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Is Antiplatelet Resistance a Potential Risk Factor? C.Richard Conti M.D. MACC Antiplatelet Agents:Mechanism of Action Collagen Thrombin TXA2 ADP ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase. Schafer AI. Am J Med. 1996;101:199209. clopidogrel bisulfate TXA2 ADP ADP GpIIb/IIIa Activation COX aspirin ReoPro, Integrilin, Aggrastat Thromboxane A2 is synthesized and released by human platelets in response to a variety of stimuli (collagen, thrombin, ADP, PAF) and amplifies platelet aggregation Is Aspirin resistance a Risk Factor? Aspirin is an effective antiplatelet agent with proven benefit for the prevention of atherothrombotic complications of CV disease However,Many patients taking aspirin have cardiac events Aspirin resistance is estimated anywhere between 5% and 40% Aspirin is cardioprotective In a meta-analysis of patients with high risk peripheral vascular disease; ASA therapy was associated with a 34% risk reduction in Non fatal MI 25% risk reduction in non fatal stroke 18% reduction in all cause mortality *BMJ 2002,324:71-86 Aspirin Resistance: A confusing Term not well defined ! TIMI Risk score Compliance “allergy”-GI intolerance True allergy Malabsorbtion Inadequate dose Smoking Increased catecholamine levels True functional resistance UA/NSTEMI TIMI RISK SCORE Variables Age 65 3 risk factors for CAD Prior 50% Cor Stenosis ST Change on admission Angina X 2 in 24 hrs ASA use within 7 days Serum Cardiac Marker Data from TIMI 11B and Essence Trials Adapted from Antman EM et al. JAMA 2000:284:835-842 Death, MI Recurrent Ischemia at 14 days What is Aspirin Resistance TIMI Risk Score Compliance “allergy”-GI intolerance True allergy Malabsorbtion Inadequate dose Smoking Increased catecholamine levels True functional resistance Why are patients aspirin resistant Clinical Variables Cigarettes NSAIDs Sub therapeutic doses of ASA Biologic Variables Alternate pathways of platelet activation Genetic Variables Mutations of the COX-1 gene What is the best way to detect Aspirin Resistance? There is no “one” good way to assess platelet function. The clinical relevance of “Aspirin Resistance” as determined by current laboratory methods is uncertain. How can aspirin resistance be detected Bedside point of care measurement of Platelet Function PFA 100(platelet function analyser)* RPFA (rapid platelet function assay)* * Dade-Behring, Deerfield, IL * Accumetrics, San Diego,CA Correlation with standard optical platelet aggregometry using epinephrine as the agonist Malinin et al EJP 462 (2003) Selected Studies of Aspirin Resistance #/pts ASA dose Method Prevalence(%) 72/SAP 160 PFA 100* 29.2 129/SAP 160 PFA 100* 1.35 422/SAP 325 RPFA* 23.0 151/PCI 80-325 RPFA* 19.2 *epi closure time 550 Image (General Cardiology)Possible Mechanisms to Account for the Apparent Failure of Aspirin to Protect Some High-Risk Individuals from Recurrent Vascular Events.22 KB File Type: GIFCitation: Reproduced with permissin from Eikelboom JW, Hankey GJ. Aspirin resistance: a new independent predictor of vascular events? J Am Coll Cardiol 2003;41:966-8. Source ACCEL image provided by the American College of Cardiology Foundation What Can be done about Aspirin resistance? Increase dose and repeat aggregation test If still resistant Switch to clopidogrel Treat ACS, HF, BMI, Insulin resistance, hyperglycemia, hypercholesterolemia Aspirin Resistance; Teaching Points (1)ASA prevents complications of CVD but recurrent vascular events in patients taking ASA remains high, suggesting that the antiplatelet effects of ASA may not be equivalent in all patients Aspirin Resistance; Teaching Points (2)Aspirin resistance generally describes the failure of ASA to produce an expected biological response i.e. platelet inhibition or to prevent atherothrombotic events( Aspirin Resistance; Teaching Points (3)ASA resistance occurs in 5-45% of the population Aspirin Resistance; Teaching Points (4)Bed side point of care measurements are now available to assess platelet aggregation (PFA 100 and RFPA) Aspirin Resistance; teaching Points Unresolved Issues Absence of Clearly defined biologic mechanisms to explain aspirin resistance Lack of standardized definition Uncertain Clinical Relevance of ASA resistance in CV Risk prevention Current use of the term Aspirin resistance implies a linkage between a laboratory test and a clinical outcome that is presently unsubstantiated Absence of a proven therapeutic intervention for affected individuals Clopidigrel Resistance Clopidogrel Resistance Terms to differentiate the effect of clopidogrel Resistance;patients for whom clopidogrel does not achieve its pharmacological effect. # varies between 4 and 30% Failure of Therapy; Patients who have recurrent events on therapy Clopidogrel Resistance Teaching Points 4 to 30 % do not have adequate platelet response to clopidogrel Resistance to clopidogrel is poorly defined Low platelet effect of clopidogrel ma