Detection of transthyretin amyloid cardiomyopathy by automated data extraction from electronic health records.

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive and fatal cardiomyopathy, is frequently misdiagnosed or entails diagnostic delays, hindering patients from timely treatment. This study aimed to generate a systematic framework based on data from electronic health records (EHRs) to assess patients with ATTR-CM in a real-world population of heart failure (HF) patients. Predictive factors or combinations of predictive factors related to ATTR-CM in a European population were also assessed. METHODS AND RESULTS: Retrospective unstructured and semi-structured data from EHRs of patients from OLV Hospital Aalst, Belgium (2012-20), were processed using natural language processing (NLP) to generate an Observational Medical Outcomes Partnership Common Data Model database. NLP model performance was assessed on a random subset of EHRs by comparing algorithm outputs to a physician-generated standard (using precision, recall, and their harmonic mean, or F1-score). Of the 3127 HF patients, 103 potentially had ATTR-CM (age 78 ± 9 years; male 55%; ejection fraction of 48% ± 16). The mean diagnostic delay between HF and ATTR-CM diagnosis was 1.8 years. Besides HF and cardiomyopathy-related phenotypes, the strongest cardiac predictor was atrial fibrillation (AF; 72% in ATTR-CM vs. 60% in non-ATTR-CM, P = 0.02), whereas the strongest non-cardiac predictor was carpal tunnel syndrome (21% in ATTR-CM vs. 3% in non-ATTR-CM, P < 0.001). The strongest combination predictor was AF, joint disorders, and HF with preserved ejection fraction (29% in ATTR-CM vs. 18% in non-ATTR-CM: odds ratio = 2.03, 95% confidence interval = 1.28-3.22). CONCLUSIONS: Not only well-known variables associated with ATTR-CM but also unique combinations of cardiac and non-cardiac phenotypes are able to predict ATTR-CM in a real-world HF population, aiding in early identification of ATTR-CM patients.

Safety, Feasibility of Controllable Decrease of Vena Cava Pressure by Doraya Catheter in Heart Failure.

Lowering elevated central venous pressure may reduce renal dysfunction in acute heart failure (AHF) patients. The Doraya catheter lowers renal venous pressure by creating a gradient in the inferior vena cava below the renal veins. Here, we present a first-in-human feasibility study of the Doraya catheter performed on 9 AHF patients. We assessed the safety, feasibility, and acute clinical (hemodynamic and renal) effects of transient Doraya catheter deployment when added to the standard diuretic-based regimen in AHF patients with a poor diuretic response. The procedures decreased central venous pressure from 18.4 ± 3.8 mm Hg to 12.4 ± 4.7 mm Hg (P < 0.001) and improved mean diuresis and clinical signs of congestion. No device-related serious adverse events were observed. Thus, Doraya catheter deployment was safe and feasible in AHF patients. (First In Human Study of the Doraya Catheter for the Treatment of AHF Patients; NCT03234647).

Cardio-renal-metabolic syndrome: clinical features and dapagliflozin eligibility in a real-world heart failure cohort.

AIMS: The Cardiovascular Outcomes Retrospective Data analysIS in Heart Failure (CORDIS-HF) is a single-centre retrospective study aimed to (i) clinically characterize a real-world population with heart failure (HF) with reduced (HFrEF) and mildly reduced ejection fraction (HFmrEF), (ii) evaluate impact of renal-metabolic comorbidities on all-cause mortality and HF readmissions, and (iii) determine patients' eligibility for sodium-glucose cotransporter 2 inhibitors (SGLT2is). METHODS AND RESULTS: Using a natural language processing algorithm, clinical data of patients diagnosed with HFrEF or HFmrEF were retrospectively collected from 2014 to 2018. Mortality and HF readmission events were collected during subsequent 1 and 2 year follow-up periods. The predictive role of patients' baseline characteristics for outcomes of interest was assessed using univariate and multivariate Cox proportional hazard models. Kaplan-Meier analysis was used to determine if type 2 diabetes (T2D) and chronic kidney disease (CKD) impacted mortality and HF readmission rates. The European SGLT2i label criteria were used to assess patients' eligibility. The CORDIS-HF included 1333 HF patients with left ventricular ejection fraction (LVEF) < 50% (413 HFmrEF and 920 HFrEF), who were predominantly male (69%) with a mean [standard deviation (SD)] age of 74.7 (12.3) years. About one-half (57%) of patients presented CKD and 37% T2D. The use of guideline-directed medical therapy (GDMT) was high (76-90%). HFrEF patients presented lower age [mean (SD): 73.8 (12.4) vs. 76.7 (11.6) years, P < 0.05], higher incidence of coronary artery disease (67% vs. 59%, P < 0.05), lower systolic blood pressure [mean (SD): 123 (22.6) vs. 133 (24.0) mmHg, P < 0.05], higher N-terminal pro-hormone brain natriuretic peptide (2720 vs. 1920 pg/mL, P < 0.05), and lower estimated glomerular filtration rate [mean (SD): 51.4 (23.3) vs. 54.1 (22.3) mL/min/1.73 m2 , P < 0.05] than those with HFmrEF. No differences in T2D and CKD were detected. Despite optimal treatment, event rates for the composite endpoint of HF readmission and mortality were 13.7 and 8.4/100 patient years. The presence of T2D and CKD negatively impacted all-cause mortality [T2D: hazard ratio (HR) = 1.49, P < 0.01; CKD: HR = 2.05, P < 0.001] and hospital readmission events in all patients with HF. Eligibility for SGLT2is dapagliflozin and empagliflozin was 86.5% (n = 1153) and 97.9% (n = 1305) of the study population, respectively. CONCLUSIONS: This study identified high residual risk for all-cause mortality and hospital readmission in real-world HF patients with LVEF < 50% despite GDMT. T2D and CKD aggravated the risk for these endpoints, indicating the intertwinement of HF with CKD and T2D. SGLT2i treatment that clinically benefits these different disease conditions can be an important driver to lower mortality and hospitalizations in this HF population.

Serial Non-Invasive Myocardial Work Measurements for Patient Risk Stratification and Early Detection of Cancer Therapeutics-Related Cardiac Dysfunction in Breast Cancer Patients: A Single-Centre Observational Study.

Serial transthoracic echocardiographic (TTE) assessment of LVEF and GLS are the gold standard in screening Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD). Non-invasive left-ventricle (LV) pressure-strain loop (PSL) emerged as a novel method to quantify Myocardial Work (MW). This study aims to describe the temporal changes and longitudinal trajectories of MW indices during cardiotoxic treatment. We included 50 breast cancer patients with normal LV function referred for anthracycline therapy w/wo Trastuzumab. Medical therapy, clinical and echocardiographic data were recorded before and 3, 6, and 12 months after initiation of the chemotherapy. MW indices were calculated through PSL analysis. According to ESC guidelines, mild and moderated CTRCD was detected in 10 and 9 patients, respectively (20% CTRCDmild, 18% CTRCDmod), while 31 patients remained free of CTRCD (62% CTRCDneg). Prior to chemotherapy MWI, MWE and CW were significantly lower in CTRCDmod than in CTRCDneg and CTRCDmild. Overt cardiac dysfunction in CTRCDmod at 6 months was accompanied by significant worse values in MWI, MWE and WW compared to CTRCDneg and CTRCDmild. MW features such as low baseline CW, especially when associated with a rise in WW at follow-up, may identify patients at risk for CTRCD. Additional studies are needed to explore the role of MW in CRTCD.

T Cell and Antibody Response Following Double Dose of BNT162b2 mRNA Vaccine in SARS-CoV-2 Naïve Heart Transplant Recipients.

Introduction: Preliminary studies have suggested a low post-vaccination antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in heart transplant(HTx)recipients. Although many studies have focused on the role of antibodies in vaccine-induced protection against SARS-CoV-2, the role of T cell immunity is less well characterized. To date, data regarding seroconversion and T cell response after mRNA SARS-CoV-2 vaccination in patients undergoing HTx are scarce. Therefore, the present study aimed to assess the specific memory humoral and cellular responses after two doses of the BNT162b2 vaccine in HTx recipients. Methods: Blood was drawn from heart transplant (HTx) recipients at two pre-specified time points after the first and second vaccine doses to measure both the anti-SARS-CoV-2 antibody response against the spike protein and the SARS-CoV-2-reactive T cell response. Results: Our study included 34 SARS-CoV-2 naïve HTx recipients (mean age, 61 ± 11 years). The mean time from transplantation to the first vaccine dose is 10 ± 10 years. Subgroup analysis (n = 21) demonstrated that after the first vaccine dose, only 14% had antibodies and 19% had a SARS-CoV-2-reactive T-cell response, which increased to 41% and 53%, respectively, after the second dose. Interestingly, 20% of patients with no antibodies after the second dose still had a positive SARS-CoV-2-reactive T cell response. The percentage of patients with positive S-IgG antibody titers was significantly higher 5 years after transplantation (18% 0-5 years post-TX vs. 65% 5 years post-TX, p = 0.013). Similarly, 5 years after heart transplantation, the percentage of patients with a T cell response was significantly higher (35% 0-5 years post-TX vs. 71% 5 years post-TX, p = 0.030). Conclusions: In SARS-CoV-2 naïve HTx recipients, post-vaccination antibody titers but also SARS-CoV-2 specific T cell response are low. Therefore, the protection from SARS-CoV-2 that is generally attributed to vaccination should be regarded with caution in HTx recipients.

Acetazolamide in Acute Decompensated Heart Failure with Volume Overload.

BACKGROUND: Whether acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption, can improve the efficiency of loop diuretics, potentially leading to more and faster decongestion in patients with acute decompensated heart failure with volume overload, is unclear. METHODS: In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned patients with acute decompensated heart failure, clinical signs of volume overload (i.e., edema, pleural effusion, or ascites), and an N-terminal pro-B-type natriuretic peptide level of more than 1000 pg per milliliter or a B-type natriuretic peptide level of more than 250 pg per milliliter to receive either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose). Randomization was stratified according to the left ventricular ejection fraction (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy. Secondary end points included a composite of death from any cause or rehospitalization for heart failure during 3 months of follow-up. Safety was also assessed. RESULTS: A total of 519 patients underwent randomization. Successful decongestion occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; P<0.001). Death from any cause or rehospitalization for heart failure occurred in 76 of 256 patients (29.7%) in the acetazolamide group and in 72 of 259 patients (27.8%) in the placebo group (hazard ratio, 1.07; 95% CI, 0.78 to 1.48). Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. The incidence of worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups. CONCLUSIONS: The addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion. (Funded by the Belgian Health Care Knowledge Center; ADVOR ClinicalTrials.gov number, NCT03505788.).

Hemodynamic Response to Acute Volume Load and Endomyocardial NO-synthase Gene Expression in Heart Transplant Recipients.

A pulmonary capillary wedge pressure (PCWP) >18 mm Hg following volume load has been proposed as a partition value for the detection of heart failure with preserved ejection fraction. As hemodynamic changes in filling pressures (FP) have been attributed to a nitric oxide (NO)-mediated rightward shift of the pressure-volume relationship, we investigated the hemodynamic response to volume load in heart transplant recipients (HTx) and examined the role of inducible NO synthase (iNOS) gene expression on diastolic function changes. Methods: In 36 HTx, FPs were measured before and after volume load, following which Starling curves were constructed using PCWP and cardiac index (CI). Patients were categorized into those with normal (group A, n = 21) and abnormal hemodynamics (group B, n = 15, PCWP >15 mm Hg at rest or >18 mm Hg following volume load). For the establishment of the potential role of NO, endomyocardial iNOS gene expression level was measured. Results: Except for PCWP (P < 0.001) and mean pulmonary artery pressure (P < 0.001) no differences in age, baseline characteristics, and ejection fraction were observed between both groups, and volume load significantly increased PCWP in both groups (group A: P < 0.001 and group B: P < 0.001) without any change in heart rate. Interestingly, volume load significantly increased CI in group A (P < 0.001) but not in group B (P = 0.654), and the Starling curves revealed a higher CI at any given PCWP in group A together with significantly higher iNOS gene expression (P = 0.009). Conclusions: In HTx, volume load increases FP and unmasks the presence of left ventricular diastolic dysfunction. Interestingly, following saline load group B shows a blunted Starling response, with higher PCWP and lack of CI increase at any given PCWP. The higher iNOS gene expression level in group A suggests a potential role of NO as mediator of diastolic function.

Utilizing longitudinal data in assessing all-cause mortality in patients hospitalized with heart failure.

AIMS: Risk stratification in patients with a new onset or worsened heart failure (HF) is essential for clinical decision making. We have utilized a novel approach to enrich patient level prognostication using longitudinally gathered data to develop ML-based algorithms predicting all-cause 30, 90, 180, 360, and 720 day mortality. METHODS AND RESULTS: In a cohort of 2449 HF patients hospitalized between 1 January 2011 and 31 December 2017, we utilized 422 parameters derived from 151 451 patient exams. They included clinical phenotyping, ECG, laboratory, echocardiography, catheterization data or percutaneous and surgical interventions reflecting the standard of care as captured in individual electronic records. The development of predictive models consisted of 101 iterations of repeated random subsampling splits into balanced training and validation sets. ML models yielded area under the receiver operating characteristic curve (AUC-ROC) performance ranging from 0.83 to 0.89 on the outcome-balanced validation set in predicting all-cause mortality at aforementioned time-limits. The 1 year mortality prediction model recorded an AUC of 0.85. We observed stable model performance across all HF phenotypes: HFpEF 0.83 AUC, HFmrEF 0.85 AUC, and HFrEF 0.86 AUC, respectively. Model performance improved when utilizing data from more hospital contacts compared with only data collected at baseline. CONCLUSIONS: Our findings present a novel, patient-level, comprehensive ML-based algorithm for predicting all-cause mortality in new or worsened heart failure. Its robust performance across phenotypes throughout the longitudinal patient follow-up suggests its potential in point-of-care clinical risk stratification.

Acetazolamide in Decompensated Heart Failure with Volume Overload trial (ADVOR): baseline characteristics.

AIMS: To describe the baseline characteristics of participants in the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial and compare these with other contemporary diuretic trials in acute heart failure (AHF). METHODS AND RESULTS: ADVOR recruited 519 patients with AHF, clinically evident volume overload, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) and maintenance loop diuretic therapy prior to admission. All participants received standardized loop diuretics and were randomized towards once daily intravenous acetazolamide (500 mg) versus placebo, stratified according to study centre and left ventricular ejection fraction (LVEF) (≤40% vs. >40%). The primary endpoint was successful decongestion assessed by a dedicated score indicating no more than trace oedema and no other signs of congestion after three consecutive days of treatment without need for escalating treatment. Mean age was 78 years, 63% were men, mean LVEF was 43%, and median NT-proBNP 6173 pg/ml. The median clinical congestion score was 4 with an EuroQol-5 dimensions health utility index of 0.6. Patients with LVEF ≤40% were more often male, had more ischaemic heart disease, higher levels of NT-proBNP and less atrial fibrillation. Compared with diuretic trials in AHF, patients enrolled in ADVOR were considerably older with higher NT-proBNP levels, reflecting the real-world clinical situation. CONCLUSION: ADVOR is the largest randomized diuretic trial in AHF, investigating acetazolamide to improve decongestion on top of standardized loop diuretics. The elderly enrolled population with poor quality of life provides a good representation of the real-world AHF population. The pragmatic design will provide novel insights in the diuretic treatment of patients with AHF.

Circulating SERPINA3 improves prognostic stratification in patients with a de novo or worsened heart failure.

AIMS: We investigated the prognostic relevance of serpin peptidase inhibitor, clade A member 3 (SERPINA3) in patients admitted with a de novo or worsened heart failure (HF). METHODS AND RESULTS: In the first stage, 83 HF-related left ventricular (LV) transcripts were examined in patients with congestive cardiomyopathy (CCMP, n = 44) who died within 5 years and compared with age-matched and haemodynamically matched CCMP survivors (n = 39) and controls with normal LV function (n = 17). Among 14 differentially expressed transcripts, myocardial gene and circulating SERPINA3 levels were up-regulated in non-survivors vs. survivors (2.40 ± 3.66 vs. 0.36 ± 0.22 units, P < 0.01 and 334.7 ± 138.7 vs. 228.2 ± 83.1 µg/mL, P < 0.01, respectively). While no significant transmyocardial gradient was detected, cytokine stimulation of human endothelial cells induced SERPINA3 secretion. In an independent validation cohort with a de novo or worsened HF (n = 387), circulating SERPINA3 levels > 316 µg/mL were associated with increased all-cause mortality {hazard ratio [HR] [95% confidence interval (CI)]: 2.4 [1.5-3.9], P = 0.0002} and its composite with unplanned cardiovascular readmission [HR (95% CI): 2.0 (1.2-3.3), P = 0.004]. Patients with elevated SERPINA3 levels and elevated either N-terminal pro brain natriuretic peptide or ST2 showed worse freedom from both endpoints. In a multivariate analysis, including established clinical risk factors, SERPINA3 remained independent predictor of all-cause mortality together with age, gender, ST2, glomerular filtration, and pulmonary capillary wedge pressure. CONCLUSION: In patients with a de novo or worsened HF, increased SERPINA3 levels > 316 µg/mL are associated with increased mortality or unplanned cardiac readmission. Elevated SERPINA3 levels on top of established clinical predictors appear to identify a subgroup of HF patients at higher mortality risk. Prospective studies should further validate its value in prognostic stratification of HF.

Vessel Fractional Flow Reserve and Graft Vasculopathy in Heart Transplant Recipients.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the Achilles' heel of long-term survival after heart transplantation (HTx). The severity and extent of CAV is graded with conventional coronary angiography (COR) which has several limitations. Recently, vessel fractional flow reserve (vFFR) derived from COR has emerged as a diagnostic computational tool to quantify the functional severity of coronary artery disease. PURPOSE: The present study assessed the usefulness of vFFR to detect CAV in HTx recipients. METHODS: In HTx patients referred for annual check-up, undergoing surveillance COR, the extent of CAV was graded according to the criteria proposed by the international society of heart and lung transplantation (ISHLT). In addition, three-dimensional coronary geometries were constructed from COR to calculate pressure losses using vFFR. RESULTS: In 65 HTx patients with a mean age of 53.7 ± 10.1 years, 8.5 years (IQR 1.90, 15.2) years after HTx, a total number of 173 vessels (59 LAD, 61 LCX, and 53 RCA) were analyzed. The mean vFFR was 0.84 ± 0.15 and median was 0.88 (IQR 0.79, 0.94). A vFFR ≤ 0.80 was present in 24 patients (48 vessels). HTx patients with a history of ischemic cardiomyopathy (ICMP) had numerically lower vFFR as compared to those with non-ICMP (0.70 ± 0.22 vs. 0.79 ± 0.13, p = 0.06). The use of vFFR reclassified 31.9% of patients compared to the anatomical ISHLT criteria. Despite a CAV score of 0, a pathological vFFR ≤ 0.80 was detected in 8 patients (34.8%). CONCLUSION: The impairment in epicardial conductance assessed by vFFR in a subgroup of patients without CAV according to standard ISHLT criteria suggests the presence of a diffuse vasculopathy undetectable by conventional angiography. Therefore, we speculate that vFFR may be useful in risk stratification after HTx.

Low MicroRNA-126 Levels in Right Ventricular Endomyocardial Biopsies Coincide With Cardiac Allograft Vasculopathy in Heart Transplant Patients.

Endothelium-enriched microRNAs (miRs) are involved in the development of cardiac allograft vasculopathy (CAV). Recently, serum-derived miR-126-3p and -5p, known endothelial microRNAs with a crucial function in angiogenesis and re-endothelialization, provided additional predictive power for cardiac allograft vasculopathy in addition to clinical predictors. However, their myocardial expression in and relationship with CAV are still unknown. Our study aim was to investigate the expression of endomyocardial microRNA-126-3p and microRNA-126-5p levels in heart transplant recipients and their relationship with allograft vasculopathy. METHODS: We studied 39 heart transplant recipients, 21 with proven allograft vasculopathy (CAV+) and 18 without allograft vasculopathy (CAV-) with serial coronary angiograms. Additionally, 8 patients with end-stage native coronary artery disease (CAD) were added to the study to investigate disease specificity of the microRNA signature. The mRNA levels of miR-126-3p and miR-126-5p were determined by qRT-PCR in the right ventricular endomyocardial biopsies obtained at baseline and during routine follow-up. RESULTS: MiR-126-3p levels were significantly lower in the CAV+ group compared to the CAV- group at follow-up, while miR-126-5p levels were unaltered. This was in stark contrast to native CAD patients in whom miR-126-3p and -5p levels were significantly higher. qPCR levels of miR-126 targets are differentially regulated in CAV versus ischemic cardiomyopathy and are influenced by the administration of immunosuppressive agents in endothelial cells. CONCLUSIONS: Our data provide evidence for a distinct microRNA signature in heart transplantation patients with allograft vasculopathy. In contrast to CAD patients, lower miR-126-3p levels coincide with the development of cardiac allograft vasculopathy. Further studies in a larger patient population are warranted to determine if the serial measurement of myocardial microRNA-126 products could help in risk assessment and early detection of CAV.

Treatment of Diuretic Resistance with a Novel Percutaneous Blood Flow Regulator: Concept and Initial Experience.

Diuretic resistance in acute heart failure is a common clinical problem, and it is associated with adverse outcomes. Effective therapies are still lacking. The Doraya catheter, a temporary intravenous flow regulator placed in the inferior vena cava below the level of the renal veins, is a novel device designed to target renal and cardiac congestion, thereby improving diuretic response. A first-in-man clinical study is currently ongoing.

Non-invasive measurement of right atrial pressure by near-infrared spectroscopy: preliminary experience. A report from the SICA-HF study.

AIMS: To assess the clinical value of measuring right atrial pressure (RAP) using near-infrared spectroscopy (NIRS) in patients with chronic heart failure (CHF). METHODS AND RESULTS: RAP was measured non-invasively using NIRS over the external jugular vein (Venus 1000, Mespere LifeSciences, Canada) in ambulatory patients with CHF enrolled in the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) programme. Comparing 243 patients with CHF (mean age 71 years; mean left ventricular ejection fraction (LVEF) 45%, median NT-proBNP 788 ng/L) to 49 controls (NT-proBNP ≤125 ng/L), RAP was 7 [interquartile range (IQR) 4-11] mmHg vs. 4 (IQR 3-8) mmHg (P < 0.001). Those with RAP ≥10 mmHg (n = 75) were older, had more severe clinical congestion and renal dysfunction, higher plasma NT-proBNP, larger left atrial volume, higher systolic pulmonary pressure and were more often in atrial fibrillation but their LVEF was similar to patients with lower RAP. During a median follow-up of 595 (IQR: 492-714) days, 49 patients (20%) died or were hospitalized for worsening CHF. Compared with patients with RAP ≤5 mmHg, those with RAP ≥10 mmHg had a greater risk of an event (hazard ratio 2.38, 95% confidence interval 1.19-4.75, P = 0.014). RAP measured by NIRS predicted outcome, competing with NT-proBNP in multivariable models. CONCLUSIONS: Measuring RAP using NIRS identifies ambulatory patients with CHF who have more severe congestion and a worse outcome. The device might be a useful objective method of monitoring RAP, especially for those inexperienced in eliciting physical signs or when measurement of natriuretic peptides is not immediately available.

What proportion of patients with chronic heart failure are eligible for sacubitril-valsartan?

AIMS: The PARADIGM-HF trial showed that sacubitril-valsartan, an ARB-neprilysin inhibitor, is more effective than enalapril for some patients with heart failure (HF). It is uncertain what proportion of patients with HF would be eligible for sacubitril-valsartan in clinical practice. METHODS AND RESULTS: Between 2001 and 2014, 6131 patients consecutively referred to a community HF clinic with suspected HF were assessed. The criteria required to enter the randomized phase of PARADIGM-HF, including symptoms, NT-proBNP, and current treatment with or without target doses of ACE inhibitors or ARBs, were applied to identify the proportion of patients eligible for sacubitril-valsartan. Recognizing the diversity of clinical opinion and guideline recommendations concerning this issue, entry criteria were applied singly and in combination. Of 1396 patients with reduced left ventricular ejection fraction (≤40%, HFrEF) and contemporary measurement of NT-proBNP, 379 were on target doses of an ACE inhibitor or ARB at their initial visit and, of these, 172 (45%) fulfilled the key entry criteria for the PARADIGM-HF trial. Lack of symptoms (32%) and NT-proBNP <600 ng/L (49%) were common reasons for failure to fulfil criteria. A further 122 patients became eligible during follow-up (n = 294, 21%). However, if background medication and doses were ignored, then 701 (50%) were eligible initially and a further 137 became eligible during follow-up. CONCLUSIONS: Of patients with HFrEF referred to a clinic such as ours, only 21% fulfilled the PARADIGM-HF randomization criteria, on which the ESC Guidelines are based; this proportion rises to 60% if background medication is ignored.

Xanthine oxidase inhibition for the treatment of cardiovascular disease: an updated systematic review and meta-analysis.

BACKGROUND: Previous studies have shown that xanthine oxidase inhibitors (XOI) might improve outcome for patients with cardiovascular disease. However, more evidence is required. METHODS AND RESULTS: We published a meta-analysis of trials conducted before 2014 examining the effects of XOI on mortality in patients with cardiovascular disease. At least two further trials (N = 323 patients) have since been published. Accordingly, we repeated our analysis after a further search for randomized controlled trials of XOI in PubMed/MEDLINE, EMBASE, and Cochrane Databases. We identified eight relevant trials with 1031 patients. The average age of the patients was 61 years and 68% were men (one study did not report gender). There were 57 deaths in these eight trials, 26 in those assigned to XOI, and 31 in those assigned to the control. The updated meta-analysis could not confirm a reduction in mortality for patients assigned to XOI compared with placebo (odds ratio 0.84) but 95% confidence intervals were wide (0.48-1.47). CONCLUSIONS: This updated meta-analysis does not suggest that XOI exert a large reduction in mortality but also cannot exclude the possibility of substantial harm or benefit.

Should MRAs be at the front row in heart failure? A plea for the early use of mineralocorticoid receptor antagonists in medical therapy for heart failure based on clinical experience.

The brand new 2016 ESC guidelines for the treatment of acute and chronic heart failure continue to give a prominent place to mineralocorticoid receptor antagonists in the treatment of chronic heart failure with reduced ejection fraction (HFrEF). In the prevention of HF hospitalization and death, a class I, level of recommendation A, is given to MRAs for patients with HFrEF, who remain symptomatic despite treatment with an ACE-inhibitor and a beta-blocker and have an LVEF below 35 %. This recommendation is primarily based on two landmark trials, the RALES trial (for spironolactone) and the EMPHASIS-HF trial (for eplerenone). A crucial question is, however, why MRAs are advised only in "third place," i.e., after optimal up-titration of ACE-inhibitors and beta-blockers. We wonder whether MRAs could not or should not be given earlier in the treatment of HFrEF, namely before or together with the up-titration of ACE-inhibitors and beta-blockers. Several arguments to support this plea are described in this short paper.