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Aims: In order to understand how sex differences impact the generalizability of randomized clinical trials (RCTs) in patients with heart failure (HF) and reduced ejection fraction (HFrEF), we sought to compare clinical characteristics and clinical outcomes between RCTs and HF observational registries stratified by sex. Methods and results: Data from two HF registries and five HFrEF RCTs were used to create three subpopulations: one RCT population (n = 16 917; 21.7% females), registry patients eligible for RCT inclusion (n = 26 104; 31.8% females), and registry patients ineligible for RCT inclusion (n = 20 810; 30.2% females). Clinical endpoints included all-cause mortality, cardiovascular mortality, and first HF hospitalization at 1 year. Males and females were equally eligible for trial enrolment (56.9% of females and 55.1% of males in the registries). One-year mortality rates were 5.6%, 14.0%, and 28.6% for females and 6.9%, 10.7%, and 24.6% for males in the RCT, RCT-eligible, and RCT-ineligible groups, respectively. After adjusting for 11 HF prognostic variables, RCT females showed higher survival compared to RCT-eligible females (standardized mortality ratio [SMR] 0.72; 95% confidence interval [CI] 0.62–0.83), while RCT males showed higher adjusted mortality rates compared to RCT-eligible males (SMR 1.16; 95% CI 1.09–1.24). Similar results were also found for cardiovascular mortality (SMR 0.89; 95% CI 0.76–1.03 for females, SMR 1.43; 95% CI 1.33–1.53 for males). Conclusion: Generalizability of HFrEF RCTs differed substantially between the sexes, with females having lower trial participation and female trial participants having lower mortality rates compared to similar females in the registries, while males had higher than expected cardiovascular mortality rates in RCTs compared to similar males in registries.

Aims: This study aimed to assess the sex-specific distribution of heart failure (HF) with preserved, mid-range, and reduced ejection fraction across three health care settings. Methods and results: In this descriptive observational study, we retrieved the distribution of HF types [with reduced ejection fraction (HFrEF), mid-range ejection fraction (HFmrEF), and preserved ejection fraction (HFpEF)] for men and women between 65 and 79 years of age in three health care settings from a single country: (i) patients with screening-detected HF in the high-risk community (i.e. those with shortness of breath, frailty, diabetes mellitus, and chronic obstructive pulmonary disease) from four screening studies, (ii) patients with confirmed HF from primary care derived from a single observational study, and (iii) patients with confirmed HF from outpatient cardiology clinics participating in a registry. Among 1407 patients from the high-risk community, 288 had screen-detected HF (15% HFrEF, 12% HFmrEF, 74% HFpEF), and 51% of the screen-detected HF patients were women. In both women (82%) and men (65%), HFpEF was the most prevalent HF type. In the routine general practice population (30 practices, 70 000 individuals), among the 160 confirmed HF cases, 35% had HFrEF, 23% HFmrEF, and 43% HFpEF, and in total, 43% were women. In women, HFpEF was the most prevalent HF type (52%), while in men, this was HFrEF (41%). In outpatient cardiology clinics (n = 34), of the 4742 HF patients (66% HFrEF, 15% HFmrEF, 20% HFpEF), 36% were women. In both women (56%) and men (71%), HFrEF was the most prevalent HF type. Conclusions: Both HF types and sex distribution vary considerably in HF patients of 65–79 years of age among health care settings. From the high-risk community through to general practice to the cardiology outpatient setting, there is a shift in HF type from HFpEF to HFrEF and a decrease in the proportion of HF patients that are women.

Document Reviewers: Rudolf A. de Boer (CPG Review Coordinator) (Netherlands), P. Christian Schulze (CPG Review Coordinator) (Germany), Magdy Abdelhamid (Egypt), Victor Aboyans (France), Stamatis Adamopoulos (Greece), Stefan D. Anker (Germany), Elena Arbelo (Spain), Riccardo Asteggiano (Italy), Johann Bauersachs (Germany), Antoni Bayes-Genis (Spain), Michael A. Borger (Germany), Werner Budts (Belgium), Maja Cikes (Croatia), Kevin Damman (Netherlands), Victoria Delgado (Netherlands), Paul Dendale (Belgium), Polychronis Dilaveris (Greece), Heinz Drexel (Austria), Justin Ezekowitz (Canada), Volkmar Falk (Germany), Laurent Fauchier (France), Gerasimos Filippatos (Greece), Alan Fraser (United Kingdom), Norbert Frey (Germany), Chris P. Gale (United Kingdom), Finn Gustafsson (Denmark), Julie Harris (United Kingdom), Bernard Iung (France), Stefan Janssens (Belgium), Mariell Jessup (United States of America), Aleksandra Konradi (Russia), Dipak Kotecha (United Kingdom), Ekaterini Lambrinou (Cyprus), Patrizio Lancellotti (Belgium), Ulf Landmesser (Germany), Christophe Leclercq (France), Basil S. Lewis (Israel), Francisco Leyva (United Kingdom), AleVs Linhart (Czech Republic), Maja-Lisa Løchen (Norway), Lars H. Lund (Sweden), Donna Mancini (United States of America), Josep Masip (Spain), Davor Milicic (Croatia), Christian Mueller (Switzerland), Holger Nef (Germany), Jens-Cosedis Nielsen (Denmark), Lis Neubeck (United Kingdom), Michel Noutsias (Germany), Steffen E. Petersen (United Kingdom), Anna Sonia Petronio (Italy), Piotr Ponikowski (Poland), Eva Prescott (Denmark), Amina Rakisheva (Kazakhstan), Dimitrios J. Richter (Greece), Evgeny Schlyakhto (Russia), Petar Seferovic (Serbia), Michele Senni (Italy), Marta Sitges (Spain), Miguel Sousa-Uva (Portugal), Carlo G. Tocchetti (Italy), Rhian M. Touyz (United Kingdom), Carsten Tschoepe (Germany), Johannes Waltenberger (Germany/Switzerland) All experts involved in the development of these guidelines have submitted declarations of interest. These have been compiled in a report and published in a supplementary document simultaneously to the guidelines. The report is also available on the ESC website www.escardio.org/guidelines For the Supplementary Data which include background information and detailed discussion of the data that have provided the basis for the guidelines see European Heart Journal online.

ObjectivePostmarketing observational studies report that a substantial percentage of patients with atrial fibrillation (AF) receive a reduced non-vitamin K antagonist oral anticoagulant (NOAC) dose without a clear indication. Recently, increasing evidence has become available to explore the clinical consequences of such off-label reduced dosing (OLRD). This study aims to systematically review and meta-analyse observational studies that report clinical outcomes associated with OLRD of NOACs compared with on-label non-reduced dosing (OLNRD) of NOACs in patients with AF.Methods and analysisWe performed a systematic literature review and meta-analysis of observational studies reporting clinical outcomes in AF patients with OLRD of an NOAC compared with AF patients with OLNRD of an NOAC. Using random effects meta-analyses, we estimated the risk of stroke/thromboembolism, bleeding and all-cause mortality.ResultsWe included 19 studies with a total of 170 394 NOAC users. In these studies, the percentage of OLRD among patients with an indication for an on-label non-reduced NOAC dose ranged between 9% and 53%. 7 of these 19 studies met the predefined criteria for meta-analysis (n=80 725 patients). The pooled HR associated with OLRD of NOACs was 1.04 (95% CI 0.83 to 1.29; 95% prediction interval (PI) 0.60 to 1.79) for stroke/thromboembolism, 1.10 (95% CI 0.95 to 1.29; 95% PI 0.81 to 1.50) for bleeding and 1.22 (95% CI 0.81 to 1.84; 95% PI 0.55 to 2.70) for all-cause mortality.ConclusionThis meta-analysis shows no statistically significant increased risk of stroke/thromboembolism, nor a decreased bleeding risk, nor a difference in risk of all-cause mortality in patients with OLRD of NOACs. Future research may focus on differences between NOACs.

Background Heart failure (HF) trials have stringent inclusion and exclusion criteria, but limited data exist regarding generalizability of trials. We compared patient characteristics and outcomes between patients with HF and reduced ejection fraction (HFrEF) in trials and observational registries. Methods and Results Individual patient data for 16 922 patients from five randomized clinical trials and 46 914 patients from two HF registries were included. The registry patients were categorized into trial-eligible and non-eligible groups using the most commonly used inclusion and exclusion criteria. A total of 26 104 (56%) registry patients fulfilled the eligibility criteria. Unadjusted all-cause mortality rates at 1 year were lowest in the trial population (7%), followed by trial-eligible patients (12%) and trial-non-eligible registry patients (26%). After adjustment for age and sex, all-cause mortality rates were similar between trial participants and trial-eligible registry patients [standardized mortality ratio (SMR) 0.97; 95% confidence interval (CI) 0.92–1.03] but cardiovascular mortality was higher in trial participants (SMR 1.19; 1.12–1.27). After full case-mix adjustment, the SMR for cardiovascular mortality remained higher in the trials at 1.28 (1.20–1.37) compared to RCT-eligible registry patients. Conclusion In contemporary HF registries, over half of HFrEF patients would have been eligible for trial enrolment. Crude clinical event rates were lower in the trials, but, after adjustment for case-mix, trial participants had similar rates of survival as registries. Despite this, they had about 30% higher cardiovascular mortality rates. Age and sex were the main drivers of differences in clinical outcomes between HF trials and observational HF registries.

In dit geblindeerde case-controlonderzoek lieten we 15 triagegesprekken op een HAP waarin een acuut coronair syndroom werd gemist en 120 vergelijkbare triagegesprekken zonder catastrofale afloop beoordelen door een panel van ervaren huisartsen, onafhankelijk van elkaar en geblindeerd voor de uitkomst. De interbeoordelaarsbetrouwbaarheid binnen het panel was laag en de gevonden verschillen tussen cases en controls zijn niet heel uitgesproken. Toch pleiten wij ervoor om calamiteiten niet alleen individueel te analyseren, maar ze ook in grotere aantallen te vergelijken met een controleconditie. Om te leren van calamiteiten zou niet alleen de fatale afloop uitgangspunt moeten zijn. Het is ook belangrijk om rekening te houden met de dagelijkse praktijk, zodat eventuele verbetermaatregelen daarbij aansluiten.

ObjectiveTo develop and validate a symptom-based prediction rule for early recognition of acute coronary syndrome (ACS) in patients with acute chest discomfort who call out-of-hours services for primary care (OHS-PC).DesignCross-sectional study. A diagnostic prediction rule was developed with multivariable regression analyses. All models were validated with internal-external cross validation within seven OHS-PC locations. Both age and sex were analysed as statistical interaction terms, applying for age non-linear effects.SettingSeven OHS-PC in the Netherlands.Participants2192 patients who called OHS-PC for acute chest discomfort (pain, pressure, tightness or discomfort) between 2014 and 2017. Backed up recordings of telephone triage conversations were analysed.Primary and secondary outcomes measuresDiagnosis of ACS retrieved from the patient’s medical records in general practice, including hospital specialists discharge letters. Performance of the prediction rules was calculated with the c-statistic and the final model was chosen based on net benefit analyses.ResultsAmong the 2192 patients who called the OHS-PC with acute chest discomfort, 8.3% females and 15.3% males had an ACS. The final diagnostic model included seven predictors (sex, age, acute onset of chest pain lasting less than 12 hours, a pressing/heavy character of the pain, radiation of the pain, sweating and calling at night). It had an adjusted c-statistic of 0.77 (95% CI 0.74 to 0.79) with good calibration.ConclusionThe final prediction model for ACS has good discrimination and calibration and shows promise for replacing the existing telephone triage rules for patients with acute chest discomfort in general practice and OHS-PC.Trial registration numberNTR7331.

Introduction In rare diseases, registry-based studies can be used to provide natural history data pre-approval and complement drug efficacy and/or safety knowledge post-approval. Objective The objective of this study was to investigate the opinion of stakeholders about key aspects of rare disease registries that are used to support regulatory decision making and to compare the responses of employees from industry to other stakeholders. Methods A web-based survey was used to gauge the importance of (1) common data elements (including safety outcomes), (2) data quality and (3) governance aspects that are generic across different rare diseases. The survey included 47 questions. The data were collected in the period April-October 2019. Results Seventy-three respondents completed ≥ 80% of the survey. Most of the respondents were from the industry (n = 42, 57%). For safety data, 31 (42%) respondents were in favour of collecting all adverse events. For data quality, the respondents found a level of 30% reasonable for source data verification. For missing data, a level of 20% was considered acceptable. Compared to responders from industry, the other stakeholders found it less relevant to share data with industry and found it less acceptable if the registry is financed by industry. Conclusions This study showed that the opinion towards data and governance is well aligned across parties, and issues of data and governance on their own should not pose a barrier to collaboration. This finding is supportive of the European Medicines Agency’s efforts to encourage stakeholders to work with existing registries when collecting data to support regulatory decision making. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01081-z.

Sinds 2011 gebruiken veel huisartsenposten de Nederlandse Triage Standaard (NTS) als beslishulp voor telefonische triage. Doordat het verhaal van de patient vaak niet in de starre structuur van de NTS te passen is, merken triagisten dat de NTS hun besluitvorming niet altijd optimaal ondersteunt. Willen we de triage verbeteren, dan zullen we meer inzicht moeten krijgen in het redeneren van triagisten en de manier waarop ze de NTS gebruiken.

’s Ochtends vroeg is de kans op een acuut coronair syndroom (ACS) het hoogst. Dat gegeven is bruikbaar voor telefonische triage op de huisartsenpost (HAP). Patienten die tussen 00:00 en 09:00 uur de HAP bellen met acute thoracale klachten hebben een bijna 2 keer zo hoge kans op een ACS als mensen die op andere tijdstippen bellen. Dat geldt vooral voor mannen. Overweeg daarom om bij mensen die ’s nachts bellen met acute thoracale klachten laagdrempelig een ambulance te sturen.

Supplemental digital content is available in the text., Objectives Serious adverse events at out-of-hours services in primary care (OHS-PC) are rare, and the most often concern is missed acute coronary syndrome (ACS). Previous studies on serious adverse events mainly concern root cause analyses, which highlighted errors in the telephone triage process but are hampered by hindsight bias. This study compared the recorded triage calls of patients with chest discomfort contacting the OHS-PC in whom an ACS was missed (cases), with triage calls involving matched controls with chest discomfort but without a missed ACS (controls), with the aim to assess the predictors of missed ACS. Methods A case-control study with data from 2013 to 2017 of 9 OHS-PC in the Netherlands. The cases were matched 1:8 with controls based on age and sex. Clinical, patient, and call characteristics were univariably assessed, and general practitioner experts evaluated the triage while blinded to the final diagnosis or the case-control status. Results Fifteen missed ACS calls and 120 matched control calls were included. Cases used less cardiovascular medication (38.5% versus 64.1%, P = 0.05) and more often experienced pain other than retrosternal chest pain (63.3% versus 24.7%, P = 0.02) compared with controls. Consultation of the supervising general practitioner (86.7% versus 49.2%, P = 0.02) occurred more often in cases than in controls. Experts rated the triage of cases more often as “poor” (33.3% versus 10.9%, P = 0.001) and “unsafe” (73.3% versus 22.5%, P < 0.001) compared with controls. Conclusions To facilitate learning from serious adverse events in the future, these should also be bundled and carefully assessed without hindsight bias and within the context of “normal” clinical practice.

ObjectiveTo estimate the incidence of ischaemic heart disease, atrial fibrillation and heart failure in community patients with or without chronic obstructive pulmonary disease (COPD).MethodsFor this population-based study, we used primary care data of the Julius General Practitioners’ Network. Eligible participants were aged 40–80 years old and contributed data between January 2014 and February 2019. Participants were divided into groups according to COPD status and were followed up for new ischaemic heart disease, atrial fibrillation and/or heart failure. Age-specific and sex-specific incidence and incidence rate ratios were calculated for patients with and without COPD.ResultsMean follow-up was 3.9 years, 6223 patients were included in the COPD group, and 137 028 individuals in the background group without COPD. Incidence rates of all three heart diseases increased with age and were higher in males, independent of presence of COPD. Incidence rate ratios for patients with COPD, adjusted for age and sex, were 1.69 (95% CI 1.49 to 1.92) for ischaemic heart disease, 1.56 (95% CI 1.38 to 1.77) for atrial fibrillation and 2.96 (95% CI 2.58 to 3.40) for heart failure.ConclusionThe incidence of all major cardiovascular diseases is higher in patients with COPD, with the highest incidence rate ratio observed for heart failure.

Root cause analyses of serious adverse events (SAE) in out-of-hours primary care (OHS-PC) often point to errors in telephone triage. Such analyses are, however, hampered by hindsight bias. We assessed whether experts, blinded to the outcome, recognize (un)safety of triage of patients with chest discomfort, and we quantified inter-rater reliability.This is a case-control study with triage recordings from 2013-2017 at OHS-PC. Cases were missed acute coronary syndromes (ACSs, considered as SAE). These cases were age- and gender-matched 1:8 with the controls, sampled from the remainder of people calling for chest discomfort. Fifteen experts listened to the recordings and rated the safety of triage. We calculated sensitivity and specificity of recognizing an ACS and the intraclass correlation.In total, 135 calls (15 SAE, 120 matched controls) were relistened. The experts identified ACSs with a sensitivity of 0.86 (95% CI: 0.71-0.95) and a specificity of 0.51 (95% CI: 0.43-0.58). Cases were rated significantly more often as unsafe than the controls (73.3% vs. 22.5%, P0.001). The inter-rater reliability for safety was poor: ICC 0.16 (95% CI: 0.00-0.32).Blinded experts rated calls of missed ACSs more often as unsafe than matched control calls, but with a low level of agreement among the experts.

Background Elderly heart failure (HF) patients are underrepresented in clinical trials, though are a large proportion of patients in real-world practice. We investigated practice-based, secondary care HF management in a large group of chronic HF patients aged >= 80 years (octogenarians). Methods We analyzed electronic health records of 3490 octogenarians with chronic HF at 34 Dutch outpatient clinics in the period between 2013 and 2016 , 49% women. Study patients were divided into HFpEF [LVEF >= 50%; n = 911 (26.1%)], HFrEF [LVEF < 40%; n = 2009 (57.6%)] and HF with mid-range EF [HFmrEF: LVEF 40-49%; n = 570 (16.3%)]. Results Most HFrEF patients aged >= 80 years received a beta blocker and a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker), i.e. 78.3% and 72.8% respectively, and a mineralocorticoid receptor antagonist (MRA) was prescribed in 52.0% of patients. All three of these guideline-recommended medications (triple therapy) were given in only 29.9% of octogenarians with HFrEF, and at least 50% of target doses of triple therapy, beta blockers, RAS inhibitor and MRA, were prescribed in 43.8%, 62.2% and 53.5% of the total group of HFrEF patients. Contraindications or intolerance for beta blockers was present in 3.5% of the patients, for RAS inhibitors and MRAs in, 7.2% and 6.1% Conclusions The majority of octogenarians with HFrEF received one or more guideline-recommended HF medications. However, triple therapy or target doses of the medications were prescribed in a minority. Comorbidities and reported contraindications and tolerances did not fully explain underuse of recommended HF therapies.[GRAPHICS].

Aims To assess whether a single training session for general practitioners (GPs) improves the evidence-based drug treatment of heart failure (HF) patients, especially of those with HF with reduced ejection fraction (HFrEF). Methods and results A cluster randomised controlled trial was performed for which patients with established HF were eligible. Primary care practices (PCPs) were randomised to care-as-usual or to the intervention group in which GPs received a half-day training session on HF management. Changes in HF medication, health status, hospitalisation and survival were compared between the two groups. Fifteen PCPs with 200 HF patients were randomised to the intervention group and 15 PCPs with 198 HF patients to the control group. Mean age was 76.9 (SD 10.8) years; 52.5% were female. On average, the patients had been diagnosed with HF 3.0 (SD 3.0) years previously. In total, 204 had HFrEF and 194 HF with preserved ejection fraction (HFpEF). In participants with HFrEF, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers decreased in 6 months in both groups [5.2%; (95% confidence interval (CI) 2.0–10.0)] and 5.6% (95% CI 2.8–13.4)], respectively [baseline-corrected odds ratio (OR) 1.07 (95% CI 0.55–2.08)], while beta-blocker use increased in both groups by 5.2% (95% CI 2.0–10.0) and 1.1% (95% CI 0.2–6.3), respectively [baseline-corrected OR 0.82 (95% CI 0.42–1.61)]. For health status, hospitalisations or survival after 12–28 months there were no significant differences between the two groups, also not when separately analysed for HFrEF and HFpEF. Conclusion A half-day training session for GPs does not improve drug treatment of HF in patients with established HF.

Aims To evaluate whether integrated care for atrial fibrillation (AF) can be safely orchestrated in primary care. Methods and results The ALL-IN trial was a cluster randomized, open-label, pragmatic non-inferiority trial performed in primary care practices in the Netherlands. We randomized 26 practices: 15 to the integrated care intervention and 11 to usual care. The integrated care intervention consisted of (i) quarterly AF check-ups by trained nurses in primary care, also focusing on possibly interfering comorbidities, (ii) monitoring of anticoagulation therapy in primary care, and finally (iii) easy-access availability of consultations from cardiologists and anticoagulation clinics. The primary endpoint was all-cause mortality during 2 years of follow-up. In the intervention arm, 527 out of 941 eligible AF patients aged ≥65 years provided informed consent to undergo the intervention. These 527 patients were compared with 713 AF patients in the control arm receiving usual care. Median age was 77 (interquartile range 72–83) years. The all-cause mortality rate was 3.5 per 100 patient-years in the intervention arm vs. 6.7 per 100 patient-years in the control arm [adjusted hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.37–0.82]. For non-cardiovascular mortality, the adjusted HR was 0.47 (95% CI 0.27–0.82). For other adverse events, no statistically significant differences were observed. Conclusion In this cluster randomized trial, integrated care for elderly AF patients in primary care showed a 45% reduction in all-cause mortality when compared with usual care.

Aim The aim of this study was to investigate whether a disease registry could serve as a suitable alternative to clinical studies to investigate safety of orphan drugs in children. Methods We used individual patient data from previously untreated patients (PUPs) with severe haemophilia A from the factor VIII (rAHF‐PFM)‐clinical study and the PedNet registry. The primary outcome was the patient characteristics at entry and the difference in inhibitor development between the clinical study and the registry‐based study at 50 exposure days. Results Clinical study patients more often had a positive family history of inhibitors (31% vs 10%) and a high‐risk F8 genotype (82% vs 63%). In the clinical study 41/55 (75%) and in the registry‐based study 162/168 (96%) patients reached 50 exposure days. Inhibitors developed in 16 of the 41 patients in the clinical study (39%) vs 44 of the 162 patients in the registry‐based study (27%); seven patients (7%) vs 28 patients (17%) had high‐titre inhibitors. The risk of developing an inhibitor during the first 50 exposure days was similar (HR 1.04; 95% CI 0.56‐1.94), when adjusted for family history of inhibitors, F8 gene mutation and intensive treatment at first exposure. Conclusion In the registry‐based study, patient numbers and completeness of follow‐up were higher. The risk of developing an inhibitor to a single product was comparable. Although the sample size of this study was too small to conclude on differences in high‐ or low‐titre inhibitors, this suggests that a registry could serve as a more suitable source for evaluation of high‐titre inhibitors in the setting of factor VIII deficiency.

Aims Left ventricular ejection fraction (EF) is required to categorize heart failure (HF) [i.e. HF with preserved (HFpEF), mid-range (HFmrEF), and reduced (HFrEF) EF] but is often not captured in population-based cohorts or non-HF registries. The aim was to create an algorithm that identifies EF subphenotypes for research purposes. Methods and results We included 42 061 HF patients from the Swedish Heart Failure Registry. As primary analysis, we performed two logistic regression models including 22 variables to predict (i) EF >= vs. = vs. = 50% and 0.76 (95% CI 0.75-0.76) for EF >= 40%. Similar results were achieved for HFrEF and HFpEF in the multinomial model, but the C-statistic for HFmrEF was lower: 0.63 (95% CI 0.63-0.64). The external validation showed similar discriminative ability to the development cohort. Conclusions Routine clinical characteristics could potentially be used to identify different EF subphenotypes in databases where EF is not readily available. Accuracy was good for the prediction of HFpEF and HFrEF but lower for HFmrEF. The proposed algorithm enables more effective research on HF in the big data setting. Funding Agencies|Swedish National Board of Health and Welfare; Swedish Association of Local Authorities and Regions; Swedish Society of Cardiology; Swedish Heart-Lung FoundationSwedish Heart-Lung Foundation; Servier, the NetherlandsNetherlands Government; EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart [116074]; Swedish Research CouncilSwedish Research Council [2013-23897-104604-23, 523-2014-2336]; Swedish Heart Lung FoundationSwedish Heart-Lung Foundation [20150557, 20170841]; Stockholm County CouncilStockholm County Council [20140220, 20170112]; UCL Hospitals NIHR Biomedical Research Centre; Dutch Heart Foundation, a part of Facts and Figures

Background Heart failure (HF) is associated with poor prognosis, high morbidity and mortality. The prognosis can be optimised by guideline adherence, which also can be used as a benchmark of quality of care. The purpose of this study was to evaluate differences in use of HF medication between Dutch HF clinics. Methods The current analysis was part of a cross-sectional registry of 10,910 chronic HF patients at 34 Dutch outpatient clinics in the period of 2013 until 2016 (CHECK-HF), and focused on the differences in prescription rates between the participating clinics in patients with heart failure with reduced ejection fraction (HFrEF). Results A total of 8,360 HFrEF patients were included with a mean age of 72.3 ± 11.8 years (ranging between 69.1 ± 11.9 and 76.6 ± 10.0 between the clinics), 63.9% were men (ranging between 54.3 and 78.1%), 27.3% were in New York Heart Association (NYHA) class III/IV (ranging between 8.8 and 62.1%) and the average estimated glomerular filtration rate (eGFR) was 59.6 ± 24.6 ml/min (ranging between 45.7 ± 23.5 and 97.1 ± 16.5). The prescription rates ranged from 58.9–97.4% for beta blockers (p p p p p p p p Conclusions The prescription rates and prescribed dosages of guideline-recommended medication differed significantly between HF outpatient clinics in the Netherlands, not fully explained by differences in patient profiles.

The heart failure syndrome has first been described as an emerging epidemic about 25 years ago. Today, because of a growing and ageing population, the total number of heart failure patients still continues to rise. However, the case mix of heart failure seems to be evolving. Incidence has stabilized and may even be decreasing in some populations, but alarming opposite trends have been observed in the relatively young, possibly related to an increase in obesity. In addition, a clear transition towards heart failure with a preserved ejection fraction has occurred. Although this transition is partially artificial, due to improved recognition of heart failure as a disorder affecting the entire left ventricular ejection fraction spectrum, links can be made with the growing burden of obesity-related diseases and with the ageing of the population. Similarly, evidence suggests that the number of patients with heart failure may be on the rise in low-income countries struggling under the double burden of communicable diseases and conditions associated with a Western-type lifestyle. These findings, together with the observation that the mortality rate of heart failure is declining less rapidly than previously, indicate we have not reached the end of the epidemic yet. In this review, the evolving epidemiology of heart failure is put into perspective, to discern major trends and project future directions.

Aims Despite previous surveys regarding device implantation rates in heart failure (HF), insight into the real-world management with devices is scarce. Therefore, we investigated device implantation rates in HF with reduced left ventricular ejection fraction (LVEF) in 34 Dutch centres.Methods and results A cross-sectional outpatient registry was conducted in 6666 patients with LVEF < 50% and with information about device implantation available [74 (66-81) years of age; 64% male]. Patients were classified into conventional pacemakers (PM, n = 562), implantable cardioverter defibrillators (ICD, n = 1165), and cardiac resynchronization therapy with defibrillator function (CRT-D, n = 885) or pacemaker function only (CRT-P, n = 248), or no device (n = 3806). Centres were divided into ICD-implanting and CRT-implanting and referral centres. Overall, 17.5% had an ICD, 13.3% CRT-D, 3.7% CRT-P, and 8.4% PM. Of those with LVEF

Whereas multiple national, international, and trial registries for heart failure have been created, international standards for clinical assessment and outcome measurement do not currently exist. The working group’s objective was to facilitate international comparison in heart failure care, using standardized parameters and meaningful patient-centered outcomes for research and quality of care assessments. The International Consortium for Health Outcomes Measurement recruited an international working group of clinical heart failure experts, researchers, and patient representatives to define a standard set of outcomes and risk-adjustment variables. This was designed to document, compare, and ultimately improve patient care outcomes in the heart failure population, with a focus on global feasibility and relevance. The working group employed a Delphi process, patient focus groups, online patient surveys, and multiple systematic publications searches. The process occurred over 10 months, employing 7 international teleconferences. A 17-item set has been established, addressing selected functional, psychosocial, burden of care, and survival outcome domains. These measures were designed to include all patients with heart failure, whether entered at first presentation or subsequent decompensation, excluding cardiogenic shock. Sources include clinician report, administrative data, and validated patient-reported outcome measurement tools: the Kansas City Cardiomyopathy Questionnaire; the Patient Health Questionnaire-2; and the Patient-Reported Outcomes Measurement Information System. Recommended data included those to support risk adjustment and benchmarking across providers and regions. The International Consortium for Health Outcomes Measurement developed a dataset designed to capture, compare, and improve care for heart failure, with feasibility and relevance for patients and clinicians worldwide., Central Illustration, Highlights • ICHOM seeks to help standardize and align outcome measurement efforts globally. • Standardization and alignment of this sort does not exist for heart failure. • The heart failure working group developed a standard set of 17 outcomes to be measured. • ICHOM hopes this standardization effort will increase quality and value in heart failure care.

Background Heart failure (HF) and chronic obstructive pulmonary disease (COPD) often remain undiagnosed in older individuals, although both disorders inhibit functionality and impair health. The aim of the study was to assess the effectiveness of a case-finding strategy of these disorders. Methods This is a clustered randomized trial; 18 general practices from the vicinity of Utrecht, the Netherlands, were randomly allocated to a case-finding strategy or usual care. Multimorbid community subjects (≥65 years) with dyspnea or reduced exercise tolerance were eligible for inclusion. The case-finding strategy consisted of history taking, physical examination, blood tests, electrocardiography, spirometry, and echocardiography. Subsequent treatment decisions were at the discretion of the general practitioner. Questionnaires regarding health status and functionality were filled out at baseline and after 6 months of follow-up. Information regarding changes in medication and health care use during the 6 months follow-up was extracted. Results A total of 829 participants were randomized: 389 in the case-finding strategy group and 440 in the usual care group. More patients in the case-finding group received a new diagnosis of HF or COPD than the usual care group (cumulative incidence 34% vs 2% and 17% vs. 2%, respectively). Scores for health status, functionality, and health care use were similar between the 2 strategies after 6 months of follow-up. Conclusions A case-finding strategy applied in primary care to multimorbid older people with dyspnea or reduced exercise tolerance resulted in a number of new diagnoses of HF and COPD but did not result in short-term improvement of health status compared to usual care.

Background Diabetes has strongly been linked to atrial fibrillation, ischaemic heart disease and heart failure. The epidemiology of these cardiovascular diseases is changing, however, due to changes in prevalence of obesity-related conditions and preventive measures. Recent population studies on incidence of atrial fibrillation, ischaemic heart disease and heart failure in patients with diabetes are needed. Methods A dynamic longitudinal cohort study was performed using primary care databases of the Julius General Practitioners’ Network. Diabetes status was determined at baseline (1 January 2014 or upon entering the cohort) and participants were followed-up for atrial fibrillation, ischaemic heart disease and heart failure until 1 February 2019. Age and sex-specific incidence and incidence rate ratios were calculated. Results Mean follow-up was 4.2 years, 12,168 patients were included in the diabetes group, and 130,143 individuals in the background group. Incidence rate ratios, adjusted for age and sex, were 1.17 (95% confidence interval 1.06–1.30) for atrial fibrillation, 1.66 (1.55–1.83) for ischaemic heart disease, and 2.36 (2.10–2.64) for heart failure. Overall, incidence rate ratios were highest in the younger age categories, converging thereafter. Conclusion There is a clear association between diabetes and incidence of the major chronic progressive heart diseases, notably with heart failure with a more than twice increased risk.

These are the clinical practice guidelines from the European Society of Cardiology for the diagnosis and treatment of acute and chronic heart failure, from 2021.

ObjectivesTo identify clinical variables that are associated with the diagnosis acute coronary syndrome (ACS) in women and men with chest discomfort who contact out-of-hours primary care (OHS-PC) by telephone, and to explore whether there are indications whether these variables differ among women and men.DesignCross-sectional study in which we compared patient and call characteristics of triage call recordings between women with and without ACS, and men with and without ACS.SettingNine OHS-PC in the Netherlands.Participants993 women and 802 men who called OHS-PC for acute chest discomfort (pain, pressure, tightness or discomfort) between 2014 and 2016.Primary outcome measureDiagnosis of ACS retrieved from the patient’s medical record in general practice, including hospital specialists’ discharge letters.ResultsAmong 1795 patients (mean age 58.8 (SD 19.5) years, 55.3% women), 15.0% of men and 8.6% of women had an ACS. In both sexes, retrosternal chest pain was associated with ACS (women with ACS vs without 62.3% vs 40.3%, p=0.002; men with ACS vs without 52.5% vs 39.7%, p=0.032; gender interaction, p=0.323), as was pressing/heavy/tightening pain (women 78.6% vs 61.5%, p=0.011; men 82.1% vs 57.4%, p=Ambulances were dispatched equally in women (72.9%) and men with ACS (70.0%).ConclusionOur results indicate there were more similarities than differences in symptoms associated with the diagnosis ACS for women and men. Important exceptions were pain severity and radiation of pain in women. Whether these differences have an impact on predicting ACS needs to be further investigated with multivariable analyses.Trial registration numberNTR7331.

Objectives The aim of this study is to determine whether combinations of specific Life’s Simple 7 (LS7) components are associated with reduced risk for heart failure (HF). Background The American Heart Association recommends the concept of LS7: healthy behaviors that have been shown to reduce cardiovascular disease. Methods A total of 37,803 participants from the EPIC-NL (European Prospective Investigation Into Cancer and Nutrition–Netherlands) cohort were included (mean age: 49.4 ± 11.9 years, 74.7% women). The LS7 score ranged from 0 to 14 and was calculated by assigning 0, 1, or 2 points for smoking, physical activity, body mass index, diet, blood pressure, total cholesterol, and blood glucose. An overall ideal score (11 to 14 points) was present in 23.2% of participants, an intermediate score (9 or 10 points) in 35.3%, and an inadequate score (0 to 8 points) in 41.5%. Results Over a median follow-up period of 15.2 years (interquartile range: 14.1 to 16.5 years), 690 participants (1.8%) developed HF. In Cox proportional hazards models, ideal and intermediate LS7 scores were associated with reduced risk for HF compared with the inadequate category (hazard ratio: 0.45 [95% confidence interval (CI): 0.34 to 0.60] and hazard ratio: 0.53 [95% CI: 0.44 to 0.64], respectively). Our analyses show that combinations with specific LS7 components, notably glucose, body mass index, smoking, and blood pressure, are associated with a lower incidence of HF. Conclusions A healthy lifestyle, as reflected in an ideal LS7 score, was associated with a 55% lower risk for HF compared with an inadequate LS7 score. Preventive strategies that target combinations of specific LS7 components could have a significant impact on decreasing incident HF in the population at large.

Objectives This study investigated adherence to drug therapy guidelines in heart failure (HF) with reduced left-ventricular ejection fraction (LVEF) of Background Despite previous surveys of HF, important uncertainties remain regarding guideline adherence in a representative real-world population. Methods A cross-sectional registry in 34 Dutch HF outpatient clinics that included 10,910 patients with the diagnosis of HF was examined. Of that number, 8,360 patients had LVEF Results In the HFrEF group, 81% of the patients were treated with loop diuretics, 84% with renin-angiotensin-system (RAS) inhibitors, 86% with β-blockers, 56% with mineralocorticoid-receptor antagonists (MRA), and 5% with If-channel inhibition. Differences in medication use were minor among the 3 groups but were significant among centers. Inability to tolerate the medications was recorded in 9.4% patients taking RAS inhibitors, 3.3% taking β-blockers, and 5.4% taking MRAs. Median loop diuretic dose was 40 mg of furosemide equivalent, RAS inhibitor dose 50% of target, β-blocker dose 25% of target, and MRA dose 12.5 mg of spironolactone equivalent. Elderly patients were treated predominantly with diuretics and less often with RAS inhibitors, β-blockers, and MRAs. Conclusions This large contemporary HF registry showed a relatively high use of evidence-based treatment, particularly in younger patients. However, the average dose of evidence-based medication was still lower than recommended by guidelines. Furthermore, the more recently introduced If-channel inhibition has hardly been adopted. There is ample room for improvement of HFrEF therapy, even more than 25 years after convincing evidence that HFrEF treatment leads to better outcome.

ObjectiveWe examined temporal heart failure (HF) prescription patterns in a large representative sample of real-world patients in the UK, using electronic health records (EHR).MethodsFrom primary and secondary care EHR, we identified 85 732 patients with a HF diagnosis between 2002 and 2015. Almost 50% of patients with HF were women and the median age was 79.1 (IQR 70.2–85.7) years, with age at diagnosis increasing over time.ResultsWe found several trends in pharmacological HF management, including increased beta blocker prescriptions over time (29% in 2002–2005 and 54% in 2013–2015), which was not observed for mineralocorticoid receptor-antagonists (MR-antagonists) (18% in 2002–2005 and 18% in 2013–2015); higher prescription rates of loop diuretics in women and elderly patients together with lower prescription rates of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, beta blockers or MR-antagonists in these patients; little change in medication prescription rates occurred after 6 months of HF diagnosis and, finally, patients hospitalised for HF who had no recorded follow-up in primary care had considerably lower prescription rates compared with patients with a HF diagnosis in primary care with or without HF hospitalisation.ConclusionIn the general population, the use of MR-antagonists for HF remained low and did not change throughout 13 years of follow-up. For most patients, few changes were seen in pharmacological management of HF in the 6 months following diagnosis.

Janssen, A (reprint author), Jessa Hosp, Heartctr Hasselt, Clin Res Dept Cardiol, Hasselt, Belgium. arne.janssen@jessazh.be

Aims: Natriuretic peptides are helpful in detecting chronic heart failure (HF) in primary care, however there are a lack of data evaluating thresholds recommended by clinical guidelines. This study assesses the diagnostic accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) using combined individual patient data from two studies in the UK and The Netherlands. Methods and results: Random effects methods were used to estimate the performance characteristics of NT-proBNP thresholds recommended by the European Society of Cardiology (ESC) and the UK National Institute for Health and Care Excellence (NICE) guidelines. New onset HF was diagnosed in 313 of 1073 (29.2%) participants. Age, sex and atrial fibrillation-adjusted NT-proBNP was a better predictor of HF with reduced ejection fraction (HFrEF) than preserved ejection fraction (HFpEF), with area under receiver operating characteristic curve of 0.82 95% CI (0.78 to 0.86) vs. 0.71 (0.66 to 0.75). In persons aged 70 years and over, the ESC threshold at 125ng/L for detection of all-cause HF had summary negative predictive value (NPV) of 84.9% (81.6 to 88.2), positive predictive value (PPV) 68.1% (63.1 to 73.3), sensitivity 74.9% (69.5 to 80.3) and specificity 80.1% (76.9 to 83.4); the NICE threshold at 400ng/L had summary NPV of 74.7% (72.1 to 77.2), PPV 81.8% (73.3 to 89.5), sensitivity 43.5% (37.2 to 49.8) and specificity 94.5% (92.3 to 96.7). Conclusion: NT-proBNP is better at detecting HFrEF than HFpEF in a primary care setting. In persons aged 70 and over, the ESC threshold of 125ng/L is more accurate at detecting and excluding HF than the higher level suggested in NICE guidelines. More prospective data are required to establish the optimal NP threshold for detecting chronic HF in general practice.