Covid-19 living Data

Intermediate-Dose prophylactic anticoagulation vs Standard-Dose prophylactic anticoagulation (RCT)

Hospitalized patients

FOREST PLOTS -2022-06-02

Studies description

Trial NCT04486508
Publication INSPIRATION - Bikdeli B, Thromb Haemost (2021) (published paper)
Dates: 2020-07-29 to 2020-11-19
Funding: Mixed (Rajaie Cardiovascular Medical and Research Center. Medications and placebo were provided through Alborz Darou, Pooyesh Darou, and Caspian Pharmaceuticals companies.)
Conflict of interest: Yes

Methods
	RCT Blinding: single blinding
	Location : Multicenter / Iran Follow-up duration (days): 90
Inclusion criteria	Adult patients (≥18 years) PCR-confirmed COVID-19 and admitted to ICU within 7 days of initial hospitalization no other firm indication for anticoagulation (such as mechanical valve, high-risk AF, VTE, or left ventricular thrombus) not enrolled in another blinded randomized trial willing to participate in the study and provide informed consent estimated survival of at least 24 hours at the discretion of enrolling physician.
Exclusion criteria	Weight <40Kg use of systemic anticoagulation for another indication (mechanical valve, ECMO, AF, left ventricular thrombus, or diagnosed VTE) overt bleeding at the day of enrollment known major bleeding within 30 days (according to the Bleeding Academic Research Consortium (BARC) definition, Appendix A) platelet count <50,000/Fl pregnancy (as confirmed by beta-HCG testing among female patients <50 years) history of heparin induced thrombocytopenia or immune thrombocytopenia ischemic stroke within the past 2 weeks major head or spinal trauma in the past 30 days craniotomy/major neurosurgery within the past 3 months known brain metastases or vascular malformations (aneurysm) presence of an epidural, spinal or pericardial catheter major surgery other than neurosurgery within 14 days prior to enrollment coexistence of severe obesity (weight >120Kg or BMI>35Kg/M2 along with severe renal insufficiency defined as CrCl<30 mL/min) allergic reaction to study medications lack or withdrawal of informed consent.
Interventions
	Treatment Intermediate dose Enoxaparin: 1 mg/kg once daily for 30 days (if weight < 120kg and creatinine clearance > 30 ml/min).
	Control Standard dose Enoxaparin: 40 mg once daily for 30 days (dosage/times per day adjusted according to creatinine clearance and body weight; unfractionated heparin 5000 units SC twice daily only for patients with creatinine clearance of ≤15 mL/min).
Participants
	Randomized participants : Standard dose=299 Intermediate dose=299
	Characteristics of participants N= 598 Mean age : NR 325 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=449 Critical: n=113
Primary outcome
	In the register A composite of acute VTE, arterial thrombosis, treatment with ECMO, or all-cause mortality [ Time Frame: 30 days from enrollment ]
	In the report Composite of adjudicated acute VTE, arterial thrombosis, treatment with extra- corporeal membrane oxygenation (ECMO), or all-cause mortality at 90 days from enrollment
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published articles, the trial registry, published and full protocol, statistical analysis plan, and information obtained from contact with the author were used in data extraction and assessment of risk of bias. There were no substantive differences between the published article and the trial registry and protocol in population, procedures and interventions. One long term outcome, included in the trial registry but not the protocol (post-COVID-19 functional status at 60 & 90 days), is not reported. All other outcomes for the reported comparison in the trial registry and protocol were reported. Some post hoc subgroup analyses were performed. Recruitment was paused by the data and safety monitoring board because of futility for efficacy and potential excess of safety events. On 30th of April, 2021, this study (90 Day results) was updated based on the published report in Thromb Haemost. On May 31st, 2021, we received additional information from authors on this study. This study was updated with data from contact with authors on May 31st, 2021.

Trial NCT04360824
Publication Perepu U, J Thromb Haemost (2021) (published paper)
Dates: 2020-04-26 to 2021-01-06
Funding: Public/non profit (National Institutes of Health Clinical and Translational Science Award)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / USA Follow-up duration (days): 30
Inclusion criteria	Adults 18 years of age or older SARS-CoV-2 infection confirmed by nasopharyngeal swab polymerase chain reaction requiring hospitalization admitted to an ICU and/or had a modified ISTH Overt DIC score ≥ 3
Exclusion criteria	Indication for full therapeutic dose anticoagulation or they had active major bleeding severe thrombocytopenia (platelet count <25,000/uL) current pregnancy a history of acute venous or arterial thrombosis within the prior 3 months or acute or chronic renal insufficiency with an estimated creatinine clearance less than 30 mL/min calculated by the modified Cockcroft and Gault formula
Interventions
	Treatment Intermediate dose 1 mg/kg daily if BMI < 30; 0.5 mg/kg twice daily if BMI ≥ 30; subcutaneously.
	Control Standard dose 40 mg daily if BMI <30 kg/m2; 30 mg twice daily or 40 mg twice daily according to the local institutional standard of practice if BMI ≥ 30; subcutaneously.
Participants
	Randomized participants : Intermediate dose=88 Standard dose=88
	Characteristics of participants N= 176 Mean age : NR 97 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=* Critical: n=*
Primary outcome
	In the register Mortality [ Time Frame: 30 Days post intervention ]
	In the report All-cause mortality at 30 days
Documents avalaible	Protocol Yes. In English Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Low
General comment	In addition to the pre-print article, the trial registry was used in data extraction and assessment of risk of bias. Neither protocol nor statistical analysis plan was available at time of extraction. There were some differences between inclusion criteria in the registry and the article: the registry required a modified ISTH Overt DIC score ≥ 3 whereas in the article the criteria included admitted to an ICU and/or a modified ISTH Overt DIC score ≥ 3. Several secondary outcomes in the registry were not reported (Packed Red Blood Cell Transfusions, Platelet Transfusions, Fresh Frozen Plasma Transfusions, Cryoprecipitate Transfusions, Prothrombin Complex Concentrate Transfusions) while other reported secondary outcomes (acute kidney injury, ischemic stroke and myocardial infarction) were not in the registry. Exploratory laboratory biomarker outcomes will be reported separately. The study achieved its target sample size. On 27th of July, 2021, this study was updated based on published article, supplemental material, and protocol.