Dataset Information

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

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.).

SUBMITTER: ATTACC Investigators

PROVIDER: S-EPMC8362594 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

Lawler Patrick R PR Goligher Ewan C EC Berger Jeffrey S JS Neal Matthew D MD McVerry Bryan J BJ Nicolau Jose C JC Gong Michelle N MN Carrier Marc M Rosenson Robert S RS Reynolds Harmony R HR Turgeon Alexis F AF Escobedo Jorge J Huang David T DT Bradbury Charlotte A CA Houston Brett L BL Kornblith Lucy Z LZ Kumar Anand A Kahn Susan R SR Cushman Mary M McQuilten Zoe Z Slutsky Arthur S AS Kim Keri S KS Gordon Anthony C AC Kirwan Bridget-Anne BA Brooks Maria M MM Higgins Alisa M AM Lewis Roger J RJ Lorenzi Elizabeth E Berry Scott M SM Berry Lindsay R LR Aday Aaron W AW Al-Beidh Farah F Annane Djillali D Arabi Yaseen M YM Aryal Diptesh D Baumann Kreuziger Lisa L Beane Abi A Bhimani Zahra Z Bihari Shailesh S Billett Henny H HH Bond Lindsay L Bonten Marc M Brunkhorst Frank F Buxton Meredith M Buzgau Adrian A Castellucci Lana A LA Chekuri Sweta S Chen Jen-Ting JT Cheng Allen C AC Chkhikvadze Tamta T Coiffard Benjamin B Costantini Todd W TW de Brouwer Sophie S Derde Lennie P G LPG Detry Michelle A MA Duggal Abhijit A Džavík Vladimír V Effron Mark B MB Estcourt Lise J LJ Everett Brendan M BM Fergusson Dean A DA Fitzgerald Mark M Fowler Robert A RA Galanaud Jean P JP Galen Benjamin T BT Gandotra Sheetal S García-Madrona Sebastian S Girard Timothy D TD Godoy Lucas C LC Goodman Andrew L AL Goossens Herman H Green Cameron C Greenstein Yonatan Y YY Gross Peter L PL Hamburg Naomi M NM Haniffa Rashan R Hanna George G Hanna Nicholas N Hegde Sheila M SM Hendrickson Carolyn M CM Hite R Duncan RD Hindenburg Alexander A AA Hope Aluko A AA Horowitz James M JM Horvat Christopher M CM Hudock Kristin K Hunt Beverley J BJ Husain Mansoor M Hyzy Robert C RC Iyer Vivek N VN Jacobson Jeffrey R JR Jayakumar Devachandran D Keller Norma M NM Khan Akram A Kim Yuri Y Kindzelski Andrei L AL King Andrew J AJ Knudson M Margaret MM Kornblith Aaron E AE Krishnan Vidya V Kutcher Matthew E ME Laffan Michael A MA Lamontagne Francois F Le Gal Grégoire G Leeper Christine M CM Leifer Eric S ES Lim George G Lima Felipe Gallego FG Linstrum Kelsey K Litton Edward E Lopez-Sendon Jose J Lopez-Sendon Moreno Jose L JL Lother Sylvain A SA Malhotra Saurabh S Marcos Miguel M Saud Marinez Andréa A Marshall John C JC Marten Nicole N Matthay Michael A MA McAuley Daniel F DF McDonald Emily G EG McGlothlin Anna A McGuinness Shay P SP Middeldorp Saskia S Montgomery Stephanie K SK Moore Steven C SC Morillo Guerrero Raquel R Mouncey Paul R PR Murthy Srinivas S Nair Girish B GB Nair Rahul R Nichol Alistair D AD Nunez-Garcia Brenda B Pandey Ambarish A Park Pauline K PK Parke Rachael L RL Parker Jane C JC Parnia Sam S Paul Jonathan D JD Pérez González Yessica S YS Pompilio Mauricio M Prekker Matthew E ME Quigley John G JG Rost Natalia S NS Rowan Kathryn K Santos Fernanda O FO Santos Marlene M Olombrada Santos Mayler M Satterwhite Lewis L Saunders Christina T CT Schutgens Roger E G REG Seymour Christopher W CW Siegal Deborah M DM Silva Delcio G DG Shankar-Hari Manu M Sheehan John P JP Singhal Aneesh B AB Solvason Dayna D Stanworth Simon J SJ Tritschler Tobias T Turner Anne M AM van Bentum-Puijk Wilma W van de Veerdonk Frank L FL van Diepen Sean S Vazquez-Grande Gloria G Wahid Lana L Wareham Vanessa V Wells Bryan J BJ Widmer R Jay RJ Wilson Jennifer G JG Yuriditsky Eugene E Zampieri Fernando G FG Angus Derek C DC McArthur Colin J CJ Webb Steven A SA Farkouh Michael E ME Hochman Judith S JS Zarychanski Ryan R

The New England journal of medicine 20210804 9

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 34351721

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

Project description:BackgroundPrior studies of therapeutic-dose anticoagulation in patients with COVID-19 have reported conflicting results.ObjectivesWe sought to determine the safety and effectiveness of therapeutic-dose anticoagulation in noncritically ill patients with COVID-19.MethodsPatients hospitalized with COVID-19 not requiring intensive care unit treatment were randomized to prophylactic-dose enoxaparin, therapeutic-dose enoxaparin, or therapeutic-dose apixaban. The primary outcome was the 30-day composite of all-cause mortality, requirement for intensive care unit-level of care, systemic thromboembolism, or ischemic stroke assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group.ResultsBetween August 26, 2020, and September 19, 2022, 3,398 noncritically ill patients hospitalized with COVID-19 were randomized to prophylactic-dose enoxaparin (n = 1,141), therapeutic-dose enoxaparin (n = 1,136), or therapeutic-dose apixaban (n = 1,121) at 76 centers in 10 countries. The 30-day primary outcome occurred in 13.2% of patients in the prophylactic-dose group and 11.3% of patients in the combined therapeutic-dose groups (HR: 0.85; 95% CI: 0.69-1.04; P = 0.11). All-cause mortality occurred in 7.0% of patients treated with prophylactic-dose enoxaparin and 4.9% of patients treated with therapeutic-dose anticoagulation (HR: 0.70; 95% CI: 0.52-0.93; P = 0.01), and intubation was required in 8.4% vs 6.4% of patients, respectively (HR: 0.75; 95% CI: 0.58-0.98; P = 0.03). Results were similar in the 2 therapeutic-dose groups, and major bleeding in all 3 groups was infrequent.ConclusionsAmong noncritically ill patients hospitalized with COVID-19, the 30-day primary composite outcome was not significantly reduced with therapeutic-dose anticoagulation compared with prophylactic-dose anticoagulation. However, fewer patients who were treated with therapeutic-dose anticoagulation required intubation and fewer died (FREEDOM COVID [FREEDOM COVID Anticoagulation Strategy]; NCT04512079).

Project description:Background: Therapeutic/intermediate-dose heparin reduces the risk of thromboembolic events but increases the risk of major bleeding in patients hospitalized for acute COVID-19 pneumonia. Objectives: To prospectively assess the incidence of objectively proven venous thromboembolism (VTE) and identify predisposing risk factors in a cohort of hospitalized patients with acute COVID-19 pneumonia undergoing prophylactic-dose heparin. Patients and methods: All consecutive patients admitted for acute COVID-19 pneumonia to the General Internal Medicine Unit of Padova University Hospital, Italy between November 2020 and April 2021, and undergoing prophylactic-dose heparin, were enrolled. Demographic and clinical characteristics and laboratory and radiological findings were recorded on admission. Cases were patients who developed VTE during their hospital stay. Univariable and multivariable logistic regression analyses were used to ascertain the risk factors associated with developing in-hospital VTE. Results: 208 patients (median age: 77 years; M/F 98/110) were included; 37 (18%) developed in-hospital VTE during a median follow-up of 10 days (IQR, 4-18). VTE patients were significantly younger (p = 0.004), more obese (p = 0.002), and had a lower Padua prediction score (p < 0.03) and reduced PaO2/FIO2 ratio (p < 0.03) vs. controls. Radiological findings of bilateral pulmonary infiltrates were significantly more frequent in VTE patients than controls (p = 0.003). Multivariable regression showed that obesity (1.75, 95% CI 1.02-3.36; p = 0.04) and bilateral pulmonary infiltrates on X-rays (2.39, 95% CI 1.22-5.69; p = 0.04) were correlated with increased risk of in-hospital VTE. Conclusions: Obesity and bilateral pulmonary infiltrates on imaging may help clinicians to identify patients admitted to medical wards for acute COVID-19 pneumonia at risk of developing VTE despite prophylactic-dose heparin. Further studies are needed to evaluate whether the administration of therapeutic/intermediate-dose heparin may help prevent VTE episodes without further increasing the bleeding risk.

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

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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