Role of DOAC in the management of COVID-19

patients
Desak Nyoman Desy Lestari
 Why anticoagulations in covid 19?

J. Clin. Med. 2020, 9(6), 1651;

Complications of Coronavirus Disease 2019 (COVID-19)*

*Caused by Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2)

https://bestpractice.bmj.com/topics/en-gb/3000201/complications
Laboratory Findings in Patients With Covid-19 on Hospital Admission

• Higher D-dimer levels in patients admitted to the ICU China

• Increasing D-dimer levels associated with prognosis of patients

Wang D et al. JAMA 2020;323(11):1061-1069

Anticoagulant Treatment Is Associated With Decreased Mortality In
Severe Coronavirus 2019 Disease Patients With Coagulopathy

China
Mortality between heparin users and nonusers in stratified patients

Journal of Thrombosis and Haemostasis, Volume: 18, Issue: 5, Pages: 1094-1099, First
published: 27 March 2020, DOI: (10.1111/jth.14817)
Incidence Of Venous Thromboembolism In Hospitalized Patients
With COVID‐19 (ICU and Non-ICU)
Netherlands

• Single-center cohort study of 198

hospitalized patients with COVID-19

• Seventy-five patients (38%) were

admitted to the ICU

• Routine thrombosis prophylaxis

• The cumulative incidences of

symptomatic and screen detected VTE
at 7, 14 and 21 days were 16% (95%
CI, 10-22), 33% (95% CI, 23-43) and
42% (95% CI 30-54)

Middledrop S et al. J Thromb Haemost. 2020;18:1995–2002

 Incidence of Venous Thromboembolism in Hospitalized Coronavirus
Disease 2019 Patients: A Systematic Review and Meta-Analysis

Incidence of venous thromboembolism. No., number; 95% CI, 95% confidence

interval.

Zhang C, Shen L, Le KJ, et al. Incidence of Venous Thromboembolism in Hospitalized Coronavirus Disease 2019 Patients: A
Systematic Review and Meta-Analysis. Front Cardiovasc Med. 2020;7:151. Published 2020 Aug 6. doi:10.3389/fcvm.2020.00151
 Incidence of Venous Thromboembolism in Hospitalized Coronavirus
Disease 2019 Patients: A Systematic Review and Meta-Analysis

• This meta-analysis revealed that the estimated VTE incidence was

25% in hospitalized COVID-19 patients. Higher incidence of VTE
was observed in COVID-19 patients with a severe condition or with a
low rate of pharmacologic thromboprophylaxis.
• Assessment of VTE risk is strongly recommended in COVID-19
patients, and effective measures of thromboprophylaxis should be
taken in a timely manner for patients with high risk of VTE.

Zhang C, Shen L, Le KJ, et al. Incidence of Venous Thromboembolism in Hospitalized Coronavirus Disease 2019 Patients: A
Systematic Review and Meta-Analysis. Front Cardiovasc Med. 2020;7:151. Published 2020 Aug 6. doi:10.3389/fcvm.2020.00151
Recommendation For VTE Prophylaxis In Patients With COVID-19
From Guidance Statement
Acute Ill; Critically ill; Acute or critically ill Escalation from Extended prophylaxis
No Bleeding risk No Bleeding Risk with CrCl <30 ml/min prophylactic to post discharge (criteria,
therapeutic or agent)
intermediate dose

ASH-FAQ LMWH or fondaparinux Same as acutely ill and UFH (BID to TID) Unknown in critically ill. Consider base on incl.
favored over UFH to recommended Reasonable to consider in criteria if from previous
reduce contact unless participation in well patients who experience trials.
the risk of bleeding is designed clinical trial recurrent clotting of Consider DOAC or ASA
judged to exceed the risk and/or epidemiologic access device s.
of thrombosis studies when available Recommended
participant in well
designed clinical trials
and/or epidemiology
studies when available

ACC LMWH may be LMWH may be UFH (BID to TID) Insufficient data majority Consider up to 45 day if
advantageous over UFH advantageous over UFH recommend against elevated VTE risk without
to reduce exposure to reduce exposure escalation. high bleeding risk.
32% favored intermediate Panelist breakdown if
and 5% therapeutic considering 51% DOAC,
24% LMWH

ISTH-SSC Standard-dose UFH or Prophylactic dose UFH or VTE prophylaxis Patients with obesity as Consider for all
LMWH should be used LMWH. Intermediate dose recommendation should defined by actual body hospitalized patients that
after careful assessment LMWH can also be be modified based on weight or BMI should be meet high VTE risk
of bleed risk with LMWH considered in high risk deteriorating renal considered for a 50% criteria.
as the preferred agent. patients. Multi modal function increase in dose of Either LMWH or a DOAC
Intermediate dose LMWH thrombophylactic with thrombophylaxis. can be approx. 14 days at
may also considered mechanical methods Treatment dose heparin least, and up to 30 days.
should be considered should not be considered
for primary prevention
until result of RCTs are
available
 ISTH interim guidance on recognition and management of
coagulopathy in COVID-19

• D-dimer, PT and platelet count in all patients who present with COVID-19
infection

• A statically significant increase in D-dimer level, and PT, and decrease in

fibrinogen levels in non-survivors at days 10 and 14  monitoring PT, D-
dimer, platelet count, and fibrinogen can be helpful in determining
prognosis in COVID-19 patients requiring hospital admission.

Journal of Thrombosis and Haemostasis, Volume: 18, Issue: 5, Pages: 1023-1026, First
published: 25 March 2020, DOI: (10.1111/jth.14810)
 ISTH interim guidance on recognition and management of
coagulopathy in COVID‐19

Journal of Thrombosis and Haemostasis, Volume: 18, Issue: 5, Pages: 1023-1026, First
published: 25 March 2020, DOI: (10.1111/jth.14810)
Suggested algorithm for anticoagulation in patients with COVID-19

J Thromb Haemost. 2020;18:2138–2144.

Thromboprophylaxis in COVID-19: CHEST Guideline 2020

• In the absence of a contraindication, in acutely ill hospitalized patients with COVID-

19, we suggest anticoagulant thromboprophylaxis over no anticoagulant
thromboprophylaxis.
• In acutely ill hospitalized patients with COVID-19, we suggest anticoagulant
thromboprophylaxis with low-molecular-weight heparin (LMWH) or fondaparinux
over anticoagulant thromboprophylaxis with unfractionated heparin (UFH)
• In acutely ill hospitalized patients with COVID-19, we recommend current standard
dose anticoagulant thromboprophylaxis over intermediate (LMWH BID or increased
weight-based dosing) or full treatment dosing, per existing guidelines.
• Remarks: Although there has been some concern for increased risk of VTE in
hospitalized COVID-19 patients, there is insufficient data to justify increased intensity
anticoagulant thromboprophylaxis in the absence of randomized controlled trials.

CHEST 2020; 153(3): 143-1163

Thromboprophylaxis in COVID-19: CHEST Guideline 2020

• In critically ill patients with COVID-19, we suggest current standard dose

anticoagulant thromboprophylaxis over intermediate (LMWH BID or
increased weight-based dosing) or full treatment dosing, per existing
guidelines.
• Remarks: Although there is anecdotal and observational data that suggest an
increased VTE risk in critically ill patients with COVID-19, it is not clear if the
most severely ill COVID-19 patients occupy a different level of risk for VTE
than other severely ill nonsurgical, medical ICU patients.

CHEST 2020; 153(3): 143-1163

Oral anticoagulant in COVID-19: CHEST Guideline 2020

• In patients with COVID-19, we recommend inpatient thromboprophylaxis

only over inpatient plus extended thromboprophylaxis after hospital
discharge.
• Remarks: Extended thromboprophylaxis in patients with COVID-19 at low risk
of bleeding should be considered

• For acutely ill hospitalized COVID-19 patients with proximal DVT or pulmonary
embolism (PE), we suggest initial parenteral anticoagulation with therapeutic
weight adjusted LMWH or IV UFH. The use of LWMH will limit staff exposure and
avoid the potential for heparin pseudo-resistance. In patients without any drug-to-
drug interactions, we suggest initial oral anticoagulation with apixaban or
rivaroxaban. Dabigatran and edoxaban can be used after initial parenteral
anticoagulation. Vitamin K antagonist therapy can be used after overlap with initial
parenteral anticoagulation.
CHEST 2020; 153(3): 143-1163
Management Of Patients On Vitamin-K Antagonists During The COVID-19
Pandemic

• Eli Yes
Resume VKA. Extend
testing intervals per
Yes
Continue warfarin, monitor
INR
Yes
Continue warfarin with INR
monitoring at clinics during
local protocols (e.g. peak hours
Were the last 2
2-3 months)
INRs therapeutic in OR
previous 30-60
days? NO
Does the patient have a Switch to LMWH therapy if
NO no contraindications
Are these options contraindication to use
OR Consider following
feasible? DOACs? (e.g. valvular AF,
options for INR
Is the time in monitoring: mechanical valve, APLS,
therapeutic range • In home INR self pregnancy,
>70% in the last 2-3 testing comedications?) NO
months? • Drive through Discontinue warfarin and
INR testing start DOACs in feasible
• Scheduled office
or lab visit during
off peak hours

Bikdeli B et al. J Am Coll Cardiol. 2020 Jun 16;75(23): 2950-2973

 Factors influencing long-term treatment decisions

Assess the risk for recurrent VTE1 Choice of therapy and its limitation

DURATION of anticoagulant treatment

LMWH2
LONGER SHORTER • Administration via injection
Male Female • Monitoring recommended
in patients with severe renal insufficiency
Proximal Distal
Unprovoked Provoked
UFH2
• Administration via injection or infusion
Abnormal BMI Normal BMI
• Monitoring and dose adjustment required
Thrombophilia No thrombophilia • Risk of heparin-induced thrombocytopenia
Positive D-dimer Negative D-dimer Oral VKAs3
Family history No family history • Narrow therapeutic window
PE DVT • Unpredictable pharmacology
• Interaction with food and drugs
Patient and physician preference • Frequent monitoring
• Dose adjustment required

LMWH, low molecular weight heparin

UFH, unfractionated heparin
1. Agnelli et al. J Thromb Thrombolysis 2008;25:37-44 VKA, vitamin K antagonist
2. Hirsh & Raschke. Chest 2004;126;188S–203S;
DTI, direct thrombin inhibitor
3. Ansell et al. Chest 2008:133;160S-198S;
DOACs for VTE: Mechanism of Action of Anticoagulant Agents
and Antidotes for DOACs

ORAL VII TF PARENTERAL

Possible locations of VTE
TF/VIIa TFPi (Tifacogin) • Legs
VKAs X IX
• Arms
IXa
Rivaroxaban Andexanet
VIIIa
Va
sTM (ART-123)n) • Pelvic area
Apixaban AT
Edoxaban
Betrixaban Xa
Idrabiotaparinux
Fondaparinux
• Lungs

II
Idarucizumab
Both andexanet alfa and idarucizumab have been approved by
Dabigatran IIa LMWH US FDA as antidote for DOAC

Fibrinogen Fibrin
Becattini C, et al. J Am Coll Cardiol. 2016;67:1941–55
NOAC Overall efficacy: VTE Recurrence

All non-inferior in efficacy

(Apixaban)

(Rivaroxaban)

(Rivaroxaban)

(Edoxaban)

(Dabigatran)

(Dabigatran)

Van Es et al. Blood 2014

NOAC Overall safety: clinically relevant non-major bleeding
 Hokusai-VTE: Study Design1,2
Randomized, double-blind, event-driven study
N=8,292
Edoxaban 60 mg*
439 sites in 37 countries

Objectively confirmed VTE Sham INR

Stratified randomization:
• DVT / PE R
• Dose of edoxaban
• Risk factors
INR

Patients followed for

12-months or until study Warfarin (INR 2.0 – 3.0)
closure regardless of
treatment duration Day 1-5 Day 6-12†
Edoxaban 3 mo 12 mo
Placebo Edoxaban *Dose was halved to 30 mg in patients perceived to be at higher risk for bleeding by predefined criteria
Warfarin †During days 6-12 edoxaban or placebo edoxaban was started once heparin was stopped
Placebo Warfarin
Low-molecular-weight heparin / UFH

1. Raskob et al. J Thromb Haemost. 2013;11:1287–1294. 2. The Hokusai-VTE Investigators. N Engl J Med .2013;369(15):1406-15. 22
 Once-daily Edoxaban Was Proven Effective Across a Broad Range of VTE Patients,
Including Those With More Severe Disease

Outcome Edoxaban Warfarin HR (95% CI)

(N = 4118) (N = 4122)

Primary efficacy outcome: first recurrent VTE or VTE-related death

All patients 130/4118 (3.2) 146/4122 (3.5) 0.89 (0.70–1.13)

DVT + PE 83/2468 (3.4) 81/2453 (3.3) 1.02 (0.75–1.38)

~ 40% whom have extensive DVT ~

PE + DVT 47/1650 (2.8) 65/1669 (3.9) 0.73 (0.50–1.06)

~ 1/3 associated with right ventricular dysfunction ~

1. Büller HR et al. N Engl J Med. 2013;369(15):1406-1415.

Bleeding Outcomes

East Asian Non-East Asian

HR HR
Edoxaban  Warfarin  Edoxaban  Warfarin
(95% CI) (95% CI)
n = 563 n = 538 n = 3555 n = 3584
P value P value
Primary safety outcome: 0.56 0.88
clinically relevant 56 (9.9) 93 (17.3) (0.40–0.78) 293 (8.2) 330 (9.2) (0.75–1.03)
bleeding* <0.001 0.113

Major bleeding 9 (1.6) 14 (2.6) 47 (1.3) 52 (1.5)

Clinically
relevant
47 (8.3) 83 (15.4) 251 (7.1) 285 (8.0)
non-major
bleeding
Any bleeding 148 (26.3) 197 (36.6) 747 (21.0) 859 (24.0)

P values are for superiority

*Overall study period = time from randomization through 12 months or study closure.
†On-treatment period = time during which patients received study drug or within 3 days following discontinuation or interruption of study drug.
CI, confidence interval; DVT, deep vein thrombosis; HR, hazard ratio; PE, pulmonary embolism; VTE, venous thromboembolism.
Different OAC, different regimen

Edo 60 mg OD
Important remarks on the DOAC studies in VTE

• In all 4 studies, 75% patients received LMWH for at least 1 day

before randomization
• For anti-Xa DOACs, it takes at least 1 hour to reach effective anti-Xa
levels (peak activity takes 3 hours)
• During acute phase, immediate effective anticoagulation is crucial.
Different NOAC regimen may relate to different result

Risk of VTE recurrence

Brekelmans MPA, et al. TH Open 2018;2:e1–e7

% patient receiving
NOAC agents Duration for lead in therapy parenteral AC
during acute phase
Mandatory heparin/LMWH Edoxaban and Dabigatran > 5 days 100%
No mandatory Rivaroxaban and No heparin pretreatment or <48 hours 73% (Rivaroxaban) |
heparin/LMWH Apixaban before randomization 88% (Apixaban)
Advantage of Lead in Heparin for acute VTE

Immediate anticoagulation efficacy

Time for adequate laboratory workup: lab (GFR, LFT, pregnancy, etc)
Time for adequate imaging: CT and RV echocardiography (!)
Fibrinolysis or mechanical reperfusion remains an option
Reversal agent is simple and everywhere available
No DOAC dose change after cessation of heparin

Verheugt FWA. Acute CVD 2019.

Treatment of VTE: DOAC dosing recommendations based on renal
function

Renal Impairment Apixaban Rivaroxaban Dabigatran Edoxaban

(CrCl) (10 mg BID for 7 days then (15 mg BID for 21 days then (150 mg BID)3 (60 mg OD)4
5 mg BID)1 20 mg OD)2

Mild No dose adjusment2 No dose adjusment3 No dose adjusment4

(50-80 or 51-80 ml/min)1-4

Moderate When the recommended
(30-49 or 30-50 ml/min) 1-3 dose is 20 mg OD, consider
a dose reduction to 15 mg
No dose adjustment1 OD if bleeding risk
outweighs recurrent DVT
and PE risk
Severe
(15-29 or 15-30 ml/min) 1-3
150 mg BID or 100 mg BID Reduce dose to 30 mg OD
based on assessment of
thromboembolic risk and
risk of bleeding
Contraindicated Reduce dose to 30 mg OD

End stage renal disease Not recommended Not recommended Contraindicated Not recommended
(<15 ml/min)

1. Apixaban SmPC 2. Rivaroxaban SmPC 3. Dabigatran SmPC 4. Edoxaban SmPC

How Do We Choose Amongst NOACs?

Adapted from ACCP 2014,

ISTH 2018, and NCCN 2018 Characteristic Rationale Drug Choice
Rivaroxaban 15mg,
Less affected by renal
CrCl 30-50 ml/min Edoxaban 30 mg or
impairment
Apixaban 5/2.5
Acute VTE (DVT/PE)
Poor expected
Only agents given once Edoxaban or
compliance with twice
daily Rivaroxaban
daily dosing

Dyspepsia with
Dyspepsia or upper GI Apixaban, Rivaroxaban
Dabigatran in up to 10%
complaints or Edoxaban
of patients

Severe PE +DVT Need for initial heparin Edoxaban or Dabigatran

Body Weight ≤ 60 kg; Evidence for dose

Edoxaban
Polypharmacy; Asians reduction and full dose

Comparable to LMWH,
Cancer associated VTE Edoxaban
more adherence with oral
Potential Drug Interaction Between Anticoagulants And Investigational
Therapy For COVID-19

https://www.escardio.org/Education/COVID-19-and-Cardiology/ESC-COVID-19-Guidance
Summary

Patients with COVID-19 are at high risk of VTE

• The Prevalence of VTE is highest in critically ill patients (1 out of 4 ICU patients is diagnosed with VTE)

Pulmonary embolism is a relatively common complication during COVID-19 pandemic and it is associated with poor prognoses
and increased risk of mortality during hospitalization.

A broad use of pharmacological thromboprophylaxis is suggested various guidance statements, in the absence of risk of bleeding
• The role of an intensified thromboprophylaxis approach needs to be investigated in trials

Management of patients on Vitamin K antagonists (VKA) during the COVID-19 pandemic

• In appropriate cases, consider switching VKA to DOAC to diminish the need for frequent INR check

Management of non-COVID-19-affected patients with VTE during the pandemic

• Treatment as in non-pandemic times – DOAC preferred treatment option
• Consider dosing recommendations for VTE treatment and potential drug-drug interactions