Aspirin and Clopidogrel Resistance Testing: Update

Transcription

1 Aspirin and Clopidogrel Resistance Testing: Update Kandice Kottke-Marchant, MD, PhD Section Head, Hemostasis & Thrombosis Cleveland Clinic Cleveland, OH USA Kandice Kottke-Marchant, MD, PhD Disclosures Relevant Financial Relationship(s) NONE Off Label Usage NONE Inflammation Atherosclerotic Plaque s EC injury - Activation Denudation Aggregation ECM Proteins Oxidized Lipids Infarct Agonists (P2Y 1 ) Thrombin Thromboxane PAF + P2X 1 Ca 2+ (P2Y 12 ) AC CLO Gi - Gq PLCβ PIP2 IP3 camp DAG GP IIb/IIIa PKC Pleckstrin TxA2 Thromboxane Ca 2+ Synthase PGG2/PGH2 ASA Cyclooxygenase Arachidonic Acid PLA2 PL α Secretion PLCγ PI3K ζ Src Fibrinogen FcRγ GPIb/V/IX Aspirin Resistance? AA Treatment failure (clinical event despite aspirin therapy) Lack of pharmacodynamic response (No platelet inhibition despite aspirin therapy) Phospholipase A2 Arachidonic Acid PGG2, PGH2 TxA2 Normal Function Aspirin Aspirin and Aggregation Agonist Final Conc. %Inhibition AA 500 um >90 % 5 um Disaggregation Collagen ug/ml >70 % Epinephrine 5 um >70 % TRAP 2 um No inhibition Haubelt Sem Thr Hem 31:404 (2005) 1

2 Aspirin Effect Aspirin Resistance Clinical Experience with ASA/CLO Aggregation Testing N=310 Arachidonic A. Therapy ASA 81 ASA 325 Max Agg (%) 50.4+/ /-20 Max AA Agg (%) 23.1+/ /-16 <40% N % 27 (29.4) 12 (10.8) AA<20% N % 41 (49.6) 42 (37.8) n Arachidonic A. ASA > / /-7 1 (14.3) 6 (85.7) 7 ASA 81 + CLO / / (64.3) 15 (53.6) 28 Gum AJC 88:230 (2001) ASA CLO / /-6 19 (86.4) 16 (72.7) Jang S, et al, to be presented at ISTH Aggregation and AR Study Definition Results Helgason, Stroke 24:345 (1993) Sane, AJC 90:893 (2002) Gum AJC 88:230 (2001) Stejskal, Eur J Int Med 17:349 (2006) AR when AA caused aggregation or normal or Epi/Col inhibited <70% 4 of 5 functional parameters >=70% + AA >=20% Spontaneous aggregation <5% Propyl Gallate aggregation slope <53%/min increased ASA dose to achieve platelet inhibition; 3/113 had partial inhibition at 1300 mg ASA AR with greater aggregation (p=0.007) 5.5% AR and 23.8% semi-responders AR 55%; 4 year follow up showed CV events in 88% AR vs. 46% non-ar (p<0.01) PFA-100 and Aspirin Resistance Study Gum 2001 Hezard 2002 Sane 2002 Ten Berg 2002 Grundmann 2003 Finding 9.5% AR by PFA-100;Low correlation with aggregation Low correlation between aggregation, PFA-100 and flow for AR No difference in CT between AR and AS PFA-100 did not distinguish low dose vs high dose aspirin therapy 53 pt on aspirin for stroke prevention; COL/EPI CT significantly shorter in patients with recurrent stroke (p<0.01) Haubelt Sem Thr Hem 31:404 (2005) Study ACS Aspirin Resistance: Adverse Outcomes Number %AR 19.2% 55% Method Ultegra Propyl Gallate Results Significant elevation of CK-MB and TnI in AR Chen W-H, JACC 43:1122 (2004). Cardiovascular events 88% AR vs. 46% non-ar (p<0.01) Stejskal D, Eur J Intern Med. 17:349 (2006). Re-Analysis Adverse Outcome of Death/MI/CVA Published Mean Values (Max Aggregation) AR 4 of 17 (24%) 2 of 8 (25%) Non-AR 30 of 309 (10%) 36 of 307 (11.7%) P HR (95% CI ; p=0.009) (95%CI ; p=0.03) (ASA+ CLO) 106 Aggregation Highest quartile response to associated with recurrent cardiovascular events (OR 22.4 ( ) Cuisset T, J Thromb Haemost. 4:542(2006). 8 patients with borderline AR: AR by Max, not Mean Aggregation decreased -1.1%, AA -0.9% Use of strict cut-off values may be problematic. Gum et al JACC 41:961 (2003) Kottke-Marchant et al JACC (in press 2007) 2

3 Tests Predict Clinical Aspirin Resistance Test Predicts MACE Bleeding Time NO PFA-100 YES J Neurology 250: IMPACT NO Aggregation (WB, PRP) YES JACC. 41: VerifyNow YES JACC 43: Plt Activation by Flow NO Plt TxB2 production NO Urinary 11-dehydro TxB2 YES Circulation 105: Journal of Thrombosis and Haemostasis;3(6): (2005). Aspirin Resistance (Lack of pharmacodynamic response) Prevalence estimates vary from 5 to 60 % No consensus definition No consensus on measurement method(s) Are results compared to patient baseline or population ranges? No consensus on cut-off, or whether one should be used No consensus on treatment options SNPs AA Uninhibited COX in Nucleated cells Potential Mechanism of Aspirin Resistance: Intrinsic Mechanisms Phospholipase A2 Arachidonic Acid PGG2, PGH2 TxA2 COX-2 Inducible COX-2; turnover P2Y1 P2Y12 SNPS GP IIb/IIIa SNPs (PLA2) Effect of NSAIDs ASA Ibuprofen Aggregation (1) 81 mg (2) 2hr 400 mg Inhibited 24hr (2)+2hr 81 mg (1) 400 mg 40% inhib 6hr 81 mg next day 400 mg tid No inhibition Catella-Lawson, et al. N Engl J Med. 2001;345: Position Paper of the ISTH A clinically meaningful definition of aspirin resistance needs to be developed, based on data linking aspirin-dependent laboratory tests to clinical outcomes in patients. The correct treatment, if any, of aspirin resistance is unknown. No published studies address the clinical effectiveness of altering therapy based on a laboratory finding of aspirin resistance. It is not currently appropriate to test for aspirin resistance in patients or to change therapy based on such tests. Michelson et al, J. Thromb Haemost. 3:1309 (2005). P2Y 12 G i2 Accelerated aggregation, release Gα i2 Clopidogrel INHIBITS Adenylate cyclase - camp VASP VASP-P PK Active Drug Decreased aggregation, Decreased release P2Y 12 STIMULATED Adenylate cyclase + G i2 Gα i2 camp VASP VASP-P PK 3

4 Clopidogrel Efficacy Effective Anti- Agent in Established Cardiovascular Disease Unstable angina (CURE): ASA+CLO reduced composite endpoint 20% vs. ASA alone Yusuf S, NEJM 345:494 (2001) Stenting (CREDO): 26.9% risk reduction Steinhubl SR, JAMA 288:2411 (2002) MI (CLARITY-TIMI 28): 20% risk reduction with addition of CLO to ASA+thrombolytics Sabatine MS, NEJM, 352:1179 (2005) Lower-risk (CHARISMA): ASA+CLO not more effective than ASA Bhatt DL, NEJM 354:1706 (2006) Clopidogrel: Aggregation Arachidonic A. Clopidogrel + Aspirin Clopidogrel Resistance <10% inhibition of aggregation vs. pre-clopidogrel baseline. Time 2 hr % CLO Resistant 5uM 20 um 63% 53% Study Jaremo 2002 Gurbel 2003 Clopidogrel Resistance N Patients Clopidogrel dose (mg) 300/75 300/75 Time 24 hr 24 hr CLO Resistance 28% 31-35% 24 hr 31% 35% Mueller /75 4 hr 5-11% 5 days 30 days 31% 32% 11% 21% Kesmarkey 2003 Total CVD 75-31% 5-35% Gurbel PA, Circ 107;2908 (2003) Gurbel PA, et al. Curr Pharm Design 2006:12:1261 Clinical Implications CLO-Res with MI and 6 mo follow-up: 40% adverse cardiovascular event vs. 0% of non-resistant patients (p=0.007). ( aggregation and Cone and Plate(let)) Matetzky Circulation 109:3171(2004) A study of vasodilator-stimulated phosphoprotein phosphorylation in CLO increased platelet activation with subacute stent thrombosis (63%) vs. those without (39.8%; p<0.0001). Barragan Cathet Cardiovasc Intervent 59:295(2003). Availability clopidogrel (Pro-Drug) 2-oxoclopidogrel Postulated Mechanisms of Clopidogrel Resistance Genetic Polymorphisms Atorvastatin (CYP3A4 inhibitor) Liver Cytochrome P450 CYP3A4 and CYP3A5 CYP1A2 and CYP2B6 Active Drug P2Y 12 Count? Other drugs? G i2 - camp Accelerated aggregation, release Adenylate cyclase Increased turnover 4

5 P2Y12 Genomics and Clopidogrel Fontana (Circulation 2003) H1 (major) i-139c, i-744t, no ins801a, G52 H2 (minor) i-139t, i-744c, +ins 801A, T52 P2Y12 H2 Haplotype Associated with Increased Aggregation 82.4% 67.9% 34.7% Fontana, et al, Circulation 108:989 (2003) Fontana, et al, Circulation 108:989 (2003) P2Y12 H2 Haplotype and Disease Fontana, et al: The H2 haplotype had an association with PAD with OR2.3 (CI, ) after adjusting for DM, smoking, HTN, Chol, polymorphisms. Circulation 108:2971 (2003) Ziegler, et al: In 473 PAD patients, 34T was associated with increased risk of ischemic stroke (4.02 Risk; 95% CI ), but not with PAD Stroke 36:1394 (2005) Von Beckerath N, et al: P2Y12 gene H2 haplotype is not associated with increased adenosine diphosphateinduced platelet aggregation after initiation of clopidogrel therapy with a high loading dose. Blood Coagul Fibrinolysis Apr;16(3): (Also Smith SM, et al s : ) CYP 3A5 Genetics and Clopidogrel Outcome 1 mo: Death, MI, CVA 1-6 mo: Death, MI, CVA 6 mo cumulative 348 stent patients: 1-6 mo Outcomes Non-Expressor Expressor P value (*3*3) n=193 (*1*1 or *1*3) n= Suh CMAJ 174:1715 (2006) WB Na Citrate hscrp, WBC, Plt, MPV, Chol, HDL GeneQuest patients with a history of MI Included 461 patients taking aspirin (325 mg qd). Excluded patients taking other anti-platelet drugs. PRP Aggregation: 10 um ACA 0.5 mg/ml Lysate Indomethacin EDTA Aggregation % at 10 minutes Aggregation % - Maximal COX-2 TxB2 (EIA) Polymorphisms in the GeneQuest2 Population Examined 7 candidate SNPs in the, COX-2, GPIIIa, P2Y1 genes Patients with P2Y1 (C/T 893) had increased association with Aspirin Resistance Gen. AS AR OR Adj OR CC CT (1.36,7.36) 2.72(1.12,6.57) TT 0 0 Jefferson, et al. Am J Cardiol 95: (2005). 5

6 Selection of Tag SNPs for P2Y12 Bins: SNP Association Summary = Significant association Odds Ratios Murugesan et al To be presented ISTH 2007 AA Aggregation >20% HX CABG #PRIOR MI S SNP No. and Base 1 C>A 2 G>A 3 ->A 4 T>C 5 G>T 6 C>T 7 C>T 8 C>T 9 C>A 10 C>T 11 C>T 12 C>T 13 A>G 14 G>A 15 T>C 16 A>G 17 A>G 18 C>G 19 A>G 20 C>A 21 G>A HX CABG = Significant association by Bonferroni and/or FDR #PRIOR MI S Summary Genomic analysis of P2Y12 gene for GQ2 shows: association with increased platelet aggregation to arachidonic acid in the region of SNPs 3,4,6 and 7 for patients on aspirin Some overlap with Fontana SNPs Includes one new SNP association with decreased prevalence of CABG for SNP18 combined mutants association with more than one prior MI for homozygous SNP 20 mutants Murugesan et al; To be presented ISTH 2007 How should Aspirin and/or clopidogrel resistant patients be treated? Ongoing studies ASCET (Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial) In aspirin resistant patients with CAD, does switching to clopidogrel improve clinical outcomes? RESISTOR (Research Evaluation to Study Individuals Who Show Thromboxane or P2Y(12) Receptor Resistance) Does modifying antiplatelet regimen prevent myonecrosis after in patients with aspirin and clopidogrel resistance? Summary Suboptimal response to aspirin and clopidogrel is seen in a substantial proportion of patients Data suggests an association with adverse outcomes more studies are needed Little agreement on optimal laboratory measurement techniques No standard definition of suboptimal response Genetic studies are starting to indicate genetic influence of phenotypes Awaiting results of treatment-based clinical trials for guidance on adjusting therapy based on laboratory testing 6