Intermediate-dose vs Standard Prophylactic Anticoagulation and Statin vs Placebo in ICU Patients With COVID-19

NCT ID: NCT04486508

Last Updated: 2021-08-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 600 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-30
• Study Completion Date: 2021-07-05

Brief Summary

In a 2x2 factorial design randomized controlled trial, the investigators aim to elaborate the safety and efficacy of two pharmacological regimens on outcomes of critically-ill patients with COVID-19. The first randomization entails open-label assignment to intermediate versus standard dose prophylactic anticoagulation. The investigators hypothesize that intermediate dose compared with standard prophylactic dose anticoagulation will have a superior efficacy with respect to a composite of venous thromboembolism (VTE), requirement for extracorporeal membrane oxygenation (ECMO), or all-cause mortality. The second randomization will be double-blind assignment of the included patients to atorvastatin 20mg daily versus matching placebo. The hypothesis is that statin therapy, compared with placebo, will reduce the composite of VTE, need for ECMO, or all-cause mortality.

Detailed Description

Coronavirus disease-2019 (COVID-19) -- a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) -- has important manifestations outside the pulmonary parenchyma, including microthrombosis and macrothrombosis, with venous thrombosis being the most common form of thrombotic involvement. Existing studies, depending on the type of outcome assessment and type and dose of prophylaxis, have reported thrombotic events in 7-85% of patients with COVID-19.

However, the optimal antithrombotic regimen in these patients remains uncertain. Although many clinicians continue to consider standard-dose prophylactic anticoagulation, other believe that more intense anticoagulation may reduce the thrombotic events, and improve outcomes. However, limited high-quality data exist to inform clinical practice and the existing guidelines recommendations are mostly based on expert opinion and consensus.

In addition, exuberant inflammatory response is known to play a role in the pathophysiology of acute respiratory distress syndrome (ARDS) and COVID-19. It is possible that the pleiotropic effects of statins, which include anti-inflammatory and antithrombotic effects, prove beneficial in patients with severe COVID-19.

This study plans to investigate the safety and efficacy of two pharmacological regimens on outcomes of critically-ill patients with COVID-19 using a 2x2 factorial design.

First, patients will be assessed for the eligibility criteria for the anticoagulation hypothesis. Those meeting the criteria, will be assigned to intermediate versus standard dose prophylactic anticoagulation. These patients will subsequently be assessed for eligibility for the second randomization, and if meeting the criteria, will be assigned to atorvastatin 20mg/d or matching placebo.

Conditions

Covid19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Intermediate dose anticoagulation

Intermediate dose anticoagulation will be the the tested regimen. The anticoagulation regimen will be modified according to weight/ body mass index, and creatinine clearance level (Cl Cr). Enoxaparin will be the primary agent for anticoagulation, with unfractionated heparin reserved only for patients with creatinine clearance of ≤15 mL/min according to Cockcroft-Gault Formula.

Group Type: EXPERIMENTAL

intermediate dose Enoxaparin/ unfractionated heparin

Intervention Type: DRUG

Intermediate dose anticoagulation according to creatinine clearance and weight

Standard Prophylaxis

Standard prophylaxis dose anticoagulation will be the anticoagulation of choice in the control arm. Enoxaparin will be the primary agent for anticoagulation, with unfractionated heparin reserved only for patients with creatinine clearance of ≤15 mL/min according Cockcroft-Gault Formula.

Group Type: ACTIVE_COMPARATOR

standard prophylactic dose Enoxaparin/ unfractionated heparin

Intervention Type: DRUG

Standard prophylaxis anticoagulation according to creatinine clearance and weight

Atorvastatin 20

Atorvastatin 20 mg daily will be the statin therapy of choice in the intervention arm

Group Type: EXPERIMENTAL

Atorvastatin 20mg

Intervention Type: DRUG

Statin

Atorvastatin 20 mg Matched placebo

Matching placebo will be used for the control arm

Group Type: PLACEBO_COMPARATOR

Matched placebo

Intervention Type: DRUG

Matched placebo to atorvastatin 20 mg

Interventions

intermediate dose Enoxaparin/ unfractionated heparin

Intermediate dose anticoagulation according to creatinine clearance and weight

Intervention Type: DRUG

standard prophylactic dose Enoxaparin/ unfractionated heparin

Standard prophylaxis anticoagulation according to creatinine clearance and weight

Intervention Type: DRUG

Atorvastatin 20mg

Statin

Intervention Type: DRUG

Matched placebo

Matched placebo to atorvastatin 20 mg

Intervention Type: DRUG

Other Intervention Names

Intermediate dose anticoagulation; Standard dose prophylaxis anticoagulation; Statin; Statin

Eligibility Criteria

Inclusion Criteria

1. Adult patients (≥18 years), with polymerase chain reaction (PCR)-confirmed COVID-19 admitted to ICU within 7 days of initial hospitalization , who do not have another firm indication for anticoagulation (such as mechanical valve, high-risk atrial fibrillation (AF), VTE, or left ventricle (LV) thrombus),who are not enrolled in another blinded randomized trial, and are willing to participate in the study and provide informed consent .

2. Estimated survival of at least 24 hours at the discretion of enrolling physician

1. Patients enrolled for the anticoagulation randomization

2. Willingness to participation in the study and providing informed consent

Exclusions Criteria for the Statin Randomization

1. Baseline liver function tests> 3 times upper normal limits (ULN) or creatine kinase (CK) >500 U/L

2. Active liver disease (LFT>3 ULN plus histologic finding including cirrhosis or inflammation or necrosis)

3. Routine use of statins prior to the index hospitalization

4. Previous documented statin intolerance

Exclusion Criteria

1. Weight <40 Kilogram (kg)

2. Overt bleeding at the day of enrollment

3. Known major bleeding within 30 days (according to the Bleeding Academic Research Consortium (BARC) definition, Appendix A)

4. Platelet count <50,000/Fl

5. Pregnancy (as confirmed by Beta human chorionic gonadotropin (HCG) testing among female patients <50 years)

6. Patients on Extracorporeal Membrane Oxygenation (ECMO)

7. History of heparin induced thrombocytopenia or immune thrombocytopenia

8. Ischemic stroke within the past 2 weeks

9. Craniotomy/major neurosurgery within the past 3 months

10. Major head or spinal trauma in the past 30 days

11. Known brain metastases or vascular malformations (aneurysm)

12. Presence of an epidural, spinal or pericardial catheter

13. Major surgery other than neurosurgery within 14 days prior to enrollment

14. Coexistence of severe obesity (weight >120 kg or BMI>35 kg/m2 along with severe renal insufficiency defined as creatinine clearance (CrCl) <30 mL/sec)

15. Allergic reaction to study medications

16. Lack or withdrawal of informed consent

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Brigham and Women's Hospital

OTHER

Sponsor Role: collaborator

Tehran Heart Center

OTHER

Sponsor Role: collaborator

Masih Daneshvari Hospital

OTHER

Sponsor Role: collaborator

Hazrat Rasool Hospital

OTHER

Sponsor Role: collaborator

Modarres Hospital

OTHER

Sponsor Role: collaborator

Firuzgar hospital affiliated to Iran University of Medical Sciences

OTHER

Sponsor Role: collaborator

Imam Khomeini Hospital

OTHER

Sponsor Role: collaborator

Sina Hospital, Iran

OTHER

Sponsor Role: collaborator

Tabriz University of Medical Sciences

OTHER

Sponsor Role: collaborator

Shariati Hospital

OTHER

Sponsor Role: collaborator

Imam Ali Hospital

UNKNOWN

Sponsor Role: collaborator

Labbafinejhad Hospital

OTHER

Sponsor Role: collaborator

Rajaie Cardiovascular Medical and Research Center

OTHER

Sponsor Role: lead

Responsible Party

Parham Sadeghipour

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Parham Sadeghipour, MD

Role: PRINCIPAL_INVESTIGATOR

Rajaie Cardiovascular Medical and Research Center

Behnood Bikdeli, MD, MS

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital, Harvard Medical School

Locations

Masih Daneshvari Hospital

Tehran, , Iran

Countries

Iran

References

Bikdeli B, Talasaz AH, Rashidi F, Sharif-Kashani B, Farrokhpour M, Bakhshandeh H, Sezavar H, Dabbagh A, Beigmohammadi MT, Payandemehr P, Yadollahzadeh M, Riahi T, Khalili H, Jamalkhani S, Rezaeifar P, Abedini A, Lookzadeh S, Shahmirzaei S, Tahamtan O, Matin S, Amin A, Parhizgar SE, Jimenez D, Gupta A, Madhavan MV, Parikh SA, Monreal M, Hadavand N, Hajighasemi A, Maleki M, Sadeghian S, Mohebbi B, Piazza G, Kirtane AJ, Lip GYH, Krumholz HM, Goldhaber SZ, Sadeghipour P. 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. Thromb Res. 2020 Dec;196:382-394. doi: 10.1016/j.thromres.2020.09.027. Epub 2020 Sep 24.

Reference Type: RESULT

PMID: 32992075 (View on PubMed)

Talasaz AH, Sadeghipour P, Bakhshandeh H, Sharif-Kashani B, Rashidi F, Beigmohammadi MT, Moghadam KG, Rezaian S, Dabbagh A, Sezavar SH, Farrokhpour M, Abedini A, Aliannejad R, Riahi T, Yadollahzadeh M, Lookzadeh S, Rezaeifar P, Matin S, Tahamtan O, Mohammadi K, Zoghi E, Rahmani H, Hosseini SH, Mousavian SM, Abri H, Sadeghipour P, Baghizadeh E, Rafiee F, Jamalkhani S, Amin A, Mohebbi B, Parhizgar SE, Soleimanzadeh M, Aghakouchakzadeh M, Eslami V, Payandemehr P, Khalili H, Talakoob H, Tojari T, Shafaghi S, Tabrizi S, Kakavand H, Kashefizadeh A, Najafi A, Jimenez D, Gupta A, Madhavan MV, Sethi SS, Parikh SA, Monreal M, Hadavand N, Hajighasemi A, Ansarin K, Maleki M, Sadeghian S, Barco S, Siegerink B, Spatz ES, Piazza G, Kirtane AJ, Tassell BWV, Lip GYH, Klok FA, Goldhaber SZ, Stone GW, Krumholz HM, Bikdeli B. Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial. Thromb Haemost. 2023 Jul;123(7):723-733. doi: 10.1055/a-2059-4844. Epub 2023 Mar 21.

Reference Type: DERIVED

PMID: 36944357 (View on PubMed)

Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.

Reference Type: DERIVED

PMID: 35244208 (View on PubMed)

Erdem S, Ipek F, Bars A, Genc V, Erpek E, Mohammadi S, Altinata A, Akar S. Investigating the effect of macro-scale estimators on worldwide COVID-19 occurrence and mortality through regression analysis using online country-based data sources. BMJ Open. 2022 Feb 14;12(2):e055562. doi: 10.1136/bmjopen-2021-055562.

Reference Type: DERIVED

PMID: 35165110 (View on PubMed)

INSPIRATION-S Investigators. Atorvastatin versus placebo in patients with covid-19 in intensive care: randomized controlled trial. BMJ. 2022 Jan 7;376:e068407. doi: 10.1136/bmj-2021-068407.

Reference Type: DERIVED

PMID: 34996756 (View on PubMed)

INSPIRATION Investigators; Sadeghipour P, Talasaz AH, Rashidi F, Sharif-Kashani B, Beigmohammadi MT, Farrokhpour M, Sezavar SH, Payandemehr P, Dabbagh A, Moghadam KG, Jamalkhani S, Khalili H, Yadollahzadeh M, Riahi T, Rezaeifar P, Tahamtan O, Matin S, Abedini A, Lookzadeh S, Rahmani H, Zoghi E, Mohammadi K, Sadeghipour P, Abri H, Tabrizi S, Mousavian SM, Shahmirzaei S, Bakhshandeh H, Amin A, Rafiee F, Baghizadeh E, Mohebbi B, Parhizgar SE, Aliannejad R, Eslami V, Kashefizadeh A, Kakavand H, Hosseini SH, Shafaghi S, Ghazi SF, Najafi A, Jimenez D, Gupta A, Madhavan MV, Sethi SS, Parikh SA, Monreal M, Hadavand N, Hajighasemi A, Maleki M, Sadeghian S, Piazza G, Kirtane AJ, Van Tassell BW, Dobesh PP, Stone GW, Lip GYH, Krumholz HM, Goldhaber SZ, Bikdeli B. 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. JAMA. 2021 Apr 27;325(16):1620-1630. doi: 10.1001/jama.2021.4152.

Reference Type: DERIVED

PMID: 33734299 (View on PubMed)

Related Links

https://pubmed.ncbi.nlm.nih.gov/32311448/

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review

https://pubmed.ncbi.nlm.nih.gov/32473596/

Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research

Other Identifiers

99060

Identifier Type: -

Identifier Source: org_study_id