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 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

The degree to which COVID-19 severity influences the development of acute cerebrovascular events (ACVE) is unknown. Therefore, we aimed to describe the prevalence and risk of ACVE in patients with severe and nonsevere COVID-19. We systematically reviewed MEDLINE, EMBASE, Web of Science, and Scopus and identified observational and interventional studies of patients with COVID-19 allocated by respiratory severity that reported ACVE development. Case reports/series were excluded. The main outcome assessed was the pooled rate of ACVE in patients with severe and nonsevere COVID-19. To determine the risk of ACVE development by COVID-19 severity, a meta-analysis was performed. PROSPERO registration number: CRD42020178905. About 19 of 5758 identified studies were analyzed. From 11,886 COVID-19 patients analyzed, 421 had at least one ACVE [3.6%, 95% confidence interval (CI) 2.904-4.179]. Severe COVID-19 increased the risk of ACVE (odds ratio 1.96, 95% CI 1.22-3.15; P = 0.005; I (2) = 64%), specifically hemorrhagic stroke (4.12, 2.0-8.53; P = 0.001; I (2) = 0%). There was no difference in the risk of developing ischemic stroke between patients with severe and nonsevere COVID-19 (1.53, 0.87-2.7; P = 0.14; I (2) = 52%). From the patients who developed any ACVE, those with severe COVID-19 had a greater mortality risk than those with nonsevere COVID-19 (3.85, 1.08-13.70; P = 0.04; I (2) = 0%). The main limitations of our study were the heterogeneity found in the main meta-analysis studies and in their reported definition for COVID-19 severity. In conclusion, our findings provide evidence that COVID-19 respiratory severity could lead to ACVE development that increases mortality. The effect of COVID-19 management in ACVE needs to be evaluated.

Abstract

OBJECTIVES This study aimed to investigate the differences in the characteristics, management, and clinical outcomes of patients with and that of those without coronavirus disease 2019 (COVID-19) infection who had ST-segment elevation myocardial infarction (STEMI). METHODS Databases including Web of Science, PubMed, Cochrane Library, and Embase were searched up to July 2021. Observational studies that reported on the characteristics, management, or clinical outcomes and those published as full-text articles were included. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of all included studies. RESULTS A total of 27,742 patients from 13 studies were included in this meta-analysis. Significant delay in symptom onset to first medical contact (SO-to-FMC) time (mean difference = 23.42 min; 95% CI: 5.85-40.99 min; p = 0.009) and door-to-balloon (D2B) time (mean difference = 12.27 min; 95% CI: 5.77-18.78 min; p = 0.0002) was observed in COVID-19 patients. Compared to COVID-19 negative patients, those who are positive patients had significantly higher levels of C-reactive protein, D-dimer, and thrombus grade (p < 0.05) and showed more frequent use of thrombus aspiration and glycoprotein IIbIIIa (Gp2b3a) inhibitor (p < 0.05). COVID-19 positive patients also had higher rates of in-hospital mortality (OR = 5.98, 95% CI: 4.78-7.48, p < 0.0001), cardiogenic shock (OR = 2.75, 95% CI: 2.02-3.76, p < 0.0001), and stent thrombosis (OR = 5.65, 95% CI: 2.41-13.23, p < 0.0001). They were also more likely to be admitted to the intensive care unit (ICU) (OR = 4.26, 95% CI: 2.51-7.22, p < 0.0001) and had a longer length of stay (mean difference = 4.63 days; 95% CI: 2.56-6.69 days; p < 0.0001). CONCLUSIONS This study revealed that COVID-19 infection had an impact on the time of initial medical intervention for patients with STEMI after symptom onset and showed that COVID-19 patients with STEMI were more likely to have thrombosis and had poorer outcomes.