Antithrombotic Therapy to Ameliorate Complications of COVID-19 ( ATTACC )

ID#: NCT04372589

Age: 18 years - 66+

Gender: All

Healthy Subjects: No

Study Phase: Phase 2/Phase 3

Recruitment Status: Recruiting

Start Date: May 20, 2020

End Date: January 01, 2021

Contact Information:
Ryan Zarychanski, MD, MSc
Patrick R. Lawler, MD, MPH
Summary: Endothelial injury as a consequence of SARS-CoV-2 infection leads to a dysregulated host inflammatory response and activation of coagulation pathways. Macro- and micro-vascular thrombosis may contribute to morbidity, organ failure, and death. Therapeutic anticoagulation with heparin may improve clinical outcomes in patients with COVID-19 through anti-thrombotic, anti-inflammatory, and anti-viral activities of heparins. This pragmatic, Bayesian adaptive randomized controlled trial will determine whether therapeutic anticoagulation with heparin (subcutaneous low molecular weight heparin or intravenous unfractionated heparin) versus usual care reduces the need for intubation or death in hospitalized patients with COVID-19 not initially requiring invasive mechanical ventilation. The trial uses an adaptive design which was chosen to overcome limitations in available data to inform a priori estimation of event rates and possible effect sizes. The adaptive design also includes response-adaptive randomization based on baseline D-dimer level, probing for differential efficacy across subgroups defined based on initial D-dimer level. This Bayesian adaptive randomized trial will stop at a conclusion 1) when the posterior probability that the proportional odds ratio is greater than 1.0 reaches 99% (definition of benefit); 2) when the posterior probability that the proportional odds ratio is greater than 1.2 is less than 10% (definition of futility) or; 3) when the posterior probability that the proportional odds ratio is less than 1.0 is greater than 90% (definition of harm). The trial will enroll a maximum of 3,000 patients, although in many simulations the trial may require fewer patients. The trial is strategically aligned with the international REMAP-CAP/COVID platform trial to accelerate evidence generation.

Inclusion Criteria:

1. Patients ≥18 years of age providing (possibly through a substitute decision maker) informed consent who require hospitalization anticipated to last ≥72 hours, with microbiologically-confirmed COVID-19, enrolled < 72 hours of hospital admission or of COVID-19 confirmation

Exclusion Criteria:

1. Receiving invasive mechanical ventilation

2. Patients for whom the intent is to not use pharmacologic thromboprophylaxis

3. Active bleeding

4. Risk factors for bleeding, including:

1. intracranial surgery or stroke within 3 months;

2. history of intracerebral arteriovenous malformation;

3. cerebral aneurysm or mass lesions of the central nervous system;

4. intracranial malignancy

5. history of intracranial bleeding

6. history of bleeding diatheses (e.g., hemophilia)

7. history of gastrointestinal bleeding within previous 3 months

8. thrombolysis within the previous 7 days

9. presence of an epidural or spinal catheter

10. recent major surgery <14 days

11. uncontrolled hypertension (sBP >200 mmHg, dBP >120 mmHg)

12. other physician-perceived contraindications to anticoagulation

5. Platelet count <50 x10^9/L, INR >2.0, or baseline aPTT >50

6. Hemoglobin <80 g/L (to minimize the likelihood of requiring red blood cell transfusion if potential bleeding were to occur)

7. Acute or subacute bacterial endocarditis

8. History of heparin induced thrombocytopenia (HIT) or other heparin allergy including hypersensitivity

9. Current use of dual antiplatelet therapy

10. Patients with an independent indication for therapeutic anticoagulation

11. Patients in whom imminent demise is anticipated and there is no commitment to active ongoing intervention

12. Pregnancy

13. Anticipated transfer to another hospital that is not a study site within 72 hours

14. Enrollment in other trials related to anticoagulation or antiplatelet therapy