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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.
Cochrane Database Syst Rev ; 6: CD008077, 2021 06 08.
Article in English | MEDLINE | ID: covidwho-1453524

ABSTRACT

BACKGROUND: Heparin is an anticoagulant medication that is usually injected subcutaneously. Subcutaneous administration of heparin may result in complications such as bruising, haematoma, and pain at the injection site. One of the factors that may affect pain, haematoma, and bruising is injection speed. Several studies have been carried out to determine if speed of injection affects the amount of pain and bruising where the injection is given; however, the results of these studies have differed, and study authors have not reached a clear final conclusion. This is the second update of a review first published in 2014. OBJECTIVES: To assess the effects of duration (speed) of subcutaneous heparin injection on pain and bruising at the injection site in people admitted to hospitals or clinics who require treatment with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). We also looked at haematoma at the injection site. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 22 June 2020. We undertook reference checking of included studies to identify additional studies. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) comparing the effects of different durations of subcutaneous injection of heparin on pain, bruising, and haematoma at the injection site. DATA COLLECTION AND ANALYSIS: For this update, two review authors independently selected studies and extracted data via Covidence software and assessed methodological quality using Cochrane's risk of bias tool. The primary outcomes of interest were pain intensity at injection site and size and incidence of bruising. The secondary outcomes of interest were size and incidence of haematoma at injection site. We calculated the odds ratio (OR), mean difference (MD), or standardised mean difference (SMD) with corresponding 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE criteria. MAIN RESULTS: We identified one new study for this update, resulting in a total of five included studies with 503 participants who received subcutaneous injections of LMWH into the abdomen. Given the nature of the intervention, it was not possible to blind participants and caregivers (personnel) in any of the included studies. Two studies described blinding of outcome assessors. Overall, the methodological quality of included studies was moderate. The duration of the fast injection was 10 seconds, and the duration of the slow injection was 30 seconds in all included studies. Four studies reported site pain intensity after each injection at different time points. Two studies assessed site pain intensity immediately after each injection; meta-analysis showed no evidence of a difference in site pain intensity immediately after slow injection when compared to fast injection (MD -1.52, 95% CI -3.56 to 0.53; 140 participants; low-certainty evidence). Meta-analysis of three studies indicated that site pain intensity may be slightly reduced 48 hours after the slow heparin injection compared to fast injection (MD -1.60, 95% CI -2.69 to -0.51; 103 participants; low-certainty evidence). Five studies assessed bruise size at 48 hours, and two studies assessed bruise size at 60 hours. Meta-analysis showed there may be a reduction in bruise size 48 hours (SMD -0.54, 95% CI -1.05 to -0.02; 503 participants; 5 studies; very low-certainty evidence) and 60 hours (SMD -0.49, 95% CI -0.93 to -0.06; 84 participants; 2 studies; low-certainty evidence) after slow injection compared to fast injection. There was no evidence of a difference in bruise size 72 hours after slow injection compared to fast injection (SMD -0.27, 95% CI -0.61 to 0.06; 140 participants; 2 studies; low-certainty evidence). Three studies evaluated incidence of bruising and showed there may be a reduction in bruise incidence 48 hours (OR 0.39, 95% CI 0.26 to 0.60; 444 participants; low-certainty evidence) and 60 hours (OR 0.25, 95% CI 0.10 to 0.65; 84 participants; 2 studies; low-certainty evidence) after slow injection compared to fast injection. We downgraded the certainty of the evidence due to risk of bias concerns, imprecision, and inconsistency. None of the included studies measured size or incidence of haematoma. AUTHORS' CONCLUSIONS: Administering medication safely and enhancing patient comfort are the main aims of clinical nurses. In this review, we identified five RCTs that evaluated the effect of subcutaneous heparin injection duration on pain intensity, bruise size and incidence. We found that pain may be slightly reduced 48 hours after slow injection. Similarly, there may be a reduction in bruise size and incidence after slow injection compared to fast injection 48 and 60 hours postinjection. We downgraded the certainty of the evidence for all outcomes to low or very low due to risk of bias concerns, imprecision, and inconsistency. Accordingly, new trials with a more robust design, more participants, and a focus on different injection speeds will be useful in strengthening the certainty of the available evidence.


Subject(s)
Anticoagulants/administration & dosage , Contusions/prevention & control , Heparin, Low-Molecular-Weight/administration & dosage , Injections, Subcutaneous/methods , Pain, Procedural/prevention & control , Anticoagulants/adverse effects , Bias , Contusions/chemically induced , Contusions/pathology , Hematoma/chemically induced , Hematoma/pathology , Heparin, Low-Molecular-Weight/adverse effects , Humans , Injections, Subcutaneous/adverse effects , Middle Aged , Pain Measurement/methods , Pain, Procedural/etiology , Randomized Controlled Trials as Topic , Time Factors
3.
Clin Appl Thromb Hemost ; 27: 10760296211039288, 2021.
Article in English | MEDLINE | ID: covidwho-1448131

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a systemic disease that can be life-threatening involving immune and inflammatory responses, and that can result in potentially lethal complications, including venous thrombo-embolism (VTE). Forming an integrative approach to thrombo-prophylaxis and coagulation treatment for COVID-19 patients ensues. We aim at reviewing the literature for anticoagulation in the setting of COVID-19 infection to provide a summary on anticoagulation for this patient population. COVID-19 infection is associated with a state of continuous inflammation, which results in macrophage activation syndrome and an increased rate of thrombosis. Risk assessment models to predict the risk of thrombosis in critically ill patients have not yet been validated. Currently published guidelines suggest the use of prophylactic intensity over intermediate intensity or therapeutic intensity anticoagulant for patients with critical illness or acute illness related to COVID-19 infection. Critically ill COVID-19 patients who are diagnosed with acute VTE are considered to have a provoking factor, and, therefore, treatment duration should be at least 3 months. Patients with proximal deep venous thrombosis or pulmonary embolism should receive parenteral over oral anticoagulants with low-molecular-weight heparin or fondaparinux preferred over unfractionated heparin. In patients with impending hemodynamic compromise due to PE, and who are not at increased risk for bleeding, reperfusion may be necessary. Internists should remain updated on new emerging evidence regarding anticoagulation for COVID-19 patients. Awaiting these findings, we invite internists to perform individualized decisions that are unique for every patient and to base them on clinical judgment for risk assessment.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/complications , SARS-CoV-2 , Thrombophilia/drug therapy , Anti-Inflammatory Agents/therapeutic use , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Consensus , Critical Illness , Disease Management , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/adverse effects , Factor Xa Inhibitors/therapeutic use , Female , Fibrin Fibrinogen Degradation Products/analysis , Fondaparinux/adverse effects , Fondaparinux/therapeutic use , Hemorrhage/chemically induced , Heparin/adverse effects , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/administration & dosage , Heparin, Low-Molecular-Weight/adverse effects , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Inpatients , Male , Practice Guidelines as Topic , Pregnancy , Pregnancy Complications, Hematologic/prevention & control , Pregnancy Complications, Infectious/blood , Pulmonary Embolism/drug therapy , Pulmonary Embolism/etiology , Pulmonary Embolism/prevention & control , Risk , Thrombophilia/etiology , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control , Venous Thrombosis/drug therapy , Venous Thrombosis/etiology , Venous Thrombosis/prevention & control
4.
J Thromb Thrombolysis ; 52(3): 772-778, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1176387

ABSTRACT

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p < 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann-Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13-0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.


Subject(s)
Anticoagulants/therapeutic use , Blood Transfusion , COVID-19/therapy , Heparin, Low-Molecular-Weight/therapeutic use , Thromboembolism/prevention & control , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Blood Transfusion/mortality , COVID-19/blood , COVID-19/diagnosis , COVID-19/mortality , Clinical Decision-Making , Female , Heparin, Low-Molecular-Weight/adverse effects , Hospital Mortality , Hospitalization , Humans , Male , Middle Aged , Protective Factors , Risk Assessment , Risk Factors , Thromboembolism/blood , Thromboembolism/diagnosis , Thromboembolism/mortality , Time Factors , Treatment Outcome
5.
An Sist Sanit Navar ; 43(2): 251-254, 2020 Aug 31.
Article in Spanish | MEDLINE | ID: covidwho-1080494

ABSTRACT

Infection caused by SARS-CoV-2 (COVID-19) is associated with an increased risk of thromboembolic disease. So-me authors recommend anticoagulation at therapeutic doses for, at least, the most severely ill patients; this practice is not free of risks, which is why only thromboembolic prophylaxis is recommended by other consensuses. In the case of previously anticoagulated patients, changing the oral anticoagulant for a low molecular weight heparin (LMWH) is generally recommended. We present the cases of two patients admitted due to COVID-19, without serious clinical data, in whom anticoagulation (acenocoumarol and rivaroxaban, respectively) was replaced by LMWH at therapeutic doses, both presenting abdominal bleeding. This type of bleeding is an infrequent complication in anticoagulated patients, but the concurrence of two cases in a short period of time in the context of the COVID-19 pandemic leads us to consider that there is not yet any clear evidence on therapeutic anticoagulation in SARS-CoV-2 infection.


Subject(s)
Anticoagulants/adverse effects , Betacoronavirus , Coronavirus Infections/complications , Hematoma/chemically induced , Pneumonia, Viral/complications , Venous Thromboembolism/prevention & control , Venous Thromboembolism/virology , Abdomen , Acenocoumarol/adverse effects , Acenocoumarol/therapeutic use , Aged, 80 and over , Anticoagulants/therapeutic use , COVID-19 , Female , Hematoma/diagnosis , Heparin, Low-Molecular-Weight/adverse effects , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Pandemics , Rivaroxaban/adverse effects , Rivaroxaban/therapeutic use , SARS-CoV-2 , Venous Thromboembolism/drug therapy
6.
Cardiovasc Drugs Ther ; 36(1): 113-120, 2022 02.
Article in English | MEDLINE | ID: covidwho-1006434

ABSTRACT

PURPOSE: To determine the association between low molecular weight heparin (LMWH) use and mortality in hospitalized COVID-19 patients. METHODS: We conducted a retrospective study of patients consecutively enrolled from two major academic hospitals exclusively for COVID-19 in Wuhan, China, from January 26, 2020, to March 26, 2020. The primary outcome was adjusted in-hospital mortality in the LMWH group compared with the non-LMWH group using the propensity score. RESULTS: Overall, 525 patients with COVID-19 enrolled with a median age of 64 years (IQR 19), and 49.33% men. Among these, 120 (22.86%) were treated with LMWH. Compared with the non-LMWH group, the LMWH group was more likely to be older and male; had a history of hypertension, diabetes, coronary heart disease (CHD), or stroke; and had more severe COVID-19 parameters such as higher inflammatory cytokines or D-dimer. Compared with non-LMWH group, LMWH group had a higher unadjusted in-hospital mortality rate (21.70% vs. 11.10%; p = 0.004), but a lower adjusted mortality risk (adjusted odds ratio [OR], 0.20; 95% CI, 0.09-0.46). A propensity score-weighting analysis demonstrated similar findings (adjusted OR, 0.18; 95% CI, 0.10-0.30). Subgroup analysis showed a significant survival benefit among those who were severely (adjusted OR, 0.07; 95% CI, 0.02-0.23) and critically ill (adjusted OR, 0.32; 95% CI, 0.15-0.65), as well as among the elderly patients' age > 65, IL-6 > 10 times upper limit level, and D-dimer > 5 times upper limit level. CONCLUSIONS: Among hospitalized COVID-19 patients, LMWH use was associated with lower all-cause in-hospital mortality than non-LMWH users. The survival benefit was particularly significant among more severely ill patients.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/drug therapy , Heparin, Low-Molecular-Weight/therapeutic use , Hospitalization , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Blood Coagulation/drug effects , COVID-19/diagnosis , COVID-19/mortality , China/epidemiology , Comorbidity , Female , Hemorrhage/chemically induced , Heparin, Low-Molecular-Weight/adverse effects , Hospital Mortality , Humans , Male , Middle Aged , Retrospective Studies , Risk Assessment , Risk Factors , Severity of Illness Index , Time Factors , Treatment Outcome
7.
Chirurgia (Bucur) ; 115(6): 798-806, 2020.
Article in English | MEDLINE | ID: covidwho-1000770

ABSTRACT

Microthrombi formation in the pulmonary circulation is one of the main pathophysiological mechanisms responsible for the unfavorable respiratory evolution of CoViD-19 patients. Low molecular weight heparin (LMWH) anticoagulant therapy is a major pillar of treatment. But sometimes LMWH causes severe complications that can result in death. This is a retrospective, descriptive study, covering September 2020 and presenting 3 cases of severe hemorrhages followed by death in COVID-19 anticoagulated patients in therapeutic doses with LMWH in the hospital units of origin. Patients had hematomas of the rectus abdominal muscles and hemoperitoneum (2 cases) respectively hematoma of left gluteal muscles (1 case). The 2 patients with hematoma of rectus abdominal muscles were operated. The death occurred between 1-4 days after hospitalization.


Subject(s)
Anticoagulants , COVID-19/complications , Hemorrhage/chemically induced , Heparin, Low-Molecular-Weight/adverse effects , Anticoagulants/adverse effects , Fatal Outcome , Humans , Retrospective Studies , Treatment Outcome
8.
Ann Saudi Med ; 40(6): 462-468, 2020.
Article in English | MEDLINE | ID: covidwho-976449

ABSTRACT

BACKGROUND: Venous thromboembolism or extensive thrombosis is relatively common in patients with severe COVID-19 infection and has been associated with increased mortality. During the current COVID-19 pandemic, several prophylactic doses and types of low-molecular-weight heparin (LMWH) are being used worldwide; however, there are no high-quality studies or recommendations for an optimal prophylactic LMWH dose. OBJECTIVES: Investigate the relationship between coagulation parameters and the LMWH dose, and mortality and ICU admission in hospitalized patients with severe COVID-19 pneumonia. DESIGN: Retrospective. SETTING: Tertiary care hospital. PATIENTS AND METHODS: Data on clinical features, coagulation parameters and anticoagulant medications of inpatients with severe COVID-19 were collected for the period between 11 March 2020 and 31 April 2020. MAIN OUTCOME MEASURES: Mortality and ICU admission for prophylactic dose LMWH (0.5 mg/kg twice daily) and therapeutic dose LMWH (1 mg/kg twice daily). SAMPLE SIZE: 154 cases. RESULTS: Ninety-eight (63.6%) patients were treated with the LMWH prophylactic dose and 56 (36.4%) patients were treated with the therapeutic dose. Forty-four (44.9%) of 98 patients using the prophylactic dose LMWH died, while 10 (17.9%) of 56 patients using the therapeutic dose LMWH died (P=.001). Mortality was 6.4-fold higher in the prophylactic dose LMWH users than in the therapeutic dose LMWH users (OR=6.5, 95% CI: 2.4-17.6, P<.001). CONCLUSIONS: Therapeutic dosing of LMWH may decrease mortality in patients with severe COVID-19 infected pneumonia. More aggressive thromboprophylaxis regimens using higher doses of heparin should be evaluated in prospective studies. LIMITATIONS: Lack of information about bleeding complications. LMWH was not compared with other anticoagulant therapies. There was no comparison between our two groups on the APACHE score. Used different doses of LMWH in different clinics in our hospital. Single-center, retrospective study. CONFLICT OF INTEREST: None.


Subject(s)
COVID-19 , Chemoprevention/methods , Heparin, Low-Molecular-Weight , SARS-CoV-2/isolation & purification , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Blood Coagulation/drug effects , COVID-19/blood , COVID-19/mortality , COVID-19/physiopathology , COVID-19/therapy , Dose-Response Relationship, Drug , Female , Heparin, Low-Molecular-Weight/administration & dosage , Heparin, Low-Molecular-Weight/adverse effects , Humans , Male , Middle Aged , Mortality , Outcome and Process Assessment, Health Care , Retrospective Studies , Thromboembolism/blood , Thromboembolism/etiology , Thromboembolism/prevention & control , Turkey/epidemiology
11.
Thromb Res ; 196: 313-317, 2020 12.
Article in English | MEDLINE | ID: covidwho-752817

ABSTRACT

BACKGROUND: Critically ill COVID-19 patients have a clear pattern of inflammation and hypercoagulable state. The main aim of the study was to evaluate the outcome of severe COVID-19 patients basing on prothrombotic risk factors (i.e. D-dimer). We also evaluated the impact of different doses of low molecular weight heparin (LMWH) on the incidence of bleedings. METHODS: The data of forty-two patients admitted to the Intensive Care Unit (ICU) were retrospectively analyzed. On ICU admission, patients with D-dimer < 3000 ng/mL (Group 1) received enoxaparin 4000 UI (6000 UI, if body mass index >35) subcutaneously b.i.d. and patients with D-dimer ≥ 3000 ng/mL (Group 2) received enoxaparin 100 UI/kg every 12 h. Aspirin was administered to all patients once a day. RESULTS: Both groups presented a high incidence of perivascular thrombosis (40.9% in Group 1 and 30% in Group 2). Patients of Group 2 suffered a higher incidence of venous thromboembolism (VTE) than Group 1 (65% vs 13.6%, p = 0.001). One patient (4.5%) of Group 1 and three patients (15%) of Group 2 suffered from minor bleeding; no patient had major bleeding. Group 2 had a longer ICU and hospital stay than Group 1 (11.5 ±â€¯5.6 vs 9.0 ±â€¯4.8 and 30 ±â€¯4.9 vs 21 ±â€¯2.3, p < 0.05, respectively) as well as increased ICU mortality (25% vs 9.1%). CONCLUSIONS: More severe critically ill COVID-19 patients have a high incidence of VTE and worse outcome, despite the use of heparin at the therapeutic dose. However, the use of heparin did not increase the incidence of bleeding complications.


Subject(s)
Anticoagulants/adverse effects , Aspirin/adverse effects , COVID-19/complications , Hemorrhage/chemically induced , Heparin, Low-Molecular-Weight/adverse effects , SARS-CoV-2 , Venous Thromboembolism/epidemiology , Adult , Aged , Critical Illness , Female , Humans , Intensive Care Units , Male , Middle Aged , Retrospective Studies
14.
J Clin Ultrasound ; 48(9): 522-526, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-694861

ABSTRACT

PURPOSE: The aim of this study was to evaluate the applicability of bedside ultrasonography for the diagnosis of deep venous thrombosis (DVT) in patients infected with corona virus disease 2019 (COVID-19) with and without treatment with low molecular weight heparin (LMWH). METHODS: We retrospectively analyzed the records of deceased and surviving patients in whom ultrasonography detected or not a DVT, and in whom LMWH was or not prescribed. RESULTS: The incidence of DVT is higher in the deceased (33/35) than in the surviving (22/46) patients. LMWH was administered in a larger proportion of surviving (18/22) than of deceased (18/33) patients. D-dimer concentrations decreased in patients who received LMWH in both groups. CONCLUSIONS: There was a high incidence of DVT in patients who succumbed to COVID-19. Bedside ultrasonography can detect the presence of DVT as early as possible and help assessing the risk of venous thromboembolism, allowing early and reasonable use of LMWH.


Subject(s)
Coronavirus Infections/diagnostic imaging , Coronavirus Infections/pathology , Heparin, Low-Molecular-Weight/administration & dosage , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/pathology , Venous Thrombosis/diagnostic imaging , Venous Thrombosis/virology , Adult , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Betacoronavirus/isolation & purification , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques/methods , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Drug Administration Schedule , Female , Heparin, Low-Molecular-Weight/adverse effects , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Point-of-Care Testing , Retrospective Studies , SARS-CoV-2 , Ultrasonography/methods , Venous Thrombosis/drug therapy
15.
Trials ; 21(1): 574, 2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-617182

ABSTRACT

OBJECTIVES: To assess whether high doses of Low Molecular Weight Heparin (LMWH) (i.e. Enoxaparin 70 IU/kg twice daily) compared to standard prophylactic dose (i.e., Enoxaparin 4000 IU once day), in hospitalized patients with COVID19 not requiring Invasive Mechanical Ventilation [IMV], are: a)more effective in preventing clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: 1.Death2.Acute Myocardial Infarction [AMI]3.Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]4.Need of either: a.Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orb.IMV in patients who at randomisation were receiving standard oxygen therapy5.IMV in patients who at randomisation were receiving non-invasive mechanical ventilationb)Similar in terms of major bleeding risk TRIAL DESIGN: Multicentre, randomised controlled, superiority, open label, parallel group, two arms (1:1 ratio), in-hospital study. PARTICIPANTS: Inpatients will be recruited from 7 Italian Academic and non-Academic Internal Medicine Units, 2 Infectious Disease Units and 1 Respiratory Disease Unit. INCLUSION CRITERIA (ALL REQUIRED): 1. Age > 18 and < 80 years 2. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) 3. Severe pneumonia defined by the presence of at least one of the following criteria: a.Respiratory Rate ≥25 breaths /minb.Arterial oxygen saturation≤93% at rest on ambient airc.PaO2/FiO2 ≤300 mmHg 4. Coagulopathy, defined by the presence of at least one of the following criteria: a.D-dimer >4 times the upper level of normal reference rangeb.Sepsis-Induced Coagulopathy (SIC) score >4 5. No need of IMV EXCLUSION CRITERIA: 1. Age <18 and >80 years 2. IMV 3. Thrombocytopenia (platelet count < 80.000 mm3) 4. Coagulopathy: INR >1.5, aPTT ratio > 1.4 5. Impaired renal function (eGFR calculated by CKD-EPI Creatinine equation < 30 ml/min) 6. Known hypersensitivity to enoxaparin 7. History of heparin induced thrombocytopenia 8. Presence of an active bleeding or a pathology susceptible of bleeding in presence of anticoagulation (e.g. recent haemorrhagic stroke, peptic ulcer, malignant cancer at high risk of haemorrhage, recent neurosurgery or ophthalmic surgery, vascular aneurysms, arteriovenous malformations) 9. Concomitant anticoagulant treatment for other indications (e.g. atrial fibrillation, venous thromboembolism, prosthetic heart valves) 10. Concomitant double antiplatelet therapy 11. Administration of therapeutic doses of LMWH, fondaparinux, or unfractionated heparin (UFH) for more than 72 hours before randomization; prophylactic doses are allowed 12. Pregnancy or breastfeeding or positive pregnancy test 13. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition) 14. Lack or withdrawal of informed consent INTERVENTION AND COMPARATOR: Control Group (Low-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at standard prophylactic dose (i.e., 4000 UI subcutaneously once day). Intervention Group (High-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at dose of 70 IU/kg every 12 hours, as reported in the following table. This dose is commonly used in Italy when a bridging strategy is required for the management of surgery or invasive procedures in patients taking anti-vitamin K oral anticoagulants Body Weight (kg)Enoxaparin dose every 12 hours (IU)<50200050-69400070-89600090-1108000>11010000 The treatment with Enoxaparin will be initiated soon after randomization (maximum allowed starting time 12h after randomization). The treatment will be administered every 12 hours in the intervention group and every 24 hours in the control group. Treatments will be administered in the two arms until hospital discharge or the primary outcomes detailed below occur. MAIN OUTCOMES: Primary Efficacy Endpoint: Clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: 1.Death2.Acute Myocardial Infarction [AMI]3.Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]4.Need of either: a.Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orb.IMV in patients who at randomisation were in standard oxygen therapy by delivery interfaces5.Need for IMV, in patients who at randomisation were in Cpap or NIV Time to the occurrence of each of these events will be recorded. Clinical worsening will be analysed as a binary outcome as well as a time-to-event one. Secondary Efficacy Endpoints: Any of the following events occurring within the hospital stay 1.Death2.Acute Myocardial Infarction [AMI]3.Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]4.Need of either: a.Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orb.IMV in patients who at randomisation were in standard oxygen therapy by delivery interfaces5.Need for IMV in patients who at randomisation were in Cpap or NIV6.Improvement of laboratory parameters of disease severity, including: o D-dimer levelo Plasma fibrinogen levelso Mean Platelet Volumeo Lymphocyte/Neutrophil ratioo IL-6 plasma levels MORTALITY AT 30 DAYS: Information about patients' status will be sought in those who are discharged before 30 days on Day 30 from randomisation. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Primary safety endpoint: Major bleeding, defined as an acute clinically overt bleeding associated with one or more of the following: Decrease in haemoglobin of 2 g/dl or more;Transfusion of 2 or more units of packed red blood cells;Bleeding that occurs in at least one of the following critical sites [intracranial, intraspinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal];Bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death);Bleeding that necessitates surgical intervention Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Secondary safety endpoint: Clinically Relevant non-major bleeding, defined as an acute clinically overt bleeding that does not meet the criteria for major and consists of: 1.Any bleeding compromising hemodynamic2.Spontaneous hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic cause3.Intramuscular hematoma documented by ultrasonography4.Epistaxis or gingival bleeding requiring tamponade or other medical intervention5.Bleeding from venipuncture for >5 minutes6.Haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures7.Haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention8.Any other bleeding requiring temporary cessation of a study drug. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. RANDOMISATION: Randomisation (with a 1:1 randomisation ratio) will be centrally performed by using a secure, web-based system, which will be developed by the Methodological and Statistical Unit at the Azienda Ospedaliero-Universitaria of Modena. Randomisation stratified by 4 factors: 1) Gender (M/F); 2) Age (<75/≥75 years); 3) BMI (<30/≥30); 4) Comorbidities (0-1/>2) with random variable block sizes will be generated by STATA software. The web-based system will guarantee the allocation concealment. Blinding (masking) The study is conceived as open-label: patients and all health-care personnel involved in the study will be aware of the assigned group. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The target sample size is based on the hypothesis that LMWH administered at high doses versus low doses will significantly reduce the risk of clinical worsening. The overall sample size in this study is expected to be 300 with 150 in the Low-Dose LMWH control group and 150 in the High-Dose LMWH intervention group, recruited over 10-11 months. Assuming an alpha of 5% (two tailed) and a percentage of patients who experience clinical worsening in the control group being between 25% and 30%, the study will have 80% power to detect at least 50% relative reduction in the risk of death between low and high doses of heparin. TRIAL STATUS: Protocol version 1.2 of 11/05/2020. Recruitment start (expected): 08/06/2020 Recruitment finish (expected): 30/04/2021 Trial registration EudraCT 2020-001972-13, registered on April 17th, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Anticoagulants/therapeutic use , Betacoronavirus , Blood Coagulation Disorders/drug therapy , Coronavirus Infections/drug therapy , Heparin, Low-Molecular-Weight/therapeutic use , Heparin/therapeutic use , Pneumonia, Viral/drug therapy , Randomized Controlled Trials as Topic , Adolescent , Adult , Aged , COVID-19 , Heparin/adverse effects , Heparin, Low-Molecular-Weight/adverse effects , Hospitalization , Humans , Middle Aged , Pandemics , Respiration, Artificial , SARS-CoV-2 , Young Adult
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