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1.
Bradbury, Charlotte A. M. D. PhD, Lawler, Patrick R. M. D. M. P. H.; Stanworth, Simon J. M. D.; McVerry, Bryan J. M. D.; McQuilten, Zoe PhD, Higgins, Alisa M. PhD, Mouncey, Paul R. MSc, Al-Beidh, Farah PhD, Rowan, Kathryn M. PhD, Berry, Lindsay R. PhD, Lorenzi, Elizabeth PhD, Zarychanski, Ryan M. D. MSc, Arabi, Yaseen M. M. D.; Annane, Djillali M. D. PhD, Beane, Abi PhD, van Bentum-Puijk, Wilma MSc, Bhimani, Zahra M. P. H.; Bihari, Shailesh PhD, M Bonten, Marc J. M. D. PhD, Brunkhorst, Frank M. M. D. PhD, Buzgau, Adrian MSc, Buxton, Meredith PhD, Carrier, Marc M. D. MSc, Cheng, Allen C. Mbbs PhD, Cove, Matthew Mbbs, Detry, Michelle A. PhD, Estcourt, Lise J. MBBCh PhD, Fitzgerald, Mark PhD, Girard, Timothy D. M. D. Msci, Goligher, Ewan C. M. D. PhD, Goossens, Herman PhD, Haniffa, Rashan PhD, Hills, Thomas Mbbs PhD, Huang, David T. M. D. M. P. H.; Horvat, Christopher M. M. D.; Hunt, Beverley J. M. D. PhD, Ichihara, Nao M. D. M. P. H. PhD, Lamontagne, Francois M. D.; Leavis, Helen L. M. D. PhD, Linstrum, Kelsey M. M. S.; Litton, Edward M. D. PhD, Marshall, John C. M. D.; McAuley, Daniel F. M. D.; McGlothlin, Anna PhD, McGuinness, Shay P. M. D.; Middeldorp, Saskia M. D. PhD, Montgomery, Stephanie K. MSc, Morpeth, Susan C. M. D. PhD, Murthy, Srinivas M. D.; Neal, Matthew D. M. D.; Nichol, Alistair D. M. D. PhD, Parke, Rachael L. PhD, Parker, Jane C. B. N.; Reyes, Luis F. M. D. PhD, Saito, Hiroki M. D. M. P. H.; Santos, Marlene S. M. D. Mshs, Saunders, Christina T. PhD, Serpa-Neto, Ary PhD MSc M. D.; Seymour, Christopher W. M. D. MSc, Shankar-Hari, Manu M. D. PhD, Singh, Vanessa, Tolppa, Timo Mbbs, Turgeon, Alexis F. M. D. MSc, Turner, Anne M. M. P. H.; van de Veerdonk, Frank L. M. D. PhD, Green, Cameron MSc, Lewis, Roger J. M. D. PhD, Angus, Derek C. M. D. M. P. H.; McArthur, Colin J. M. D.; Berry, Scott PhD, G Derde, Lennie P. M. D. PhD, Webb, Steve A. M. D. PhD, Gordon, Anthony C. Mbbs M. D..
JAMA ; 327(13):1247, 2022.
Article in English | ProQuest Central | ID: covidwho-1801957

ABSTRACT

Importance The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control;n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures The primary end point was organ support–free days (days alive and free of intensive care unit–based respiratory or cardiovascular organ support) within 21 days, ranging from −1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support–free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years;521 [33.6%] female). The median for organ support–free days was 7 (IQR, −1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23];95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62];adjusted absolute difference, 5% [95% CrI, −0.2% to 9.5%];97% posterior probability of efficacy). Among survivors, the median for organ support–free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28];adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%];99.4% probability of harm). Conclusions and Relevance Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support–free days within 21 days.

2.
Antic, Darko, Milic, Natasa, Chatzikonstantinou, Thomas, Scarfò, Lydia, Otasevic, Vladimir, Rajovic, Nina, Allsup, David, Cabrero, Alejandro Alonso, Andres, Martin, Gonzales, Monica Baile, Capasso, Antonella, Collado, Rosa, Cordoba, Raul, Cuéllar-García, Carolina, Correa, Juan Gonzalo, De Paoli, Lorenzo, De Paolis, Maria Rosaria, Poeta, Giovanni Del, Dimou, Maria, Doubek, Michael, Efstathopoulou, Maria, El-Ashwah, Shaimaa, Enrico, Alicia, Espinet, Blanca, Farina, Lucia, Ferrari, Angela, Foglietta, Myriam, Lopez-Garcia, Alberto, García-Marco, José, García-Serra, Rocío, Gentile, Massimo, Gimeno, Eva, Silva, Maria Gomes, Gutwein, Odit, Hakobyan, Yervand, Herishanu, Yair, Hernández-Rivas, José Ángel, Herold, Tobias, Itchaki, Gilad, Jaksic, Ozren, Janssens, Ann, Kalashnikova, Оlga, Kalicińska, Elżbieta, Kater, Arnon, Kersting, Sabina, Koren-Michowitz, Maya, Gomez, Jorge Labrador, Lad, Deepesh, Laurenti, Luca, Fresa, Alberto, Levin, Mark-David, Bastida, Carlota Mayor, Malerba, Lara, Marasca, Roberto, Marchetti, Monia, Marquet, Juan, Mihaljevic, Biljana, Milosevic, Ivana, Mirás, Fatima, Morawska, Marta, Motta, Marina, Munir, Talha, Murru, Roberta, Nunes, Raquel, Olivieri, Jacopo, Pavlovsky, Miguel Arturo, Piskunova, Inga, Popov, Viola Maria, Quaglia, Francesca Maria, Quaresmini, Giulia, Reda, Gianluigi, Rigolin, Gian Matteo, Shrestha, Amit, Šimkovič, Martin, Smirnova, Svetlana, Špaček, Martin, Sportoletti, Paolo, Stanca, Oana, Stavroyianni, Niki, Raa, Doreen Te, Tomic, Kristina, Tonino, Sanne, Trentin, Livio, Spek, Ellen Der, Gelder, Michel, Varettoni, Marzia, Visentin, Andrea, Vitale, Candida, Vukovic, Vojin, Wasik-Szczepanek, Ewa, Wróbel, Tomasz, Segundo, Lucrecia Yáñez San, Yassin, Mohamed, Coscia, Marta, Rambaldi, Alessandro, Montserrat, Emili, Foà, Robin, Cuneo, Antonio, Carrier, Marc, Ghia, Paolo, Stamatopoulos, Kostas.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-334383

ABSTRACT

Background: Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. In this retrospective multicenter study, conducted by ERIC, the European Research Initiative on CLL, we assessed the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods: : The study included patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. Results: : A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 518 were defined as having severe COVID: 162 were admitted to the ICU while 356 received oxygen supplementation outside the ICU. Most patients (90%) were receiving thromboprophylaxis. During COVID-19 treatment, 8.8% developed a thromboembolic event, while 4.8% experienced bleeding. Thrombosis developed in 20.5% of patients who were not receiving thromboprophylaxis, but only in 8.1% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (11.1% vs. 4.2%, respectively) and in elderly. In multivariate analysis, peak D-dimer level was a poor prognostic factor for thrombosis occurrence (OR=1.020, 95%CI 1.006‒1.033), while thromboprophylaxis use was protective (OR=0.194, 95%CI 0.061‒0.614). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR=1.055, 95%CI 1.013-1.103 and OR=2.490, 95%CI 1.044-5.935, respectively). Conclusions: : Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.

3.
JAMA ; 327(13): 1247-1259, 2022 Apr 05.
Article in English | MEDLINE | ID: covidwho-1750260

ABSTRACT

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.


Subject(s)
COVID-19 , Venous Thromboembolism , Adult , Anticoagulants/therapeutic use , Aspirin/adverse effects , Bayes Theorem , Critical Illness/therapy , Female , Hemorrhage/chemically induced , Humans , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Respiration, Artificial , Venous Thromboembolism/drug therapy
6.
Chest ; 2022 Feb 12.
Article in English | MEDLINE | ID: covidwho-1676672

ABSTRACT

BACKGROUND: Patients hospitalized with COVID-19 often exhibit markers of a hypercoagulable state and have an increased incidence of VTE. In response, CHEST issued rapid clinical guidance regarding prevention of VTE. Over the past 18 months the quality of the evidence has improved. We thus sought to incorporate this evidence and update our recommendations as necessary. METHODS: This update focuses on the optimal approach to thromboprophylaxis in hospitalized patients. The original questions were used to guide the search, using MEDLINE via PubMed. Eight randomized controlled trials and one observational study were included. Meta-analysis, using a random effects model, was performed. The panel created summaries using the GRADE Evidence-to-Decision framework. Updated guidance statements were drafted, and a modified Delphi approach was used to obtain consensus. RESULTS: We provide separate guidance statements for VTE prevention for acutely (moderately) ill hospitalized patients and critically ill patients in the ICU. However, we divided each original question and resulting recommendation into two questions: standard prophylaxis vs therapeutic (or escalated dose) prophylaxis and standard prophylaxis vs intermediate dose prophylaxis. This led to a change in one recommendation, and an upgrading of three additional recommendations based upon higher quality evidence. CONCLUSIONS: Advances in care for patients with COVID-19 have improved overall outcomes. Despite this, rates of VTE in these patients remain elevated. Critically ill patients should receive standard thromboprophylaxis for VTE, and moderately ill patients with a low bleeding risk might benefit from therapeutic heparin. We see no role for intermediate dose thromboprophylaxis in either setting.

7.
Thrombosis Update ; 2022.
Article in English | EuropePMC | ID: covidwho-1615072

ABSTRACT

Cancer patients exhibit an increased risk of venous thromboembolism (VTE), with VTE being the second leading cause of morbidity and mortality in these patients. The implementation of lockdowns following the COVID-19 pandemic has resulted in decreased mobility and delayed access to care, thus further increasing the susceptibility to VTE. Cancer patients may also be at a higher risk of SARS-CoV-2 infection and have been shown to be more likely to experience severe COVID-19 disease compared to patients without cancer. Given that both cancer and COVID-19 exhibit a hypercoagulable state, stasis of blood flow, and endothelial injury, cancer patients with COVID-19 constitute a vulnerable population with a high risk of thrombosis and bleeding. However, to date there are limited studies evaluating whether cancer patients infected with SARS-CoV-2 have a higher VTE incidence than COVID-19 patients without cancer, how to assess the risk of VTE, prophylaxis and treatment in this special population. Herein, we highlight the urgent need for studies in cancer patients with COVID-19 to ensure appropriate patient care and improve clinical outcomes. Graphical Image 1

8.
Res Pract Thromb Haemost ; 5(8): e12638, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1588881

ABSTRACT

Background: Pulmonary endothelial injury and microcirculatory thromboses likely contribute to hypoxemic respiratory failure, the most common cause of death, in patients with COVID-19. Randomized controlled trials (RCTs) suggest differences in the effect of therapeutic heparin between moderately and severely ill patients with COVID-19. We did a systematic review and meta-analysis of RCTs to determine the effects of therapeutic heparin in hospitalized patients with COVID-19. Methods: We searched PubMed, Embase, Web of Science, medRxiv, and medical conference proceedings for RCTs comparing therapeutic heparin with usual care, excluding trials that used oral anticoagulation or intermediate doses of heparin in the experimental arm. Mantel-Haenszel fixed-effect meta-analysis was used to combine odds ratios (ORs). Results and Conclusions: There were 3 RCTs that compared therapeutic heparin to lower doses of heparin in 2854 moderately ill ward patients, and 3 RCTs in 1191 severely ill patients receiving critical care. In moderately ill patients, there was a nonsignificant reduction in all-cause death (OR, 0.76; 95% CI, 0.57-1.02), but significant reductions in the composite of death or invasive mechanical ventilation (OR, 0.77; 95% CI, 0.60 0.98), and death or any thrombotic event (OR, 0.58; 95% CI, 0.45-0.77). Organ support-free days alive (OR, 1.29; 95% CI, 1.07-1.57) were significantly increased with therapeutic heparin. There was a nonsignificant increase in major bleeding. In severely ill patients, there was no evidence for benefit of therapeutic heparin, with significant treatment-by-subgroup interactions with illness severity for all-cause death (P = .034). In conclusion, therapeutic heparin is beneficial in moderately ill patients but not in severely ill patients hospitalized with COVID-19.

9.
BMJ ; 375: n2400, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1470506

ABSTRACT

OBJECTIVE: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN: Randomised controlled, adaptive, open label clinical trial. SETTING: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m2. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362085.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/mortality , COVID-19/therapy , Heparin/therapeutic use , Hospitalization/statistics & numerical data , Respiration, Artificial , Biomarkers/blood , Female , Humans , Intensive Care Units/statistics & numerical data , Male , Middle Aged , SARS-CoV-2 , Severity of Illness Index
10.
Res Pract Thromb Haemost ; 5(5): e12532, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1372774

ABSTRACT

This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) was hosted virtually from Philadelphia July 17-21, 2021. The conference, now held annually, highlighted cutting-edge advances in basic, population and clinical sciences of relevance to the Society. Despite being held virtually, the 2021 congress was of the same scope and quality as an annual meeting held in person. An added feature of the program is that talks streamed at the designated times will then be available on-line for asynchronous viewing. The program included 77 State of the Art (SOA) talks, thematically grouped in 28 sessions, given by internationally recognized leaders in the field. The SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. The topics, across the main scientific themes of the congress, include Arterial Thromboembolism, Coagulation and Natural Anticoagulants, COVID-19 and Coagulation, Diagnostics and Omics, Fibrinogen, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostasis in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Angiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the congress.

11.
Chest ; 161(2): 418-428, 2022 02.
Article in English | MEDLINE | ID: covidwho-1363121

ABSTRACT

BACKGROUND: Critically ill adults are at increased risk of VTE, including DVT, and pulmonary embolism. Various agents exist for venous thromboprophylaxis in this population. RESEARCH QUESTION: What is the comparative efficacy and safety of prophylaxis agents for prevention of VTE in critically ill adults? STUDY DESIGN AND METHODS: Systematic review and network meta-analysis of randomized clinical trials (RCTs) evaluating efficacy of thromboprophylaxis agents among critically ill patients. We searched six databases (including PubMed, EMBASE, and Medline) from inception through January 2021 for RCTs of patients in the ICU receiving pharmacologic, mechanical, or combination therapy (pharmacologic agents and mechanical devices) for thromboprophylaxis. Two reviewers performed screening, full-text review, and extraction. We used the Grading of Recommendations Assessment, Development, and Evaluation to rate certainty of effect estimates. RESULTS: We included 13 RCTs (9,619 patients). Compared with control treatment (a composite of no prophylaxis, placebo, or compression stockings only), low-molecular-weight heparin (LMWH) reduced the incidence of DVT (OR, 0.59 [95% credible interval [CrI], 0.33-0.90]; high certainty) and unfractionated heparin (UFH) may reduce the incidence of DVT (OR, 0.82 [95% CrI, 0.47-1.37]; low certainty). LMWH probably reduces DVT compared with UFH (OR, 0.72 [95% CrI, 0.46-0.98]; moderate certainty). Compressive devices may reduce risk of DVT compared with control treatments; however, this is based on low-certainty evidence (OR, 0.85 [95% CrI, 0.50-1.50]). Combination therapy showed unclear effect on DVT compared with either therapy alone (very low certainty). INTERPRETATION: Among critically ill adults, compared with control treatment, LMWH reduces incidence of DVT, whereas UFH and mechanical compressive devices may reduce the risk of DVT. LMWH is probably more effective than UFH in reducing incidence of DVT and should be considered the primary pharmacologic agent for thromboprophylaxis. The efficacy and safety of combination pharmacologic therapy and mechanical compressive devices were unclear. TRIAL REGISTRY: Open Science Framework; URL: https://osf.io/694aj.


Subject(s)
Anticoagulants/therapeutic use , Critical Illness , Intermittent Pneumatic Compression Devices , Venous Thromboembolism/prevention & control , Adult , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Pulmonary Embolism/prevention & control , Randomized Controlled Trials as Topic
12.
N Engl J Med ; 385(9): 790-802, 2021 Aug 26.
Article in English | MEDLINE | ID: covidwho-1343498

ABSTRACT

BACKGROUND: Thrombosis 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. METHODS: In 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. RESULTS: The 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. CONCLUSIONS: In 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.).


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Heparin/administration & dosage , Thrombosis/prevention & control , Adult , Aged , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , COVID-19/mortality , Female , Hemorrhage/chemically induced , Heparin/adverse effects , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Hospital Mortality , Humans , Male , Middle Aged , Survival Analysis
13.
N Engl J Med ; 385(9): 777-789, 2021 Aug 26.
Article in English | MEDLINE | ID: covidwho-1343497

ABSTRACT

BACKGROUND: Thrombosis 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. METHODS: In 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. RESULTS: The 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. CONCLUSIONS: In 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.).


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Heparin/administration & dosage , Thrombosis/prevention & control , Aged , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , COVID-19/mortality , Critical Illness , Female , Hemorrhage/chemically induced , Heparin/adverse effects , Heparin/therapeutic use , Hospital Mortality , Humans , Logistic Models , Male , Middle Aged , Odds Ratio , Respiration, Artificial , Treatment Failure
15.
Res Pract Thromb Haemost ; 5(5): e12532, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1321717

ABSTRACT

This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) was hosted virtually from Philadelphia July 17-21, 2021. The conference, now held annually, highlighted cutting-edge advances in basic, population and clinical sciences of relevance to the Society. Despite being held virtually, the 2021 congress was of the same scope and quality as an annual meeting held in person. An added feature of the program is that talks streamed at the designated times will then be available on-line for asynchronous viewing. The program included 77 State of the Art (SOA) talks, thematically grouped in 28 sessions, given by internationally recognized leaders in the field. The SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. The topics, across the main scientific themes of the congress, include Arterial Thromboembolism, Coagulation and Natural Anticoagulants, COVID-19 and Coagulation, Diagnostics and Omics, Fibrinogen, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostasis in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Angiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the congress.

16.
J Thromb Haemost ; 19(10): 2373-2382, 2021 10.
Article in English | MEDLINE | ID: covidwho-1316906

ABSTRACT

A heightened risk of thrombosis noted early on with the severe acute respiratory syndrome coronavirus 2 infection led to the widespread use of heparin anticoagulation in the coronavirus disease 2019 (COVID-19) pandemic. However, reports soon started appearing in the literature where an apparent failure of heparin to prevent thrombotic events was observed in hospitalized patients with this viral infection. In this review, we explore the likely mechanisms for heparin failure with particular relevance to COVID-19. We also explore the role of anti-Xa assays and global hemostatic tests in this context. The current controversy of dosing heparin in this disease is detailed with some possible mechanistic reasons for anticoagulant failure. We hope that lessons learnt from the use of heparin in COVID-19 could assist us in the appropriate use of this anticoagulant in the future.


Subject(s)
COVID-19 , Heparin , Anticoagulants/adverse effects , Heparin/adverse effects , Humans , Pandemics , SARS-CoV-2
17.
Can J Surg ; 64(3): E289-E297, 2021 05 12.
Article in English | MEDLINE | ID: covidwho-1225820

ABSTRACT

Since COVID-19 was declared a pandemic a year ago, our understanding of its effects on the vascular system has slowly evolved. At the cellular level, SARS-CoV-2 - the virus that causes COVID-19 - accesses the vascular endothelium through the angiotensin-converting enzyme 2 (ACE-2) receptor and induces proinflammatory and prothrombotic responses. At the clinical level, these pathways lead to thromboembolic events that affect the pulmonary, extracranial, mesenteric, and lower extremity vessels. At the population level, the presence of vascular risk factors predisposes individuals to more severe forms of COVID-19, whereas the absence of vascular risk factors does not spare patients with COVID-19 from unprecedented rates of stroke, pulmonary embolism and acute limb ischemia. Finally, at the community and global level, the fear of COVID-19, measures taken to limit the spread of SARS-CoV-2 and reallocation of limited hospital resources have led to delayed presentations of severe forms of ischemia, surgery cancellations and missed opportunities for limb salvage. The purpose of this narrative review is to present some of the data on COVID-19, from cellular mechanisms to clinical manifestations, and discuss its impact on the local and global surgical communities from a vascular perspective.


Depuis que la COVID-19 s'est vu donner le statut de pandémie il y a 1 an, notre connaissance des effets de cette maladie sur le système vasculaire a évolué. À l'échelle cellulaire, le SRAS-CoV-2 ­ le virus qui cause la COVID-19 ­ accède à l'endothélium vasculaire par le récepteur de l'enzyme de conversion de l'angiotensine-2 (ACE-2) et provoque des réponses proinflammatoires et prothrombotiques. À l'échelle clinique, ces réponses peuvent mener à une activité thromboembolique touchant les vaisseaux pulmonaires, extracrâniens, mésentériques et des membres inférieurs. À l'échelle populationnelle, la présence chez certaines personnes de facteurs de risque vasculaires les prédispose à une forme plus grave de la COVID-19, mais l'absence de ces facteurs n'empêche pas les patients atteints de la COVID-19 de présenter des taux sans précédent d'AVC, d'embolie pulmonaire et d'ischémie aiguë aux membres. Enfin, à l'échelle locale et mondiale, la peur entourant la COVID-19, les mesures prises pour en endiguer la propagation et le redéploiement des ressources limitées des hôpitaux ont mené au report de visites à l'hôpital pour des formes graves d'ischémie, à l'annulation de chirurgies et à des occasions manquées de préserver des membres. La présente revue non systématique a pour objectif de présenter une partie des données sur la COVID-19, de ses mécanismes cellulaires à ses manifestations cliniques, et de discuter des répercussions de la crise sur les communautés chirurgicales locales et mondiales, dans une optique vasculaire.


Subject(s)
COVID-19/complications , Vascular Diseases/etiology , Cells/virology , Elective Surgical Procedures , Humans , Internationality , SARS-CoV-2/pathogenicity
18.
J Thromb Haemost ; 19(5): 1161-1167, 2021 05.
Article in English | MEDLINE | ID: covidwho-1136010

ABSTRACT

COVID-19 continues to dominate the health-care burden in the twenty-first century. While health-care professionals around the world try their best to minimize the mortality from this pandemic, we also continue to battle the high mortality from different types of cancer. For the hemostasis and thrombosis specialist, these two conditions present some unusual similarities including the high rate of thrombosis and marked elevation of D-dimers. In this forum article, we discuss these similarities and provide some considerations for future research and therapeutic trials.


Subject(s)
COVID-19 , Neoplasms , Thrombosis , Humans , Neoplasms/therapy , Pandemics , SARS-CoV-2
19.
Trials ; 22(1): 202, 2021 Mar 10.
Article in English | MEDLINE | ID: covidwho-1127720

ABSTRACT

OBJECTIVES: To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days. TRIAL DESIGN: Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial PARTICIPANTS: The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: 1) Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; 2) Admitted to hospital for COVID-19; 3) One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: a. D-Dimer ≥2 times ULN OR b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; 4) > 18 years of age; 5) Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: 1) pregnancy; 2) hemoglobin <80 g/L in the last 72 hours; 3) platelet count <50 x 109/L in the last 72 hours; 4) known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 5) known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 6) patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); 7) patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; 8) patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; 9) known bleeding within the last 30 days requiring emergency room presentation or hospitalization; 10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder; 11) known history of heparin-induced thrombocytopenia; 12) known allergy to UFH or LMWH; 13) admitted to the intensive care unit at the time of screening; 14) treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; 15) Imminent death according to the judgement of the most responsible physician; 16) enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients. INTERVENTION AND COMPARATOR: Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care. MAIN OUTCOMES: The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Secondary outcomes include (evaluated up to day 28): 1. All-cause death 2. Composite of ICU admission or all-cause death 3. Composite of mechanical ventilation or all-cause death 4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; 5. Red blood cell transfusion (>1 unit); 6. Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; 7. Renal replacement therapy; 8. Hospital-free days alive; 9. ICU-free days alive; 10. Ventilator-free days alive; 11. Organ support-free days alive; 12. Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 13. Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 14. Heparin induced thrombocytopenia; 15. Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers. RANDOMISATION: Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment. BLINDING (MASKING): No blinding involved. This is an open-label trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05. TRIAL STATUS: Protocol Version Number 1.4. Recruitment began on May 11th, 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of 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 , Blood Coagulation Disorders/drug therapy , COVID-19/drug therapy , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/complications , COVID-19/blood , COVID-19/complications , COVID-19/physiopathology , Clinical Trials, Phase III as Topic , Fibrin Fibrinogen Degradation Products/metabolism , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Hospitalization , Humans , Intensive Care Units/statistics & numerical data , Noninvasive Ventilation/statistics & numerical data , Pragmatic Clinical Trials as Topic , Randomized Controlled Trials as Topic , Respiration, Artificial/statistics & numerical data , SARS-CoV-2
20.
Chest ; 158(3): 1143-1163, 2020 09.
Article in English | MEDLINE | ID: covidwho-987247

ABSTRACT

BACKGROUND: Emerging evidence shows that severe coronavirus disease 2019 (COVID-19) can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and VTE. This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE. METHODS: A group of approved panelists developed key clinical questions by using the PICO (Population, Intervention, Comparator, Outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis, and treatment of VTE in patients with COVID-19. MEDLINE (via PubMed or Ovid), Embase, and Cochrane Controlled Register of Trials were systematically searched for relevant literature, and references were screened for inclusion. Validated evaluation tools were used to grade the level of evidence to support each recommendation. When evidence did not exist, guidance was developed based on consensus using the modified Delphi process. RESULTS: The systematic review and critical analysis of the literature based on 13 Population, Intervention, Comparator, Outcome questions resulted in 22 statements. Very little evidence exists in the COVID-19 population. The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements. CONCLUSIONS: The evidence on the optimal strategies to prevent, diagnose, and treat VTE in patients with COVID-19 is sparse but rapidly evolving.


Subject(s)
Betacoronavirus , Consensus , Coronavirus Infections/complications , Evidence-Based Medicine/standards , Pneumonia, Viral/complications , Venous Thromboembolism , COVID-19 , Coronavirus Infections/epidemiology , Humans , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Venous Thromboembolism/diagnosis , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control
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