1. Aspirin Resistance Issa Majed Ghanma MD.

2. Platelets Function - Platelets play an important role in homeostasis. - they bind to collagen and to each other forming a barrier to blood loss at the site of injury.

6. Cont. Platelets Function they accelerate the rate of activation of coagulation proteins and release granules that promote further platelet activation and healing.

7. Cont. Platelet Function - There are many important platelets agonists: 1- thrombin 2- thromboxane A2 3- ADP

9. Antiplatelet Agents Several antiplatelet agents are available that work at different sites of platelet activation: 1- Aspirin. 2- Clopidogrel. 3- dipyridamole. 4- thrombin inhibitors (bivalirudin, lepirudin). 5- IIb / IIIa receptor blockers.

11. The History of Aspirin

12. - Salicylates have been used to treat pain and inflammation associated with rheumatism. - Industrial production of salicylic acid started in 1859, however early preparation were associated with side effects, such as unpleasant taste and dyspepsia. - Felix Hoffman of Friedrich Bayer & Co. developed a stable and better-tolerated form of the drug (acetylsalicylic acid).

15. Cont. Aspirin History 1950 … Reports linked aspirin use with prolongation of bleeding time. 1970 … Aspirin demonstrated to be a potent inhibitor of prostaglandin synthesis.

16. Later … It was confirmed that aspirin acetylates serine 529 in the active site of the cyclooxygenase-1 enzyme (prostaglandin H2 synthase-1), permanently deactivating it and preventing thromboxane A2 platelet activation.

18. These observations paved the way for the clinical investigation of aspirin's antiplatelet effects in preventing thrombotic events, such as ischemic strokes and acute myocardial infarction.

20. Mechanism Of Action Of Aspirin Aspirin inhibit the cyclooxygenase (COX) activity of prostaglandin (PG), which in turn blocks the metabolism of arachidonic acid to cyclic prostanoids such as thromboxane A2 (TXA2).

21. AspirinMembrane Phospholipids (Phospholipase A) Arachidonic Acid (COX-1/PGH-Synthase) Prostaglandin G2 Prostaglandin H2 (HOX/PGH-Synthase) (PGH-Synthase) TXA2 - Increased platelet aggregation. - Vasoconstriction. Platelet COX-1 inhibition

22. Pharmacokinetics Of Aspirin -Aspirin is rapidly absorbed from the gastrointestinal tract and peak plasma concentration are achieved in 30 to 40 minutes. -Significant platelet inhibition is noted within 60 minute of ingestion and a single dose of 100mg of aspirin can completely block TXA2 production for the life of the platelet in most individual.

23. -The plasma half-life of aspirin is only 20 minutes but the irreversible nature function makes once-daily dosing sufficient to maintain its antithrombotic benefit. Cont. Pharmacokinetics Of Aspirin

24. Aspirin Efficacy - Aspirin plays an important role in primary and secondary prevention of vascular events. - Aspirin is very effective therapy for patients suffering an acute M.I, as demonstrated by (ISIS-2) trial in which aspirin administration reduced mortality by 23%, a comparable effect to thrombolytic therapy.

26. People still have events while on ASA!!! Do all patients respond in the same way?

27. Definition(s) of “ APT Resistance? ” The fact that some patients may experience recurrent vascular events despite the use of APT should be properly defined as “ treatment failure ” rather than “ APT resistance ” (multiple pathways mediate thrombotic events). APT Resistance/Non-responsiveness=failure to inhibit the target APT Resistance/Non-responsiveness≠clinical failure

28. Antiplatelet Drug Resistance 1- What do we know about it ? 2- How do we define it ? 3- What do we do about it ?

29. Aspirin Resistance - Clinical observation of aspirin's inability to protect individuals from thrombotic complications. - Laboratory phenomenon of absence of aspirin's effect on one or more tests of platelets function.

30. Aspirin Resistance No … formal diagnostic criteria … but aspirin resistance generally describes the failure of aspirin to produce an expected biological response or the failure of aspirin to prevent atherothrombotic events. Aspirin resistance has been reported to occur in 5% to 45% of the general population.

31. The exact prevalence of aspirin resistance remains uncertain … but Measurement of platelet aggregation, platelet activation, and bleeding time have all confirmed variability in patient's anti-thrombotic responses to aspirin therapy. Cont. Aspirin Resistance

33. Platelet Function Tests. Platelet aggregation Light transmittance aggregometry (LTA)←gold standard impedance platelet aggregation Light transmittance aggregometry (LTA)←gold standard impedance platelet aggregation. Flow Cytometry GPIIb/IIIa receptors activation GPIIb/IIIa receptors activation P-selectin expression P-selectin expression Monocyte-platelet aggregates Monocyte-platelet aggregates Vasodilator-associated stimulated phosphoprotein (VASP) Vasodilator-associated stimulated phosphoprotein (VASP). Point-of-care Ultegra rapid platelet function analyzer (Verify Now) Ultegra rapid platelet function analyzer (Verify Now) Thromboelastagraph (TEG) Thromboelastagraph (TEG) Platelet works Platelet works Cone and platel(let) analyzer (IMPACT) Cone and platel(let) analyzer (IMPACT).Genetic testing.Genetic testing

38. Potential mechanisms /causes of aspirin resistance Although the mechanism for aspirin resistance remains uncertain, it is likely due to a combination of clinical, biological, and genetic properties affecting platelet function.

40. Aspirin Resistance Patient Management - Educate patients on importance of compliance - Eliminate interfering substances (ibuprofen) - Increase aspirin dose(?) ( ….increasing the dose of aspirin does not enhance COX-1 inhibition) - Use other anti-platelet medications (e.g. clopidogrel) (?) ( ….no scientific evidence that switching to alternative treatment strategies improves outcomes).

41. Main points 1-Aspirin is effective antiplatelet agent with proven benefit in the prevention of atherothrombotic complications of cardiovascular; however, the absolute risk of recurrent vascular events among patients taking aspirin relatively high. 2-Although formal diagnostic criteria are lacking, aspirin resistance generally describes the failure of aspirin to produce an expected biological response (ie, platelet inhibition) or to prevent atherothrombotic events

42. 3-Aspirin resistance has been estimated to exist in anywhere from 5% to 45% of the population, representing a phenomenon of possible clinical significance. 4-Traditionally, platelet aggregation has been measured in platelet-rich plasma using an optical aggregometer. Other effective means of analizing platelet function include the platelet function analyzer (PFA)-100 and the rapid platelet function assay (RPFA).

43. Conclusions - Variability in individual responsiveness to antiplatelet agents is an emerging clinical problem: poor responsiveness has been associated with an increased risk of ischemic events, including stent thrombosis. - WHAT and HOW to measure antiplatelet drug responsiveness still needs to be fully defined. - WHAT do we do with the results coming from the “ test tube ” ? (No demonstration of an association with clinical events conditioning cost-effective changes in treatment). - responsiveness to antiplatelet therapy should be evaluated for mainly investigation purposes!!!

44. Thank You

50. Aspirin Resistance: Relative Risk Of Different events Events Relative risk Events Relative risk M.I or UAP 3.8 Stroke or TIA 4.1