In-hospital course of patients with heart failure with improved ejection fraction in the DELIVER trial.

AIMS: Patients with heart failure (HF) with improved ejection fraction (HFimpEF) may face residual risks of clinical events that are comparable to those experienced by patients with HF whose left ventricular ejection fraction (LVEF) has consistently been above 40%. However, little is known about the clinical course of patients with HFimpEF during hospitalization for HF. METHODS AND RESULTS: DELIVER randomized patients with HF and LVEF >40% to dapagliflozin or placebo, including HFimpEF (LVEF previously ≤40%). We evaluated all HF hospitalizations adjudicated by the clinical endpoints committee with available data for determination of in-hospital course. Complicated hospitalization was defined as any hospitalization requiring intensive care unit stay, intravenous vasopressors/inotropes/vasodilators, invasive or non-invasive ventilation, mechanical fluid removal, ultrafiltration, or mechanical circulatory support. LVEF changes were extracted using a validated GPT-3.5, a large language model, via a secure private endpoint. Of the 6263 patients enrolled in DELIVER, 1151 (18%) had HFimpEF. During a median follow-up of 2.3 years, there were 224 total HF hospitalizations in 144 patients with HFimpEF and 985 in 603 patients with LVEF consistently >40%. Patients with HFimpEF experienced higher rates of complicated HF hospitalization as compared with patients with LVEF consistently >40% (39% vs. 27%; p < 0.001). Among those who experienced a first HF hospitalization, there was no significant difference in length of stay or in-hospital mortality between patients with HFimpEF versus LVEF consistently >40%. In a subset of participants who had at least one LVEF measurement available during HF hospitalization, 66% of those with HFimpEF and 29% of patients with LVEF consistently >40% experienced a reduction in their LVEF to ≤40% from the time of enrolment (p < 0.001). In the entire DELIVER cohort, dapagliflozin reduced total uncomplicated and complicated HF hospitalizations, irrespective of HFimpEF status (pinteraction ≥0.30). CONCLUSIONS: Among patients hospitalized for HF in DELIVER, those with HFimpEF experienced a more adverse in-hospital clinical course, necessitating higher resource utilization beyond standard diuretic therapy compared with patients with HF and LVEF consistently >40%, but had similar in-hospital mortality. Treatment benefits of dapagliflozin were not modified by hospitalization type.

Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation.

The phospholamban (PLN) pathogenic gene variant, p.Arg14del (PLN-R14del), can lead to dilated and arrhythmogenic cardiomyopathy, resulting in heart failure. PLN-R14del cardiomyopathy has been conceptualized as a disease caused by sarco/endoplasmic reticulum calcium adenosine triphosphatase 2a (SERCA2a) superinhibition. However, recent studies raised controversy regarding the effect of PLN-R14del on SERCA activity and revealed a prominent role for abnormal PLN protein distribution and sarco/endoplasmic reticulum disorganization as underlying disease mechanism. Strategies targeting sarco/endoplasmic reticulum malformation may, therefore, prove more effective than SERCA activity modulation. This review reassesses the disease mechanisms of PLN-R14del cardiomyopathy and emphasizes the importance of dissecting the underlying molecular mechanisms to uncover targets for innovative treatments.

Screening for Heart Failure: Biomarkers to Detect Heightened Risk in the General Population.

PURPOSE OF REVIEW: Heart failure (HF) represents a growing global burden of morbidity and mortality. Identifying individuals at risk for HF development is increasingly important, particularly given the advent of disease-modifying therapies for HF as well as its major risk factors such as obesity actalnd diabetes. We aim to review the key circulating biomarkers associated with future HF which may contribute to HF risk prediction. RECENT FINDINGS: While current guidelines recommend the use of natriuretic peptides and cardiac troponins in HF risk stratification, there are a diverse array of other emerging protein, metabolic, transcriptomic, and genomic biomarkers of future HF development. These biomarkers not only lend insight into the underlying pathophysiology of HF, which spans inflammation to cardiac fibrosis, but also offer an opportunity to further refine HF risk in addition to established biomarkers. As evolving techniques in molecular biology enable an increased understanding of the complex biologic contributions to HF pathophysiology, there is an important opportunity to construct integrated clinical and multi-omic models to best capture HF risk. Moving forward, future studies should seek to understand the contributions of sex differences, underlying comorbidity burden, and HF subtypes to an individual's HF risk. Further studies are necessary to fully define the clinical utility of biomarker screening approaches to refine HF risk assessment, as well as to link risk assessment directly to preventive strategies for HF.

Beta-blocker use and outcomes in patients with heart failure and mildly reduced and preserved ejection fraction.

AIMS: In the absence of randomized trial evidence, we performed a large observational analysis of the association between beta-blocker (BB) use and clinical outcomes in patients with heart failure (HF) and mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF). METHODS AND RESULTS: We pooled individual patient data from four large HFmrEF/HFpEF trials (I-Preserve, TOPCAT, PARAGON-HF, and DELIVER). The primary outcome was the composite of cardiovascular death or HF hospitalization. Among the 16 951 patients included, the mean left ventricular ejection fraction (LVEF) was 56.8%, and 13 400 (79.1%) had HFpEF (LVEF ≥50%). Overall, 12 812 patients (75.6%) received a BB. The median bisoprolol-equivalent dose of BB was 5.0 (Q1-Q3: 2.5-5.0) mg with BB continuation rates of 93.1% at 2 years (in survivors). The unadjusted hazard ratio (HR) for the primary outcome did not differ between BB users and non-users (HR 0.98, 95% confidence interval [CI] 0.91-1.05), but the adjusted HR was lower in BB users than non-users (0.81, 95% CI 0.74-0.88), and this association was maintained across LVEF (pinteraction = 0.88). In subgroup analyses, the adjusted risk of the primary outcome was similar in BB users and non-users with or without a history of myocardial infarction, hypertension, or a baseline heart rate <70 bpm. By contrast, a better outcome with BB use was seen in patients with atrial fibrillation compared to those without atrial fibrillation (pintreraction = 0.02). CONCLUSIONS: In this observational analysis of non-randomized BB treatment, there was no suggestion that BB use was associated with worse HF outcomes in HFmrEF/HFpEF, even after extensive adjustment for other prognostic variables.

Association of fibrotic markers with diastolic function after STEMI.

Galectin-3 and Suppression of tumorigenicity-2 (ST2) are known markers of cardiac fibrosis. We investigated the prognostic value of fibrotic markers for the development of diastolic dysfunction and long-term outcome in patients suffering an ST-elevated myocardial infarction (STEMI). We analyzed 236 patients from the GIPS-III cohort with available echocardiographic studies and plasma measurements at hospitalization and after 4 months follow-up. Adjusted logistic mixed effects modelling revealed no association between the occurrence of diastolic dysfunction over time with abnormal plasma levels of galectin-3 and ST2. We observed no differences regarding survival outcome at follow-up of 5 years between patients with normal versus abnormal values in both galectin-3 (P = 0.75), and ST2 (P = 0.85). In conclusion, galectin-3 and sST2 were not associated with the development of diastolic dysfunction in non-diabetic patients that presented with a STEMI.

Shared care for patients with a left ventricular assist device: a scoping review.

Left ventricular assist devices (LVADs) are increasingly implanted in patients with advanced heart failure. Currently, LVAD care is predominantly concentrated at specialized tertiary care hospitals. However, the increasing workload and logistical burden for implanting centres pose significant challenges to accessing care for individual patients in remote areas. An emerging approach to LVAD patient management is the use of a shared care model (SCM), which facilitates collaboration between implanting centres and local non-implanting hospitals. This scoping review explores and synthesizes the current scientific evidence on the use of SCMs in LVAD care management. Eligible studies were identified in EMBASE, PubMed MEDLINE, Web of Science, Cochrane and Google Scholar. Findings were synthesized in accordance with PRISMA-ScR guidelines. Of the 950 records screened, five articles met the inclusion criteria. Four review articles focused on the proposed benefits and challenges of using SCMs. Main benefits included improved patient satisfaction and continuity of care. Important challenges were initial education of non-implanting centre staff and maintaining competency. One prospective study showed that absence of LVAD-specific care was associated with impaired survival and higher rates of pump thrombosis and LVAD-related infections. The use of SCMs is a promising approach in the long-term management of LVAD patients. However, sufficient evidence about the impact of SCMs on patients and the healthcare system is not currently available. Standardized protocols based on prospective studies are needed to develop safe and effective shared care for LVAD patients.

Clinical characteristics and outcomes of patients aged 80 years and over with heart failure: Need for better treatment.

AIMS: Although the prevalence of heart failure (HF) increases markedly with advancing age, surprisingly little is known about HF in the very elderly. The aim of this study was to describe the clinical characteristics and outcomes of octogenarians with HF. METHODS AND RESULTS: Individual participant meta-analysis of patients with HF and reduced, mildly reduced, and preserved ejection fraction (HFrEF, HFmrEF, and HFpEF, respectively) enrolled in eight large randomized trials. Overall, the proportion of octogenarians was 1518 of 20 168 patients (7.5%) with HFrEF, 610 of 4609 (13.2%) with HFmrEF, and 3130 of 15 354 (20.4%) with HFpEF. Regardless of HF phenotype, octogenarian patients were more often female and had more comorbidities, more symptoms and signs of congestion, and worse health status (but not quality of life), in comparison to patients aged <80 years. The incidence (per 100 person-years) of the composite of cardiovascular death or HF hospitalization was 13.3 (95% confidence interval [CI] 12.7-14.0) in octogenarians versus 9.5 (95% CI 9.3-9.7) in non-octogenarians (adjusted hazard ratio [aHR] 1.40, 95% CI 1.32-1.48). Each component of the composite was more frequent in octogenarians with rates of cardiovascular mortality of 7.0 (95% CI 6.5-7.4) per 100 person-years versus 4.9 (95% CI 4.8-5.1) in non-octogenarians (aHR 1.60, 95% CI 1.48-1.72, p < 0.001). Octogenarians received less evidence-based therapy, especially mineralocorticoid receptor antagonists, than younger patients. CONCLUSION: Despite worse health status and higher hospitalization and mortality rates, octogenarians were undertreated compared to younger patients.

Cardiovascular toxicities of immune therapies for cancer - a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology.

The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.

The Effect of Dapagliflozin on Accelerometer-Based Measures of Physical Activity in Patients with Heart Failure: An Analysis of the DETERMINE Trials.

Background: Wearable accelerometers can quantify the frequency and intensity of physical activity during everyday life and may provide complementary data to established functional outcome measures on the effect of heart failure therapies on functional limitations. Methods: In a voluntary substudy of the DETERMINE (Dapagliflozin EffecT on ExeRcise capacity using a 6-MINutE walk test in patients with HF) trials, patients wore a waist-worn tri-axial accelerometer for as long as possible (ideally for 24 hours/day for 7 days) at 3 points during the trial; between the screening visit and randomization (baseline data), and during weeks 8 and 14-16. Accelerometer outcomes included the change from baseline to week 16 in the total number of steps, time spent in light-to-vigorous physical activity (LVPA), time spent in moderate-to-vigorous physical activity (MVPA), movement intensity during walking, number of vector magnitude units (VMUs)' and total activity counts. Results: Adequate baseline and week 16 accelerometer data were available for 211 of 817 (26%) randomized patients (defined as ≥10 hours of wear-time for ≥3 days). Dapagliflozin had a favorable effect on the mean change from baseline at 16 weeks in the number of steps (between-group difference 778 [95%CI 240, 1315]), time spent in MVPA (0.16 hours [95%CI 0.03, 0.29]) and in the mean VMUs (25 counts per minute [95%CI 0.1, 49]). There were no between-group differences in the other accelerometer outcomes of interest. Conclusions: In this exploratory analysis of the DETERMINE trials, dapagliflozin had a beneficial effect on selected accelerometer-based measures of physical activity in patients with HF across the entire left ventricular ejection fraction spectrum, yet did not improve 6MWD, as previously reported. These data suggest that accelerometer-based measurements of everyday activity may provide complementary information to 6MWD and identify beneficial effects of treatment not detected by 6MWD. Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT03877237 and NCT03877224.

Clinical Significance of Exercise Pulmonary Hypertension With a Negative Diastolic Stress Test for Suspected Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Half of patients with heart failure with preserved ejection fraction (HFpEF) remain undiagnosed by resting evaluation alone. Therefore, exercise testing is proposed. The diastolic stress test (DST), however, has limited sensitivity. We aimed to determine the clinical significance of adding the mean pulmonary artery pressure over cardiac output (mPAP/CO) slope to the DST in suspected HFpEF. METHODS AND RESULTS: In this prospective cohort study, consecutive patients (n=1936) with suspected HFpEF underwent exercise echocardiography with simultaneous respiratory gas analysis. These patients were stratified by exercise E over e' (exE/e') and mPAP/CO slope, and peak oxygen uptake, natriuretic peptides (NT-proBNP [N-terminal pro-B-type natriuretic peptide]), and score-based HFpEF likelihood were compared. Twenty-two percent of patients (n=428) had exE/e'<15 despite a mPAP/CO slope>3 mm Hg/L per min, 24% (n=464) had a positive DST (exE/e'≥15), and 54% (n=1044) had a normal DST and slope. Percentage of predicted oxygen uptake was similar in the group with exE/e'<15 but high mPAP/CO slope and the positive DST group (-2% [-5% to +1%]), yet worse than in those with normal DST and slope (-12% [-14% to -9%]). Patients with exE/e'<15 but a high slope had NT-proBNP levels and H2FPEF (heavy, hypertensive, atrial fibrillation, pulmonary hypertension, elder; filling pressure) scores intermediate to the positive DST group and the group with both a normal DST and slope. CONCLUSIONS: Twenty-two percent of patients with suspected HFpEF presented with a mPAP/CO slope>3 mm Hg/L per min despite a negative DST. These patients had HFpEF characteristics and a peak oxygen uptake as low as patients with a positive DST. Therefore, an elevated mPAP/CO slope might indicate HFpEF irrespective of the DST result.

Association of baseline and longitudinal changes in insulin-like growth factor-binding protein-7 with the risk of incident heart failure: Data from the PREVEND study.

AIM: Senescence is a major risk factor for heart failure (HF), and insulin-like growth factor-binding protein-7 (IGFBP7) has been identified as an important senescence-inducing factor. The aim of this study was to examine the value of baseline and repeat IGFBP7 measurements in predicting future HF among community-dwelling Dutch adults from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. METHODS AND RESULTS: Individuals without prevalent HF who attended PREVEND visits 2 and 4 median of 5.1 years apart (25th-75th percentile, 4.9-5.2) with measurements of IGFBP7 were included. We used Cox proportional hazards models to investigate the association between IGFBP7 and HF incidence. A total of 6125 participants attending visit 2 (mean ± standard deviation [SD] age 53.1 ± 12.2 years; 3151 [51.4%] men) were followed for a median of 8.4 (7.8-8.9) years, and 194 participants (3.2%) developed incident HF. Median baseline IGFBP7 concentration was 87.0 (75.1-97.3) ng/ml, and baseline IGFBP7 levels were significantly associated with risk for incident HF (HF risk factors adjusted hazard ratio [HR] per 1 SD change in log-transformed IGFBP7: 1.22, 95% confidence interval [CI] 1.03-1.46). Baseline IGFBP7 was also significantly associated with incident HF in individuals with N-terminal pro-B-type natriuretic peptide <125 ng/L. Among 3879 participants attending both visits 2 and 4 (mean ± SD age 57.5 ± 11.3 years; 1952 [50.3%] men), 93 individuals developed HF (after visit 4) during a median follow-up of 3.2 (2.8-3.9) years. Median increase in IGFBP7 concentration between visits was 0.68 (-7.09 to 8.36) ng/ml, and changes in IGFBP7 levels were significantly associated with risk for incident HF (HF risk factors adjusted HR per 1 SD change in log-transformed IGFBP7: 1.68, 95% CI 1.19-2.36). CONCLUSIONS: Both baseline as well as repeat IGFBP7 measurements provide information about the risk of developing HF.

Effects of dapagliflozin according to QRS duration across the spectrum of left ventricular ejection fraction: An analysis of DAPA-HF and DELIVER.

AIMS: The primary aim was to evaluate the effect of dapagliflozin according to QRS duration across the spectrum of left ventricular ejection fraction (LVEF), given that prolongation of QRS duration is associated with less favourable ventricular remodelling with pharmacological therapy and worse outcomes. METHODS AND RESULTS: A pooled analysis of the DAPA-HF and DELIVER trials, excluding patients with a paced rhythm and cardiac resynchronization therapy. Overall, 4008 patients had heart failure (HF) with reduced ejection fraction (HFrEF), and 5816 had HF with mildly reduced/preserved ejection fraction (HFmrEF/HFpEF). QRS duration was <120 ms in 7039 patients (71.7%), 120-149 ms in 1725 (17.6%), and ≥150 ms in 1060 patients (10.8%). The median follow-up time was 23 months. The rate of the primary composite outcome of cardiovascular death or worsening HF was 9.2 (95% confidence interval [CI] 8.7-9.7), 14.3 (13.0-15.7), and 15.9 (14.1-17.9) per 100 patient-years in the <120, 120-149, and ≥150 ms groups, respectively. This gradient in event rates was observed both in HFrEF and HFmrEF/HFpEF. Dapagliflozin, compared with placebo, reduced the risk of the primary outcome consistently across the QRS duration subgroups (hazard ratio [95% CI] 0.75 [0.67-0.85], 0.79 [0.65-0.96], and 0.89 [0.70-1.13] in the <120, 120-149, and ≥150 ms groups, respectively; p for interaction = 0.28). The effect of dapagliflozin on the primary outcome was consistent across the QRS duration regardless of HF phenotype that is, HFrEF or HFmrEF/HFpEF. CONCLUSIONS: Prolongation of QRS duration is associated with worse outcomes irrespective of HF phenotype. Dapagliflozin reduced the risk of the primary outcome, regardless of QRS duration, in DAPA-HF and DELIVER.

Proteomic biomarkers related to obesity in heart failure with reduced ejection fraction and their associations with outcome.

OBJECTIVE: Heart failure (HF) pathophysiology in patients with obesity may be distinct. To study these features, we identified obesity-related biomarkers from 4210 circulating proteins in patients with HF with reduced ejection fraction (HFrEF) and examined associations of these proteins with HF prognosis and biological mechanisms. METHODS: In 373 patients with trimonthly blood sampling during a median follow-up of 2.1 (25th-75th percentile: 1.1-2.6) years, we applied an aptamer-based multiplex approach measuring 4210 proteins in baseline samples and the last two samples before study end. Associations between obesity (BMI > 30 kg/m2) and baseline protein levels were analyzed. Subsequently, associations of serially measured obesity-related proteins with biological mechanisms and the primary endpoint (PEP; composite of cardiovascular mortality, HF hospitalization, left ventricular assist device implantation, and heart transplantation) were examined. RESULTS: Obesity was identified in 26% (96/373) of patients. A total of 30% (112/373) experienced a PEP (with obesity: 26% [25/96] vs. without obesity: 31% [87/277]). A total of 141/4210 proteins were linked to obesity, reflecting mechanisms of neuron projection development, cell adhesion, and muscle cell migration. A total of 50/141 proteins were associated with the PEP, of which 12 proteins related to atherosclerosis or hypertrophy provided prognostic information beyond clinical characteristics, N-terminal pro-B-type natriuretic peptide, and high-sensitivity troponin T. CONCLUSIONS: Patients with HFrEF and obesity show distinct proteomic profiles compared to patients with HFrEF without obesity. Obesity-related proteins are independently associated with HF outcome. These proteins carry potential to improve management of obesity-related HF and could be leads for future research.

Serial cardiac biomarkers, pulmonary artery pressures and traditional parameters of fluid status in relation to prognosis in patients with chronic heart failure: Design and rationale of the BioMEMS study.

AIMS: Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms. METHODS: The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death. CONCLUSION: Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively.

Pulmonary artery pressure monitoring in chronic heart failure: effects across clinically relevant subgroups in the MONITOR-HF trial.

BACKGROUND AND AIMS: In patients with chronic heart failure (HF), the MONITOR-HF trial demonstrated the efficacy of pulmonary artery (PA)-guided HF therapy over standard of care in improving quality of life and reducing HF hospitalizations and mean PA pressure. This study aimed to evaluate the consistency of these benefits in relation to clinically relevant subgroups. METHODS: The effect of PA-guided HF therapy was evaluated in the MONITOR-HF trial among predefined subgroups based on age, sex, atrial fibrillation, diabetes mellitus, left ventricular ejection fraction, HF aetiology, cardiac resynchronization therapy, and implantable cardioverter defibrillator. Outcome measures were based upon significance in the main trial and included quality of life-, clinical-, and PA pressure endpoints, and were assessed for each subgroup. Differential effects in relation to the subgroups were assessed with interaction terms. Both unadjusted and multiple testing adjusted interaction terms were presented. RESULTS: The effects of PA monitoring on quality of life, clinical events, and PA pressure were consistent in the predefined subgroups, without any clinically relevant heterogeneity within or across all endpoint categories (all adjusted interaction P-values were non-significant). In the unadjusted analysis of the primary endpoint quality-of-life change, weak trends towards a less pronounced effect in older patients (Pinteraction = .03; adjusted Pinteraction = .33) and diabetics (Pinteraction = .01; adjusted Pinteraction = .06) were observed. However, these interaction effects did not persist after adjusting for multiple testing. CONCLUSIONS: This subgroup analysis confirmed the consistent benefits of PA-guided HF therapy observed in the MONITOR-HF trial across clinically relevant subgroups, highlighting its efficacy in improving quality of life, clinical, and PA pressure endpoints in chronic HF patients.

Dutch cardio-oncology cohort: Incident cardiovascular disease predisposes to a higher cancer mortality rate.

BACKGROUND: Cardiovascular disease (CVD) and cancer are the two leading causes of death worldwide. Given their high prevalence, it is important to understand the disease burden of cancer mortality in CVD patients. OBJECTIVE: We aimed to evaluate whether patients with incident CVD have a higher risk of malignancy-related mortality, compared to the general population without CVD. METHODS: We performed a national population-based cohort study selecting patients with incident CVD in the Netherlands between 01 April 2000 and 31 December 2005. A reference cohort was selected from the Dutch population using age, sex and ethnicity. Mortality follow-up data were evaluated after data linkage of national registries from Statistics Netherlands until 31 December 2020. RESULTS: A total of 2,240,879 individuals were selected with a mean follow-up of 12 years (range 0.4-21.0), of which 738,666 patients with incident CVD with a mean age of 71 ± 15 years. Malignancy mortality per 1000 person years was 84 for the reference group and 118 for patients with CVD, with the highest rate of 258 in patients with heart failure. Patients with CVD had a higher malignancy mortality risk, compared to the reference group: HR 1.35 (95%CI 1.33-1.36). Highest risks were observed in patients with venous diseases (HR 2.27, 95%CI 2.17-2.36) and peripheral artery disease (HR 1.87, 95%CI 1.84-2.01). CONCLUSION: Results show that CVD predisposes to a higher cancer mortality rate. Of all CVD subtypes, HF patients have the highest cancer mortality rate and the hazards were highest in patients with venous diseases and peripheral artery disease.

Dapagliflozin and quality of life measured using the EuroQol 5-dimension questionnaire in patients with heart failure with reduced and mildly reduced/preserved ejection fraction.

AIMS: Although much is known about the usefulness of heart failure (HF)-specific instruments for assessing patient well-being, less is known about the value of generic instruments for the measurement of health-related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores. METHODS AND RESULTS: We performed a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ-5D-5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator-reported (New York Heart Association class) and patient-self-reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N-terminal pro-B-type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ-5D-5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72-0.91) in Q2, 0.74 (0.65-0.84) in Q3, and 0.62 (0.54-0.72) in Q4. The risk of each component of the composite outcome, and all-cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ-5D-5L VAS and index scores across the range of ejection fraction. CONCLUSIONS: Both higher (better) EQ-5D-5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ-5D-5L VAS and index scores, irrespective of ejection fraction.

Effect of dapagliflozin in patients with diabetes and heart failure with mildly reduced or preserved ejection fraction according to background glucose-lowering therapy: A pre-specified analysis of the DELIVER trial.

AIMS: Type 2 diabetes (T2D) and heart failure (HF) frequently coexist, but whether clinical outcomes and treatment effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vary in relation to background glucose-lowering therapy (GLT) in this population is uncertain. METHODS AND RESULTS: DELIVER randomized patients with HF and left ventricular ejection fraction (LVEF) >40% to dapagliflozin or placebo. The primary outcome was a composite of worsening HF (HF hospitalization or urgent HF visit) or cardiovascular death. In this pre-specified analysis of participants with T2D, treatment effects were assessed by number and class of background GLT(s). Of 3150 participants with T2D at baseline, 22.9% were on no GLT, 36.5% were treated with 1 GLT, and 40.6% with ≥2 GLTs. During follow-up (median: 2.3 years), treatment benefits of dapagliflozin (vs. placebo) on the primary outcome were consistent irrespective of the number of background GLTs (0 GLTs: hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50-1.00; 1 GLT: HR 1.04, 95% CI 0.80-1.34; ≥2 GLTs: HR 0.71, 95% CI 0.56-0.90; pinteraction = 0.59). Similar findings were observed among participants with (HR 0.73, 95% CI 0.59-0.92) and without background metformin use (HR 0.89, 95% CI 0.72-1.11; pinteraction = 0.22) and in participants with (HR 0.89, 95% CI 0.69-1.16) and without background insulin use (HR 0.78, 95% CI 0.65-0.95; pinteraction = 0.45). Dapagliflozin was well-tolerated irrespective of the number of background GLTs. CONCLUSIONS: Dapagliflozin safely and consistently improved clinical outcomes among individuals with T2D and HF with LVEF >40% irrespective of the number and class of background GLTs, and the benefits were not influenced by concomitant metformin or insulin use. These data bolster contemporary guidelines supporting first-line SGLT2i among individuals with T2D and HF, irrespective of background GLT.