Therapeutic-dose Anticoagulation Research Articles

Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19

Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19

Longitudinal Aspects of VITT

In hundreds of patients worldwide, vaccination against COVID-19 with adenovirus vector vaccines (ChAdOx1 nCoV-19; Ad26.COV2.S) triggered platelet-activating anti-platelet factor 4 (PF4) antibodies inducing vaccine-induced immune thrombotic thrombocytopenia (VITT). In most VITT patients, platelet-activating anti-PF4-antibodies are transient and the disorder is discrete and non-recurring. However, in some patients platelet-activating antibodies persist, associated with recurrent thrombocytopenia and sometimes with relapse of thrombosis despite therapeutic-dose anticoagulation. Anti-PF4 IgG antibodies measured by enzyme-immunoassay (EIA) are usually detectable for longer than platelet-activating antibodies in functional assays, but duration of detectability is highly assay-dependent. As more than 1 vaccination dose against COVID-19 is required to achieve sufficient protection, at least 69 VITT patients have undergone subsequent vaccination with an mRNA vaccine, with no relevant subsequent increase in anti-PF4 antibody titers, thrombocytopenia, or thrombotic complications. Also, re-exposure to adenoviral vector-based vaccines in 5 VITT patients was not associated with adverse reactions. Although data are limited, vaccination against influenza also appears to be safe. SARS-CoV-2 infection reported in 1 patient with preceding VITT did not influence anti-PF4 antibody levels. We discuss how these temporal characteristics of VITT provide insights into pathogenesis.

241 Is There a Role for Empirical Treatment of Orthopaedic Patients with Suspected, but Not Confirmed, VTE in the Post-Operative Period?

Abstract Introduction Major surgery, including major orthopaedic surgery, is a key risk factor for developing venous thromboembolism (VTE). This poses a challenge in the post-operative phase when considering initiation of therapeutic-dose anticoagulation for suspected VTE due to the risk of major bleeding. Method A search strategy was developed with inclusion criteria involving all studies relating to the treatment of suspected VTE in the post-operative orthopaedic patient. Journal articles predating 3rd June 2021 were searched for in Medline, Embase and PubMed. Titles and s were reviewed based on clinical relevance. Results 56 articles were generated using this search strategy. 22 results were excluded as conference papers and/or case reports. Title and review of the remaining 34 studies did not identify any relevant articles reporting outcomes. Conclusions No evidence is available to guide recommendations for the empirical treatment of suspected VTE in the post-operative orthopaedic patient prior to a confirmed VTE diagnosis. This is therefore a risk-benefit clinical decision to be undertaken based on individual patient factors. Current American College of Chest Physicians guidelines advise initiation of anticoagulation for suspected acute VTE in cases with a high clinical suspicion, or intermediate clinical suspicion with expected delay in diagnostic imaging for at least 4 hours. However, this does not apply to patients following recent surgery who are at increased risk of bleeding post-operatively. Empirical systemic treatment dose anticoagulation for VTE in the post-operative period should therefore only be initiated when timely image-based diagnosis cannot be achieved.

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and massive hemoptysis: The rationale for bronchial artery embolization

IntroductionIn many patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH), bronchial artery hypertrophy is observed. Patients with bronchial dilatation have been shown to be at increased risk of hemoptysis introducing the risk of airway obstruction. In this study from an academic tertiary referral center, we aimed to assess the incidence of massive hemoptysis in our CTEPH patients, the success of bronchial artery embolization (BAE), recurrence, and hemoptysis-related mortality. MethodsRetrospective cohort study of all adults with CTEPH who underwent BAE for massive hemoptysis between 1 January 2015 and 30 July 2021. Primary endpoints were hemoptysis relapse and hemoptysis-related mortality. ResultsThere were 367 patients who were being treated and managed with a diagnosis of CTEPH at our institution. There were 24 bronchial artery embolization procedures performed for all causes. A total of 3 patients during this time met inclusion criteria with acute massive hemoptysis and CTEPH. All patients were taking therapeutic-dose anticoagulation. Technical success after BAE was 100%. No hemoptysis recurrence was demonstrated at 17, 24, and 40-months follow-up respectively. No patient died from hemoptysis. However, 1 patient died 24 months after the embolization procedure due to a non-hemoptysis cause. ConclusionThis study highlights the low but important incidence of massive hemoptysis in patients with CTEPH. Unlike other causes of hemoptysis, this unique cohort requires balancing anticoagulation and hemorrhage control. Given the high degree of success, BAE is a viable option, allowing continuation or early re-establishment of anticoagulation.

Anticoagulation practices and venous thromboembolism in COVID-19 patients in a Philippine tertiary hospital

Funding AcknowledgementsType of funding sources: None.INTRODUCTIONCOVID-19 poses an increased risk for thrombosis and initiation of prophylactic anticoagulation has been shown to have mortality benefit in earlier studies. However, the use of full dose anticoagulation as prophylaxis and evidence of the efficacy and safety of anticoagulation on COVID-19 patients remains to be a topic of interest. This study aimed to explore the aspects of anticoagulation applied in a tertiary hospital in the Philippines and to further elucidate on its outcomes and development of complications among COVID-19 patients.METHODSIn this retrospective, observational study, we collected data from the case record forms of 945 patients with COVID-19 from two tertiary centers. Patients given anticoagulant therapy were classified as treated with standard, intermediate and therapeutic dose anticoagulation. The incidence of mortality and venous thromboembolism (VTE) among the three groups were compared as well as the risk for bleeding complications. Categorical variables were analyzed using the Chi-squared test and logistic regression analysis was done to quantify odds for mortality and complications among the treatment groups.RESULTSAmong available agents, Enoxaparin was the anticoagulant of choice in 96.1% of cases. The percentage of patients given anticoagulation was noted to increase with increasing severity. Overall, there were 168 (17.8%) inpatient deaths wherein 128 received anticoagulation. 51.3% of those who received therapeutic anticoagulation were intubated at any time during their hospital stay (p value 0.00). In-hospital survival for patients given prophylactic anticoagulation was 78.3% with the highest mortality among patients given therapeutic anticoagulation at 53.8%. Using binary logistic regression, there was increasing odds of mortality as anticoagulant dosage increased with an odds ratio of 2.818 for therapeutic anticoagulation (p = 0.00, b = 1.036). There was significantly lower incidence of pulmonary embolism and among patients given standard prophylactic therapy. The odds of incurring VTE (OR = 3.38, p = 0.001) and PE (OR = 4.315, p = 0.000) were found to increase as dosage increased. Major bleeding after given anticoagulant therapy was recorded in 4.7% of patients. Although half of the patients who presented with bleeding were given standard dose prophylaxis, the incidence of bleeding was highest within the intermediate dose category at 9.2%.CONCLUSIONTherapeutic dose anticoagulation was associated with higher odds of mortality. The incidence of recorded venous thromboembolism was low but still showed increasing odds as dosage of anticoagulation increased. In lieu of these findings, we recommend that therapeutic dose anticoagulation be given with caution to patients diagnosed with COVID-19, especially among those with severe to critical disease. Patients with the highest risks for VTE and requiring higher anticoagulant dosages should be monitored closely due to higher odds of bleeding. Figure. Figure.

Prophylactic versus therapeutic dose anticoagulation effects on survival among critically ill patients with COVID-19.

Although patients with severe COVID-19 are known to be at high risk of developing thrombotic events, the effects of anticoagulation (AC) dose and duration on in-hospital mortality in critically ill patients remain poorly understood and controversial. The goal of this study was to investigate survival of critically ill COVID-19 patients who received prophylactic or therapeutic dose AC and analyze the mortality rate with respect to detailed demographic and clinical characteristics. We conducted a retrospective, observational study of critically ill COVID-19 patients admitted to the ICU at Stony Brook University Hospital in New York who received either prophylactic (n = 158) or therapeutic dose AC (n = 153). Primary outcome was in-hospital death assessed by survival analysis and covariate-adjusted Cox proportional hazard model. For the first 3 weeks of ICU stay, we observed similar survival curves for prophylactic and therapeutic AC groups. However, after 3 or more weeks of ICU stay, the therapeutic AC group, characterized by high incidence of acute kidney injury (AKI), had markedly higher death incidence rates with 8.6 deaths (95% CI = 6.2-11.9 deaths) per 1,000 person-days and about 5 times higher risk of death (adj. HR = 4.89, 95% CI = 1.71-14.0, p = 0.003) than the prophylactic group (2.4 deaths [95% CI = 0.9-6.3 deaths] per 1,000 person-days). Among therapeutic AC users with prolonged ICU admission, non-survivors were characterized by older males with depressed lymphocyte counts and cardiovascular disease. Our findings raise the possibility that prolonged use of high dose AC, independent of thrombotic events or clinical background, might be associated with higher risk of in-hospital mortality. Moreover, AKI, age, lymphocyte count, and cardiovascular disease may represent important risk factors that could help identify at-risk patients who require long-term hospitalization with therapeutic dose AC treatment.

Pulmonary Embolism in Patients with COVID-19

Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) and the resulting syndrome, COVID-19, have been associated with inflammation and a prothrombotic state, with increases in fibrin, fibrinogen, fibrin degradation products and D-dimers. In some studies, elevations in these markers have been associated with worse clinical outcomes. Several studies have demonstrated a high prevalence of venous thromboembolism (VTE), and pulmonary embolism (PE), particularly in patients admitted to the intensive care unit (ICU), even in those receiving prophylactic anticoagulation. The high rate of thrombosis in COVID-19 is driven by at least two interrelated processes: a hypercoagulable state responsible for large-vessel thrombosis and thromboembolism and direct vascular and endothelial injury responsible for in situ microvascular thrombosis. The presence of PE and pulmonary thrombosis may explain why hypoxemia is out of proportion to impairment in lung compliance in some patients with COVID-19 pneumonia. Diagnosing PE in patients with COVID-19 pneumonia may be challenging, because the two pathologies share many signs and symptoms. It has been demonstrated that the administration of prophylactic anticoagulation within 24 h of admission in patients with COVID-19 was associated with decreased mortality when compared with no prophylactic anticoagulation. Given the antithrombotic, anti-inflammatory and possibly antiviral properties of heparins, it has been hypothesized that anticoagulation with heparin administered at doses higher than conventionally used for venous thromboprophylaxis may improve outcomes. In non-critically ill patients hospitalized with COVID-19, therapeutic-dose anticoagulants with heparin (most commonly, low-molecular-weight heparin) increased the probability of survival until hospital discharge with a reduced need for ICU-level organ support at 21 days as compared with usual-care thromboprophylaxis. In Critically ill patients with confirmed COVID-19, therapeutic-dose anticoagulation did not increase the probability of survival to hospital discharge or the number of days free of cardiovascular o respiratory organ support and had a 95% probability of being inferior to usual-care pharmacologic thromboprophylaxis. Currently, randomized trials evaluating the use of tissue plasminogen activator and Tenecteplase in patients with COVID-19 ARDS are underway.

Safety and Efficacy of Intermediate- and Therapeutic-Dose Anticoagulation for Hospitalised Patients with COVID-19: A Systematic Review and Meta-Analysis.

Background: COVID-19 patients are at high thrombotic risk. The safety and efficacy of different anticoagulation regimens in COVID-19 patients remain unclear. Methods: We searched for randomised controlled trials (RCTs) comparing intermediate- or therapeutic-dose anticoagulation to standard thromboprophylaxis in hospitalised patients with COVID-19 irrespective of disease severity. To assess efficacy and safety, we meta-analysed data for all-cause mortality, clinical status, thrombotic event or death, and major bleedings. Results: Eight RCTs, including 5580 patients, were identified, with two comparing intermediate- and six therapeutic-dose anticoagulation to standard thromboprophylaxis. Intermediate-dose anticoagulation may have little or no effect on any thrombotic event or death (RR 1.03, 95% CI 0.86–1.24), but may increase major bleedings (RR 1.48, 95% CI 0.53–4.15) in moderate to severe COVID-19 patients. Therapeutic-dose anticoagulation may decrease any thrombotic event or death in patients with moderate COVID-19 (RR 0.64, 95% CI 0.38–1.07), but may have little or no effect in patients with severe disease (RR 0.98, 95% CI 0.86–1.12). The risk of major bleedings may increase independent of disease severity (RR 1.78, 95% CI 1.15–2.74). Conclusions: Certainty of evidence is still low. Moderately affected COVID-19 patients may benefit from therapeutic-dose anticoagulation, but the risk for bleeding is increased.

Anticoagulation in COVID-19

Anticoagulation in COVID-19

Tissue plasminogen activator for the treatment of adults with critical COVID-19: A pilot randomized clinical trial

Tissue plasminogen activator for the treatment of adults with critical COVID-19: A pilot randomized clinical trial

Anticoagulation Management and Outcomes in Patients With Covid-19 With Propensity Score Matching: A Multicenter Retrospective Cohort Study.

Therapeutic doses of anticoagulation have been administered to patients with coronavirus-19 disease (Covid-19) without thromboembolism, although there is a lack of robust evidence supporting this practice. To compare outcomes between patients admitted to the hospital for Covid-19 who received full-dose anticoagulation purely for the indication of Covid-19 and patients who received prophylactic doses of anticoagulation. This is a multicenter retrospective cohort study, including 7 community hospitals in Michigan. Patients were >18 years of age, confirmed positive for Covid-19 by polymerase chain reaction, and admitted to the hospital between March 10 and May 3, 2020. Exposed group: Patients receiving therapeutic dose anticoagulation for Covid-19 for any duration excluding clinically evident venous thromboembolism, atrial fibrillation, and myocardial infarction; control group: Patients receiving prophylactic anticoagulation. Propensity score matching was used to adjust for the nonrandomized nature of the study. The primary endpoint: 30-day in-hospital mortality. Secondary endpoints: intubation, length of hospital stay, and readmissions in survivors. A total of 115 exposed and 115 control patients were analyzed. Rates of 30-day in-hospital mortality were similar (exposed: 33.0% vs. control: 28.7%). Controlling for institution, there was no significant association between treatment and 30-day in-hospital mortality (hazard ratio: 0.63; 95% confidence interval: 0.37-1.06). Survivors had statistically similar length of hospital stay and readmission rates. We found no difference in mortality in patients with Covid-19 without clinically evident venous thromboembolism, atrial fibrillation, and myocardial infarction who received therapeutic versus prophylactic doses of anticoagulation.

Validation of a Prognostic Score to Identify Hospitalized Patients with COVID-19 at Increased Risk for Bleeding

Introduction: Hospitalized patients with COVID-19 are at increased risk for venous thromboembolism (VTE), but also for bleeding. We previously derived a prognostic score including four variables (elevated D-dimer, elevated ferritin, critical illness, and therapeutic-dose anticoagulation) that identified those at increased risk for major bleeding. Methods: We aimed to validate the score in a subsequent cohort of hospitalized patients with COVID-19 receiving standard-, intermediate- or therapeutic doses of VTE prophylaxis. We evaluated its capacity to predict major bleeding, non-major bleeding, and bleeding-related death. Results: The cohort included 972 patients from 29 hospitals, of whom 280 (29%) received standard-; 412 (42%) intermediate-, 157 (16%) therapeutic doses of VTE prophylaxis and 123 (13%) other drugs. Median duration of prophylaxis was 14.7 ± 10.3 days. Major bleeding occurred in 65 patients (6.7%) and non-major bleeding in 67 (6.9%). Thirty patients with major bleeding (46%) died within the first 30 days after bleeding. The prognostic score identified 203 patients (21%) at very low risk, 285 (29%) at low risk, 263 (27%) intermediate-risk and 221 (23%) at high risk for bleeding. Major bleeding occurred in 1.0%, 2.1%, 8.7% and 15.4% of the patients, respectively. Non-major bleeding occurred in 0.5%, 3.5%, 9.5% and 14.2%, respectively. The c-statistics was: 0.74 (95% confidence intervals [CI]: 0.68–0.79) for major bleeding, 0.73 (95% CI: 0.67–0.78) for non-major bleeding and 0.82 (95% CI: 0.76–0.87) for bleeding-related death. Conclusions: In hospitalized patients with COVID-19, we validated that a prognostic score including 4 easily available items may identify those at increased risk for bleeding.

The Impact of Degree of Anticoagulation on Thrombotic and Other Complications in Hospitalized COVID-19 Patients

Introduction:In hospitalized patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the frequency of venous thromboembolism (VTE) is increased. Retrospective studies suggested that an elevated D-dimer level is associated with increased mortality and predictive of thrombosis in these patients. In the spring of 2020, our institution developed a risk protocol for stratification of hospitalized COVID-19 patients into high, intermediate, or low risk groups, based upon history of thrombosis and D-dimer level. These patients were treated with full-dose anticoagulation, high- or standard-dose prophylaxis, respectively. The goal of this project was to determine the impact of this protocol on VTE frequency, need for intensive care unit (ICU) admission, organ failure and in-hospital mortality while assessing the frequency of hemorrhagic complications when compared to standard prophylactic anticoagulation.Methods:We performed a retrospective chart review of adults hospitalized between March 1 - June 1, 2020 who tested positive for SARS-CoV-2 by nasopharyngeal polymerase chain reaction (PCR). Patients were excluded if they were initially admitted to the ICU. VTE was defined as either a deep vein thrombosis (DVT) on Duplex ultrasound and/or pulmonary embolism (PE) on computed tomography (CT) angiogram. We collected demographic data, medical histories, laboratory and radiologic data on all subjects. Data were analyzed using the Chi Square test and Fisher's Exact Test to establish significant association with clinical outcomes between 3 anticoagulation regimens. Statistical significance was assessed at the p<0.05 level.Results:Data were analyzed from 910 patients; 496 (54.6%) were male and the mean age was 57.8 ± 16.9 years. 419 (46%) subjects were Black, 151 (16.6%) Caucasian, 133 (14.6%) Latinx. Diabetes mellitus (35.3%) and hypertension (59.8%) were common in our cohort as were tobacco (12.6%) and alcohol (20.4%) use. Only 69 (7.6%) were treated with chronic anticoagulation and 216 (23.7%) were on antiplatelet agents. 123 (13.5%) required an ICU transfer and the overall mortality was 5.3%. Most patients, 809 (88.9%), received standard prophylactic anti-coagulation initially (Group A); 32 (3.5%) received high dose prophylaxis (Group B) and 69 (7.6%) received therapeutic dose anticoagulation (Group C). In the entire cohort, 46 (5.1%) developed VTE; 29 (3.6%) in Group A, 2 (6.3%) in Group B, and 15 (22%) in Group C (p<0.0001). ICU admission was required for 102 (12.6%) in Group A, 7 (21.9%) in Group B, and 14 (20.3%) in Group C (p=0.075). 73 ICU patients (8%) required vasopressors, including 57 (7%) in Group A, 6 (18.8%) in Group B and 10 (14.5%) in Group C (p=0.175). 81 ICU patients (8.9%) required mechanical ventilation, including 66 (8.2%) in Group A, 6 (18.8%) in Group B, and 9 (13%) in Group C (p=0.513). One patient in Group B developed an intracerebral hemorrhage. Gastrointestinal hemorrhage occurred in 11 (1.2%) of the cohort; similar rates were observed across treatment arms. The overall in-hospital mortality was 5.3% in this cohort (4.7% in Group A, 12.5% in Group B, and 8.6% in Group C, p=0.064).Conclusion:The rate of VTE in COVID-19 patients receiving any form of anti-coagulation was low. There was an increased rate of VTE, but not rates of ICU admission, mortality, mechanical ventilation nor vasopressor use in those receiving either high dose prophylaxis or therapeutic anticoagulation, suggesting an increased propensity for thrombosis either related to prior thrombotic events or reflected by increased D-dimer levels. These findings need to be confirmed in prospective studies. DisclosuresDiLorenzo: Abbott: Current holder of individual stocks in a privately-held company; Merck & Co: Current holder of individual stocks in a privately-held company; Glaxo Smith Kline: Current holder of individual stocks in a privately-held company. Sloan: Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Stemline: Honoraria. Weinberg: Janssen Pharmaceuticals: Other: Serve on data safety monitoring boards; Merck & Co: Current holder of individual stocks in a privately-held company. Klings: CSL Behring: Other: Consultant; Omeros: Other: Consultant; Bluebird Bio: Other: Consultant; Bayer: Research Funding; Novartis: Research Funding; FORM therapeutics: Research Funding.

INCIDENTAL AND ASYMPTOMATIC SPLENIC INFRACTION AND INFRARENAL THORMBUS IN A PATIENT WITH COVID-19

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: In the COVID-19 pandemic, pathogenesis and complications of COVID-19 were studied intently. Due to the associated cytokine storm, it is theorized that this triggers a hypercoagulable state for venous and arterial thromboembolism. Elevated D-dimer, fibrinogen, c-reactive protein (CRP), ferritin, and procalcitonin were seen in thrombotic complications. CASE PRESENTATION: A 66 year old male with dyslipidemia presented 11 days after diagnosis of COVID-19. He had worsening shortness of breath, myalgias, and loss of taste. He denied any diarrhea, nausea, or vomiting. On physical exam, he had crackles with diminished lung sounds using his accessory muscles. He was hypoxic with oxygen saturation of 81% on room air. Labs showed normal WBC count, d-dimer of 1.42 mg/L, ferritin of 961 ng/mL, lactate dehydrogenase of 621 U/L, and CRP of 2.1 mg/dL. Chest x-ray showed atypical pneumonitis with patchy abnormalities. He was started on vapotherm 40 L with FiO2 of 100% proning as tolerated. He received dexamethasone, prophylactic enoxaparin, 1 unit of plasma therapy, remdesevir, ceftriaxone, and azithromycin. On day 2, dexamethasone was increased to twice daily due to hypoxemia. Due to elevated d-dimer of 2.64 mg/L, enoxaparin was changed to twice daily. On day 5, he required continuous positive airway pressure (CPAP) with pressure support of 10 and FiO2 of 85% with dexamethasone every eight hours. His d-dimer increased from 1.65 to 3.51 mg/L. Computed tomography angiogram (CTA) of chest showed extensive ground glass opacities and 2.4 x 1.9 x 1.3 cm distal thoracic aortic intraluminal thrombus. He was started on a heparin drip, and enoxaparin was discontinued. CTA of aorta showed thrombus or hypoattenuation within splenic artery and areas of wedge-shaped extending from the hilum and possible infarction with a six mm thrombus in the infrarenal abdominal aorta. Vascular surgeon recommended no surgical intervention since he was asymptomatic. His d-dimer peaked to 6.92 mg/L but trended down. After two days of heparin drip, he was transition to enoxaparin 1 mg/kg twice daily. He remained asymptomatic with no flank pain. DISCUSSION: At least 17 cases thus far found splenic infarction as a rare thrombotic complication of COVID-19. Presentation is usually with left flank pain, which our patient did not have. Elevation of d-dimer were predictive of thrombosis complications in those hospitalized. Management includes therapeutic dose anticoagulation like subcutaneous low molecular weight heparin before being discharge home with oral anticoagulant. CONCLUSIONS: Although pulmonary embolism is the most common thromboembolism complication of COVID-19, arterial thrombosis are common especially in critically ill patients. Physicians need to consider arterial and venous thrombosis and investigate appropriately based on symptoms in order to manage. Prophylactic anticoagulation is recommended for hospitalized COVID-19. REFERENCE #1: Santos Leite Pessoa M, Franco Costa Lima C, Farias Pimentel AC, et. al. Multisystemic Infarctions in COVID-19: Focus on the Spleen. Eur J Case Rep Intern Med. 2020 Jun 3;7(7):001747. doi: 10.12890/2020_001747. REFERENCE #2: 2. Klok FA, Kruip MJHA, van der Meer NJM, et. al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 Jul;191:145-147. doi: 10.1016/j.thromres.2020.04.013. REFERENCE #3: 3. Besutti G, Bonacini R, Iotti V, et. al. Abdominal Visceral Infarction in 3 Patients with COVID-19. Emerg Infect Dis. 2020 Aug;26(8):1926-1928. doi: 10.3201/eid2608.201161. DISCLOSURES: No relevant relationships by Jayaramakrishna Depa, source=Web Response No relevant relationships by Cassandra Do, source=Web Response No relevant relationships by shyam Ganti, source=Web Response No relevant relationships by Mythili Kanthi Gudipati, source=Web Response

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

BackgroundThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.MethodsIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.ResultsThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.ConclusionsIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.)

Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

BackgroundThrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.MethodsIn an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.ResultsThe trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support–free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.ConclusionsIn critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.)

Therapeutic Anticoagulation May Be Associated with Reduced 14-day Mortality in Mechanically Ventilated Patients with COVID-19.

Purpose: To assess the impact of therapeutic dose versus prophylactic dose anticoagulation regimens on outcomes in mechanically ventilated patients with COVID-19. Methods: We performed a retrospective cohort analysis of consecutive mechanically ventilated adult patients with COVID-19 admitted to the intensive care unit (ICU) and initiated on anticoagulation from February 1 st to May 31 st , 2020. The primary endpoint was 14-day mortality. Secondary endpoints included 30-day mortality, hospital length of stay (LOS), duration of mechanical ventilation, major bleeding, and new thromboembolic event. Results: Of the 121 mechanically ventilated patients with COVID-19, 33 in the therapeutic-dose group and 34 patients in the prophylactic-dose group were included in the final analysis. The therapeutic-dose group had a decreased 14-day mortality compared to the prophylaxis dose group (9.1% vs 41.2%, p=0.004). In addition, 30-day mortality was also lower in the therapeutic anticoagulation group (24.2% vs. 52.9%, p=0.024). A longer hospital LOS (45.7 vs 26 days, p=0.003) and duration of mechanical ventilation (33.9 vs 13.3 days, p<0.001) were observed in patients on therapeutic anticoagulation in comparison to the prophylaxis dosing group. A higher rate of major bleeding was observed in patients who received therapeutic anticoagulation. Conclusion: In this analysis of mechanically ventilated COVID-19 patients in the ICU, therapeutic dose anticoagulation was associated with a significantly lower 14-day mortality, but increased bleeding.

Thrombosis and Anticoagulation in Malignant Superior Vena Cava Syndrome

▪Background:Superior Vena Cava (SVC) Syndrome (SVCS), defined by obstruction of blood flow through the SVC, is commonly caused by a mediastinal tumor (i.e. malignant SVCS, m-SVCS). Little is known regarding co-existing SVC thrombosis at diagnosis in this high risk setting. Anticoagulation (AC) is often utilized even in the absence of thrombosis or stents, but evidence is lacking.Aims:1) To determine factors associated with thrombosis and AC at m-SVCS diagnosis; 2) To evaluate the effect of baseline AC and SVC thrombosis on outcomes.Methods:The electronic records of 2 academic medical centers in Israel were screened for diagnostic codes compatible with SVCS and malignancy between 2007 and 2015. Patients were included if they had active cancer and m-SVCS reported in chest computerized tomography (CT) with intravenous (IV) contrast medium. Records were followed from m-SVCS diagnosis for 6 months.Baseline patient, cancer and m-SVCS-related characteristics were collected. AC use and endovascular SVC stent placement were recorded throughout the study. Accessible diagnostic and follow-up IV contrast CTs were reviewed by two radiologists to confirm m-SVCS diagnosis and evaluate thrombosis. The primary endpoint was death from any cause. Secondary endpoints included new/recurrent SVC thrombosis. Baseline variables that had a statistically significant association with baseline thrombosis or death on univariate analysis were entered into a General Linear Model and multivariable cox regression model, respectively, for multivariable analysis. Significance was set at p < 0.05.Results:The cohort included the 183 patients, 70% (129) of whom had a reviewable baseline CT. Baseline characteristics are shown in Table 1. Briefly, 65% (119/183) had newly diagnosed cancer of any histology, 22% (40/183) had hematological malignancy (mainly aggressive lymphoma), and 16% (29/183) had no symptoms attributable to m-SVCS (i.e. clinical grade 0). Thrombosis of the SVC or tributaries at diagnosis was seen in 24% (30/127). Baseline AC (within 21 days of m-SVCS diagnosis) was used in 51% of patients for a median duration of 68 days [range: 14-179]. Thirty percent of thrombotic cases received no AC, while 52% of non-thrombotic cases received AC at varying doses. Patients receiving baseline AC were more likely to have had a SVC stent placed at baseline, and had higher grade venous occlusion and a trend to more thrombosis of SVC and tributaries (univariate analysis; Table 1). On multivariate analysis, only symptomatic m-SVCS (P<0.01) and increasing Khorana score (p<0.05) were associated with baseline thrombosis (univariate analysis shown in Table 1).Over a median FU of 44 [IQR 22-93] days, 49% (90/182) of patients died. A follow up CT was performed in 61/129 (47%) patients at a median of 138 days [IQR 71-182] from diagnosis, 30% (18) of whom died. New thrombosis of SVC and tributaries was identified in 10/61 (16%) at a median of 74 days [IQR: 53-150]. Patients with baseline AC had thrombosis on follow-up CT in 21% of cases (8/40) compared to 10% (2/20) in those without baseline AC (p=0.471). Among the 68/129 without a follow up CT, 45 (66%) died over a median follow up of 72 days (IQR 23-182).In time dependent cox analysis, baseline AC (compared to none) was not associated with risk of death (HR 0.85; 95% CI 0.55-1.29). In multiple regression analysis of baseline variables, increasing age (HR 1.04, 95% CI 1.02-1.06), malignancy stage IV (HR 4.57, 95% CI 2.29-9.13) and refractory cancer (HR 1.95, 95% CI 1.17-3.25) were associated with death.Conclusion:Thrombosis of SVC and tributaries is a common complication of m-SVCS, and is associated with symptomatic presentation and a high Khorana score. Prognosis in m-SVCS is dismal and appears to be determined by the prognosis of the underlying cancer and responsiveness to prior anticancer therapy and not by the presence of thrombosis at diagnosis. The high early death rate, low numbers of thrombotic events and confounding by AC indication, preclude ruling out a role for AC in selected cases. We propose that therapeutic dose AC in thrombotic m-SVCS and prophylactic AC in non-thrombotic m-SVCS be evaluated prospectively in newly diagnosed patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical Course and Risk Factors for In-Hospital Mortality of 205 Patients with SARS-CoV-2 Pneumonia in Como, Lombardy Region, Italy.

The aim of this study is to explore risk factors for in-hospital mortality and describe the effectiveness of different treatment strategies of 205 laboratory-confirmed cases infected with SARS-CoV-2 during the Lombardy outbreak. All patients received the best supportive care and specific interventions that included the main drugs being tested for repurposing to treat COVID-19, such as hydroxychloroquine, anticoagulation and antiviral drugs, steroids, and interleukin-6 pathway inhibitors. Clinical, laboratory, and treatment characteristics were analyzed with univariate and multivariate logistic regression methods to explore their impact on in-hospital mortality. Univariate analyses showed prognostic significance for age greater than 70 years, the presence of two or more relevant comorbidities, a P/F ratio less than 200 at presentation, elevated LDH (lactate dehydrogenase) and CRP (C-reactive protein) values, intermediate- or therapeutic-dose anticoagulation, hydroxychloroquine, early antiviral therapy with lopinavir/ritonavir, short courses of steroids, and tocilizumab therapy. Multivariable regression confirmed increasing odds of in-hospital death associated with age older than 70 years (OR 3.26) and a reduction in mortality for patients treated with anticoagulant (−0.37), antiviral lopinavir/ritonavir (−1.22), or steroid (−0.59) therapy. In contrast, hydroxychloroquine and tocilizumab have not been confirmed to have a significant effect in the treatment of SARS-CoV-2 pneumonia. Results from this real-life single-center experience are in agreement and confirm actual literature data on SARS-CoV-2 pneumonia in terms of both clinical risk factors for in-hospital mortality and the effectiveness of the different therapies proposed for the management of COVID19 disease.

Initial report on hospitalized cancer patients with COVID-19 from the National Cancer Institute (NCI) COVID-19 in Cancer Patients Study (NCCAPS).

6566 Background: Hospitalized cancer patients (pts) with COVID-19 have a severe disease course and high mortality. Pts with lung cancer, hematologic malignancies and metastatic disease may be at higher risk. Detailed prospective inpatient data may help to identify those at greatest risk for poor outcomes. Methods: NCCAPS is a longitudinal study aiming to accrue 2,000 cancer pts undergoing treatment for hematologic malignancy or solid tumor with COVID-19. For pts’ first COVID-19 hospitalization, clinical data, research blood specimens and imaging are collected, and additional clinical data are collected during subsequent hospitalizations. Results: As of Jan. 22, 2021, among 757 enrolled adult patients from 204 sites, 124 (16.3%) reported at least one hospitalization for COVID-19, and discharge data was available for 98 hospitalizations in 88 patients. The median age was 67 (range 21-93, 1Q:56, 3Q:72), 35/88 (40%) were female. The most common malignancies in hospitalized adult pts were lymphoma (18.2%), lung cancer (15.9%) and multiple myeloma (10.2%). The most common presenting symptoms were shortness of breath (65%), fatigue/malaise (64%), and fever (49%). 8/88 (9%) pts were neutropenic (ANC &lt; 1000) at presentation; 17/88 (19%) were thrombocytopenic. Median length of stay was 6.5 days (range 1-41, 1Q:4, 3Q:12). Among those hospitalized, 20/88 (22.7%) received care in the ICU or high dependency unit, with a median ICU stay of 7 days (range 1-22, 1Q:2.5, 3Q:9.5); of those admitted to the ICU, 25% (5/20) received invasive mechanical ventilation. Of those in whom inpatient medications were recorded (n = 63), 63% received corticosteroids, 46% received remdesivir, and 14% received convalescent plasma. One pt received bamlanivimab and 2 patients received tocilizumab. Most (46/63; 73%) received anticoagulation, primarily prophylactic low molecular weight heparin; 11/63 (17%) received therapeutic dose anticoagulation. Inpatient D-dimer values were recorded in 43 inpatients, 26 of whom had multiple measurements. 16/98 hospitalizations ended with death (16%). Conclusions: Preliminary analysis of NCCAPS data reveals that inpatient hospital admission is common among oncology patients with COVID-19 and mortality rates appear high within this cohort. Hematologic malignancies and lung cancer are the most common underlying diagnoses in patients requiring hospitalization. Corticosteroids and anti-coagulation were the most commonly used therapies. Despite high rates of ICU admission, invasive mechanical ventilation may be instituted less often in an oncology cohort. These observations may inform decisions about vaccine policy and decisions to limit life sustaining treatment. Clinical trial information: NCT04387656.