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ASPIRIN RESISTANCE

ASPIRIN RESISTANCE. Oxford 1763. Paul RJ Ames, MD, MSc, PhD Immunoclot Ltd, Leeds, UK William Harvey Research Institute. Queen Mary University London Department of Haematology , St George’s Hospital, London, United Kindom. Introduction. Aspirin Resistance

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ASPIRIN RESISTANCE

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  1. ASPIRINRESISTANCE Oxford 1763 Paul RJ Ames, MD, MSc, PhD Immunoclot Ltd, Leeds, UK William Harvey Research Institute. Queen Mary University London Department of Haematology, St George’s Hospital, London, United Kindom

  2. Introduction • Aspirin Resistance • Urinary 11-dehydro Thromboxane B2 measurement in Diabetes Mellitus and ACS

  3. ASPIRIN AND VASCULAR DISEASE • ASA weak agent for prevention of vascular disease • Relative risk reduction in MI is 20-25% • Relative risk of cardiac death is 25% • Relative risk reduction in IS is 15-20% (low rates) • Re-stroke prevalence on ASA is 30-40% • ASA safe and inexpensive

  4. ASA INHIBITION OF CYCLO-OXYGENASE Sweeny JM et al. Nat Rev Cardiol 2009

  5. THOMBOXANE GENERATION

  6. ASPIRIN RESISTANCE CLINICAL ASA resistance Persistent platelet reactivity despite ASA use ASA failure Thrombotic event despite ASA use BIOCHEMICAL ASA insensitive thromboxane generation

  7. ASPIRIN RESISTANCE • DRUG RELATED • Pharmacokinetics • Insufficient bioavailability (low dose) • Prevention of access to COX-1 binding site by NSAIDS • Pharmacodynamics • Impaired sensitivity of platelet COX-1 (CABG) • COX-1 gene polymorphism

  8. ASPIRIN RESISTANCE • DISEASE RELATED • PLT reactivity (residual PLT activity) • PLT stimulation by ASA insensitive mechanisms (ADP, shear stress) • PLT stimulation by COX-2 dependent TBX generation (PLT mediated) • PLT sensitising by isoprostanes

  9. OVERCOMING ASA RESISTANCE

  10. Cut-off determination • Studied over 300 apparently healthy adults before and after receiving controlled doses of ASA • Based on the resulting frequency of 11dhTxB2 levels, a cut-off value was established to assess an adequate ASA response at 1,500 pg/mg of 11dhTxB2/creatinine • This cut-off has been re-confirmed in subsequent studies using both healthy and diseased populations before and after ASA ingestion [27]. • Those individuals with urinary 11dhTxB2 levels after ASA ingestion below the cut-off of 1,500 pg/mg are considered good ASA responders while those with levels above 1,500 pg/mg are poor ASA responders (“ASA resistance”).

  11. Atherosclerotic Cardio Vascular Disease (CVD) Chronic, progressive (frequently asymptomatic) disease that may start early in life. Multi-factorial with 2 main components: • Systemic (circulation) • Platelet activation/aggregation (thromboxane-mediated) • resulting in arterial (and venous) hypercoagulability, • endothelial dysfunction, clotting factor activation, etc. • Focal (tissue) • Oxidative & nitrativechronic inflammation (dyslipidemia, oxLDL) macrophage activation, foam cell fomation, lymphocytes (immune response) with plaque formation in arterial wall.

  12. THROMBOXANE BIOSYNTHESIS BY CYCLOOXYGENASE ACTIVATION PATHWAYS Membranephospholipids Inflammatory COX-2 Pathway Platelet COX-1 Pathway PLA2 PLC Aspirin TX-synthase/Peroxidase Peroxidase/TX-synthase Arachidonic acid TXA2 TXA2 PGH2/PGG2 PGG2/PGH2 COX-2 COX-1 Hydrolytic inactivation Hydrolytic inactivation Serum TXB2 Urinary 11dhTXB2 AspirinWorks® ELISA test measures TxBCardio Assay

  13. Key Publications on 11dhTxB2 HOPE Study (2002) • Multi-centre study in Canada • 976 aspirin-treated patients who had suffered a previous CVD event • Sub-study of a larger 5000 patient clinical trial on clopidogrel • 11dhTxB2 (Corgenix assay) measured at baseline, then patients followed for 5 years • 488 patients suffered another event (case), 488 did not (controls)

  14. Key Publications on 11dhTxB2 HOPE Study (2002) Results: • Increased 11dhTxB2 predicts increased composite risk of MI, stroke or death • For death in particular, the highest quartile of 11dhTxB2 concentrations equated to a 3.5 fold increased risk • 11dhTxB2 could be used to prospectively identify aspirin resistant patients who may benefit from additional aspirin doses or additional medication

  15. Key Publications on 11dhTxB2 HOPE Study (2002)

  16. Key Publications on 11dhTxB2 CHARISMA Study (2008) • Follow-up to HOPE (2002) study, in an attempt to validate the findings • Sub-study of main CHARISMA (multi-centre, multi-national 15,000 patient trial on clopidogrel) • Measured 11dhTxB2 (Corgenix assay) in 3261 aspirin-treated patients at least one month after being assigned to placebo or clopidogrel

  17. Key Publications on 11dhTxB2 CHARISMA Study (2008) Results: • Validated findings of HOPE study in this new cohort • 11dhTxB2 is an independent, modifiable predictor of CVD risk • Found that both increased aspirin & statin therapy reduced 11dhTxB2 & risk

  18. URINARY 11DHTXB2 PRE POST ASA IN 49 HEALTHY VOLUNTEERS PRE POST 81 mg ASA PRE POST 325 mg ASA ASPIRIN WORKS KIT: 1500 pg/mg cut-off to discriminate ASA responders from non-responders established on healthy volunteers post ASA ingestion (7 Days)

  19. URINARY 11DHTXB2 PRE POST ASA 81 MG IN 117 HEALTHY INDIVIDUALS PRE POST ASPIRIN WORKS KIT: 1500 pg/mg cut-off to discriminate ASA responders from non-responders established on healthy volunteers post ASA ingestion (7 Days)

  20. 1- DM STUDY: 11DHTXB2 BY SEX, AGE, DISEASE DURATION Females 50.9% higher than males

  21. 1- DM STUDIES BASELINE 11DHTXB2 PG/MG CREATININE Healthy controls Diabetes Melitus DM 69.5% higher than healthy controls

  22. 2- DM STUDIES 11dhTxB2 PRE POST ASA 71.5% suppression 14.8% AR 75.1% suppression 8.4% AR Level of 11dhTxB2 suppression equal, but DM more Aspirin “resistance” (8 vrs 15%).

  23. 2-DM: INFLAMMATORY/OXIDATIVE MARKERS UNAFFECTED BY ASA 11dhTxB2 and 8-isoPGF2a pre & post ASA PRE POST 81 mg ASA PRE POST 81 mg ASA DM significantly higher baseline and post-ASA TxB2 and PGF2a than controls. But only TxB2 (COX-1) was affected by ASA. Ames PRJ et al. Aspirin insensitive thromboxane generation is associated with oxidative stress in type 2 diabetes mellitus Thromb Res 2012; 130:350-354

  24. 3- ACS PCI STUDIES (BEFORE AND AFTER ASA) 81.6% suppression 28.7% AR Matsuura EE. On aspirin treatment but not baseline thromboxane B2 levels predict adverse outcomes in patients with acute coronary syndromes. J ThrombHeamost 2012;

  25. SUMMARY 11DHTXB2 STUDIES OF DM AND ACS Baseline 11dhTxB2 levels 100,000 % ASA poor-responders Upper range 20,000 10,000

  26. MEAN URINARY EXCRETION OF 8-ISO-PGF2Α IN UNSTABLE ANGINA, CHRONIC STABLE ANGINA AND IN HEALTHY SUBJECTS. Cipollone F et al. Circulation. 2000;102:1007-1013

  27. URINARY 11-DEHYDRO-TXB2 IN MATCHED PATIENTS WITH UNSTABLE ANGINA AND CHRONIC STABLE ANGINA. Cipollone F et al. Circulation. 2000;102:1007-1013

  28. CORRELATION BETWEEN URINARY EXCRETION RATES OF 8-ISO-PGF2Α AND 11-DEHYDRO-TXB2 IN PATIENTS WITH SEVERE UNSTABLE ANGINA. Cipollone F et al. Circulation. 2000;102:1007-1013

  29. URINARY 8-ISO-PGF2a & 11-DEHYDRO-TXB2 IN PATIENTS WITH STABLE ANGINA WITH CHRONIC ASA THERAPY COMPARED WITH NON ASA REATMENT. Cipollone F et al. Circulation. 2000;102:1007-1013

  30. Assay Key Features

  31. TxB Cardio vs Corgenix ELISA Correlation Data 11dhTxB2 (pg/ml) – TxB Cardio ITA 11dhTxB2 (pg/ml) – Corgenix EIA

  32. CLINICAL INTERPRETATION OF 11DHTXB2 LEVELS PRE & POST ASA TREATMENT AND DECISION MAKING ALGORITHM 11dhTxB2 levels before ASA ASA effect for CVD risk assessment <2,500 OK ASA i n g e s t I o n <1,500 Good response OK Consider: CVD risk factors and ASA response 2,500- 10,000 “Increased Risk” >1,500 Poor response Evaluate: CVD risk factors and ASA response >10,000 • poor COX-1 TxA2 inhibition – modify ASA dose or add other anti-platelet drugs. • Non-platelet COX-2 TxA2 production from pro-atherogenic oxidative inflammation – modify/treat CVD risk factors.

  33. Summary • Up to 30% patients prescribed aspirin may still undergo vascular occlusions • Urinary 11-dehydro-Thromboxane excretion reflects platelet activity in vivo • Measured using TxBCardio assay • Correlates with ELISA assay • Available for automated clinical chemistry analysers.

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