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Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies.

ABSTRACT: BACKGROUND:Microvascular and macrovascular thrombotic events are among the hallmarks of coronavirus disease 2019 (COVID-19). Furthermore, the exuberant immune response is considered an important driver of pulmonary and extrapulmonary manifestations of COVID-19. The optimal management strategy to prevent thrombosis in critically-ill patients with COVID-19 remains unknown. METHODS:The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) studies test two independent hypotheses within a randomized controlled trial with 2 × 2 factorial design. Hospitalized critically-ill patients with reverse transcription polymerase chain reaction confirmed COVID-19 will be randomized to intermediate-dose versus standard dose prophylactic anticoagulation. The 600 patients undergoing this randomization will be screened and if meeting the eligibility criteria, will undergo an additional double-blind stratified randomization to atorvastatin 20 mg daily versus matching placebo. The primary endpoint, for both hypotheses will be tested for superiority and includes a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Key secondary endpoints include all-cause mortality, adjudicated VTE, and ventilator-free days. Key safety endpoints include major bleeding according to the Bleeding Academic Research Consortium definition and severe thrombocytopenia (platelet count <20,000/fL) for the anticoagulation hypothesis. In a prespecified secondary analysis for non-inferiority, the study will test for the non-inferiority of intermediate intensity versus standard dose anticoagulation for major bleeding, considering a non-inferiority margin of 1.8 based on odds ratio. Key safety endpoints for the statin hypothesis include rise in liver enzymes >3 times upper normal limit and clinically-diagnosed myopathy. The primary analyses will be performed in the modified intention-to-treat population. Results will be tested in exploratory analyses across key subgroups and in the intention-to-treat and per-protocol cohorts. CONCLUSIONS:INSPIRATION and INSPIRATON-S studies will help address clinically-relevant questions for antithrombotic therapy and thromboinflammatory therapy in critically-ill patients with COVID-19.

SUBMITTER: Bikdeli B

PROVIDER: S-EPMC7513771 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies.

Bikdeli Behnood B Talasaz Azita H AH Rashidi Farid F Sharif-Kashani Babak B Farrokhpour Mohsen M Bakhshandeh Hooman H Sezavar Hashem H Dabbagh Ali A Beigmohammadi Mohammad Taghi MT Payandemehr Pooya P Yadollahzadeh Mahdi M Riahi Taghi T Khalili Hossein H Jamalkhani Sepehr S Rezaeifar Parisa P Abedini Atefeh A Lookzadeh Somayeh S Shahmirzaei Shaghayegh S Tahamtan Ouria O Matin Samira S Amin Ahmad A Parhizgar Seyed Ehsan SE Jimenez David D Gupta Aakriti A Madhavan Mahesh V MV Parikh Sahil A SA Monreal Manuel M Hadavand Naser N Hajighasemi Alireza A Maleki Majid M Sadeghian Saeed S Mohebbi Bahram B Piazza Gregory G Kirtane Ajay J AJ Lip Gregory Y H GYH Krumholz Harlan M HM Goldhaber Samuel Z SZ Sadeghipour Parham P

Thrombosis research 20200924

<h4>Background</h4>Microvascular and macrovascular thrombotic events are among the hallmarks of coronavirus disease 2019 (COVID-19). Furthermore, the exuberant immune response is considered an important driver of pulmonary and extrapulmonary manifestations of COVID-19. The optimal management strategy to prevent thrombosis in critically-ill patients with COVID-19 remains unknown.<h4>Methods</h4>The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVI ...[more]

PMID: 32992075

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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.

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

Project description:IntroductionCOVID-19 induces venous, arterial and microvascular thrombosis, involving several pathophysiological processes. In patients with severe COVID-19 without macrovascular thrombosis, escalating into high-dose prophylactic anticoagulation (HD-PA) or therapeutic anticoagulation (TA) could be beneficial in limiting the extension of microvascular thrombosis and forestalling the evolution of lung and multiorgan microcirculatory dysfunction. In the absence of data from randomised trials, clinical practice varies widely.Methods and analysisThis is a French multicentre, parallel-group, open-label, randomised controlled superiority trial to compare the efficacy and safety of three anticoagulation strategies in patients with COVID-19. Patients with oxygen-treated COVID-19 showing no pulmonary artery thrombosis on computed tomography with pulmonary angiogram will be randomised to receive either low-dose PA, HD-PA or TA for 14 days. Patients attaining the extremes of weight and those with severe renal failure will not be included. We will recruit 353 patients. Patients will be randomised on a 1:1:1 basis, and stratified by centre, use of invasive mechanical ventilation, D-dimer levels and body mass index. The primary endpoint is a hierarchical criterion at day 28 including all-cause mortality, followed by the time to clinical improvement defined as the time from randomisation to an improvement of at least two points on the ordinal clinical scale. Secondary outcomes include thrombotic and major bleeding events at day 28, individual components of the primary endpoint, number of oxygen-free, ventilator-free and vasopressor-free days at day 28, D-dimer and sepsis-induced coagulopathy score at day 7, intensive care unit and hospital stay at day 28 and day 90, and all-cause death and quality of life at day 90.Ethics and disseminationThe study has been approved by an ethical committee (Ethics Committee, Ile de France VII, Paris, France; reference 2020-A03531-38). Patients will be included after obtaining their signed informed consent. The results will be submitted for publication in peer-reviewed journals.Trial registration numberNCT04808882.

Project description:BackgroundAnticoagulation in hospitalized COVID-19 patients has been associated with survival benefit; however, the optimal anticoagulant strategy has not yet been defined. The objective of this meta-analysis was to investigate the effect of intermediate-to-therapeutic versus prophylactic anticoagulation for thromboprophylaxis on the primary outcome of in-hospital mortality and other patient-centered secondary outcomes in COVID-19 patients.MethodsMEDLINE, EMBASE, and Cochrane databases were searched from inception to August 10th 2021. Cohort studies and randomized clinical trials that assessed the efficacy and safety of intermediate-to-therapeutic versus prophylactic anticoagulation in hospitalized COVID-19 patients were included. Baseline characteristics and relevant data of each study were extracted in a pre-designed standardized data-collection form. The primary outcome was all-cause in-hospital mortality and the secondary outcomes were incidence of thrombotic events and incidence of any bleeding and major bleeding. Pooled analysis with random effects models yielded relative risk with 95 % CIs.ResultsThis meta-analysis included 42 studies with 28,055 in-hospital COVID-19 patients totally. Our pooled analysis demonstrated that intermediate-to-therapeutic anticoagulation was not associated with lower in-hospital mortality (RR=1.12, 95 %CI 0.99-1.25, p=0.06, I2=77 %) and lower incidence of thrombotic events (RR=1.30, 95 %CI 0.79-2.15, p=0.30, I2=88 %), but increased the risk of any bleeding events (RR=2.16, 95 %CI 1.79-2.60, p<0.01, I2=31 %) and major bleeding events significantly (RR=2.10, 95 %CI 1.77-2.51, p<0.01, I2=11 %) versus prophylactic anticoagulation. Moreover, intermediate-to-therapeutic anticoagulation decreased the incidence of thrombotic events (RR=0.71, 95 %CI 0.56-0.89, p=0.003, I2=0 %) among critically ill COVID-19 patients admitted to intensive care units (ICU), with increased bleeding risk (RR=1.66, 95 %CI 1.37-2.00, p<0.01, I2=0 %) and unchanged in-hospital mortality (RR=0.94, 95 %CI 0.79-1.10, p=0.42, I2=30 %) in such patients. The Grading of Recommendation, Assessment, Development, and Evaluation certainty of evidence ranged from very low to moderate.ConclusionsWe recommend the use of prophylactic anticoagulation against intermediate-to-therapeutic anticoagulation among unselected hospitalized COVID-19 patients considering insignificant survival benefits but higher risk of bleeding in the escalated thromboprophylaxis strategy. For critically ill COVID-19 patients, the benefits of intermediate-to-therapeutic anticoagulation in reducing thrombotic events should be weighed cautiously because of its association with higher risk of bleeding.Trial registrationThe protocol was registered at PROSPERO on August 17th 2021 ( CRD42021273780 ).

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.).

Dataset Information

Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies.

Publications

Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies.

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