Design and rationale of FINE-REAL: A prospective study of finerenone in clinical practice.

AIMS: Contemporary patterns of care of patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D) and the adoption of finerenone are not known. The FINE-REAL study (NCT05348733) is a prospective observational study in patients with CKD and T2D to provide insights into the use of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone in clinical practice. METHODS: FINE-REAL is an international, prospective, multicenter, single-arm study enrolling approximately 5500 adults with CKD and T2D in an estimated 200 sites across 22 countries. The study is anticipated to be ongoing until 2027. RESULTS: The primary objective is to describe treatment patterns in patients with CKD and T2D treated with finerenone in routine clinical practice. Secondary objectives include assessment of safety with finerenone. Other endpoints include characterization of healthcare resource utilization and occurrence of newly diagnosed diabetic retinopathy or its progression from baseline in patients with existing disease. A biobank is being organized for future explorative analyses with inclusion of participants from the United States. CONCLUSIONS: FINE-REAL is the first prospective observational study with a nonsteroidal MRA in a population with CKD and T2D and is expected to provide meaningful insights into the treatment of CKD associated with T2D. FINE-REAL will inform decision-making with respect to initiation of finerenone in patients with CKD and T2D.

Renin-Angiotensin-Aldosterone Inhibitors and COVID-19 Infection.

PURPOSE OF REVIEW: This review summarises the literature data and provides an overview of the role and impact of the use of renin-angiotensin-aldosterone system (RAAS) inhibitors in patients with coronavirus disease 2019 (COVID-19) infection. RECENT FINDINGS: The angiotensin-converting enzyme 2 (ACE2) has a key role in the regulation of the RAAS pathway, downregulating angiotensin II and attenuating inflammation, vasoconstriction and oxidative stress. Additionally, it plays an instrumental part in COVID-19 infection as it facilitates the cell entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and enables its replication. The use and role of RAAS inhibitors therefore during the COVID-19 pandemic have been intensively investigated. Although it was initially assumed that RAAS inhibitors may relate to worse clinical outcomes and severe disease, data from large studies and meta-analyses demonstrated that they do not have an adverse impact on clinical outcomes or prognosis. On the contrary, some experimental and retrospective observational cohort studies showed a potential protective mechanism, although this effect remains to be seen in large clinical trials.

Association of Finerenone Use With Reduction in Treatment-Emergent Pneumonia and COVID-19 Adverse Events Among Patients With Type 2 Diabetes and Chronic Kidney Disease: A FIDELITY Pooled Secondary Analysis.

Importance: Patients with chronic kidney disease and type 2 diabetes have a higher risk of developing pneumonia as well as an increased risk of severe COVID-19-associated adverse events and mortality. Therefore, the anti-inflammatory effects of mineralocorticoid receptor antagonists via blockade of the mineralocorticoid receptor may alter the risk of pneumonia and COVID-19-associated adverse events in patients with chronic kidney disease and type 2 diabetes. Objective: To evaluate whether the selective, nonsteroidal mineralocorticoid receptor antagonist finerenone is associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Design, Setting, and Participants: This secondary analysis used patient-level data from FIDELITY, a prespecified pooled analysis of 2 multicenter, double-blind, placebo-controlled, event-driven, phase 3 randomized clinical trials: FIDELIO-DKD and FIGARO-DKD, conducted between September 2015 and February 2021. Patients in FIDELIO-DKD or FIGARO-DKD with type 2 diabetes and chronic kidney disease (urine albumin to creatine ratio, 30-5000 mg/g, estimated glomerular filtration rate ≥25 mL/min/1.73 m2) were assessed. Data were analyzed from May 15, 2021, to July 28, 2022. Exposure: Patients were randomized to finerenone (10 or 20 mg once daily) or matching placebo. Main Outcomes and Measures: The main outcomes were investigator-reported incidences of treatment-emergent infective pneumonia adverse events and serious adverse events (during and up to 3 days after treatment) and any COVID-19 adverse events. Results: Of 13 026 randomized patients (mean [SD] age, 64.8 [9.5] years; 9088 [69.8%] men), 12 999 were included in the FIDELITY safety population (6510 patients receiving finerenone; 6489 patients receiving placebo). Over a median (range) treatment duration of 2.6 (0-5.1) years, finerenone was consistently associated with reduced risk of pneumonia and serious pneumonia vs placebo. Overall, 307 patients (4.7%) treated with finerenone and 434 patients (6.7%) treated with placebo experienced pneumonia (hazard ratio [HR], 0.71; 95% CI, 0.64-0.79; P < .001). Serious pneumonia occurred in 171 patients (2.6%) treated with finerenone and 250 patients (3.9%) treated with placebo (HR, 0.69; 95% CI, 0.60-0.79; P < .001). Incidence proportions of COVID-19 adverse events were 86 patients (1.3%) in the finerenone group and 118 patients (1.8%) in the placebo group (HR, 0.73; 95% CI, 0.60-0.89; P = .002). Conclusions and Relevance: These findings suggest that mineralocorticoid receptor blockade with finerenone was associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Further clinical studies may be warranted. Trial Registration: ClinicalTrials.gov identifiers: FIDELIO-DKD: NCT02540993; FIGARO-DKD: NCT02545049.

Mineralocorticoid receptor-antagonism prevents COVID-19-dependent glycocalyx damage.

Proinflammatory cytokines target vascular endothelial cells during COVID-19 infections. In particular, the endothelial glycocalyx (eGC), a proteoglycan-rich layer on top of endothelial cells, was identified as a vulnerable, vasoprotective structure during infections. Thus, eGC damage can be seen as a hallmark in the development of endothelial dysfunction and inflammatory processes. Using sera derived from patients suffering from COVID-19, we could demonstrate that the eGC became progressively worse in relation to disease severity (mild vs severe course) and in correlation to IL-6 levels. This could be prevented by administering low doses of spironolactone, a well-known and highly specific aldosterone receptor antagonist. Our results confirm that SARS-CoV-2 infections cause eGC damage and endothelial dysfunction and we outline the underlying mechanisms and suggest potential therapeutic options.

Impact of the withdrawal of renin-angiotensin-aldosterone inhibitors on mortality in COVID-19 patients.

Background: Chronic use of Angiotensin-converting enzyme (ACE) inhibitors (ACEi) and aldosterone-receptor blockers (ARB) is not associated with worse outcomes in patients with COVID-19. However, evidence on the impact of their discontinuation during hospital admission is scarce. Our aim was to determine whether withdrawal of ACEi, ARB and mineralocorticoid receptor antagonists (MRA) is associated with all-cause mortality in a real-life large cohort of patients with SARS-CoV-2 infection. Methods: Observational cohort study from a large referral center from 1 March 2020 to 20 April 2020. Withdrawal of renin-angiotensin-aldosterone system inhibitors was defined as the absence of any received dose during hospital admission in patients receiving chronic treatment. Prescriptions during admission were confirmed by data from the central pharmacy computerized system. Results: A total of 2042 patients (mean age 68.4±17.6, 57.1% male) with confirmed COVID-19 were included. During a median follow-up of 57 (21-55) days, 583 (28.6%) died. Prior to hospital admission 468 (22.9%), 343 (16.8%) and 83 (4.1%) patients were receiving ACEi, ARB and MRA respectively. During the study period, 216 (46.2%), 193 (56.3%) and 41 (49.4%) were withdrawn from the corresponding drug. After adjusting for age, cardiovascular risk factors, baseline comorbidities and in-hospital COVID-19 dedicated treatment, withdrawal of ACE inhibitors (hazard ration [HR] 1.48 [95% confidence interval -CI- 1.16-1.89]) and MRA (HR 2.01 [95% CI 1.30-3.10]) were shown to be independent predictors of all-cause mortality. No independent relationship between ARB withdrawal and mortality was observed. Conclusion: ACEi and MRA withdrawal were associated with higher mortality. Strong consideration should be given to not discontinuing these medications during hospital admission.

Introdução: O uso crónico de inibidores da ECA (IECA) e de antagonistas dos recetores de aldosterona (ARA) não está associado a resultados piores em doentes com Covid-19. No entanto, a evidência relativa ao impacto da sua retirada durante a admissão hospitalar é escassa. O nosso objetivo foi determinar se a retirada do IECA, ARA e antagonistas dos recetores dos mineralocorticóides (ARM) está associada à mortalidade por todas as causas numa grande coorte real de doentes com infeção por SRA-CoV-2. Métodos: Estudo coorte observacional a partir de um grande centro de referência de 1 de março de 2020 a 20 de abril de 2020. A retirada dos inibidores do sistema RAAS foi definida como a ausência de qualquer dose recebida durante a admissão hospitalar em doentes que recebem tratamento prolongado. As prescrições durante a admissão foram confirmadas por dados do sistema informático da farmácia central. Resultados: Um total de 2042 doentes (idade média de 68,4 ±17,6, 57,1% do sexo masculino) com COVID-19 confirmado foram incluídos. Durante um acompanhamento médio de 57 (21-55) dias, 583 (28,6%) morreram. Conclusão: A retirada do IECA e do ARM foi associada a uma mortalidade mais elevada. Deve ser dada grande atenção para não interromper estes medicamentos durante a admissão hospitalar.

Association of Renin-Angiotensin-Aldosterone Inhibitors with COVID-19 Infection and Disease Severity among Individuals with Hypertension.

BACKGROUND: The association between use of renin-angiotensin-aldosterone (RAAS) inhibitors and both SARS-CoV-2 infection and the development of severe COVID-19 has been presented in the recent medical literature with inconsistent results. OBJECTIVES: To assess the association between RAAS inhibitor use and two outcomes: infection with SARS-CoV-2 (Model 1) and severe COVID-19 among those infected (Model 2). METHODS: We accessed used electronic health records of individuals from Israel who were receiving anti-hypertensive medications for this retrospective study. For Model 1 we used a case-control design. For Model 2 we used a cohort design. In both models, inverse probability weighting adjusted for identified confounders as part of doubly robust outcome regression. RESULTS: We tested 38,554 individuals for SARS-CoV-2 who had hypertension and were being treated with medication; 691 had a positive test result. Among those with a positive test, 119 developed severe illness. There was no association between RAAS inhibitor use and a positive test. Use of RAAS inhibitors was associated with a decreased risk for severe COVID-19 (adjusted odds ratio [OR] 0.47, 95% confidence interval [95%CI] 0.29-0.77) compared with users of non-RAAS anti-hypertensive medication. The association remained significant when use of angiotensin-converting-enzyme inhibitors (adjusted OR 0.46, 95%CI 0.27-0.77) and angiotensin II receptor blockers (adjusted OR 0.39, 95%CI 0.16-0.95) were analyzed separately. CONCLUSIONS: Among individuals with hypertension using RAAS inhibitors, we found a lower risk of severe disease compared to those using non-RAAS anti-hypertensive medications. This finding suggests that RAAS inhibitors may have a protective effect on COVID-19 severity among individuals with medically treated hypertension.

Economic Issues in Heart Failure in the United States.

The cost of heart failure care is high owing to the cost of hospitalization and chronic treatments. Heart failure treatments vary in their benefit and cost. The cost effectiveness of therapies can be determined by comparing the cost of treatment required to obtain a certain benefit, often defined as an increase in 1 year of life. This review was sponsored by the Heart Failure Society of America and describes the growing economic burden of heart failure for patients and the health care system in the United States. It also provides a summary of the cost effectiveness of drugs, devices, diagnostic tests, hospital care, and transitions of care for patients with heart failure. Many medications that are no longer under patent are inexpensive and highly cost-effective. These include angiotensin-converting enzyme inhibitors, beta-blockers and mineralocorticoid receptor antagonists. In contrast, more recently developed medications and devices, vary in cost effectiveness, and often have high out-of-pocket costs for patients.

Spironolactone effect on the blood pressure of patients at risk of developing heart failure: an analysis from the HOMAGE trial.

AIMS: Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined. To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone's effect. METHODS AND RESULTS: HOMAGE (Heart OMics in Aging) was a prospective multicentre randomized open-label blinded endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25-50 mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, Months 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations was used. The median (percentile25-75) age was 73 (69-79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by -10.3 (-13.0 to -7.5) mmHg and DBP by -3.2 (-4.8 to -1.7) mmHg (P < 0.001 for both). A higher proportion of patients on spironolactone had controlled BP <130/80 mmHg (36 vs. 26%; P = 0.014). Lower baseline renin levels predicted a greater response to spironolactone (interactionP = 0.041). CONCLUSION: Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.

[Expert opinion. Spironolactone: a new twist on an old story].

The article presents recent data on possibilities of a broader use of mineralocorticoid receptor antagonists for existing indications and of expanding indications for the use of this pharmaceutical group in the context of the novel coronavirus infection COVID-19. The authors discussed prospects for expanded detection of aldosteronism using a new diagnostic approach, including an additional evaluation of blood pressure response to spironolactone.

[New clinical opportunities for mineralocorticoid receptor antagonists: focus on antifibrotic effects].

Mineralocorticoid receptor antagonists have been successfully used for many years to treat patients with primary hyperaldosteronism, refractory arterial hypertension and chronic heart failure. The increased interest in this drug in recent years is due to new information about its antifibrotic and antiproliferative effects, both cardiac and extracardiac. The article also discusses the possibility of using spironolactone in patients with the new coronavirus infection SARS-CoV-2 (COVID-19).

The LIFT trial: study protocol for a double-blind, randomised, placebo-controlled trial of K+-binder Lokelma for maximisation of RAAS inhibition in CKD patients with heart failure.

BACKGROUND: CKD is common in heart failure (HF) and associated with morbidity and mortality, yet life-prolonging medications such as renin-angiotensin-aldosterone inhibitors (RAASi) are underused due to risk of hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is a potassium-binding medication that has been shown to reduce incidence of hyperkalaemia in CKD, non-CKD, and HF populations, which we propose will support maximisation of RAASi therapy. METHODS: We propose a 1:1 randomised, double-blind, placebo-controlled trial in which participants will receive either SZC or placebo. We will up-titrate participants' RAASi therapy while monitoring their serum potassium levels and adjusting their SZC dose if necessary. Participants with CKD and HF will be recruited from CKD and HF clinics at St George's Hospital. The total study period will be 18 months; 130 participants will be enrolled for approximately two months each following screening. Our primary outcome will be the proportion of participants who achieve maximum RAASi dose while maintaining normokalaemia. Secondary outcomes include participants reaching maximum RAASi dose without severe hyperkalaemia; time from randomisation to hyperkalaemia; time from randomisation to severe hyperkalaemia; number of RAASi dose escalations per participant; final doses of RAASi therapy; changes in quality of life score, eGFR, ACR, serum sodium, troponin T; number and duration of hospital admissions; and within-participant change in serum potassium compared to baseline. DISCUSSION: This trial will be the first to examine the use of SZC for the maximisation of RAASi dosing in patients with advanced CKD and HF. We will assess the impact of achieving target RAASi dosing on hospital admission rates and duration of stay, with the hope that optimum RAASi treatment will translate into reduced morbidity and improved QoL. If clinical benefit is demonstrated, we hope that the joint multidisciplinary CKD-HF approach will be expanded. TRIAL REGISTRATION: EudraCT number 2020-002946-18. Registered on 08 June 2020. Online record pending.

Effects of Renin-Angiotensin-Aldosterone Inhibitors on Early Outcomes of Hypertensive COVID-19 Patients: A Randomized Triple-Blind Clinical Trial.

BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) has been addressed in some studies related to the current coronavirus disease-2019 (COVID-19) pandemic with possible higher severity and mortality in patients with hypertension. A triple-blind randomized controlled trial was designed to evaluate the effects of these medications on the COVID-19 progression. METHODS: Patients were enrolled in this trial between April and September 2020. They were randomized in 2 groups. The former dosage of ACEis/ARBs was continued in one group while in another group, the ACEis/ARBs were replaced by amlodipine ± carvedilol according to the dose equivalents. The primary outcomes were length of stay in hospitals and intensive care units (ICUs). Other outcomes include mechanical ventilation, noninvasive ventilation, readmission, and COVID-19 symptoms after discharge. RESULTS: We randomized 64 patients with COVID-19 into 2 groups. Most patients were aged 66-80 and 46-65 years-old, 33 (51.6%) and 27 (42.2%), respectively. The study groups were nearly similar in baseline vital signs and characteristics. In addition, there was no significant difference in terms of recorded systolic and diastolic blood pressure measurements between groups. Furthermore, we did not find a significant difference between the days of ICU or ward admission, the discharge rate, or readmission rates between the 2 groups. CONCLUSIONS: This randomized triple-blind multicentric clinical trial did not show any deleterious effects of ACEi/ARB medications in hypertensive COVID-19 patients. CLINICAL TRIALS REGISTRATION: The trial acquired the ethical code, IR.TUMS.VCR.REC.1399.028 and was registered in the Iranian randomized controlled trial system (registration no. IRCT20151113025025N3), https://en.irct.ir/trial/46531.

Tailoring the management of hypertension to comorbidities.

PURPOSE OF REVIEW: In this article, we review the most current evidence for initiation and maintenance of various antihypertension (HTN) drug classes, including other misconceptions with respect to common comorbidities in patients with HTN. RECENT FINDINGS: Although the currently available anti-HTN agents have broad applicability in treating HTN, additional agents, such as angiotensin receptor-neprilysin inhibitors and novel nonsteroidal mineralocorticoid antagonists, have recently gained clinical significance. In addition, there have been some anecdotal concerns regarding the adverse effects, indications, and risks of COVID-19 infection/mortality when using certain anti-HTN agents. SUMMARY: Current guidelines currently address the treatment of primary HTN. However, isolated HTN is uncommon and often involves comorbid diseases that require specific regimentation. Several experimental medications are currently in late-stage trials showing potential superiority over current drugs that are available in the market.

Chronic use of renin-angiotensin-aldosterone inhibitors in hypertensive COVID-19 patients: Results from a Spanish registry and meta-analysis.

BACKGROUND: Hypertension is a prevalent condition among SARS-CoV-2 infected patients. Whether renin-angiotensin-aldosterone system (RAAS) inhibitors are beneficial or harmful is controversial. METHODS: We have performed a national retrospective, nonexperimental comparative study from two tertiary hospitals to evaluate the impact of chronic use of RAAS inhibitors in hypertensive COVID-19 patients. A meta-analysis was performed to strengthen our findings. RESULTS: Of 849 patients, 422 (49.7%) patients were hypertensive and 310 (73.5%) were taking RAAS inhibitors at baseline. Hypertensive patients were older, had more comorbidities, and a greater incidence of respiratory failure (-0.151 [95% CI -0.218, -0.084]). Overall mortality in hypertensive patients was 28.4%, but smaller among those with prescribed RAAS inhibitors before (-0.167 [95% CI -0.220, -0.114]) and during hospitalization (0.090 [-0.008,0.188]). Similar findings were observed after two propensity score matches that evaluated the benefit of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers among hypertensive patients. Multivariate logistic regression analysis of hypertensive patients found that age, diabetes mellitus, C-reactive protein, and renal failure were independently associated with all-cause mortality. On the contrary, ACEIs decreased the risk of death (OR 0.444 [95% CI 0.224-0.881]). Meta-analysis suggested a protective benefit of RAAS inhibitors (OR 0.6 [95% CI 0.42-0.8]) among hypertensive COVID-19. CONCLUSION: Our data suggest that RAAS inhibitors may play a protective role in hypertensive COVID-19 patients. This finding was supported by a meta-analysis of the current evidence. Maintaining these medications during hospital stay may not negatively affect COVID-19 outcomes.

Type 2 myocardial infarction and myocardial injury: eligibility for novel medical therapy to derisk clinical trials.

BACKGROUND: Patients with type 2 myocardial infarction (T2MI) and other mechanisms of nonthrombotic myocardial injury have an unmet therapeutic need. Eligibility for novel medical therapy is generally uncertain. METHODS: We predefined colchicine, eplerenone and ticagrelor as candidates for repurposing towards novel therapy for T2MI or myocardial injury. Considering eligibility for randomisation in a clinical trial, each drug was classified according to indications and contraindications for therapy and survival for at least 24 hours following admission. Eligibility criteria for prescription were evaluated against the Summary of Medical Product Characteristics. Consecutive hospital admissions were screened to identify patients with ≥1 high-sensitivity troponin-I value >99th percentile. Endotypes of myocardial injury were adjudicated according to the Fourth Universal Definition of MI. Patients' characteristics and medication were prospectively evaluated. RESULTS: During 1 March to 15 April 2020, 390 patients had a troponin I>URL. Reasons for exclusion: type 1 MI n=115, indeterminate diagnosis n=42, lack of capacity n=14, death <24 hours n=7, duplicates n=2. Therefore, 210 patients with T2MI/myocardial injury and 174 (82.8%) who survived to discharge were adjudicated for treatment eligibility. Patients who fulfilled eligibility criteria initially on admission and then at discharge were colchicine 25/210 (11.9%) and 23/174 (13.2%); eplerenone 57/210 (27.1%) and 45/174 (25.9%); ticagrelor 122/210 (58.1%) and 98/174 (56.3%). Forty-six (21.9%) and 38 (21.8%) patients were potentially eligible for all three drugs on admission and discharge, respectively. CONCLUSION: A reasonably high proportion of patients may be considered eligible for repurposing novel medical therapy in secondary prevention trials of type 2 MI/myocardial injury.

Report from the CVOT Summit 2020: new cardiovascular and renal outcomes.

The 6th Cardiovascular Outcome Trial (CVOT) Summit "Cardiovascular and Renal Outcomes 2020" was the first to be held virtually on October 29-30, 2020. As in previous years, this summit served as reference meeting for in-depth discussions on the topic of recently completed and presented major outcome trials. This year, focus was placed on the outcomes of VERTIS-CV, EMPEROR-Reduced, DAPA-CKD, and FIDELIO-DKD. Trial implications for diabetes management and the impact on new treatment algorithms were highlighted for diabetologists, cardiologists, endocrinologists, nephrologists, and general practitioners. Discussion evolved from major outcome trials using SGLT-2 inhibitors for treatment and prevention of heart failure and chronic kidney disease in people with and without diabetes, to additional therapy options for chronic kidney disease with a novel mineralocorticoid receptor antagonist. Furthermore, challenges in diabetes management like COVID-19 and obesity, as well as novel treatment strategies and guidelines, were discussed.The 7th Cardiovascular Outcome Trial Summit will be held virtually on November, 18-19, 2021 ( http://www.cvot.org ).

Is Spironolactone the Preferred Renin-Angiotensin-Aldosterone Inhibitor for Protection Against COVID-19?

ABSTRACT: The high mortality of specific groups from COVID-19 highlights the importance of host-viral interactions and the potential benefits from enhancing host defenses. SARS-CoV-2 requires angiotensin-converting enzyme (ACE) 2 as a receptor for cell entry and infection. Although both ACE inhibitors and spironolactone can upregulate tissue ACE2, there are important points of discrimination between these approaches. The virus requires proteolytic processing of its spike protein by transmembrane protease receptor serine type 2 (TMPRSS2) to enable binding to cellular ACE2. Because TMPRSS2 contains an androgen promoter, it may be downregulated by the antiandrogenic actions of spironolactone. Furin and plasmin also process the spike protein. They are inhibited by protease nexin 1 or serpin E2 (PN1) that is upregulated by angiotensin II but downregulated by aldosterone. Therefore, spironolactone should selectively downregulate furin and plasmin. Furin also promotes pulmonary edema, whereas plasmin promotes hemovascular dysfunction. Thus, a downregulation of furin and plasmin by PN1 could be a further benefit of MRAs beyond their well-established organ protection. We review the evidence that spironolactone may be the preferred RASSi to increase PN1 and decrease TMPRSS2, furin, and plasmin activities and thereby reduce viral cell binding, entry, infectivity, and bad outcomes. This hypothesis requires direct investigation.

New Horizons: Does Mineralocorticoid Receptor Activation by Cortisol Cause ATP Release and COVID-19 Complications?

This paper attempts to explain how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes the complications that make coronavirus disease 2019 (COVID-19) a serious disease in specific patient subgroups. It suggests that cortisol-associated activation of the mineralocorticoid receptor (MR) in epithelial and endothelial cells infected with the virus stimulates the release of adenosine 5'-triphosphate (ATP), which then acts back on purinergic receptors. In the lung this could produce the nonproductive cough via purinergic P2X3 receptors on vagal afferent nerves. In endothelial cells it could stimulate exocytosis of Weibel-Palade bodies (WPBs) that contain angiopoietin-2, which is important in the pathogenesis of acute respiratory distress syndrome (ARDS) by increasing capillary permeability and von Willebrand factor (VWF), which mediates platelet adhesion to the endothelium and hence clotting. Angiopoietin-2 and VWF levels both are markedly elevated in COVID-19-associated ARDS. This paper offers an explanation for the sex differences in SARS-CoV-2 complications and also for why these are strongly associated with age, race, diabetes, and body mass index. It also explains why individuals with blood group A have a higher risk of severe infection than those with blood group O. Dexamethasone has been shown to be of benefit in coronavirus ARDS patients and has been thought to act as an anti-inflammatory drug. This paper suggests that a major part of its effect may be due to suppression of cortisol secretion. There is an urgent need to trial the combination of dexamethasone and an MR antagonist such as spironolactone to more effectively block the MR and hence the exocytosis of WPBs.

[Impact of the COVID-19 pandemic on the management of heart failure outpatient clinics. Lessons during the lockdown restrictions]. / Le ricadute della pandemia COVID-19 sulla gestione dell'Ambulatorio Scompenso. Esperienze e considerazioni operative dopo il lockdown.

BACKGROUND: During the COVID-19 pandemic, non-urgent outpatient activities were temporarily suspended. The aim of this study was to assess the impact of this measure on the management of the heart failure outpatient clinic at our institution. METHODS: We analyzed the clinical outcome of 110 chronic heart failure patients (mean age 73 ± 9 years) whose follow-up visit had been delayed. RESULTS: At their last visit before the lockdown, 80.9% was in NYHA class II, had an ejection fraction of 37 ± 7%, and B-type natriuretic peptide level was moderately elevated (266 ± 138 pg/ml). All patients received loop diuretics, 97.2% beta-blockers, 64.9% an aldosterone antagonist, 60.9% sacubitril/valsartan (S/V), and 72.2% of the remaining patients were on angiotensin-converting enzyme inhibitor or valsartan therapy. Patients were contacted by phone during and at the end of the lockdown period to fix a new appointment and underwent a structured interview to assess their clinical conditions and ongoing therapy and to verify whether they had contracted SARS-CoV-2 infection. Twelve patients (13.2%) contracted COVID-19. None was hospitalized for worsening heart failure or reported defibrillator shocks and none changed autonomously the prescribed therapy. Overall, 75% of patients reported stable or improved general well-being from the last in-person visit, while 25% described subjective worsening due to the social effect of the pandemic. Unchanged body weight and blood pressure values were reported by 86% and 78.4% of patients, respectively. Lower blood pressure values compared to baseline were recorded in 15.2% of patients on conventional renin-angiotensin system inhibition vs 21% of those on S/V, one of whom had to down-titrate S/V for persistent but asymptomatic hypotension; 4 patients up-titrated S/V to 200 mg/day following phone indications. CONCLUSIONS: Cancellation of scheduled follow-up visits during 3 months did not have significant negative effects in a cohort of stable patients with chronic heart failure on optimized medical therapy. Telephone support was effective in keeping connections with the patients during the lockdown, allowing appropriate management and implementation of drug therapy. In particular, patients who received S/V were not affected by delays in scheduled visits, confirming the tolerability and safety of this novel therapy in terms of both clinical and biohumoral parameters.

Currently prescribed drugs in the UK that could upregulate or downregulate ACE2 in COVID-19 disease: a systematic review.

OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.