Heart failure with preserved ejection fraction (HFpEF) is common, debilitating, and has limited availability of disease-modifying therapies. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide improved symptoms and weight in the Semaglutide Treatment Effect in People with obesity and HFpEF (STEP-HFpEF) trial but their economic value in HFpEF is unclear. We developed a cohort state-transition (Markov) model based on STEP-HFpEF to evaluate semaglutide versus placebo in patients with HFpEF and obesity from the German statutory health insurance (SHI) perspective. Health states were defined by Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS) quartiles and death. Outcomes included costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Deterministic, probabilistic, time-horizon, and structural KCCQ trajectory scenario analyses were performed. A 1-year prevalence-based budget impact analysis estimated additional SHI expenditure under alternative eligibility and uptake scenarios. Over 5 years, semaglutide increased total costs (2025 €) (17,690.5 € versus 12,748.6 €) and QALYs (3.371 versus 3.208), yielding an ICER of 30,443 €/QALY and a positive incremental net monetary benefit. Over 1 year, the ICER was 82,237 €/QALY. At the base-case price, the probability that semaglutide is cost-effective at 100,000 €/QALY was 0.911, rising with further price reductions. The 1-year budget impact ranged from approximately 168 million € to 864 million €, depending on eligibility and uptake. Semaglutide appears cost-effective for HFpEF with obesity under the base-case assumptions and over longer analytic horizons. Yet it generates substantial budget impact, indicating that affordability and pricing will be critical for its sustainable implementation.

BACKGROUND:Transthyretin amyloid cardiomyopathy (ATTR-CM) causes heart failure with substantial morbidity, mortality, and healthcare utilization. ATTRibute-CM showed that acoramidis improves clinical outcomes, but its cost-effectiveness and budget impact in the German statutory health insurance (SHI) system remain uncertain. METHODS:We developed a cohort Markov model (lifetime horizon) discounting costs and outcomes at 3% annually. Overall survival was modeled with recalibrated Weibull functions fitted to randomized-phase ATTRibute-CM data and anchored to match month-30 survival. Health-related quality of life used Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) trajectories mapped to EQ-5D utilities, with a plateau after 30 months in the base case. Direct medical costs (2025€) included drug, background management and hospitalization costs. Uncertainty was assessed with sensitivity analyses, scenario analyses and a budget impact analysis. RESULTS:Discounted mean lifetime costs were €13,881.50 (placebo) and €828,127.07 (acoramidis), for an incremental €814,245.57. QALYs increased from 2.743 to 4.029 (incremental 1.286) and life-years from 4.023 to 6.045 (incremental 2.022), yielding an ICER of €633,081 per QALY. Survival scenario analyses produced lifetime ICERs from €458,953/QALY in an optimistic scenario to €2,139,712/QALY in a pessimistic waning-benefit scenario. At a WTP of €100,000/QALY, the probability of cost-effectiveness was very low and results were driven primarily by acoramidis acquisition cost. In the budget impact analysis, year-1 SHI expenditure was €80,813,995, €134,689,992, and €269,379,983 for 30%, 50%, and 100% uptake, respectively. CONCLUSIONS:Despite benefits, acoramidis is unlikely to be cost-effective at current prices in Germany and could increase SHI spending. Price reductions could better align value with affordability.

Aims:Asymptomatic severe aortic stenosis (aSAS) is associated with morbidity, with mortality increasing once symptoms develop. Benefits of early aortic valve replacement (AVR) over clinical surveillance (CS) with delayed AVR upon symptom onset have been demonstrated, and it is now recommended from the latest European Guidelines if procedural risk is low (Class IIa, Level A). The aim of this study is to estimate the economic impact of transcatheter aortic valve implantation (TAVI) for the treatment of aSAS. Methods and results:A cost-utility analysis compared TAVI using the SAPIEN 3/SAPIEN 3 Ultra valve vs. CS in patients with aSAS across nine European countries. A lifetime Markov model captured peri-procedural and long-term outcomes across three health states: alive and well, stroke, and death. Inputs were derived from the EARLY TAVR trial (NCT03042104) and literature sources. Clinical event rates were estimated via parametric survival analysis. Transcatheter aortic valve implantation treatment for patients with aSAS was modelled to be the economically dominant strategy for treating aSAS across all nine European healthcare systems, with cost-effectiveness probabilities ranging from 97.3% (UK) to 99.9% (Belgium). Incremental results per person included cost savings from -£1788 (UK) to -CHF15 802 (Switzerland), quality-adjusted life years gains of 0.18 (Germany, UK) to 0.23 (Switzerland), and life-year gains of 0.12 (UK) to 0.17 (Belgium). Annual discounting of upfront TAVI costs vs. delayed AVR costs drove results. Conclusion:For patients with aSAS, early intervention with TAVI is estimated to deliver greater health benefits and reduce costs compared with CS. These findings support policies promoting early detection and timely intervention before symptom onset.

AIMS:Acute decompensated heart failure (ADHF) represents a major clinical and economic burden in Germany, primarily due to the frequent need for hospitalizations and high rehospitalization rates. Acetazolamide, a carbonic anhydrase inhibitor, has been shown in the ADVOR trial to improve early decongestion when added to loop diuretics. However, its economic impact within the German healthcare system has not yet been evaluated. METHODS AND RESULTS:We developed a decision-analytic cost-effectiveness model using a 3-month time horizon to evaluate the addition of acetazolamide to standard diuretic therapy in hospitalized ADHF patients, based on data from the ADVOR trial. The analysis was conducted from the perspective of the German statutory health insurance (GKV). Model inputs included clinical probabilities, utilities from German heart failure populations, and healthcare costs (2025 values). Both deterministic and probabilistic sensitivity analyses were performed. A complementary budget impact analysis (BIA) estimated national-level financial implications under various adoption scenarios. In the base-case analysis, acetazolamide was technically dominant, incurring lower cost (4495€ vs. 4959€ per patient) and slightly higher quality-adjusted life years (QALYs: 0.132287 vs. 0.127710, difference 0.00458 ≈ 1.7 quality-adjusted days over 3 months) resulting in an ICER of -101 449€ per QALY. In a scenario using arm-specific outcomes from ADVOR, acetazolamide remained cost-saving with a minimal QALY decrement (-0.00024). The BIA estimated annual savings of €11-217 million depending on uptake and patient eligibility, with €39 million under full uptake when ADVOR exclusion criteria are applied. CONCLUSION:Acetazolamide appears to be a cost-effective and potentially cost-saving adjunct to standard care in patients hospitalized with ADHF in Germany. Broad adoption of acetazolamide could reduce inpatient costs for ADHF, with potential annual savings ranging from tens to hundreds of millions of euros depending on eligibility and uptake.

The Endothelial Activation and Stress Index (EASIX) is a routinely available marker of endothelial activation and systemic stress. Although baseline EASIX predicts mortality in chronic heart failure, its long-term longitudinal behavior and prognostic relevance during follow-up remain insufficiently characterized. To assess whether serial EASIX measurements identify clinically relevant risk trajectories and improve dynamic mortality risk stratification in chronic heart failure. We analyzed 1924 patients with chronic heart failure from the Heidelberg chronic heart failure outpatient registry with at least two available EASIX measurements. The main landmark transition analysis included 1789 patients with valid first-to-second transition assignment, follow-up after the second EASIX measurement, and complete covariate data for the adjusted Cox model. Patients were categorized into early EASIX transition groups using the median baseline log2(EASIX) threshold applied to the first and second measurements. Survival analyses were landmarked at the second EASIX measurement. Associations with all-cause mortality were assessed using multivariable Cox regression, patient-specific EASIX slopes derived from linear mixed-effects models, and time-updated Cox models. In the full longitudinal cohort, 330 deaths occurred. In the adjusted landmark transition cohort, patients rising from low to high EASIX had markedly increased subsequent mortality compared with stable low patients (adjusted HR 2.33, 95

BACKGROUND:Endothelial dysfunction accompanies chronic heart failure (CHF) but is hard to quantify in routine practice. The Endothelial Activation and Stress Index (EASIX), calculated from creatinine, lactate dehydrogenase, and platelets, predicts mortality and complications in conditions like allogeneic stem cell transplantation, COVID-19, and coronary artery disease. Aim To evaluate if EASIX is a prognostic biomarker in patients with CHF. METHODS:Training (n = 1796) and validation cohorts (n = 1796) included all patients from the outpatients' CHF registry of the University of Heidelberg, Germany, with available laboratory parameters for EASIX calculations at first clinical presentation. Five-year overall survival was assessed by multivariable Cox regression adjusting for age, sex, New York Heart Association (NYHA) score, etiology of heart failure, heart failure category, and NT- proBNP as covariates. Fractional polynomials modeled non-linear relationships, and prognostic performance was evaluated using the Brier score and concordance index. RESULTS:EASIX moderately correlated with NT- proBNP, NYHA stage and left ventricular ejection fraction (LVEF), and associated with increased hazard of death in both cohorts (hazard ratio (HR) per log2 increase: training 1.51 (1.14-2.01), p < 0.01; validation 1.59 (1.25-2.01, p < 0.001). The effect was consistent across all etiologies, classes and stages of heart failure as assessed by fractional polynomials. Pre-established EASIX cut-offs independently predicted increased risk of mortality (cut-off 2.32: training: HR 2.14 (1.52-3.02), p < 0.001; validation: HR 3.34 (1.88-5.93), p < 0.0001). Both models (continuous and discrete EASIX values) were validated in the validation cohort using integrated Brier score and C-index. CONCLUSIONS:EASIX is a novel biomarker to predict risk of mortality in patients with CHF.

The need to perform endomyocardial biopsy (EMB) in patients with non-ischaemic dilated cardiomyopathies (DCM) is debated. Here we sought to determine the extent of left ventricular collagen volume fraction (LV-CVF) in DCM patients and to evaluate it as a prognostic marker. In this retrospective longitudinal study, we included 524 patients with suspected DCM who underwent left ventricular EMB (LV-EMB) as a part of their clinical work-up. LV-CVF was quantified using automated image processing of high-resolution scans of LV-EMB. Deep phenotyping was performed including assessment of late gadolinium enhancement on cardiac magnetic resonance imaging. Endpoints were (i) composite endpoint of heart failure-related death, sudden cardiac death, aborted sudden cardiac death (appropriate implantable cardioverter-defibrillator shock, reported sustained ventricular tachycardia, or cardiopulmonary resuscitation), or cardiac transplantation, and (ii) all-cause mortality. LV-EMB was associated with 0.76% major and 2.1% minor complications. No death occurred due to EMB. LV-CVF could be reliably quantified using Bayesian classification. During a median follow-up of 43.2 months (2084 patient-years), 48 patients with LV-CVF >32% and 14 patients with LV-CVF ≤32% reached the composite endpoint (log-rank p < 0.0001). A total of 62 patients reached the endpoint all-cause mortality, from which 38 presented with LV-CVF >32% and 17 with LV-CVF ≤32% (log-rank p = 0.009). In multivariable analyses, LV-CVF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (hazard ratio 2.03, 95% confidence interval 1.32–3.11) were independent predictors of unfavourable outcome. Left ventricular EMB is a safe diagnostic procedure. The extent of CVF in LV-EMB provides prognostic information in patients with DCM in addition to existing measures of left ventricular ejection fraction or NT-proBNP.

BackgroundPatients with chronic heart failure (CHF) frequently suffer from depressive comorbidity. CHF and depressive comorbidity can cause somatic symptoms. The correct attribution of somatic symptoms is important. Thus, we aimed to assess potential differences in somatic symptom severity between CHF patients with and without depressive comorbidity.MethodsWe evaluated depressive comorbidity using the Patient Health Questionnaire-9 (PHQ-9), somatic symptom severity with the Patient Health Questionnaire-15 (PHQ-15), and sociodemographic and medical variables in 308 CHF outpatients. To compare somatic symptom severity between CHF patients with and without depressive comorbidity, we conducted item-level analyses of covariance.ResultsOf the 308 participating patients, 93 (30.3%) met the PHQ-9 criteria for depressive comorbidity. These patients did not differ from those without depressive comorbidity with regard to age, sex, left ventricular function, and multimorbidity. Patients with depressive comorbidity scored significantly higher on ten out of thirteen PHQ-15 items than patients without depressive comorbidity. The largest effect sizes (0.71-0.80) were shown for symptoms of headache, chest pain, shortness of breath, and palpitations, and the latter three were potentially attributable to heart failure.ConclusionsAmong patients with CHF, somatic symptoms are more pronounced in those with depressive comorbidity than those without depressive comorbidity. This finding is especially true for cardiac symptoms independent of CHF severity. The potential interpretation of somatic symptoms as correlates of depressive comorbidity must be recognized in clinical practice.

There is scarce information about the influence of prior myocardial infarction (pMI) on outcomes in patients (pts) with ischaemic HFrEF. We analysed data from the EVIdence based TreAtment in Heart Failure (EVITA-HF) registry. EVITA-HF comprises web-based case report data on demography, diagnostic measures, adverse events and 1-year follow-up of patients hospitalized for chronic heart failure ≥ 3 months (CHF) and an ejection fraction ≤ 40

Abstract Background Pulmonary lymphangiomatosis (PL) is an ultrarare disease characterized by diffuse infiltration of the lung, pleura and/or mediastinum by abnormal lymphatic proliferation. Consented diagnostic or treatment approaches are not established. We therefore aimed to collect data on diagnostics and treatments in a cohort of patients with PL from a tertiary center for rare lung diseases. Methods Clinical, radiological and outcome data from PL patients were collected retrospectively. Results 12 patients were diagnosed between 1996 and 2022 in our center. PL was diagnosed more commonly in female (58%), never smokers (75%) and younger patients (mean age 42 years). Main clinical symptoms comprised haem- and chyloptysis (58%) and dyspnea on exertion (83%). Pulmonary function was mostly restrictive (mean VC 59%) with impaired DLCO (mean 65%). Radiological assessment mainly showed mediastinal involvement (83%), and pleural effusion (67%), pleural thickening (67%) and bronchial wall thickening (67%) while interstitial changes were rare. Diagnosis was confirmed by surgical or transbronchial cryobiopsy. 8 patients were treated with sirolimus, 3 of these combined with a surgical intervention and in one case surgical intervention was necessary 9 months after initiation of sirolimus. Clinical and radiological improvement was demonstrated for all patients treated with sirolimus. 1 patient received a lung transplant due disease progression. Survival rates were 90% after a mean follow up of at least 3 months. Conclusion This case series illustrates the variability of the clinical presentation of PL. Among our patients, those treated with sirolimus showed significant clinical, functional and radiological improvement. However, further investigation is needed to understand the pathogenesis of lymphangiomatosis in order to establish therapeutic approaches.

In the randomized PARTNER 3 trial, transcatheter aortic valve implantation (TAVI) with the SAPIEN 3 device significantly reduced a composite of all-cause death, stroke, and rehospitalization, compared with surgical aortic valve replacement (SAVR), in patients with severe symptomatic aortic stenosis and low risk of surgical mortality. Furthermore, TAVI has been shown to be cost-effective in low-risk patients, compared with SAVR, in a number of countries. This study aimed to determine the cost-effectiveness of TAVI with SAPIEN 3 versus SAVR in Germany. A previously published two-stage Markov-based model that captured clinical outcomes from the PARTNER 3 trial was adapted for the German context using the German Statutory Health Insurance perspective. The model had a lifetime horizon. The cost–utility analysis estimated changes in direct healthcare costs as well as survival and health-related quality of life using TAVI with SAPIEN 3 compared with SAVR. TAVI with SAPIEN 3 increased quality-adjusted life years (QALYs) by + 0.72 at an increased cost of €8664 per patient. The incremental cost-effectiveness/QALY ratio was €12,037, which fell below that of other cardiovascular interventions in use in Germany. The cost-effectiveness of TAVI over SAVR remained robust across multiple challenging scenarios and was driven by lower longer-term management costs compared with SAVR. TAVI with SAPIEN 3 appears to be a clinically meaningful, cost-effective treatment option over SAVR for patients with severe symptomatic aortic stenosis and low risk for surgical mortality in Germany. www.clinicaltrials.gov identifier: NCT02675114.

Der ILR ist etabliert in der leitliniengerechten weiterführenden Rhythmusdiagnostik bei wiederholten Synkopen ohne fassbare Ursache und eine mögliche Option zur erweiterten Rhythmusdiagnostik bei embolischen Schlaganfällen unklarer Genese und vermuteter kardialer Ursache. In ausgewählten Fällen kann der ILR im Rahmen der Risikostratifikation des plötzlichen Herztods bei vermutetem erhöhtem Risiko eingesetzt werden. Darüber hinaus können ILR mit intelligenten Algorithmen atriale Arrhythmien detektieren und sind damit möglicherweise in der Lage, das Rhythmusmanagement und die Thrombembolieprophylaxe nach Katheterablation von Vorhofflimmern/-flattern zu verbessern. Durch die eingeschränkten Kostenerstattungsmöglichkeiten im stationären Sektor und die fehlende Berücksichtigung des entsprechenden OPS-Codes im Katalog des ambulanten Operierens ist der Einsatz eines ILR heute in Deutschland mit einem sehr hohen bürokratischen Aufwand verbunden und der Zugang zu dieser modernen Telemedizin-tauglichen Diagnostik erheblich eingeschränkt.

Introduction: The long-term evolution of clinical, echocardiographic and laboratory parameters of cardiac function in patients with chronic heart failure (HF) with either reduced (HFrEF) or mildly reduced (HFmrEF) left ventricular ejection fraction (LVEF) is incompletely characterized. Methods: We identified patients with chronic stable HF who presented at least twice to a university HF outpatient clinic between 1995 and 2021. Trajectories of NYHA functional class, LVEF, left ventricular internal enddiastolic diameter (LVIDD), NT-proBNP concentrations and HF treatment over ten years follow-up were analysed using fractional polynomials. Analyses were repeated after stratifying patients according to aetiology (ischemic vs. dilated) or HF category (HFrEF vs. HFmrEF). Results: A total of 2,132 patients were included, of whom 51% had ischemic and 49% had dilated HF. 86% and 14% were classified as HFrEF and HFmrEF, respectively. Mean LVEF was 28±10%, and median NT-proBNP and eGFR values were 1,170 (385-3,176) pmol/L and 81 (62-100) ml/min/1.73m², respectively. Median follow-up was 5.2 (2.6-9.2) years. Overall, NYHA functional class and LVIDD trajectories were U-shaped, whereas LVEF and NT-proBNP concentrations markedly improved during the first year and remained stable thereafter. However, the evolution of HF parameters significantly differed with respect to HF category and aetiology, with greater improvements seen in patients with HFrEF of non-ischemic origin. Improvements in HF variables were associated with optimization of HF therapy, notably with initiation and up-titration of renin-angiotensin-system blockers. Discussion/Conclusion: This study provides insights into the natural history of HF in a large cohort of well-treated chronic HF outpatients with respect to subgroups of HF and different etiologist.

BackgroundIn patients with cardiovascular (CV) comorbidities that necessitate antiplatelet therapy (APT), its optimal management during chemotherapy-induced thrombocytopenia remains elusive, as the risk of bleeding has to be balanced against the risk of CV events. The purpose of this study was to assess the risk for bleeding with APT during thrombocytopenia in patients with multiple myeloma undergoing high-dose chemotherapy and subsequent autologous stem-cell transplantation (ASCT) with and without acetylsalicylic acid (ASA) as comedication.MethodsWe assessed patients who underwent ASCT at the Heidelberg University Hospital between 2011 and 2020 for bleeding events, management strategies for ASA intake during thrombocytopenia, transfusion requirements, and the occurrence of CV events.ResultsThere were 57/1,113 patients who continued ASA until at least 1 day after ASCT; thus, a continuous platelet inhibition during thrombocytopenia was assumed. Most of the patients (41/57) continued ASA until they had a platelet count of 20–50/nl. This range reflects the kinetics of thrombocytopenia and nondaily measurements of platelets during ASCT. A tendency toward a higher risk for bleeding events in the ASA group was demonstrated (1.9% (control group) vs. 5.3% (ASA), p = 0.082). The risk factors for bleeding in multivariate analysis were the duration of thrombocytopenia < 50/nl, a history of gastrointestinal bleeding, and diarrhea. The factors predicting the duration of thrombocytopenia were age >60 years, a hematopoietic stem-cell transplantation comorbidity index ≥3, and an impaired bone marrow reserve at admission. CV events occurred in three patients; none of them took ASA or had an indication for APT.ConclusionsThe intake of ASA until thrombocytopenia with a platelet count of 20–50/nl appears safe, although an elevated risk cannot be excluded. If ASA is indicated for the secondary prevention of CV events, the evaluation of risk factors for bleeding and a prolonged time of thrombocytopenia before conditioning is crucial to adapt the strategy for ASA intake during thrombocytopenia.

Die Ambulantisierung bisher stationärer durchgeführter Eingriffe ist aufgrund der technischen Fortschritte bei vielen Eingriffen, des Pflegepersonalmangels, des Kostendrucks im Gesundheitswesen und der Ausrichtung auf Patientenbedürfnisse sinnvoll. Gerade die Kardiologie ist mit den zahlreichen, interventionellen Eingriffen und Geräteimplantationen in hohem Maße betroffen. Gleichzeitig nehmen Alter und Morbidität der Patienten aufgrund der demografischen Entwicklung zu, sodass die strukturellen, personellen und prozeduralen Aspekte, unter denen kardiologische Eingriffe ambulant durchgeführt werden sollen ohne die Patientensicherheit zu gefährden, definiert werden müssen. In diesem Positionspapier werden Kriterien für das deutsche Gesundheitssystem definiert, basierend auf dem aktuellen Stand der Wissenschaft und einem Expertenkonsensus. Die letzte Entscheidung, ob ein Eingriff ambulant durchführbar ist, sollte beim behandelnden Arzt verbleiben und gemeinsam mit dem Patienten getroffen werden („shared decision making“).

Background A high body mass index (BMI) confers a paradoxical survival benefit in patients with heart failure (HF) or diabetes mellitus (DM). There is, however, controversy whether an obesity paradox is also present in patients with HF and concomitant DM. In addition, the influence of glycaemic control and diabetes treatment on the presence or absence of the obesity paradox in patients with HF and DM is unknown. Methods We identified 2936 patients with HF with reduced ejection fraction (HFrEF) in the HF registries of the universities of Heidelberg, Germany, and Hull, UK (general sample). Of these, 598 (20%) were treated for concomitant DM (DM subgroup). The relationship between BMI and all-cause mortality was analysed in both the general sample and the DM subgroup. Patients with concomitant DM were stratified according to HbA1c levels or type of diabetes treatment and analyses were repeated. Results We found an inverse BMI-mortality relationship in both the general sample and the DM subgroup. However, the obesity paradox was less pronounced in patients with diabetes treated with insulin and it disappeared in those with poor glycaemic control as defined by HbA1c levels > 7.5%. Conclusion In patients with HFrEF, a higher BMI is associated with better survival irrespective of concomitant DM. However, insulin treatment and poor glycaemic control make the relationship much weaker. Graphical abstract