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

Intermediate-dose Versus Standard Prophylactic Anticoagulation In cRitically-ill pATIents With COVID-19: An opeN Label Randomized Controlled Trial---A Randomized Trial of Atorvastatin vs. Placebo In Critically-ill Patients With COVID-19

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.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: intermediate dose Enoxaparin/ unfractionated heparin; Drug: standard prophylactic dose Enoxaparin/ unfractionated heparin; Drug: Atorvastatin 20mg; Drug: Matched placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 600
• Phase: Phase 3

Contacts and Locations

Study Locations

• Iran, Islamic Republic of
  • Tehran, Iran, Islamic Republic of, 199691110
    • Masih Daneshvari Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria for Anticoagulation Hypothesis

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

Exclusion Criteria for Anticoagulation Hypothesis

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

Inclusion Criteria for the Statin Randomization

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: intermediate dose Enoxaparin/ unfractionated heparin; Intermediate dose anticoagulation according to creatinine clearance and weight; Other Names: Intermediate dose anticoagulation
Active Comparator: 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.	Drug: standard prophylactic dose Enoxaparin/ unfractionated heparin; Standard prophylaxis anticoagulation according to creatinine clearance and weight; Other Names: Standard dose prophylaxis anticoagulation
Experimental: Atorvastatin 20; Atorvastatin 20 mg daily will be the statin therapy of choice in the intervention arm	Drug: Atorvastatin 20mg; Statin; Other Names: Statin
Placebo Comparator: Atorvastatin 20 mg Matched placebo; Matching placebo will be used for the control arm	Drug: Matched placebo; Matched placebo to atorvastatin 20 mg; Other Names: Statin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
a composite of acute VTE, arterial thrombosis, treatment with ECMO, or all-cause mortality	composite of adjudicated 30-day acute VTE, arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality.	30 days from enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of all-cause mortality	Patient status regarding to being alive or dead at the end of 30-day follow up	30 days from enrollment
Rate of objectively-confirmed VTE	Distal or proximal deep vein thrombosis which has been confirmed by ultrasonography or venography/ PE confirmed by at least one CTPA or lung scan	30 days from enrollment
Ventilator free days	Difference between days of ICU stay and days on invasive mechanical ventilation	30 days from enrollment
Rate of major bleeding	According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding)	30 days from enrollment
Rate of clinically-relevant non-major bleeding	Clinically-significant bleeding, not fulfilling criteria for major bleeding)	30 days from enrollment
Rate of severe thrombocytopenia	Platelet count <20.000	30 days from enrollment
Rate of rise in liver enzymes	Increase liver function tests 3 times greater than upper limit of normal	30 days from enrollment
Clinically-diagnosed myopathy	Assessed by clinical and biomarker tests according to the treating physicians.	30 days from enrollment
Objectively-confirmed arterial thrombosis	Imaging confirmed acute arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)	30 days from enrollment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of objectively clinically-diagnosed type I acute myocardial infarction	According to the fourth universal definition of myocardial infraction and confirmed by coronary angiography, intravascular imaging or autopsy	30 days from enrollment
Rate of objectively clinically -diagnosed stroke	Any stroke episode which has been confirmed with appropriate diagnostic imaging (brain CT and/or brain MRI)	30 days from enrollment
Rate of objectively clinically -diagnosed acute peripheral arterial thrombosis	Imaging confirmed acute peripheral arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography)	30 days from enrollment
Median ICU length of stay	Number of days that a patient has stayed in the ICU	30 days from enrollment
ICU discharge status	Status of patients regarding to mortality (alive/dead) at the time of discharge from ICU	30 days from enrollment
Incident atrial fibrillation	Any AF episode which has been confirmed by at least one ECG or telemetry monitoring, in patients without prior history of AF	30 days from enrollment
Rate of need for renal replacement therapy	Use hemodialysis or veno-venous hemofiltration or peritoneal dialysis for a patient during the hospitalization period, due to acute kidney injury	30 days from enrollment
Post-COVID-19 Functional Status	Based on Post-COVID-19 Functional Status questionnaire, which varies fro score 0 to 4, and higher scores mean worse outcome.	60 and 90 -day

Collaborators and Investigators

• Sponsor: Rajaie Cardiovascular Medical and Research Center
• Collaborators: Brigham and Women's Hospital; Tehran Heart Center; Imam Khomeini Hospital; Masih Daneshvari Hospital; Hazrat Rasool Hospital; Modarres Hospital; Firuzgar hospital affiliated to Iran University of Medical Sciences; Sina Hospital, Iran; Tabriz University of Medical Sciences; Shariati Hospital; Imam Ali Hospital; Labbafinejhad Hospital
• Investigators: Principal Investigator: Parham Sadeghipour, MD, Rajaie Cardiovascular Medical and Research Center; Principal Investigator: Behnood Bikdeli, MD, MS, Brigham and Women's Hospital, Harvard Medical School

Publications and helpful links

General Publications

• 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.
• 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.
• Erdem S, Ipek F, Bars A, Genç V, Erpek E, Mohammadi S, Altınata 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.
• 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.
• 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.

Helpful Links

• COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review
• Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2020
• Primary Completion (Actual): April 4, 2021
• Study Completion (Actual): July 5, 2021

Study Registration Dates

• First Submitted: July 22, 2020
• First Submitted That Met QC Criteria: July 22, 2020
• First Posted (Actual): July 24, 2020

Study Record Updates

• Last Update Posted (Actual): August 17, 2021
• Last Update Submitted That Met QC Criteria: August 14, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: anticoagulation; statin
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Anticoagulants; Atorvastatin; Heparin; Enoxaparin; Calcium heparin; Enoxaparin sodium; Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Other Study ID Numbers: 99060

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No