-5D did not show any benefit for either of the combined anteversion definitions. CONCLUSIONS: Standard combined cup and stem anteversion rules do not improve postoperative outcome as measured by gait analysis and clinical scores within one year after THA.

Improved kinematics of total knee replacement following partially navigated modified gap-balancing technique.

PURPOSE: Navigation-based total knee arthroplasty (TKA) has proven its value for restoration of the limb axis. However, patient-orientated results after TKA show a wide variation from the correct implantation technique. Nonphysiological kinematics without posterior femoral rollback and tibial internal rotation in flexion could be one reason for this. We postulated that a modified gap-balancing technique with navigation of the tibia alone, in comparison to a conventional navigated technique, would: (1) obtain lateral femoral rollback, (2) alter condylar liftoff without midflexion instability, (3) significantly differ in femoral and tibial cuts, (4) not be inferior in leg-axis restoration and (5) be comparable in clinical short-term scores. METHODS: In this prospective study, we compared in vivo navigation-based kinematics pre- and postoperatively of 40 consecutive TKA comprising 21 conventional navigation-based TKA and 19 TKA with the modified gap-balancing technique and a reduced navigation workflow. All cuts were double checked and compared with cuts proposed by the navigation system. Clinical results were assessed preoperatively and six months postoperatively. RESULTS: The modified gap-balancing technique resulted in significantly increased lateral femoral rollback (mean 16.3 mm) and lateral condylar liftoff (mean 1.3 mm) compared to the conventional group. The modified technique comprised an average of 2.1 mm less distal femoral resection and an average of 4° less external rotation and 3.5° more flexion of the femoral component compared with the control group. Average tibial resection height was 1.1 mm greater and average tibial slope was 0.5° elevated compared to the control group. A neutral leg axis was achieved in all cases. Results showed no significant differences in clinical scores between groups. CONCLUSION: A partial navigation solely of the tibial cut can securely restore the leg axis. Modification of the surgical technique can possibly reproduce more physiological knee kinematics with higher lateral femoral rollback in flexion without midflexion instability. This might help reduce postoperative problems with the new implant and thus reduce the amount of unsatisfactory results. Despite equal short-term results, mid- to long-term results are needed to prove whether or not this correlates with better clinical results and at least equal implant longevity.

Mono- versus polyaxial locking plates in distal femur fractures: a prospective randomized multicentre clinical trial.

PURPOSE: Treatment of complex fractures of the distal femur utilizing monoaxial locking plates (e.g. Less Invasive Stabilisation System, LISS®, Synthes) is considered to be superior to conventional plating systems. Due to the limitation that the thread forces the screw into pre-determined positions, modifications have been made to allow screw positioning within a range of 30° (Non Contact Bridging, NCB®-DF, Zimmer). For the first time, this multicenter prospective randomized clinical trial (RCT) investigates the outcome of LISS® vs. NCB®-DF treatment following complex fractures of the distal femur. METHODS: Since June 2008, 27 patients with a fracture of the distal femur (AO ASIF 33-A-C and periprosthetic fractures) were enrolled in this study by four university trauma centres in southern Germany. Clinical (e.g. range of motion, Oxford knee score, Tegner score) and radiological (e.g. axis deviation, secondary loss of realignment) follow-ups were conducted one and six weeks, as well as three, six, and 12 months after the operation. RESULTS: This study comprises data of 27 patients (8 male, 19 female; 15 NCB®-DF, 12 LISS®). Polyaxial osteosynthesis using the NCB® system tended to result in better functional knee scores and a higher range of motion. Interestingly, fracture union tended to be more rapid using the polyaxial plating system. CONCLUSIONS: We present the analysis of a multicenter prospective RCT to compare the monoaxial LISS® vs. the polyaxial NCB®-DF treatment following complex fractures of the distal femur. NCB®-DF treatment tended to result in better functional and radiological outcomes than LISS® treatment. LEVEL OF EVIDENCE: Level I.

Obesity in heart failure with preserved ejection fraction: Insights from the REDUCE LAP-HF II trial.

AIMS: Obesity is causally related to the development of heart failure with preserved ejection fraction (HFpEF) but complicates the diagnosis and treatment of this disorder. We aimed to determine the relationship between severity of obesity and clinical, echocardiographic and haemodynamic parameters in a large cohort of patients with documented HFpEF. METHODS AND RESULTS: The REDUCE LAP-HF II trial randomized 626 patients with ejection fraction ≥40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg to atrial shunt or sham procedure. We tested for associations between body mass index (BMI), clinical characteristics, cardiac structural and functional abnormalities, physical limitations, quality of life and outcomes with atrial shunt therapy. Overall, 60.9% of patients had BMI ≥30 kg/m2 . As the severity of obesity increased, symptoms (Kansas City Cardiomyopathy Questionnaire score) and 6-min walk distance worsened. More severe obesity was associated with lower natriuretic peptide levels despite more cardiac remodelling, higher cardiac filling pressures, and higher cardiac output. Lower cut points for E/e' were needed to identify elevated PCWP in more obese patients. Strain measurements in all four chambers were maintained as BMI increased. Pulmonary vascular resistance at rest and exercise decreased with higher BMI. Obesity was associated with more first and recurrent heart failure events. However, there was no significant interaction between obesity and treatment effects of the atrial shunt. CONCLUSIONS: Increasing severity of obesity was associated with greater cardiac remodelling, higher right and left ventricular filling pressures, higher cardiac output and increased subsequent heart failure events. Despite significant obesity, many HFpEF patients have preserved right heart and pulmonary vascular function and thus, may be appropriate candidates for atrial shunt therapy.

2-Year Outcomes of an Atrial Shunt Device in HFpEF/HFmrEF: Results From REDUCE LAP-HF II.

BACKGROUND: The REDUCE LAP-HF II (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II) trial found that, compared with a sham procedure, the Corvia Atrial Shunt did not improve outcomes in heart failure with preserved or mildly reduced ejection fraction. However, after 12-month follow-up, "responders" (peak-exercise pulmonary vascular resistance <1.74 WU and absence of a cardiac rhythm management device) were identified. OBJECTIVES: This study sought to determine: 1) the overall efficacy and safety of the atrial shunt vs sham control after 2 years of follow-up; and 2) whether the benefits of atrial shunting are sustained in responders during longer-term follow-up or are offset by adverse effects of the shunt. METHODS: The study analyzed 2-year outcomes in the overall REDUCE LAP-HF II trial, as well as in responder and nonresponder subgroups. The primary endpoint was a hierarchical composite of cardiovascular death or nonfatal ischemic/embolic stroke, total heart failure events, and change in health status. RESULTS: In 621 randomized patients, there was no difference between the shunt (n = 309) and sham (n = 312) groups in the primary endpoint (win ratio: 1.01 [95% CI: 0.82-1.24]) or its individual components at 2 years. Shunt patency at 24 months was 98% in shunt-treated patients. Cardiovascular mortality and nonfatal ischemic stroke were not different between the groups; however, major adverse cardiac events were more common in those patients assigned to the shunt compared with sham (6.9% vs 2.7%; P = 0.018). More patients randomized to the shunt had an increase in right ventricular volume of ≥30% compared with the sham control (39% vs 28%, respectively; P < 0.001), but right ventricular dysfunction was uncommon and not different between the treatment groups. In responders (n = 313), the shunt was superior to sham (win ratio: 1.36 [95% CI: 1.02-1.83]; P = 0.037, with 51% fewer HF events [incidence rate ratio: 0.49 [95% CI: 0.25-0.95]; P = 0.034]). In nonresponders (n = 265), atrial shunting was inferior to sham (win ratio: 0.73 [95% CI: 0.54-0.98]). CONCLUSIONS: At 2 years of follow-up in REDUCE LAP-HF II, there was no difference in efficacy between the atrial shunt and sham groups in the overall trial group. The potential clinical benefit identified in the responder group after 1 and 2 years of follow-up is currently being evaluated in the RESPONDER-HF (Re-Evaluation of the Corvia Atrial Shunt Device in a Precision Medicine Trial to Determine Efficacy in Mildly Reduced or Preserved Ejection Fraction Heart Failure) trial. (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II [REDUCE LAP-HF II]; NCT03088033).

Effects of remote patient management on self-care behaviour in heart failure patients: results from the randomized TIM-HF2 trial.

AIMS: Remote patient management (RPM) in heart failure (HF) patients has beneficial clinical effects. This analysis investigates the effects of RPM used in the Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial on HF-specific self-care. METHODS AND RESULTS: From 2013 to 2017, 1538 HF outpatients (age 70.3 ± 10.5 years, 70% men, 52%/47% NYHA II/III, 65% LVEF ≤45%) with a recent HF hospitalization were included to the study and randomized to usual care (UC) plus RPM (n = 796) or UC only (n = 775), with a 12-month follow-up. Self-reported self-care behaviour at baseline and at end of study was assessed with the 9-item European Heart Failure Self-care Behaviour Scale (EHFScBS-9), obtaining 1321 patients with valid baseline and follow-up questionnaires for the analysis. EHFScBS-9 sum scores increased in the RPM group (n = 667) from 78.7 ± 17 to 84.5 ± 14 and in the UC group (n = 654) from 79.0 ± 17 to 80.0 ± 16 from baseline to 12 months [difference in means (MD) 4.58 (3.02, 6.14); P < 0.001] with highest improvement [8.66 (3.52; 13.81)] in patients living alone and having an inadequate (<70) baseline EHFScBS-9. There were differences between both groups in item 'I weight myself every day' [MD -1.13 (-1.24, -1.02); P < 0.001] and item 'I take my medication as prescribed' [MD -0.06 (-0.10, -0.01); P = 0.014]. No correlation was found between the EHFScBS-9 score and the efficacy of RPM on the TIM-HF2 primary endpoint of percentage of days lost due to unplanned cardiovascular hospitalization or death of any cause. CONCLUSIONS: RPM improves HF-specific self-care behaviour by achieving a better adherence to recommended HF regimen. REGISTRATION: ClinicalTrials.gov: NCT01878630.

Patient reported experience and adherence to remote patient management in chronic heart failure patients: a posthoc analysis of the TIM-HF2 trial.

AIMS: Remote patient management (RPM) enables early detection and prevention of deterioration in heart failure (HF) patients by measuring vital parameters. The analysis objective is to assess patient reported experience with RPM, adherence to daily measurements, and outline affecting factors both. METHODS AND RESULTS: Telemedical interventional management in-HF2 was conducted in 2013-18 with 1 538 HF patients with a 12-month follow-up. Under guidance of HF nurses, patients had to measure daily weight, blood pressure, electrocardiogram, and self-rated health status. At the end of the study, patients received a programme survey to analyse patient perceptions and satisfaction with telemedicine care and study organization. Adherence was distinguished between measurement of at least one [incomplete adherence (IA)] and all vital parameters [complete adherence (CA)] and defined as ratio of the number of days of measurements taken divided by the number of days of possible measurements. All data and group differences were analysed descriptively (mean ± SD) and by analysis of variance and t-test. Survey response rate was 79.7%. Patients were satisfied with the programme and device usability. CA was 89.1 ± 14.1%, consistently high over the study course and independent of severity of disease (left ventricular ejection fraction, N terminals pro brain natriuretic peptide, New York Heart Association). Lower IA was found with patients <70 years and prior to unplanned cardiovascular (CV) hospitalizations (difference by -5.2 ± 20.5%) and after unplanned CV hospitalizations compared with the entire study period (lower by -12.8 ± 24.7%). Patients from rural areas were found to have higher CA than patients from urban regions. CONCLUSIONS: With user-friendly devices, pre-interventional patient training, regular patient contact and close cooperation between primary physicians and telemedical centre, a long-lasting high adherence and satisfaction could be achieved. A change in adherence might detect health deterioration and indicate the need to intensify RPM. REGISTRATION: ClinicalTrials.gov (NCT01878630) and Deutsches Register Klinischer Studien (DRKS00010239).

Simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF trial.

BACKGROUND: The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing first data from the randomized, double-blinded DIGIT-HF trial. METHODS AND RESULTS: In DIGIT-HF, digitoxin was started with a dose of 0.07 mg once daily (o.d.) in all patients. For score derivation, 317 patients were analyzed who had been randomized to digitoxin. In these patients, after scheduled determination of serum levels at study week 6, the digitoxin dose had remained unchanged or had been reduced to 0.05 mg o.d. (97% of patients) to achieve serum concentrations within a predefined range (10.5-23.6 nmol/l). In logistic regression analyses, sex, age, body mass index (BMI), and estimated glomerular filtration rate (eGFR) were associated with need for dose reduction and, therefore, selected for further developing the dosing score. Optimal cut-points were derived from ROC curve analyses. Finally, female sex, age ≥ 75 years, eGFR < 50 ml/min/1.73 m2, and BMI < 27 kg/m2 each were assigned one point for the digitoxin dosing score. A score of ≥ 1 indicated the need for dose reduction with sensitivity/specificity of 81.6%/49.7%, respectively. Accuracy was confirmed in a validation data set including 64 patients randomized to digitoxin yielding sensitivity/specificity of 87.5%/37.5%, respectively. CONCLUSION: In patients with HFrEF, treatment with digitoxin should be started at 0.05 mg o.d. in subjects with either female sex, eGFR < 50 ml/min/1.73m2, BMI < 27 kg/m2, or age ≥ 75 years. In any other patient, digitoxin may be safely started at 0.07 mg o.d.

Impact of remote telemedical management on mortality and hospitalizations in ambulatory patients with chronic heart failure: the telemedical interventional monitoring in heart failure study.

BACKGROUND: This study was designed to determine whether physician-led remote telemedical management (RTM) compared with usual care would result in reduced mortality in ambulatory patients with chronic heart failure (HF). METHODS AND RESULTS: We enrolled 710 stable chronic HF patients in New York Heart Association functional class II or III with a left ventricular ejection fraction ≤35% and a history of HF decompensation within the previous 2 years or with a left ventricular ejection fraction ≤25%. Patients were randomly assigned (1:1) to RTM or usual care. Remote telemedical management used portable devices for ECG, blood pressure, and body weight measurements connected to a personal digital assistant that sent automated encrypted transmission via cell phones to the telemedical centers. The primary end point was death from any cause. The first secondary end point was a composite of cardiovascular death and hospitalization for HF. Baseline characteristics were similar between the RTM (n=354) and control (n=356) groups. Of the patients assigned to RTM, 287 (81%) were at least 70% compliant with daily data transfers and no break for >30 days (except during hospitalizations). The median follow-up was 26 months (minimum 12), and was 99.9% complete. Compared with usual care, RTM had no significant effect on all-cause mortality (hazard ratio, 0.97; 95% confidence interval, 0.67 to 1.41; P=0.87) or on cardiovascular death or HF hospitalization (hazard ratio, 0.89; 95% confidence interval, 0.67 to 1.19; P=0.44). CONCLUSIONS: In ambulatory patients with chronic HF, RTM compared with usual care was not associated with a reduction in all-cause mortality. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00543881.