Antithrombotic therapy in the management of hospitalised patients with COVID-19.

Hospitalised patients with coronavirus disease 2019 (COVID-19) are at a significantly higher risk of having thromboembolic events while in hospital and in the immediate post-hospital discharge period. Based on early data from observational studies, multiple high quality randomised controlled trials have been conducted worldwide to evaluate optimal thromboprophylaxis regimens to reduce thromboembolism and other COVID-19-related adverse outcomes in hospitalised patients. The International Society on Thrombosis and Haemostasis has published evidence-based guideline recommendations using established methodology for the management of antithrombotic therapy of COVID-19 patients, both in-hospital and in the immediate post-hospital discharge period. A good clinical practice statement supplemented these guidelines based on topics for which there was no or limited high-quality evidence. This review summarises the main recommendations of these documents to serve as a quick access tool for hospital doctors to use in their everyday practice when treating COVID-19 patients.

Rivaroxaban for Prevention of Thrombotic Events, Hospitalization, and Death in Outpatients With COVID-19: A Randomized Clinical Trial.

BACKGROUND: COVID-19 (coronavirus disease 2019) is associated with heightened risks of venous and arterial thrombosis and hospitalization due to respiratory failure. To assess whether prophylactic anticoagulation can safely reduce the frequency of venous and arterial thrombosis, hospitalization, and death in nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor, we conducted the PREVENT-HD double-blind, placebo-controlled randomized trial (A Study of Rivaroxaban to Reduce the Risk of Major Venous and Arterial Thrombotic Events, Hospitalization and Death in Medically Ill Outpatients With Acute, Symptomatic COVID-19] Infection). METHODS: PREVENT-HD was conducted between August 2020 and April 2022 at 14 US integrated health care delivery networks. A virtual trial design used remote informed consent and clinical monitoring and facilitated data collection through electronic health record integration with a cloud-based research platform. Nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor were enrolled and randomly assigned to either 10 mg of oral rivaroxaban or placebo daily for 35 days. The primary efficacy outcome was time to first occurrence of a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic arterial embolism, hospitalization, or death through day 35. The principal safety end point was International Society on Thrombosis and Hemostasis critical-site or fatal bleeding. The last study visit was on day 49. RESULTS: The study was terminated prematurely because of enrollment challenges and a lower-than-expected blinded pooled event rate. A total of 1284 patients underwent randomization with complete accrual of primary events through May 2022. No patients were lost to follow-up. The primary efficacy outcome occurred in 22 of 641 in the rivaroxaban group and 19 of 643 in the placebo group (3.4% versus 3.0%; hazard ratio, 1.16 [95% CI, 0.63-2.15]; P=0.63). No patient in either group experienced critical-site or fatal bleeding. One patient receiving rivaroxaban had a major bleed. CONCLUSIONS: The study was terminated prematurely after enrollment of 32% of planned accrual because of recruitment challenges and lower-than-expected event rate. Rivaroxaban prescribed for 35 days in nonhospitalized patients with symptomatic COVID-19 at risk for thrombosis did not appear to reduce a composite end point of venous and arterial thrombotic events, hospitalization, and death. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04508023.

Risk Factors for Postdischarge Major Thromboembolism and Mortality in Hospitalized Patients with COVID-19 with Cardiovascular Comorbidities: Insights from the CORE-19 Registry.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with venous and arterial thromboembolism (VTE and ATE) and all-cause mortality (ACM) in hospitalized patients. High-quality data are needed on postdischarge outcomes in patients with cardiovascular disease. OBJECTIVES: To analyze outcomes and identify risk factors for ATE, VTE, and ACM in a high-risk subgroup of hospitalized COVID-19 patients with baseline cardiovascular disease. METHODS: We investigated postdischarge rates and associated risk factors of ATE, VTE, and ACM in 608 hospitalized COVID-19 patients with coronary artery disease, carotid artery stenosis (CAS), peripheral arterial disease (PAD), or ischemic stroke. RESULTS: Through 90 days postdischarge, outcome rates were: ATE 27.3% (10.2% myocardial infarction, 10.1% ischemic stroke, 13.2% systemic embolism, 12.7% major adverse limb event); VTE 6.9% (4.1% deep vein thrombosis, 3.6% pulmonary embolism); composite of ATE, VTE, or ACM 35.2% (214/608). Multivariate analysis showed significant association between this composite endpoint and age >75 years (odds ratio [OR]: 1.90, 95% confidence interval [CI]: 1.22-2.94, p = 0.004), PAD (OR: 3.23, 95% CI: 1.80-5.81, p ≤ 0.0001), CAS (OR: 1.74, 95% CI: 1.11-2.75, p = 0.017), congestive heart failure (CHF) (OR: 1.84, 95% CI: 1.02-3.35, p = 0.044), previous VTE (OR: 3.08, 95% CI: 1.75-5.42, p < 0.0001), and intensive care unit (ICU) admission (OR: 2.93, 95% CI: 1.81-4.75, p < 0.0001). CONCLUSION: COVID-19 inpatients with cardiovascular disease experience high rates of ATE, VTE, or ACM through 90 days postdischarge. Age >75 years, PAD, CAS, CHF, previous VTE, and ICU admission are independent risk factors.

Complement-mediated microvascular injury and thrombosis in the pathogenesis of severe COVID-19: A review.

Coronavirus disease 2019 (COVID-19) causes acute microvascular thrombosis in both venous and arterial structures which is highly associated with increased mortality. The mechanisms leading to thromboembolism are still under investigation. Current evidence suggests that excessive complement activation with severe amplification of the inflammatory response (cytokine storm) hastens disease progression and initiates complement-dependent cytotoxic tissue damage with resultant prothrombotic complications. The concept of thromboinflammation, involving overt inflammation and activation of the coagulation cascade causing thrombotic microangiopathy and end-organ damage, has emerged as one of the core components of COVID-19 pathogenesis. The complement system is a major mediator of the innate immune response and inflammation and thus an appealing treatment target. In this review, we discuss the role of complement in the development of thrombotic microangiopathy and summarize the current data on complement inhibitors as COVID-19 therapeutics.

Good practice statements for antithrombotic therapy in the management of COVID-19: Guidance from the SSC of the ISTH.

Despite the emergence of high quality randomized trial data with the use of antithrombotic agents to reduce the risk of thromboembolism, end-organ failure, and possibly mortality in patients with coronavirus disease 2019 (COVID-19), questions still remain as to optimal patient selection for these strategies, the use of antithrombotics in outpatient settings and in-hospital settings (including critical care units), thromboprophylaxis in special patient populations, and the management of acute thrombosis in hospitalized COVID-19 patients. In October 2021, the International Society on Thrombosis and Haemostasis (ISTH) formed a multidisciplinary and international panel of content experts, two patient representatives, and a methodologist to develop recommendations on treatment with anticoagulants and antiplatelet agents for COVID-19 patients. The ISTH Guideline panel discussed additional topics to be well suited to a non-Grading of Recommendations Assessment, Development, and Evaluation (GRADE) for Good Practice Statements (GPS) to support good clinical care in the antithrombotic management of COVID-19 patients in various clinical settings. The GPS panel agreed on 17 GPS: 3 in the outpatient (pre-hospital) setting, 12 in the hospital setting both in non-critical care (ward) as well as intensive care unit settings, and 2 in the immediate post-hospital discharge setting based on limited evidence or expert opinion that supports net clinical benefit in enacting the statements provided. The antithrombotic therapies discussed in these GPS should be available in low- and middle-income countries.

Use of Anticoagulants in COVID-19: A Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with elevated rates of major and fatal thrombotic events, postulated to be the result of a hypercoagulable state mediated through inflammatory and immunomodulatory mechanisms. Early observational studies showed that disease severity and elevated serum D-dimer levels can predict thrombotic risk in patients hospitalized with COVID-19 and reported an alarming phenomenon of breakthrough thrombosis despite standard-of-care prophylaxis, suggesting the need for enhanced thromboprophylactic strategies. AREAS OF UNCERTAINTY: Data on anticoagulant agent selection, dosing, and duration for COVID-19 inpatients are now poised to inform updated professional society guidance. However, there remains limited high-quality data regarding postdischarge and especially ambulatory patients with COVID-19. DATA SOURCES: This review includes published, peer-reviewed, observational, and randomized controlled trial data and major professional society guidance informing thrombosis prevention and treatment in patients with COVID-19. THERAPEUTIC ADVANCES: There remains great variability in the approach to anticoagulation in COVID-19. This article will review pathogenesis of COVID-related thrombosis and the evidence guiding thromboprophylaxis particularly in inpatients, with attention to the INSPIRATION, ACTION, RAPID, HEP-COVID, and multiplatform trials. Emerging thromboprophylaxis data from the postdischarge setting (particularly the recently published MICHELLE trial), and the outpatient setting, will be examined. Finally, thrombosis treatment considerations will briefly be reviewed. CONCLUSIONS: Substantial high-quality data support practice changes to COVID-19 thromboprophylaxis. Risk stratification by setting, disease severity, and biomarkers such as D-dimer is critical in considering choice, dose, and duration of anticoagulants.

External validation of the IMPROVE-DD risk assessment model for venous thromboembolism among inpatients with COVID-19.

There is a need to discriminate which COVID-19 inpatients are at higher risk for venous thromboembolism (VTE) to inform prophylaxis strategies. The IMPROVE-DD VTE risk assessment model (RAM) has previously demonstrated good discrimination in non-COVID populations. We aimed to externally validate the IMPROVE-DD VTE RAM in medical patients hospitalized with COVID-19. This retrospective cohort study evaluated the IMPROVE-DD VTE RAM in adult patients with COVID-19 admitted to one of thirteen Northwell Health hospitals in the New York metropolitan area between March 1, 2020 and April 27, 2020. VTE was defined as new-onset symptomatic deep venous thrombosis or pulmonary embolism. To assess the predictive value of the RAM, the receiver operating characteristic (ROC) curve was plotted and the area under the curve (AUC) was calculated. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Of 9407 patients who met study criteria, 274 patients developed VTE with a prevalence of 2.91%. The VTE rate was 0.41% for IMPROVE-DD score 0-1 (low risk), 1.21% for score 2-3 (moderate risk), and 5.30% for score ≥ 4 (high risk). Approximately 45.7% of patients were classified as high VTE risk, 33.3% moderate risk, and 21.0% low risk. Discrimination of low versus moderate-high VTE risk demonstrated sensitivity 0.971, specificity 0.215, PPV 0.036, and NPV 0.996. ROC AUC was 0.703. In this external validation study, the IMPROVE-DD VTE RAM demonstrated very good discrimination to identify hospitalized COVID-19 patients at low, moderate, and high VTE risk.

Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial.

Importance: Hospitalized patients with COVID-19 are at risk for venous and arterial thromboembolism and death. Optimal thromboprophylaxis dosing in high-risk patients is unknown. Objective: To evaluate the effects of therapeutic-dose low-molecular-weight heparin (LMWH) vs institutional standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19. Design, Setting, and Participants: The HEP-COVID multicenter randomized clinical trial recruited hospitalized adult patients with COVID-19 with D-dimer levels more than 4 times the upper limit of normal or sepsis-induced coagulopathy score of 4 or greater from May 8, 2020, through May 14, 2021, at 12 academic centers in the US. Interventions: Patients were randomized to institutional standard prophylactic or intermediate-dose LMWH or unfractionated heparin vs therapeutic-dose enoxaparin, 1 mg/kg subcutaneous, twice daily if creatinine clearance was 30 mL/min/1.73 m2 or greater (0.5 mg/kg twice daily if creatinine clearance was 15-29 mL/min/1.73 m2) throughout hospitalization. Patients were stratified at the time of randomization based on intensive care unit (ICU) or non-ICU status. Main Outcomes and Measures: The primary efficacy outcome was venous thromboembolism (VTE), arterial thromboembolism (ATE), or death from any cause, and the principal safety outcome was major bleeding at 30 ± 2 days. Data were collected and adjudicated locally by blinded investigators via imaging, laboratory, and health record data. Results: Of 257 patients randomized, 253 were included in the analysis (mean [SD] age, 66.7 [14.0] years; men, 136 [53.8%]; women, 117 [46.2%]); 249 patients (98.4%) met inclusion criteria based on D-dimer elevation and 83 patients (32.8%) were stratified as ICU-level care. There were 124 patients (49%) in the standard-dose vs 129 patients (51%) in the therapeutic-dose group. The primary efficacy outcome was met in 52 of 124 patients (41.9%) (28.2% VTE, 3.2% ATE, 25.0% death) with standard-dose heparins vs 37 of 129 patients (28.7%) (11.7% VTE, 3.2% ATE, 19.4% death) with therapeutic-dose LMWH (relative risk [RR], 0.68; 95% CI, 0.49-0.96; P = .03), including a reduction in thromboembolism (29.0% vs 10.9%; RR, 0.37; 95% CI, 0.21-0.66; P < .001). The incidence of major bleeding was 1.6% with standard-dose vs 4.7% with therapeutic-dose heparins (RR, 2.88; 95% CI, 0.59-14.02; P = .17). The primary efficacy outcome was reduced in non-ICU patients (36.1% vs 16.7%; RR, 0.46; 95% CI, 0.27-0.81; P = .004) but not ICU patients (55.3% vs 51.1%; RR, 0.92; 95% CI, 0.62-1.39; P = .71). Conclusions and Relevance: In this randomized clinical trial, therapeutic-dose LMWH reduced major thromboembolism and death compared with institutional standard heparin thromboprophylaxis among inpatients with COVID-19 with very elevated D-dimer levels. The treatment effect was not seen in ICU patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04401293.

Postdischarge thromboembolic outcomes and mortality of hospitalized patients with COVID-19: the CORE-19 registry.

Thromboembolic events, including venous thromboembolism (VTE) and arterial thromboembolism (ATE), and mortality from subclinical thrombotic events occur frequently in coronavirus disease 2019 (COVID-19) inpatients. Whether the risk extends postdischarge has been controversial. Our prospective registry included consecutive patients with COVID-19 hospitalized within our multihospital system from 1 March to 31 May 2020. We captured demographics, comorbidities, laboratory parameters, medications, postdischarge thromboprophylaxis, and 90-day outcomes. Data from electronic health records, health informatics exchange, radiology database, and telephonic follow-up were merged. Primary outcome was a composite of adjudicated VTE, ATE, and all-cause mortality (ACM). Principal safety outcome was major bleeding (MB). Among 4906 patients (53.7% male), mean age was 61.7 years. Comorbidities included hypertension (38.6%), diabetes (25.1%), obesity (18.9%), and cancer history (13.1%). Postdischarge thromboprophylaxis was prescribed in 13.2%. VTE rate was 1.55%; ATE, 1.71%; ΑCM, 4.83%; and MB, 1.73%. Composite primary outcome rate was 7.13% and significantly associated with advanced age (odds ratio [OR], 3.66; 95% CI, 2.84-4.71), prior VTE (OR, 2.99; 95% CI, 2.00-4.47), intensive care unit (ICU) stay (OR, 2.22; 95% CI, 1.78-2.93), chronic kidney disease (CKD; OR, 2.10; 95% CI, 1.47-3.0), peripheral arterial disease (OR, 2.04; 95% CI, 1.10-3.80), carotid occlusive disease (OR, 2.02; 95% CI, 1.30-3.14), IMPROVE-DD VTE score ≥4 (OR, 1.51; 95% CI, 1.06-2.14), and coronary artery disease (OR, 1.50; 95% CI, 1.04-2.17). Postdischarge anticoagulation was significantly associated with reduction in primary outcome (OR, 0.54; 95% CI, 0.47-0.81). Postdischarge VTE, ATE, and ACM occurred frequently after COVID-19 hospitalization. Advanced age, cardiovascular risk factors, CKD, IMPROVE-DD VTE score ≥4, and ICU stay increased risk. Postdischarge anticoagulation reduced risk by 46%.

Treatment-Dose LMWH versus Prophylactic/Intermediate Dose Heparins in High-Risk COVID-19 Inpatients: Rationale and Design of the HEP-COVID Trial.

Coronavirus disease-2019 (COVID-19) has been associated with significant risk of venous thromboembolism (VTE), arterial thromboembolism (ATE), and mortality particularly among hospitalized patients with critical illness and elevated D-dimer (Dd) levels. Conflicting data have yet to elucidate optimal thromboprophylaxis dosing. HEP-COVID (NCT04401293) is a phase 3, multicenter, pragmatic, prospective, randomized, pseudo-blinded, active control trial to evaluate efficacy and safety of therapeutic-dose low-molecular-weight heparin (LMWH) versus prophylactic-/intermediate-dose LMWH or unfractionated heparin (UFH) for prevention of a primary efficacy composite outcome of VTE, ATE, and all-cause mortality 30 ± 2 days post-enrollment. Eligible patients have COVID-19 diagnosis by nasal swab or serologic testing, requirement for supplemental oxygen per investigator judgment, and Dd >4 × upper limit of normal (ULN) or sepsis-induced coagulopathy score ≥4. Subjects are randomized to enoxaparin 1 mg/kg subcutaneous (SQ)/two times a day (BID) (creatinine clearance [CrCl] ≥ 30 mL/min) or 0.5 mg/kg (CrCl 15-30 mL/min) versus local institutional prophylactic regimens including (1) UFH up to 22,500 IU (international unit) daily (divided BID or three times a day), (2) enoxaparin 30 and 40 mg SQ QD (once daily) or BID, or (3) dalteparin 2,500 IU or 5,000 IU QD. The principal safety outcome is major bleeding. Events are adjudicated locally. Based on expected 40% relative risk reduction with treatment-dose compared with prophylactic-dose prophylaxis, 308 subjects will be enrolled (assuming 20% drop-out) to achieve 80% power. Distinguishing design features include an enriched population for the composite endpoint anchored on Dd >4 × ULN, stratification by intensive care unit (ICU) versus non-ICU, and the ability to capture asymptomatic proximal deep venous thrombosis via screening ultrasonography prior to discharge.

Incidence of Venous Thromboembolism and Mortality in Patients with Initial Presentation of COVID-19.

Venous thromboembolism (VTE) has emerged as an important issue in patients with COVID-19. The purpose of this study is to identify the incidence of VTE and mortality in COVID-19 patients initially presenting to a large health system. Our retrospective study included adult patients (excluding patients presenting with obstetric/gynecologic conditions) across a multihospital health system in the New York Metropolitan Region from March 1-April 27, 2020. VTE and mortality rates within 8 h of assessment were described. In 10,871 adults with COVID-19, 118 patients (1.09%) were diagnosed with symptomatic VTE (101 pulmonary embolism, 17 deep vein thrombosis events) and 28 patients (0.26%) died during initial assessment. Among these 146 patients, 64.4% were males, 56.8% were 60 years or older, 15.1% had a BMI > 35, and 11.6% were admitted to the intensive care unit. Comorbidities included hypertension (46.6%), diabetes (24.7%), hyperlipidemia (14.4%), chronic lung disease (12.3%), coronary artery disease (11.0%), and prior VTE (7.5%). Key medications included corticosteroids (22.6%), statins (21.2%), antiplatelets (20.6%), and anticoagulants (20.6%). Highest D-Dimer was greater than six times the upper limit of normal in 51.4%. Statin and antiplatelet use were associated with decreased VTE or mortality (each p < 0.01). In COVID-19 patients who initially presented to a large multihospital health system, the overall symptomatic VTE and mortality rate was over 1.0%. Statin and antiplatelet use were associated with decreased VTE or mortality. The potential benefits of antithrombotics in high risk COVID-19 patients during the pre-hospitalization period deserves study.

Validation of the IMPROVE-DD risk assessment model for venous thromboembolism among hospitalized patients with COVID-19.

BACKGROUND: Antithrombotic guidance statements for hospitalized patients with coronavirus disease 2019 (COVID-19) suggest a universal thromboprophylactic strategy with potential to escalate doses in high-risk patients. To date, no clear approach exists to discriminate patients at high risk for venous thromboembolism (VTE). OBJECTIVES: The objective of this study is to externally validate the IMPROVE-DD risk assessment model (RAM) for VTE in a large cohort of hospitalized patients with COVID-19 within a multihospital health system. METHODS: This retrospective cohort study evaluated the IMPROVE-DD RAM on adult inpatients with COVID-19 hospitalized between March 1, 2020, and April 27, 2020. Diagnosis of VTE was defined by new acute deep venous thrombosis or pulmonary embolism by Radiology Department imaging or point-of-care ultrasound. The receiver operating characteristic (ROC) curve was plotted and area under the curve (AUC) calculated. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated using standard methods. RESULTS: A total of 9407 patients were included, with a VTE prevalence of 2.9%. The VTE rate was 0.4% for IMPROVE-DD score 0-1 (low risk), 1.3% for score 2-3 (moderate risk), and 5.3% for score ≥ 4 (high risk). Approximately 45% of the total population scored high VTE risk, while 21% scored low VTE risk. IMPROVE-DD discrimination of low versus medium/high risk showed sensitivity of 0.971, specificity of 0.218, PPV of 0.036, and NPV of 0.996. ROC AUC was 0.702. CONCLUSIONS: The IMPROVE-DD VTE RAM demonstrated very good discrimination to identify hospitalized patients with COVID-19 as low, moderate, and high VTE risk in this large external validation study with potential to individualize thromboprophylactic strategies.

Prevalence and Predictors of Venous Thromboembolism or Mortality in Hospitalized COVID-19 Patients.

BACKGROUND: We aimed to identify the prevalence and predictors of venous thromboembolism (VTE) or mortality in hospitalized coronavirus disease 2019 (COVID-19) patients. METHODS: A retrospective cohort study of hospitalized adult patients admitted to an integrated health care network in the New York metropolitan region between March 1, 2020 and April 27, 2020. The final analysis included 9,407 patients with an overall VTE rate of 2.9% (2.4% in the medical ward and 4.9% in the intensive care unit [ICU]) and a VTE or mortality rate of 26.1%. Most patients received prophylactic-dose thromboprophylaxis. Multivariable analysis showed significantly reduced VTE or mortality with Black race, history of hypertension, angiotensin converting enzyme/angiotensin receptor blocker use, and initial prophylactic anticoagulation. It also showed significantly increased VTE or mortality with age 60 years or greater, Charlson Comorbidity Index (CCI) of 3 or greater, patients on Medicare, history of heart failure, history of cerebrovascular disease, body mass index greater than 35, steroid use, antirheumatologic medication use, hydroxychloroquine use, maximum D-dimer four times or greater than the upper limit of normal (ULN), ICU level of care, increasing creatinine, and decreasing platelet counts. CONCLUSION: In our large cohort of hospitalized COVID-19 patients, the overall in-hospital VTE rate was 2.9% (4.9% in the ICU) and a VTE or mortality rate of 26.1%. Key predictors of VTE or mortality included advanced age, increasing CCI, history of cardiovascular disease, ICU level of care, and elevated maximum D-dimer with a cutoff at least four times the ULN. Use of prophylactic-dose anticoagulation but not treatment-dose anticoagulation was associated with reduced VTE or mortality.