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Introduction to Aspirin Resistance.

Introduction to Aspirin Resistance. May 10, 2004 Steven R. Steinhubl, MD. Aspirin History. (From the German a cetyl spir saure + chemical suffix – in ). First synthesized in pure form by Felix Hoffman of Friedr. Bayer & Co. in 1897. Aspirin History.

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Introduction to Aspirin Resistance.

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  1. Introduction to Aspirin Resistance. May 10, 2004 Steven R. Steinhubl, MD

  2. Aspirin History (From the German acetylspirsaure + chemical suffix – in) First synthesized in pure form by Felix Hoffman of Friedr. Bayer & Co. in 1897.

  3. Aspirin History Due to problems with the original Aspirin powder being counterfeited, it became the first pharmaceutical agent ever sold in pill form in early 1900’s. First pill in USA was 5 grains (~325 mg).

  4. Aspirin Metabolic Pathways ofArachadonic Acid Membrane Phospholipids ARACHIDONIC ACID COX-1 Prostaglandin H2 • Thromboxane A2 •  Platelet Aggregation • Vasoconstriction • Prostacyclin •  Platelet Aggregation • Vasodilitation

  5. Aspirin in the Treatment of ACS 0.25 0.20 0.15 0.10 0.05 0.00 Placebo Probabilityof Death or MI Aspirin 75 mg Risk ratio 0.5295% CL 0.37-0.72 0 3 6 9 12 Months Wallentin LC, et al. JACC 1991;18:1587-93.

  6. Placebo alone: 568/4300 (13.2%) 600 Aspirin alone: 461/4295 (10.7%) 500 Streptokinase alone: 448/4300 (10.4%) 400 Cumulative Number of Vascular Deaths 300 Streptokinase plus aspirin: 343/4292 (8.0%) 200 100 0 7 14 21 28 35 Aspirin in Acute Myocardial Infarction: ISIS-2 Days From Randomization

  7. Heparin 10,000 units ASA / Dipyridamole + Heparin 12.6 Ticlopidine + Heparin 6.9 • 75% P<0.001 • 77% P=0.0113 3.2 2.4 1.6 Randomized Trials of Aspirin in PTCA % Major Ischemic Complications 12 8 4 0 Schwartz et al N=376 White et al N=337 Schwartz, N Engl J Med 1988;318:1714 White, Coronary Artery Disease 1991;2:757

  8. What is “Aspirin Resistance?” • Inability of ASA to prevent treated patients from having thrombotic events. • Inability of ASA therapy to prolong bleeding time. • Inability of treatment with ASA to prevent thromboxane biosynthesis. • Inability 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;1:1710-3

  9. Inter-Individual Variability in Response to Aspirin N=10 Quick AJ. American Journal of Medical Science Sept 1966:265-9

  10. Responders (58%) Mean BT  58 + 10 % Non-responders (42%) Mean BT  2 + 4 % Interpatient Variability in Aspirin Response - Bleeding Time Aspirin, 325 mg daily in 40 CABG patients 900 700 Bleeding Time Post-ASA 500 300 100 100 300 500 700 900 Bleeding Time, Pre-ASA Buchanan,Can J Cardiol 1995;11(3):221

  11. Aspirin Responsiveness and Clinical Outcome 181 patients, following CVA. Aspirin 500 mg TID. Followed-up for 24 months. % of Patients Without Event 100 95% Aspirin Responders N=114 75 P<0.0001 60% Aspirin Non-responders N=60 50 6 12 18 24 Months of Observation Grotemeyer, Thrombosis Research 1993;71:397

  12. Odds Ratio for MI, Stroke or CV Death 2 1.8 1.4 1.3 1 1.0 0 < 15.1 15.1 - 21.8 21.9 - 33.8 > 33.8 Uninary 11-dehydro thromboxane B2 (ng/mmole creatinine) Thromboxane Biosynthesis on Aspirin and CV Events Eikelboom Circ 2002;105:1650 HOPE Trial N=488, with 5 yr f/u

  13. Aspirin Responsiveness By PFA-100 and Aggregometry 325 patients with stable ASCAD Partial Responders 23.8% Resistant 5.5% 9.5% 90.5% Aspirin Sensitive 70.7% Aspirin Sensitive Aggregometry Response to ADP and AA PFA-100 Gum P. Am J Cardiol 2001;88:230-235

  14. % Death, MI, CVA 20 P=0.4 15 Clinical Outcomes based on PFA-100 Results 15.1 12.9 10 5 0 ASA Responder N=294 ASA Non-Responder N=32 Clinical Outcomes: Aspirin Responsive-ness by Aggregometry And PFA-100 % Death, MI, CVA Not Aspirin Resistant, N = 309 40 Aspirin Resistant, N = 17 Log rank 2=5.05, p=0.03 20 0 0 200 400 600 800 0 200 400 600 800 Days after Treatment Gum, P. JACC 2003;41:961-5

  15. Possible Mechanisms for Variability in Response to Aspirin • Decreased bioavailability • Non-compliance • Concomitant NSAIDs • Platelet function • Accelerated platelet turnover • Increased platelet COX-2 • Platelet Receptor Polymorphisms • Other factors DeGaetano G. J Thromb Haemost 2003;1:2048-50

  16. Non-Enzymatic Lipid Peroxidation Catalyzed by Free Radicals 12-Lipoxygenase 12-HETE, 12-HPETE -  Platelet Adhesivity • Isoprostanes • Amplifies platelet response • to other agonists. • Vasoconstrictor • Plasma levels 1-2 orders • of magnitude > COX • -derived metabolites. Metabolic Pathways of Arachadonic Acid Membrane Phospholipids ARACHIDONIC ACID COX-1 Aspirin Prostaglandin H2 • Thromboxane A2 •  Platelet Aggregation • Vasoconstriction • Prostacyclin •  Platelet Aggregation • Vasodilitation

  17. % Aggregation 80 PlA1/A1 P=0.02 60 P=0.01 40 PlA1/A2 20 0 0.1 1 10 100 Aspirin µmol/L PlA2 Polymorphism and Aspirin Resistance PlA2 Polymorphism Single nucleotide polymorphism - Proline for a leucine at position 33 of 3 subunit. ~25% of individuals of N. European ancestry are PlA2 +. Cooke, Lancet 1998;351:

  18. Aspirin Resistance: Role of COX-2 ? • Aspirin is 170-fold more potent inhibitor of COX-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) Weber A-A Lancet 1999;353:900

  19. Conclusions • Every study that has ever evaluated individual responsiveness to ASA has found marked variability. • Most studies have been able to correlate this variability with a clinically significant increase in thrombotic events. • The 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.

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