European Society Research Articles

Nitisinone attenuates progression of aortic stenosis in patients with alkaptonuria: an analysis of the SONIA 2 study

Abstract Background/introduction Alkaptonuria (AKU) is a rare metabolic disorder caused by a defective enzyme, resulting in deposition of unmetabolised homogentisic acid in various connective tissues throughout the body (also termed "ochronosis"). Ochronosis of the aortic valve leading to progressive aortic stenosis is a rare but serious complication. Nitisinone decreases urinary and serum homogentisic acid levels and has been shown to improve morbidity and slow disease progression in AKU but the effects of this treatment on the progression of aortic stenosis have not yet been described. This review extrapolated from the data set of the SONIA 2 study, a 4-year multi-centre, randomised controlled trial investigating the effect of nitisinone on a composite clinical measure of AKU disease activity, but looked more specifically at measures of aortic stenosis disease progression. Methods Data was obtained from echocardiograms performed on 138 patients at baseline, 12, 24, 36 and 48 months of follow-up. In measuring the degree of aortic stenosis, the peak trans-aortic velocity (Vmax) was examined. A linear mixed effects regression model was used to assess the association between treatment and Vmax and to ascertain the difference in this measure at baseline and 48 months between the treatment and control groups. The mixed effects model incorporated both fixed effects for population parameters (age, sex, baseline Vmax, follow-up time) and treatment; and random effects, to account for intra-subject correlation of longitudinal observations of Vmax, inter-subject variability of baseline measurements of Vmax, and centre. Results At baseline, 19/138 patients (13.8%) had aortic stenosis, as classified by echocardiogram findings in accordance with the European Society of Cardiology (ESC) guidance on valvular heart disease, with 9/19 having mild aortic stenosis, 6/19 having moderate aortic stenosis and 4/19 having severe aortic stenosis. 25/138 had aortic sclerosis (see figure 1). The prevalence of aortic valve disease increased with age. From the 4-year follow-up period, 613 longitudinal observations of 138 subjects across all sites were obtained. At baseline, the difference in Vmax between the control and treatment groups was 0.063 m/s [95% CI: -0.054 m/s to 0.18 m/s] and did not reach statistical significance (p=0.23). At the end of the 4-year treatment period, the difference in Vmax was 0.10 m/s [95% CI: -0.0007 m/s to 0.20 m/s] and was statistically significant (p=0.05) (see figure 2). Conclusion Nitisinone slowed progression of aortic stenosis in patients with AKU. This may be grounds for timely initiation of nitisinone in those deemed to be at high risk, as identified by echocardiography. Of note, this is the first time that any medical therapy has ever been shown to affect the natural history of aortic stenosis.

Sub-Saharan Africa's contribution to clinical trials in international acute coronary syndromes and heart failure guidelines

Abstract Introduction There is a growing burden of acute coronary syndrome (ACS) and heart failure (HF) in sub-Saharan Africa (SSA), yet outcomes remain poor compared to high-income countries (HICs). Global clinical guidelines are pivotal to the delivery of evidence based cardiovascular care, however their applicability to populations in SSA remains unclear. Purpose To evaluate the extent to which populations from SSA contribute to pharmacotherapeutic randomised clinical trials informing international ACS and HF clinical guidelines. Methods We extracted details on pharmacotherapeutic randomised control trials (RCTs) contributing to Class I or II guideline recommendations from the 2023 European Society of Cardiology (ESC) guidelines for ACS and the 2021 ESC guidelines for HF. Data on RCTs contributing to these guidelines were extracted from the ClinicalTrials.gov or published articles. We analysed the proportion of RCTs which had a contribution from countries in each World Bank income group. Then we specifically assessed the contribution of SSA countries to clinical trials and analysed temporal trends. Results Of 119 RCTs from the ESC HF guidelines and the 343 pharmacotherapy RCTs from the ESC ASC guidelines 75.9% were exclusively conducted in high-income countries, 22.2% of the trials included at least one site from a middle-income country and none included sites from a low-income country (figure 1). The global distribution of HF (figure 2a) and ACS (figure 2b) pharmacotherapy guidelines is demonstrated in figure 2. The only country represented from SSA was South Africa which is an upper middle-income country. A site from South Africa was included in 17 (14.2%) HF RCTs and 28 (8.2%) ACS RCTs. There has been a significant increase in the proportion HF RCTs conducted in SSA, increasing from 2.6% between 1990 and 1999 to 50% since 2020 (OR 28.8, 95% CI 2.6 – 983.4, p-value for trend< 0.0001). For ACS RCTs, the proportion of trials conducted in SSA increased from 1.8% pre 1990 to 23.4% during 2000-2009 (OR 15.9, 95% CI 4.2 - 112.9, p value for trend = 0.003) then declined to 11.3% from 2010-2019. Conclusions There is a marked under-representation of SSA countries in ACS and HF pharmacotherapy RCTs, despite the region's escalating cardiovascular disease burden. South Africa is the sole contributor from the region, with all other SSA countries absent. This finding could potentially affect the applicability and generalisability of global guidelines to populations in SSA with distinct clinical presentations and healthcare challenges.Figure 1 Figure 2

Impact of various iron deficiency definitions on mortality risk in chronic heart failure across the spectrum of left ventricular ejection fraction spectrum

Abstract Introduction Iron deficiency (ID) is prevalent in chronic heart failure (HF) but lacks a consensus definition. Purpose This study evaluates the prevalence of ID and its association with all-cause mortality and first hospitalization for HF, using current European Society of Cardiology (ESC) guidelines, transferrin saturation (TSAT) <20%, ferritin <100 ng/ml, and serum iron ≤13 μmol/L as ID criteria. Methods and Results Of 8587 new-onset HF patients registered in the Danish Heart Failure Registry from April 2003 to July 2021, we found varying ID prevalence (35.4% to 67%) based on different definitions. In heart failure with reduced ejection fraction (HFrEF) patients, irrespective of anemia, ID defined by TSAT <20% and serum iron ≤13 μmol/L was associated with all-cause mortality (non-anemic, HR: 1.42, 95% CI:1.22-1.64 and HR: 1.25, 95% CI: 1.1-1.43; anemic, HR: 1.22, 95% CI: 1.1-1.35 and HR: 1.26, 95% CI: 1.12-1.41, respectively) and first HF hospitalization (non-anemic, HR:1.41, 95% CI:1.23-1.62, HR: 1.33, 95% CI: 1.18-1.51; anemic, HR:1.27, 95% CI:1.12-1.45 and HR: 1.26, 95% CI:1.09-1.45, respectively). ID per ESC guidelines was only associated to mortality in non-anemic HFrEF (HR: 1.24, 95% CI:1.09-1.42) and first HF hospitalization in HFrEF, irrespective of anemia (non- anemic, HR:1.24, 95% CI:1.09-1.42; anemic, HR:1.35, 95% CI:1.2-1.52). No association was observed between the various definitions and outcomes in patients with heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction. Conclusion ID, when defined by TSAT <20% or serum iron ≤13 μmol/L, is associated with increased mortality and first hospitalization in HFrEF patients, regardless of anemia. Conversely, ID as per ESC guidelines is associated with mortality in non-anemic HFrEF patients and first hospitalization in HFrEF, irrespective of anemia status.Figure 1:Forest plot mortalityFigure 2:Forest plot hospitalization

Effects of beta blockers on outcome in patients with PAH with and without comorbid conditions: a Multicenter Prospective Cohort Study (BNP-PL)

Abstract Background The current guidelines do not recommend the use of beta-blockers (BB) in patients with pulmonary arterial hypertension (PAH) unless necessitated by comorbidities. However, the evidence regarding the role of BB in PAH is contradictory. This study investigates the effects of BB on clinical outcomes in patients newly diagnosed with PAH, stratified by the presence of cardiovascular comorbidities that justify their use. Methods We analyzed data from 806 patients newly diagnosed with PAH, who were prospectively enrolled from March 1, 2018, to August 31, 2023, in the multicentre registry, Database of Pulmonary Hypertension in the Polish population (BNP-PL). The primary endpoints were all-cause mortality and a composite of hospitalization due to right heart exacerbation, syncope, or death. The follow-up period for these patients extended until August 31, 2023. Comorbidities in the study group that indicated the need for BB therapy included hypertension, significant arrhythmia, and coronary artery disease. In the Cox regression analysis, the association between BB use and the predefined endpoints was adjusted for age, baseline European Society of Cardiology risk score, and upfront therapy. Results Among the 806 patients, BBs were administered to 469 (58.2%) at the time of PAH diagnosis. In the entire cohort, BB therapy was linked to increased all-cause mortality (29.6% vs 21.4%; p=0.005, Fig 1.A) and a higher incidence of the composite endpoint (34.1% vs 22.6%; p<0.0001, Fig 1.B). The Number Needed to Harm (NNH) for BB treatment, regarding mortality and the composite endpoint, were 12.1 and 8.7, respectively. In patients without comorbidities, BB use significantly raised the risk of both all-cause mortality (Hazard Ratio [HR] 1.81, 95% Confidence Interval [CI]: 1.01-3.15) and the composite endpoint (HR 1.85, 95% CI 1.09-3.14), after adjustments for age, baseline three-strata PAH mortality risk, and upfront therapy. However, in patients with at least one comorbidity, BB therapy showed a neutral effect on both outcomes. Across the whole group, the use of nonselective BB was associated with a higher risk of the composite endpoint (HR 1.78, 95% CI 1.13-2.82, p=0.01) compared to selective β1 agents, although this did not extend to all-cause mortality (HR 1.34, 95% CI 0.79-2.25, p=0.28). Conclusion BBs, particularly nonselective, pose significant risks in patients with PAH who lack comorbidities that justify their use.

What does routinely-collected electronic health record data tell us about the use of heart failure medication among older people in Wales? Making progress but could do better

Abstract Background European Society of Cardiology 2021 guidelines recommend 4 pillars of treatment to reduce mortality for those with heart failure (HF) and reduced ejection fraction (HFrEF): pillar 1) angiotensin converting enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), pillar 2) beta-blocker (BB), pillar 3) mineralocorticoid receptor antagonist (MRA), pillar 4) sodium-glucose co-transporter 2 inhibitor (SGLT2i). When there is heart failure with preserved ejection fraction (HFpEF), guidelines recommend diuretics to alleviate congestion and treatment of risk factors such as hypertension and diabetes. Prior to 2021, United Kingdom guidelines did not include SGLT2i. Purpose To examine how HF treatment is recorded in routinely-collected electronic health record (EHR) data for older people in Wales, and to explore how that has changed since 2015. Methods We conducted a retrospective, population-level, observational study using linked anonymised EHR data in Wales (2015-22). 737,230 individuals were aged 65y+ in the study period (21.5% of population in 2022). Of these, 65,010 had a code for heart failure in their primary or secondary care records. We excluded 13,990 individuals with fewer than 12 months data pre- or post-diagnosis. We looked forward, from HF diagnosis, for codes associated with specific medications. Results The final cohort comprised 51,020 individuals aged 65y and over with a diagnosis of heart failure between 2015-2022. Incidence and prevalence of heart failure increased across the study period (1.4-1.5% and 8.5-9.1% respectively). Preceding cardiovascular diagnoses included hypertension (69.5%), atrial fibrillation (36.7%), myocardial infarction (30.5%), coronary artery disease (25.7%), and valve disease (17.7%). Diabetes (41.7%), chronic kidney disease (30.9%) and cancer (26.4%) were the most common comorbidities. The subtype of HF (HFrEF or HFpEF) was only evident in 5,850. Treatments recorded most often were loop diuretics, ACE-I, and BB (Table 1). SGLT2i codes increased in 2020/2021(Figure 1). At 10-12 months post diagnosis, the proportion with simultaneous pillar combinations was; 27.4% 1 + 2, 12.5% 1, 2 + 3, and only 2% 1, 2, 3 + 4. Conclusions In Wales, there is a need to improve the coding of HF subtype in primary care records. We suggest interpreting data with the assumption that approximately half of the cohort are likely to have HFrEF. While the cohort proportion on ACE-I or beta-blockers may be appropriate, the proportion with more than 1 simultaneous pillar of treatment recorded appears low. The use of SGLT2i in codes is increasing. These results are important in evaluating health service delivery and in establishing baseline data from which to monitor improvements.

Limited visibility and uptake of the clopidogrel pharmacogenomic guidelines among cardiologists

Abstract Background Clopidogrel is an antiplatelet agent widely utilised in the treatment of acute coronary syndromes and following coronary interventions. Clopidogrel is a prodrug activated in the liver, mostly by cytochrome P450 2C19 that is encoded by a gene (CYP2C19). Variability in CYPC2C19 affects enzymatic activity and leads to variability in the activation and efficacy of clopidogrel. In 2011, the Clinical Pharmacogenetics Implementation Consortium (CPIC) produced the first set of detailed guidelines on the use of genetic testing to guide the clinical utilization of clopidogrel. Updates on these guidelines were published in 2013 and 2022. However, pre-prescription genetic testing is seldom performed. Purpose To establish whether these pharmacogenomics guidelines have visibility within the cardiovascular (CVD)community and have been incorporated into CVD guidelines. Methods (i) We examine the impact of the CPIC Clopidogrel guidelines released in 2013 and 2022 by looking at the citation patterns in CVD journals indexed in PubMed. (ii) We reviewed the guidelines released by the European Society of Cardiology and the American College of Cardiology on the management of coronary interventions and coronary artery disease over the last 15 years to establish whether CPIC guidelines are making any impact on practice. Results The CPIC 2022 guidelines were cited by 88 articles (49 journals) of which 13 citations (14.7%) appear in CVD journals. None of these citations are in the five major journals in which CVD guideline statements are most frequently published (Nature Review Cardiology, European Heart Journal, Circulation, Journal of the American College of Cardiology, and Journal of the American Medical Association - Cardiology). The 2013 guideline received 366 citations (183 PubMed journals). Of these, 47 were in cardiology journals (12.8%), but only 4 citations were in one of the same five major cardiology journals (2 in Nature Review Cardiology, 1 in Circulation and 1 in JAMA Cardiology). Of the 14 guidelines published by the ESC and ACC over the last 14 years, none cited the CPIC clopidogrel guidelines. Only 6 out of the 14 guidelines mentioned that the efficacy of clopidogrel was modulated by genetic factors but none of them included details or practical implications. Conclusion(s) Whilst sufficient time has not yet elapsed for the 2022 CPIC guidelines to have an impact on the specialist literature, the 2013 guidelines have had limited visibility within the CVD community. Undoubtedly, given the potential contribution of PGx, discussions on its uptakes are ongoing thus far, without resolution. Some considerations of clopidogrel genetics are diffusing into the specialty; however, from the citation evidence, it appears that CPIC clopidogrel guidelines of any vintage have had limited impact in terms of adoption and/or endorsement by cardiologists.

Blood pressure control and cardiovascular risk assessment in patients with hypertension: a pooled analysis of 6 countries in Eastern and Southern Europe (SNAPSHOT study)

Abstract Background Recent guidelines of the European Society of Cardiology (ESC) introduced stricter recommendations regarding blood pressure (BP) control, based on recommended levels following an assessment of cardiovascular (CV) risk. However, data are lacking on perception and actual BP control, and CV risk assessment. Purpose To assess BP control and CV risk assessment in patients with hypertension. Methods This is a cross-sectional multicentre study (SNAPSHOT) including pooled data from 6 countries in Europe. 9466 patients with hypertension were included from 513 participating investigators (69.6% general practitioners [GPs], 17.4% cardiologists, 6.2% endocrinologists). BP control and CV risk were assessed by investigators and compared to the re-assessment based on current ESC guidelines (SCORE1 and SCORE2&2-OP). Results 9443 patients with complete data (65.6±10.7 years, 57.0% female) were analysed from Bulgaria (35.6%), Romania (26.8%), Croatia (13.8%), Serbia (12.5%), Georgia (6.4%), and Spain (4.9%). Most patients had additional risk factors, such as overweight/obesity (81.6%), dyslipidaemia (80.8%), type 2 diabetes (32.8%) or current/former smoking (29.5%). Two or more risk factors (male gender, age ≥65 years, obesity, smoking) were more frequent in patients with very high calculated CV risk (60.9% by SCORE1, 57.7% by SCORE2&2-OP). Systolic and diastolic BPs were 139.3±17.3 mmHg and 82.3±10.9 mmHg, respectively. Almost all patients (98.5%) had their hypertension treated, 54.5% taking a single-pill combination (SPC). The most used drug classes were diuretics (59.6%), angiotensin-converting enzyme inhibitors (59.4%), and beta-blockers (57.0%). Combination therapy of 2 or 3 drug classes (SPC or not) was used in 33.2% and 34.4% of patients, respectively. According to investigators, BP was considered controlled in 75.0% of patients, whereas 48.0% of patients had BP <140/90 mmHg, and only 24.4% of patients were controlled at BP target according to guidelines (Figure 1). CV risk was estimated by investigators as low, moderate, high or very high for 10.1%, 34.9%, 32.0% and 23.0% of patients, respectively, whereas calculated CV risk was very high in most patients (59.1% by SCORE1, 86.8% by SCORE2&2-OP). CV risk estimated by investigators varied by country and by speciality, being high (29.4%, 35.0% and 32.0%) and very high (32.4%, 49.8% and 18.6%) for cardiologists, endocrinologists and GPs, respectively. Compared to calculated CV risk, CV risk estimated by investigators was frequently underestimated (54.4% by SCORE1, 67.6% by SCORE2&2-OP), varying between 30.8% in Spain and 68.2% in Bulgaria for SCORE1, and between 42.1% in Spain and 84.8% in Serbia for SCORE2&2-OP (Figure 2). Conclusion Physicians across 6 European countries tended to overestimate control of BP and underestimate CV risk in patients with hypertension. Our findings highlight the need for better assessment and management of patients according to the latest ESC guidelines.

Association between wearable activity trackers usage and levels of physical activity among Athens Medical Society members

Abstract Introduction Wearable Activity Trackers (WAT) provide real-time feedback on activity levels and play a pivotal role in fostering an active lifestyle. Moreover, WAT can encourage doctors’ awareness to be more conscious of their daily physical activity whose exercise habits range between different medical specialties. Purpose The aim of this study is to evaluate the influence of WAT usage on physicians’ exercise habits according to the recommendations of ESC Guidelines. Methods This cross-sectional study comprised 742 physicians of the Athens Medical Society (AMS), Greece. The study instrument was a self-administered questionnaire mailed in October 2023 to evaluate physicians’ usage of WAT, baseline characteristics of population, specialty, and physical exercise habits. European Society of Cardiology (ESC) Guidelines recommend at least 150 min/week of moderate-intensity exercise in all healthy adults. Subjects were divided in two groups according to their usage of WAT or not in their everyday life: 1. Daily usage of WAT (Group A); 2. No regular or even on usage of WAT (Group B). Results A considerably high proportion of the total population use WAT daily (38%). Between Group A and Group B there was no difference in age (49±12 years vs. 51±13 years, p=0.07), male sex prevalence (55% vs. 49%, p=0.08) and BMI (25.7± 4.6 kg/m2 vs. 25.2± 4.1 kg/m2, p=0.11). Interestingly, there was statistically significant difference in mean exercise endurance training time between Group A and Group B (301±304 min. vs. 209±268 min., p<0.001) (Figure 1) and in the proportion of the doctors who follow the ESC Recommendations (63.5% vs. 47.2%, p<0.001). Furthermore, most of the physicians who use WAT have awareness for ESC Guidelines (59% vs. 47%, p<0.001), and most of them apply diet to lose weight (36% vs. 29%, p=0.04). Finally, WAT were mostly used by 4 main specialties: Cardiology (47%), Endocrinology (44%), Surgery (35%) and Internal Medicine (25%), with cardiologists reporting the higher use (p=0.045). Conclusion This study underscores the widespread adoption of WAT among physicians, highlighting their potential to positively influence exercise habits and adherence to ESC Guidelines. Physicians using WAT demonstrated increased exercise endurance training time, greater awareness of ESC Guidelines, and a higher propensity to implement weight loss diets compared to non-users. Additionally, variations in WAT usage and awareness of ESC Guidelines across medical specialties emphasize the need for targeted interventions to promote physical activity and enhance overall health among healthcare professionals.

Incidence of silent brain injury in pacemaker implanted patients with atrial high-speed episodes (AHRE)

Abstract Purpose Atrial high rate episodes (AHRE) are tachyarrhythmia attacks that can be detected by implantable cardiac devices. In the European Society of Cardiology (ESC) 2020 AF guideline, AHRE is defined as ≥ 175 bpm for the device-programmed rate criterion and ≥ 5 minutes for the duration criterion. AHRE has been shown to be one of the predisposing factors of AF and stroke. However, the relationship between AHRE and SBI has not been clarified yet. Neuron spesific enolase (NSE) is a valid biomarker for quantifying the volume of neuronal damage. In this study, we aimed to evaluate the incidence of silent brain injury (SBI), defined as elevated NSE levels in AHRE detected patients. Method Between January 2021 and June 2022, 80 patients who underwent routine pacemaker control, met the inclusion and exclusion criteria, and had AHRE detected in their permanent pacemaker records were included in a university faculty of medicine cardiology arrhythmia polyclinic. For the control group, patients who had a permanent pacemaker and did not have AHRE or any other arrhythmia were included. Of patients with AHRE detected in the last 6 months and those who had an AHRE attack within the last 72 hours were examined. Results Individuals included in the study were divided into subgroups according to AHRE duration. Group 1 (non-AHRE) 80 (50.0%), Group 2 (AHRE lasting <5 min) 24 (15.0%), Group 3 (≥5 min - <1h) 33 (20.6%), 19 (11.9%) patients in Group 4 (lasting ≥1 h - <24 h) and 4 (2.5%) patients in Group 5 (lasting ≥24 h). There was a statistically significant difference in NSE median values between groups (p=<0.001). In Mann Whitney U test with Bonferronni correction, the median values of all other groups were significantly different from each other (p=<0.001). In the correlational analysis, there was a statistically significant positive relationship between AHRE duration and NSE values (r=0.842; p=<0.001). Additionally, there was correlation between AHRE duration and age (r=0.235; p=0.036), CHA2DS2-VASc score (r=0.226, p=0.044) and LA diameter (r=0.300; p=0.007). NSE levels were positively correlated with AHRE duration (r=0.842; p=<0.001) and LA diameter (r=0.242; p=0.030). Conclusion AHRE duration was longer in patients with advanced age, increased CHA2DS2-VASc score, and increased LA diameter. This may play a role in explaining the underlying pathophysiological changes in AHRE before AF develops. Since NSE levels are related to LA diameter as well as AHRE duration, it can be thought that increasing LA diameter contributes to the development of thrombus.

A cross-country comparison of the organisation and reimbursement of intensive care in Europe

Abstract Background During the pandemic, intensive care capacity was a heavily discussed topic in Europe. Many European countries have increased their intensive care capacities to ensure treatment of all COVID-19 patients. A study, however, revealed that organisational characteristics, among other factors, were associated with in-hospital mortality. Our study thus aimed at reviewing international models for the organisation and reimbursement of intensive care. Methods Based on a scoping review, a number of European countries (Denmark, England, France, Germany, Italy, the Netherlands, Sweden) was selected for a questionnaire-based expert survey. Results In most countries, intensive care is defined by law, while the definition in two countries has a recommendatory character and/or is driven by reimbursement. In line with the European Society of Intensive Care Medicine’s recommendations, the majority of countries has organised intensive care around 2-3 different (heterogeneously defined) levels of care for which reimbursement sometimes differs according to the level. For most countries, the number of physical (i.e., number of operable beds) as well as human resources (i.e., nurses) in intensive care is unknown. Many countries have an intensive care register which, in the case of Germany, was only implemented as a response to the pandemic. However, comparability is limited due to differences in indicators used. Although promising telemedical approaches in intensive care do exist, their use is not yet formalized in most countries. Conclusions Most countries rely on a level-based organisation of intensive care, even though clear evidence on their effect is missing. Heterogeneity of definitions as well as quality monitoring makes a comparison difficult. Further research is needed to better understand best practices and thus increase resilience as well as pandemic preparedness. Telemedical interventions could elevate (access to) high-quality care, especially in times of crises. Key messages • Further research is needed to better understand best practices and thus increase resilience as well as pandemic preparedness. • Telemedicine could elevate (access to) high-quality intensive care, especially in times of crises.

Comparing combined testing of cMyBP-C and hs-cTnT with other algorithms for rapid rule-out of acute myocardial infarction in suspected acute coronary syndrome patients

Abstract Background We aimed to compare the diagnostic accuracy of a dual-marker strategy (DMS), incorporating cardiac myosin-binding protein C (cMyBP-C) and high-sensitivity cardiac troponin T (hs-cTnT) testing, against other rapid rule-out algorithms for acute myocardial infarction (AMI). Methods We enrolled 2059 patients presenting to the emergency department with suspected AMI and compared diagnostic measures using the DMS (cMyBP-C <10 ng/L and hs-cTnT≤14 ng/L), serial hs-cTnT sampling (hs-cTnT<14ng/L at different time points within 1-3h), modified European Society of Cardiology (ESC) 0/1h- or 0/3h-protocol (hs-cTnT<5ng/L or <12ng/L & ∆hs-cTnT<3ng/L at 1h or <7ng/L at 3h if hs-cTnT at 1h was not available), as well as the hs-cTnT limit-of-blank (LoB, <3ng/L) and -detection (LoD, <5ng/L) were compared. Negative predictive values (NPV) and sensitivities for AMI rule-out were assessed. Results True-negative rule-out rates using the DMS ranged from 38.1% to 51.6% across all patients, surpassing rates of 6.2%, 17.4%, 45%, and 50.8% achieved by LoB, LoD, serial hs-cTnT sampling, and ESC 0/1h or 0/3h algorithms, respectively. The DMS demonstrated an NPV of 99.7%, similar to serial hs-cTnT sampling and ESC 0/1h or 0/3h algorithms, and 100% for both LoB and LoD. Sensitivities were 98.9%, 98.9%, 100%, and 100%, respectively. Conclusions The DMS - incorporating cMyBP-C and hs-cTnT - effectively rules out AMI, showing non-inferiority to hs-cTnT-only-based rapid rule-out algorithms and offers a promising alternative, potentially enhancing clinical decision-making in emergency settings.

Unveiling the intrinsic role of malnutrition in patients with Crohn's disease undergoing major surgery using entropy balancing weighting analysis.

The negative role of malnutrition in patients with Crohn's disease is known; however, many coexisting disease-related factors could cause misinterpretation of the real culprit. This study aimed to describe the role of malnutrition using a novel methodology, entropy balancing. This was a retrospective analysis of consecutive patients undergoing elective major surgery for Crohn's disease, preoperatively screened following the European Society for Clinical Nutrition guidelines. Two-step entropy balancing was applied to the group of malnourished patients to obtain an equal cohort having a null or low risk of malnutrition. The first reweighting homogenised the cohorts for non-modifiable confounding factors. The second reweighting matched the two groups for modifiable nutritional factors, assuming successful treatment of malnutrition. The entropy balancing was evaluated using the d-value. Postoperative results are reported as mean difference or OR, with a 95 % CI. Of the 183 patients, 69 (37·7 %) were at moderate/high risk for malnutrition. The malnourished patients had lower BMI (d = 1·000), Hb (d = 0·715), serum albumin (d = 0·981), a higher lymphocyte count (d = 0·124), Charlson Comorbidity Index (d = 0·257), American Society of Anaesthesiologists (d = 0·327) and Harvey-Bradshaw scores (d = 0·696). Protective loop ileostomy was more frequently performed (d = 0·648) in the malnourished group. After the first reweighting, malnourished patients experienced a prolonged length of stay (mean difference = 1·9; 0·11, 3·71, days), higher overall complication rate (OR 4·42; 1·39, 13·97) and higher comprehensive complication index score (mean difference = 8·9; 2·2 15·7). After thesecond reweighting, the postoperative course of the two groups was comparable. Entropy balancing showed the independent role of preoperative malnutrition and the possible advantages obtainable from a pre-habilitation programme in Crohn's disease patients awaiting surgery.

Increased adoption of IL-1 pathway inhibition and the steroid-sparing paradigm shift: temporal trends in recurrent pericarditis treatment from the RESONANCE patient registry

Abstract Background Recurrent pericarditis (RP) is a chronic autoinflammatory disease mediated by IL-1 that requires long-term treatment. While the 2015 European Society of Cardiology Guidelines position IL-1 pathway inhibition only after corticosteroids, complications associated with long-term steroid use underscore the importance of steroid-sparing strategies. Rilonacept, an IL-1α and IL-1β cytokine trap, is the only FDA-approved treatment for RP (available since April 2021). RESONANCE, an ongoing 5-year non-interventional US registry of patients (pts) with RP, has collected real-world data from pts cared for by cardiologists with a focus on pericardial disease, with a goal of informing contemporary RP clinical management. Purpose Analysis of temporal trends in RP management from RESONANCE. Methods From a database cut-off (DCO) on 21 December 2023, patient demographics and disease characteristics are reported for 242 active RP pts (excluding RHAPSODY prior participants) at 20 US sites (median [Q1:Q3] 2.1 [1.5:2.6] years and 556 patient-years [PY] of observation). Complete medication class use data were available for 239 pts (total 546 PY). Proportional medication class use prior to initiating rilonacept was analyzed annually across the observation period. Results Mean (standard deviation) age at DCO was 50.2 (16.6) years; 58.1% were female. Median [Q1:Q3] disease duration at DCO from index pericarditis episode was 3.1 [2.2:5] years. Median [Q1:Q3] number of prior recurrences at enrollment was 3 [2:5]. Prior to rilonacept availability, NSAIDs/Colchicine/Aspirin represented the highest proportion of treatment (73% of PY); steroid use was 9% of PY, IL-1 pathway inhibition (anakinra) was 13% of PY, and conventional synthetic disease modifying antirheumatic drugs (csDMARDs) were 0.46% PY (no RP-specific treatment was 5% of PY) (Fig 1). In the years since rilonacept availability, proportional IL-1 pathway inhibition use has increased, from 13% of PY in 2020-21 to 26% of PY in 2023, driven by an increase in rilonacept use (6%, 13%, 16% of PY in 2021, 2022, and 2023, respectively). Over that same period, proportional NSAIDs/Colchicine/Aspirin use (57%-63% of PY) has been consistently 6-times more than proportional steroid use (10%-11% of PY). Among pts who initiated rilonacept (n=81), similar proportions transitioned from NSAIDs/Colchicine/Aspirin as from corticosteroids (Fig 2), a robust trend observed each year. Of those pts transitioning from corticosteroids, 1/3 had used corticosteroids for <30 days and 1/3 for >6 months. Conclusions Real-world data from the RESONANCE registry reveal a temporal shift in RP management in US centers with RP-focused cardiologists, with increased proportional IL-1 pathway inhibition use since rilonacept availability in 2021. Advancing beyond 2015 guideline recommendations, IL-1 pathway inhibition is often being used as steroid-sparing treatment, i.e., after colchicine instead of chronic corticosteroids.

Association of cardio-cerebrovascular death with isolated diastolic hypertension: a nationally representative survey of 85, 138 adults

Abstract Background Recently, the 2023 European Society of Hypertension (ESH) guideline for hypertension management include isolated diastolic hypertension (IDH) as a distinct classification. But, studies have yielded inconsistent associations between IDH and cardiovascular disease (CVD) events. Method We obtained data from 85138 participants without CVD and antihypertensive medication use who included in the China Chronic Disease and Risk Factors Surveillance (CCDRFS) project 2010. We extracted data on deaths from any cause, cardiovascular diseases, and stroke during follow up. The hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality, cardiovascular mortality, and stroke mortality associated with each blood pressure (BP) group were calculated using Cox proportional hazards models, with the normotension group as the reference. Our analyses were performed with sequential adjustment. In the first step, we carried out unadjusted analyses (model 1). In model 2, we added age, sex, ethnic, location, educational attainment, smoking status, alcohol drinking status, exercise, BMI, high-density-lipoprotein cholesterol, low-density-lipoprotein cholesterol, fasting glucose level as adjustment covariates. Results Overall, 57144 (67.1%) participants had normotension, 3826 (4.5%) participants had IDH, 11013 (12.9%) participants had isolated systolic hypertension (ISH), 13155 (15.5%) participants had systolic and diastolic hypertension (SDH). Compared with normotension, IDH was not statistically associated with a significantly increased risk of all-cause mortality (HR, 1.09 [95% CI, 0.86–1.39], model 2), or cardiovascular mortality (HR, 1.21 [95% CI, 0.74–1.96], model 2). On the contrary, IDH was significantly associated with a modestly higher risk of stroke mortality (HR, 1.84 [95% CI, 1.13–3.00], model 2). IDH was significantly associated with a modestly higher risk of stroke mortality in middle aged and older adults, but not young adults (age <45years). Similar results were obtained for men, while for women the associations between the prevalence of IDH and a higher incidence of stroke mortality were not significant. Stage 1 to stage 3 ISH or SDH were associated with a higher risk for all-cause mortality, cardiovascular mortality, and stroke mortality. Conclusion IDH was associated with an increased risk of stroke mortality among the large nationally representative Chinese population. Intervention for IDH may be effective in reducing the burden of stroke in China.

Derivation and external validation of new ESC 0/1-h algorithm cut-offs for high-sensitivity troponin T and I in the cancer population

Abstract Background The diagnostic performance of high-sensitivity cardiac troponin T/I (hs-cTnT/I) and the efficacy of the European Society of Cardiology (ESC) 0/1h-hs-cTnT/I-algorithms for the early diagnosis of non-ST-elevation myocardial infarction (NSTEMI) is reduced in cancer patients presenting to the emergency department (ED) with chest pain.[1] Purpose This study aimed to derive and externally validate new cut-offs for the ESC 0/1h-hs-cTnT/I-algorithms in chest pain patients with active or past cancer. Methods Patients presenting with acute chest discomfort to the ED were prospectively enrolled in an international multicenter diagnostic study. Final diagnoses were centrally adjudicated by 2 independent cardiologists applying the fourth universal definition of myocardial infarction using all available medical records, cardiac imaging, and serial hs-cTnT/I. Hs-cTn concentrations were measured at presentation and after 1 hour. New assay-specific cutoffs for the ESC 0/1h-hs-cTnT/I-algorithm were derived and externally validated in two independent cohorts. Results Among 541 and 516 eligible patients with 0h and 1h hs-cTnT and hs-cTnI values, respectively, application of the current ESC 0/1h-hs-cTnT/I algorithm triaged 317 (58.6%) and 306 (59.3%) patients to either rule-out or rule-in, leaving 224 (41.4%) and 210 (40.7%) patients in the observe-zone of the ESC 0/1h-hs-cTnT/I algorithm, respectively. The novel ESC 0/1h-hs-cTnT cut-offs ruled out NSTEMI with a cut-off <8 ng/L at presentation (if chest pain onset >3 hours) or <14 ng/L together with a 0/1-hour delta <3 ng/L, ruling-out 241 patients (44.5%) with a sensitivity and negative predictive value (NPV) of 99.2% and 99.6%, respectively. The novel ESC 0/1h-hs-cTnI cutoffs ruled out NSTEMI with a cut-off <7 ng/L at presentation (if chest pain onset >3 hours) or <10 ng/L together with a 0/1-hour delta <3 ng/L, ruling-out 281 patients (54.5%) with a sensitivity and NPV of 99.1% and 99.6, respectively. Findings were confirmed in both internal and external validation (Figure 1). A total of 167 (32.8%) patients died at 5-years, of whom 61 died of cardiovascular causes, and 30 (5.9%) patients had an MI at 5 years. 5-year all-cause mortality for the rule-out group was similar for both the current and the novel ESC 0/1-h algorithm, although the novel one identified patients in the observe zone group as having the highest mortality (Figure 2). Incidence of 5-year cardiovascular mortality or AMI provided by the current ESC 0/1h-algorithm was similar for the rule-in and observe zone groups for both hs-cTnT and hs-cTnI. Conclusions In chest pain patients with a history of cancer, new derived assay-specific cutoffs for the ESC 0/1h-hs-cTnT/I-algorithm achieved a higher proportion of patients triaged to either rule-out or rule-in without decreasing safety. The low mortality rate of the rule-out group identified by the new algorithm further reassures on the safety of the new derived cut-offs.Sensitivity analysis in the APACE cohort5-year all-cause mortality

Role of the cardiology pharmacist in improving quality of care for patients with acute myocardial infarction based on ESC-ACCA quality indicators

Abstract Background The European Society of Cardiology-Acute Cardiovascular Care Association (ESC-ACCA) suggested the use of quality indicators (QIs) to improve quality of care for patients with acute myocardial infarction (AMI). Among these QIs are prescribing of angiotensin-converting enzyme inhibitor (ACEi) and beta blocker (BB) if left ventricular ejection fraction (LVEF) was ≤40%, and prescribing high intensity statin and dual antiplatelet therapy (DAPT) before discharging patients from the coronary care unit (CCU). Purpose To identify the role of cardiology clinical pharmacy specialist in improving quality of care for patients with AMI based on ESC-ACCA QIs. Methods A cross-sectional study was conducted at a single CCU in Iraq between January 2021 and August 2023. Patients with AMI with or without LVEF ≤40% were included in the study. Patients' profiles were reviewed to collect data about suggestions by the cardiology clinical pharmacy specialist to initiate high intensity statin, addition of a second antiplatelet therapy to keep patients on DAPT, or addition of ACEi and/or BB if LVEF ≤40%. Results Total number of patients included was 326 of whom 119 (37%) patients had LVEF ≤40%. Drug interventions by the cardiology clinical pharmacy specialist with the initiation of statin and addition of a second antiplatelet therapy to optimize DAPT for patients with AMI and initiation of ACEi and/or BB for patients with AMI and LVEF ≤40% are shown in table 1 and figure 1. Drug interventions were based on the updated ESC guidelines and agreed by the interventional cardiologists. Conclusions Role of the cardiology clinical pharmacy specialist was important in bridging gaps in the medical therapy and improving quality of care for patients with AMI and/or LVEF ≤40% by optimizing patients medications particularly for the initiation of ACEi. ACEi was initiated in about one-quarter of the patients with AMI and LVEF ≤40% based on the suggestion of the cardiology clinical pharmacy specialist and approved by the interventional cardiologists.

Long-standing response to calcium channel blocker therapy on patients with various types of pulmonary hypertension: a systematic review and meta analysis

Abstract Background It is widely acknowledged that the extended use of calcium channel blocker (CCBs) therapy in patients diagnosed with Idiopathic Pulmonary Arterial Hypertension (IPAH), Heritable Pulmonary Arterial Hypertension (HPAH), or Drug- or Toxin-Associated Pulmonary Arterial Hypertension (DPAH) who exhibit a positive acute vasoreactivity test (VdT+) provides benefits to patients. However, this practice is supported by a limited body of evidence in the scientific literature, mainly derived from expert consensus and/or small-scale studies, retrospective analyses, and registries, as per the European Society of Cardiology (ESC) guidelines. Objectives We performed a meta-analysis to evaluate the long-standing response to CCBs in patients diagnosed with various forms of pulmonary hypertension. Design We conducted searches in PubMed, Embase, and Cochrane to select both randomised and non-randomised studies. The primary outcomes of interest identified were Mean Pulmonary Artery Pressure (mPAP), 6-minute walk distance (6MWD), Cardiac Index (CI), Mean Right Atrial Pressure (mRAP), and Mixed venous oxygen saturation (SvO₂) measured at the beginning and end of the studies. Additionally, we performed subgroup analyses for all outcomes based on age groups: ≤18 years and >18 years. Statistical analysis was carried out using OpenMeta[Analyst] 12.11.14, and heterogeneity was assessed using I² statistics. Results We identified 7 non-randomised studies comprising a total of 131 patients with an average follow-up duration of 2.74 (1.3) years. The following are the mean values observed for individual outcomes: mPAP (33.1 mmHg; 95% CI [31.6, 34.6]; p < 0.001; I²=0%), 6MWD (470.1 m; 95% CI [452.6, 487.7]; I²=0%), Cardiac index (3.8 L/min/m²; 95% CI [3.6, 4.0]; I²=0%), mRAP (4.2 mmHg; 95% CI [3.6, 4.8]; I²=0%) and SvO₂ (73.9%; 95% CI [72.5, 75.3]; I²=0%) in patients with positive acute vasoreactivity test (VdT+) treated long-term with CCBs. Additionally, at study initiation, we found the following means: mPAP (51.2 mmHg; 95% CI [49.3, 53.0]; I²=0%), 6MWD (428.4 m; 95% CI [410.3, 446.6]; I²=0%), Cardiac index (2.8 L/min/m²; 95% CI [2.7, 2.9]; I²=0%), mRAP (6.4 mmHg; 95% CI [5.6, 7.2]; I²=0%), and SvO₂ (68.5%; 95% CI [66.5, 70.5]; I²=0%). Conclusion The findings from this meta-analysis suggest that in VdT+ patients, the means of certain haemodynamic parameters with long-standing use of CCBs are similar or nearly similar to those of patients without any subtype of PAH. These results align with current guidelines and reinforce their level of evidence.

National trends of left ventricular assist device therapy in Germany

Abstract Background The prevalence of advanced heart failure (HF) is increasing and prognosis remains poor. Although heart transplantation is still considered to be the gold standard for the treatment of advanced HF in selected patients, its use is limited by organ donor shortage and a growing burden of cormorbidities among potential recipients. The 2021 European Society of Cardiology (ESC) guidelines recommend consideration of long-term mechanical circulatory support with a left ventricular assist device (LVAD) in eligible patients with advanced heart failure (HF) who are refractory to medical/device therapy. Purpose The purpose of this study was to evaluate the national trends of LVAD in Germany. The main hypothesis was that LVAD therapy is still underutilized. Methods From the national database of the German Federal Statistical Office (DESTATIS), we identified all patients who underwent LVAD implantation in Germany between January 2011 and December 2022 (n = 9,232). We compared temporal trends and in-hospital outcomes. Results From 2011 to 2022, number of LVAD implantation was highest in the year 2017 (n = 914) and steadily decreased over the following years (2022: n = 617). Mean age of LVAD recipients was 56.2 years (2011-2015) and increased to 58.4 years (2020-2022). The majority of LVAD recipients are male (84,8 %), and this trend has been stable during the entire time period. In-hospital mortality after LVAD remains high, but has been decreasing (25.8% during 2011-2015 compared to 20.2% during 2020-2022). Conclusion Although LVAD is recommended in eligible patients with advanced HF, our study suggests an underutilization of LVAD in this patient population and especially in female patients.

Modern heart failure treatment is superior to conventional treatment across the left ventricular ejection spectrum: Real-life data from the Swedish Heart Failure Registry 2013-2020

Abstract Background Heart failure (HF) is a clinical syndrome characterized by high mortality and morbidity. In 2016, Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was recommended as a new treatment option for HF in patients with HFrEF. In the 2021 European Society of Cardiology guidelines for treatment of HFrEF patients Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were introduced because they demonstrated significantly reduced HF events or cardiovascular (CV) mortality. Since ARNI and SGLT2i were introduced to treat HF, its therapeutic regimen has modernized from previous treatment with beta-blocker (BB) and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) with mineralocorticoid receptor antagonist (MRA) as added-on in HF with reduced ejection fraction (HFrEF). Purpose This study is aimed to compare effectiveness of modern therapy including ARNI and SGLT2i with conventional heart failure treatment. Conventional HF treatment includes (BB, ACEi/ARB, with or without MRA) and modern heart failure treatment (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i) in real-world. Methods This observational study (2013-2020), using the Swedish HF Registry, involved 20,849 HF patients. Patients received either conventional (BB, ACEi/ARB, with/without MRA, n=20,140) or modern (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i, n=709) treatment at the index visit. The endpoints were all-cause and cardiovascular (CV) mortality. Results Modern HF therapy was associated with a significant 28% reduction in all-cause mortality compared to conventional HF treatment (adjusted HR [aHR]: 0.72 (95% CI 0.54 - 0.96), p=0.024), and had 33% reduced all-cause mortality (aHR: 0.67 (95% CI 0.48 - 0.94), p=0.019) within 2 years of index registration. Similarly, modern HF therapy was associated with a significant 62% reduction in CV mortality compared to conventional HF treatment (aHR: 0.38 (95% CI 0.21 - 0.68), p=0.0013). In addition, we found a 58% reduced CV mortality (aHR 0.42 (95% CI 0.22 - 0.79), p=0.0067) within 2 years of index registration. In the propensity score 1:1 matched cohort in which ARNI was included in the matching procedure, i.e., no ARNI was used in any of the two treatment groups and the effect of SGLT2i was the target assessment. The results were associated with a statistically significant risk reduction of 42% in all-cause mortality in the modern HF treatment group compared to the conventional treatment group (aHR: 0.58 (95% CI 0.36 - 0.94), p=0.028), and a 49% (aHR: 0.51 (95% CI 0.29 - 0.89), p=0.018) risk reduction within 2 years of index registration. Conclusion This study demonstrates that modern HF therapy in a real-world Swedish HF population is associated with a statistically significant risk reduction in all-cause and CV mortality, regardless of EF, sex, age, eGFR, and etiology of HF compared to conventional HF therapy.Central Illustration

Practicing what you preach. Do cardiology trainees in the United Kingdom follow the lifestyle advice that they would give to patients?

Abstract Background The role of lifestyle factors in determining the risk of cardiovascular disease is well established. As a result, lifestyle modification is recommended as part of numerous European Society of Cardiology guidelines. However, it remains uncertain how closely cardiologists adhere to guidelines in their personal life. Poor lifestyle among clinicians can contribute to poor health and may increase absenteeism and potentially reduce the quality of patient care. Purpose To establish whether cardiology trainees in the UK follow appropriate guideline-directed lifestyle advice in their personal life. Methods All cardiology trainees within the UK were eligible to participate in the 2023 British Junior Cardiologists' Association (BJCA) training survey and the survey was advertised through national and local campaigns. The survey contained questions on smoking status, alcohol intake, healthy diet, partaking in regular exercise, frequency of adequate quality of sleep, and demographic questions. Responders were eligible for inclusion if they consented to participate in health and wellbeing survey questions, and if they had completed four demographic questions. Results Of the 398 responders to the 2023 BJCA survey, 212 consented to answer health and wellbeing questions (66% male, age 34±4 years, 42% had dependents) and were included. Responders included trainees representing all four UK nations. Very few cardiology trainees were current smokers either of cigarettes/cigars (n=2, 1%), or e-cigarettes (n=2, 1%), with 12 (6%) being ex-smokers. Few trainees (n=13, 6%) consumed alcohol above the UK recommended maximum of 14 units per week (Fig 1A). However, only 14% (n=29) regularly achieved 30 minutes of moderate or 15 minutes of intense exercise on at least 5 days each week (Fig 1B). Most trainees (n=167, 80%) only obtained adequate sleep on four or fewer nights each week (Fig 1C). Only 37% (n=78) of trainees agreed or strongly agreed that they were able to maintain a healthy diet most days (Fig 1D). Conclusions Most UK cardiology trainees followed guidance related to smoking and alcohol intake. However, far fewer trainees followed healthy lifestyle guidance relating to exercise, sleep, and diet. Whether these findings are similar across other ESC nations should be investigated. Further work is required to establish the impact of healthy living on clinician working activity and subsequent quality of patient care. Training bodies should consider how occupational factors may contribute to a trainee’s adverse healthy living.