Presentation on theme: "Stroke Impact It was then that it happened. To my shock and incredulity, I could not speak. That is, I could utter nothing intelligible. All that would."— Presentation transcript:
Stroke Impact It was then that it happened. To my shock and incredulity, I could not speak. That is, I could utter nothing intelligible. All that would come from my lips was the sound ab which I repeated again, again…then as I watched it, the telephone hand-piece slid slowly from my grasp, and I in turn, slid slowly from my chair and landed on the floor behind the desk. At 5:45 in that January dusk I had been a person; now at 6:45 I was a case. Eric Hodgin Report on the Accident Inside My Skull
Normal platelet physiology The generation of thromboxane A2:(TXA2) Cyclooxygenase I (COX-1) uses arachidonic acid to form intermediate prostaglandins (PGG2 and PGH2). In the platelet, thromboxane synthase further transforms these intermediate prostaglandins to thromboxane A2. TXA2 generation induces further platelet aggregation and induces blood vessel contraction and vasoconstriction.
Normal platelet physiology Release of adenosine 5′-diphosphate (ADP) The binding of (ADP) to the platelet P2Y12 receptor elicits progressive and sustained platelet aggregation.
Normal platelet physiology Glycoproteins IIb and IIIa are members of the integrin superfamily Heterodimer GPIIb-IIIa. This heterodimer exposes a receptor for binding arginine- glycine-aspartic acid amino acid sequences, most notably the arginine-glycine-aspartic acid sequence of fibrinogen.
Antiplatelet drugs Aspirin: Inhibition of COX-1 activity Clopidogrel: irreversibly inhibiting the low-affinity ADP receptor, P2Y12, on the platelet membrane. Phosphodiesterase inhibitors: Dipyridamole reversibly inhibits platelet aggregation Glycoprotein IIb-IIIa antagonists: abciximab (ReoPro), tirofiban (Aggrastat), and eptifibatide (Integrilin) Antiplatelet effect of currently available GpIIb/IIIa inhibitors is reversible
Acute Stroke Treatment: Antiplatelet Agents Rational :Rupture of an atherosclerotic plaque in the high flow state of the arterial system mandates a rapid platelet reaction. Antiplatelet agents may inhibit clot propagation within small and large arteries and hence should improve outcome.
Two large prospective, randomized, placebo-controlled trials included aspirin given within 48 hours of stroke onset.
Chinese Acute Stroke Trial (CAST) Aspirin at 160 mg/day started within 48 hours of onset of suspected acute ischemic stroke 21,106 patients Mean of 25 hours after the onset of symptoms Aspirin reduced early mortality rate (3.3 vs 3.9%; p 0.04) Aspirin therapy did not significantly reduce the rate of PE (aspirin, 0.1% vs placebo, 0.2%)
International Stroke Trial (IST) A total of 19,436 patients were randomized A combined analysis of the results of these two trials shows that aspirin (160 mg or 325 mg daily) had a small but statistically significant reduction of 9 fewer deaths or nonfatal strokes per 1000 treated patients (absolute risk reduction 0.9%). Based on CAST2 and IST,aspirin increases the risk of systemic and CNS hemorrhage.
A meta-analysis of 2 large placebo controlled randomized trials (IST, CAST ) evaluating the efficacy of Aspirin for acute stroke treatment showed the following: A significant modest reduction in those who died or were dependant at follow up in the aspirin group. A significant modest reduction in the rate of recurrent stroke and death in the Aspirin group.
Recommendations Patients with acute ischemic stroke presenting within 48 hours of symptom onset should be given aspirin (160 to 325 mg/day) to reduce stroke mortality and decrease morbidity, provided contraindications such as allergy and gastrointestinal bleeding are absent, and the patient has or will not be treated with recombinant tissue- type plasminogen activator (Grade A). The data are insufficient at this time to recommend the use of any other platelet antiaggregant in the setting of acute ischemic stroke.
Resistance and Failure Aspirin and Other Antiplatelet Agents Resistance may be defined as persistence of platelet activation and adhesion (as determined by platelet function studies) despite the administration of the drug Failure as the occurrence of recurrent stroke or TIA despite administration of antiplatelet. Studies have demonstrated that patients with resistance to aspirin were more likely to be female, smokers, and older
Cause of failure Non-atherothrombotic causes of vascular events (heart embolism,lacunar) Inadequate intake Concurrent intake of certain NSAID (for example ibuprofen, indomethacin) Alternative pathways of platelet activation Increased turnover of platelets Genetic polymorphisms
AHA/ASA Guideline 2006 Secondary Prevention For patients who have an ischemic stroke while taking aspirin, there is no evidence that increasing the dose of aspirin provides additional benefit. Although alternative antiplatelet agents are often considered for noncardioembolic patients, no single agent or combination has been studied in patients who have had an event while receiving aspirin