Prostacyclin in Intubated Patients with COVID-19 and Severe Endotheliopathy: A Multicenter, Randomized Clinical Trial.

Rationale: The mortality in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who require mechanical ventilation remains high, and endotheliopathy has been implicated. Objectives: To determine the effect of prostacyclin infusion in mechanically ventilated patients infected with SARS-CoV-2 with severe endotheliopathy. Methods: We conducted a multicenter, randomized clinical trial in adults infected with coronavirus disease (COVID-19) who required mechanical ventilation and had a plasma level of thrombomodulin >4 ng/ml; patients were randomized to 72-hour infusion of prostacyclin 1 ng/kg/min or placebo. Measurements and Main Results: The main outcome was the number of days alive and without mechanical ventilation within 28 days. Key secondary outcomes were 28-day mortality and serious adverse events within 7 days. Eighty patients were randomized (41 prostacyclin and 39 placebo). The median number of days alive without mechanical ventilation at 28 days was 16.0 days (SD, 12) versus 5.0 days (SD, 10) (difference of the medians, 10.96 days; 95% confidence interval [CI], -5 to 21; P = 0.07) in the prostacyclin and the placebo groups, respectively. The 28-day mortality was 21.9% versus 43.6% in the prostacyclin and the placebo groups, respectively (risk ratio, 0.50; 95% CI, 0.24 to 0.96; P = 0.06). The incidence of serious adverse events within 7 days was 2.4% versus 12.8% (risk ratio, 0.19; 95% CI, 0.001 to 1.11; P = 0.10) in the prostacyclin and the placebo groups, respectively. Conclusions: Prostacyclin was not associated with a significant reduction in the number of days alive and without mechanical ventilation within 28 days. The point estimates, however, favored the prostacyclin group in all analyses, including 28-day mortality, warranting further investigation in larger trials. Clinical trial registered with www.clinicaltrials.gov (NCT04420741); EudraCT Identifier: 2020-001296-33.

Focal Cerebral Arteriopathy in a Young Adult Following SARS-CoV2 Reinfection.

Ten days after SARS-Cov2 reinfection with mild gastrointestinal symptoms and headache that occurred 2 months after an initial infection, a previously healthy 37-year-old woman developed fluctuating facial and upper limb paresthesia and weakness. Diffusion-weighted magnetic resonance imaging revealed ischemic lesions in the right parietal region of different stages within the same vascular territory. A cerebral angiography demonstrated an isolated focal arteriopathy with no other arterial involvement. Focal cerebral arteriopathy is exceedingly rare among adults and most commonly triggered by varicella-zoster virus reactivation. We present a case of focal cerebral arteriopathy in a patient with a recent reinfection with SARS-CoV-2.

The impact of frailty on epistaxis admission, a retrospective cohort study.

OBJECTIVES: Epistaxis is frequently managed with intra-nasal packing devices, traditionally requiring patient admission. Current COVID-19 guidelines encourage ambulatory care where possible in this patient cohort. This paper aims to establish the impact of the Clinical Frailty Scale, anticoagulant/antiplatelet therapeutics and season variation on pre-pandemic admissions to help identify patients suitable for ambulatory epistaxis management. DESIGN: Retrospective cohort study SETTING: Scottish Regional Health Board PARTICIPANTS: Adult patients attending secondary care with epistaxis between March 2019 and March 2020. MAIN OUTCOME MEASURES: Likelihood of epistaxis hospital admission based on Clinical Frailty Scale. RESULTS: 299 epistaxis presentations were identified, of which 122 (40.8%) required admission. Clinical Frailty Scale of ≥4 had an increased likelihood of admission (OR 3.15 (95% CI:1.94-5.16), P < .05). In the majority of presentations (66.2%), patients were taking either an antiplatelet or anticoagulant. Of these presentations, the use of an anticoagulant (OR: 2.00 (95% CI: 1.20-3.33), P < .05 and dual antiplatelet (OR: 2.82 (95% CI: 1.02-7.86), P < .05) demonstrated increased likelihood of admission. CONCLUSIONS: We have shown that frailty increases the risk of admission in adult patients presenting with epistaxis. Clinical Frailty Scale (CFS) could be utilised in risk stratification to identify suitable patients for outpatient management. Patients with CFS ≤ 3 could be considered for outpatient management of their epistaxis. It is likely that patients with CFS ≥4 on anticoagulant or dual antiplatelet will require admission.

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: A propensity score-matched analysis.

Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. We examined in-hospital mortality with intermediate- compared to prophylactic-dose anticoagulation, and separately with in-hospital aspirin compared to no antiplatelet therapy, in a large, retrospective study of 2785 hospitalized adult COVID-19 patients. In this analysis, we established two separate, nested cohorts of patients (a) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (b) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). To minimize bias and adjust for confounding factors, we incorporated propensity score matching and multivariable regression utilizing various markers of illness severity and other patient-specific covariates, yielding treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death. Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate- compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]). In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.

Impact of oral anticoagulation on clinical outcomes of COVID-19: a nationwide cohort study of hospitalized patients in Germany.

OBJECTIVES: The aim of this study was to investigate the impact of concomitant long-term medication-with a focus on ACE inhibitors and oral anticoagulation-on clinical outcomes in patients hospitalized with coronavirus disease 2019. METHODS: This is a retrospective cohort study using claims data of the biggest German health insurance company AOK, covering 26.9 million people all over Germany. In particular, patient-related characteristics and co-medication were evaluated. A multivariable logistic regression model was adopted to identify independent predictors for the primary outcome measure of all-cause mortality or need for invasive or non-invasive ventilation or extracorporeal membrane oxygenation. RESULTS: 6637 patients in 853 German hospitals were included. The primary outcome occurred in 1826 patients (27.5%). 1372 patients (20.7%) died, 886 patients (13.3%) needed respiratory support, and 53 patients (0.8%) received extracorporeal membrane oxygenation. 34 of these patients survived (64.2%). The multivariable model demonstrated that pre-existing oral anticoagulation therapy with either vitamin-K antagonists OR 0.57 (95% CI 0.40-0.83, p = 0.003) or direct oral anticoagulants OR 0.71 (95% CI 0.56-0.91, p = 0.007)-but not with antiplatelet therapy alone OR 1.10 (95% CI 0.88-1.23, p = 0.66)-was associated with a lower event rate. This finding was confirmed in a propensity match analysis. CONCLUSIONS: In a multivariable analysis, a therapy with both direct oral anticoagulants or vitamin-K antagonists-but not with antiplatelet therapy-was associated with improved clinical outcomes. ACE inhibitors did not impact outcomes. Prospective randomized trials are needed to verify this hypothesis.

Proteinase-activated receptor 1: A target for repurposing in the treatment of COVID-19?

In the search to rapidly identify effective therapies that will mitigate the morbidity and mortality of COVID-19, attention has been directed towards the repurposing of existing drugs. Candidates for repurposing include drugs that target COVID-19 pathobiology, including agents that alter angiotensin signalling. Recent data indicate that key findings in COVID-19 patients include thrombosis and endotheliitis. Activation of proteinase-activated receptor 1 (PAR1), in particular by the serine protease thrombin, is a critical element in platelet aggregation and coagulation. PAR1 activation also impacts on the actions of other cell types involved in COVID-19 pathobiology, including endothelial cells, fibroblasts and pulmonary alveolar epithelial cells. Vorapaxar is an approved inhibitor of PAR1, used for treatment of patients with myocardial infarction or peripheral arterial disease. We discuss evidence for a possible beneficial role for vorapaxar in the treatment of COVID-19 patients and other as-yet non-approved antagonists of PAR1 and proteinase-activated receptor 4 (PAR4). LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

Bilateral, vertical supranuclear gaze palsy following unilateral midbrain infarct.

A 60-year-old man recently admitted for bipedal oedema, endocarditis and a persistently positive COVID-19 swab with a history of anticoagulation on rivaroxaban for atrial fibrillation, transitional cell carcinoma, cerebral amyloid angiopathy, diabetes and hypertension presented with sudden onset diplopia and vertical gaze palsy. Vestibulo-ocular reflex was preserved. Simultaneously, he developed a scotoma and sudden visual loss, and was found to have a right branch retinal artery occlusion. MRI head demonstrated a unilateral midbrain infarct. This case demonstrates a rare unilateral cause of bilateral supranuclear palsy which spares the posterior commisure. The case also raises a question about the contribution of COVID-19 to the procoagulant status of the patient which already includes atrial fibrillation and endocarditis, and presents a complex treatment dilemma regarding anticoagulation.

Antiplatelet/anticoagulant agents for preventing thrombosis events in patients with severe COVID-19: A protocol for systematic review and meta-analysis.

BACKGROUND: On March 11, 2020, World Health Organization announced that severe acute respiratory syndrome coronavirus 2 caused COVID-19 was a global pandemic. COVID-19 is associated with venous thromboembolism including deep vein thrombosis and pulmonary embolism. To further identify the current role of antiplatelet/anticoagulant therapy in the prophylaxis and treatment of COVID-19 patients is important. METHODS: We will conduct a systematic review based on searches of major databases (eg, Pubmed, Web of Science, EMBASE, CENTRAL, MEDLINE, SCI-EXPANDED, CPCI-S, CBM, CNKI, and Wanfang Database) and clinical trial registries from inception to present without limitations of language and publication status. All published randomized control trials, quasi-randomized trials, retrospective and observational studies related to prophylactic antiplatelet/anticoagulant for severe COVID-19 will be included. Primary outcome includes incident acute thrombosis events. Second outcome is the incidence and severity of adverse effects. Full-text screening, data extraction and quality assessment will be conducted by 2 reviewers independently. The reporting quality, risk of bias, sensitivity analysis and subgroup analysis will be performed to ensure the reliability of our findings by other 2 researchers. The statistical analysis will be performed by RevMan V.5.3 software and Stata V.12.0 software. RESULTS: The result of this systematic review will provide valid advice and consultation for clinicians on the management of prophylactic antiplatelet/anticoagulant for severe COVID-19 patients. CONCLUSION: This systematic review will provide evidence for prophylactic antiplatelet/anticoagulant of severe COVID-19 patients. PROSPERO REGISTRATION: CRD42020186928.

The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications.

The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing global pandemic has presented a health emergency of unprecedented magnitude. Recent clinical data has highlighted that coronavirus disease 2019 (COVID-19) is associated with a significant risk of thrombotic complications ranging from microvascular thrombosis, venous thromboembolic disease, and stroke. Importantly, thrombotic complications are markers of severe COVID-19 and are associated with multiorgan failure and increased mortality. The evidence to date supports the concept that the thrombotic manifestations of severe COVID-19 are due to the ability of SARS-CoV-2 to invade endothelial cells via ACE-2 (angiotensin-converting enzyme 2), which is expressed on the endothelial cell surface. However, in patients with COVID-19 the subsequent endothelial inflammation, complement activation, thrombin generation, platelet, and leukocyte recruitment, and the initiation of innate and adaptive immune responses culminate in immunothrombosis, ultimately causing (micro)thrombotic complications, such as deep vein thrombosis, pulmonary embolism, and stroke. Accordingly, the activation of coagulation (eg, as measured with plasma D-dimer) and thrombocytopenia have emerged as prognostic markers in COVID-19. Given thrombotic complications are central determinants of the high mortality rate in COVID-19, strategies to prevent thrombosis are of critical importance. Several antithrombotic drugs have been proposed as potential therapies to prevent COVID-19-associated thrombosis, including heparin, FXII inhibitors, fibrinolytic drugs, nafamostat, and dipyridamole, many of which also possess pleiotropic anti-inflammatory or antiviral effects. The growing awareness and mechanistic understanding of the prothrombotic state of COVID-19 patients are driving efforts to more stringent diagnostic screening for thrombotic complications and to the early institution of antithrombotic drugs, for both the prevention and therapy of thrombotic complications. The shifting paradigm of diagnostic and treatment strategies holds significant promise to reduce the burden of thrombotic complications and ultimately improve the prognosis for patients with COVID-19.

SEDAR-SEMICYUC consensus recommendations on the management of haemostasis disorders in severely ill patients with COVID-19 infection. / Recomendaciones de consenso SEDAR-SEMICYUC sobre el manejo de las alteraciones de la hemostasia en los pacientes graves con infección por COVID-19.

The infection by the coronavirus SARS-CoV-2, which causes the disease called COVID-19, mainly causes alterations in the respiratory system. In severely ill patients, the disease often evolves into an acute respiratory distress syndrome that can predispose patients to a state of hypercoagulability, with thrombosis at both venous and arterial levels. This predisposition presents a multifactorial physiopathology, related to hypoxia as well as to the severe inflammatory process linked to this pathology, including the additional thrombotic factors present in many of the patients. In view of the need to optimise the management of hypercoagulability, the working groups of the Scientific Societies of Anaesthesiology-Resuscitation and Pain Therapy (SEDAR) and of Intensive, Critical Care Medicine and Coronary Units (SEMICYUC) have developed a consensus to establish guidelines for actions to be taken against alterations in haemostasis observed in severely ill patients with COVID-19. These recommendations include prophylaxis of venous thromboembolic disease in these patients, and in the peripartum, management of patients on long-term antiplatelet or anticoagulant treatment, bleeding complications in the course of the disease, and the interpretation of general alterations in haemostasis.

Reorganizing the treatment of cardiovascular disease in response to coronavirus disease 2019; time for the polypill?

PURPOSE OF REVIEW: The coronavirus disease 2019 (COVID-19) pandemic has forced a redesign of healthcare services. Resource reallocation will have consequences on the routine management of chronic diseases, including cardiovascular disease (CVD). We consider how to mitigate potential adverse effects. RECENT FINDINGS: Combination therapy is well established in hypertension. Many guidelines recommend dual antihypertensive therapy as the initial treatment step as this results in faster blood pressure control, albeit with limited evidence of improved outcomes. Control of CVD risk factors through multiclass combination therapy (the polypill) was proposed many years ago. This approach has not been adopted by Western healthcare systems despite improving surrogate outcomes. Recently, the PolyIran trials have demonstrated improved CVD outcomes without increased adverse events, in both primary and secondary prevention. SUMMARY: The COVID-19 pandemic allows models of chronic healthcare to be rethought. Current practices are resource-intensive and there is a need to simplify titration and monitoring protocols in CVD. Moving toward the use of polypill combinations allied with telehealth consultations may be one solution.