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Heart failure with preserved ejection fraction: diagnosis, risk assessment, and treatment.
von Haehling, S, Assmus, B, Bekfani, T, Dworatzek, E, Edelmann, F, Hashemi, D, Hellenkamp, K, Kempf, T, Raake, P, Schütt, KA, et al
Clinical research in cardiology : official journal of the German Cardiac Society. 2024
Abstract
The aetiology of heart failure with preserved ejection fraction (HFpEF) is heterogenous and overlaps with that of several comorbidities like atrial fibrillation, diabetes mellitus, chronic kidney disease, valvular heart disease, iron deficiency, or sarcopenia. The diagnosis of HFpEF involves evaluating cardiac dysfunction through imaging techniques and assessing increased left ventricular filling pressure, which can be measured directly or estimated through various proxies including natriuretic peptides. To better narrow down the differential diagnosis of HFpEF, European and American heart failure guidelines advocate the use of different algorithms including comorbidities that require diagnosis and rigorous treatment during the evaluation process. Therapeutic recommendations differ between guidelines. Whilst sodium glucose transporter 2 inhibitors have a solid evidence base, the recommendations differ with regard to the use of inhibitors of the renin-angiotensin-aldosterone axis. Unless indicated for specific comorbidities, the use of beta-blockers should be discouraged in HFpEF. The aim of this article is to provide an overview of the current state of the art in HFpEF diagnosis, clinical evaluation, and treatment.
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2.
Management of Resistant Hypertension.
Lauder, L, Mahfoud, F, Böhm, M
Annual review of medicine. 2024;:443-457
Abstract
Resistant hypertension (RH) is a severe form of hypertension associated with increased cardiovascular risk. Although true RH affects less than 10% of the patients receiving antihypertensive therapy, the absolute number is high and continues to increase. The workup of these patients requires screening for secondary hypertension and pseudoresistance, including poor adherence to prescribed medicines and the white-coat phenomenon. The treatment of RH consists of lifestyle modifications and pharmacological therapies. Lifestyle modifications include dietary adjustments, weight loss, physical activity, and limiting alcohol consumption; pharmacological therapies include diuretics, mineralocorticoid receptor antagonists, beta blockers, angiotensin receptor-neprilysin inhibitors, and others. Over the last 15 years, interventional approaches have emerged as adjunct treatment options; we highlight catheter-based renal denervation. This review summarizes the rationales and latest clinical evidence and, based thereon, proposes an updated algorithm for the management of RH.
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3.
Latest pharmaceutical approaches across the spectrum of heart failure.
Bismpos, D, Wintrich, J, Hövelmann, J, Böhm, M
Heart failure reviews. 2024;(3):675-687
Abstract
Despite major advances in prevention and medical therapy, heart failure (HF) remains associated with high morbidity and mortality, especially in older and frailer patients. Therefore, a complete, guideline-based treatment is essential, even in HF patients with conditions traditionally associated with a problematic initiation and escalation of the medical HF therapy, such as chronic kidney disease and arterial hypotension, as the potential adverse effects are overcome by the overall decrease of the absolute risk. Furthermore, since the latest data suggest that the benefit of a combined medical therapy (MRA, ARNI, SGLT2i, beta-blocker) may extend up to a LVEF of 65%, further trials on these subgroups of patients (HFmrEF, HFpEF) are needed to re-evaluate the guideline-directed medical therapy across the HF spectrum. In particular, the use of SGLT2i was recently extended to HFpEF patients, as evidenced by the DELIVER and EMPEROR-preserved trials. Moreover, the indication for other conservative treatments in HF patients, such as the intravenous iron supplementation, was accordingly strengthened in the latest guidelines. Finally, the possible implementation of newer substances, such as finerenone, in guideline-directed medical practice for HF is anticipated with great interest.
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Impact of Empagliflozin in Heart Failure With Reduced Ejection Fraction in Patients With Ischemic Versus Nonischemic Cause.
Khan, MS, Butler, J, Anker, SD, Filippatos, G, Ferreira, JP, Pocock, SJ, Januzzi, JL, Piña, IL, Böhm, M, Ponikowski, P, et al
Journal of the American Heart Association. 2023;(1):e027652
Abstract
Background Outcomes and treatment effects of therapy may vary according to the cause of heart failure (HF). Methods and Results In this post hoc analysis of the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) trial, the effect of empagliflozin on cardiovascular and renal outcomes was assessed according to the cause of HF. The cause of HF was investigator reported and stratified as ischemic or nonischemic. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs. Of the 3730 patients enrolled, 1929 (51.7%) had ischemic cause. In the placebo arm, patients with ischemic cause of HF did not have a significantly higher risk of cardiovascular mortality (HR, 1.21 [95% CI, 0.90-1.63]) and hospitalization for HF (HR, 0.90 [95% CI, 0.72-1.12]) compared with nonischemic cause. Empagliflozin compared with placebo significantly reduced the risk of cardiovascular death or hospitalization for HF in patients with ischemic and nonischemic cause (HR, 0.82 [95% CI, 0.68-0.99] for ischemic and HR, 0.67 [95% CI, 0.55-0.82] for nonischemic cause; P interaction=0.15). The benefit of empagliflozin on HF hospitalization, the renal composite end point, estimated glomerular filtration slope changes, and health status scores were also consistent in both groups without treatment by cause modification. Conclusions Empagliflozin offers cardiovascular and renal benefits in patients with heart failure with reduced ejection fraction regardless of the cause of HF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.
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Efficacy and safety of intravenous iron repletion in patients with heart failure: a systematic review and meta-analysis.
Vukadinović, D, Abdin, A, Emrich, I, Schulze, PC, von Haehling, S, Böhm, M
Clinical research in cardiology : official journal of the German Cardiac Society. 2023;(7):954-966
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Abstract
INTRODUCTION AFFIRM-AHF and IRONMAN demonstrated lower rates of the combined endpoint recurrent heart failure (HF) hospitalizations and cardiovascular death (CVD) using intravenous (IV) ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), respectively in patients with HF and iron deficiency (ID) utilizing prespecified COVID-19 analyses. MATERIAL AND METHODS We meta-analyzed efficacy, between trial heterogeneity and data robustness for the primary endpoint and CVD in AFFIRM-AHF and IRONMAN. As sensitivity analysis, we analyzed data from all eligible exploratory trials investigating FCM/FDI in HF. RESULTS FCM/FDI reduced the primary endpoint (RR = 0.81, 95% CI 0.69-0.95, p = 0.01, I2 = 0%), with the number needed to treat (NNT) being 7. Power was 73% and findings were robust with fragility index (FI) of 94 and fragility quotient (FQ) of 0.041. Effects of FCM/FDI were neutral concerning CVD (OR = 0.88, 95% CI 0.71-1.09, p = 0.24, I2 = 0%). Power was 21% while findings were fragile with reverse FI of 14 and reversed FQ of 0.006. The sensitivity analysis from all eligible trials (n = 3258) confirmed positive effects of FCM/FDI on the primary endpoint (RR = 0.77, 95% CI 0.66-0.90, p = 0.0008, I2 = 0%), with NNT being 6. Power was 91% while findings were robust (FI of 147 and FQ of 0.045). Effect on CVD was neutral (RR = 0.87, 95% CI 0.71-1.07, p = 0.18, I2 = 0%). Power was 10% while findings were fragile (reverse FI of 7 and reverse FQ of 0.002). Rate of infections (OR = 0.85, 95% CI 0.71-1.02, p = 0.09, I2 = 0%), vascular disorder (OR = 0.84, 95% CI 0.57-1.25, p = 0.34, I2 = 0%) and general or injection-site related disorders (OR = 1.39, 95% CI 0.88-1.29, p = 0.16, I2 = 30%) were comparable between groups. There was no relevant heterogeneity (I2 > 50%) between the trials for any of the analyzed outcomes. CONCLUSIONS Use of FCM/FDI is safe and reduces the composite of recurrent HF hospitalizations and CVD, while effects on CVD alone are based on available level of data indeterminate. Findings concerning composite outcomes exhibit a high level of robustness without heterogeneity between trials with FCM and FDI.
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Hidden sodium in effervescent-tablet dietary supplements and over-the-counter drugs: a comparative cross-sectional study.
Kunz, M, Götzinger, F, Jacobs, CM, Lauder, L, Ukena, C, Meyer, MR, Laufs, U, Schulz, M, Böhm, M, Mahfoud, F
BMJ open. 2023;(11):e076302
Abstract
OBJECTIVE Dietary sodium intake represents a risk factor for cardiovascular disease and mortality. The study sought to analyse the sodium content of effervescent dietary supplements and drugs in Germany and the USA. DESIGN Comparative cross-sectional study. SETTING AND METHODS The sodium content of 39 dietary supplement effervescent tablets available in Germany was measured in May and June 2022 using optical emission spectrometry with inductively coupled argon plasma. The sodium content of 33 common pharmacy-only effervescent tablets (over-the-counter (OTC) drugs) in Germany was obtained from the summary of product characteristics. We compared the sodium content of the measured German dietary supplement effervescent tablets to that of 51 dietary supplement effervescent tablets available in the USA (data: National Institutes of Health's Dietary Supplement Label Database). RESULTS The measured sodium content in the German dietary supplements was 283.9±122.6 mg sodium/tablet, equivalent to 14±6% of the maximum recommended daily sodium intake (MRDSI). Vitamin products had the highest (378.3±112.8 mg, 19±6% of MRDSI), and calcium products had the lowest mean sodium content (170.4±113.2 mg, 9±6% of MRDSI). Vitamin products contained significantly more sodium than magnesium (378.3 mg vs 232.7 mg; p=0.004), calcium (378.3 mg vs 170.4 mg; p=0.006) and mineral products (378.3 mg vs 191.6 mg; p=0.048). The sodium content measured in products available in Germany was higher when compared with the declared sodium content on the label of the products sold in the USA (283.9 mg vs 190.0 mg; p<0.001). The median summary of product characteristics-declared sodium content of a single dose of the German OTC drugs was 157.0 mg (IQR: 98.9-417.3 mg); pain/common cold drugs contained the most sodium (median: 452.1 mg; IQR: 351.3-474.0 mg). CONCLUSION Effervescent tablets of nutritional supplements and OTC drugs contain high amounts of sodium, which often is not disclosed.
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Pleiotropic effects of NOACs with focus on edoxaban: scientific findings and potential clinical implications.
Goette, A, Mollenhauer, M, Rudolph, V, Lamparter, M, Meier, M, Böhm, M
Herzschrittmachertherapie & Elektrophysiologie. 2023;(2):142-152
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Abstract
Non-vitamin K antagonist oral anticoagulants (NOACs) are well-established as inhibitors of factor Xa (FXa) and thrombin in the treatment and prevention of thrombosis. However, there is growing evidence that beneficial outcomes might be based on additional pleiotropic effects beyond anticoagulation. FXa and thrombin are also known to activate protease-activated receptors (PARs), which can mediate pro-inflammatory and pro-fibrotic effects. Since PAR‑1 and PAR‑2 play an important role in the development of atherosclerosis, the inhibition of this pathway represents an interesting potential target for preventing the progression of atherosclerosis and fibrosis. This review focuses on potential pleiotropic effects of FXa inhibition with edoxaban seen in a variety of studies in different in vitro and in vivo test systems. As common findings from these experiments, edoxaban was able to attenuate FXa- and thrombin-induced pro-inflammatory and pro-fibrotic effects and decrease pro-inflammatory cytokine expression. In some, but not all experiments edoxaban was also shown to decrease the levels of PAR‑1 and PAR‑2 expression. Further studies are required to clarify the clinical implications of the pleiotropic effects mediated by NOACs.
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Hypertension management in patients with cardiovascular comorbidities.
Lauder, L, Mahfoud, F, Azizi, M, Bhatt, DL, Ewen, S, Kario, K, Parati, G, Rossignol, P, Schlaich, MP, Teo, KK, et al
European heart journal. 2023;(23):2066-2077
Abstract
Arterial hypertension is a leading cause of death globally. Due to ageing, the rising incidence of obesity, and socioeconomic and environmental changes, its incidence increases worldwide. Hypertension commonly coexists with Type 2 diabetes, obesity, dyslipidaemia, sedentary lifestyle, and smoking leading to risk amplification. Blood pressure lowering by lifestyle modifications and antihypertensive drugs reduce cardiovascular (CV) morbidity and mortality. Guidelines recommend dual- and triple-combination therapies using renin-angiotensin system blockers, calcium channel blockers, and/or a diuretic. Comorbidities often complicate management. New drugs such as angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists improve CV and renal outcomes. Catheter-based renal denervation could offer an alternative treatment option in comorbid hypertension associated with increased sympathetic nerve activity. This review summarises the latest clinical evidence for managing hypertension with CV comorbidities.
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Medication-Attributable Adverse Events in Heart Failure Trials.
Harrington, J, Fonarow, GC, Khan, MS, Hernandez, A, Anker, S, Böhm, M, Greene, SJ, Felker, GM, Vaduganathan, M, Butler, J
JACC. Heart failure. 2023;(4):425-436
Abstract
BACKGROUND Initiation and up-titration of guideline-directed medical therapies (GDMTs) for heart failure with reduced ejection fraction (HFrEF) remains suboptimal, in part because of concerns regarding tolerability and adverse events (AEs). OBJECTIVES The authors sought to compare rates of AE in patients randomized to GDMT medication vs placebo in a meta-analysis of landmark cardiovascular outcomes trials. METHODS The authors assessed rates of reported AE in 17 landmark HFrEF clinical trials across each class of GDMT in the placebo and intervention arms. The overall rates of AE for each drug class, the absolute difference in frequency in AEs between the placebo and intervention arms, and the odds of each AE according based on randomization strata were calculated. RESULTS AE were reported commonly in trials across each class of GDMT, with 75% to 85% of participants reporting at least 1 AE. There was no significant difference in the frequency of AE between the intervention and placebo arms, except for angiotensin-converting enzyme inhibitors (87.0% [95% CI: 85.0%-88.8%] vs 82.0% [95% CI: 79.8%-84.0%], absolute difference: +5% with intervention; P < 0.001). There was no significant difference in drug discontinuation because of AE between placebo and intervention arms in angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists, sodium glucose cotransporter 2 inhibitors, or angiotensin receptor neprilysin inhibitor/angiotensin II receptor blocker trials. Patients randomized to beta-blocker were significantly less likely to stop study drug because of AE than placebo (11.3% [95% CI: 10.3%-12.3%] vs 13.7% [95% CI: 12.5%-14.9%], absolute difference: -1.1%; P = 0.015). When individual types of AE were assessed, the initiation of an intervention vs placebo resulted in small differences in absolute frequency of AE that were largely not statistically significant. CONCLUSIONS In clinical trials of GDMT for HFrEF, AEs are observed frequently. However, rates of AE are similar between active medication and control, suggesting these may reflect the high risk nature of the heart failure disease state rather than be attributive to a specific therapy.
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Patient phenotype profiling in heart failure with preserved ejection fraction to guide therapeutic decision making. A scientific statement of the Heart Failure Association, the European Heart Rhythm Association of the European Society of Cardiology, and the European Society of Hypertension.
Anker, SD, Usman, MS, Anker, MS, Butler, J, Böhm, M, Abraham, WT, Adamo, M, Chopra, VK, Cicoira, M, Cosentino, F, et al
European journal of heart failure. 2023;(7):936-955
Abstract
Heart failure with preserved ejection fraction (HFpEF) represents a highly heterogeneous clinical syndrome affected in its development and progression by many comorbidities. The left ventricular diastolic dysfunction may be a manifestation of various combinations of cardiovascular, metabolic, pulmonary, renal, and geriatric conditions. Thus, in addition to treatment with sodium-glucose cotransporter 2 inhibitors in all patients, the most effective method of improving clinical outcomes may be therapy tailored to each patient's clinical profile. To better outline a phenotype-based approach for the treatment of HFpEF, in this joint position paper, the Heart Failure Association of the European Society of Cardiology, the European Heart Rhythm Association and the European Hypertension Society, have developed an algorithm to identify the most common HFpEF phenotypes and identify the evidence-based treatment strategy for each, while taking into account the complexities of multiple comorbidities and polypharmacy.