Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial | Critical Care Medicine | JAMA | JAMA Network
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Figure 1.  Flow of Participants in a Study of the Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation Among Patients With COVID-19 Admitted to the Intensive Care Unit
Flow of Participants in a Study of the Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation Among Patients With COVID-19 Admitted to the Intensive Care Unit

aSome patients had more than 1 reason for exclusion from the primary analysis cohort.

bReasons for discontinuation of the trial regimen are summarized in eTable 4 in Supplement 3.

cPatients who were randomized and were not excluded due to violation of the eligibility criteria or withdrawal of informed consent and continued their assigned anticoagulation regimen until 30-day follow-up or the occurrence of the prespecified efficacy outcome. See eTable 13 in Supplement 3 for the per-protocol safety cohort.

Figure 2.  Primary Outcome in the Prespecified Primary Cohort in a Study of the Effect of Intermediate-Dose vs Standard-Dose Prophylactic Among Patients With COVID-19 Admitted to the Intensive Care Unit
Primary Outcome in the Prespecified Primary Cohort in a Study of the Effect of Intermediate-Dose vs Standard-Dose Prophylactic Among Patients With COVID-19 Admitted to the Intensive Care Unit

The primary outcome was a composite of adjudicated acute arterial thrombosis, venous thromboembolism, extracorporeal membrane oxygenation, or all-cause mortality during 30 days from enrollment. The prespecified primary cohort consisted of patients who received at least 1 dose of the study drug, were not excluded, and did not withdraw consent. The median (interquartile range) follow-up time was 30 (9-30) days in the intermediate-dose group and 30 (10-30) days in the standard-dose prophylactic anticoagulation group.

aAll-cause mortality events were censored by precedent venous thromboembolism (VTE) events. In some cases, the thrombotic events occurred in the prior window (ie, in the first 5 days).

bOne of the 2 VTE events was censored by a precedent ischemic stroke event.

Figure 3.  Subgroup Analysis for the Primary Outcome in a Study of the Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation Among Patients With COVID-19 Admitted to the Intensive Care Unit
Subgroup Analysis for the Primary Outcome in a Study of the Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation Among Patients With COVID-19 Admitted to the Intensive Care Unit

P values indicate tests of interaction between the treatment group and each of the assessed variables for the primary composite outcome.

Table 1.  Baseline Characteristics of the Prespecified Primary Analysis Population in a Study of the Effect of Intermediate- vs Standard-Dose Prophylactic Anticoagulation Among Patients With COVID-19 Admitted to the Intensive Care Unit
Baseline Characteristics of the Prespecified Primary Analysis Population in a Study of the Effect of Intermediate- vs Standard-Dose Prophylactic Anticoagulation Among Patients With COVID-19 Admitted to the Intensive Care Unit
Table 2.  Primary, Secondary, and Exploratory Outcomes Within 30 Days of Enrollment in the Prespecified Primary Analysis in a Study of the Effect of Intermediate- vs Standard-Dose Prophylactic Anticoagulation Among Patients With COVID-19 Admitted to the Intensive Care Unit (ICU)
Primary, Secondary, and Exploratory Outcomes Within 30 Days of Enrollment in the Prespecified Primary Analysis in a Study of the Effect of Intermediate- vs Standard-Dose Prophylactic Anticoagulation Among Patients With COVID-19 Admitted to the Intensive Care Unit (ICU)
Supplement 3.

Investigators and Committees

Eligibility criteria

Definitions of Outcome Events

eMethods

Study outcomes in hospitalized versus post-discharged patients

Prespecified subgroup analysis of primary outcome in patients with or without D-dimer >1000 ng/mL

Post hoc subgroup analysis of major bleeding among aspirin and non-aspirin users

eFigure 1. Kaplan-Meier curve for all-cause mortality in the prespecified primary cohort

eFigure 2. Kaplan-Meier curve for the venous thromboembolism in the prespecified primary cohort.

eFigure 3. Kaplan-Meier curve for the landmark analysis showing the primary composite outcome in the first ten days and from 11 to 30 days of enrollment in the prespecified primary cohort

eFigure 4. Post-hoc subgroup analysis

eTable 1. Intervention and comparator dosing for the anticoagulation hypothesis

eTable 2. Dosing strategies for intermediate dose applied in study sites

eTable 3. Dosing strategies for standard dose anticoagulation applied in study sites

eTable 4. Reasons for post-randomization changes in the assigned treatment of patients in the prespecified primary cohort

eTable 5. Treatment adherence in the two study groups in the prespecified primary cohort

eTable 6. Demographic and clinical characteristics at baseline according to the assigned anticoagulation therapy in the total study population

eTable 7. Demographic and clinical characteristics at baseline according to the assigned anticoagulation therapy in patients who were randomized and were not excluded due to violation of the eligibility criteria nor withdrawal of informed consent

Table 8. Primary, Secondary and exploratory outcomes within 30 days from enrollment in the prespecified primary analysis incorporating the center random effect

eTable 9. Primary, Secondary and exploratory outcomes within 30 days from enrollment in the total study population who allowed their data to contribute to the final results

eTable 10. Primary, Secondary and exploratory outcomes within 30 days from enrollment in the total study population who allowed their data to contribute to the final results incorporating the center random effect

eTable 11. Primary, Secondary and exploratory outcomes within 30 days from enrollment in randomized patients who were not excluded due to violation of the eligibility criteria or withdrawal of informed consent.

eTable 12. Primary, Secondary and exploratory outcomes within 30 days from enrollment in randomized patients who were not excluded due to violation of the eligibility criteria or withdrawal of informed consent incorporating center random effect

eTable 13. Primary, Secondary and exploratory outcomes within 30 days from enrollment per-protocol cohort

eTable 14. Primary, Secondary and exploratory outcomes within 30 days from enrollment per-protocol cohort incorporating center random effect

eTable 15. Primary, Secondary and exploratory efficacy outcomes within 30 days from enrollment in patients with baseline D-dimer >1000 ng/ml in the prespecified primary analysis

eTable 16. Primary, Secondary and exploratory efficacy outcomes within 30 days from enrollment in patients with baseline D-dimer >1000 ng/ml in the prespecified primary analysis incorporating center random effect

eTable 17. In-hospital Primary, Secondary and exploratory outcomes within 30 days from enrollment in the prespecified primary analysis

eTable 18. In-hospital Primary, Secondary and exploratory outcomes within 30 days from enrollment in the prespecified primary analysis incorporating center random effect

eTable 19. Summary of venous thromboembolism diagnostic tests performed by enrolling centers

eTable 20. Study outcomes and laboratory tests in patients with severe thrombocytopenia

eTable 21. Selected baseline characteristics and assigned anticoagulation regimen in patients with major bleeding

eTable 22. Anatomical characteristics of adjudicated venous thromboembolic events

eReferences

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    Original Investigation
    March 18, 2021

    Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial

    INSPIRATION Investigators
    JAMA. 2021;325(16):1620-1630. doi:10.1001/jama.2021.4152
    Key Points

    Question  What are the effects of intermediate-dose compared with standard-dose prophylactic anticoagulation in patients with COVID-19 admitted to the intensive care unit (ICU)?

    Findings  In this randomized clinical trial that included 562 patients with COVID-19 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 45.7% of patients in the intermediate-dose prophylactic anticoagulation group and 44.1% of patients in the standard-dose prophylactic anticoagulation group, a difference that was not statistically significant (odds ratio, 1.06).

    Meaning  The results do not support routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients with COVID-19 admitted to the ICU.

    Abstract

    Importance  Thrombotic events are commonly reported in critically ill patients with COVID-19. 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-19 admitted to the intensive care unit (ICU).

    Design, Setting, and Participants  Multicenter 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.

    Interventions  Intermediate-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 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 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated.

    Results  Among 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 Relevance  Among 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 Registration  ClinicalTrials.gov Identifier: NCT04486508

    Introduction

    In the context of endothelial injury1,2 and a prothrombic milieu,1,3 venous and arterial microthrombosis and macrothrombosis are common manifestations of COVID-19.4 Venous thromboembolism (VTE) is the most commonly reported thrombotic complication, with higher incidence rates among critically ill patients.5 A 2020 systematic review estimated that 28% of critically ill patients with COVID-19 had VTE.6

    However, limited evidence exists to guide the prophylactic antithrombotic regimen.7 Some retrospective observational studies suggest that anticoagulation beyond standard prophylactic doses was associated with reduced mortality,8 but others did not confirm these findings and, rather, suggested an elevated risk of bleeding.9 A small randomized trial suggested improved oxygenation with therapeutic anticoagulation compared with standard prophylaxis.10 However, the small sample size and other drawbacks limit the strength of this evidence.11 The uncertainty in optimal prophylactic anticoagulant regimen has translated into variability in expert recommendations, hospital policies, and clinicians’ decisions to use a variety of types and intensities of antithrombotic regimens.4,12-15 The present multicenter randomized trial investigated the effects of intermediate-dose vs standard-dose prophylactic anticoagulation in patients with COVID-19 admitted to the intensive care unit (ICU).

    Methods
    Trial Oversight

    The Intermediate vs Standard-Dose Prophylactic Anticoagulation in Critically-ill Patients With COVID-19: An Open Label Randomized Controlled Trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) studies, designed by an international committee, had a 2 × 2 factorial design and was conducted in Iran with 10 enrolling centers in Tehran and Tabriz. The Rajaie Cardiovascular Medical and Research Center and the Tehran Heart Center were the study coordinating centers. 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.

    Design

    The trial design has been described previously16 and the study protocol and statistical analysis plan are provided in Supplement 1 and Supplement 2. This study was a multicenter randomized trial with a 2 × 2 factorial design comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis) among patients with COVID-19 admitted to the ICU. 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.

    Trial Population

    Patients admitted to the ICU with polymerase chain reaction testing–confirmed COVID-19 within 7 days of the index hospitalization were eligible for inclusion. Patients with life expectancy less than 24 hours, an established indication for therapeutic-dose anticoagulation, weight less than 40 kg, pregnancy, history of heparin-induced thrombocytopenia, platelet count less than 50 ×103/µL, or overt bleeding were excluded. The full list of eligibility criteria16 are available in the study protocol in Supplement 1.

    Randomization and Study Drugs

    Randomization was done using an electronic web-based system with permuted blocks of 4 and allocation sequence concealment. Eligible patients were allocated in 1:1 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. For patients who weighed less than 120 kg and had a creatinine clearance greater than 30 mL/min, enoxaparin, 1 mg/kg daily, was assigned as intermediate-dose anticoagulation. 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 1-3 in Supplement 3). The assigned treatments were planned to be continued until the 30-day follow-up, irrespective of hospital discharge status.

    Study Outcomes

    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.

    The prespecified safety outcomes included major bleeding (Bleeding Academic Research Consortium type 3 or 517) and severe thrombocytopenia (platelet count <20 ×103/µL). Clinically relevant nonmajor bleeding was defined as clinically significant bleeding that warranted attention from medical personnel but did not fulfil criteria for major bleeding. Mild thrombocytopenia (platelet count <100 ×103/µL) and moderate thrombocytopenia (platelet count <50 ×103/µL) were also assessed as post hoc safety outcomes.

    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.

    Statistical Analysis

    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).16 According to the estimates obtained from the enrolling centers, a 55% event rate for the primary outcome in the standard-dose prophylactic group was presumed. Considering a 2-sided α of .05 and using the Z approximation formula for comparing 2 proportions between independent groups, a sample size of 544 patients (272 per group) was estimated to provide 80% power to detect a 12% absolute risk reduction in the primary outcome with intermediate-dose compared with standard-dose prophylactic anticoagulation (eMethods in Supplement 3). Considering a 10% dropout rate during the study for withdrawal of consent or postrandomization exclusions, 600 patients were planned for enrollment. No interim efficacy analyses were planned to minimize the type I error rate.

    In a prespecified secondary analysis, estimating bleeding event rates of 5.5% in the standard-dose group and 6.5% in the intermediate-dose anticoagulation group18,19 and a 1-sided α of .025, the same sample size provided 79.5% power to show noninferiority of intermediate-dose anticoagulation compared with standard-dose prophylactic anticoagulation with respect to major bleeding, with a noninferiority margin of 1.8 based on the odds ratio. The selection of a 12% difference in the primary outcome as the minimal clinically important difference to power the study, as well as the selection of an odds ratio of 1.8 as the basis for declaring noninferiority with regard to major bleeding events, were based on investigator consensus (eMethods in Supplement 3).

    Because the study included a 2 × 2 factorial design, a Mantel-Haenszel χ2 test was performed to assess the interaction between anticoagulation intensity and statin use for the primary outcomes prior to the assessment of the primary efficacy and prespecified safety outcomes. Because the tests of interaction between the 2 interventions were nonsignificant (P = .97 for the primary efficacy outcome and P = .22 for major bleeding), the anticoagulation hypothesis is presented independently.

    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 rate of missing values for baseline characteristics was trivial (<5% in all cases) and did not warrant multiple imputations according to the prespecified statistical analysis plan. The only exception was baseline D-dimer, which was not available in 66.5% of the patients at baseline due to unprecedented national increase in use of D-dimer assays leading to temporary shortage. Because the rate of missing rate data was greater than 20%, according to the prespecified statistical analysis plan, multiple imputations were not performed.

    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. The interaction between the intervention and specific subgroups was assessed via the Cochran-Mantel-Haenszel χ2 test. All hypothesis tests, except for the test of noninferiority for major bleeding, were 2-sided. A P value <.05 was considered significant for the primary efficacy outcome. For noninferiority testing for major bleeding, a 1-sided P value <.025 was considered significant. 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 4.0.3 (R Core Team).

    Results

    Between July 29, 2020, and November 19, 2020, a total of 1692 patients were screened for eligibility and 600 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, 562 patients (93.7%) were included in the prespecified primary analysis (Figure 1; eTable 4 in Supplement 3).

    As shown in Table 1, the study population had a median (interquartile range [IQR]) age of 62 (50-71) years, 237 patients (42.2%) were women, and the median (IQR) body mass index was 27 (24.6-29.4). 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 [7-30] days in both groups). Overall, 442 patients (78.6%) received the assigned treatment for the full study duration or until reaching an efficacy outcome (eTables 4 and 5 in Supplement 3).

    Efficacy Outcomes

    In the prespecified primary analysis cohort, the primary efficacy outcome occurred in 126 of 276 patients (45.7%) in the intermediate-dose group and 126 of 286 patients (44.1%) in the standard-dose prophylactic anticoagulation 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) (Table 2). With respect to secondary efficacy outcomes, during 30-day follow-up, all-cause mortality occurred in 236 patients (42.0%) and was not significantly different in the intermediate-dose group compared with the standard-dose prophylaxis group (119 [43.1%] vs 117 [40.9%]; risk difference, 2.2% [95% CI, −5.9% to 10.3%]; odds ratio, 1.09 [95% CI, 0.78-1.53]; P = .50). VTE events occurred in 19 patients (3.4%), including 12 episodes of deep vein thrombosis and 7 pulmonary embolism events. The risk of VTE was not significantly different between the intermediate-dose and standard-dose groups (3.3% vs 3.5%; risk difference, −0.2% [95% CI, −3.2% to 2.7%]; odds ratio, 0.93 [95% CI, 0.37-2.32]; P = .94) (Table 2). The median (IQR) number of ventilator-free days was 30 (1-30) in the study population, with no significant difference between the intermediate-dose and standard-dose groups (30 [3-30] vs 30 [1-30] days; P = .50). The 30-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 0.3% in the intermediate-dose group and 0.4% in the standard-dose group (risk difference, 0.1% [95% CI, −0.9% to 0.9%]; odds ratio, 1.03 [95% CI, 0.06-16.65]; P = .97). No other acute arterial thrombotic events were identified. No patients received ECMO during the study period.

    The median (IQR) ICU length of stay was 6 (2-11) days (5 [2-10] days in the intermediate-dose group vs 6 [3-11] days in the standard-dose group; P = .14), and a total of 343 patients (61.0%) were discharged from the ICU, including 169 patients (61.2%) assigned to receive the intermediate-dose regimen and 174 patients (60.8%) assigned to receive the standard-dose prophylaxis regimen (risk difference, 0.3% [95% CI, −7.8% to 8.4%]; odds ratio, 1.01 [95% CI, 0.72-1.42]; P = .72). New in-hospital kidney replacement therapy was performed in 17 patients (3.0%) (3.6% in the intermediate-dose group vs 2.4% in the standard-dose group; risk difference, 1.1% [95% CI, −1.6% to 4.0%]; odds ratio, 1.49 [95% CI, 0.58-3.86]; P = .41) and new atrial fibrillation was detected in 8 patients (1.4%), without a significant difference between the intermediate-dose group and the standard-dose group (0.7% vs 2.1%; difference, −1.3% [95% CI, −3.3% to 0.5%]; odds ratio, 0.34 [95% CI, 0.00-1.49]; P = .16).

    Safety Outcomes

    There were 7 (2.5%) major bleeding events in the intermediate-dose group and 4 (1.4%) in the standard-dose prophylactic anticoagulation 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]), which did not meet the noninferiority criteria (Pfor noninferiority >.99). 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 (4.3%) in the intermediate-dose group and 5 patients (1.7%) in the standard-dose group (risk difference, 2.5% [95% CI, −0.2% to 5.4%]; odds ratio, 2.55 [95% CI, 0.92-7.04]; P = .07) (Table 2). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0; risk difference, 2.2% [95% CI, 0.4%-3.8%]) (Table 2). No significant differences were observed between the 2 study groups with respect to less severe forms of thrombocytopenia (Table 2).

    Sensitivity Analysis

    Findings from the per-protocol analyses and other sensitivity analyses were similar to those from the primary analyses (eTables 8-18 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).

    Discussion

    In this multicenter randomized clinical trial of patients with COVID-19 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. Although bleeding events were rare, both major and clinically relevant nonmajor bleeding events were nonsignificantly more frequent with intermediate-dose anticoagulation, and noninferiority for major bleeding was not demonstrated. Furthermore, severe thrombocytopenia was observed only in patients assigned to receive intermediate-dose prophylactic anticoagulation.

    Establishing the optimal antithrombotic prophylactic regimen in patients with COVID-19 is essential because of the reported excess rates of microvascular and macrovascular thrombosis.4,20-22 The observation of heightened VTE risk in patients receiving standard-dose prophylaxis23-25 encouraged some experts to advocate escalated-dose prophylaxis.26 Although the primary end point event rate was slightly lower than expected, there was no signal for benefit. Further, noninferiority for major bleeding was not confirmed. In line with these results, an interim analysis of critically ill patients enrolled in 3 pivotal trials testing therapeutic-dose vs standard prophylactic anticoagulation (ACTIV-4a, REMAP-CAP, and ATTACC) led the data and safety monitoring board to pause further enrollment because of futility for efficacy and potential excess of safety events, and additional clarifications are awaited.27

    Several potential explanations exist for the observed lack of benefit with intermediate-dose prophylactic anticoagulation in this study. First, the intensity of intermediate-dose anticoagulation might have been insufficient to prevent thrombotic events compared with the standard-dose prophylactic regimen. Some studies completed before the COVID-19 pandemic indicated that intermediate-dose regimens may be effective for preventing thrombotic events.19,28 At the time of study design, some experts hypothesized that intermediate intensity of anticoagulation may be suitable for patients with COVID-19. Second, the timing of anticoagulation administration and its relation to the symptom onset might affect the effectiveness of anticoagulation.29 However, in this study, the results were consistent even among patients who received anticoagulation within the first 7 days from symptom onset.

    Third, the study recruited a broad population of patients admitted to the ICU rather than targeting metrics such as D-dimer or specific metrics of illness severity. This was a pragmatic choice. A subgroup analysis showed that patients with baseline D-dimer elevation had outcomes consistent with the primary analysis. Fourth, the number of patients receiving mechanical ventilation at the time of enrollment in the present study was lower than some other cohorts.30,31 The study population correlated with the eligibility criteria of this trial, which did not allow the enrollment of the patients with extremely severe disease with estimated survival less than 24 hours. Nevertheless, many of the study participants were very ill, as indicated by the requirements for cardiopulmonary support and evidenced by the 30-day mortality rates. The possibility of a potential effect among patients who were admitted to the ICU and had more severe illness cannot be excluded or, alternatively, that heparin-based regimens might be effective in hospitalized patients not admitted to the ICU with an earlier stage of disease. In addition, it is possible that heparin-based regimens are not beneficial in critically ill patients with COVID-19,32 but that other agents may confer benefit.

    Although the present study was unable to demonstrate noninferiority for the prespecified bleeding end point, major bleeding was infrequent in both study groups. Also, severe thrombocytopenia was noted in 6 patients who received intermediate-dose prophylactic anticoagulation, compared with zero patients who received standard-dose prophylactic anticoagulation, although no significant differences were noted in other platelet count measures. Because this outcome was not powered for hypothesis testing and its results were not adjusted for multiplicity, this finding should be considered exploratory. Numerous additional randomized trials with heparin-based and nonheparin agents are ongoing across the spectrum of COVID-19 illness severity and could identify potentially effective therapies in various subgroups of illness severity with COVID-19.33

    Limitations

    This study has several limitations First, this trial, by design, required the estimated survival of greater than 24 hours at the determination of site physicians and exclusion of patients receiving ECMO at the time of randomization (because ECMO needs escalated-dose anticoagulation). This meant that the most severely ill patients (eg, those with unstable maximized ventilatory support or those receiving multiple vasopressor agents at the time of screening) were not included in the trial. This issue should be considered for the external validity of the findings. Second, anticoagulation assignment was open-label. Using a double-dummy design during the COVID-19 pandemic was not considered feasible. However, the allocation sequence was concealed and outcomes were blindly adjudicated and analyzed. Third, the VTE event rate in the present study was lower than that reported in some other studies.6,25,34 This may in part correlate with lack of systematic routine screening, similar to results from other multicenter studies that did not use systematic screening and reported lower rates of VTE.9,35 Other factors that may have contributed include lower acuity of care in patients admitted to the ICU in this study compared with some other studies36,37 or the possible effect of anti-inflammatory therapies (including steroids38) on mitigating microthrombosis or macrothrombosis.7 Some recent studies suggest that the majority of thrombotic events in critically ill patients with COVID-19 include catheter-associated thrombosis, isolated distal deep vein thrombosis, or subsegmental pulmonary embolism, all of which are less severe forms of VTE and less likely to affect mortality.6,34 Fourth, although all-cause mortality rates in the present study are in line with other reports of critically ill patients,30,31,34 the CI for the primary outcome was relatively wide. Consequently, the possibility of a small benefit or a small and important harm cannot be excluded. Fifth, due to resource limitations, the study focused only on clinical events that were assumed to directly affect hard clinical end points. In this setting, the case report form did not collect information related to radial arterial line exchange (due to nonfunctioning) or nonfunctioning dialysis lines. Sixth, only 4 study participants weighed more than 120 kg, limiting the generalizability of the results to patients with higher body weight or obesity.

    Conclusions

    Among patients with COVID-19 admitted to the ICU, 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 venous or arterial thrombosis, treatment with ECMO, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients with COVID-19 admitted to the ICU.

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    Article Information

    Corresponding Authors: Parham Sadeghipour, MD, Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Vali-Asr Ave, Niyayesh Blvd, Tehran 1996911101, Iran (psadeghipour@hotmail.com); Behnood Bikdeli, MD, MS, Cardiovascular Medicine Division, Brigham and Women’s Hospital, 75 Francis St, Shapiro 5, Ste 5156, Boston, MA 02115 (bbikdeli@bwh.harvard.edu; behnood.bikdeli@yale.edu).

    Accepted for Publication: March 4, 2021.

    Published Online: March 18, 2021. doi:10.1001/jama.2021.4152

    Authors/INSPIRATION Investigators: Parham Sadeghipour, MD; Azita H. Talasaz, PharmD; Farid Rashidi, MD; Babak Sharif-Kashani, MD; Mohammad Taghi Beigmohammadi, MD; Mohsen Farrokhpour, MD; Seyed Hashem Sezavar, MD; Pooya Payandemehr, MD; Ali Dabbagh, MD; Keivan Gohari Moghadam, MD; Sepehr Jamalkhani, MD (’23); Hossein Khalili, PharmD; Mahdi Yadollahzadeh, MD; Taghi Riahi, MD; Parisa Rezaeifar, MD; Ouria Tahamtan, MD; Samira Matin, MD; Atefeh Abedini, MD; Somayeh Lookzadeh, MD; Hamid Rahmani, PharmD; Elnaz Zoghi, PharmD; Keyhan Mohammadi, PharmD; Pardis Sadeghipour, MD; Homa Abri, MD; Sanaz Tabrizi, MD; Seyed Masoud Mousavian, MD; Shaghayegh Shahmirzaei, MD; Hooman Bakhshandeh, MD, PhD; Ahmad Amin, MD; Farnaz Rafiee, MD; Elahe Baghizadeh, MD; Bahram Mohebbi, MD; Seyed Ehsan Parhizgar, MD; Rasoul Aliannejad, MD; Vahid Eslami, MD; Alireza Kashefizadeh, MD; Hessam Kakavand, PharmD; Seyed Hossein Hosseini, PharmD; Shadi Shafaghi, MD; Samrand Fattah Ghazi, MD; Atabak Najafi, MD; David Jimenez, MD, PhD; Aakriti Gupta, MD, MS; Mahesh V. Madhavan, MD; Sanjum S. Sethi, MD, MPH; Sahil A. Parikh, MD; Manuel Monreal, MD; Naser Hadavand, PharmD; Alireza Hajighasemi, PharmD; Majid Maleki, MD; Saeed Sadeghian, MD; Gregory Piazza, MD, MS; Ajay J. Kirtane, MD, SM; Benjamin W. Van Tassell, PharmD; Paul P. Dobesh, PharmD; Gregg W. Stone, MD; Gregory Y. H. Lip, MD; Harlan M. Krumholz, MD, SM; Samuel Z. Goldhaber, MD; Behnood Bikdeli, MD, MS.

    Affiliations of Authors/INSPIRATION Investigators: Cardiovascular Intervention Research Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran (Parham Sadeghipour, Mohebbi); Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran (Parham Sadeghipour, Bakhshandeh); Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran (Talasaz, Hajighasemi, Sadeghian); Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran (Rashidi, Rezaeifar, Tahamtan, Matin); Tobacoo Prevention and control Research center, National Research institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran (Sharif-Kashani); Lung Transplantation Research Center, Department of Cardiology, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran (Sharif-Kashani, Shafaghi); Anesthesiology and Intensive Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran (Beigmohammadi, Ghazi); Firouzgar hospital, Department of internal medicine, Iran University of Medical Sciences, Tehran, Iran (Farrokhpour, Yadollahzadeh, Pardis Sadeghipour, Abri); Research Center for Prevention of Cardiovascular Disease, Institute of Endocrinology & Metabolism, Iran University of Medical Sciences, Tehran, Iran (Sezavar); Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran (Payandemehr, Shahmirzaei, Najafi); Department of Anesthesiology, School of Medicine Anesthesiology Research Center Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran (Dabbagh); School of Medicine, Department of Internal Medicine, Shariati Hospital, Tehran, Iran (Moghadam); Student Research Committee, Iran University of Medical Sciences, Tehran, Iran (Jamalkhani); Department of Pharmacotherapy, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran (Khalili); Rasoul-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran (Riahi, Tabrizi, Mousavian); Chronic Respiratory Disease Research Center, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran (Abedini, Lookzadeh); Department of Pharmacotherapy, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran (Rahmani); School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran (Zoghi, Mohammadi, Kakavand, Hosseini); Rajaie Cardiovascular Medical and Research Center, Iran university of Medical sciences, Tehran, Iran (Bakhshandeh, Amin, Rafiee, Baghizadeh, Parhizgar, Hadavand, Maleki); School of Medicine, Department of Pulmonary and Critical Care, Shariati Hospital, Tehran, Iran (Aliannejad); Advanced Thoracic Research Center, Tehran University of Medical Sciences, Tehran, Iran (Aliannejad); Cardiovascular Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran (Eslami); Shahid Dr Labbafinejad Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran (Kashefizadeh); Respiratory Department, Hospital Ramón y Cajal (IRYCIS), Madrid, Spain (Jimenez); Medicine Department, Universidad de Alcalá (IRYCIS), Madrid, Spain (Jimenez); CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain (Jimenez); Cardiovascular Research Foundation (CRF), New York, New York (Gupta, Madhavan, Sethi, Parikh, Kirtane, Stone, Bikdeli); Division of Cardiology, Columbia University Irving Medical Center/NewYork-Presbyterian Hospital, New York, New York (Gupta, Madhavan, Sethi, Parikh, Kirtane); Yale/YNHH Center for Outcomes Research & Evaluation, New Haven, Connecticut (Gupta, Krumholz, Bikdeli); Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Barcelona, Universidad Católica de Murcia, Murcia, Spain (Monreal); Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Piazza, Goldhaber, Bikdeli); School of Pharmacy, Department of Pharmacotherapy and Outcome Science, Virginia Commonwealth University, Richmond, Virginia (Van Tassell); School of Pharmacy, Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia (Van Tassell); College of Pharmacy, University of Nebraska Medical Center, Omaha (Dobesh); The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York (Stone); Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom (Lip); Aalborg University, Aalborg, Denmark (Lip); Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut (Krumholz); Department of Health Policy and Administration, Yale School of Public Health, New Haven, Connecticut (Krumholz).

    Author Contributions: Dr Sadeghipour had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Parham Sadeghipour, Talasaz, Rashidi, Sharif-Kashani, Beigmohammadi, Sezavar, Payandemehr, Dabbagh, Gohari Moghadam, Riahi, Abedini, Mohebbi, Kakavand, Fattah Ghazi, Najafi, Jimenez, Sethi, Monreal, Hajighasemi, Sadeghian, Piazza, Kirtane, Dobesh, Bikdeli.

    Acquisition, analysis, or interpretation of data: Parham Sadeghipour, Talasaz, Sharif-Kashani, Beigmohammadi, Farrokhpour, Payandemehr, Dabbagh, Jamalkhani, Khalili, Yadollahzadeh, Rezaeifar, Tahamtan, Matin, Lookzadeh, Rahmani, Zoghi, Mohammadi, Pardis Sadeghipour, Abri, Tabrizi, Mousavian, Shahmirzaei, Bakhshandeh, Amin, Rafiee, Baghizadeh, Mohebbi, Parhizgar, Aliannejad, Eslami, Kashefizadeh, Hosseini, Shafaghi, Jimenez, Gupta, Madhavan, Sethi, Parikh, Hadavand, Maleki, Piazza, Van Tassell, Stone, Lip, Krumholz, Goldhaber, Bikdeli.

    Drafting of the manuscript: Parham Sadeghipour, Talasaz, Sharif-Kashani, Farrokhpour, Payandemehr, Jamalkhani, Khalili, Yadollahzadeh, Riahi, Rezaeifar, Tahamtan, Matin, Lookzadeh, Pardis Sadeghipour, Abri, Tabrizi, Mousavian, Shahmirzaei, Rafiee, Baghizadeh, Mohebbi, Parhizgar, Eslami, Kashefizadeh, Hosseini, Shafaghi, Fattah Ghazi, Najafi, Bikdeli.

    Critical revision of the manuscript for important intellectual content: Parham Sadeghipour, Talasaz, Rashidi, Beigmohammadi, Sezavar, Payandemehr, Dabbagh, Gohari Moghadam, Abedini, Rahmani, Zoghi, Mohammadi, Bakhshandeh, Amin, Mohebbi, Aliannejad, Kakavand, Najafi, Jimenez, Gupta, Madhavan, Sethi, Parikh, Monreal, Hadavand, Hajighasemi, Maleki, Sadeghian, Piazza, Kirtane, Van Tassell, Dobesh, Stone, Lip, Krumholz, Goldhaber, Bikdeli.

    Statistical analysis: Parham Sadeghipour, Bakhshandeh, Mohebbi, Jimenez.

    Obtained funding: Parham Sadeghipour, Abedini, Najafi.

    Administrative, technical, or material support: Parham Sadeghipour, Talasaz, Beigmohammadi, Payandemehr, Gohari Moghadam, Khalili, Abedini, Rahmani, Zoghi, Mohammadi, Amin, Mohebbi, Parhizgar, Aliannejad, Kakavand, Fattah Ghazi, Najafi, Sethi, Hadavand, Hajighasemi, Maleki, Sadeghian, Piazza, Bikdeli.

    Supervision: Parham Sadeghipour, Talasaz, Rashidi, Sharif-Kashani, Beigmohammadi, Payandemehr, Gohari Moghadam, Riahi, Mohebbi, Gupta, Monreal, Piazza, Van Tassell, Dobesh, Goldhaber, Bikdeli.

    Other - monitoring of the study progress, supporting patient recruitment, data clarifications, and data entry: Sharif-Kashani, Farrokhpour, Sezavar, Jamalkhani, Yadollahzadeh, Rezaeifar, Tahamtan, Matin, Lookzadeh, Pardis Sadeghipour, Abri, Tabrizi, Mousavian, Shahmirzaei, Eslami, Kashefizadeh, Hosseini, Shafaghi.

    Conflict of Interest Disclosures: Dr Jimenez reported receiving personal fees from Bristol Myers Squibb, Daiichi-Sankyo, Bayer, Pfizer, Rovi, and Leo-Pharma and grants from Sanofi outside the submitted work. Dr Gupta reported receiving consulting fees from Edwards Lifesciences, Arnold Porter Law Firm, and Ben C. Martin Law Firm and equity from Heartbeat Health Inc outside the submitted work. Dr Madhavan reported receiving an institutional research grant to Columbia University Irving Medical Center (T32 HL007854) from the National Institutes of Health/National Heart, Lung, and Blood Institute during the conduct of the study. Dr Sethi reported receiving personal fees from Janssen and Chiesi and grants from the American Heart Association outside the submitted work. Dr Parikh reported receiving grants from Abbott Vascular, Boston Scientific, Surmodics, and TriReme Medical; nonfinancial support from Cordis, Medtronic, Philips, and Cardiovascular Systems Inc; and personal fees from Terumo, Abiomed, Inari, and Penumbra outside the submitted work. Dr Monreal reported receiving grants from Sanofi outside the submitted work. Dr Piazza reported receiving grants from Bristol Myers Squibb/Pfizer, Janssen, Portola, Boston Scientific, and Bayer and serving on a data and safety monitoring board for Prairie Education and Research Cooperative outside the submitted work. Dr Kirtane reported receiving institutional funding to Columbia University and/or the Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, Cardiovascular Systems Inc, CathWorks, Siemens, Philips, and ReCor Medical, including fees paid to Columbia University and/or the Cardiovascular Research Foundation for speaking engagements and/or consulting; consulting fees from Neurotronic; and travel expenses/meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, Cardiovascular Systems Inc, CathWorks, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron. Dr Dobesh reported receiving personal fees from the Pfizer/Bristol Myers Squibb Alliance and Janssen Pharmaceuticals outside the submitted work. Dr Stone reported receiving personal fees from Terumo, Cook, TherOx, Reva, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Matrizyme, Miracor Neovasc, V-wave, Abiomed, MAIA Pharmaceuticals, Shockwave, Vectorious, Cardiomech , and Elucid Bio; equity/equity options from Applied Therapeutics, MedFocus, Biostar, Aria, Cagent, Cardiac Success; personal fees and equity/equity options from Spectrawave, Valfix, Ancora; and personal fees, equity/equity options, and honorarium from Orchestra Biomed, and outside the submitted work. Dr Lip reported being a consultant and speaker for Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo outside the submitted work. Dr Krumholz reported receiving personal fees from UnitedHealth, IBM Watson Health, Element Science, Aetna, Facebook, Siegfried & Jensen Law Firm, Arnold & Porter Law Firm, Martin/Baughman Law Firm, F-Prime, and the National Center for Cardiovascular Diseases, Beijing; being the cofounder of HugoHealth, a personal health information platform, and Refactor Health, an enterprise health care artificial intelligence–augmented data management company; receiving contracts from the Centers for Medicare & Medicaid Services, through Yale New Haven Hospital, to develop and maintain measures of hospital performance; and receiving grants from Medtronic, the US Food and Drug Administration, Johnson & Johnson, and the Shenzhen Center for Health Information outside the submitted work. Dr Goldhaber reported receiving grants from Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Boston Scientific, Janssen, the National Heart, Lung, and Blood Institute, and Pfizer and personal fees from Agile, Bayer, Boehringer-Ingelheim, and Pfizer outside the submitted work. Dr Bikdeli reported being a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of inferior vena cava filters. No other disclosures were reported.

    Funding/Support: The study was funded by the Rajaie Cardiovascular Medical and Research Center. Some study authors, including the lead author, are affiliated with the Rajaie Cardiovascular Medical and Research Center. Enoxaparin was provided through Alborz Darou, Pooyesh Darou, and Caspian Pharmaceuticals companies, and atorvastatin and matching placebo was provided by Sobhan Darou. None of these companies were study sponsors.

    Role of the Funder/Sponsor: Some study authors are affiliated with the study funder (Rajaie Cardiovascular and Medical Research Center). Neither the funder, nor the companies who donated the study drugs (Alborz Darou, Pooyesh Darou and Caspian Pharmaceuticals) had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Group Information: A list of the INSPIRATION collaborators appears in Supplement 4.

    Data Sharing Statement: See Supplement 5.

    Additional Contributions: The authors would like to thank the members of the data and safety monitoring board, Saeideh Mazloomzadeh, MD, PhD; Shiva Khaleghparast, PhD; Behshid Ghadrdoost, PhD; Mostafa Mousavizadeh, MD; and Mohammad Reza Baay, MD (Rajaie Cardiovascular, Medical and Research Center). The authors would also like to thank Feridoun Noohi, MD (Rajaie Cardiovascular, Medical and Research Center), for his support for performing this study, Hamidreza Sharifnia, MD; Arezoo Ahmadi, MD (Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran); Sasan Tavana, MD; Nasser Malekpour Alamdari, MD; Mohammad Fathi, MD; Mahshid Soleimanzadeh, MD (Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran); Mostafa Mohammadi, MD (Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran); and Navid Davoody, MD (Rasoul-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran), for their kind support for patient recruitment and Maryam Zarinsadaf, Sara Tayyebi, MS; Fahimeh Farrokhzadeh, MS; Faeze Nezamabadi, MS; and Esmaeil Soomari, MS (Rajaie Cardiovascular, Medical and Research Center), for their support and contribution to the INSPIRATION study.

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