PCSK9 Inhibition During the Inflammatory Stage of SARS-CoV-2 Infection.

BACKGROUND: The intensity of inflammation during COVID-19 is related to adverse outcomes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in low-density lipoprotein receptor homeostasis, with potential influence on vascular inflammation and on COVID-19 inflammatory response. OBJECTIVES: The goal of this study was to investigate the impact of PCSK9 inhibition vs placebo on clinical and laboratory outcomes in patients with severe COVID-19. METHODS: In this double-blind, placebo-controlled, multicenter pilot trial, 60 patients hospitalized for severe COVID-19, with ground-glass opacity pneumonia and arterial partial oxygen pressure to fraction of inspired oxygen ratio ≤300 mm Hg, were randomized 1:1 to receive a single 140-mg subcutaneous injection of evolocumab or placebo. The primary endpoint was death or need for intubation at 30 days. The main secondary endpoint was change in circulating interleukin (IL)-6 at 7 and 30 days from baseline. RESULTS: Patients randomized to receive the PCSK9 inhibitor had lower rates of death or need for intubation within 30 days vs placebo (23.3% vs 53.3%, risk difference: -30%; 95% CI: -53.40% to -6.59%). Serum IL-6 across time was lower with the PCSK9 inhibitor than with placebo (30-day decline: -56% vs -21%). Patients with baseline IL-6 above the median had lower mortality with PCSK9 inhibition vs placebo (risk difference: -37.50%; 95% CI: -68.20% to -6.70%). CONCLUSIONS: PCSK9 inhibition compared with placebo reduced the primary endpoint of death or need for intubation and IL-6 levels in severe COVID-19. Patients with more intense inflammation at randomization had better survival with PCSK9 inhibition vs placebo, indicating that inflammatory intensity may drive therapeutic benefits. (Impact of PCSK9 Inhibition on Clinical Outcome in Patients During the Inflammatory Stage of the COVID-19 [IMPACT-SIRIO 5]; NCT04941105).

Clinical Characteristics and Predictors of In-Hospital Mortality of Patients Hospitalized with COVID-19 Infection.

Background: The identification of parameters that would serve as predictors of prognosis in COVID-19 patients is very important. In this study, we assessed independent factors of in-hospital mortality of COVID-19 patients during the second wave of the pandemic. Material and methods: The study group consisted of patients admitted to two hospitals and diagnosed with COVID-19 between October 2020 and May 2021. Clinical and demographic features, the presence of comorbidities, laboratory parameters, and radiological findings at admission were recorded. The relationship of these parameters with in-hospital mortality was evaluated. Results: A total of 1040 COVID-19 patients (553 men and 487 women) qualified for the study. The in-hospital mortality rate was 26% across all patients. In multiple logistic regression analysis, age ≥ 70 years with OR = 7.8 (95% CI 3.17−19.32), p < 0.001, saturation at admission without oxygen ≤ 87% with OR = 3.6 (95% CI 1.49−8.64), p = 0.004, the presence of typical COVID-19-related lung abnormalities visualized in chest computed tomography ≥40% with OR = 2.5 (95% CI 1.05−6.23), p = 0.037, and a concomitant diagnosis of coronary artery disease with OR = 3.5 (95% CI 1.38−9.10), p = 0.009 were evaluated as independent risk factors for in-hospital mortality. Conclusion: The relationship between clinical and laboratory markers, as well as the advancement of lung involvement by typical COVID-19-related abnormalities in computed tomography of the chest, and mortality is very important for the prognosis of these patients and the determination of treatment strategies during the COVID-19 pandemic.

Comparison of reorganized versus unaltered cardiology departments during the COVID-19 era: A subanalysis of the COV-HF-SIRIO 6 study.

BACKGROUND: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, numerous cardiology departments were reorganized to provide care for COVID-19 patients. We aimed to compare the impact of the COVID-19 pandemic on hospital admissions and in-hospital mortality in reorganized vs. unaltered cardiology departments. METHODS: The present research is a subanalysis of a multicenter retrospective COV-HF-SIRIO 6 study that includes all patients (n = 101,433) hospitalized in 24 cardiology departments in Poland between January 1, 2019 and December 31, 2020, with a focus on patients with acute heart failure (AHF). RESULTS: Reduction of all-cause hospitalizations was 50.6% vs. 21.3% for reorganized vs. unaltered cardiology departments in 2020 vs. 2019, respectively (p < 0.0001). Considering AHF alone respective reductions by 46.5% and 15.2% were registered (p < 0.0001). A higher percentage of patients was brought in by ambulance to reorganized vs. unaltered cardiology departments (51.7% vs. 34.6%; p < 0.0001) alongside with a lower rate of self-referrals (45.7% vs. 58.4%; p < 0.0001). The rate of all-cause in-hospital mortality in AHF patients was higher in reorganized than unaltered cardiology departments (10.9% vs. 6.4%; p < 0.0001). After the exclusion of patients with concomitant COVID-19, the mortality rates did not differ significantly (6.9% vs. 6.4%; p = 0.55). CONCLUSIONS: A greater reduction in hospital admissions in 2020 vs. 2019, higher rates of patients brought by ambulance together with lower rates of self-referrals and higher all-cause in-hospital mortality for AHF due to COVID-19 related deaths were observed in cardiology departments reorganized to provide care for COVID-19 patients vs. unaltered ones.

Determinants of the Level of Anti-SARS-CoV-2 IgG ANTibodiEs after Vaccination (DANTE-SIRIO 7) Study in a Large Cohort of Healthcare Workers.

The aim of this study was to determine anti-SARS-CoV-2 IgG concentrations and their major determinants in healthcare workers (HCWs) after full vaccination with the BNT162b2 vaccine. We recruited 847 individuals vaccinated with two doses of the BNT162b2 vaccine, who completed the questionnaire, and whose antibody concentrations were tested after 3 and 6 months after full vaccination. Anti-SARS-CoV-2 IgG levels were measured on the routinely employed Siemens Atellica system. The cutoff for positivity was ≥21.8 BAU/mL. Three and 6 months after vaccination, the majority of participants were seropositive. Median concentrations of anti-SARS-CoV-2 IgG significantly decreased from 1145 BAU/mL (IQR: 543-2095) to 225 BAU/mL (IQR: 100-510). Major positive determinants of antibody levels were fever after both doses of vaccine, prior-COVID-19 exposure, and muscle pain after the first dose. Lack of symptoms after the second dose and time since vaccination were significant negative determinants of anti-SARS-CoV-2 IgG concentrations. No other factors, including age and gender, or underlying comorbidities had a significant effect on antibody levels in HCWs. The anti-SARS-CoV-2 response after two doses of BNT162b2 vaccine was independently associated with prior-COVID-19 exposure, time since vaccination, and the occurrence of symptoms after either dose of vaccine. Easily reportable adverse reactions may facilitate the identification of immune response in HCWs.

Dutogliptin in Combination with Filgrastim in Early Recovery Post-Myocardial Infarction-The REC-DUT-002 Trial.

Patients with acute myocardial infarction are at high risk for developing heart failure due to scar development. Although regenerative approaches are evolving, consistent clinical benefits have not yet been reported. Treatment with dutogliptin, a second-generation DPP-4 inhibitor, in co-administration with filgrastim (G-CSF) has been shown to enhance endogenous repair mechanisms in experimental models. The REC-DUT-002 trial was a phase 2, multicenter, double-blind placebo-controlled trial which explored the safety, tolerability, and efficacy of dutogliptin and filgrastim in patients with ST-elevation Myocardial Infarction (STEMI). Patients (n = 47, 56.1 ± 10.7 years, 29% female) with STEMI, reduced left ventricular ejection fraction (EF ≤ 45%) and successful revascularization following primary PCI were randomized to receive either study treatment or matching placebo. Cardiac magnetic resonance imaging (cMRI) was performed within 72 h post-PCI and repeated after 3 months. The study was closed out early due to the SARS-CoV-2 pandemic. There was no statistically significant difference between the groups with respect to serious adverse events (SAE). Predefined mean changes within cMRI-derived functional and structural parameters from baseline to 90 days did not differ between placebo and treatment (left ventricular end-diastolic volume: +13.7 mL vs. +15.7 mL; LV-EF: +5.7% vs. +5.9%). Improvement in cardiac tissue health over time was noted in both groups: full-width at half-maximum late gadolinium enhancement (FWHM LGE) mass (placebo: -12.7 g, treatment: -19.9 g; p = 0.23). Concomitant treatment was well tolerated, and no safety issues were detected. Based on the results, the FDA and EMA have already approved an adequately powered large outcome trial.

Ion channel inhibition with amiodarone or verapamil in symptomatic hospitalized nonintensive-care COVID-19 patients: The ReCOVery-SIRIO randomized trial.

BACKGROUND: Ion channel inhibition may offer protection against coronavirus disease 2019 (COVID-19). Inflammation and reduced platelet count occur during COVID-19 but precise quantification of risk thresholds is unclear. The Recov ery-SIRIO study aimed to assess clinical effects of amiodarone and verapamil and to relate patient phenotypes to outcomes. METHODS: RECOVERY-SIRIO is a multicenter open-label 1:1:1 investigator-initiated randomized trial with blinded event adjudication. A sample of 804 symptomatic hospitalized nonintensive-care COVID-19 patients, follow-up for 28 days was initially planned. RESULTS: The trial was stopped when a total of 215 patients had been randomized to amiodarone (n = 71), verapamil (n = 72) or standard care alone (n = 72). At 15 days, the hazard ratio (hazard ratio [HR], 95% confidence interval [CI]) for clinical improvement was 0.77 (0.52-1.14) with amiodarone and 0.97 (0.81-1.17) with verapamil as compared to usual care. Clinically relevant associations were found between mortality or lack of clinical improvement and higher peak C-reactive protein (CRP) levels or nadir platelet count at 7, 10 and 15 days. Mortality rate increased by 73% every 5 mg/dL increment in peak CRP (HR 1.73, 95% CI 1.27-2.37) and was two-fold higher for every decrement of 100 units in nadir platelet count (HR 2.19, 95% CI 1.37-3.51). By cluster analysis, thresholds of 5 mg/dL for peak CRP and 187 × 103/mcL for nadir platelet count identified the phenogroup at greatest risk of dying. CONCLUSIONS: In this randomized trial, neither amiodarone nor verapamil were found to significantly accelerate short-term clinical improvement. Peak CRP and nadir platelet counts were associated with increased mortality both in isolation and by cluster analysis.

The spoils of war and the long-term spoiling of health conditions of entire nations.

The healthcare system of Ukraine was already suffering from several shortfalls before February 2022, but the war of aggression started by the Russian leadership is poised to inflict a further severe blow that will have long-lasting consequences for the health of all Ukrainians. In pre-war Ukraine, noncommunicable diseases (NCDs) contributed to 91% of deaths, especially cardiovascular diseases (67%). Ukrainians have a high prevalence of risk factors for NCDs ranking among the highest levels reported by the World Health Organization (WHO) in the European (EU) Region. Cardiovascular disease is one of the key health risks for the conflict-affected Ukrainian population due to significant limitations in access to health care and interruptions in the supply of medicines and resources. The excess mortality observed during the COVID-19 pandemic, due to a combination of viral illness and chronic disease states, is bound to increase exponentially from poorly treated NCDs. In this report, we discuss the impact of the war on the public health of Ukraine and potential interventions to provide remote health assistance to the Ukrainian population.

Aspirin as an Adjunctive Pharmacologic Therapy Option for COVID-19: Anti-Inflammatory, Antithrombotic, and Antiviral Effects All in One Agent.

INTRODUCTION: Pharmacologic therapy options for COVID-19 should include antiviral, anti-inflammatory, and anticoagulant agents. With the limited effectiveness, currently available virus-directed therapies may have a substantial impact on global health due to continued reports of mutant variants affecting repeated waves of COVID-19 around the world. METHODS: We searched articles pertaining to aspirin, COVID-19, acute lung injury and pharmacology in PubMed and provide a comprehensive appraisal of potential use of aspirin in the management of patients with COVID-19. The scope of this article is to provide an overview of the rationale and currently available clinical evidence that supports aspirin as an effective therapeutic option in COVID-19. RESULTS: Experimental and clinical evidence are available for the potential use of aspirin in patients with COVID-19. DISCUSSION: Aspirin targets the intracellular signaling pathway that is essential for viral replication, and resultant inflammatory responses, hypercoagulability, and platelet activation. With these multiple benefits, aspirin can be a credible adjunctive therapeutic option for the treatment of COVID-19. In addition, inhaled formulation with its rapid effects may enhance direct delivery to the lung, which is the key organ damaged in COVID-19 during the critical initial course of the disease, whereas the 150-325 mg/day can be used for long-term treatment to prevent thrombotic event occurrences. Being economical and widely available, aspirin can be exploited globally, particularly in underserved communities and remote areas of the world to combat the ongoing COVID-19 pandemic.

Impact of COVID-19 pandemic on acute heart failure admissions and mortality: a multicentre study (COV-HF-SIRIO 6 study).

AIMS: The coronavirus disease-2019 (COVID-19) pandemic has changed the landscape of medical care delivery worldwide. We aimed to assess the influence of COVID-19 pandemic on hospital admissions and in-hospital mortality rate in patients with acute heart failure (AHF) in a retrospective, multicentre study. METHODS AND RESULTS: From 1 January 2019 to 31 December 2020, a total of 101 433 patients were hospitalized in 24 Cardiology Departments in Poland. The number of patients admitted due to AHF decreased by 23.4% from 9853 in 2019 to 7546 in 2020 (P < 0.001). We noted a significant reduction of self-referrals in the times of COVID-19 pandemic accounting 27.8% (P < 0.001), with increased number of AHF patients brought by an ambulance by 15.9% (P < 0.001). The length of hospital stay was overall similar (7.7 ± 2.8 vs. 8.2 ± 3.7 days; P = not significant). The in-hospital all-cause mortality in AHF patients was 444 (5.2%) in 2019 vs. 406 (6.5%) in 2020 (P < 0.001). A total number of AHF patients with concomitant COVID-19 was 239 (3.2% of AHF patients hospitalized in 2020). The rate of in-hospital deaths in AHF patients with COVID-19 was extremely high accounting 31.4%, reaching up to 44.1% in the peak of the pandemic in November 2020. CONCLUSIONS: Our study indicates that the COVID-19 pandemic led to (i) reduced hospital admissions for AHF; (ii) decreased number of self-referred AHF patients and increased number of AHF patients brought by an ambulance; and (iii) increased in-hospital mortality for AHF with very high mortality rate for concomitant AHF and COVID-19.

Endogenous fibrinolysis-Relevance to clinical thrombosis risk assessment.

The development of an obstructive luminal thrombus is pathological and considered a failure of endogenous fibrinolysis. The consequences may be fatal, or result in lasting downstream organ damage. Therefore, assessment of endogenous fibrinolytic status in an individual may identify those at risk of occlusive thrombus formation and provide prognostic information. Arterial thrombi are more platelet rich and more resistant to fibrinolysis than venous thrombi. Several recent studies using global tests of fibrinolysis in patients with acute coronary syndromes (ACS) have shown that despite dual antiplatelet therapy, patients with impaired fibrinolytic status have an increased risk of adverse cardiovascular events, compared with those with effective fibrinolytic function. Such data add significantly to the predictive value of established cardiovascular risk factors and conventional biomarkers. Most data reported have been obtained with the Global Thrombosis Test and the turbidimetric plasma clot lysis assay. A few small studies in patients with ischaemic stroke suggest a similar predictive role of fibrinolytic status assessment in these patients. Studies reporting an association between impaired fibrinolysis and future venous thrombotic events are limited, and in the form of case-control studies. Viscoelastic assays may have a role in the prediction of venous thromboembolic risk. Assays of fibrinolytic function should be used to obtain a more accurate risk of future thrombotic events, particularly in the setting of ACS. The availability of point-of-care tests helps facilitate this and should encourage future studies to assess personalised antithrombotic treatment combinations to optimise fibrinolytic status and reduce thrombosis risk.