Abstract

PURPOSE As no reported randomized control trials (RCTs) directly compare the three administration doses of anticoagulants (prophylactic dose, treatment dose, and no treatment), the most recommended dose to be administered to patients with coronavirus disease 2019 (COVID-19) remains unclear. The purpose of this study was to examine the effects of anticoagulant doses administered to patients with COVID-19, using a network meta-analysis (NMA) including high-quality studies. METHODS All eligible trials from the Cochrane Central Register of Controlled Trials, MEDLINE, and Clinicaltrials.gov were included. We included RCTs and observational studies adjusted for covariates for patients aged ≥ 18 years and hospitalized due to objectively confirmed COVID-19. The main study outcome was mortality. RESULTS In patients with moderate COVID-19, the prophylactic (relative risk (RR) 0.64 [95% confidence interval (CI) 0.52-0.80]) and treatment dose (RR 0.57 [95% CI 0.45-0.72] were associated with a lower risk of short-term mortality than that with no anticoagulant treatment. However, the prophylactic and treatment dose groups were not significantly different. The hierarchy for efficacy in reducing short-term mortality was treatment dose (P score 92.4) > prophylactic dose (57.6) > no treatment (0.0). In patients with severe COVID-19, due to the absence of trials with the no-treatment group, NMA could not be conducted. However, pairwise comparison did not show a significant difference between the prophylactic and treatment dose groups. CONCLUSIONS Treatment and prophylactic doses of anticoagulants showed similar effects on mortality; however, the treatment dose is preferred over the prophylactic dose for patients with both moderate and severe COVID-19. TRIAL REGISTRATION NUMBER AND REGISTRATION DATES PROSPERO (registration number: CRD42021245308, 05/21/2021).

Abstract

Background: Coronavirus disease 2019, caused by SARS-CoV-2 (SCV-2) was stated as a pandemic on March 11 2020 by World Health Organization (WHO), and since then, it has become a major health issue worldwide. It mainly attacks the respiratory system with various accompanying complications, including cardiac injury, renal failure, encephalitis and Stroke.Materials and Methods: The current systematic review has been compiled to summarize the available literature on SCV-2 induced ischemic Stroke and its subtypes. Further, the mechanisms by which the virus crosses the blood-brain barrier (BBB) to enter the brain have also been explored. The role of CRP and D-dimer as potent prognostic markers was also explored. The literature search was carried out comprehensively on Google scholar, PubMed, SCOP US, Embase and Cochrane databases by following guidelines.Results: All the studies were reviewed thoroughly by authors and disagreements were resolved by consensus and help of the senior authors. The most common subtype of the IS was found to be large artery atherosclerosis in SCV-2 induced IS. Hypertension emerged as the most significant risk factor. The mechanism resulting in elevated levels of CRP and D-dimer have also been discussed. However, there is a scarcity of definitive evidence on how SCV-2 enters the human brain. The available literature based on various studies demonstrated that SCV-2 enters through the nasopharyngeal tract via olfactory cells to olfactory neurons, astrocytes and via choroid plexus through endothelial cells. Further, disruption of gut-brain axis has been also discussed.Conclusion: Data available in the literature is not adequate to come to a conclusion. Therefore, there is a need to carry out further studies to delineate the possible association between SCV-2 induced IS.

Abstract

BACKGROUND The primary manifestation of coronavirus disease 2019 (COVID-19) is respiratory insufficiency that can also be related to diffuse pulmonary microthrombosis and thromboembolic events, such as pulmonary embolism, deep vein thrombosis, or arterial thrombosis. People with COVID-19 who develop thromboembolism have a worse prognosis. Anticoagulants such as heparinoids (heparins or pentasaccharides), vitamin K antagonists and direct anticoagulants are used for the prevention and treatment of venous or arterial thromboembolism. Besides their anticoagulant properties, heparinoids have an additional anti-inflammatory potential. However, the benefit of anticoagulants for people with COVID-19 is still under debate. OBJECTIVES To assess the benefits and harms of anticoagulants versus active comparator, placebo or no intervention in people hospitalised with COVID-19. SEARCH METHODS We searched the CENTRAL, MEDLINE, Embase, LILACS and IBECS databases, the Cochrane COVID-19 Study Register and medRxiv preprint database from their inception to 14 April 2021. We also checked the reference lists of any relevant systematic reviews identified, and contacted specialists in the field for additional references to trials. SELECTION CRITERIA Eligible studies were randomised controlled trials (RCTs), quasi-RCTs, cluster-RCTs and cohort studies that compared prophylactic anticoagulants versus active comparator, placebo or no intervention for the management of people hospitalised with COVID-19. We excluded studies without a comparator group and with a retrospective design (all previously included studies) as we were able to include better study designs. Primary outcomes were all-cause mortality and necessity for additional respiratory support. Secondary outcomes were mortality related to COVID-19, deep vein thrombosis, pulmonary embolism, major bleeding, adverse events, length of hospital stay and quality of life. DATA COLLECTION AND ANALYSIS We used standard Cochrane methodological procedures. We used Cochrane RoB 1 to assess the risk of bias for RCTs, ROBINS-I to assess risk of bias for non-randomised studies (NRS) and GRADE to assess the certainty of evidence. We meta-analysed data when appropriate. MAIN RESULTS We included seven studies (16,185 participants) with participants hospitalised with COVID-19, in either intensive care units, hospital wards or emergency departments. Studies were from Brazil (2), Iran (1), Italy (1), and the USA (1), and two involved more than country. The mean age of participants was 55 to 68 years and the follow-up period ranged from 15 to 90 days. The studies assessed the effects of heparinoids, direct anticoagulants or vitamin K antagonists, and reported sparse data or did not report some of our outcomes of interest: necessity for additional respiratory support, mortality related to COVID-19, and quality of life. Higher-dose versus lower-dose anticoagulants (4 RCTs, 4647 participants) Higher-dose anticoagulants result in little or no difference in all-cause mortality (risk ratio (RR) 1.03, 95% CI 0.92 to 1.16, 4489 participants; 4 RCTs) and increase minor bleeding (RR 3.28, 95% CI 1.75 to 6.14, 1196 participants; 3 RCTs) compared to lower-dose anticoagulants up to 30 days (high-certainty evidence). Higher-dose anticoagulants probably reduce pulmonary embolism (RR 0.46, 95% CI 0.31 to 0.70, 4360 participants; 4 RCTs), and slightly increase major bleeding (RR 1.78, 95% CI 1.13 to 2.80, 4400 participants; 4 RCTs) compared to lower-dose anticoagulants up to 30 days (moderate-certainty evidence). Higher-dose anticoagulants may result in little or no difference in deep vein thrombosis (RR 1.08, 95% CI 0.57 to 2.03, 3422 participants; 4 RCTs), stroke (RR 0.91, 95% CI 0.40 to 2.03, 4349 participants; 3 RCTs), major adverse limb events (RR 0.33, 95% CI 0.01 to 7.99, 1176 participants; 2 RCTs), myocardial infarction (RR 0.86, 95% CI 0.48 to 1.55, 4349 participants; 3 RCTs), atrial fibrillation (RR 0.35, 95% CI 0.07 to 1.70, 562 participants; 1 study), or thrombocytopenia (RR 0.94, 95% CI 0.71 to 1.24, 2789 participants; 2 RCTs) compared to lower-dose anticoagulants up to 30 days (low-certainty evidence). It is unclear whether higher-dose anticoagulants have any effect on necessity for additional respiratory support, mortality related to COVID-19, and quality of life (very low-certainty evidence or no data). Anticoagulants versus no treatment (3 prospective NRS, 11,538 participants) Anticoagulants may reduce all-cause mortality but the evidence is very uncertain due to two study results being at critical and serious risk of bias (RR 0.64, 95% CI 0.55 to 0.74, 8395 participants; 3 NRS; very low-certainty evidence). It is uncertain if anticoagulants have any effect on necessity for additional respiratory support, mortality related to COVID-19, deep vein thrombosis, pulmonary embolism, major bleeding, stroke, myocardial infarction and quality of life (very low-certainty evidence or no data). Ongoing studies We found 62 ongoing studies in hospital settings (60 RCTs, 35,470 participants; 2 prospective NRS, 120 participants) in 20 different countries. Thirty-five ongoing studies plan to report mortality and 26 plan to report necessity for additional respiratory support. We expect 58 studies to be completed in December 2021, and four in July 2022. From 60 RCTs, 28 are comparing different doses of anticoagulants, 24 are comparing anticoagulants versus no anticoagulants, seven are comparing different types of anticoagulants, and one did not report detail of the comparator group. AUTHORS' CONCLUSIONS When compared to a lower-dose regimen, higher-dose anticoagulants result in little to no difference in all-cause mortality and increase minor bleeding in people hospitalised with COVID-19 up to 30 days. Higher-dose anticoagulants possibly reduce pulmonary embolism, slightly increase major bleeding, may result in little to no difference in hospitalisation time, and may result in little to no difference in deep vein thrombosis, stroke, major adverse limb events, myocardial infarction, atrial fibrillation, or thrombocytopenia. Compared with no treatment, anticoagulants may reduce all-cause mortality but the evidence comes from non-randomised studies and is very uncertain. It is unclear whether anticoagulants have any effect on the remaining outcomes compared to no anticoagulants (very low-certainty evidence or no data). Although we are very confident that new RCTs will not change the effects of different doses of anticoagulants on mortality and minor bleeding, high-quality RCTs are still needed, mainly for the other primary outcome (necessity for additional respiratory support), the comparison with no anticoagulation, when comparing the types of anticoagulants and giving anticoagulants for a prolonged period of time.

Abstract

BACKGROUND Patients with severe COVID-19 seem to evolve with a compromised antiviral response and hyperinflammation. Neutrophils are critical players in COVID-19. IL-17A plays a major role in protection against extracellular pathogens and neutrophil attraction/activation. We hypothesized that secukinumab, an anti-IL17A monoclonal antibody, could prevent the deleterious hyperinflammation in COVID-19. METHODS BISHOP was a randomized, open-label, single-centre, phase-II controlled trial. Fifty adult patients hospitalized with PCR-positive Covid-19, were randomized 1:1 to receive 300 mg of secukinumab subcutaneously at day-0 plus standard of care (group A) or standard of care alone (group B). A second dose of 300 mg of secukinumab could be administered on day-7, according to staff judgement. The primary endpoint was ventilator-free days at day-28 (VFD-28). Secondary efficacy and safety outcomes were also explored. RESULTS An intention-to-treat analysis showed no difference in VFD-28: 23.7 (95%CI 19.6-27.8) in group A vs. 23.8 (19.9-27.6) in group B, p = .62; There was also no difference in hospitalization time, intensive care unit demand and the incidence of circulatory shock, acute kidney injury, fungal or bacterial co-infections. There was no difference in the incidence of severe adverse events. Pulmonary thromboembolism occurred only in males and was less frequent in secukinumab-treated patients (4.2% vs. 26.2% p = .04). There was one death in each group. Upper airway viral clearance was also similar in both groups. CONCLUSION The efficacy of secukinumab in the treatment of Covid19 was not demonstrated. Secukinumab decreased pulmonary embolism in male patients. There was no difference between groups in adverse events and no unexpected events were observed.

Abstract

BACKGROUND Infection with the SARS-CoV-2 virus can lead to myocardial injury, evidenced by increases in specific biomarkers and imaging. OBJECTIVE To quantify the association between biomarkers of myocardial injury, coagulation, and severe COVID-19 and death in hospitalized patients. METHODS Studies were identified through a systematic search of indexed articles in PubMed, Embase, CINAHL, Cochrane, Web of Science, and Scopus, published between December 2019 to August 2021. Effect estimates from individual studies for association between markers of myocardial injury (Troponin), myocardial stretch (N-terminal-pro hormone BNP, NT-proBNP), and coagulopathy (D-Dimer) and death or severe/critical COVID-19 were pooled using inverse variance weighted random-effects model. Odds Ratios (OR), Hazard Ratios (HR), and 95% Confidence Intervals (CI) were pooled separately and reported by outcomes of critical/severe COVID-19 and death. A meta-analysis of proportions was also performed to summarize the pooled prevalence of co-morbidities in patients hospitalized with COVID-19. RESULTS We included 62 articles, with a total of 41,013 patients. The pooled proportion of patients with history of hypertension was 39% (95% CI: 34-44%); diabetes, 21% (95% CI: 18%-24%); coronary artery disease, 13% (95% CI: 10-16%); chronic obstructive pulmonary disease, 7% (95% CI: 5-8%), and history of cancer, 5% (95% CI: 4-7%). Elevated troponin was associated with higher pooled odds of critical/severe COVID-19 and death [Odds Ratio (OR: 1.76, 95% CI: 1.42-2.16)]; and also separately for death (OR: 1.72, 95% CI: 1.32-2.25), and critical/severe COVID-1919 (OR: 1.93, 95% CI: 1.45-2.40). Elevations in NT-proBNP were also associated with higher severe COVID-19 and death (OR: 3.00, 95% CI: 1.58-5.70). Increases in D-dimer levels was also significantly associated with critical/severe COVID-19 and death (pooled OR: 1.38, 95% CI: 1.07-1.79). CONCLUSIONS This meta-analysis synthesizes existing evidence showing that myocardial injury, and coagulopathy are complications of COVID-19. The durability of these complications and their contributions to long-term cardiac implications of the disease is still being investigated. Patients who have recovered from COVID-19 may benefit from minimally invasive assessment for markers of myocardial injury, stretch and coagulopathy for early risk stratification purposes.

Abstract

BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 virus has resulted in significant mortality and burdening of healthcare resources. While initially noted as a pulmonary pathology, subsequent studies later identified cardiovascular involvement with high mortalities reported in specific cohorts of patients. While cardiovascular comorbidities were identified early on, the exact manifestation and etiopathology of the infection remained elusive. This systematic review aims to investigate the role of inflammatory pathways, highlighting several culprits including neutrophil extracellular traps (NETs) which have since been extensively investigated. METHOD A search was conducted using three databases (MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations and EMBASE). Data from randomized controlled trials (RCT), prospective series, meta-analyses, and unmatched observational studies were considered for the processing of the algorithm and treatment of inflammatory response during SARS-CoV-2 infection. Studies without the SARS-CoV-2 Infection period and case reports were excluded. RESULTS A total of 47 studies were included in this study. The role of the acute inflammatory response in the propagation of the systemic inflammatory sequelae of the disease plays a major part in determining outcomes. Some of the mechanisms of activation of these pathways have been highlighted in previous studies and are highlighted. CONCLUSION NETs play a pivotal role in the pathogenesis of the inflammatory response. Despite moving into the endemic phase of the disease in most countries, COVID-19 remains an entity that has not been fully understood with long-term effects remaining uncertain and requiring ongoing monitoring and research.

Abstract

OBJECTIVE Although the application of venovenous extracorporeal membrane oxygenation (VV-ECMO) in coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome (ARDS) is accumulating, the feasibility and safety of this therapy remain controversial. We aimed to evaluate the effect of VV-ECMO in the treatment of these patients. METHODS A comprehensive literature search was performed using PubMed, Embase, the Cochrane Library, and International Clinical Trials Registry Platform databases through November 2021. According to the inclusion and exclusion criteria, the included studies were screened, and meta-analysis was performed by R software (version 4.0.2). RESULTS Forty-two studies including 2037 COVID-19 patients supported with VV-ECMO due to ARDS were identified. The pooled analysis revealed that 30-, 60-, and 90-day mortality among patients were respectively 46% (95% CI 37%-57%, I(2) = 66%), 46% (95% CI 30%-70%, I(2) = 93%), and 49% (95% CI 43%-58%, I(2) = 52%), and the pooled incidence rate of in-hospital mortality, major bleeding, hemorrhagic stroke, thrombosis, pulmonary embolism, deep venous thrombosis, and renal replacement therapy were respectively 35%, 39%, 11%, 40%, 15%, 21%, and 44%. CONCLUSION Although COVID-19 patients may have a higher risk of bleeding, hemorrhagic stroke, and acute kidney injury during ECMO therapy, the survival rate was more than half of the cases. Our data may support the application of VV-ECMO in COVID-19 patients.

Abstract

BACKGROUND Venous Thromboembolism (VTE) is common among patients with severe Coronavirus Disease 2019 (COVID-19). Anticoagulation in hospitalized COVID-19 patients has been associated with survival benefit; however, the optimal thromboprophylaxis strategy has not yet been defined. OBJECTIVE To identify published guidance reports by national and international societies regarding thromboprophylaxis strategies in COVID-19 patients in different settings (outpatients, hospitalized, post-discharge). METHODS A systematic review of the literature (Pubmed/EMBASE) was conducted independently by two investigators. RESULTS Among 1942 initially identified articles, 33 guidance documents were included: 20 published by national and 13 by international societies. These documents provide recommendations mainly for hospitalized (97% of reports) and post-discharge (75%) COVID-19 patients, and less so for outpatients (34%). Thrombotic and bleeding risk stratification prior to any treatment decision is the cornerstone of all suggested thromboprophylaxis strategies; 81% of the documents recommend thromboprophylaxis for all hospitalized patients with a prophylactic dosage of low molecular weight heparin irrespective of VTE risk. Intermediate or therapeutic dose intensity is recommended in high VTE risk patients by 56% and 28% of documents, respectively. Mechanical thromboprophylaxis is suggested in case of high bleeding risk or contraindication to pharmacological thromboprophylaxis (59% of documents). Extended pharmacological thromboprophylaxis is recommended for patients with high VTE risk after hospital discharge (63% of documents). For non-hospitalized outpatients, 28% of documents recommend pharmacological thromboprophylaxis for high VTE risk. CONCLUSION The current guidance identifies thromboprophylaxis in COVID-19 patients, especially during hospitalization, as of major importance for the prevention of VTE. Recommendations are derived from limited evidence from observational studies.

Abstract

BACKGROUND Pulmonary embolisms are frequently and prognostically in individuals infected by coronavirus disease 2019 (COVID-19); the incidence of pulmonary embolisms is varied across numerous studies. This study aimed to assess the pooled incidence of pulmonary embolic events and the prognostic value of such events in intensive care unit (ICU) admissions of patients with COVID-19. METHODS The Cochrane Library, PubMed, and EmBase were systematically searched for eligible studies published on or before October 20, 2021. The pooled incidence of pulmonary embolism was calculated using the random-effects model. Moreover, the prognostic value was assessed by measuring the sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR), diagnostic odds ratio (DOR), and the area under the receiver operating characteristic curve (AUC). RESULTS Thirty-six studies involving 10,367 COVID-19 patients were selected for the final meta-analysis. The cumulative incidence of pulmonary embolism in patients with COVID-19 was 21% (95% confidence interval [95%CI]: 18-24%; P<0.001), and the incidence of pulmonary embolism in ICU and non-ICU patients was 26% (95%CI: 22-31%; P<0.001) and 17% (95%CI: 14-20%; P<0.001), respectively. The predictive role of pulmonary embolism in ICU admission was also assessed, and the sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.31 (95%CI: 0.21-0.42), 0.84 (95%CI: 0.75-0.90), 1.88 (95%CI: 1.45-2.45), 0.83 (95%CI: 0.75-0.91), 2.25 (95%CI: 1.64-3.08), and 0.61 (95%CI: 0.57-0.65), respectively. CONCLUSION This study found that the incidence of pulmonary embolism was relatively high in COVID-19 patients, and the incidence of pulmonary embolism in ICU patients was higher than that in non-ICU patients.

Abstract

IMPORTANCE The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. OBJECTIVE To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). INTERVENTIONS Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. MAIN OUTCOMES AND MEASURES The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. RESULTS The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). CONCLUSIONS AND RELEVANCE Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02735707.