1、Is Antiplatelet Resistance a Potential Risk Factor?C.Richard Conti M.D. MACCAntiplatelet Agents:Mechanism of Action CollagenThrombinTXA2ADPADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.Schafer AI. Am J Med. 1996;101:199209.clopidogrel bisulfateTXA2ADPADPGpIIb/IIIaActivatio

2、nCOXaspirinReoPro, Integrilin, AggrastatThromboxane 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 benef

3、it for the prevention of atherothrombotic complications of CV diseaseHowever,Many patients taking aspirin have cardiac eventsAspirin resistance is estimated anywhere between 5% and 40%Aspirin is cardioprotectiveIn a meta-analysis of patients with high risk peripheral vascular disease;ASA therapy was

4、 associated with a34% risk reduction in Non fatal MI25% risk reduction in non fatal stroke18% reduction in all cause mortality*BMJ 2002,324:71-86 Aspirin Resistance: A confusing Term not well defined !TIMI Risk scoreCompliance“allergy”-GI intoleranceTrue allergyMalabsorbtionInadequate doseSmokingInc

5、reased catecholamine levelsTrue functional resistanceUA/NSTEMI TIMI RISK SCOREVariablesAge 65 3 risk factors for CADPrior 50% Cor StenosisST 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 2000:2

6、84:835-842Death, MI Recurrent Ischemia at 14 daysWhat is Aspirin ResistanceTIMI Risk ScoreCompliance“allergy”-GI intoleranceTrue allergyMalabsorbtionInadequate doseSmokingIncreased catecholamine levelsTrue functional resistanceHow can aspirin resistance be detectedBedside point of care measurement o

7、f Platelet FunctionPFA 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

8、#/ptsASA dose MethodPrevalence(%)72/SAP160PFA 100*29.2129/SAP160PFA 100*1.35422/SAP325RPFA*23.0151/PCI80-325RPFA*19.2*epi closure time 186 sec* epi closure time550What Can be done about Aspirin resistance?Increase dose and repeat aggregation testIf still resistant Switch to clopidogrelTreat ACS, HF,

9、 BMI, Insulin resistance, hyperglycemia, hypercholesterolemiaAspirin 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 Resista

10、nce; 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 populationAspirin Resistance; teachin

11、g PointsUnresolved IssuesAbsence of Clearly defined biologic mechanisms to explain aspirin resistanceLack 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 clini

12、cal outcome that is presently unsubstantiatedAbsence of a proven therapeutic intervention for affected individualsClopidigrel ResistanceClopidogrel ResistanceTerms to differentiate the effect of clopidogrelResistance;patients for whom clopidogrel does not achieve its pharmacological effect. # varies

13、 between 4 and 30%Failure of Therapy; Patients who have recurrent events on therapyClopidogrel ResistanceTeaching Points4 to 30 % do not have adequate platelet response to clopidogrelResistance to clopidogrel is poorly definedLow platelet effect of clopidogrel may lead to MACEOptimal level of platelet inhibition