Facilitated Data Relay and Effects on Treatment of Severe Aortic Stenosis in Europe

Background: Many patients with severe aortic stenosis are referred late with advanced symptoms or inappropriately denied intervention. The objective was to investigate whether a structured communication to referring physicians (facilitated data relay) might improve the rate and timeliness of intervention. Methods and Results: A prospective registry of consecutive patients with severe aortic stenosis at 23 centers in 9 European countries with transcatheter as well as surgical aortic valve replacement being available was performed. The study included a 3-month documentation of the status quo (phase A), a 6-month intervention phase (implementing facilitated data relay), and a 3-month documentation of a legacy effect (phase-B). Two thousand one hundred seventy-one patients with severe aortic stenoses were enrolled (phase A: 759; intervention: 905; phase-B: 507). Mean age was 77.9±10.0 years, and 80% were symptomatic, including 52% with severe symptoms. During phase A, intervention was planned in 464/696 (67%), 138 (20%) were assigned to watchful waiting, 8 (1%) to balloon aortic valvuloplasty, 60 (9%) were listed as not for active treatment, and in 26 (4%), no decision was made. Three hundred sixty-three of 464 (78%) patients received the planned intervention within 3 months. Timeliness of the intervention improved as shown by the higher number of aortic valve replacements performed within 3 months (59% versus 51%, P=0.002) and a significant decrease in the time to intervention (36±38 versus 30±33 days, P=0.002). Conclusions: A simple, low-cost, facilitated data relay improves timeliness of treatment for patients diagnosed with severe aortic stenosis, resulting in a shorter time to transcatheter aortic valve replacement. This effect was mainly driven by a significant improvement in timeliness of intervention in transcatheter aortic valve replacement but not surgical aortic valve replacement. Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02241447

Symptoms, disease severity and treatment of adults with a new diagnosis of severe aortic stenosis

Objective Contemporary data on patients with previously undiagnosed severe aortic stenosis (AS) are scarce. We aimed to address this gap by gathering data from consecutive patients diagnosed with severe AS on echocardiography. Methods This was a prospective, multicentre, multinational, registry in 23 tertiary care hospitals across 9 European countries. Patients with a diagnosis of severe AS were included using echocardiography (aortic valve area (AVA) <1 cm 2, indexed AVA <0.6 cm 2 /m 2, maximum jet-velocity (V max) >4 m/s and/or mean transvalvular gradient >40 mm Hg). Results The 2171 participants had a mean age of 77.9 years and 48.0% were female. The mean AVA was 0.73 cm 2, V max 4.3 m/s and mean gradient 47.1 mm Hg; 62.1% had left ventricular hypertrophy and 27.3% an ejection fraction (EF) <50%. 1743 patients (80.3%) were symptomatic (shortness-of-breath 91.0%; dizziness 30.2%, chest pain 28.9%). Patients had a EuroSCORE II of 4.0; 25.3% had a creatinine clearance <50 mL/min, and 3.2% had an EF <30%. Symptomatic patients were older and had more comorbidities than asymptomatic patients. Despite European Society of Cardiology 2017 valvular heart disease guideline class I recommendation, in only 76.2% a decision was made for an intervention (transcatheter 50.4%, surgical aortic valve replacement 25.8%). In asymptomatic patients, 57.7% with a class I/IIa indication were scheduled for a procedure, while 36.3% patients without an indication had their valve replaced. Conclusions The majority of patients with severe AS presented at an advanced disease stage. Management of severe AS remained suboptimal in a significant proportion of contemporary patients with severe AS. Trial registration number NCT02241447;Results

Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis

The authors investigated whether PCSK9 inhibition could represent a therapeutic strategy in calcific aortic valve stenosis (CAVS). A meta-analysis of 10 studies was performed to determine the impact of the PCSK9 R46L variant on CAVS, and the authors found that CAVS was less prevalent in carriers of this variant (odds ratio: 0.80 [95% confidence interval: 0.70 to 0.91]; p = 0.0011) compared with noncarriers. PCSK9 expression was higher in the aortic valves of patients CAVS compared with control patients. In human valve interstitials cells submitted to a pro-osteogenic medium, PCSK9 levels increased and a PCSK9 neutralizing antibody significantly reduced calcium accumulation

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

IMPULSE: the impact of gender on the presentation and management of aortic stenosis across Europe.

AIMS: There is an increasing awareness of gender-related differences in patients with severe aortic stenosis and their outcomes after surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI). METHODS: Data from the IMPULSE registry were analysed. Patients with severe aortic stenosis (AS) were enrolled between March 2015 and April 2017 and stratified by gender. A subgroup analysis was performed to assess the impact of age. RESULTS: Overall, 2171 patients were enrolled, and 48.0% were female. Women were characterised by a higher rate of renal impairment (31.7 vs 23.3%; p<0.001), were at higher surgical risk (EuroSCORE II: 4.5 vs 3.6%; p=0.001) and more often in a critical preoperative state (7.0vs 4.2%; p=0.003). Men had an increased rate of previous cardiac surgery (9.4 vs 4.7%; p<0.001) and a reduced left ventricular ejection fraction (4.9 vs 1.3%; p<0.001). Concomitant mitral and tricuspid valve disease was substantially more common among women. Symptoms were highly prevalent in both women and men (83.6 vs 77.3%; p<0.001). AVR was planned in 1379 cases. Women were more frequently scheduled to undergo TAVI (49.3 vs 41.0%; p<0.001) and less frequently for SAVR (20.3 vs 27.5%; p<0.001). CONCLUSIONS: The present data show that female patients with severe AS have a distinct patient profile and are managed in a different way to males. Gender-based differences in the management of patients with severe AS need to be taken into account more systematically to improve outcomes, especially for women

Impact of tricuspid regurgitation on survival in patients with heart failure: a large electronic health record patient-level database analysis.

AIMS: More evidence is needed to quantify the association between tricuspid regurgitation (TR) and mortality in patients with heart failure (HF). METHODS AND RESULTS: Between 2008-2017, using the Optum longitudinal database, a patient-level database that integrates multiple US-based electronic health and claim records from several health care providers, we identified 435 679 patients with new HF diagnosis and both an assessment of the left ventricular ejection fraction and at least 1 year of history. TR was graded as mild, moderate or severe and classified as prevalent (at the time of the initial HF diagnosis) or incident (subsequent new cases thereafter). For prevalent TR, the analysis was performed using a Cox proportional hazards model with adjustment for patient covariates. Incident TR was modelled as a time-updated covariate, as were other non-fatal events during follow-up. Prevalence of mild, moderate and severe TR at baseline was 10.1%, 5.1% and 1.4%, respectively. Over a median follow-up of 1.5 years, 121 273 patients (27.8%) died and prevalent TR was independently associated with survival. Compared to patients with no TR at baseline, the adjusted hazard ratios for mortality were 0.99 [95% confidence interval (CI) 0.97-1.01], 1.17 (95% CI 1.14-1.20) and 1.34 (95% CI 1.28-1.39) for mild, moderate and severe TR, respectively. In the 363 270 patients free from TR at baseline, incident TR (at least mild, at least moderate, or severe) developed during follow-up in 12.1%, 5.1% and 1.1%, respectively. Adjusted mortality hazard ratios for such new cases were 1.48 (95% CI 1.44-1.52), 1.92 (95% CI 1.86-1.99) and 2.44 (95% CI 2.32-2.57), respectively. Findings were consistent across all patient subgroups based on age, gender, rhythm, associated comorbidities, prior cardiac surgery, B-type natriuretic peptide/N-terminal pro-B-type natriuretic peptide, and left ventricular ejection fraction. CONCLUSIONS: In this large contemporary patient-level database of almost half-million US patients with HF, TR was associated with a marked increases in mortality risk overall and in all subgroups. Future randomized controlled trials will evaluate the impact of TR correction on clinical outcomes and the causal relationship between TR and mortality

Management of patients with severe aortic stenosis in the TAVI-era: How recent recommendations are translated into clinical practice

Objective Approximately 3.4% of adults aged &gt;75 years suffer from aortic stenosis (AS). Guideline indications for aortic valve replacement (AVR) distinguish between patients with symptomatic and asymptomatic severe AS. The present analysis aims to assess contemporary practice in the treatment of severe AS across Europe and identify characteristics associated with treatment decisions, namely denial of AVR in symptomatic patients and assignment of asymptomatic patients to AVR. Methods Participants of the prospective, multinational IMPULSE database of patients with severe AS were grouped according to AS symptoms, and stratified into subgroups based on assignment to/denial of AVR. Results Of 1608 symptomatic patients, 23.8% did not undergo AVR and underwent medical treatment. Denial was independently associated with multiple factors, including severe frailty (p=0.024); mitral (p=0.002) or tricuspid (p=0.004) regurgitation grade III/IV, and the presence of renal impairment (p=0.017). Of 392 asymptomatic patients, 86.5% had no prespecified indication for AVR. Regardless, 36.3% were assigned to valve replacement. Those with an indexed aortic valve area (AVA; p=0.045) or left ventricular ejection fraction (LVEF; p&lt;0.001) below the study median; or with a left ventricular end systolic diameter above the study median (p=0.007) were more likely to be assigned to AVR. Conclusions There may be considerable discrepancies between guideline-based recommendations and clinical practice decision-making in the treatment of AS. It appears that guidelines may not fully capture the complete clinical spectrum of patients with AS. Thus, there is a need to find ways to increase their acceptance and the rate of adoption

IMPULSE: The impact of gender on the presentation and management of aortic stenosis across Europe

Aims There is an increasing awareness of gender-related differences in patients with severe aortic stenosis and their outcomes after surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI). Methods Data from the IMPULSE registry were analysed. Patients with severe aortic stenosis (AS) were enrolled between March 2015 and April 2017 and stratified by gender. A subgroup analysis was performed to assess the impact of age. Results Overall, 2171 patients were enrolled, and 48.0% were female. Women were characterised by a higher rate of renal impairment (31.7 vs 23.3%; p&lt;0.001), were at higher surgical risk (EuroSCORE II: 4.5 vs 3.6%; p=0.001) and more often in a critical preoperative state (7.0vs 4.2%; p=0.003). Men had an increased rate of previous cardiac surgery (9.4 vs 4.7%; p&lt;0.001) and a reduced left ventricular ejection fraction (4.9 vs 1.3%; p&lt;0.001). Concomitant mitral and tricuspid valve disease was substantially more common among women. Symptoms were highly prevalent in both women and men (83.6 vs 77.3%; p&lt;0.001). AVR was planned in 1379 cases. Women were more frequently scheduled to undergo TAVI (49.3 vs 41.0%; p&lt;0.001) and less frequently for SAVR (20.3 vs 27.5%; p&lt;0.001). Conclusions The present data show that female patients with severe AS have a distinct patient profile and are managed in a different way to males. Gender-based differences in the management of patients with severe AS need to be taken into account more systematically to improve outcomes, especially for women

Impact of selected comorbidities on the presentation and management of aortic stenosis

Background Contemporary data regarding the impact of comorbidities on the clinical presentation and management of patients with severe aortic stenosis (AS) are scarce. Methods Prospective registry of severe patients with AS across 23 centres in nine European countries. Results Of the 2171 patients, chronic kidney disease (CKD 27.3%), left ventricular ejection fraction (LVEF) &lt;50% (22.0%), atrial fibrillation (15.9%) and chronic obstructive pulmonary disease (11.4%) were the most prevalent comorbidities (49.3% none, 33.9% one and 16.8% ≥2 of these). The decision to perform aortic valve replacement (AVR) was taken in a comparable proportion (67%, 72% and 69%, in patients with 0, 1 and ≥2 comorbidities; p=0.186). However, the decision for TAVI was more common with more comorbidities (35.4%, 54.0% and 57.0% for no, 1 and ≥2; p&lt;0.001), while the decision for surgical AVR (SAVR) was decreased with increasing comorbidity burden (31.9%, 17.4% and 12.3%; p&lt;0.001). The proportion of patients with planned AVRs that were performed within 3 months was significantly higher in patients with 1 or ≥2 comorbidities than in those without (8.7%, 10.0% and 15.7%; p&lt;0.001). Furthermore, the mean time to AVR was significantly shorter in patients with one (30.5 days) or ≥2 comorbidities (30.8 days) than in those without (35.7 days; p=0.012). Patients with reduced LVEF tended to be offered an AVR more frequently and with a shorter delay while patients with CKD were less frequently treated. Conclusions Comorbidities in severe patients with AS affect the presentation and management of patients with severe AS. TAVI was offered more often than SAVR and performed within a shorter time period