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Selected baseline characteristics and assigned anticoagulation regimen in patients with major bleeding. Anatomical characteristics of adjudicated venous thromboembolic events. Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.
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Not all submitted comments are published. Please see our commenting policy for details. Question What are the effects of intermediate-dose compared with standard-dose prophylactic anticoagulation in patients with COVID admitted to the intensive care unit ICU? Findings In this randomized clinical trial that included patients with COVID admitted to the ICU, the primary outcome a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days occurred in Limited data exist to guide the intensity of antithrombotic prophylaxis.
Objective To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID admitted to the intensive care unit ICU.
Patients were recruited between July 29, , and November 19, The final follow-up date for the day primary outcome was December 19, The assigned treatments were planned to be continued until completion of day follow-up.
Main Outcomes and Measures The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment.
Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium type 3 or 5 definition , powered for noninferiority a noninferiority margin of 1. All outcomes were blindly adjudicated. Results Among randomized patients, The primary efficacy outcome occurred in patients Major bleeding occurred in 7 patients 2. Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group 6 vs 0 patients; risk difference, 2.
Conclusions and Relevance Among patients admitted to the ICU with COVID, 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 Trial Registration ClinicalTrials. In the context of endothelial injury 1 , 2 and a prothrombic milieu, 1 , 3 venous and arterial microthrombosis and macrothrombosis are common manifestations of COVID However, limited evidence exists to guide the prophylactic antithrombotic regimen.
The study protocol was approved by the Rajaie Cardiovascular Medical and Research Center ethics committee and accepted by other participating sites. All patients or their health care proxies provided written informed consent.
An independent data and safety monitoring committee monitored the study results. The trial design has been described previously 16 and the study protocol and statistical analysis plan are provided in Supplement 1 and Supplement 2. The current article summarizes the results from the first hypothesis, an open-label randomized clinical trial with blinded outcome adjudication. Patient recruitment for the second statin hypothesis is underway.
Patients admitted to the ICU with polymerase chain reaction testing—confirmed COVID within 7 days of the index hospitalization were eligible for inclusion. The full list of eligibility criteria 16 are available in the study protocol in Supplement 1. Randomization was done using an electronic web-based system with permuted blocks of 4 and allocation sequence concealment.
Eligible patients were allocated in ratio to receive intermediate-dose or standard-dose prophylactic anticoagulation. The primary anticoagulant agent in both groups was enoxaparin. Unfractionated heparin was used in the case of severe kidney insufficiency. Enoxaparin, 40 mg daily, was the control group standard-dose prophylactic anticoagulation regimen.
In both groups, predefined modifications were advised according to body weight and creatinine clearance eTables in Supplement 3. The assigned treatments were planned to be continued until the day follow-up, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated acute VTE, arterial thrombosis, treatment with extracorporeal membrane oxygenation ECMO , or all-cause mortality within 30 days of enrollment.
Secondary efficacy outcomes included all-cause mortality, adjudicated VTE, and ventilator-free days. Prespecified exploratory outcomes included objectively clinically diagnosed type I acute myocardial infarction, stroke, and acute peripheral arterial thrombosis; rate of discharge from the ICU; incident atrial fibrillation; new in-hospital kidney replacement therapy; and ICU length of stay.
Diagnostic tests were performed based on clinical judgment of the treating clinicians; no systematic screening for thrombotic events was required by the study protocol.
Clinically relevant nonmajor bleeding was defined as clinically significant bleeding that warranted attention from medical personnel but did not fulfil criteria for major bleeding. The full list of study outcomes and their definitions can be found in Supplement 3. For patients who did not die during hospitalization, regular follow-up was pursued by structured weekly phone interviews.
A clinical events committee blinded to the treatment assignment adjudicated the primary, secondary, and exploratory outcomes. Power calculation was performed for 2-sided superiority testing for the primary efficacy outcome in patients who were randomized and were not excluded due to violation of the eligibility criteria, did not withdraw consent, and received at least 1 dose of the study drug see Supplement 2 for terms used previously for describing the analytic populations.
No interim efficacy analyses were planned to minimize the type I error rate. In a prespecified secondary analysis, estimating bleeding event rates of 5. Given the short follow-up duration, logistic regression with odds ratio as the effect measure was prespecified for the primary analyses. Accounting for study sites as random effect was done post hoc in sensitivity analyses using mixed-effects logistic regression models for binary outcomes and linear mixed-effects models for interval outcomes.
Time to events for the primary outcomes were plotted with Kaplan-Meier curves. In sensitivity analyses, the proportionality assumption was met based on Schoenfeld residuals and results were repeated with unadjusted Cox proportional hazards models.
Definitions of different cohorts used for sensitivity analyses can be found in Supplement 3. There were no missing outcomes for participants in the final analysis. The only exception was baseline D-dimer, which was not available in The association between the assigned anticoagulation regimen and the primary outcome was assessed in the study subgroups.
Prespecified subgroup analyses based on age, sex, cigarette smoking, diabetes, hypertension, heart failure, obstructive airway disease, time from symptom onset to randomization, corticosteroid use, renin-angiotensin-aldosterone system inhibitor use, and baseline D-dimer level as well as post hoc subgroup analyses based on coronary artery disease, body mass index, time receiving the assigned treatment, and aspirin use were performed.
For evaluation of the homogeneity of odds ratios across subgroups, the Woolf test was applied. All hypothesis tests, except for the test of noninferiority for major bleeding, were 2-sided. No adjustment was performed for the P value thresholds with respect to multiplicity of comparisons.
Because of the potential for type I error, findings for analyses of all other outcomes should be interpreted as exploratory.
Statistical analyses were performed using R statistical software package, version 4. Between July 29, , and November 19, , a total of patients were screened for eligibility and underwent randomization, of whom 4 died before receiving the first dose of the study drug, 2 were excluded due to duplicate entry, and 32 were excluded for other reasons Figure 1. Ultimately, patients As shown in Table 1 , the study population had a median interquartile range [IQR] age of 62 years, patients The 2 study groups were balanced with respect to baseline characteristics, expect for history of cigarette smoking, which was more frequent in the intermediate-dose group Table 1.
The median IQR duration of receiving the assigned treatment was similar between the 2 groups 20 [] days in both groups. Overall, patients In the prespecified primary analysis cohort, the primary efficacy outcome occurred in of patients With respect to secondary efficacy outcomes, during day follow-up, all-cause mortality occurred in patients VTE events occurred in 19 patients 3.
The risk of VTE was not significantly different between the intermediate-dose and standard-dose groups 3. The day Kaplan-Meier curves for the primary composite outcome, VTE, and all-cause mortality are shown in Figure 2 and eFigures 1 and 2 in Supplement 3. No statistically significant differences were detected in the exploratory outcomes.
There were no cases of adjudicated type I myocardial infarction. The rate of ischemic stroke was 0. No other acute arterial thrombotic events were identified. No patients received ECMO during the study period. New in-hospital kidney replacement therapy was performed in 17 patients 3.
There were 7 2. There was 1 case of intracranial hemorrhage and 2 cases of fatal bleeding events in the intermediate-dose group. Clinically relevant nonmajor bleeding occurred in 12 patients 4. Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group 6 vs 0; risk difference, 2.
No significant differences were observed between the 2 study groups with respect to less severe forms of thrombocytopenia Table 2. Findings from the per-protocol analyses and other sensitivity analyses were similar to those from the primary analyses eTables in Supplement 3. Findings were consistent in subgroup analyses. No particular subgroups were identified in which use of intermediate-dose prophylactic anticoagulation was associated with significant reduction in the primary outcome Figure 3 ; eFigure 4 in Supplement 3.
In this multicenter randomized clinical trial of patients with COVID admitted to the ICU, intermediate-dose compared with standard-dose prophylactic anticoagulation did not improve the primary composite efficacy outcome or its major components, including all-cause mortality and VTE.
Results were consistent in sensitivity analyses and in key prespecified subgroups. Full Specifications. What's new in version 8a. Release November 8, Date Added October 19, Version 8a. Operating Systems. Additional Requirements None. Total Downloads 98, Downloads Last Week Report Software. Related Software. Learn to touch type and enhance your typing speed and performance. Free QuizMaker Free. Create quizzes and surveys with three question types of graded quizzes and surveys.
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