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1.
Pol Merkur Lekarski ; 50(296): 118-123, 2022 Apr 19.
Article in English | MEDLINE | ID: covidwho-1790558

ABSTRACT

COVID-19 patients, particularly those with severe pulmonary involvement, are at an increased thromboembolic risk related, among various causes, to the cytokine storm and excessive activation of the coagulation cascade and platelets. Different intensity of anticoagulation for them is proposed, mainly with low molecular weight heparins (LMWHs); in a confirmed pulmonary embolism (PE) the therapeutic dose of LMWH is routinely used. Some authors suggest that hemorrhagic complications in COVID-19 patients are rare. At the same time, one can find reports on internal bleeding, including retroperitoneal hematoma (RPH) and other abdominal hematomas. CASE REPORTS: The authors describe 5 cases (3 of those aged more than 80 years) with giant RPHs and with moderate/severe COVID-19 pneumonia, treated before RPH diagnosis with different enoxaparin doses. The therapeutic dose was given to the male with verified PE limited to the segmental/subsegmental pulmonary arteries and initially to the female in whom echocardiography was strongly suggestive of PE, yet this diagnosis was excluded on CT angiography. In one patient, the enoxaparin dose was escalated from 40 mg bd to 60 mg bd after the D-dimer increase. Two patients had bleeding complications despite the enoxaparin dose restricted to 40 mg/daily or bd. Two males had a coexistent psoas hematoma while in only one female there was a coexistent femoral hematoma. RPHs occurred between day 4 and 14 of hospitalization and all were treated conservatively. Three patients who died were particularly charged, so their deaths were not merely directly associated with RPH, which was closely analyzed in one autopsy performed. The authors underline that the choice of anticoagulation intensity in patients with COVID-19 pneumonia without venous thromboembolism seems sometimes difficult but recent publications indicate the low prophylactic enoxaparin dose as an optimal option. Anticoagulation dose escalation based only on the D-dimer level may not be appropriate for certain patients; moreover, the D-dimer increase is commonly observed during internal bleeding.


Subject(s)
COVID-19 , Pulmonary Embolism , Adult , Aged , Aged, 80 and over , Anticoagulants , COVID-19/complications , Enoxaparin/adverse effects , Enoxaparin/therapeutic use , Female , Hematoma/chemically induced , Hematoma/drug therapy , Heparin, Low-Molecular-Weight/adverse effects , Humans , Male , Middle Aged , Pulmonary Embolism/drug therapy
2.
World Neurosurg ; 157: e357-e363, 2022 01.
Article in English | MEDLINE | ID: covidwho-1757929

ABSTRACT

BACKGROUND: Prior studies demonstrated reduced risk for venous thromboembolism (VTE) in neurosurgical patients secondary to prophylaxis with both heparin and low-molecular-weight heparin. The ability to monitor low-molecular-weight heparin by obtaining anti-factor Xa (anti-Xa) serum levels provides an opportunity to evaluate safety and efficacy. The aim of this study was to describe characteristics of patients who have anti-Xa levels outside of the goal range (0.2-0.4/0.5 IU/mL) and investigate incidence of major bleeding and VTE. METHODS: A single-center, retrospective, observational study was conducted on neurosurgical patients receiving enoxaparin for VTE prophylaxis between August 2019 and December 2020. Significance testing was conducted via Fisher exact test and independent samples t test. RESULTS: The study included 85 patients. Patients were less likely to have an anti-Xa level in the goal range if they were male, had a higher weight, or were morbidly obese. Three neuroendovascular patients (3.5%) experienced a major bleed. Serum anti-Xa levels were significantly higher in patients who experienced major bleeds compared with patients who did not (0.45 ± 0.16 IU/mL vs. 0.28 ± 0.09 IU/mL, P = 0.003). Patients with a supraprophylactic anti-Xa level (>0.5 IU/mL) were more likely to experience a major bleed (P = 0.005). One VTE event occurred: the patient experienced a pulmonary embolism with anti-Xa level at goal. CONCLUSIONS: Anti-Xa-guided enoxaparin dosing for VTE prophylaxis in neurosurgical patients may help prevent major bleeding. These data suggest that a higher anti-Xa level may predispose patients to major bleeding. Further evaluation is needed to identify the goal anti-Xa level for VTE prophylaxis in this population.


Subject(s)
Enoxaparin/blood , Factor Xa Inhibitors/blood , Hemorrhage/blood , Neurosurgical Procedures/trends , Pre-Exposure Prophylaxis/trends , Adult , Aged , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Anticoagulants/blood , Drug Monitoring/methods , Enoxaparin/administration & dosage , Enoxaparin/adverse effects , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/adverse effects , Female , Hemorrhage/prevention & control , Humans , Male , Middle Aged , Obesity, Morbid/blood , Obesity, Morbid/surgery , Pre-Exposure Prophylaxis/methods , Retrospective Studies , Sex Factors , Venous Thromboembolism/blood , Venous Thromboembolism/prevention & control
3.
BMJ Case Rep ; 15(1)2022 Jan 07.
Article in English | MEDLINE | ID: covidwho-1612961

ABSTRACT

Postoperative fevers are common in hospitalised patients and warrant workup beyond the early post-op period. A 50-year-old man was admitted after sustaining a tibial plateau fracture. Fevers began 3 days after external fixation and persisted through a second surgery despite initial negative workup. Careful review of medications revealed enoxaparin as the instigating agent of a febrile drug reaction, and the fevers resolved after discontinuing the drug. On further questioning, it was discovered the patient had an allergy to pork, from which the main components of enoxaparin are typically derived. To our knowledge, this is the first reported enoxaparin-induced fever in the setting of a pork allergy. Enoxaparin-induced fevers should be considered in patients with unexplained post-op fever. Our case demonstrates the importance of analysing newly administered medications. Simple detailed history may significantly reduce patient morbidity and help to broaden differentials during investigation.


Subject(s)
Fever of Unknown Origin , Hypersensitivity , Pork Meat , Red Meat , Animals , Anticoagulants/adverse effects , Enoxaparin/adverse effects , Humans , Male , Middle Aged , Postoperative Complications/chemically induced , Swine
4.
Rev Cardiovasc Med ; 22(4): 1685-1691, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1592003

ABSTRACT

Coronavirus disease 2019 (COVID-19) is associated with various hemostatic abnormalities requiring constant search for better delicate antithrombotic management in these high-risk patients. The choice and the optimal dose of anticoagulant is important, but unclear, especially for mild COVID-19. Enoxaparin has been tested in several COVID trials with mixed results regarding hard clinical outcomes including mortality. We analyzed clinical, laboratory data and changes in platelets, erythrocytes and leukocytes by scanning electron microscopy on admission and at hospital discharge in patients with confirmed COVID-19 treated with enoxaparin (n = 31) and matched healthy controls (n = 32) in a retrospective observational study. The data were triaged by enoxaparin dose comparing 40 mg/daily prophylactic enoxaparin dose (PED) with 80 mg/daily therapeutic (TED) regimens. All patients experienced mild disease, none required pulmonary support, and all survived. The impact of enoxaparin dose was prominent for platelets and erythrocytes, but less evident for leukocytes. PED was associated with significant platelet activation, diminished numbers of silent nonactive discoid cells, and increased number and size of platelet microaggregates with leukocyte involvement. In contrast, TED did not cause extra platelet activation, while circulating platelet microaggregates were smaller and lacking leukocytes in their construction. PED caused significant increase of erythrocyte-platelet aggregates formation, and numerically higher proportion of circulating echinocytes. TED was associated with significant decrease of rouleaux sludge formation compared to only some trend after PED. Changes in leukocytes were less dependent on enoxaparin dose. However, PED has been associated with enhanced aggregate formation in 7 out of 10 patients, while trap net formation has been decreased in 17 out of 21 TED patients. We conclude that over hospital stay TED was superior to PED in patients with mild COVID-19. The inability of PED to adequately protect major circulating blood cells is probably due to enhanced clearance or/and diminished bioavailability of enoxaparin during COVID. These retrospective observational small sample size data may be relevant to better understanding of the mixed results in controlled outcome-driven trials exploring optimal COVID-19 anticoagulant strategies.


Subject(s)
COVID-19 , Anticoagulants/adverse effects , Blood Platelets , Enoxaparin/adverse effects , Humans , Phenotype , Retrospective Studies , SARS-CoV-2
5.
J Cosmet Dermatol ; 21(1): 13-15, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1537838
6.
BMJ Case Rep ; 14(10)2021 Oct 07.
Article in English | MEDLINE | ID: covidwho-1462937

ABSTRACT

Wunderlich syndrome is a rare condition characterised by acute spontaneous non-traumatic renal haemorrhage into the subcapsular and perirenal spaces. Our case of anti-GAD65-associated autoimmune encephalitis (AE), aged 30 years, developed this complication following use of enoxaparin and was managed by selective glue embolisation of subsegmental branches of right renal cortical arteries. Our case had opsoclonus as one of the clinical manifestations, which has till now been described in only two patients of this AE. This patient received all forms of induction therapies (steroids, plasmapheresis, intravenous immunoglobulin and rituximab) following which she had good improvement in her clinical condition. The good response to immunotherapy is also a point of discussion as this has been rarely associated with anti-GAD65 AE.


Subject(s)
Encephalitis , Limbic Encephalitis , Ocular Motility Disorders , Enoxaparin/adverse effects , Female , Humans , Rare Diseases
7.
N Engl J Med ; 385(7): 609-617, 2021 08 12.
Article in English | MEDLINE | ID: covidwho-1354155

ABSTRACT

BACKGROUND: The role of factor XI in the pathogenesis of postoperative venous thromboembolism is uncertain. Abelacimab is a monoclonal antibody that binds to factor XI and locks it in the zymogen (inactive precursor) conformation. METHODS: In this open-label, parallel-group trial, we randomly assigned 412 patients who were undergoing total knee arthroplasty to receive one of three regimens of abelacimab (30 mg, 75 mg, or 150 mg) administered postoperatively in a single intravenous dose or to receive 40 mg of enoxaparin administered subcutaneously once daily. The primary efficacy outcome was venous thromboembolism, detected by mandatory venography of the leg involved in the operation or objective confirmation of symptomatic events. The principal safety outcome was a composite of major or clinically relevant nonmajor bleeding up to 30 days after surgery. RESULTS: Venous thromboembolism occurred in 13 of 102 patients (13%) in the 30-mg abelacimab group, 5 of 99 patients (5%) in the 75-mg abelacimab group, and 4 of 98 patients (4%) in the 150-mg abelacimab group, as compared with 22 of 101 patients (22%) in the enoxaparin group. The 30-mg abelacimab regimen was noninferior to enoxaparin, and the 75-mg and 150-mg abelacimab regimens were superior to enoxaparin (P<0.001). Bleeding occurred in 2%, 2%, and none of the patients in the 30-mg, 75-mg, and 150-mg abelacimab groups, respectively, and in none of the patients in the enoxaparin group. CONCLUSIONS: This trial showed that factor XI is important for the development of postoperative venous thromboembolism. Factor XI inhibition with a single intravenous dose of abelacimab after total knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Anthos Therapeutics; ANT-005 TKA EudraCT number, 2019-003756-37.).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Anticoagulants/therapeutic use , Arthroplasty, Replacement, Knee , Enoxaparin/therapeutic use , Factor XI/antagonists & inhibitors , Postoperative Complications/prevention & control , Venous Thromboembolism/prevention & control , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Dose-Response Relationship, Drug , Enoxaparin/adverse effects , Factor XI/metabolism , Female , Hemorrhage/chemically induced , Humans , Infusions, Intravenous , Injections, Subcutaneous , Male , Middle Aged , Partial Thromboplastin Time
8.
Am Heart J ; 238: 1-11, 2021 08.
Article in English | MEDLINE | ID: covidwho-1309127

ABSTRACT

BACKGROUND: Observational studies have suggested a higher risk of thrombotic events in patients with coronavirus disease 2019 (COVID-19). Moreover, elevated D-dimer levels have been identified as an important prognostic marker in COVID-19 directly associated with disease severity and progression. Prophylactic anticoagulation for hospitalized COVID-19 patients might not be enough to prevent thrombotic events; therefore, therapeutic anticoagulation regimens deserve clinical investigation. DESIGN: ACTION is an academic-led, pragmatic, multicenter, open-label, randomized, phase IV clinical trial that aims to enroll around 600 patients at 40 sites participating in the Coalition COVID-19 Brazil initiative. Eligible patients with a confirmed diagnosis of COVID-19 with symptoms up to 14 days and elevated D-dimer levels will be randomized to a strategy of full-dose anticoagulation for 30 days with rivaroxaban 20 mg once daily (or full-dose heparin if oral administration is not feasible) vs standard of care with any approved venous thromboembolism prophylaxis regimen during hospitalization. A confirmation of COVID-19 was mandatory for study entry, based on specific tests used in clinical practice (RT-PCR, antigen test, IgM test) collected before randomization, regardless of in the outpatient setting or not. Randomization will be stratified by clinical stability at presentation. The primary outcome is a hierarchical analysis of mortality, length of hospital stay, or duration of oxygen therapy at the end of 30 days. Secondary outcomes include the World Health Organization's 8-point ordinal scale at 30 days and the following efficacy outcomes: incidence of venous thromboembolism , acute myocardial infarction, stroke, systemic embolism, major adverse limb events, duration of oxygen therapy, disease progression, and biomarkers. The primary safety outcomes are major or clinically relevant non-major bleeding according to the International Society on Thrombosis and Haemostasis criteria. SUMMARY: The ACTION trial will evaluate whether in-hospital therapeutic anticoagulation with rivaroxaban for stable patients, or enoxaparin for unstable patients, followed by rivaroxaban through 30 days compared with standard prophylactic anticoagulation improves clinical outcomes in hospitalized patients with COVID-19 and elevated D-dimer levels.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/complications , Enoxaparin/therapeutic use , Rivaroxaban/therapeutic use , Thrombosis/prevention & control , Administration, Oral , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Brazil , COVID-19/blood , COVID-19/mortality , Drug Administration Schedule , Enoxaparin/administration & dosage , Enoxaparin/adverse effects , Fibrin Fibrinogen Degradation Products/analysis , Hemorrhage/chemically induced , Hospitalization , Humans , Oxygen Inhalation Therapy , Rivaroxaban/administration & dosage , Rivaroxaban/adverse effects , Thrombosis/etiology , Time Factors
9.
J Thromb Haemost ; 19(9): 2225-2234, 2021 09.
Article in English | MEDLINE | ID: covidwho-1301535

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with coagulopathy but the optimal prophylactic anticoagulation therapy remains uncertain and may depend on COVID-19 severity. OBJECTIVE: To compare outcomes in hospitalized adults with severe COVID-19 treated with standard prophylactic versus intermediate dose enoxaparin. METHODS: We conducted a multi-center, open-label, randomized controlled trial comparing standard prophylactic dose versus intermediate dose enoxaparin in adults who were hospitalized with COVID-19 and admitted to an intensive care unit (ICU) and/or had laboratory evidence of coagulopathy. Patients were randomly assigned in a 1:1 ratio to receive standard prophylactic dose enoxaparin or intermediate weight-adjusted dose enoxaparin. The primary outcome was all-cause mortality at 30 days. Secondary outcomes included arterial or venous thromboembolism and major bleeding. RESULTS: A total of 176 patients (99 males and 77 females) underwent randomization. In the intention-to-treat population, all-cause mortality at 30 days was 15% for intermediate dose enoxaparin and 21% for standard prophylactic dose enoxaparin (odds ratio, 0.66; 95% confidence interval, 0.30-1.45; P = .31 by Chi-square test). Unadjusted Cox proportional hazards modeling demonstrated no significant difference in mortality between intermediate and standard dose enoxaparin (hazard ratio, 0.67; 95% confidence interval, 0.33-1.37; P = .28). Arterial or venous thrombosis occurred in 13% of patients assigned to intermediate dose enoxaparin and 9% of patients assigned to standard dose enoxaparin. Major bleeding occurred in 2% of patients in each arm. CONCLUSION: In hospitalized adults with severe COVID-19, standard prophylactic dose and intermediate dose enoxaparin did not differ significantly in preventing death or thrombosis at 30 days.


Subject(s)
COVID-19 , Thrombosis , Adult , Anticoagulants/adverse effects , Enoxaparin/adverse effects , Female , Humans , Male , SARS-CoV-2
10.
Thromb Haemost ; 122(1): 131-141, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1258614

ABSTRACT

BACKGROUND: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. METHODS: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. RESULTS: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). CONCLUSION: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Enoxaparin/administration & dosage , SARS-CoV-2 , Thrombosis/prevention & control , Aged , Anticoagulants/adverse effects , COVID-19/complications , COVID-19/mortality , Cohort Studies , Critical Care , Dose-Response Relationship, Drug , Enoxaparin/adverse effects , Extracorporeal Membrane Oxygenation , Female , Hemorrhage/chemically induced , Humans , Intensive Care Units , Iran/epidemiology , Kaplan-Meier Estimate , Male , Middle Aged , Pandemics , Thrombosis/etiology , Thrombosis/mortality
11.
JAMA ; 325(16): 1620-1630, 2021 04 27.
Article in English | MEDLINE | ID: covidwho-1239957

ABSTRACT

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/complications , Enoxaparin/administration & dosage , Extracorporeal Membrane Oxygenation , Oxygen Inhalation Therapy/methods , Thrombosis/prevention & control , Aged , Anticoagulants/adverse effects , COVID-19/mortality , Drug Administration Schedule , Enoxaparin/adverse effects , Female , Hemorrhage/chemically induced , Hospitalization , Humans , Intensive Care Units , Iran , Length of Stay/statistics & numerical data , Male , Middle Aged , Odds Ratio , Outcome Assessment, Health Care , Pulmonary Embolism/epidemiology , Thrombocytopenia/chemically induced , Thrombosis/etiology , Thrombosis/mortality , Treatment Outcome , Venous Thrombosis/epidemiology , Venous Thrombosis/mortality
12.
Thromb Haemost ; 121(12): 1684-1695, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1171416

ABSTRACT

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.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Enoxaparin/administration & dosage , Thromboembolism/drug therapy , Anticoagulants/adverse effects , COVID-19/complications , COVID-19/diagnosis , Clinical Trials, Phase III as Topic , Enoxaparin/adverse effects , Humans , Pragmatic Clinical Trials as Topic , Prospective Studies , Risk Assessment , Risk Factors , Thromboembolism/diagnosis , Thromboembolism/etiology , Time Factors , Treatment Outcome , United States , Venous Thromboembolism/diagnosis , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control
13.
JAMA ; 325(16): 1620-1630, 2021 04 27.
Article in English | MEDLINE | ID: covidwho-1139203

ABSTRACT

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/complications , Enoxaparin/administration & dosage , Extracorporeal Membrane Oxygenation , Oxygen Inhalation Therapy/methods , Thrombosis/prevention & control , Aged , Anticoagulants/adverse effects , COVID-19/mortality , Drug Administration Schedule , Enoxaparin/adverse effects , Female , Hemorrhage/chemically induced , Hospitalization , Humans , Intensive Care Units , Iran , Length of Stay/statistics & numerical data , Male , Middle Aged , Odds Ratio , Outcome Assessment, Health Care , Pulmonary Embolism/epidemiology , Thrombocytopenia/chemically induced , Thrombosis/etiology , Thrombosis/mortality , Treatment Outcome , Venous Thrombosis/epidemiology , Venous Thrombosis/mortality
14.
J Med Virol ; 93(7): 4303-4318, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1118166

ABSTRACT

Here we analyze hospitalized andintensive care unit coronavirus disease 2019 (COVID-19) patient outcomes from the international VIRUS registry (https://clinicaltrials.gov/ct2/show/NCT04323787). We find that COVID-19 patients administered unfractionated heparin but not enoxaparin have a higher mortality-rate (390 of 1012 = 39%) compared to patients administered enoxaparin but not unfractionated heparin (270 of 1939 = 14%), presenting a risk ratio of 2.79 (95% confidence interval [CI]: [2.42, 3.16]; p = 4.45e-52). This difference persists even after balancing on a number of covariates including demographics, comorbidities, admission diagnoses, and method of oxygenation, with an increased mortality rate on discharge from the hospital of 37% (268 of 733) for unfractionated heparin versus 22% (154 of 711) for enoxaparin, presenting a risk ratio of 1.69 (95% CI: [1.42, 2.00]; p = 1.5e-8). In these balanced cohorts, a number of complications occurred at an elevated rate for patients administered unfractionated heparin compared to patients administered enoxaparin, including acute kidney injury, acute cardiac injury, septic shock, and anemia. Furthermore, a higher percentage of Black/African American COVID patients (414 of 1294 [32%]) were noted to receive unfractionated heparin compared to White/Caucasian COVID patients (671 of 2644 [25%]), risk ratio 1.26 (95% CI: [1.14, 1.40]; p = 7.5e-5). After balancing upon available clinical covariates, this difference in anticoagulant use remained statistically significant (311 of 1047 [30%] for Black/African American vs. 263 of 1047 [25%] for White/Caucasian, p = .02, risk ratio 1.18; 95% CI: [1.03, 1.36]). While retrospective studies cannot suggest any causality, these findings motivate the need for follow-up prospective research into the observed racial disparity in anticoagulant use and outcomes for severe COVID-19 patients.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/mortality , Enoxaparin/therapeutic use , Healthcare Disparities , Heparin/therapeutic use , Thrombosis/prevention & control , Anticoagulants/adverse effects , Blood Coagulation/drug effects , COVID-19/blood , COVID-19/drug therapy , Enoxaparin/adverse effects , Female , Heparin/adverse effects , Hospitalization , Humans , Male , Middle Aged , Retrospective Studies , SARS-CoV-2 , Thrombosis/drug therapy
15.
J Thromb Thrombolysis ; 52(3): 782-790, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1111318

ABSTRACT

A pro-thrombotic milieu and a higher risk of thrombotic events were observed in patients with CoronaVirus disease-19 (COVID-19). Accordingly, recent data suggested a beneficial role of low molecular weight heparin (LMWH), but the optimal dosage of this treatment is unknown. We evaluated the association between prophylactic vs. intermediate-to-fully anticoagulant doses of enoxaparin and in-hospital adverse events in patients with COVID-19. We retrospectively included 436 consecutive patients admitted in three Italian hospitals. Outcome according to the use of prophylactic (4000 IU) vs. higher (> 4000 IU) daily dosage of enoxaparin was evaluated. The primary end-point was in-hospital death. Secondary outcome measures were in-hospital cardiovascular death, venous thromboembolism, new-onset acute respiratory distress syndrome (ARDS) and mechanical ventilation. A total of 287 patients (65.8%) were treated with the prophylactic enoxaparin regimen and 149 (34.2%) with a higher dosing regimen. The use of prophylactic enoxaparin dose was associated with a similar incidence of all-cause mortality (25.4% vs. 26.9% with the higher dose; OR at multivariable analysis, including the propensity score: 0.847, 95% CI 0.400-0.1.792; p = 0.664). In the prophylactic dose group, a significantly lower incidence of cardiovascular death (OR 0.165), venous thromboembolism (OR 0.067), new-onset ARDS (OR 0.454) and mechanical intubation (OR 0.150) was observed. In patients hospitalized for COVID-19, the use of a prophylactic dosage of enoxaparin appears to be associated with similar in-hospital overall mortality compared to higher doses. These findings require confirmation in a randomized, controlled study.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/therapy , Enoxaparin/administration & dosage , Hospitalization , Thromboembolism/prevention & control , Aged , Aged, 80 and over , Anticoagulants/adverse effects , COVID-19/blood , COVID-19/diagnosis , COVID-19/mortality , Enoxaparin/adverse effects , Female , Hospital Mortality , Humans , Italy , Male , Middle Aged , Protective Factors , Respiration, Artificial , Retrospective Studies , Risk Assessment , Risk Factors , Thromboembolism/blood , Thromboembolism/diagnosis , Thromboembolism/mortality , Time Factors , Treatment Outcome
17.
BMJ ; 372: n311, 2021 02 11.
Article in English | MEDLINE | ID: covidwho-1083594

ABSTRACT

OBJECTIVE: To evaluate whether early initiation of prophylactic anticoagulation compared with no anticoagulation was associated with decreased risk of death among patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United States. DESIGN: Observational cohort study. SETTING: Nationwide cohort of patients receiving care in the Department of Veterans Affairs, a large integrated national healthcare system. PARTICIPANTS: All 4297 patients admitted to hospital from 1 March to 31 July 2020 with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without a history of anticoagulation. MAIN OUTCOME MEASURES: The main outcome was 30 day mortality. Secondary outcomes were inpatient mortality, initiating therapeutic anticoagulation (a proxy for clinical deterioration, including thromboembolic events), and bleeding that required transfusion. RESULTS: Of 4297 patients admitted to hospital with covid-19, 3627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3600) of treated patients received subcutaneous heparin or enoxaparin. 622 deaths occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospital stay. Using inverse probability of treatment weighted analyses, the cumulative incidence of mortality at 30 days was 14.3% (95% confidence interval 13.1% to 15.5%) among those who received prophylactic anticoagulation and 18.7% (15.1% to 22.9%) among those who did not. Compared with patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30 day mortality (hazard ratio 0.73, 95% confidence interval 0.66 to 0.81). Similar associations were found for inpatient mortality and initiation of therapeutic anticoagulation. Receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion (hazard ratio 0.87, 0.71 to 1.05). Quantitative bias analysis showed that results were robust to unmeasured confounding (e-value lower 95% confidence interval 1.77 for 30 day mortality). Results persisted in several sensitivity analyses. CONCLUSIONS: Early initiation of prophylactic anticoagulation compared with no anticoagulation among patients admitted to hospital with covid-19 was associated with a decreased risk of 30 day mortality and no increased risk of serious bleeding events. These findings provide strong real world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial treatment for patients with covid-19 on hospital admission.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/mortality , Enoxaparin/therapeutic use , Thromboembolism/prevention & control , Adult , Aged , Aged, 80 and over , Anticoagulants/adverse effects , COVID-19/complications , Enoxaparin/adverse effects , Female , Hemorrhage/chemically induced , Humans , Male , Middle Aged , Patient Admission , SARS-CoV-2 , Thromboembolism/virology , Time Factors , United States/epidemiology
19.
J Cardiovasc Pharmacol ; 76(4): 369-371, 2020 10.
Article in English | MEDLINE | ID: covidwho-835200

ABSTRACT

The use of heparin has been shown to decrease the mortality in hospitalized patients with severe COVID-19. The aim of our study was to evaluate the clinical impact of venous thromboembolism prophylaxis with fondaparinux versus enoxaparin among 100 hospitalized COVID-19 patients. The incidence of pulmonary embolism, deep venous thrombosis, major bleeding (MB), clinically relevant non-MB, acute respiratory distress syndrome, and in-hospital mortality was compared between patients on fondaparinux versus enoxaparin therapy. The 2 groups were homogeneous for demographic, laboratory, and clinical characteristics. In a median follow-up of 28 (IQR: 12-45) days, no statistically significant difference in venous thromboembolism (14.5% vs. 5.3%; P = 0.20), MB and clinically relevant non-MB (3.2% vs. 5.3%, P = 0.76), ARDS (17.7% vs. 15.8%; P = 0.83), and in-hospital mortality (9.7% vs. 10.5%; P = 0.97) has been shown between the enoxaparin group versus the fondaparinux group. Our preliminary results support the hypothesis of a safe and effective use of fondaparinux among patients with COVID-19 hospitalized in internal medicine units.


Subject(s)
Antithrombins/therapeutic use , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Factor Xa Inhibitors/therapeutic use , Fondaparinux/therapeutic use , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Venous Thrombosis/etiology , Venous Thrombosis/prevention & control , Aged , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Antithrombins/adverse effects , COVID-19 , Enoxaparin/adverse effects , Enoxaparin/therapeutic use , Factor Xa Inhibitors/adverse effects , Female , Fondaparinux/adverse effects , Hemorrhage/chemically induced , Hospital Mortality , Humans , Incidence , Male , Middle Aged , Pandemics , Pulmonary Embolism/complications , Retrospective Studies , Venous Thromboembolism/epidemiology , Venous Thromboembolism/prevention & control , Venous Thrombosis/epidemiology
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