NEWER ANTI-PLATELETS IN STROKE

DR. SUMIT KAMBLEDM RESIDENTDEPT. OF NEUROLOGYGMC, KOTA

• 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.

PLATELET ADHESION AND AGGREGATION

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)

CLASSIFICATION

• TXA2 inhibitors – Aspirin (non selective COX inhibitor)

• Phosphodiesterase inhibitors – Dipyridamole

• Thienopyridine derivatives – Ticlopidine, Clopidogrel, Prasugrel

• Glycoprotein (GP) IIb/IIIa inhibitor – Abciximab, Eptifibatide, Tirofiban

• Newer anti-platelet agents – Cangrelor, Ticagrelor, SCH530348 (vorapaxar) and E5555 (atopaxar)

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).

• 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).

• 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).

• 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).

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).

• 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).

• 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).

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

• 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).

• 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).

• 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).

• 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.

Mechanisms of Action of Antiplatelet Agents

AspirinTiclopidine/Clopidogrel Dipyridamole

Inhibition of plateletactivation and aggregation

Block ADP receptors

Inhibitscyclooxygenase and thromboxane A2

Increasesplasma adenosine

Inhibits platelet phosphodiesterase

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.∼

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.

Benefits of Aspirin 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

Dose Of Aspirin: 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

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

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.

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.

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.

Prevention Regimen for Effectively Avoiding 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)

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.

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).

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.

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.

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

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

DIPYRIDAMOLEMechanism 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)

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).

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).

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)

Combination Clopidogrel and Aspirin

• 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).

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.

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.

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

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.

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.

GPIIb/IIIa RECEPTOR ANTAGONISTS

• 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).

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.

Abciximab-rt-PA combination therapy in AIS:

• 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).

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

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.

EPITIFIBATIDECombined 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.

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.

• 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

THANK YOU

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