阿司匹林抵抗与临床预后课件

1、Daniel I. Simon, M.D.Associate Director, Interventional CardiologyBrigham and Womens HospitalAssociate Professor of MedicineHarvard Medical SchoolBoston, MA USAASA Resistance andClinical Outcomes2020年10月2日1Daniel I. Simon, M.D.ASA ResisASA Resistance: Key QuestionsDoes a standardized definition exis

2、t?Are there reliable tests to diagnose this phenomenon?What are the possible mechanisms and future implications?Does it have any clinical significance?How do we manage patients with Aspirin resistance?2020年10月2日2ASA Resistance: Key QuestionsDEstablished Platelet Function TestsHarrison P. Br J Hemato

3、logy 2000;111:733-744Platelet Function TestBleeding timeAggregometry-turbidometric methodsAggregometry-impedance methodsAggregometry & luminescenceAdenine nucleotidesThromboelastography (TEG)Glass filterometerPlatelet release markersIn Vivo screening testResponsiveness to panel agonistsResponsivenes

4、s to panel agonistsCombined aggregation and ADP releaseStored and released ADPGlobal HemostasisHigh shear platelet functionIn vivo platelet activation markersAdvantagesPhysiological DiagnosticWhole blood testMore informationSensitivePredicts bleedingSimpleSimple, systemic measure of platelet activat

5、ionDisadvantagesInsensitive, invasive & high variabilityLabor intensive & non-physiologicalInsensitive Semi-quantitative Specialized equipmentMeasures clot properties only, insensitive to ASARequires blood counterProne to artifactPlt Function TestDisadvantagesAdvantagesAssay2020年10月2日3Established Pl

6、atelet Function Newer Platelet Function Tests(PFA)-100 Whole blood + Primary Limited range-most ptshemostasis after GP IIb/IIIa inhibitors have (high shear closure times 300 sec, so may adhes/aggreg) not be able to discern diff. Used to assay ADP antagonist Clot Signature Whole blood + Adhesion, Lar

7、ge instrument for routine useAnalyzeraggregation and interpretation of results is complexRapid platelet Whole blood + Aggregation GP IIb/IIa: baseline sample req. function assay Clinical outcome data (GOLD)Aspirin: AA-like agonistHarrison P. Br J Hematology 2000;111:733-744Mukherjee D & Moliterno DJ

8、. Clin Pharmacokinet 2000;39(6): 445-458Flow cytometry Whole blood - Platelet GP, Flexible & powerful. Requires activation markers, specialized operator. ExpensivePlatelet functionAssaySubstrate BedsidePrincipleComments 2020年10月2日4Newer Platelet Function Tests(Prevalence of ASA Resistance Gum PA et

9、al. Am J Cardiol 2001;88:230-235ASA-R: mean aggregation 70% with M 10 ADP & 20% with 0.5 mg/ml AA 325 patients with stable CVD taking ASA 325 mg 7days2020年10月2日5Prevalence of ASA Resistance GWang JC et al. Amer J Cardiol 2003;92:1492-4422 patients presenting to cardiac cath lab on ASA 81-325 mg 7dPr

10、evalence of Aspirin Resistance 23.4% Aspirin non-responsiveAccumetrics VerifyNow AspirinDefinition: ARU 550Multivariate analysis: history of CAD associated with twice the odds of being ASA non-responder (odds ratio 2.09, 95% CI 1.189-3.411, p=0.009)No association with gender, DM, smoking, ASA dose20

11、20年10月2日6Wang JC et al. Amer J CardiolClinical Studies2020年10月2日7Clinical Studies2020年10月2日7ASA Resistance: Long-term Clinical StudiesStroke1 1500 mg Plt Reactivity 24 mStroke/MI/ 10-fold lower (n=180) Vascular death risk in ASA respondersPVD2 100 mg Whole blood 18 m Arterial 87% higher risk (n=100)

12、 aggregometry Occlusion in ASA-R CVD/CVA3 100 mg PFA-1060 mRecurrent CVA/ Recurrent CVA 34% (n=53) TIA TIA ASA-R vs. 0% no recurrent eventsSubgroup 75-325 mg Urinary 11-dehydro 5 yrs MI/Stroke/ 1.8 times HOPE4 TX B2 CVDeath higher risk in (n=967) upper vs. lower quartileCVD5 325 mg Optical platelet

13、679185 Death/MI/CVA 24% ASA-R vs.(n=326) aggregation days 10% ASA-S HR 3.12 (95% CI 1.1-8.9, p=0.03)Grotemeyer KH, et al. Thromb Res 1993; 71:397-403Mueller MR, et al. Thromb Haemost 1997; 78:1003-1007Grundmann K, et al. J Neurol 2003; 250: 63-66Eikelboom JW, et al. Circulation 2002; 105:1650-1655Gu

14、m PA, et al. J Am Coll Cardiol 2003; 41:961-965 PtsASA doseTestF/UEnd-pointResults 2020年10月2日8ASA Resistance: Long-term ClinASA Resistance and Clinical Outcome in CAD PatientsEikelboom JW, et al. Circulation 2002; 105:1650-1655HOPE Trial Substudy: ASA 75-325 mg2020年10月2日9ASA Resistance and Clinical

15、OuASA Resistance and Clinical Outcome in CVD PatientsGum PA, et al. J Am Coll Cardiol 2003; 41:961-965 ASA-R: mean aggregation 70% with 10 M ADP & 20% with 0.5 mg/ml AA326 CVD patients on ASA 325 mg 7 daysp=0.032020年10月2日10ASA Resistance and Clinical OuASA Resistance and Clinical Outcome in PVD Pati

16、entsMueller MR et al. Thromb Haemost 1997; 78:1003-10072020年10月2日11ASA Resistance and Clinical OuASA Resistance and Clinical Outcome in Stroke PatientsGrotemeyer KH et al. Thromb Res 1993; 71:397-4032020年10月2日12ASA Resistance and Clinical OuASA Resistance and Clinical Outcome in Stroke PatientsGrund

17、mann K et al. J Neurol 2003; 250: 63-6653 CVA pts on ASA 100 mg for secondary prevention 60 months 2020年10月2日13ASA Resistance and Clinical OuChen et al. J Amer Coll Cardiol 2004;43:1122-6ASA Resistance in PCIRPFA-ASA, ASA/clopidogrel (n=151), 19.2% ASA resistant2020年10月2日14Chen et al. J Amer Coll Ca

18、rdi Oral Antiplatelet AgentsCollagenThrombinTXA2AspirinADP(FibrinogenReceptor)clopidogrel bisulfateTXA2ADPDipyridamolePhosphodiesteraseADPGp IIb/IIIaActivationCOXticlopidine HClADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.Schafer AI. Am J Med 1996;101:199209.2020年10月2日15

19、Oral Antiplatelet AgentsCollaClopidogrel in Unstable Angina to Prevent Recurrent Ischemic EventsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.Aspirin 75-325mgAspirin 75-325mgPlaceboClopidogrel 300mg loading dosePatients withNon-ST elevation Acute CoronarySyndromeR 1 3 6 9 12 Months3 m

20、onths double-blind treatment 12 monthsClopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients)Placebo + ASA 75-325 mg q.d.*(6303 patients)2020年10月2日16Clopidogrel in Unstable Angina* In combination with standard therapyThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.0.140.000.020.040.

21、060.080.100.12Cumulative Hazard RateClopidogrel + ASA*369Placebo + ASA*Months of Follow-Up11.4%9.3%20% RRRP 0.001N = 12,562012Primary Endpoint: MI/Stroke/CV Death2020年10月2日17* In combination with standardPCIPLACEBO + ASA *CLOPIDOGREL300 mg3-24h pre-PCI+ ASA *30 days post PCIEnd of follow-upUp to 12 monthsafter randomizationClopidogrel 75 QDPretreatmentClopidogrel 75 QDPretreatmentN = 2,116 patients undergoing elective PCI* In combination with standard therapyN = 1345N = 1313RCREDO2020年10月2