Anticoagulation expanding steadily over the past few decades. In addition to Heparins and vitamin K antagonist, other anticoagulants that directly target the enzymatic activity of thrombin and factor Xa have been developed.

1. UTILITY OF NOACs IN NEUROLOGY
DR.PRAMOD MEENA
SR NEUROLOGY
GMC,KOTA

2. INTRODUCTION
• Anticoagulation expanding steadily over the past few decades.
• In addition to Heparins and vitamin K antagonist, other
anticoagulants that directly target the enzymatic activity of
thrombin and factor Xa have been developed.
• Appropriate use of these agents requires knowledge of their
individual characteristics, risks, and benefits.

5. Vitamin K Antagonists (warfarin &
coumarins)
 Vit.k antagonists acts by inhibiting vit.k epoxide reductase
thereby blocking gamma carboxylation of factor ii,vii,ix,x and
protein C & S.
 Vitamin K antagonists (VKAs) are the mainstay of
management of thromboembolic events for >5 decades.
 Despite its unquestionable impact to prevent strokes, they
have significant limitations, such as common drug or food
interactions, and the necessity of regular monitoring to adjust
doses and interpersonal variation in response.

6. Limitation of warfarin therapy

7. ADVANTAGES OF NOAC OVER
WARFARIN

8. AVAILABLE
NOACs
 Dabigatran etexilate 110 mg/150 mg
 Rivoroxaban 2.5 /10 /15/20 mg
 Apixaban 2.5/5mg
 Edoxaban 30/60 mg
 Betrixaban 80/160 mg

9. DABIGATRAN ETEXILATE
 Dabigatran etexilate, a prodrug of dabigatran, which
reversibly inhibits both free and clot bound thrombin,
 It has an oral bio-availability of only 6-7% and the remainder
unabsorbed drug passes through the gut (Dyspepsia occurs in
up to 10% of patients treated with Dabigatran). It should be
taken with food to minimise dyspepsia (this problem improves
with continued medication ).

10.  Dabigatran etexilate (prodrug) is rapidly and completely
converted to dabigatran by esterases.
 Plasma levels of dabigatran peak in 2hours.
 Half-life of 12 to 17hours .
 80% of the drug is excreted unchanged by the kidneys.

11. DRUG INTERACTION

13. DOSE REGIMEN
 NVAF-stroke prophylaxis 150 mg BD (75 mg BD CrCL 15–30
mL/min)
 Acute VTE treatment: 150mg BD after a minimum of a 5-day course of
heparin or LMWH;
COMMON SIDE EFFECTS–
 Bleeding risk
 Dyspepsia
 Allergic reaction

14. RE-LY trial (Dabigatran vs warfarin
prophylaxis in NVAF Patients)
 150mg BD dose –superior to warfarin for reduction of stroke
and systemic embolism with similar majorbleeding.
 110mg BD dose –non inferior to warfarin but with significant
lower bleeding rates.
 ICH is significantly low with both doses .

16. RIVAROXABAN
 Dose dependent bioavailability of 60-100% .
 Bioavailability of 2.5/10 mg tab is 80-100% (unaffected by food)
 whereas bioavailability of 15 /20 mg tab is 66% if taken fasting
which is increased up to 100% if taken with food.

17.  Rapid onset and t1/2 of 7- 11hours.
 Dual mode of elimination –
 1/3rd is cleared as unchanged drug via the kidneys
 1/3rd is metabolized by the liver via CYP3A 4 then
excreted in the faeces, and
 1/3rd is converted inactive metabolites in liver then
eliminated via thekidneys.

18. DRUG INTERACTION

19. Start-up for RIVAROXABAN

21. DOSE REGIMEN
 NVAF-stroke prevention: 20 mg OD (15 mg OD in patients
with a creatinine clearance of 15–49 mL/min ).
 Acute VTE treatment: 15 mg BD for initial 21 days then 20 mg
OD With evening meal
 VTE prevention after knee or hip replacement surgery (14 or
35 days, respectively): 10 mg daily

22. ROCKET AF study (Rivaroxaban vs
warfarin in NVAF Patients)
 Rivaroxaban was noninferior to warfarin for the prevention
of stroke or systemic embolism.
 Less fatal bleeding with rivaroxaban .
 Gastrointestinal bleeding and transfusion requirements
were greater with rivaroxaban.

24. APIXABAN
 Apixaban is a direct, reversible, competitive, and selective
inhibitor of factor Xa .
 It is well absorbed achieving peak plasma concentration in 1–4
h.
 It is a mild P- glycoprotein inhibitor.
 Compared to other NOACS it has least bleeding complications
and greater efficacy.

25.  It is predominantly metabolized in liver.

26. Start-up for APIXABAN

28. DRUG INTERACTION
 Only a minor interaction between apixaban and verapamil unlike dabigatran and
edoxaban.
 There is no need dose reduction of rivaroxaban if Co-administer with FLUVASTATIN or
ROSUVASTATIN.

29. DOSE REGIMEN
 Stroke prevention in NVAF : 5 mg BD with a dose reduction to
2.5 mg BD for patients with age of 80 years or more, body
weight of ≤60 kg , and serum creatinine >1.5 g/dl (2/3).
 Treatment of VTE : 10 mg BD for 7 days, then 5 mg BD for the
following 6 months after which the dose can be further
reduced to 2.5 mg twice daily .
 Thromboprophylaxis after elective hip or knee replacement
surgery:2.5 mg BD.

30. ARISTOTLE TRIAL (APIXABAN VS
WARFARIN IN NVAF)
 Apixaban was significantly better than warfarin.
 No significant differences in rates of ischaemic strokes.
 Patients treated with apixaban had significantly fewer
intracranial bleeds, but GI bleedings were similar between
both groups.

32. EDOXABAN
 EDOXABAN is another reversible factor Xa inhibitor, recently approved by
the FDA .
 It is rapidly absorbed and reaches peak plasma concentration within 1–2h.
 It is also a substrate for P-gp-concomitant administration with quinidine,
amiodarone, and verapamil will result in a significant increase of plasma
levels .
 Therefore, in patients under concomitant use of potent glycoprotein
inhibitors , body weight <60kg, or moderate– severe renal impairment
(CrCl < 50mL/min), edoxaban dose should be reduced by 50%.

33.  Up to 50%of edoxaban is eliminated by the kidneys and rest through multiple
pathways in liver.

34. DOSES IN RENAL IMPAIRMENT
Blood levels of edoxaban were reduced and a higher rate of ischemic stroke was
observed in patients with AF and CrCl >95 mL/minute who were treated with
edoxaban compared with those receiving warfarin

35. Start-up for Edoxaban

37. BETRIXIBAN (BEVYXXA)
 Oral direct inhibitor of factor Xa for the prophylaxis of venous
thromboembolism (VTE) in adult patients.
 Bioavailability is 34%.Max concentration 3-4 hours after
administering.
 Half-life 19-27 hours (maximum)
 85% eliminated by hepatobiliary route .<7% is renal (minimal renal
clearance in NOAC)

38. NOAC COMPARISON

40. Indications
for NOACs
 Prevention of arterial thromboembolic events in non- valvular
atrial fibrillation and
 Venous Thrombo-Embolism (VTE) prophylaxis following major
surgeries
 VTE (DVT & PE) treatment
 For prevention of athero-thrombotic events in patient with CAD
and PAD (Peripheral arterial disease) along with aspirin and/or
clopidogrel )
 Heparin induced thrombocytopenia (HIT)

44. Dosing of NOACs

45. NOACs
IN PREGNANCY
 As small molecules, the NOACs can all pass through the
placenta.
 Consequently, these agents are contraindicated in
pregnancy, and when used by women of childbearing age,
appropriate contraception is important.
 The NOACs should be avoided in nursing mothers and their
safety in children has yet to be established

46. NOACs
MONITORING
Although designed to be administered without routine monitoring,
but there are situations where monitoring is needed.
 These include detection of overdose, identification of bleeding
mechanisms, and determination of activity prior to surgery or
intervention.
 For qualitative assessment of anticoagulant activity, the prothrombin
time can be used for factor Xa inhibitors and the aPTT for dabigatran.
 For quantitative assessment of dabigatran a diluted thrombin clotting
time and for factor Xa inhibitors Chromogenic anti-factor Xa assay is
used.

47. Contraindications
for NOACs
 Mechanical heart valve
 Valvular atrial fibrillation
 Severe renal impairment with creatinine clearance (CrCl) < 30
mL/min;
 Severe liver dysfunction
 Pregnant women
 APLA syndrome
 Need to take a potent P-gp or CYP3A4 inhibitors or inducer
 GI disease (H/O GI bleeding),GI bypass surgeries
 Heparin or warfarin preferred in above conditions.
 LMWH is preffered in VTE with active malignancy .

48. NOACs
SIDE EFFECTS
 Bleeding manifestation ( increased risk of gastrointestinal
bleeding due to unabsorbed active drug in the gut exacerbates
bleeding from lesions).
 Dyspepsia (due to unabsorbed drug in GIT ).
 Premature discontinuation NOACs, increases the risk of
thrombotic events.

49. Transition
of Patient from warfarin to NOACs
 If a patient on warfarin not maintaining required INR
or
 Patient has major bleeding or any indication requiring shifting
of the patient from warfarin to NOAC.

50. WARFARIN TO NOACs SWITCHING

51. Transition
of Patient from NOAC to warfarin
 If a patient has severe Renal and hepatic impairment or
 Affordability issue or any other indication requiring shift from
NOAC to Warfarin

52. NOACs TO WARFARIN SWITCHING

53. NOACs TO WARFARIN SWITCHING

54. What if a Patient on NOACs has a
bleeding complication
 Specific strategies to reverse anticoagulant effect arelimited.
 Time is the best advantage of NOACs, in view of their relatively short
elimination half-lives. Supportive measures recommended for all
patients
 If ingested within 2 hours, administer activated charcoal
 Reversal agent is recommended ONLY if bleeding is life-
threatening or into a critical organ
 Reversal agent not recommended for DOAC overdose without
bleeding

55. Cont..
 Haemodialysis can accelerate drug removal in those patients receiving
dabigatran.
 In contrast, dialysis is not effective for factor Xa
inhibitors due to their high plasma binding and lower renal
clearance.
 The administration of prothrombin complex concentrate (PCC) or
activated prothrombin complex (aPCC) concentrates can be
considered in life-threatening bleeding, despite the scarce evidence.

56. There are currently
3NOAC
specific reversal agents:
I. ANDEXANET ALFA
II. IDARUCIZUMAB, and
III. CIRAPARANTAG (PER977)

57. ANDEXANET ALFA
“Andexanet alfa” is a recombinant, modified human factor
Xa that is being developed as a direct factor Xa reversal agent.
It has been shown to rapidly attenuate the anti-FXa activity of
apixaban, rivaroxaban, edoxaban.

58. Apixaban reversal by andexanet alfa:
 Last dose < 5 mg AND within 8 hours: Low-dose andexanet alfa ( initial
400 mg intravenous bolus at target rate of 30 mg/min followed by
continuous infusion at 4 mg/min for up to 120 min).

 Last dose > 5 mg AND within 8 hours: High-dose andexanet alfa ( initial
800 mg intravenous bolus at target rate of 30 mg/min followed by
continuous infusion at 8 mg/min for up to 120 min).
 Last dose > 8 hours ago: low dose andexanet alfa
•
 If andexanet alfa is not available: administer four-factor PCC 2000 units

59. Rivaroxaban reversal by andexanet alfa :
 Last dose < 10 mg AND within 8 hours: Low-dose andexanet alfa
 Last dose > 15 mg AND within 8 hours: High-dose andexanet
alfa
 Last dose > 8 hours ago: low dose
 If andexanet alfa is not available: administer four-factor PCC
2000 units

60. Idarucizumab
 Idarucizumab” is a fully humanized antibody fragment (Fab)
that binds dabigatran with high affinity andspecificity.
 Idarucizamab 5 g IV bolus.
 If idarucizamab is not available: administer APCC 50 units/kg
intravenously

61. PER977(ciraparantag)
 PER977 (ciraparantag) is a water-soluble small molecule nonspecific
reversal agent & also known as universal antidote.
 In preclinical testing and during testing with edoxaban in healthy male
volunteers, it rapidly reversed the effect of multiple anticoagulants, mainly
via hydrogen bonding.

63. NOACs IN
NEUROLOGY

64. Cerebral venous thrombosis
Symptoms and signs:
Grouped into three major syndromes:
1. Isolated intracranial hypertension syndrome
(headache with or without vomiting,
papilledema, and visual problems).
2. Focal syndrome (focal deficits, seizures, or
both)
3. Encephalopathy (multifocal signs, mental
status changes, stupor, or coma

65. MANAGEMENT
• Initial anticoagulation
recommend anticoagulation with subcutaneous LMWH or intravenous
heparin for adults with symptomatic CVT who have no
contraindication.
• The presence of hemorrhagic venous infarction, intracerebral
hemorrhage, or isolated subarachnoid hemorrhage are not
contraindications for anticoagulant treatment in CVT.

66. Einhäupl et al 1991, intravenous heparin versus placebo
Heparin versus placebo Outcome at three months
Heparin group (n = 10)
Total recovery 8 patients
Residual motor deficit 2 patients
Placebo group (n = 10)
Total recovery 1 patient
Minor residual deficit 6 patients
Deaths 3 patients
Placebo-controlled randomized trials of
anticoagulants in acute cerebral venous thrombosis

67. Long-term anticoagulation
• The Aim
of continuing anticoagulation after the acute phase is to
prevent CVT recurrence, which affects 2 to 7% of patients, and to
prevent extracerebral venous thrombosis, which occurs in up to 5% of
patients with CVT, mainly from deep venous thrombosis of the limbs or
pelvis,& pulmonary embolism.

68. SELECTION
of Anticoagulant
• For most adults with CVT, we suggest anticoagulation with warfarin or
a direct oral anticoagulant after the acute phase.
• Direct oral anticoagulants may be preferable for most patients, based
upon the lower burden of blood monitoring and dose adjustments,
fewer drug interactions, and lack of dietary restrictions when
compared with warfarin.
• When warfarin is used, the dose should be adjusted to an
international normalized ratio (INR) target of 2.5 (acceptable range: 2
to 3).

69. Duration
of anticoagulation
• For patients with a provoked CVT associated with a transient risk
factor Anticoagulation is continued for 3-6 months.
• For patients with an unprovoked CVT Anticoagulation is
continued for 6 to 12 months.
• For patients
with recurrent CVT, VTE after CVT, or a first CVT with a severe
thrombophilia (i.e. homozygous prothrombin gene G20210A variant,
homozygous factor V Leiden genetic variant, deficiencies of protein C,
protein S, or antithrombin, combined thrombophilia defects, or
antiphospholipid syndrome) anticoagulation may be continued
indefinitely.

70. Transient risk factors
Infection
Central nervous system
Ear, sinus, mouth, face, and neck
Systemic infectious disease
Pregnancy and puerperium
Dehydration
Mechanical precipitants
Head injury
Lumbar puncture
Neurosurgical procedures
Jugular catheter occlusion
Drugs
Oral contraceptives
Hormone replacement therapy
Androgens
Asparaginase
Tamoxifen
Glucocorticoids
Systemic and local conditions increasing the risk of
cerebral venous thrombosis
Permanent risk factors
Inflammatory diseases
Systemic lupus erythematosus
Behçet disease
Granulomatosis with polyangiitis
Thromboangiitis obliterans
Inflammatory bowel disease
Sarcoidosis
Malignancy
Central nervous system
Solid tumour outside central nervous system
Hematologic
Hematologic condition
Prothrombotic states, genetic or acquired
Protein C deficiency
Protein S deficiency
Antithrombin deficiency
Factor V Leiden mutation
G20210A prothrombin gene mutation
Antiphospholipid syndrome
Myeloproliferative neoplasms
Nephrotic syndrome
Paroxysmal nocturnal hemoglobinuria
Hyperhomocysteinemia
Polycythemia, thrombocythemia
Severe anemia, including paroxysmal nocturnal hemoglobinuria
Central nervous system disorders
Dural fistulae
Other disorders
Congenital heart disease
Thyroid disease

71. • The CVT risk score was designed to estimate the functional prognosis at six
months after CVT onset; the score was derived using data from the original
ISCVT cohort of 624 patients and validated in two smaller cohorts [83]. The
score as follows:
1. Presence of malignancy – 2 points
2. Coma on admission – 2 points
3. Thrombosis involving the deep venous system – 2 points
4. Mental status disturbance on admission – 1 point
5. Male sex – 1 point
6. Intracranial hemorrhage on admission – 1 point
• A CVT risk score ≥3 was associated with a poor outcome.

75. Cardioembolic stroke
• Increased clinical severity -AF is associated with more severe
ischemic strokes and "longer" transient ischemic attacks (TIAs) than
emboli from carotid disease, presumably due to embolization of
larger thrombi with AF.
• Radiologic patterns – Cardioembolic stroke from AF may affect any
vascular territory or multiple vascular territories of the brain with one
or more wedge-shaped infarcts involving the cortex and the
underlying subcortical white matter, borderzone infarcts.

76. 2021 Guideline for the Secondary Prevention of Ischemic
Stroke

79. ROPE SCORE
RoPE score identifies patients with cryptogenic stroke who are likely to have a PFO that is
pathogenic rather than incidental.

80. APPROACH of pt. on
Anticoagulation p/w
with ICH….

82. CONCLUSION
 New oral anticoagulants have shown to have a favourable balance
between efficacy and safety compared with VKAs.
 Advantages Of NOACs include fewer interactions with medications
and no interaction with food, rapid onset, fast clearance, and no
need for laboratory monitoring.
 Individualized anticoagulant treatment should be based on
patients’ age, renal function, and concomitant treatments.
 Further research is underway to develop reliable and accessible
measures to monitor the anticoagulant effects of the new agents,
as well as antidotes with the ability to effectively reverse
anticoagulation effect.

83. REFRENCES
• Bradely′s Neurology in clinical practice, 8th edition
• Di Nisio M, Middeldorp S, Büller HR. Direct thrombin inhibitors. N
Engl J Med 2005; 353:1028.
• 2022 Guideline for the Management of Patients With Spontaneous
Intracerebral Hemorrhage: A Guideline From the American Heart
Association/American Stroke Association
• American Academy of Neurology; Report of the Guideline
Development Subcommittee of the American Academy of Neurology;
February 24, 2014,