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 = .006; 44% reduction in HF events [shunt 9 vs. control 16 per 100 patient-years], P = .005; and greater improvement in KCCQ overall summary score [+17.9 ± 20.0 vs. +7.6 ± 20.4], P < .001), while nonresponders 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 = .032) and lower incidence of worsening kidney dysfunction (10.7% vs. 19.3%, P = .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. 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.