Newer oral anticoagulants

1. ROLE OF NOACs IN COVID-19 TREATMENT
B Y
D R . J AY K I S H A N S I N G H
N A R W A R I YA
R M O M E D I C I N E
M O D E R A T O R
D R .V. P. PA N D E Y
P R O F E S S O R A N D H E A D
D E P A R T M E N T O F M E D I C I N E
M G M M C & M Y H H O S P I T A L I N D O R E

2. • TOTAL CASES in world : 86,196,009
• CASES in India : 10,373,287
• Total deaths in World
1,867,481 (2.16%)
• Total deaths in India
150,106 (1.45%)
CURRENT STATUS

3. • Clinical spectrum range from asymptomatic to profound, rapid multiple
organ dysfunction syndrome and death.
• MULTISYSTEM DISORDER NOT JUST RESPIRATORY DISEASE
A. Acute respiratory failure
B. ARDS
C. Sepsis
D. Venous and arterial thromboembolism
• DIC is a strong predictor of mortality, with 71.4% of non-survivors
meeting criteria for disseminated intravascular coagulation.
COVID-19
E. DIC
F. Acute kidney injury
G. Acute liver failure

4. COVID-19 Hypercoagulability
• Is it the first virus which is associated with hypercoagulable states???
NO
• Viral infections are associated with increased risk of thrombosis.
• Coagulopathy was first reported in viral infection during
1918 influenza pandemic
• In 2004 SARS related macrovascular complication of stroke were
reported during Singapore SARS-CoV outbreak.
• AIDS, Dengue and Ebola virus disease- Thrombosis reported

5. Incidence Overall
ICU
patients
Non ICU
patients
Post-mortem
studies
Venous thromboembolism 21% 31% 5% 22%
DVT 20% 28% 8%
Pulmonary embolism 13% 19% 7%
Arterial
thromboembolism
2% 5% 1%
CVA 1%
Myocardial infarction 0.5%
Acute limb Ischemia 0.4%
Incidence of thromboembolic complication in COVID-19

6. COVID-19 and Hypercoagulability
• Among critically ill patients, incidence of was pulmonary thrombosis 30% in
COVID-19 patients as compared to 1.3% of non-Covid-19 patients.
• Other studies from France and the Netherlands have also suggested that
thrombosis occurs in 20-30% of critically ill covid-19 patients, even with
prophylaxis.
• An analysis of contrast-enhanced CT findings in a case series of ICU patients
showed the presence of pulmonary artery thrombosis in 20.6% of 107 patients
admitted to ICU with COVID-19, compared with 7.5% of 40 influenza patients
admitted during the previous year.

7. Pathogenesis of COVID-19 associated thrombosis
Two mechanisms
• 1ST : HIGH CYTOKINE PRODUCTION
- Increased fibrinogen production and subsequent thrombosis.
- Sepsis and cytokine mediated increased thrombosis (Decreased antithrombin, protein C, TFPI & Increased TF)
- eg. Fibrinogen in critically ill COVID patient – 10-14 g/L (Normal- 2-4g/L)
• 2ND : ENDOTHELIAL INJURY-
-High conc. of ACE2 receptors in respiratory mucosa, vascular endothelium, organs like kidney, heart,
intestinal tract.
-Direct vascular endothelial injury starts a chain of thrombosis.
-This explains why thrombosis can also be seen in patients without significant pneumonia.

8. Test for detecting thrombosis
• D-dimer: It is a fibrin degradation product and named as it contains 2 D- fragments of fibrin protein linked by a cross link.
Normal value:
Individuals with D-dimer >2000 ng/ml had highest risk of critical illness (66%), thrombotic events (58.3%),
death(47%).
D-dimer value alone should not be used to guide the clinical decision making in COVID-19.
• High clinical suspicion : If d dimer raises >5 times ULN within 48 hours.
If acute worsening of oxygenation.
• PT/aPTT: These are mildly deranged in COVID-19 induced thrombosis.
• DVT screening by doppler, CT pulmonary angiography
<0.5 mg/L
<0.5 microgram/ml
<500 ng/ml

9. Management of thrombosis associated with COVID-19
• Who should receive anticoagulants
1. Routine anticoagulant prophylaxis is NOT RECOMMENDED for COVID-19
patients who are not hospitalized.
2. ALL COVID-19 PATIENTS who require hospitalization should receive
anticoagulation prophylaxis unless contraindicated.
(The dose and type of anticoagulant has to be individualized on the basis of
clinical condition of the patient.)
(Reference latest 2020: Anticoagulation Forum,the American College of Chest Physicians, the American
Society of Hematology,the International Society of Thrombosis and Haemostasis (ISTH),the Italian Society
on Thrombosis and Haemostasis, the Royal College of Physicians, NIH maryland )

10. Contraindications to anticoagulation
1. Active bleeding within 3 months
2. Intracranial bleed within 1 year
3. Known potential bleed site (eg. Peptic ulcer, bronchiectasis)
4. Thrombocytopenia ( Platelet count < 50000/cumm)
5. Significant liver disease (INR >1.4)
6. Lumbar puncture/epidural/spinal anaesthesia within previous 4 hours or expected within next 12
hours
7. Uncontrolled systemic hypertension ( BP >230/120mmHg)

11. COVID-19 treatment
guidelines
by
BOSTON UNIVERSITY
SCHOOL OF MEDICINE
A
B
C

12. What is the status of NOAC in In-hospital management of
COVID-19
• NOACs have significant drug interaction with some antiviral medications.

13. What is the status of NOAC in In-hospital management of
COVID-19
• NOACs have significant drug interaction with some antiviral medications whereas LMWH/ UFH have
no interaction with antiviral drugs.
1. All patients who are admitted to ICU or are critically ill should receive LMWH (Preferred) / UFH.
(NOACs not given)
2. Patients who are not managed in ICU can be given either LMWH (Preferred)/ UFH/ NOAC.
3. Patients who develop DVT/ PE in hospital and it is hemodynamically stable, can be started on
NOAC/LMWH/UFH .
4. If PE is hemodynamically unstable (E.g. BP <90 systolic). LMWH/ UFH/ thrombolysis with tPA
should be used. (NOAC are not to be given in case of hemodynamic unstable PE)
5. Patient on chronic NOAC/ Warfarin for chronic indication contracts COVID-19
If managed in non-ICU - should continue NOAC/Warfarin.
ICU admission or if antiviral medication needed - Switch to LMWH (Preferred)/ UFH

14. POST-DISCHARGE EXTENDED ANTICOAGULATION
IN COVID-19
1. Post discharge anticoagulant prophylaxis is not indicated for all patients
2. It is given to selective patients with high risk of VTE.
a) D-dimer >2 times ULN at time of discharge
b) Stay in ICU/ CCU
c) Age >60 Years
d) Immobilized for at least 7 days
e) Prior venous thromboembolism
f) Diagnosed thrombophilia
g) Current lower limb paralysis
h) Current cancer
AGENT for Post discharge extended anticoagulation
1. Tab Rivaroxaban 10mg daily
2. Tab Apixaban 2.5mg BD
3. Tab Betrixaban 160mg on day 1 f/b 80mg OD
4. S/C Enoxaparin 40mg OD
DURATION for post discharge extended anticoagulation
Minimum 4 weeks

15. The study of thromboembolic and bleeding events 30 days post discharge COVID-
19 patients was conducted & published in American society of haematology in
September 2020.
• Dr. Lara Roberts, MD, Kings college hospital NHS foundation trust London
• Dr. Jeffrey Zwicker, MD, Beth Israel deaconess center in Boston
Risk of VTE following COVID-19 is not significantly higher than patients
without COVID-19.
• Thus recommending post discharge anticoagulant prophylaxis to be
individualized.
DILEMMA

16. 3. Patients on chronic anticoagulant and antiplatelet therapy: Should continue
taking their medication. Switching to NOACs from parenteral and VKAs should be
individualized.
4. Pregnant and lactating COVID-19 patients: The anticoagulant prophylaxis
indication are same as non-pregnant patient but the choice of anticoagulant should
be taken into account. Heparin, enoxaparin and warfarin are not secreted in breast
milk so these are recommended. NOACs are not recommended due to lack of safety
data.

17. Why is NOACs important in COVID-19 ERA
• COVID-19 pandemic and health crisis
 Requires containment for hundreds and millions of people.
 Restrictions on mobility
 Reduces access to medical care, both general practitioners and hospitals
 Reduces access to pharmacies, laboratories and nursing care.
 Many hospitals are saturated and devote most of their resources to the
management of COVID-19 patients.
• Traditional anticoagulants have 2 major limitation
1. Narrow therapeutic window of adequate anticoagulation without bleeding
2. Highly variable dose response, requiring lab monitoring

18. Advantages of NOACs over warfarin
ADVANTAGE REAL WORLD IMPLICATION
Low risk of bleeding Less need for emergency access and blood
products
Rapid onset of action No need for bridging with IV heparin
Predictable anticoagulant effect No need for routine monitoring of INR
Specific coagulation enzyme is targeted Low risk of off-target adverse effects
Low food interaction Can eat greens and salads
Lower risk of drug interaction Few restriction in using other drugs
Lower adverse effects Skin necrosis in protein C and S deficiency
Risk of osteoporosis
THE ANTITHROMBOTIC EFFICACY OF NOACS IS SUPERIOR TO ANTICOAGULATION WITH VITAMIN K
ANTAGONISTS (VKAS)

19. THE COVID-19 CRISIS IS AN OPPORTUNITY FOR
 For patients in whom oral anticoagulation must be started, it seems legitimate to
favor the use of NOACs.
 For patients on long-term VKA, the current crisis is probably an opportunity to
switch them to a NOAC.
 For patients who should imperatively be or remain on VKAs
1. Valvular atrial fibrillation
2. Mechanical cardiac valve
3. Antiphospholipid syndrome
4. Renal impairment depending on its severity
the use of point-of-care (POC) devices for measuring INR should be promoted.

20. Factors to consider before starting NOAC
1. Renal function
2. Concurrent medication intake especially CYP3A4 and P-gp
inhibitors
3. Food intake
4. Clinical condition of patient such as heart failure
5. Whether patient will be compliant.

21. Characteristic WARFARIN
DABIGATRAN
(Pradaxatm) 2015
RIVAROXABAN
(Xareltotm) 2011
APIXABAN
(Eliquistm) 2014
EDOXABAN
2014
Target
Vitamin K epoxide
reductase (VKOR)
Direct thrombin
(Factor IIa) inhibitor
Factor Xa Factor Xa Factor Xa
Onset of action
Slow onset
May take upto 5 or
more days
Rapid
2 hours
Rapid
2.5 to 4 hours
Administered with full
meal
Rapid
3 hours
Rapid
1 to 2 hours
Half-life (Hours) 20-60 12-14 7-13 8-13 9-11
Time to wear of
drug`s effect once
stopped
Usually 4 days 14-17 hours 9-13 hours 8-15 hours 10-14 hours
Elimination
Liver
Not excreted in
kidney
Kidney (80%) Kidney (33%) + Liver Kidney (27%) + Liver Kidney (35%) + Liver
Drug Interactions
CYP2C9
Agents which increase
bleeding risks
Rifampin, Quinidine,
Amiodarone, P-gp
inhibitors
CYP3A4 inhibitors
P-gp inhibitors
CYP3A4 inhibitors
CYP3A4 inhibitors
P-gp inhibitors

22. Yi-Hsin Chan et al, Efficacy and safety of apixaban, dabigatran, rivaroxaban and warfarin in Asians with nonvalvular Atrial fibrillation, Journal of American heart
association 7(8):e008150 (Year 2018)
AMERICAN
HEART
ASSOCIATION

23. Disadvantages of NOACs
• Very short half-lives, which will be hazardous if patient is not
compliant
• Lack of effect assay (We do not know if patient is compliant or not)
• Renal function needs to be monitored
• No reversal agent at present except (Idarucizumab is antidote for
Dabigatran Cost:3500$/5g).

24. References:
• Covid19 treatment guidelines, 17 Dec 2020, NIH Maryland
• Considerations on the Use of Anticoagulants in COVID-19 Patients, 10 June 2020, European
society of cardiology
• Anticoagulant Therapy for Patients with Coronavirus Disease 2019: Urgent Need for Enhanced
Awareness, 21 June 2020, JAPAN, European cardiology review
• icmanaesthesiacovid-19.org/ 24 Dec 2020
• Prevention, Diagnosis, and Treatment of VTE in Patients With Coronavirus Disease 2019, CHEST
Guideline and Expert Panel Report
• Anticoagulation guidelines for COVID 19 patients Riverside Health System

25. THANKYOU