1、Is Antiplatelet Resistance a Potential Risk Factor?C.Richard Conti M.D.MACCAntiplatelet Agents:Mechanism of ActionCollagenThrombinTXA2ADPclopidogrel bisulfateTXA2ADPaspirinReoPro,Integrilin,AggrastatThromboxane A2 is synthesized and released by human platelets in response to a variety of stimuli(col
2、lagen,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
3、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 2002,324:71-8
4、6 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 resistanceUA/NSTEMI TIMI RISK SCORE VariablesAge 65 3 risk factors for CADPrior 50%Cor StenosisS
5、T Change on admissionAngina X 2 in 24 hrsASA use within 7 days Serum Cardiac MarkerData from TIMI 11B and Essence TrialsAdapted from Antman EM et al.JAMA 2000:284:835-842Death,MI Recurrent Ischemia at 14 daysWhat is Aspirin Resistance TIMI Risk Score Compliance“allergy”-GI intolerance True allergy M
6、alabsorbtion Inadequate dose Smoking Increased catecholamine levels True functional resistanceWhy 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 gen
7、eWhat 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
8、PFA 100(platelet function analyser)*RPFA(rapid platelet function assay)*Dade-Behring,Deerfield,IL*Accumetrics,San Diego,CACorrelation with standard optical platelet aggregometry using epinephrine as the agonistMalinin et alEJP 462(2003)Selected Studies of Aspirin Resistance#/ptsASA dose MethodPreval
9、ence(%)72/SAP160PFA 100*29.2129/SAP160PFA 100*1.35422/SAP325RPFA*23.0151/PCI80-325RPFA*19.2*epi closure time 186 sec*epi closure time550ejt 0104107Baseline CharacteristicsBaseline Characteristics422 Patients422 PatientsHistory of Coronary artery diseaseHistory of Coronary artery disease64%*64%*Aspir
10、in doseAspirin dose 81(mg)81(mg)33%33%162 and 162 and 325(mg)325(mg)66%66%Aspirin Aspirin nonrespondersnonresponders23%23%Wang et al.,Am J Wang et al.,Am J CardiolCardiol 92:1492-4,2003 92:1492-4,2003*Multivariate OR=2.01(1.2,3.4);No dose effect*Multivariate OR=2.01(1.2,3.4);No dose effectImage (Gen
11、eral 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?
12、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,hypercholesterol
13、emiaAspirin 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 patientsAspirin Resistance;Teaching Points(2)Aspirin resistance generally describe
14、s 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 populationAspirin Resistance;Teaching Points(4)Bed side point of care measurements are now available
15、 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 t
16、erm 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 individualsClopidigrel ResistanceClopidogrel Resistance Terms to differentiate the effect of clopidogrel Resistance;pa
17、tients for whom clopidogrel does not achieve its pharmacological effect.#varies between 4 and 30%Failure of Therapy;Patients who have recurrent events on therapyClopidogrel Resistance Teaching Points 4 to 30%do not have adequate platelet response to clopidogrel Resistance to clopidogrel is poorly de
18、fined Low platelet effect of clopidogrel may lead to MACE Optimal level of platelet inhibition not yet defined.Variability of response to clopidogrel is multifactorial Cannot predict clopidogrel resistance Increased loading dose of clopidogrel may prove effective but must be tested in clinical trials
