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16th National Conference on Anticoagulation TherapyOctober 28-30, 2021

COVID-19 Lessons Learned

16th National Conference on Anticoagulation Therapy28 October 2021

Recorded 9/27/21

Presenter:

Scott Kaatz, DO, MSc, SFHMHenry Ford Hospital

Potential Conflict of Interest Consultant

– Janssen– Pfizer– Portola/Alexion– Bristol Myer Squibb– Norvartis– CSL Behring– Gilead

Research funding (to institution)– Janssen– BMS– Osmosis research– NIH

Board membership (non-profit)– AC Forum– National Blood Clot Alliance Medical and Scientific Advisory Board

COVID 19 – Lessons Learned

Immune mediated inflammatory micro thrombosis ‘Pre’ hospitalization anticoagulation prophylaxis Hospitalized moderately ill anticoagulation prophylaxis Hospitalized severely/critically ill anticoagulation prophylaxis Post discharge anticoagulation prophylaxis

COVID-19 Immuno-micro

pulmonary thrombosis

Wiersinga WJ. JAMA. 2020 Aug 25;324(8):782-793. PMID: 32648899.

Series of 7 autopsies

Ackermann M. N Engl J Med. 2020 May 21. PMID: 32437596.

JACC State of the Art Review

Ongoing and Completed COVID-19

Antithrombotic Trials

Talasaz AH. J Am Coll Cardiol. 2021 Apr 20;77(15):1903-1921. PMID: 33741176.

JACC State of the Art Review

Ongoing and Completed COVID-19 Antithrombotic Trials

Talasaz AH. J Am Coll Cardiol. 2021 Apr 20;77(15):1903-1921. PMID: 33741176.

Example Randomized Trials

Completed• ACTIV 4cRecruiting• PREVENT

Completed• mpRCT• ACTION• RAPID

Completed• mpRCT• Inspiration

Environment of care

ASH Guidelines

COVID-19 and Thrombosis: Searching for Evidence - Anticoagulation Thromboprophylaxis

Completed• MichelleRecruiting• ACTIV 4b

“Pre-hospitalization” Hospital floor ICU Post discharge

No prophylaxis

How I treatFDA approved DOAC in highly selected patients

No prophylaxis

No prophylaxisProphylactic dose Prophylactic dose

Prophylactic doseTherapeutic dose

Case 62 yo physician working on COVID-19 ward very early in the

pandemic Cough, congestion, fever, body aches (‘hurts’) Normal oxygen saturation Would you prescribe anticoagulation prophylaxis?

A. YesB. No

ACTIV 4b Trial Press Release June 22, 2021

Trial stopped early because of low event rates Question: will antithrombotic therapy prevent thromboembolic complications in early

mild COVID-19? Design: RCT double blinded Patients: “pre” hospitalization Interventions:

– Apixaban 5 mg bid– Apixaban 2.5 mg bid– ASA 81 mg qd

Comparison: placebo Outcome: composite of all-cause mortality, symptomatic venous thromboembolism,

myocardial infarction, stroke, transient ischemic attack, systemic embolism, major adverse limb events, and hospitalization for cardiovascular or pulmonary cause

Timeframe: 45 days

BWH Press Release - Brigham and Women's Hospital

Case Patient worsens over a week and O2 saturation drops and is

admitted to hospital requiring 3 L oxygen Classic chest x-ray and inflammatory markers Normal kidney and liver function D-dimer elevated What dose of anticoagulation prophylaxis would you use?

A. Prophylactic doseB. Intermediate doseC. Therapeutic dose

Moderately Ill COVID-19mpRCTs – ATTACC, ACTIV-4a and REMAP-CAP

Question: Is therapeutic anticoagulation better than usual care in non-critically ill hospitalized COVID -19?

Design: RCT, open label, 3 multi-platform RCTs Patients: 2219 in 129 global sites hospitalized without need for ICU-level

care of – high flow oxygen, mechanical ventilation (invasive and non-invasive), vasopressors

or inotropes within 72 hours-ish of admission – from April 21, 2020, to January 22, 2021, with high, low or unknown D-dimer

Intervention: Therapeutic anticoagulation with LMWH (94.7%) or heparin Comparison: Usual care with 71.7% low-dose and 26.5% intermediate dose

anticoagulation Outcome: organ-support-free days

– alive at 21 days (or discharged) without organ support Timeframe: 21 days for organ support and 90 days for death

ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators, Lawler PR. N Engl J Med. 2021 Aug 4. PMID: 34351721.

ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators, Lawler PR. N Engl J Med. 2021 Aug 4. PMID: 34351721.

Moderately Ill COVID-19mpRCTs – ATTACC, ACTIV-4a and REMAP-CAP

ACTION Trial Question: Is therapeutic anticoagulation primarily with rivaroxaban

better than prophylactic dose in hospitalized COVID-19 Design: RCT, open label Patients: 615 hospitalized with COVID-19 with elevated D-dimer at 31

Brazilian sites from June 24, 2020, to February 26, 2021– Approximately 90% moderately ill

Intervention: Rivaroxaban 20 mg (15 mg if CrCL 30-49) for 30 days– initial therapeutic does enoxaparin or heparin if unstable

Comparison: Prophylactic dose enoxaparin or heparin while in hospital and provider discretion for extended prophylaxis

Outcome: Hierarchical composite of time to death, duration of hospitalization or duration of oxygen

Timeframe: 30 Days

ACTION Investigators; Lopes R.D., et al. Lancet. 2021 Jun 4:S0140-6736(21)01203-4. PMID: 34097856.

ACTION Trial

ACTION Investigators; Lopes R.D., et al. Lancet. 2021 Jun 4:S0140-6736(21)01203-4.PMID: 34097856.

Composite outcome: VTE, MI, stroke, Systemic embolism, major adverse limb event

Metanalysis of RAPID and mpRCT

COVID-19 Trials Design: RCT, unblinded Patients: 465 with

moderate disease Intervention: Therapeutic

dose LMWH or heparin Comparison: prophylactic

dose LMWH or heparin Outcome: composite of

death, mechanical ventilation (invasive and non-invasive) or ICU admission

Sholzberg M. medRxiv [Preprint]. 2021 Jul 12:2021.07.08.21259351. PMID: 34268513.

RAPID Trial Preprint


Immune mediated inflammatory micro thrombosis ‘Pre’ hospitalization anticoagulation prophylaxis Hospitalized moderately ill anticoagulation prophylaxis Hospitalized severely/critically ill anticoagulation

prophylaxis Post discharge anticoagulation prophylaxis

Case Patient worsens and transferred to ICU for high flow oxygen

and progresses to septic shock and intubation What dose of anticoagulation prophylaxis would you use?

A. Prophylactic doseB. Intermediate doseC. Therapeutic dose

Critically Ill COVID-19INSPIRATION Trial

Design: RCT, open label Patients: 562 SARS-CoV-2 positive patients admitted to ICU Intervention: intermediate dose LMWH (enoxaparin 1 mg/kg daily) or

unfractionated heparin in renal failure patients for 30 days– adjusted for body weight and creatinine clearance

Comparison: enoxaparin 40 mg daily or heparin in renal failure for 30 days– adjusted for body weight and creatinine clearance

Outcome: composite VTE, arterial thrombosis, ECMO and all cause mortality

Timeframe: 30 days

INSPIRATION Investigators, Sadeghipour P. JAMA. 2021 Apr 27;325(16):1620-1630. PMID: 33734299.

INSPIRATION Investigators, Sadeghipour P. JAMA. 2021 Apr 27;325(16):1620-1630. PMID: 33734299.

Critically Ill COVID-19INSPIRATION Trial

Question: will therapeutic LMWH/heparin decrease the need for organ support in critically ill COVID-19

Design: RCT, open label Patients: 1098 critically ill patients from 9 countries from April 2020 to

December 2020 Intervention: therapeutic dose LMWH/heparin (89% LMWH) Comparison: usual care, 40% low, remainder intermediate or higher

dose Outcome: Survival to 21 days and organ support free days

– High flow oxygen, mechanical ventilation (with or without intubation) vasopressor/inotrope support

Critically Ill COVID-19mpRCTs – ATTACC, ACTIV-4a and REMAP-CAP

REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators, Goligher EC, N Engl J Med. 2021 Aug 26;385(9):777-789. PMID: 34351722

Critically Ill COVID-19mpRCTs – ATTACC, ACTIV-4a and REMAP-CAP

REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators, Goligher EC, N Engl J Med. 2021 Aug 26;385(9):777-789. PMID: 34351722

Case He recovers and is ready for discharge on day 21 Liver and kidney function remain normal Would you prescribe post discharge prophylaxis?

A. YesB. No

AC Forum Rapid ResourceVTE prophylaxis in Medically Ill

1702-2021-03-03-142440.pdf (acforum-excellence.org)

MICHELLE TrialAbstract

Question: does prophylactic dose rivaroxaban prevent major adverse vascular events after discharge for COVID-19?

Design: RCT, open label Patients: hospitalized for at least 3 days and receiving standard dose thromboprophylaxis

– Elevated IMPROVE DD score at discharge Intervention: rivaroxaban 10 mg qd (prophylactic dose) Comparison: no anticoagulants Outcome: Composite of

– symptomatic VTE, – VTE-related death, and – VTE detected at bilateral lower limbs venous duplex scan and computed tomography pulmonary

angiogram and – symptomatic arterial thromboembolism, – myocardial infarction (MI), – non-hemorrhagic stroke, – major adverse limb event (MALE), and – cardiovascular (CV) death

Timeframe: 35 daysDr. Renato Lopes and Dr. C. Michael Gibson Discuss: The MICHELLE trial: Medically Ill hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis with rivaroxaban ThErapy – Clinical Trial Results

MICHELLE Trial

Dr. Renato Lopes and Dr. C. Michael Gibson Discuss: The MICHELLE trial: Medically Ill hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis with rivaroxaban ThErapy – Clinical Trial Results

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