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Abstract Worsening heart failure (HF) is a vulnerable period in which the patient has a markedly high risk of death or HF hospitalization (up to 10% and 30%, respectively, within the first weeks after episode). The prognosis of HF patients can be improved through a comprehensive approach that considers the different neurohormonal systems, with the early introduction and optimization of the quadruple therapy with sacubitril–valsartan, beta‐blockers, mineralocorticoid receptor antagonists, and inhibitors. Despite that, there is a residual risk that is not targeted with these therapies. Currently, it is recognized that the cyclic guanosine monophosphate deficiency has a negative direct impact on the pathogenesis of HF, and vericiguat, an oral stimulator of soluble guanylate cyclase, can restore this pathway. The effect of vericiguat has been explored in the VICTORIA study, the largest chronic HF clinical trial that has mainly focused on patients with recent worsening HF, evidencing a significant 10% risk reduction of the primary composite endpoint of cardiovascular death or HF hospitalization (number needed to treat 24), after adding vericiguat to standard therapy. This benefit was independent of background HF therapy. Therefore, optimization of treatment should be performed as earlier as possible, particularly within vulnerable periods, considering also the use of vericiguat.

Abstract Aims Red cell distribution width (RDW) is a strong prognostic marker in patients with heart failure (HF) and reduced ejection fraction and other conditions. However, very little is known about its prognostic significance in HF with preserved ejection fraction. We examined the relationship between RDW and outcomes and the effect of sacubitril/valsartan, compared with valsartan, on RDW and clinical outcomes in PARAGON‐HF. Methods and results PARAGON‐HF enrolled patients with a left ventricular ejection fraction of ≥45%, structural heart disease, and elevated N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). The primary endpoint was a composite of total HF hospitalizations and cardiovascular deaths. Median RDW at randomization was 14.1% (interquartile range 13.5–15.0%). Patients with higher RDW levels were more often men and had more comorbidity, a higher heart rate and NT‐proBNP concentration, more advanced New York Heart Association class, and worse Kansas City Cardiomyopathy Questionnaire scores. There was a graded relationship between quartiles of RDW at randomization and the primary endpoint, with a significantly higher risk associated with increasing RDW, even after adjustment for NT‐proBNP and other prognostic variables {Quartile 1, reference; Quartile 2, rate ratio 1.03 [95% confidence interval (CI) 0.83 to 1.28]; Quartile 3, 1.25 [1.01 to 1.54]; Quartile 4, 1.70 [1.39 to 2.08]}. This association was seen for each of the secondary outcomes, including cardiovascular and all‐cause death. Compared with valsartan, sacubitril/valsartan reduced RDW at 48 weeks [mean change −0.09 (95% CI −0.15 to −0.02)]. The effect of sacubitril/valsartan vs. valsartan was not significantly modified by RDW levels at randomization. Conclusions RDW, a routinely available and inexpensive biomarker, provides incremental prognostic information when added to established predictors. Compared with valsartan, sacubitril/valsartan led to a small reduction in RDW.

Abstract Aims Inhibitors of SGLT2 (SGLT2i) have shown a positive impact in patients with chronic heart failure and reduced ejection fraction (HFrEF). Nonetheless, the direct effects of SGLT2i on cardiac cells and how their association with main drugs used for HFrEF affect the behaviour and signalling pathways of myocardial fibroblasts are still unknown. We aimed to determine the effects of dapagliflozin alone and in combination with sacubitril/valsartan (LCZ696) or spironolactone on the function of myocardial fibroblasts of patients with heart failure and reduced ejection fraction (HFrEF). Methods and results Myocardial fibroblasts isolated from HFrEF patients (n = 5) were treated with dapagliflozin alone (1 nM–1 μM) or combined with LCZ696 (100 nM) or spironolactone (100 nM). The migratory rate was determined by wound‐healing scratch assay. Expression of heart failure (HF) markers and signalling pathways activation were analysed with multiplexed protein array. Commercially available cardiac fibroblasts from healthy donors were used as Control (n = 4). Fibroblasts from HFrEF show higher migratory rate compared with control (P = 0.0036), and increased expression of HF markers [fold‐change (Log2): COL1A1–1.3; IL‐1b–1.9; IL‐6–1.7; FN1–2.9 (P

Background PARAGON‐HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) suggested a potential benefit of sacubitril–valsartan in women with preserved ejection fraction. Among patients with heart failure previously treated with angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), we studied whether effectiveness of treatment with sacubitril–valsartan compared with ACEI/ARB monotherapy differed between men and women for both preserved and reduced ejection fraction. Methods and Results Data were derived from the Truven Health MarketScan Databases between January 1, 2011, and December 31, 2018. We included patients with a primary diagnosis of heart failure on treatment with ACEIs, ARBs, or sacubitril–valsartan on the basis of the first prescription after diagnosis. A total of 7181 patients treated with sacubitril–valsartan, 25 408 patients using an ACEI, and 16 177 patients treated with ARBs were included. A total of 790 readmissions or deaths occurred among 7181 patients in the sacubitril–valsartan group and 11 901 events in 41 585 patients treated with an ACEI/ARB. Adjusted for covariates, the hazard ratio (HR) for treatment with sacubitril–valsartan compared with an ACEI or ARB was 0.74 (95% CI, 0.68–0.80). The protective effect of sacubitril–valsartan was evident for men and women (women: HR, 0.75 [95% CI, 0.66–0.86]; P

Abstract Aims We aimed to investigate whether sacubitril–valsartan could further improve the prognosis, cardiac function, and left ventricular (LV) remodelling in patients following acute myocardial infarction (AMI). Methods and results We searched the PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI) from inception to 10 May 2021 to identify potential articles. Randomized controlled trials (RCTs) meeting the inclusion criteria were included and analysed. Thirteen RCTs, covering 1358 patients, were analysed. Compared with angiotensin‐converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB), sacubitril–valsartan did not significantly reduced the cardiovascular mortality [risk ratio (RR) 0.65, 95% confidence interval (CI) 0.22 to 1.93, P = 0.434] and the rate of myocardial reinfarction (RR 0.65, 95% CI 0.29 to 1.46, P = 0.295) of patients following AMI, but the rate of hospitalization for heart failure (HF) (RR 0.48, 95% CI 0.35 to 0.66, P

Background Angiotensin receptor neprilysin inhibitors (ARNI) reduce mortality and hospitalization for patients with heart failure. However, relatively high copayments for ARNI may contribute to suboptimal adherence, thus potentially limiting their benefits. Methods and Results We conducted a retrospective cohort study within a large, multi‐site health system. We included patients with: ARNI prescription between November 20, 2020 and June 30, 2021; diagnosis of heart failure or left ventricular ejection fraction ≤40%; and available pharmacy or pharmacy benefit manager copayment data. The primary exposure was copayment, categorized as $0, $0.01 to $10, $10.01 to $100, and >$100. The primary outcome was prescription fill nonadherence, defined as the proportion of days covered $100. Patients with higher copayments had higher rates of nonadherence, ranging from 17.2% for $0 copayment to 34.2% for copayment >$100 (P$100 (OR, 2.58 [95% CI, 1.63–4.18], P

Abstract Aims We systematically reviewed the European real‐world evidence (RWE) about sacubitril‐valsartan for heart failure with reduced ejection fraction. Methods and results Twenty‐one articles, including 16 952 subjects, were identified until 31 October 2020. Taking as reference the PARADIGM‐HF cohort, few baseline characteristics were presented in >80% of these studies, most often with high heterogeneity. In random‐effects model meta‐analysis, age was higher (mean difference +3.84, 95% CI 1.92–5.76), ischaemic aetiology (OR 0.76, 95% CI 0.64–0.91), hypertension (OR 0.55, 95% CI 0.37–0.82), and diabetes (OR 0.77, 95% CI 0.64–0.92) were less common, and the use of mineralocorticoid receptor antagonists was more frequent (OR 3.54, 95% CI 2.27–5.53) in real‐life than in PARADIGM‐HF. Other clinical and medical features were presented in 19–76% of the selected publications and suggested more severe heart failure with reduced ejection fraction. Sacubitril‐valsartan was titrated to 97/103 mg b.i.d. in 35% (95% CI 23–47) and discontinued in 12.8% (95% CI 7.4–18.3) patients. When reported, the incidence of hyperkalaemia (six studies, no. 1076), all‐cause mortality (five studies, no. 684), and any hospitalization (three studies, no. 390) was 12 (95% CI 5–19)/100 person‐year, 8 (95% CI 4–12)/100 person‐year, and 24 (95% CI 5–42)/100 person‐year, respectively. Knowledge contribution, a metric measuring the proportion of RWE provided by each article based on the number of reported variables and the sample size, was 58.8% and 13.6% for the two biggest investigations (12 082 and 2037 patients), and

Abstract Aims Optimizing medical cardiac treatment for sleep apnoea (SA) in patients with chronic heart failure and reduced ejection fraction (HFrEF) is an expert Grade C recommendation based on six studies encompassing a total of 67 patients only. Whether sacubitril–valsartan (SV), a cornerstone of HFrEF medical treatment, impacts SA is unknown and requires evaluation. Methods and results The ENTRESTO‐SAS trial is a six‐centre, prospective, open‐label real‐life cohort study (NCT02916160). Ambulatory patients eligible for SV (i.e. HFrEF adults who remain symptomatic despite optimal treatment) were evaluated before and after 3 months of SV (including nocturnal ventilatory polygraphy); 118 patients were final analysed [median age was 66 (IQ25–75: 56–73) years, 81.4% male, 36.5% New York Heart Association III–IV, N‐terminal pro‐B‐type natriuretic peptide level of 1564 (701–3376) ng/L, left ventricular ejection fraction of 30 (25–34)%, 60.7% ischaemic HFrEF, 97.5% initially treated with angiotensin‐converting enzyme inhibitors or angiotensin II receptor blockers, 83.9% with beta‐blockers, 64.4% with mineralocorticoid receptor antagonists, and 74.6% with diuretics]. Three groups were defined according to initial central/obstructive apnoea–hypopnoea indices (AHIs): G1 (n = 49, AHIcentral ≥ 5/h and AHIobstructive

Abstract Aims Sacubitril‐valsartan has been shown to have superior effects over angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers in patients with heart failure (HF) and hypertension. The efficacy and safety of sacubitril‐valsartan in patients with HF are controversial. We performed a meta‐analysis of randomized controlled trials to assess and compare the effect and adverse events of sacubitril‐valsartan, valsartan, and enalapril in patients with HF. Methods and results We conducted a systematic search using PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov. Randomized controlled trials involving the use of sacubitril‐valsartan in patients with HF were included. We assessed the pooled odds ratio (OR) of all‐cause mortality, cardiovascular mortality, and hospitalization for HF in fixed‐effects models and the pooled risk ratio (RR) of symptomatic hypotension, worsening renal function, and hyperkalaemia in fixed‐effects models. Of the 315 identified records, six studies involving 14 959 patients were eligible for inclusion. Sacubitril‐valsartan reduced the endpoints of all‐cause mortality and cardiovascular mortality in patients with HF with reduced ejection fraction (HFrEF) in three trials with pooled ORs of 0.83 (P = 0.0006) and 0.78 (P

Abstract Aims Large‐scale clinical trials have demonstrated clinical benefits of sacubitril–valsartan in symptomatic heart failure with reduced ejection fraction patients (PARADIGM‐HF), with potential benefits in patients hospitalized for acute decompensated heart failure (ADHF) (PIONEER‐HF) and fewer benefits in patients with heart failure with preserved ejection fraction (PARAGON‐HF). The aim of this study was to evaluate eligibility for sacubitril–valsartan using criteria described in PIONNER‐HF in non‐selected patients hospitalized for ADHF. Methods and results Between November 2014 and May 2019, 799 patients were recruited in a prospective registry of acute heart failure at the University Hospitals of Geneva (ClinicalTrials.gov: NCT02444416). The cohort consists of consecutive patients admitted to the Department of Medicine with ADHF. Eligibility for sacubitril–valsartan was determined using criteria described in PIONEER‐HF, including left ventricular ejection fraction, clinical parameters, and co‐morbidities. Of 799 patients, 123 (15.39%) were eligible for sacubitril–valsartan treatment. Clinical outcomes including all‐cause mortality and readmission were similar in eligible and non‐eligible groups, hazard ratio 1.02 (95% confidence interval 0.81–1.29, P = 083). Conclusions Using current criteria from randomized controlled trials, only 15% of non‐selected patients admitted for ADHF are theoretically eligible for sacubitril–valsartan. Eligibility for sacubitril–valsartan using published criteria is not associated with worse outcome, suggesting that further evaluation of benefits of sacubitril–valsartan in heart failure patients based on parameters other than left ventricular ejection fraction may be of interest.

Abstract Aims Sacubitril/Valsartan (Sac/Val) was proven more effective than enalapril for symptomatic patients with heart failure (HF) with reduced ejection fraction (HFrEF). This study aimed to investigate eligibility, titration, and tolerability for Sac/Val in a real‐world clinical setting. Methods and results This retrospective cohort study consists of two parts. In Part 1 (eligibility study), all patients discharged from Sahlgrenska University Hospital due to HF were consecutively included during 1 year. Data from the patients' medical records were collected. Patients were adjudicated to be eligible based on European Society of Cardiology (ESC) criteria for angiotensin receptor neprilysin inhibitor (ARNI) with the exception of N‐terminal (NT)‐proBNP levels. Patients who received

Abstract Aims Current guidelines recommend sacubitril/valsartan for patients with heart failure and reduced left ventricular ejection fraction (LVEF), but there is lack of evidence of its efficacy and safety in cancer therapy‐related cardiac dysfunction (CTRCD). Our aim was to analyse the potential benefit of sacubitril/valsartan in patients with CTRCD. Methods and results We performed a retrospective multicentre registry (HF‐COH) in six Spanish hospitals with cardio‐oncology clinics including all patients treated with sacubitril/valsartan. Demographic and clinical characteristics and laboratory and echocardiographic data were collected. Median follow‐up was 4.6 [1; 11] months. Sixty‐seven patients were included (median age was 63 ± 14 years; 64% were female, 87% had at least one cardiovascular risk factor). Median time from anti‐cancer therapy to CTRD was 41 [10; 141] months. Breast cancer (45%) and lymphoma (39%) were the most frequent neoplasm, 31% had metastatic disease, and all patients were treated with combination antitumor therapy (70% with anthracyclines). Thirty‐nine per cent of patients had received thoracic radiotherapy. Baseline median LVEF was 33 [27; 37], and 21% had atrial fibrillation. Eighty‐five per cent were on beta‐blocker therapy and 76% on mineralocorticoid receptor antagonists; 90% of the patients were symptomatic NYHA functional class ≥II. Maximal sacubitril/valsartan titration dose was achieved in 8% of patients (50 mg b.i.d.: 60%; 100 mg b.i.d.: 32%). Sacubitril/valsartan was discontinued in four patients (6%). Baseline N‐terminal pro‐B‐type natriuretic peptide levels (1552 pg/mL [692; 3624] vs. 776 [339; 1458]), functional class (2.2 ± 0.6 vs. 1.6 ± 0.6), and LVEF (33% [27; 37] vs. 42 [35; 50]) improved at the end of follow‐up (all P values ≤0.01). No significant statistical differences were found in creatinine (0.9 mg/dL [0.7; 1.1] vs. 0.9 [0.7; 1.1]; P = 0.055) or potassium serum levels (4.5 mg/dL [4.1; 4.8] vs. 4.5 [4.2; 4.8]; P = 0.5). Clinical, echocardiographic, and biochemical improvements were found regardless of the achieved sacubitril–valsartan dose (low or medium/high doses). Conclusions Our experience suggests that sacubitril/valsartan is well tolerated and improves echocardiographic functional and structural parameters, N‐terminal pro‐B‐type natriuretic peptide levels, and symptomatic status in patients with CTRCD.

Abstract Aims In the PARADIGM‐heart failure trial, sacubitril‐valsartan demonstrated a reduction in heart failure admissions and reduced all‐cause mortality in patients with heart failure with reduced ejection fraction. Although real world data have shown similar benefits regarding efficacy and safety, there has been difficulty in achieving the target dose (TD). The factors preventing the achievement of TD remains unclear. This study assesses the tolerability, ability to achieve, and factors linked to attaining TD in a routine clinical population. Methods and results This is a retrospective single‐centre review of patients switched from angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers to sacubitril‐valsartan between May 2016 and August 2018. Baseline and follow‐up clinical characteristics and biomarker profiles were collected. Univariate and multivariate analyses were used to analyse predictors of achieving TD. Clinical response to sacubitril‐valsartan was defined as a reduction in N terminal pro BNP of ≥30%, or an increase in left ventricular ejection fraction of ≥5% compared with baseline values. To date, a total of 322 patients (75% male patients) have been switched to sacubitril‐valsartan. Those still in the titration phase were excluded (n = 25). Sacubitril‐valsartan was not tolerated in 40 patients (12.4%). Those intolerant were older (73.4 years [68.3, 80.6] vs. 69.1 years [61.2, 76]; P = 0.003) and had worse renal function with estimated glomerular filtration rate (53.5 mL/min/1.72 m2 [36.8, 60.2] vs 60 mL/min/1.72 m2 [47, 77]; P ≤ 0.001). Of the remaining 257 patients, TD (97/103 mg BD) was achieved in 194 patients (75.5%), while 37 patients (11.4%) were maintained on 49/51 mg BD and 26 patients (8.1%) remained on 24/26 mg BD. Symptomatic hypotension (74.6%) was the main impediment to attaining TD, followed by renal deterioration (12.7%), and to a lesser extent hyperkalaemia and gastrointestinal symptoms (4.8% each). Diuretic dose decrease was achieved in 37.2% of patients, and this was the strongest independent predictor of achieving TD (odds ratio = 2.1; 95% confidence interval [1.16, 3.8]; P = 0.014). Responder status by N terminal pro BNP criterion was observed in 99 of 214 patients (46.3%) while 70 of 142 (49.3%) attained the left ventricular ejection fraction response status. Achieving this response was independently linked to achieving TD. Conclusions Sacubitril‐valsartan was well tolerated. Achievement of TD was possible in the majority of the cohort and was linked to response metrics. Reduction in diuretic was required in a large percentage of the population and was the strongest predictor of attaining TD. Therefore, careful clinical attention to volume status assessment is essential to maximising the benefits of sacubitril‐valsartan.

Abstract This review aims to assess the benefits and adverse effects of sacubitril/valsartan in heart failure, with a focus on important patient outcomes. A systematic review was conducted of double‐blind randomized controlled trials (RCTs) comparing sacubitril/valsartan versus a reference drug, in heart failure patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction, published in French or English. Searches were undertaken of Medline, Cochrane Central, and Embase. The primary outcomes were all‐cause mortality and adverse events. From 2 082 articles analyzed, 5 were included. For all‐cause mortality, the absolute numbers for HFrEF (2 RCTs, 4627 patients) were 16% on sacubitril/valsartan and 18% on enalapril, with a risk ratio (RR) of 0.85 [CI = 0.78, 0.93], and 13% vs 14% in with HFpEF (2 RCTs, 5097 patients), with no statistical difference. Under the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, the evidence for HFrEF patients was of moderate quality. For HFrEF patients, an increased risk of symptomatic hypotension and angioedema (low quality of evidence) was shown. There was no statistical difference for the risk of hyperkalemia or worsening renal function. There was a protective RR (0.50 [0.34, 0.75]) for worsening renal function for patients with HFpEF, with a high quality of evidence despite similar absolute numbers (1.4% vs. 2.8%). To keep in mind for shared decision‐making, sacubitril/valsartan reduces all‐cause mortality in HFrEF patients but for HFpEF further data are needed. Take into consideration the small number of studies to date to assess the risks.

Aims: The associations between potassium level and outcomes, the effect of sacubitril-valsartan on potassium level, and whether potassium level modified the effect of sacubitril-valsartan in patients with heart failure and a reduced ejection fraction were studied in PARADIGM-HF. Several outcomes, including cardiovascular death, sudden death, pump failure death, non-cardiovascular death and heart failure hospitalization, were examined., Methods and Results: A total of 8399 patients were randomized to either enalapril or sacubitril-valsartan. Potassium level at randomization and follow-up was examined as a continuous and categorical variable (≤3.5, 3.6-4.0, 4.1-4.9, 5.0-5.4 and ≥5.5 mmol/L) in various statistical models. Hyperkalaemia was defined as K +  ≥5.5 mmol/L and hypokalaemia as K +  ≤3.5 mmol/L. Compared with potassium 4.1-4.9 mmol/L, both hypokalaemia [hazard ratio (HR) 2.40, 95% confidence interval (CI) 1.84-3.14] and hyperkalaemia (HR 1.42, 95% CI 1.10-1.83) were associated with a higher risk for cardiovascular death. However, potassium abnormalities were similarly associated with sudden death and pump failure death, as well as non-cardiovascular death and heart failure hospitalization. Sacubitril-valsartan had no effect on potassium overall. The benefit of sacubitril-valsartan over enalapril was consistent across the range of baseline potassium levels., Conclusions: Although both higher and lower potassium levels were independent predictors of cardiovascular death, potassium abnormalities may mainly be markers rather than mediators of risk for death., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: This study aimed to determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure (HF) with preserved ejection fraction (HFpEF), and whether sacubitril-valsartan reduces SUA and use of SUA-related therapies., Methods and Results: We analysed 4795 participants from the Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial. We related baseline hyperuricaemia (using age and gender adjusted assay definitions) to the primary outcome [cardiovascular (CV) death and total HF hospitalizations]. We assessed the associations between changes in SUA and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) and other cardiac biomarkers from baseline to 4 months. We simultaneously adjusted for baseline and time-updated SUA to determine whether lowering SUA was associated with clinical benefit. The mean (± standard deviation) age of patients was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricaemia was associated with increased risk for the primary outcome [rate ratio 1.61, 95% confidence interval (CI) 1.37-1.90]. The treatment effect of sacubitril-valsartan for the primary endpoint was not significantly modified by hyperuricaemia (P-value for interaction = 0.14). Sacubitril-valsartan reduced SUA by 0.38 mg/dL (95% CI 0.31-0.45) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (-0.51 mg/dL vs. -0.32 mg/dL) (P-value for interaction = 0.031). Sacubitril-valsartan reduced the odds of initiating SUA-related treatments by 32% during follow-up (P < 0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ-OSS and directly associated with high-sensitivity troponin T (P < 0.05). Time-updated SUA was a stronger predictor of adverse outcomes than baseline SUA., Conclusions: Serum uric acid independently predicted adverse outcomes in HFpEF. Sacubitril-valsartan reduced SUA and the initiation of related therapy compared with valsartan. Reductions in SUA were associated with improved outcomes., (© 2020 European Society of Cardiology.)

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., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)