1、Introduction to Aspirin Resistance.May 10,2004Steven R.Steinhubl,MDAspirin HistoryFirst synthesized in pure form by Felix Hoffman of Friedr.Bayer&Co.in 1897.Aspirin HistoryDue to problems with the original Aspirin powder being counterfeited,it became the first pharmaceutical agent ever sold in pill
2、form in early 1900s.First pill in USA was 5 grains(325 mg).Metabolic Pathways ofArachadonic AcidMembrane PhospholipidsARACHIDONIC ACIDProstaglandin H2COX-1Thromboxane A2-Platelet Aggregation-VasoconstrictionProstacyclin-Platelet Aggregation-VasodilitationAspirin in the Treatment of ACSWallentin LC,e
3、t al.JACC 1991;18:1587-93.0.000.050.100.150.200.25036912MonthsProbabilityof Death or MIPlaceboAspirin 75 mgRisk ratio 0.5295%CL 0.37-0.72Aspirin in Acute Myocardial Infarction:ISIS-21002003004005006000714212835Placebo alone:568/4300(13.2%)Aspirin alone:461/4295(10.7%)Streptokinase alone:448/4300(10.
4、4%)Streptokinase plus aspirin:343/4292(8.0%)Cumulative Number of Vascular DeathsDays From RandomizationRandomized Trials of Aspirin in PTCASchwartz,N Engl J Med 1988;318:1714 White,Coronary Artery Disease 1991;2:75704812Schwartz et alN=376White et alN=337%Major Ischemic Complications6.912.6Heparin 1
5、0,000 units2.4Ticlopidine+Heparin1.6ASA/Dipyridamole+Heparin77%P=0.01133.275%P0.001What is“Aspirin Resistance?”lInability of ASA to prevent treated patients from having thrombotic events.lInability of ASA therapy to prolong bleeding time.lInability of treatment with ASA to prevent thromboxane biosyn
6、thesis.lInability of ASA to achieve a pre-defined effect on an ex vivo or in vitro measure of platelet function.Patrono C.J Thromb Haemost 2003;1:1710-3Inter-Individual Variability in Response to AspirinQuick AJ.American Journal of Medical Science Sept 1966:265-9N=10Interpatient Variability in Aspir
7、in Response-Bleeding TimeAspirin,325 mg daily in 40 CABG patientsBuchanan,Can J Cardiol 1995;11(3):221 100 300 500 700 900100300500700900Bleeding Time,Pre-ASABleedingTimePost-ASAResponders(58%)Mean BT 58+10%Non-responders(42%)Mean BT 2+4%Aspirin Responsiveness and Clinical Outcome181 patients,follow
8、ing CVA.Aspirin 500 mg TID.Followed-up for 24 months.10075506121824%of Patients Without EventMonths of ObservationAspirin RespondersN=114Aspirin Non-respondersN=6060%95%P0.0001Grotemeyer,Thrombosis Research 1993;71:397Thromboxane Biosynthesis on Aspirin and CV Events1.01.31.41.8012 33.8Uninary 11-de
9、hydro thromboxane B2(ng/mmole creatinine)Odds Ratio for MI,Stroke or CV DeathEikelboom Circ 2002;105:1650 HOPE Trial N=488,with 5 yr f/uAspirin Responsiveness By PFA-100 and Aggregometry23.8%5.5%70.7%Aspirin SensitiveResistantPartial Responders9.5%90.5%Aspirin Sensitive 325 patients with stable ASCA
10、DAggregometryResponse to ADP and AAPFA-100Gum P.Am J Cardiol 2001;88:230-235Clinical Outcomes:Aspirin Responsive-ness by Aggregometry And PFA-100 020400 0200200400400600600800800Days after TreatmentNot Aspirin Resistant,N=309Aspirin Resistant,N=17Gum,P.JACC 2003;41:961-505101520ASA ResponderN=294ASA
11、 Non-ResponderN=3212.915.1P=0.4Clinical Outcomes based on PFA-100 ResultsPossible Mechanisms for Variability in Response to AspirinlDecreased bioavailabilitylNon-compliancelConcomitant NSAIDs lPlatelet functionlAccelerated platelet turnoverlIncreased platelet COX-2lPlatelet Receptor PolymorphismslOt
12、her factorsDeGaetano G.J Thromb Haemost 2003;1:2048-50Metabolic Pathways of Arachadonic AcidMembrane PhospholipidsARACHIDONIC ACIDProstaglandin H2COX-1Thromboxane A2-Platelet Aggregation-VasoconstrictionProstacyclin-Platelet Aggregation-Vasodilitation12-Lipoxygenase12-HETE,12-HPETE-Platelet Adhesivi
13、tyNon-EnzymaticLipid Peroxidation Catalyzed by Free Radicals Isoprostanes-Amplifies platelet response to other agonists.-Vasoconstrictor-Plasma levels 1-2 orders of magnitude COX -derived metabolites.AspirinPlA2 Polymorphism and Aspirin Resistance0204060800.1110100%AggregationAspirin mol/LP=0.02P=0.
14、01PlA1/A1PlA1/A2Cooke,Lancet 1998;351:PlA2 PolymorphismSingle nucleotide polymorphism -Proline for a leucine at position 33 of 3 subunit.25%of individuals of N.European ancestry are PlA2 +.Aspirin Resistance:Role of COX-2?Weber A-A Lancet 1999;353:900 Aspirin is 170-fold more potent inhibitor of COX
15、-1 than COX-2.Platelets from 20 different donors were COX-2 positive.COX-2 expression in platelets increased 16-fold in 9 post-CABG patients.(Zimmermann AHA 1999)ConclusionslEvery study that has ever evaluated individual responsiveness to ASA has found marked variability.lMost studies have been able
16、 to correlate this variability with a clinically significant increase in thrombotic events.lThe ability to identify the substantial proportion of patients who are unable to achieve an adequate response to ASA has the potential to dramatically improve their antithrombotic regimen and with it,long-term outcomes.
