Systematic Review and Meta-Analysis: Can We Compare Direct Oral Anticoagulants to Warfarin in Patients With Atrial Fibrillation and Bio-Prosthetic Valves?

Background There are no clear consensus guidelines on the indications and types of anticoagulation therapies in patients with bio-prosthetic valves either with concomitant atrial fibrillation (AF) or sinus rhythm. In our meta-analysis, we assessed the safety and efficacy of DOACs as compared to the standard treatment with warfarin in patients with AF and bioprosthetic valves. Methods We included randomized controlled trials (RCTs), cohort studies in the English language, and studies reporting patients with valvular heart disease that included bioprosthetic valvular disease. A systematic literature review using Embase, PubMed, and Web of Science was performed using the terms "Direct Acting Oral Anticoagulant," "Oral Anticoagulants," "Non-Vitamin K Antagonist Oral Anticoagulant," "Atrial Fibrillation," "Bioprosthetic Valve" for literature published prior to January 2021. Extraction of data from included studies was carried out independently by three reviewers from Covidence. We assessed the methodical rigor of the included studies using the modified Downs and Black checklist. Results Four RCTs and one observational study (n=1776) were included in our study. A random-effect model using RevMan (version 5.4; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen) was used for data analysis. The pooled data showed that there was a non-significant reduction in the incidence of stroke and systemic embolism in the patients taking DOACs as compared to warfarin (HR 0.69; 95% CI, 0.29, 1.67; I2 = 50%). The incidence of major bleeding was lower in the DOACs group; the difference was statistically significant (HR 0.42; 95% CI, 0.26, 0.67; I2 = 7%). The difference was not statistically significant for all-cause mortality in both groups (HR 1.24; 95% CI, 0.91, 1.67; I2 = 0%). Conclusion Our results showed that there was no difference in the outcomes of stroke and systemic embolism between DOACs and warfarin but there were statistically significantly lower major bleeding events. We conclude that larger clinical trials are needed to assess the true safety and efficacy of DOACs in patients with AF and bioprosthetic valves.

Review of Medical Therapies for the Management of Pulmonary Embolism.

Traditionally, the management of patients with pulmonary embolism has been accomplished with anticoagulant treatment with parenteral heparins and oral vitamin K antagonists. Although the administration of heparins and oral vitamin K antagonists still plays a role in pulmonary embolism management, the use of these therapies are limited due to other options now available. This is due to their toxicity profile, clearance limitations, and many interactions with other medications and nutrients. The emergence of direct oral anticoagulation therapies has led to more options now being available to manage pulmonary embolism in inpatient and outpatient settings conveniently. These oral therapeutic options have opened up opportunities for safe and effective pulmonary embolism management, as more evidence and research is now available about reversal agents and monitoring parameters. The evolution of the pharmacological management of pulmonary embolism has provided us with better understanding regarding the selection of anticoagulants. There is also a better understanding and employment of anticoagulants in pulmonary embolism in special populations, such as patients with liver failure, renal failure, malignancy, and COVID-19.

Antithrombotic prophylaxis in children and adolescents' patients with SARS-CoV-2 (COVID-19) infection: A practical guidance for clinicians.

Severe coronavirus disease 2019 (COVID-19) is often associated with features of hypercoagulable state which can manifest as venous thromboembolism (VTE) and/or microthrombosis. Given the high risk of VTE in critically ill COVID-19 patients, appropriate VTE prophylaxis seems to be an important part of managing these patients. Although many protocols regarding venous thromboembolism (VTE) prophylaxis or therapeutic (full-dose) anticoagulation have been conducted worldwide, primarily in hospitalised adult patients, details on paediatric patients, if included, are limited or incomplete. The current evidences suggest that anticoagulation therapy with low molecular weight heparins (LMWH) appears to be associated with better prognosis in patients with moderate to severe COVID-19 induced coagulopathies or elevated D-dimer levels.  Our recommendations are intended to offer guidance for anticoagulation prophylaxis and treatment in COVID-19 children and adolescent patients and not intend to supersede the clinician judgement. We are also conscious that several clinical questions deserve further studies and clarifications because this area is rapidly evolving.

A Retrospective Analysis of Thromboembolic Phenomena in Mechanically Ventilated Patients with COVID-19.

BACKGROUND: Recent studies have shown an increased prevalence of thromboembolic disease in critically ill patients with the novel SARS-CoV-2 disease (COVID-19). However, the use of enhanced anticoagulation therapy in these patients remains controversial. OBJECTIVES: To determine the incidence of thromboembolic phenomena (TEP) and hemorrhagic events (HEs) in intensive care unit (ICU) COVID-19 patients. METHODS: One hundred and sixty ICU patients with COVID-19 were enrolled. Clinical examination results, laboratory data, and imaging studies (computed tomography/Doppler ultrasound scans) for these patients were retrospectively collected and analyzed. Outcome measures including days on mechanical ventilation, ICU length of stay, and day-28 mortality were recorded. RESULTS: Sixty patients (37.5%) developed TEP including thirty patients with deep vein thrombosis, 55 patients with pulmonary embolism, and 7 patients with arterial thromboembolism. Cardiac arrhythmias, lymphocytopenia, and increased D-dimers were more frequently observed in the TEP group compared to the non-TEP group of patients (all p < 0.05). The sensitivity, specificity, and positive and negative predictive values of a cutoff D-dimer level of 3.0 µg/mL for predicting PE were 74.5%, 95.1%, 86.8%, and 91.9%, respectively. Thirteen patients experienced HEs, which were more frequently observed in the TEP group (p < 0.05). Twenty-eight-day mortality was higher in the TEP group (60%) compared to the non-TEP group (30%) of patients (p=0.02). CONCLUSIONS: The rates of TEP and HEs in mechanically ventilated critically ill COVID-19 patients were 37. 5% and 8.1%. Twenty-eight-day mortality was higher in the TEP group (60%) compared to the non-TEP group (30%) of patients.

Clinical Characteristics of Patients with Severe and Critical COVID-19 in Wuhan: A Single-Center, Retrospective Study.

INTRODUCTION: This retrospective, single-center study was performed to systemically describe the characteristics and outcomes of patients with severe and critical coronavirus disease 2019 (COVID-19) in Wuhan, analyze the risk factors, and propose suggestions for clinical diagnosis and treatment to guide the subsequent clinical practice. METHODS: A total of 753 consecutive patients with COVID-19 admitted to the West Campus of Wuhan Union Hospital from January 22, 2020 to May 7, 2020 were enrolled in this study. Demographic, clinical, laboratory, and outcome data were extracted from the electronic medical records of Wuhan Union Hospital and were exhaustively analyzed using R (version 3.6.1). RESULTS: A total of 493 severe and 228 critical cases out of 753 COVID-19 cases were considered in this study. Among the critical cases, the death rate was 79.4%, and age was a risk factor for death. Compared to the severe disease group, the critical disease group had higher white blood cell (WBC) and neutrophil counts and a decreased lymphocyte count at admission. Compared to early death cases (death within 1 week after admission), a more prolonged course of the disease was associated with a higher risk of hypoproteinemia, liver injury, thrombocytopenia, anemia, disseminated intravascular coagulation (DIC), coagulation disorders, acute kidney injury (AKI), and infection. Higher creatine kinase (CK) and lactate dehydrogenase (LDH) levels were related to early death events, but univariate and multivariate analyses confirmed only LDH as an independent predictor of early death. Notably, anticoagulation therapy was associated with an improved prognosis of critical cases in this cohort. CONCLUSION: Our results showed large differences between patients with severe and critical COVID-19. During the course of COVID-19 in the critical disease group, the incidence of hypoproteinemia, anemia, thrombocytopenia, and coagulation disorders increased significantly, which highlighted the importance of medical care in the first week after admission. LDH could act as an independent predictor of early death in critical cases, and anticoagulation therapy was correlated with an improved prognosis of patients with critical COVID-19.

A considerable asymptomatic proportion and thromboembolism risk of pregnant women with COVID-19 infection in Wuhan, China.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) had become a worldwide pandemic, however, information is limited on the asymptomatic proportion and thromboembolism risk of pregnant women with infection. METHODS: All 32 pregnant women with COVID-19 who were admitted to the hospital in Wuhan during the outbreak from January 20 to March 18, 2020, were retrospectively reviewed for the clinical records, laboratory tests, chest CT scans, and neonatal outcomes. RESULTS: There were 17 of the 32 patients (53%) with no subjective symptoms before admission, and 13 (41%) remained asymptomatic throughout hospitalization. There were 28 patients (88%) showing typical radiographic evidence of pneumonia on chest CT. The patients with COVID-19 were found in an increased risk of thromboembolism with much higher D-dimer levels than uninfected pregnant women. One neonate with asphyxia and positive immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies was reported. CONCLUSIONS: The considerable asymptomatic proportion of pregnant women with COVID-19 indicates symptom-based screening would miss a number of cases. Chest CT could provide a useful screening resource during the COVID-19epidemic outbreak. Anticoagulation therapy for the postpartum patients may be helpful for good prognosis. The findings provide important information for the hospital isolation, control strategies and clinical therapy.

Superficial Cerebral Venous Thrombosis and Intracerebral Hematoma in a 48-Year-Old Man with SARS-CoV-2 Infection: A Case Report.

BACKGROUND Pandemic coronavirus disease 2019 (COVID-19) originated in Wuhan, China, and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Severe respiratory symptoms are a hallmark of the disease, which may also include complications related to a hypercoagulable state and central nervous system involvement. These complications can occur during either the acute or the recovery phase. The cerebral involvement typically manifests as intracranial hypertension, intracerebral hemorrhage, diffuse encephalopathy, or cerebral venous thrombosis. The hemorrhagic form of cerebral venous thrombosis can be a diagnostic challenge and is treated by anticoagulation therapy, despite the existence of an intracerebral hemorrhage. This report describes a case of superficial cerebral venous thrombosis and intracerebral hematoma in a 48-year-old man weeks after recovering from the acute phase of SARSCoV-2 infection. CASE REPORT A 48-year-old man with a past medical history of SARS-CoV-2 infection confirmed by SARS-CoV-2 reverse-transcription polymerase chain reaction presented with left upper-limb numbness, weakness, and impaired positional sensorium. After initial stabilization, noncontrast computerized tomography and magnetic resonance imaging confirmed an intracerebral hemorrhage with underlying cerebral venous thrombosis. The patient was successfully treated with enoxaparin anticoagulation therapy, and symptoms improved over the following 12 days. CONCLUSIONS Central nervous system venous thrombosis is an atypical presentation of the hypercoagulable state primarily seen in younger patients, and it can occur in a delayed fashion after recovery from mild forms of COVID-19.

Thrombocytopenia and thrombosis in hospitalized patients with COVID-19.

As our understanding on coronavirus disease 2019 (COVID-19) deepens, it is increasingly recognized that COVID-19 is more than a respiratory condition. Thrombocytopenia and thromboembolic complications are a composite factor associated with critical COVID-19 and increased mortality. Immune-inflammation-mediated destruction, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection per se and increased consumption are proposed to be responsible for thrombocytopenia. Multiple concomitant conditions or results caused by SARS-CoV-2 infection are high risk factors for thrombosis. Recently, platelet activation and platelet-mediated immune inflammation induced by SARS-CoV-2 infection were also found to be the contributors to the thrombosis in COVID-19 patients. In addition to thrombus scoring system, D-dimer is an excellent indicator for monitoring thrombosis. COVID-19 patients with high risk for thrombosis should be subjected to early thromboprophylaxis, and prolonged activated partial-thromboplastin time should not be a barrier to the use of anticoagulation therapies in the control of thrombosis in COVID-19 patients.

Pathogenesis-directed therapy of 2019 novel coronavirus disease.

The 2019 novel coronavirus disease (COVID-19) now is considered a global public health emergency. One of the unprecedented challenges is defining the optimal therapy for those patients with severe pneumonia and systemic manifestations of COVID-19. The optimal therapy should be largely based on the pathogenesis of infections caused by this novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the onset of COVID-19, there have been many prepublications and publications reviewing the therapy of COVID-19 as well as many prepublications and publications reviewing the pathogenesis of SARS-CoV-2. However, there have been no comprehensive reviews that link COVID-19 therapies to the pathogenic mechanisms of SARS-CoV-2. To link COVID-19 therapies to pathogenic mechanisms of SARS-CoV-2, we performed a comprehensive search through MEDLINE, PubMed, medRxiv, EMBASE, Scopus, Google Scholar, and Web of Science using the following keywords: COVID-19, SARS-CoV-2, novel 2019 coronavirus, pathology, pathologic, pathogenesis, pathophysiology, coronavirus pneumonia, coronavirus infection, coronavirus pulmonary infection, coronavirus cardiovascular infection, coronavirus gastroenteritis, coronavirus autopsy findings, viral sepsis, endotheliitis, thrombosis, coagulation abnormalities, immunology, humeral immunity, cellular immunity, inflammation, cytokine storm, superantigen, therapy, treatment, therapeutics, immune-based therapeutics, antiviral agents, respiratory therapy, oxygen therapy, anticoagulation therapy, adjuvant therapy, and preventative therapy. Opinions expressed in this review also are based on personal experience as clinicians, authors, peer reviewers, and editors. This narrative review linking COVID-19 therapies with pathogenic mechanisms of SARS-CoV-2 has resulted in six major therapeutic goals for COVID-19 therapy based on the pathogenic mechanisms of SARS-CoV-2. These goals are listed below: 1. The first goal is identifying COVID-19 patients that require both testing and therapy. This is best accomplished with a COVID-19 molecular test from symptomatic patients as well as determining the oxygen saturation in such patients with a pulse oximeter. Whether a symptomatic respiratory illness is COVID-19, influenza, or another respiratory pathogen, an oxygen saturation less than 90% means that the patient requires medical assistance. 2. The second goal is to correct the hypoxia. This goal generally requires hospitalization for oxygen therapy; other respiratory-directed therapies such as prone positioning or mechanical ventilation are often used in the attempt to correct hypoxemia due to COVID-19. 3. The third goal is to reduce the viral load of SARS-CoV-2. Ideally, there would be an oral antiviral agent available such as seen with the use of oseltamivir phosphate for influenza. This oral antiviral agent should be taken early in the course of SARS-CoV-2 infection. Such an oral agent is not available yet. Currently, two options are available for reducing the viral load of SARS-CoV-2. These are post-Covid-19 plasma with a high neutralizing antibody titer against SARS-CoV-2 or intravenous remdesivir; both options require hospitalization. 4. The fourth goal is to identify and address the hyperinflammation phase often seen in hospitalized COVID-19 patients. Currently, fever with an elevated C-reactive protein is useful for diagnosing this hyperinflammation syndrome. Low-dose dexamethasone therapy currently is the best therapeutic approach. 5. The fifth goal is to identify and address the hypercoagulability phase seen in many hospitalized COVID-19 patients. Patients who would benefit from anticoagulation therapy can be identified by a marked increase in d-dimer and prothrombin time with a decrease in fibrinogen. To correct this disseminated intravascular coagulation-like phase, anticoagulation therapy with low molecular weight heparin is preferred. Anticoagulation therapy with unfractionated heparin is preferred in COVID-19 patients with acute kidney injuries. 6. The last goal is prophylaxis for persons who are not yet infected. Potential supplements include vitamin D and zinc. Although the data for such supplements is not extremely strong, it can be argued that almost 50% of the population worldwide has a vitamin D deficiency. Correcting this deficiency would be beneficial regardless of any impact of COVID-19. Similarly, zinc is an important supplement that is important in one's diet regardless of any effect on SARS-CoV-2. As emerging therapies are found to be more effective against the SARS-CoV-2 pathogenic mechanisms identified, they can be substituted for those therapies presented in this review.

Preliminary Experience With Low Molecular Weight Heparin Strategy in COVID-19 Patients.

BACKGROUND: Heparin administration in COVID-19 patients is recommended by expert consensus, although evidence about dosage, duration and efficacy are limited. We aim to investigate the association between different dosages of low molecular weight heparin (LMWH) and mortality among COVID-19 hospitalized patients. METHODS AND RESULTS: Retrospective study of 450 laboratory-confirmed COVID-19 patients admitted to Sant'Orsola Bologna Hospital from March 01 to April 10, 2020. Clinical, laboratory and treatment data were collected and analyzed. The in-hospital mortality between COVID-19 patients treated with standard prophylactic LMWH dosage vs. intermediate LMWH dosage was compared. Out of 450 patients, 361 received standard deep vein thrombosis (DVT) prophylaxis enoxaparin treatment (40-60mg daily) and 89 patients received intermediate enoxaparin dosage (40-60 mg twice daily) for 7 days. No significant differences in the main demographic characteristics and laboratory testings at admission were observed in the two heparin regimen subgroups, except for older age and prevalence of hypertension in the group treated with "standard" prophylaxis LMWH dosage. The intermediate LMWH administration was associated with a lower in-hospital all-cause mortality compared to the "standard" prophylactic LMWH dosage (18.8% vs. 5.8%, p = 0.02). This difference remained significant after adjustment with the propensity score for variables that differed significantly between the dosage groups (OR= 0.260, 95% CI 0.089-0.758, p=0.014). CONCLUSIONS: Intermediate LMWH dosage seems to be associated with lower incidence of mortality compared to standard DVT prophylaxys in hospitalized COVID-19 patients. Our study paves the way to further pathophysiological investigations and controlled studies of anticoagulation therapy in Covid-19 disease.