1. Platelets play an important role in both normal hemostasis and pathological thromboses like myocardial infarction and stroke. Antiplatelet drugs are commonly used to prevent strokes. 2. Aspirin is recommended for both primary and secondary stroke prevention. Clopidogrel and dipyridamole are also options for secondary prevention. Combination aspirin/dipyridamole may be better than aspirin alone. 3. Newer antiplatelets like ticagrelor inhibit the P2Y12 receptor more effectively than clopidogrel, but trials found no clear benefit over aspirin for acute stroke. Combining aspirin and clopidogrel long-term increases bleeding risk without

1. NEWERANTI-PLATELETS
IN STROKE
DR. SUMIT KAMBLE
DM RESIDENT
DEPT. OF NEUROLOGY
GMC, KOTA

2. • Platelets provide the initial hemostatic plug at sites of vascular
injury.
• Participate in pathological thromboses that lead to myocardial
infarction, stroke, and peripheral vascular thromboses.

3. PLATELETADHESIONANDAGGREGATION

4. Receptors on platelets:
• GpIa/IIa: receptors for collagen
• GpIb: receptor for vWF
• GpIIb/IIIa: receptor for fibrinogen
• P2Y1/P2Y12: purinergic receptors for ADP
• PAR1/PAR4: protease activated receptors for thrombin (IIa)

5. CLASSIFICATION
• TXA2 inhibitors – Aspirin (non selective COX inhibitor)
• Phosphodiesterase inhibitors – Dipyridamole
• Thienopyridine derivatives – Ticlopidine, Clopidogrel,
Prasugrel

6. • Glycoprotein (GP) IIb/IIIa inhibitor – Abciximab, Eptifibatide,
Tirofiban
• Newer anti-platelet agents – Cangrelor, Ticagrelor, SCH530348
(vorapaxar) and E5555 (atopaxar)

7. ROLE OF ANTIPLATELETS IN NON
CARDIOEMBOLIC STROKE
PRIMARY PREVENTION
• 1. Use of aspirin for cardiovascular prophylaxis is reasonable
for people whose risk is sufficiently high (10-year risk >10%)
for the benefits to outweigh the risks associated with treatment.
(Class IIa; Level of Evidence A).

8. • 2. Aspirin (81 mg daily or 100 mg every other day) can be
useful for the prevention of a first stroke among women,
including those with diabetes mellitus, whose risk is sufficiently
high for the benefits to outweigh the risks associated with
treatment (Class IIa; Level of Evidence B).
• 3. Aspirin might be considered for the prevention of a first
stroke in people with chronic kidney disease (ie, estimated
glomerular filtration rate <45 mL/min/1.73 m2) (Class IIb;
Level of Evidence C).

9. • 4. Cilostazol may be reasonable for the prevention of a first
stroke in people with peripheral arterial disease (Class IIb;
Level of Evidence B).
• 5. Aspirin is not useful for preventing a first stroke in low-risk
individuals (Class III; Level of Evidence A).
• 6. Aspirin is not useful for preventing a first stroke in people
with diabetes mellitus in the absence of other high-risk
conditions (Class III; Level of Evidence A).

10. • 7. Aspirin is not useful for preventing a first stroke in people
with diabetes mellitus and asymptomatic peripheral artery
disease (defined as asymptomatic in the presence of an ankle
brachial index ≤0.99) (Class III; Level of Evidence B).
• 8. As a result of a lack of relevant clinical trials, antiplatelet
regimens other than aspirin and cilostazol are not recommended
for the prevention of a first stroke (Class III; Level of Evidence
C).

11. ACUTE ISCHEMIC STROKE
• 1. Oral administration of aspirin (initial dose is 325 mg) within
24 to 48 hours after stroke onset is recommended for treatment
of most patients (Class I; Level of Evidence A).
• 2. The usefulness of clopidogrel for the treatment of acute
ischemic stroke is not well established (Class IIb; Level of
Evidence C).

12. • 3. The efficacy of intravenous tirofiban and eptifibatide is not
well established, and these agents should be used only in the
setting of clinical trials (Class IIb; Level of Evidence C).
• 4. Aspirin is not recommended as a substitute for other acute
interventions for treatment of stroke, including intravenous rtPA
(Class III; Level of Evidence B).

13. • 5. The administration of other intravenous antiplatelet agents
that inhibit the glycoprotein IIb/IIIa receptor is not
recommended (Class III; Level of Evidence B).
• 6. The administration of aspirin (or other antiplatelet agents) as
an adjunctive therapy within 24 hours of intravenous
fibrinolysis is not recommended (Class III; Level of Evidence
C).

14. SECONDARY PREVENTION
• 1. For patients with noncardioembolic ischemic stroke or TIA,
the use of antiplatelet agents rather than oral anticoagulation is
recommended to reduce the risk of recurrent stroke and other
cardiovascular events (Class I; Level of Evidence A).
• 2. Aspirin (50–325 mg/d) monotherapy (Class I; Level of
Evidence A) or the combination of aspirin 25 mg and extended-
release dipyridamole 200 mg twice daily (Class I; Level of
Evidence B) is indicated as initial therapy after TIA or ischemic
stroke for prevention of future stroke

15. • 3. Clopidogrel (75 mg) monotherapy is a reasonable option for
secondary prevention of stroke in place of aspirin or
combination aspirin/dipyridamole (Class IIa; Level of Evidence
B). This recommendation also applies to patients who are
allergic to aspirin.
• 4. The selection of an antiplatelet agent should be individualized
on the basis of patient risk factor profiles, cost, tolerance,
relative known efficacy of the agents, and other clinical
characteristics (Class I; Level of Evidence C).

16. • 5. The combination of aspirin and clopidogrel might be
considered for initiation within 24 hours of a minor ischemic
stroke or TIA and for continuation for 90 days (Class IIb; Level
of Evidence B).
• 6. The combination of aspirin and clopidogrel, when initiated
days to years after a minor stroke or TIA and continued for 2 to
3 years, increases the risk of hemorrhage relative to either agent
alone and is not recommended for routine long-term secondary
prevention after ischemic stroke or TIA (Class III; Level of
Evidence A).

17. • 7. For patients who have an ischemic stroke or TIA while taking
aspirin, there is no evidence that increasing the dose of aspirin
provides additional benefit. Although alternative antiplatelet
agents are often considered, no single agent or combination has
been adequately studied in patients who have had an event
while receiving aspirin (Class IIb; Level of Evidence C).

18. • 8. For patients with a history of ischemic stroke or TIA, AF, and
CAD, the usefulness of adding antiplatelet therapy to VKA
therapy is uncertain for purposes of reducing the risk of
ischemic cardiovascular and cerebrovascular events (Class IIb;
Level of Evidence C). Unstable angina and coronary artery
stenting represent special circumstances in which management
may warrant DAPT/VKA therapy.

19. Mechanisms ofAction of AntiplateletAgents
Aspirin
Ticlopidine/
Clopidogrel
Dipyridamole
Inhibition of platelet
activation and aggregation
Block
ADP
receptors
Inhibits
cyclooxygenase and
thromboxane A2
Increases
plasma
adenosine
Inhibits
platelet
phosphodiesterase

20. ANTIPLATELETS IN STROKE
ASPIRIN
• 50–325 mg/d of aspirin is recommended for stroke prevention.
Mechanism of action
• Irreversibly acetylating and inhibiting platelet cyclooxygenase
(COX)-1
• High doses (∼1 g/d), aspirin also inhibits COX-2.

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

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

23. Dose OfAspirin: Indirect Comparisons
% Reduction
Regimen No. Trials (SE) P value
Aspirin Alone (mg)
500-1500 34 19 (3) <0.00001
160-325 19 26 (3) <0.00001
75-150 12 32 (6) <0.0001
<75 3 13 (8) NS
Total 68 23 (2) <0.0001
.AntiThrombotic Trialists Collaboration. Lancet, 2002

24. THIENOPYRIDINES
• Include ticlopidine, clopidogrel, and prasugrel
Mechanism of action
• Selectively inhibit ADP-induced platelet aggregation by
irreversibly blocking P2Y 12
• Ticlopidine and clopidogrel are prodrugs

25. Side effects
• Ticlopidine – gastrointestinal, hematologic side effects, which
include neutropenia, thrombocytopenia, and thrombotic
thrombocytopenic purpura.
• Gastrointestinal and hematologic side effects are rare with
clopidogrel and prasugrel.

26. CLOPIDROGEL
• Has Class IIa; Level of Evidence B for secondary prevention of
non cardioembolic stroke.
• Onset: 4-6 hours
• Variable response: 25-30% of patients achieve less than 25%
inhibition of platelet activity
• Must undergo 2 step metabolism (CYP3A4 mediated) to active
agent
• Binds irreversibly to P2Y12 receptor.
• Interaction with PPIs.

27. Clopidogrel VersusAspirin 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.

28. Prevention Regimen for EffectivelyAvoiding Second
Strokes (PRoFESS) trial
• Clopidogrel was compared with combination aspirin and
extended-release dipyridamole
• N=20,332 patients with recent non cardioembolic ischemic
stroke
• Aspirin-dipyridamole (n=10,181)
• Clopidogrel (n=10,151)
Primary Outcomes
Adverse Events
• Major hemorrhage 4.1% vs. 3.6% (HR 1.15; 95% CI 1.00-1.32)

29. TICLOPIDINE
• Ticlopidine is a platelet ADP receptor antagonist.
• Evaluated in 3 randomized trials
• Ticlopidine was superior to placebo in 1 trial and to aspirin in
another, and a third trial found no benefit compared with
aspirin.
• Because of the side effect profile and availability of newer
agents, ticlopidine has no role in current guidelines.

30. Canadian American Ticlopidine Study,
• Included 1,072 patients with ischemic stroke.
• Patients in the ticlopidine group had a significant 23.3%
reduction in the combined end point of stroke, MI, or vascular
death compared with the placebo group (11.3% per year vs
14.8% per year; P = 0.02).

31. Ticlopidine Aspirin Stroke Study (TASS)
• Compared ticlopidine with high-dose aspirin (650 mg) in 3,069
patients with TIA or stroke.
• There was a 12% reduction in the primary end point of nonfatal
stroke or death in patients receiving ticlopidine compared with
those receiving aspirin (17% vs 19%; P = 0.048)
• Negative results in this trial along with the hematologic side
effects of ticlopidine and the availability of clopidogrel have
significantly reduced the use of this drug for recurrent stroke
prevention in patients with ischemic stroke.

32. TICAGRELOR
• Orally active, reversible inhibitor of P2Y 12 .
• Has a more rapid onset and offset of action than clopidogrel
• Produces greater and more predictable inhibition of ADP-
induced platelet aggregation.

33. Platelet Inhibition and Patient Outcomes (PLATO) trial
• Ticagrelor versus clopidogrel in patients with acute coronary
syndromes
• Compared to clopidogrel, ticagrelor significantly reduced the
rate of CV death, MI, or stroke without an increase in the rate of
overall major bleeding

34. Ticagrelor versus Aspirin in Acute Stroke or Transient
Ischemic Attack
• 13,199 patients with a nonsevere ischemic stroke or high-risk
transient ischemic attack were randomly assigned within 24
hours after symptom onset, in a 1:1 ratio, to receive either
ticagrelor (180 mg loading dose on day 1 followed by 90 mg
twice daily for days 2 through 90) or aspirin (300 mg on day 1
followed by 100 mg daily for days 2 through 90)
• Ticagrelor was not found to be superior to aspirin in reducing
the rate of stroke, myocardial infarction, or death at 90 days

35. DIPYRIDAMOLE
Mechanism of action
• Inhibiting phosphodiesterase, blocks the breakdown of cyclic
AMP.
• Increased levels of cyclic AMP reduce intracellular calcium and
inhibit platelet activation.
• Also blocks the uptake of adenosine by platelets and other cells.
Side effects
• Gastrointestinal complaints, headache, facial flushing,
dizziness, and hypotension.
Combination of aspirin 25 mg and extended-release dipyridamole
200 mg twice daily (Class I; Level of Evidence B)

36. European Stroke Prevention Study (ESPS-1)
• Randomized patients to placebo or the combination of 325 mg
of aspirin plus 75 mg of immediate-release dipyridamole 3
times per day.
• Rate of stroke or death was 16% among patients assigned to
aspirin/dipyridamole compared with 25% among patients
assigned to placebo (RRR, 33%; P<0.001).

37. European Stroke Prevention Study (ESPS-2)
• Compared with placebo, risk of stroke was reduced by 18%
with aspirin monotherapy (P=0.013), 16% with dipyridamole
monotherapy (P=0.039), and 37% (P<0.001) with the
combination.
• Compared with aspirin alone, combination therapy reduced the
risk of stroke by 23% (P=0.006) and of stroke or death by 13%
(P=0.056).

38. European/Australasian Stroke Prevention in Reversible
Ischaemia Trial (ESPRIT)
Aspirin plus dipyridamole versus aspirin alone after cerebral
ischemia of arterial origin
Primary Outcomes
• Vascular mortality, non-fatal stroke, non-fatal MI, or non-fatal
major bleeding
• 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)

39. Combination Clopidogrel andAspirin
• Combination of aspirin and clopidogrel considered for initiation
within 24 hours of a minor ischemic stroke or TIA and for
continuation for 90 days (Class IIb; Level of Evidence B).

40. Management of Atherothrombosis With Clopidogrel in High-
Risk Patients With Recent Transient Ischemic Attacks or
Ischemic Stroke (MATCH) trial
• There was no significant benefit of combination therapy
compared with clopidogrel alone in reducing the primary
outcome of ischemic stroke, MI, vascular death, or
rehospitalization for any central or peripheral ischemic event.

41. Clopidogrel for High Atherothrombotic Risk and Ischemic
Stabilization, Management, and Avoidance (CHARISMA)
trial
• Primary outcome (MI, stroke, or death of cardiovascular causes)
was observed in 6.8% of patients assigned to combination
therapy compared with 7.3% assigned to aspirin (RR, 0.93; 95%
CI, 0.83–1.05; P=0.22).
• CHARISMA demonstrated no significant benefit long term
when clopidogrel is added to aspirin.

42. • Two trials have examined the effectiveness of the combination
of aspirin and clopidogrel for prevention of stroke in the months
immediately after a TIA.

43. Fast Assessment of Stroke and Transient Ischemic Attack to
Prevent Early Recurrence (FASTER) trial
• Designed to test the effectiveness of combination therapy
(aspirin 81 mg daily plus clopidogrel 300-mg loading dose
followed by 75 mg daily) compared with aspirin alone for
preventing stroke among patients with a TIA or minor stroke
within the previous 24 hours.
• Reduced rate of ischemic outcome events with combination
therapy, with only a small 1% increased risk for symptomatic
ICH.

44. Clopidogrel in High-Risk Patients With Acute Nondisabling
Cerebrovascular Events (CHANCE) trial
• Primary outcome of ischemic or hemorrhagic stroke was
observed in 8.6% of participants assigned to combination
therapy compared with 11.7% assigned to aspirin monotherapy
(HR, 0.68; 95% CI, 0.57–0.81).
• Rates of moderate or severe bleeding were similar in the 2
groups.

45. GPIIb/IIIa RECEPTORANTAGONISTS
• Include Abciximab , Tirofiban and Eptifibatide .
• Side effects - bleeding, thrombocytopenia
• All of the GPIIb/IIIa antagonists are given as an IV bolus
followed by an infusion.
• Cleared by the kidneys,
• Efficacy of intravenous tirofiban and eptifibatide is not well
established in ischemic stroke (Class IIb; Level of Evidence C).

47. ABCIXIMAB
• It has been found to be safe, except for a nonsignificant
increase in the risk of bleeding complications.
• However, it has not resulted in any significant improvement in
the functional outcome.

48. Abciximab-rt-PAcombination therapy inAIS:
• 47 patients with acute vertebrobasilar stroke were treated with
abciximab and low-dose rt-PA (FAST)
• Neurological outcome appeared better under combined therapy
(FAST versus rtPA: favorable outcome rate: 34% versus 17%)
with a significantly lower mortality rate (FAST versus rtPA:
38% versus 68%; P=0.006).

49. TIROFIBAN
• Currently no role in acute ischemic stroke or prophylaxis.

50. Safety of Tirofiban in acute Ischemic Stroke: SaTIS trial.
• Subjects with a NIHS between 4 and 18 received intravenously
either tirofiban or placebo within 3 to 22 hours after symptom
onset for 48 hours.
• Rate of cerebral hemorrhagic transformation (I/II) and
parenchymal hemorrhage (I/II) did not differ between both groups
• Mortality after 5 months was significantly lower in patients
treated with tirofiban.
• No difference in neurological/functional outcome was found after
1 week and after 5 months.

51. EPITIFIBATIDE
Combined Approach to Lysis Utilizing Eptifibatide and rt-PA
in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER)
• rt-PA-eligible AIS patients were randomized to .6 mg/kg rt-PA
plus eptifibatide (135 mcg/kg bolus and .75mcg/kg/min two-
hour infusion) versus standard rt-PA (.9 mg/kg).
• One (1.8%) sICH occurred in each group.
• At 90 days, 51.8% of the CLEAR-ER group had good outcomes
versus 46.3% in the NINDS rt-PA.
• A phase III trial is needed to determine the efficacy of
eptifibatide plus rt-PA for improving long-term outcomes after
AIS.

52. CILASTAZOLE
• Phosphodiesterase 3 inhibitor that is used mainly for
intermittent claudication in patients with peripheral artery
disease.
• There are as yet no high-quality data regarding the use of
cilostazol for secondary stroke prevention.
• Lower tolerability and higher cost of cilostazol compared
with aspirin may limit its more widespread use for stroke
prevention.

53. • In the CSPS ( Cilostazol stroke prevention study) trial of over
1000 patients from Japan, cilostazol (100 mg twice daily)
compared with placebo significantly reduced the risk of stroke
(relative risk reduction 42 percent, 95% CI 9.2-62.5 percent).
• In the CASISP (Cilostazol vs Aspirin for Secondary Ischemic
Stroke Prevention) trial from China of 720 patients with recent
ischemic stroke, the composite endpoint (any stroke, ischemic
or hemorrhagic) at 12 to 18 months of follow-up was lower in
the cilostazol group compared with the aspirin group (3.3 versus
5.6 percent, hazard ratio [HR] 0.62, 95% CI 0.30-1.26) but this
result was not statistically significant

54. THANKYOU

55. REFERENCES
• AHA/ASA guidelines 2014
• Glycoprotein IIb-IIIa inhibitors for acute ischaemic stroke
(Review) Cochrane Database of Systematic Reviews
• Antiplatelet Treatment for Prevention of Cerebrovascular
Events in Patients With Vascular Diseases aha journal 2014
• New Directions in Antiplatelet Therapy AHA journal 2014