This document discusses antiplatelet and anticoagulant treatments for stroke prevention in the context of valvular heart disease, non-valvular heart disease, and atrial fibrillation. It classifies antiplatelet drugs and describes the mechanisms and uses of aspirin, clopidogrel, ticlopidine, dipyridamole, abciximab, eptifibatide, tirofiban, vorapaxar and various oral anticoagulants including warfarin, acenocoumarol, dabigatran, rivaroxaban, apixaban and edoxaban. It also outlines guidelines for initiating and transitioning between different antico

1. New antiplatelet/anticoagulant &
stroke treatment with emphasis on
valvular and non valvular heart
disease
Dr Bhavin J Patel
DM Neurology Resident
MBS Hospital

2. Antiplatelet
 Platelet plays pivotal role in formation of cerebral thrombosis.
 Drugs which interfere with platelet function and are useful in prophylaxis of
thromboembolic disorders
 Antiplatelet medications prevent platelet adhesion and aggregation which
ultimately prevent thrombus formation of propagation.
 Mainstay of treatment as well as secondary prevention in ischemic stroke.

3. Role of platelet in thrombus formation

5. Classification of antiplatelet
 TXA2 synthesis inhibitor:- Aspirin
 Thienopyridine derivatives (ADP antagonist)
• Clopidogrel, ticlopidine, ticagrelor, prasugrel
 GP 2b/3a receptor antagonist
• Abciximab, eptifibatide, tirofiban
 Phosphodiesterase inhibitor:-
• Dipyridamole, cilostazole
 Newer antiplatelet

6. ASPIRIN
 MOA: Acetylates COX 1 and TX-synthase – irreversible
inactivation
 At low doses (75 – 150 mg/day) – selective suppression of TXA2 –
higher doses – both TXA2 and PGI2
 Prolongation of bleeding time for 5 – 7 days
 DOSE:- 50–325 mg/d of aspirin is recommended for stroke
prevention.

7. ASPIRIN
Side effects
• Dyspepsia. erosive gastritis or peptic ulcers
• Risk of major bleeding with aspirin is 1–3% per year.
• Allergy
• Hepatic and renal toxicity are observed with aspirin
overdose.

8. Benefits of Aspirin on Risk of Stroke
 In 158 trials, there were 3,522 nonfatal and 1,424 fatal strokes after
randomization.
 Antiplatelet therapy, principally with aspirin, reduced stroke by
about 25%, regardless of whether the patient entered the trial with
prior MI, stroke, TIA, or other high-risk conditions.
 Antiplatelet therapy, principally with aspirin, increases the absolute
risk of hemorrhagic stroke by 3 per 10,000 treated patients
AntiThrombotic Trialists Collaboration. Lancet, 2002

9. The review provided strong evidence for the benefits of aspirin 160
to 300 mg, given as soon as is practicable (and continued as a once
daily dose), in people with suspected acute ischaemic stroke.
In view of the potential interaction, people who have been treated
with thrombolytic therapy should not be started on aspirin for 24 to
48 hours

10. It did provide limited evidence on the effects of aspirin in people
in whom intracranial haemorrhage had not been ruled out by
brain scanning before treatment was started and who subsequently
were shown to have had an intracranial haemorrhage.
There was no evidence of net harm in such people.
It may be reasonable to give aspirin until the scan result is known

11. ASA Guideline 2018

12. ASA Guideline 2018

13. Clopidogrel
 MOA:- Gi coupled P2Y12 (P2YAC ) receptor mediates ADP induced
adenylyl cyclase inhibition – blocked – platelet activation interfered
 Kinetics:
 Onset: 4-6 hours (after loading dose with 8 x maintenance dose)
 Prodrug:-Must undergo 2 step metabolism
 Only a fraction is activated in liver by CYP2C19 – CYP2C19 –
genetic polymorphism

14. Clopidogrel
Variable response: 25-30% of patients achieve less than
25% inhibition of platelet activity
ADRs:
 Bleeding – double with aspirin
 Neutropenia, thrombocytopenia are rarer than Ticlodipine
 Interaction with PPIs.

15. Clopidogrel Versus Aspirin in Patients at
Risk of Ischemic Events (CAPRIE) trial
• Clopidogrel was compared with aspirin alone 19183
patients with stroke, MI, or peripheral vascular disease were
randomized to aspirin 325 mg/d or clopidogrel 75 mg/d.
• Clopidogrel had a lower event rate per year compared with
aspirin, 5.32% vs 5.83%, respectively, which resulted in an
overall risk reduction of 8.7% (P = 0.045) vs aspirin.
• There were no major differences in terms of safety.

18. ASA Guidelines 2018

19. CHARISMA
A randomized, double-blind placebo controlled trial of 15,603
patients (79% ) with established CVD and 21% with multiple
risk factors designed to test whether clopidogrel should be
continued beyond 1 year in addition to aspirin.
All patients received daily aspirin(75-162mg) and were
randomized to daily clopidogrel(75mg) or placebo
Clopidogrel patients had an event rate of 6.8% and placebo
patients had an event rate of 7.3%.
Bhatt DL, et al; N Engl J Med. 2006. 54: 1706-1717

20. CHARISMA
CHARISMA demonstrated no significant benefit long
term when clopidogrel is added to aspirin.
Rates of severe bleeding were similar but clopidogrel
patients experienced significantly higher rates of
moderate bleeding.
Bhatt DL, et al; N Engl J Med. 2006. 54: 1706-1717

21. Ticlodipine
 MOA:- same as clopidogrel
 Kinetics:
 Well absorbed orally – converts to active metabolite in body
 Single dose Half life 8 hrs - lasts for 5-6 days
 ADRs:
 Diarrhoea, vomiting, abdominal pain, headache, tinnitus, skin rash
 Bleeding, neutropenia, thrombocytopemia and jaundice

24. Dipyridamol
 MOA:
 Phosphodiesterase enzyme inhibitor – increases cAMP conc.
 Inhibits uptake of Adenosine in Platelets – increase c AMP
 Uses: Used to enhance the action of Warfarin and Aspirin in TE
events
 Side effects
• Gastrointestinal complaints, headache, facial flushing, dizziness, and
hypotension.

25. Aspirin + Dipyrimadole:
Second European Stroke Study (ESPS-2)
 Randomized, double-blind placebo controlled 2x2 factorial trial
 6602 patients with prior ischemic stroke or TIA
 ASA (25mg bid) and/or dipyrimadole (200mig bid sustained
release)
 Deaths from stroke were reduced
13% by ASA (p=0.016)
15% by dipyrimadole (p=0.039)
24% by the combination of ASA and dipyrimadole
(p<0.001)Diener, HC et al J Neurol Sci .1996 Nov; 143: (1-2)1-13

26. European/Australasian Stroke Prevention in
Reversible Ischaemia Trial (ESPRIT)
 Aspirin plus dipyridamole versus aspirin alone after cerebral
ischemia of arterial origin
 Primary Outcomes:-
• Primary outcome results showed no difference between the
groups. 12.7% vs. 15.7% (HR 0.80; 95% CI 0.66-0.98; NNT=33)

27. Ticagrelor
Cyclo-pentyl-trazo-pyramidine
More rapid onset of action than CPG
Reversible inhibitor of the P2Y12 receptor
In addition to bleeding, most common side effect is
dyspnea

31. ASA Guidelines 2018

32. GPIIb/IIIa receptor antagonists
Newer potent platelet aggregation inhibitor -
Abciximab, eptifibatide and tirofiban
 GPIIb/IIIa is an adhesive receptor aggregation –
antagonists block aggregation -

33. GPIIb/IIIa receptor antagonists
 Side effects:-
 Haemorrhage, Thrombocytopenia – should not be repeated 2nd time,
paralytic ileus, constipation, arrhythmia

34. Abciximab

35. Abciximab

36. Abciximab

37. Eptifibatide

38. Eptifibatide

39. Tirofiban

41. ASA Guidelines 2018

42. Vorapaxar
 Protease activated receptor 1 (Par 1) receptor antagonist

45. Anticoagulant
 Coagulation occurs through the action of discrete enzyme
complexes, which are composed of a vitamin K–dependent enzyme
and a nonenzyme cofactor.
 Anticoagulant medication act at various stage of coagulation
cascade and prevent thrombosis.

46. Anticoagulation mechanism

47. Classification

48. Parenteral anticoagulant

49. Advantages of Low-Molecular-Weight
Heparin and Fondaparinux over Heparin

50. Parenteral Direct thrombin inhibitor

51. Parenteral Direct thrombin inhibitor
Monitoring:-
 aPTT used for monitoring except desirudin
 Target aPTT is 1.5-3 times of baseline value.
 Lepirudin better monitored by ecarin cloting time.
Side effect:- bleeding..

52. Oral anticoagulant

53. Warfarin
Bioavailabily nearly complete; absorption dampered by
food
Can cross placental barrier
Half-life: 25 - 60 hr; Excreted in urine and stool
Toxicities: bleeding, fetal bone abnormalities, skin
necrosis

54. Problems with Warfarin
Food and drug interactions
Genetic variation in metabolism
• narrow therapeutic window
slow onset of action
dosage adjustments
&
freq. monitor with INR
overlap with parenteral drugs

55. Acenocoumarol(acitrom)
Same as warfarin with following differences:
 Shorter half life 10-16 hrs
 More rapid onset of action on PT
 Shorter duration of action (2 days)
 Causes GI disturbances, oral ulcerations and dermatitis

56.  THE OVERALL ANTICOAGULATION QUALITY IS SIGNIFICANTLY BETTER
WITH WARFARIN AS COMPARED TO ACENOCOUMAROL
Thrombosis And Haemostasis 1994; 71(2): 188-191

57. Commencement of oral anticoagulant
therapy
 If the baseline INR≤1.3 the patient will receive 5mg of warfarin
once daily on days 1 and 2. The INR is checked on day 3 and 4 and
the warfarin dose is adjusted according to the schedule.

58. Monitoring
INR daily until it is in therapeutic range
3 times weekly for 2 weeks
Once stable & warfarin dose is known
INR every 3-4 weeks or more frequently if
introduction of any new medications

59. Why we need alternatives to warfarin???
 Narrow therapeutic range
 Slow onset of action
 Slow offset of action (long duration of action, long elimination half
life)
 Multiple drug and dietary interactions
 Monitoring required to maintain in therapeutic range
 Difficult to manage for invasive procedures
 Under-use of therapy due to fear of adverse events and complexity
of management

60. Dabigatran
 A prodrug of dabigatran, which reversibly inhibits the active site of
thrombin
 Kinetics:-
 Plasma levels of dabigatran peak 2 hours after drug administration.
 Dabigatran has a half-life of 14 to 17 hours, which permits once- or
twice-daily administration
 80% of the drug is excreted unchanged by the kidneys
 Coadministration of dabigatran etexilate and amiodarone, a weak P-
gp inhibitor, increases dabigatran levels by 50% without
significantly affecting those of amiodarone

61. Dabigatran
 Adverse effects:-
 Bleeding – increases with age
 GI events
 Dyspepsia (12%)
 Abdominal pain
 Gastritis including GERD, esophagitis, erosive gastritis,
 Gastric hemorrhage and GI ulcers
 Hypersensitivity reaction (<0.1%)
 An unexplained increase in acute myocardial infarction in the
dabigatran group versus warfarin (~0.2% increased risk for a AMI
re-ly trial)

62. Dabigatran
 Monitoring anticoagulant effect of dabigatran
 Need not to assess regularly (ex. In the setting of emergency
surgery)
 In emergency most accessible tests are
1. TCT
2. aPTT
 If the TCT is normal, it is safe to assume that the level of dabigatran
is very low and that the patient’s risk of bleeding development is
similar to that of other patients undergoing the procedure

63. Dabigatran
 From warfarin to dabigatran
 Stop warfarin & start dabigatran once INR fall below 2
 From dabigatran to warfarin
 Adjust the starting time of warfarin based on creatinine clearance
 CrCL (ml/min) Days before stopping
dabigatran
> 50 3 days
50 - 30 2 days
30 - 15 1 day
< 15 or dialysis not recommended

64. Dabigatran
 From parenteral anticoagulants to dabigatran
 Intermittent parenteral anticoagulant:- Start dabigatran 0-2 hrs
before next dose
 Continuous parenteral anticoagulant (e.g. UFH) :- Start dabigatran
at the time of stopping parenteral anticoagulant
 From dabigatran to parenteral anticoagulants
 Wait for 12 hrs (CrCl> 30 ml/min) or 24 hrs (CrCl< 30 ml/min)
after last dose of dabigatran before starting parenteral anticoagulant

65. Oral fXa Inhibitors: Rivaroxaban,
apixaban and edoxaban

66. Oral fXa Inhibitors: Rivaroxaban,
apixaban and edoxaban
 Monitoring:-
 Xa inhibitors:- PT-INR
 Dabigatran :- aPTT
 Antifactor xa assay for apixaban
 Side Effects:-
 Intracranial bleed compare to warfarin is less
 GI bleeding
 Dyspepsia

67. Oral fXa Inhibitors: Rivaroxaban,
apixaban and edoxaban
Dose:-
 Rivaroxaban 20 mg once a day
 Apixaban 5 mg BD
 Dabigatran 150 mg BD

68. Anticoagulant in stroke

74. ASA Guidelines 2018

77. ASA Guidelines 2018

78. Cardioembolic stroke
Valvular heart disease Non valvular heart disease
Major risk Minor risk Major risk Minor risk
 Rheumatic MS
 Prosthetic valves
 Infective
endocarditis
 Marantic
endocarditis
 Calcified AS
 Bicuspid aortic
valve
 Mitral annular
calcification
 MVP
 Inflammatory
valvulitis
 Left ventricular
thrombi
 Prothrombotic
state
 IHD
 Ventricular
aneurysm
 Cardimyopathies
 Left atrial thrombi
 Atr. Fibrillation
 Flutter
 Atrial myxoma
 IHSS
 Trauma
 Sinus node
dysfunction
 Atrial septal
aneurysm
 Cardiac sarcoma
 Metastasis
 Paradoxical
emboli
 ASD
 VSD
 PFO

79. Preventive treatment for Cardioembolic
stroke

80. Atrial fibrillation
Reduction in ischemic stroke in AF patients with
warfarin outweigh risk of intracranial bleed.
FDA approved dabigatran (150 mg, 2010),
Rivaroxaban (nov 4, 2011) and Apixaban (28
dec,2012) for nonvalvular Atrial fibrillation.
.

81. Preventive treatment for Cardioembolic
stroke
Clinical condition Antithrombotic therapy
Rheumatic MS(AF)
Oral anticoagulation(2-3)
Sinus node dysfunction
Sustained flutter
Prosthetic Valves(mechanical) Oral anticoagulation(2.5-3.5)
Prosthetic valves (biosynthetic) Aspirin
Infective Endocarditis  Anticoagulation is contraindicated.
 In prosthetic valve endocarditis anticoagulation is
recommended.
Marantic endocarditis  Treatment is directed towards underlying disease.
 I.V heparin/ LMWH in acute stage
 No benefit with warfarin

82. Preventive treatment for Cardioembolic
stroke
Clinical condition Antithrombotic therapy
Acute MI
 Congestive HF
 LVEF<30%
 Large ventricular aneurysm
 Large ant. Wall MI
Oral Anticoagulation (INR 2-3)
PFO  Medical therapy
 Closure in case of failure
Atrial septal aneurysm with PFO Oral Anticoagulation
MVP Antiplatelet if fail then anticoagulation
Calcified AS. Bicuspid Aortic valve and
mitral annular stenosis
 Antiplatelet empiric approach
 Anticoagulation not recommended

83. Cardio embolic stroke:-Acute treatment
1) Thrombolysis:-
 I.V thrombolysis increase rate of neurological outcome
 Thrombolysis can be done in patients taking warfarin if INR<1.7.
 Expert opinion recommends avoiding thrombolytic therapy in patients with
NOAC except
 NOAC not taken in 48 hrs
 Normal renal function with coagulation parameter.
2) Mechanical thrombectomy:-
 Recent trial shows improved long term neurological outcome with newer
generation cathaters and stent retrievers. ( class 1, LOE A)

84. Cardio embolic stroke:-Acute treatment
3) Anti thrombotic therapy:-
 Antiplatelet in acute stage
 Early anticoagulation is associated with
 Non-significant reduction in recurrence of ischemic stroke
 No substantial reduction in death and disability
 Increased risk of bleeding.
 So, usually anticoagulation started after 1-2 wk of stroke.

85. References
New England journal of medicine
Bradely’s neurology in clinical Practice, 7th edition
Harrison’s principle of internal medicine, 19th edition
Braunwald’s heart disease, 10th edition
The Lancet neurology
ASA Guidelines 2018
Uptodate.com
Medscape.com

86. THANK YOU