Myeloperoxidase Inhibition in Heart Failure With Preserved or Mildly Reduced Ejection Fraction: SATELLITE Trial Results.

BACKGROUND: Inflammation is a key driver of heart failure with preserved left ventricular ejection fraction. AZD4831 inhibits extracellular myeloperoxidase, decreases inflammation, and improves microvascular function in preclinical disease models. METHODS AND RESULTS: In this double-blind phase 2a study (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure [SATELLITE]; NCT03756285), patients with symptomatic heart failure, left ventricular ejection fraction of ≥40%, and elevated B-type natriuretic peptides were randomized 2:1 to once-daily oral AZD4831 5 mg or placebo for 90 days. We aimed to assess target engagement (primary end point: myeloperoxidase specific activity) and safety of AZD4831. Owing to coronavirus disease 2019, the study was terminated early after randomizing 41 patients (median age 74.0 years, 53.7% male). Myeloperoxidase activity was decreased by more than 50% from baseline to day 30 and day 90 in the AZD4831 group, with a placebo-adjusted decreased of 75% (95% confidence interval, 48, 88, nominal P < .001). No improvements were noted in secondary or exploratory end points, apart from a trend in Kansas City Cardiomyopathy Questionnaire overall summary score. No deaths or treatment-related serious adverse events occurred. AZD4831 treatment-related adverse events were generalized maculopapular rash, pruritus, and diarrhea (all n = 1). CONCLUSIONS: AZD4831 inhibited myeloperoxidase and was well tolerated in patients with heart failure and left ventricular ejection fraction of 40% or greater. Efficacy findings were exploratory owing to early termination, but warrant further clinical investigation of AZD4831. LAY SUMMARY: Few treatments are available for patients with the forms of heart failure known as heart failure with preserved or mildly reduced ejection fraction. Current treatments do not target inflammation, which may play an important role in this condition. We tested a new drug called AZD4831 (mitiperstat), which decreases inflammation by inhibiting the enzyme myeloperoxidase. Among the 41 patients in our clinical trial, AZD4831 had a good safety profile and inhibited myeloperoxidase by the expected amount. Results mean we can conduct further trials to see whether AZD4831 decreases the symptoms of heart failure and improves patients' ability to participate in physical exercise.

Association between use of novel glucose-lowering drugs and COVID-19 hospitalization and death in patients with type 2 diabetes: a nationwide registry analysis.

AIMS: Type 2 diabetes (T2DM) in patients with coronavirus disease-19 (COVID-19) is associated with worse prognosis. We separately investigated the associations between the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i), and the risk of COVID-19 hospitalization and death. METHODS AND RESULTS: Patients with T2DM registered in the Swedish National Patient Registry and alive on 1st February 2020 were included. "Incident severe COVID-19" was defined as the first hospitalization and/or death from COVID-19. A modified Poisson regression approach was applied to a 1:1 propensity score-matched population receiving vs. not receiving SGLT2i, GLP-1 RA and DPP-4i to analyze the associations between their use and I) incident severe COVID-19, II) risk of 30-day mortality in patients hospitalized for COVID-19.Among 344,413 patients, 39,172 (11%) were treated with SGLT2i, 34,290 (10%) with GLP-1 RA and 53,044 (15%) with DPP-4i; 9,538 (2.8%) had incident severe COVID-19 by 15th May 2021. SGLT2i and DPP-4i were associated with a 10% and 11% higher risk of incident severe COVID-19, respectively, whereas there was no association for GLP-1 RA. DPP-4i were also associated with a 10% higher 30-day mortality in patients hospitalized for COVID-19, whereas there was no association for SGLT2i and GLP-1 RA. CONCLUSION: SGLT2i and DPP-4i use was associated with higher risk of incident severe COVID-19. DPP-4i use was associated with higher 30-day mortality in patients with COVID-19, whereas SGLT2i use was not. No increased risk for any outcome was observed with GLP-1 RA.

COVID-19 vaccination in patients with heart failure: a position paper of the Heart Failure Association of the European Society of Cardiology.

Patients with heart failure (HF) who contract SARS-CoV-2 infection are at a higher risk of cardiovascular and non-cardiovascular morbidity and mortality. Regardless of therapeutic attempts in COVID-19, vaccination remains the most promising global approach at present for controlling this disease. There are several concerns and misconceptions regarding the clinical indications, optimal mode of delivery, safety and efficacy of COVID-19 vaccines for patients with HF. This document provides guidance to all healthcare professionals regarding the implementation of a COVID-19 vaccination scheme in patients with HF. COVID-19 vaccination is indicated in all patients with HF, including those who are immunocompromised (e.g. after heart transplantation receiving immunosuppressive therapy) and with frailty syndrome. It is preferable to vaccinate against COVID-19 patients with HF in an optimal clinical state, which would include clinical stability, adequate hydration and nutrition, optimized treatment of HF and other comorbidities (including iron deficiency), but corrective measures should not be allowed to delay vaccination. Patients with HF who have been vaccinated against COVID-19 need to continue precautionary measures, including the use of facemasks, hand hygiene and social distancing. Knowledge on strategies preventing SARS-CoV-2 infection (including the COVID-19 vaccination) should be included in the comprehensive educational programmes delivered to patients with HF.

Heart failure in COVID-19: the multicentre, multinational PCHF-COVICAV registry.

AIMS: We assessed the outcome of hospitalized coronavirus disease 2019 (COVID-19) patients with heart failure (HF) compared with patients with other cardiovascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia). We further wanted to determine the incidence of HF events and its consequences in these patient populations. METHODS AND RESULTS: International retrospective Postgraduate Course in Heart Failure registry for patients hospitalized with COVID-19 and CArdioVascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia) was performed in 28 centres from 15 countries (PCHF-COVICAV). The primary endpoint was in-hospital mortality. Of 1974 patients hospitalized with COVID-19, 1282 had cardiovascular disease and/or risk factors (median age: 72 [interquartile range: 62-81] years, 58% male), with HF being present in 256 [20%] patients. Overall in-hospital mortality was 25% (n = 323/1282 deaths). In-hospital mortality was higher in patients with a history of HF (36%, n = 92) compared with non-HF patients (23%, n = 231, odds ratio [OR] 1.93 [95% confidence interval: 1.44-2.59], P < 0.001). After adjusting, HF remained associated with in-hospital mortality (OR 1.45 [95% confidence interval: 1.01-2.06], P = 0.041). Importantly, 186 of 1282 [15%] patients had an acute HF event during hospitalization (76 [40%] with de novo HF), which was associated with higher in-hospital mortality (89 [48%] vs. 220 [23%]) than in patients without HF event (OR 3.10 [2.24-4.29], P < 0.001). CONCLUSIONS: Hospitalized COVID-19 patients with HF are at increased risk for in-hospital death. In-hospital worsening of HF or acute HF de novo are common and associated with a further increase in in-hospital mortality.

Mechanistic and Therapeutic Implications of Extracellular Vesicles as a Potential Link Between Covid-19 and Cardiovascular Disease Manifestations.

Extracellular vesicles (EVs), which are cell released double layered membrane particles, have been found in every circulating body fluid, and provide a tool for conveying diverse information between cells, influencing both physiological and pathological conditions. Viruses can hijack the EVs secretory pathway to exit infected cells and use EVs endocytic routes to enter uninfected cells, suggesting that EVs and viruses can share common cell entry and biogenesis mechanisms. SARS-CoV-2 is responsible of the coronavirus disease 2019 (Covid-19), which may be accompanied by severe multi-organ manifestations. EVs may contribute to virus spreading via transfer of virus docking receptors such as CD9 and ACE2. Covid-19 is known to affect the renin angiotensin system (RAS), and could promote secretion of harmful EVs. In this scenario EVs might be linked to cardiovascular manifestations of the Covid-19 disease through unbalance in RAS. In contrast EVs derived from mesenchymal stem cells or cardiosphere derived cells, may promote cardiovascular function due to their beneficial effect on angiogenesis, fibrosis, contractility and immuno-modulation. In this article we assessed the potential impact of EVs in cardiovascular manifestations of Covid-19 and highlight potential strategies to control the extracellular signaling for future therapies.

Association between renin-angiotensin-aldosterone system inhibitor use and COVID-19 hospitalization and death: a 1.4 million patient nationwide registry analysis.

AIMS: Renin-angiotensin-aldosterone system inhibitors (RAASi) improve outcomes in cardiorenal disease but concerns have been raised over increased risk of incident hospitalization and death from coronavirus disease 2019 (COVID-19). We investigated the association between use of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs) or mineralocorticoid receptor antagonists (MRAs) and COVID-19 hospitalization/death in a large nationwide population. METHODS AND RESULTS: Patients with hypertension, heart failure, diabetes, kidney disease, or ischaemic heart disease registered in the Swedish National Patient Registry until 1 February 2020 were included and followed until 31 May 2020. COVID-19 cases were defined based on hospitalization/death for COVID-19. Multivariable logistic and Cox regressions were fitted to investigate the association between ACEi/ARB and MRA and risk of hospitalization/death for COVID-19 in the overall population, and of all-cause mortality in COVID-19 cases. We performed consistency analysis to quantify the impact of potential unmeasured confounding. Of 1 387 746 patients (60% receiving ACEi/ARB and 5.8% MRA), 7146 (0.51%) had incident hospitalization/death from COVID-19. After adjustment for 45 variables, ACEi/ARB use was associated with a reduced risk of hospitalization/death for COVID-19 (odds ratio 0.86, 95% confidence interval 0.81-0.91) in the overall population, and with reduced mortality in COVID-19 cases (hazard ratio 0.89, 95% confidence interval 0.82-0.96). MRA use was not associated with risk of any outcome. Consistency analysis showed that unmeasured confounding would need to be large for there to be harmful signals associated with RAASi use. CONCLUSIONS: In a 1.4 million nationwide cohort, use of RAASi was not associated with increased risk of hospitalization for or death from COVID-19.

Impact of Coronavirus Disease 2019 (COVID-19) Outbreak on Acute Admissions at the Emergency and Cardiology Departments Across Europe.

PURPOSE: We evaluated whether the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) pandemic was associated with changes in the pattern of acute cardiovascular admissions across European centers. METHODS: We set-up a multicenter, multinational, pan-European observational registry in 15 centers from 12 countries. All consecutive acute admissions to emergency departments and cardiology departments throughout a 1-month period during the COVID-19 outbreak were compared with an equivalent 1-month period in 2019. The acute admissions to cardiology departments were classified into 5 major categories: acute coronary syndrome, acute heart failure, arrhythmia, pulmonary embolism, and other. RESULTS: Data from 54,331 patients were collected and analyzed. Nine centers provided data on acute admissions to emergency departments comprising 50,384 patients: 20,226 in 2020 compared with 30,158 in 2019 (incidence rate ratio [IRR] with 95% confidence interval [95%CI]: 0.66 [0.58-0.76]). The risk of death at the emergency departments was higher in 2020 compared to 2019 (odds ratio [OR] with 95% CI: 4.1 [3.0-5.8], P < 0.0001). All 15 centers provided data on acute cardiology departments admissions: 3007 patients in 2020 and 4452 in 2019; IRR (95% CI): 0.68 (0.64-0.71). In 2020, there were fewer admissions with IRR (95% CI): acute coronary syndrome: 0.68 (0.63-0.73); acute heart failure: 0.65 (0.58-0.74); arrhythmia: 0.66 (0.60-0.72); and other: 0.68(0.62-0.76). We found a relatively higher percentage of pulmonary embolism admissions in 2020: odds ratio (95% CI): 1.5 (1.1-2.1), P = 0.02. Among patients with acute coronary syndrome, there were fewer admissions with unstable angina: 0.79 (0.66-0.94); non-ST segment elevation myocardial infarction: 0.56 (0.50-0.64); and ST-segment elevation myocardial infarction: 0.78 (0.68-0.89). CONCLUSION: In the European centers during the COVID-19 outbreak, there were fewer acute cardiovascular admissions. Also, fewer patients were admitted to the emergency departments with 4 times higher death risk at the emergency departments.