Practical Recommendations for Optimal Thromboprophylaxis in Patients with COVID-19:A Consensus Statement Based on Available Clinical Trials

Coronavirus disease 2019 (COVID-19) has been shown to be strongly associated with increased risk for venous thromboembolism events (VTE) mainly in the inpatient but also in the outpatient setting. Pharmacologic thromboprophylaxis has been shown to offer significant benefits in terms of reducing not only VTE events but also mortality, especially in acutely ill patients with COVID-19. Although the main source of evidence is derived from observational studies with several limitations, thromboprophylaxis is currently recommended for all hospitalized patients with acceptable bleeding risk by all national and international guidelines. Recently, high quality data from randomized controlled trials (RCTs) further support the role of thromboprophylaxis and provide insights into the optimal thromboprophylaxis strategy. The aim of this statement is to systematically review all the available evidence derived from RCTs regarding thromboprophylaxis strategies in patients with COVID-19 in different settings (either inpatient or outpatient) and provide evidence-based guidance to practical questions in everyday clinical practice. Clinical questions accompanied by practical recommendations are provided based on data derived from 20 RCTs that were identified and included in the present study. Overall, the main conclusions are: (i) thromboprophylaxis should be administered in all hospitalized patients with COVID-19, (ii) an optimal dose of inpatient thromboprophylaxis is dependent upon the severity of COVID-19, (iii) thromboprophylaxis should be administered on an individualized basis in post-discharge patients with COVID-19 with high thrombotic risk, and (iv) thromboprophylaxis should not be routinely administered in outpatients. Changes regarding the dominant SARS-CoV-2 variants, the wide immunization status (increasing rates of vaccination and reinfections), and the availability of antiviral therapies and monoclonal antibodies might affect the characteristics of patients with COVID-19; thus, future studies will inform us about the thrombotic risk and the optimal therapeutic strategies for these patients

The Effect of Anakinra in Hospitalized Patients with COVID-19: An Updated Systematic Review and Meta-Analysis

The role of immunomodulatory agents in the treatment of hospitalized patients with COVID-19 has been of increasing interest. Anakinra, an interleukin-1 inhibitor, has been shown to offer significant clinical benefits in patients with COVID-19 and hyperinflammation. An updated systematic review and meta-analysis regarding the impact of anakinra on the outcomes of hospitalized patients with COVID-19 was conducted. Studies, randomized or non-randomized with adjustment for confounders, reporting on the adjusted risk of death in patients treated with anakinra versus those not treated with anakinra were deemed eligible. A search was performed in PubMed/EMBASE databases, as well as in relevant websites, until 1 August 2021. The meta-analysis of six studies that fulfilled the inclusion criteria (n = 1553 patients with moderate to severe pneumonia, weighted age 64 years, men 66%, treated with anakinra 50%, intubated 3%) showed a pooled hazard ratio for death in patients treated with anakinra at 0.47 (95% confidence intervals 0.34, 0.65). A meta-regression analysis did not reveal any significant associations between the mean age, percentage of males, mean baseline C-reactive protein levels, mean time of administration since symptoms onset among the included studies and the hazard ratios for death. All studies were considered as low risk of bias. The current evidence, although derived mainly from observational studies, supports a beneficial role of anakinra in the treatment of selected patients with COVID-19

The Effect of Anakinra in Hospitalized Patients with COVID-19: An Updated Systematic Review and Meta-Analysis

The role of immunomodulatory agents in the treatment of hospitalized patients with COVID-19 has been of increasing interest. Anakinra, an interleukin-1 inhibitor, has been shown to offer significant clinical benefits in patients with COVID-19 and hyperinflammation. An updated systematic review and meta-analysis regarding the impact of anakinra on the outcomes of hospitalized patients with COVID-19 was conducted. Studies, randomized or non-randomized with adjustment for confounders, reporting on the adjusted risk of death in patients treated with anakinra versus those not treated with anakinra were deemed eligible. A search was performed in PubMed/EMBASE databases, as well as in relevant websites, until 1 August 2021. The meta-analysis of six studies that fulfilled the inclusion criteria (n = 1553 patients with moderate to severe pneumonia, weighted age 64 years, men 66%, treated with anakinra 50%, intubated 3%) showed a pooled hazard ratio for death in patients treated with anakinra at 0.47 (95% confidence intervals 0.34, 0.65). A meta-regression analysis did not reveal any significant associations between the mean age, percentage of males, mean baseline C-reactive protein levels, mean time of administration since symptoms onset among the included studies and the hazard ratios for death. All studies were considered as low risk of bias. The current evidence, although derived mainly from observational studies, supports a beneficial role of anakinra in the treatment of selected patients with COVID-19

Statin use and mortality in COVID-19 patients: Updated systematic review and meta-analysis

Background and aims: Statin therapy is administered to patients with high cardiovascular risk. These patients are also at risk for severe course of coronavirus disease 2019 (COVID-19). Statins exhibit not only cardioprotective but also immunomodulatory and anti-inflammatory effects. This study performed a systematic review of published evidence regarding statin treatment and COVID-19 related mortality. Methods: A systematic PubMed/Embase search was performed from February 10, 2020 until March 05, 2021 for studies in COVID-19 patients that reported adjusted hazard or odds ratio for death in statin users versus nonusers. Results: 22 studies fulfilled the inclusion criteria and were included in the systematic review. Meta-analysis of 10 studies (n = 41,807, weighted age 56 +/- 8 years, men 51%, hypertension 34%, diabetes 21%, statin users 14%) that reported adjusted hazard ratios for mortality in statin users versus non-users showed pooled estimate at 0.65 (95% confidence intervals [CI] 0.53, 0.81). Meta-analysis of 6 studies that reported continuation of statin therapy during hospitalization (58-100% of patients) revealed a pooled hazard ratio of 0.54 (95% CI 0.47, 0.62). Metaanalysis of 12 studies (n = 72,881, weighted age 65 +/- 2 years, men 54%, hypertension 66%, diabetes 43%, statin users 30%) that reported adjusted odds ratios for mortality showed pooled estimate at 0.65 (95% CI 0.55, 0.78). Multivariable meta-regression analysis did not reveal any significant association of hazard or odds ratios with anthropometric characteristics or comorbidities. Conclusions: This meta-analysis of retrospective observational studies showed that statin therapy was associated with an about 35% decrease in the adjusted risk of mortality in hospitalized COVID-19 patients

Clinical examination practices and perceptions in the era of COVID-19

Introduction The art of clinical examination has been the cornerstone of medical practices since ancient years. Recent technological achievements and their overuse have led falsely to underestimation of their significance, which has been further questioned during the coronavirus disease 2019 (COVID-19) pandemic, due to concerns regarding exposure risk and use of personal protective equipment. Areas covered The role of clinical examination (namely chest examination) during the pandemic is discussed. Emerging evidence is being accumulated concerning alternatives to traditional practices. Telemedicine stands out as a promising tool, allowing inspection and interaction between physicians and patients, proved to be useful for many medical specialties but not enough for some others. Medical practices cannot remain the same in the era of the COVID-19 pandemic, yet realistic strategies should be adopted for their optimal and safe implementation. Expert opinion The experiences of a dedicated Reference Center for COVID-19 along with a suggested algorithm for conducting clinical examinations are presented. According to our experience, an initial detailed clinical examination upon admission of each COVID-19 patient appears to be necessary. Then, vital signs and signs of respiratory distress using inspection should be checked frequently. A focused examination approach should be adopted, in case of new onset clinical problems

High versus Standard Intensity of Thromboprophylaxis in Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis

Thromboprophylaxis in hospitalized patients with COVID-19 has been associated with a survival benefit and is strongly recommended. However, the optimal dose of thromboprophylaxis remains unclear. A systematic review and meta-analysis (PubMed/EMBASE) of studies comparing high (intermediate or therapeutic dose) versus standard (prophylactic dose) intensity of thrombo-prophylaxis with regard to outcome of hospitalized patients with COVID-19 was performed. Randomized and non-randomized studies that provided adjusted effect size estimates were included. Meta-analysis of 7 studies comparing intermediate versus prophylactic dose of thromboprophylaxis (2 randomized and 5 observational, n = 2009, weighted age 61 years, males 61%, ICU 53%) revealed a pooled adjusted relative risk (RR) for death at 0.56 (95% confidence intervals (CI) 0.34, 0.92) in favor of the intermediate dose. For the same comparison arms, the pooled RR for venous thromboembolism was 0.84 (95% CI 0.54, 1.31), and for major bleeding events was 1.63 (95% CI 0.79, 3.37). Meta-analysis of 17 studies comparing therapeutic versus prophylactic dose of thromboprophylaxis (2 randomized and 15 observational, n = 7776, weighted age 64 years, males 54%, ICU 21%) revealed a pooled adjusted RR for death at 0.73 (95% CI 0.47, 1.14) for the therapeutic dose. An opposite trend was observed in the unadjusted analysis of 15 observational studies (RR 1.24 (95% CI 0.88, 1.74)). For the same comparison arms, the pooled RR for venous thromboembolism was 1.13 (95% CI 0.52, 2.48), and for major bleeding events 3.32 (95% CI 2.51, 4.40). In conclusion, intermediate compared with standard prophylactic dose of thromboprophylaxis appears to be rather safe and is associated with additional survival benefit, although most data are derived from observational retrospective analyses. Randomized studies are needed to define the optimal thromboprophylaxis in hospitalized patients with COVID-19

Cardiac Injury in COVID-19: A Systematic Review of Relevant Meta-Analyses

Background: Cardiac injury (CI) is not a rare condition among hospitalized patients with coronavirus disease 2019 (COVID-19). Its prognostic value has been extensively reported through the literature, mainly in the context of observational studies. An impressive number of relevant meta-analyses has been conducted. These meta-analyses present similar and consistent results; yet interesting methodological issues emerge. Methods: A systematic literature search was conducted aiming to identify all relevant meta-analyses on (i) the incidence, and (ii) the prognostic value of CI among hospitalized patients with COVID-19. Results: Among 118 articles initially retrieved, 73 fulfilled the inclusion criteria and were included in the systematic review. Various criteria were used for CI definition mainly based on elevated cardiac biomarkers levels. The most frequently used biomarker was troponin. 30 meta-analyses reported the pooled incidence of CI in hospitalized patients with COVID-19 that varies from 5% to 37%. 32 meta-analyses reported on the association of CI with COVID-19 infection severity, with only 6 of them failing to show a statistically significant association. Finally, 46 meta-analyses investigated the association of CI with mortality and showed that patients with COVID-19 with CI had increased risk for worse prognosis. Four meta-analyses reported pooled adjusted hazard ratios for death in patients with COVID-19 and CI vs those without CI ranging from 1.5 to 3. Conclusions: The impact of CI on the prognosis of hospitalized patients with COVID-19 has gained great interest during the pandemic. Methodological issues such as the inclusion of not peer-reviewed studies, the inclusion of potentially overlapping populations or the inclusion of studies with unadjusted analyses for confounders should be taken into consideration. Despite these limitations, the adverse prognosis of patients with COVID-19 and CI has been consistently demonstrated