Multiple Pathways Lead to Platelet Adhesion Activation and

Multiple Pathways Lead to Platelet Adhesion, Activation and Aggregation Flowing disc-shaped platelet Rolling ball-shaped platelet Hemisphere-shaped platelet Spreading platelet

Thromboxane A 2 is a Key Participant in Recruiting Additional Platelets to the Arterial Thrombus Tx. A 2 5 -HT DENSE GRANULE ADP Non-activated Platelet

Aspirin in Acute Coronary Syndromes • Aspirin 160 -325 mg immediately • Not enteric coated aspirin 6 -8 hr delay in peak effect!

TREATMENT AND PREVENTION OF ARTERIAL THROMBOSIS WITH ASPIRIN • ACUTE CORONARY SYNDROMES: Unstable Angina Non-ST-Segment Elevation MI (NSTEMI) ST-Segment Elevation MI Loading dose, then continued low daily dose ∙ PERCUTANEOUS CORONARY INTERVENTIONS Therapeutic Regimen: Immediate loading dose Concurrent antiplatelet drugs Continuing administration, 2º Prevention

TREATMENT AND PREVENTION OF ARTERIAL THROMBOSIS WITH ASPIRIN • STATUS POST-MI 2º Prevention • STROKE AND TIA 2º Prevention • STABLE ANGINA PERIPHERAL VASCULAR DISEASE

Benefits and Risks of Low-Dose Aspirin in Primary-Prevention Trials Patrono C et al. N Engl J Med 2005; 353: 2373 -2383

LOW DOSE ASPIRIN SELECTIVELY TARGETS THE PLATELET CYCLOOXYGENASE

Aspirin’s Effect on the Platelet Cyclooxygenase • Aspirin inhibits the cyclooxygenase irreversibly by acetylating the enzyme on a serine in the catalytic site (serine 529 in human COX-1). • Platelet can’t express new cyclooxygenase • Inhibition of the cyclooxygenase for the lifetime of the platelet (~ 10 days) • Cumulative inhibition of platelet cyclooxygenase with low dose aspirin

ACCUMULATION OF EFFECT OF LOW DOSE ASPIRIN ON PLATELET COX 2 4 6 DAYS 8 10 12 14

Effect of Aspirin on Thromboxane A 2 Biosynthesis by Platelets Thromboxane B 2 (pg/mg) Single dose of aspirin (mg)

Effect of Daily Dose vs. Single Dose of Aspirin on Thromboxane A 2 Biosynthesis by Platelets

Effect of Aspirin on Thromboxane A 2 Biosynthesis by Platelets Thromboxane B 2 (pg/mg) Single dose of aspirin (mg)

Effect of Aspirin on Prostacyclin Biosynthesis in Human Aorta 6 -keto-PGF 1 (pg/mg) Single dose aspirin (mg)

Concentration of Aspirin Portal Vein Hepatic Vein Systemic Circulation Peripheral Vessels & Tissues

RELATION OF ASPIRIN DOSE TO INHIBITION OF PROSTACYCLIN BIOSYNTHESIS

Major Bleeds CURE Study, Circ 108: 1682, 2003

DAILY DOSE OF ASPIRIN FOR CARDIOVASCULAR PREVENTION 81 mg. (75 – 100 mg. )

The Effect of Aspirin Alone and of Aspirin Plus Ibuprofen on Platelet Cyclooxygenase-1 Catella-Lawson F et al. N Engl J Med 2001; 345: 1809 -1817

Interaction of Aspirin with Other Cyclooxygenase Inhibitors • NSAIDs block access of aspirin to the serine in the COX catalytic site And block aspirin’s antiplatelet effect • COX-2 inhibitors do not interfere with the antiplatelet effect of aspirin, BUT they increase cardiovascular thrombotic events!?

CLOPIDOGREL PHARMACOLOGY • Blocks binding and action of ADP • Converted to active metabolite via CYP 3 A 4 • Active metabolite irreversibly binds the P 2 Y 12 ADP receptor • At steady state, T/2 > 24 hours • Effect additive to aspirin

CLOPIDOGREL • Effective in Unstable Angina, Non-ST-Segment Elevation MI, and Percutaneous Coronary Interventions (combined with aspirin) • Effective in Secondary Prevention of Stroke & MI (not combined with aspirin) • Loading dose 600 Mg; Maintenance dose 75 mg/day • Neutropenia NOT the problem seen with ticlopidine • Thrombotic Thrombocytopenic Purpura

Before clopidogrel Inhibition of ADP-induced aggregation by clopidogrel is greatest in individuals with high CYP 3 A 4 activity. On clopidogrel CYP 3 A 4 activity measured by erythromycin breath test (expressed as % 14 CO 2 exhaled/hr)

Highly variable response to clopidogrel Matetzky: Circulation, Volume 109(25). June 29, 2004. 3171 -3175

Mechanisms of Variability in Clopidogrel Effect • Oral bioavailability limited by P-glycoprotein - polymorphisms in P-gp • Metabolism to active metabolite dependent on CYP 3 A 4 - polymorphisms in CYP 3 A 4 - inhibitors of CYP 3 A 4

PRASUGREL A thienopyridine P 2 Y 12 antagonist • Prasugrel currently in advanced development • Onset of action more rapid than clopidogrel • Larger fraction converted to active metabollite • Less variability in inhibiting ADP-induced aggregation (cf. clopidogrel)

FIBRINOGEN RECEPTOR ANTAGONISTS • Intravenous agents: - abciximab (Reopro) antibody - tirofiban (Aggrastat) small molecule - eptifibatide (Integrilin) peptide • Oral agents: - ineffective or worse

DIPYRIDAMOLE • Augments adenosine action by blocking its uptake and removal from plasma. • Sustained release dipyridamole 200 mg combined with aspirin 25 mg (Aggrenox) given BID • Effective in the secondary prevention of stroke.

Multiple Pathways Lead to Platelet Adhesion, Activation and Aggregation Flowing disc-shaped platelet Rolling ball-shaped platelet Hemisphere-shaped platelet Spreading platelet

Thromboxane A 2 Metabolite Predicts Cardiovascular Events During Aspirin Therapy Eikelboom et al, Circ. , 2002

RELATION OF ASPIRIN DOSE TO INHIBITION OF PROSTACYCLIN BIOSYNTHESIS PGI-M (%control)