Conflicts of interest Very balanced Lilly and team, AZ and BMS
Distal microcirculation receives platelet microparticles Release TxA 2 and plugs microcapillaries
Healthy vascular endothelium Prevents (antithrombotic factors) CD39 (ectoadpase), prostaglandin, nitric oxide, heparin, matrix metalloproteinase-9, protein S, and thrombomodulin
Risk factors.just add wall stress Collagen type 1 Very thin cap Large atheroma volume Increased necrotic core Thin cap Plaque burden >70% Risk factors in ACS for a CV event Minimal luminal area <4 mm 2 Collagen type III Very thick cap (reparative) 22% event rate / yr PROSPECT trial Motoyama Moreno et al JACC img 2012;5:178
Ruptured plaque with prothrombosis and platelet microparticles chest pain
Acute coronary syndrome Unstable angina Negative biomarkers NSTEMI Positive biomarkers ST elevation MI Positive biomarkers Higher biomarkers---higher mortality
Elevated Cardiac TnI Predicts Increased Mortality at 42 Days in Patients With ACS Patients with unstable angina or non Q wave MI enrolled in a multicenter study (N=1,404) Cardiac TnI (ng/ml) n Mortality at 42 days (%) 0 to <0.4 831 1.0 0.4 to <1.0 174 1.7 1.0 to <2.0 148 3.4 2.0 to <5.0 134 3.7 5.0 to <9.0 50 6.0 Risk Ratio (95% CI) 1.0 1.7 3.5 3.9 6.2 7.8 9.0 67 7.5 0 10 20 Antman EM, et al. N Engl J Med. 1996;335(18):1342-1349
Increased 1-year Survival in TnI- Negative ACS Patients Subgroup of patients (n=734) with suspected ACS enrolled in a phase III study -TnI +TnI Newby LK, et al. Circulation. 1998;98(18):1853-1859
Events leading to Reperfusion Induced inflammatory Injury Time is Muscle 80 70 60 50 40 30 20 10 0 % Necrosis 28 70 72 Most viable area subepicardial tissue 79 40 minutes 3 hours 6 hours Closed molecular changes during MI.pdf Time of reperfusion Ambrosio Am Heart J 1999;138:s69 Reimer KA. Lab Invest. 1979 Jun;40(6):633-44
LV remodeling correlates with death Unstable angina Non STEMI Acute Cellular protection Acute MI (ST; + biomarkers) Long-term Matrix remodeling BB and ACEI
Age- and Sex-Adjusted Incidence Rates of Acute Myocardial Infarction, 1999 to 2008 N Engl J Med 2010;362:2155-65
ACS, patients with diabetes and UA/NSTEMI the risk of similar to non diabetes patient with STEMI (7.2% vs 8.1%) UA/NSTEMI STEMI TIMI study group ( 11 trials) 62 036 patients Cumulative Incidence of All- Cause Mortality through 1 year after ACS Diabetes No diabetes Diabetes No diabetes Thrombolysis in Myocardial Infarction (TIMI) Study Group JAMA. 2007;298(7):765-775
Basic science-cardiovascular hematology
oxldl & monocyte derived tissue factors activate thrombosis and inflammation Injury to endothelial wall LDL infiltrate wall Autoantibodies against oxldl oxldl Monocytes recruited and up LDL via TLR4 receptor Activation of platelets / tissue factor Microparticle (MP)TF activity
Humans with FH have increased prothrombotic / inflammatory risk TAT- thrombin-anti-thrombin complex JCI 2012;122:558
Statin significantly lower tissue factor activity TAK-242-inhibits TLR-4 JCI 2012;122:558
Statins work N engl j med 366;19 nejm.org may 10, 2012:1752
Lipids are involved in the prothrombotic state
Statins significantly reduce inflammation and prothrombosis Reduce LDL in lipid core Reduce oxidative stress Reduce oxidation of LDL Inhibit expression of CD36/TLR4/TLR6 Inhibit expression of monocyte tissue factor Inhibit release of tissue factor + microparticles
Platelets are activated by many conditionsincreasing prothrombotic state Anti-thrombins Agonist Receptor LDL Activation of platelets is mediated by CD36 CD-36 Platelet IP3 Arachidonic acid Prost G2 Prostacyclin ADP TxA 2 others Thromboxane A2 IP3 ADP ADP receptor Irreversible Oral clopidogrel/ prasugrel Inflamed MONOCYTE Ticagrelor (reversible) 2b3a receptor oxldl JCI 2012;122:558 Nat Med. 2007;13(9):1086 1095 Fibrinogen 2b3a receptor
Thrombin / necrotic core are the most potent activator of platelets High Glucose Activation of PKC & NFkB Induce PAR-4 expression VSMC Thrombin Responsiveness Enhancing vascular response to thrombin Control Dangwal et Arterioscler Thromb Vasc Biol. Mar 2011;31:xxx High Glucose
Thrombin is the most potent activator of platelets PAR-4 Increases Phosphoinositide hydrolysis Thromboxane A2 formation Increases Ca++ Suppresses camp by blocking adenylyl cyclase PAR 1 and 4 in humans PAR 1 most receptors on platelets PAR 4 increased with high glucose Non-Diabetes PAR 1 found on Platelets VSMCs Endothelial cells Fibroblasts Neurones PAR 4 located on Platelets VSMCs Others Diabetes Purple (b and e), PAR-4 on human saphenous vein Dangwal et Arterioscler Thromb Vasc Biol. Mar 2011;31:xxx
Platelet receptors Thrombin / necrotic core are the most potent agonist for human platelets, whereas serotonin and epinephrine are weak agonists Size of arrow = strength of stimulus Blood, Vol 93, No 10 (May 15), 1999: pp 3408-3417
Tissue factor Collagen Factor VIIa X IX IXa Warfarin (Vit K antagonist) Synthesis of factors II, VII, IX, and X requires vitamin K Propagation Key position VIIa Va Xa Direct thrombin inhibitors Platelets II (prothrombin) Thrombin Activation Thrombin (IIa) Fibrinogen Fibrin Aggregation Clotting
Inflammation leads to increased prothrombosis Vascular inflammation Prothrombosis Positive staining (brown) for C-reactive protein (CRP) in macrophage foam cells (arrows) in intima Platelets to damaged areas of blood vessels and contribute to the formation of clots. Turk et al J Appl Physiol 2003;95: 1301 1304 NIH.gov
GOLD trial-how much platelet inhibition do you need Summary of anti-platelet trials TIMI-38 Prasugrel, age less than 75 and pre cath PLATO- Ticagrelor, >75 and all comers Rivaroxaban in Patients with a Recent Acute Coronary Syndrome ACS clinical trials
GOLD Trial: PCI major adverse cardiac events with poor platelet inhibition N=500 PCI patients 25 20 25 2b3a inhibitors MACE Composite of death, myocardial infarction, and urgent target vessel revascularization 15 14.4 P<0.006 P<0.009 10 6.4 8.1 5 0 <95% INHIB 10 min >95% INHIB 10 min <70% INHIB @ 8 hrs >70% INHIB @ 8 hrs Circulation. 2001;103:2572-2578
Landmark anti-platelet trials in ACS Placebo arm Ticagrelor NEJM 2009;361:1108
TIMI 38: Study Design ACS (STEMI or UA/NSTEMI) & Planned PCI ASA required Clopidogrel 300 mg LD 75 mg MD Double-blind N = 13,608 Prasugrel 60 mg LD 10 mg MD 1 o endpoint: CV death, MI, Stroke 2 o endpoints: Stent Thrombosis CV death, MI, Stroke, Rehosp-Rec Isch 30, 90 day: CV death, MI, Stroke, 30, 90 day: CV death, MI, UTVR Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies: Pharmacokinetic, Genomic Median duration of therapy:12 months Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
Primary Endpoint (CV death, MI, stroke, %) 15 TRITON TIMI 38 (ACS) HR 0.77 P = 0.0001 Clopidogrel 12.1 (781) 10 5 HR 0.80 P = 0.0003 Prasugrel 9.9 (643) HR 0.81 (0.73-0.90) P = 0.0004 NNT = 46 0 ITT = 13,608 LTFU = 14 (0.1%) 0 30 60 90 180 270 360 450 Days Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
TIMI 38 Bleeding Endpoints Overall cohort at 15 months Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
Ticagrelor vs Clopidogrel for ACS: PLATO PLATelet inhibition and patient Outcomes In NSTEMI and STEMI, current guidelines recommend 12 months aspirin and clopidogrel Efficacy of clopidogrel is hampered by Slow and variable transformation to the active metabolite Modest and variable platelet inhibition Increased risk of bleeding Risk of stent thrombosis and MI in poor responders Wallentin L, et al. N Engl J Med. 2009;361(11):1045-1057.
PLATO Study Design NSTEMI-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomized within 24 hours of index event (N = 18,624) Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre-pci) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-pci) 6 12-month exposure Primary endpoint: Vascular death + MI + Stroke Primary safety endpoint: Total major bleeding Wallentin L, et al. N Engl J Med. 2009;361(11):1045-1057.
Cumulative Incidence (%) Primary Efficacy Endpoint 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Clopidogrel 11.7 9.8 Ticagrelor HR 0.84 (95% CI 0.77 0.92) P = 0.0003 0 60 120 180 240 300 360 No. at risk Days after Randomization Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 Positive efficacy effect not observed in North American subgroup Wallentin L, et al. N Engl J Med. 2009;361(11):1045-1057.
Cumulative Incidence (%) Cumulative Incidence (%) Secondary Efficacy Endpoints Myocardial Infarction Cardiovascular Death 7 Clopidogrel 6.9 7 6 5 Ticagrelor 5.8 6 5 Clopidogrel 5.1 4 4 4.0 3 3 Ticagrelor 2 1 HR 0.84 (95% CI 0.75 0.95), P = 0.005 2 1 HR 0.79 (95% CI 0.69 0.91), P = 0.001 0 0 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Days after Randomization Days after Randomization Wallentin L, et al. N Engl J Med. 2009;361(11):1045-1057.
PLATO -major endpoints Ticagrelor (n=9,333) Clopidogrel (n=9,291) HR for (95% CI) p value 864 (9.8) 1,014 (11.7) 0.84 (0.77 0.92) <0.001 901 (10.2) 1,065 (12.3) 0.84 (0.77 0.92) <0.001 1,290 (14.6) 1,456 (16.7) 0.88 (0.81 0.95) <0.001 504 (5.8) 593 (6.9) 0.84 (0.75 0.95) 0.005 353 (4.0) 442 (5.1) 0.79 (0.69 0.91) 0.001 125 (1.5) 106 (1.3) 1.17 (0.91 1.52) 0.22 399 (4.5) 506 (5.9) 0.78 (0.69 0.89) <0.001 The percentages are K-M estimates of the rate of the endpoint at 12 months. N Engl J Med 2009; 361:1045-1057
K-M Estimated Rate (% per year) Time to Major Bleeding Primary Safety Event 15 10 Ticagrelor Clopidogrel 11.58 11.20 5 0 HR 1.04 (95% CI 0.95 1.13), P = 0.434 0 60 120 180 240 300 360 Days from First IP Dose Increased frequency of dyspnea observed with ticagrelor (13.8% vs 7.8%, P < 0.001) Wallentin L, et al. N Engl J Med. 2009;361(11):1045-1057.
NDA 22-433 Briefing Document for Cardiovascular and Renal Drugs Advisory Committee Meeting www.fda.gov/downloads/advisorycommitte es/.../ucm220197.pdf P. 106
CV Death, MI, or stroke (K-M%) at 12 months PLATO: use low dose aspirin n=956 n=15,439 n=1,052 BRILINTA Clopidogrel + aspirin + aspirin Aspirin 100 mg HR 0.77 (95% CI: 0.69-0.86) BRILINTA Clopidogrel + aspirin + aspirin Aspirin >100 mg - <300 mg HR 0.99 (95% CI: 0.70-1.40) BRILINTA Clopidogrel + aspirin + aspirin Aspirin 300 mg HR 1.45 (95% CI: 1.01-2.09) Caution
ASA dosage and Ticagrelor-CR advisory committee Platelet testing of active compounds and metabolites of ticagrelor, prasugrel and clopidogrel Panel of receptors and enzymes Found NO potential off target interactions Thromboxane A2 are potently inhibited by all 3 Hypothesis only High degree of p2y12 inhibition with all 3 agents Addition of ASA would not further improve platelet inhibition.but higher doses could reduce prostacyclin (PGI2) longer thus unopposed reduction of PGI2 leaves Thrombogenic and vasoconstrictive effect of ASA Short term reduces prostacyclin ASA-usually Blocks COX 1- reducing TxA2 Prostacyclin (PGI 2 ) chiefly prevents formation of the platelet plug and powerful vasodilator P86 NDA
NDA conclusion relative to ASA and Ticagrelor High-level P2Y 12 antagonism can inhibit both ADP-dependent and platelet TXA 2 -dependent pathways of platelet activation independently of ASA ASA dose-dependently inhibits TXA 2 synthesis, which reaches maximum effect at relatively low doses ASA reduces PGI 2 levels dose-dependently which could, particularly at high doses, negatively affect endothelial function, potentially facilitate platelet activation, and ultimately contribute to increased thrombotic risk.
P127 NDA
AHA/ACCF Secondary Prevention and Risk Reduction Therapy Guidelines: Use of Antiplatelets Class I Recommendation A P2Y 12 receptor antagonist in combination with aspirin is indicated in patients after ACS (Level of Evidence: A) For patients receiving a bare-metal stent or drug-eluting stent during PCI for ACS, clopidogrel 75 mg daily, prasugrel 10 mg daily, or ticagrelor 90 mg twice daily should be given for at least 12 months (Level of Evidence: A) Class IIa Recommendation After PCI, it is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses (Level of Evidence: B)
ACCF/AHA/SCAI Guidelines for PCI Class I Recommendations A loading dose of a P2Y 12 receptor inhibitor should be given to patients undergoing PCI with stenting (Level of Evidence: A). Options include (Level of Evidence: B): Clopidogrel 600 mg (ACS and non-acs patients) Prasugrel 60 mg (ACS patients) Ticagrelor 180 mg (ACS patients) The duration of P2Y 12 inhibitor therapy after stent implantation should generally be as follows: In patients receiving a stent (bare-metal stent [BMS] or drug-eluting stent [DES]) during PCI for ACS, P2Y 12 inhibitor therapy should be given for at least 12 months. Options include clopidogrel 75 mg daily, prasugrel 10 mg daily, and ticagrelor 90 mg twice daily (Level of Evidence: B) Class IIa After PCI, it is reasonable to use aspirin 81 mg per day in preference to higher maintenance doses (Level of Evidence: B)
4 take home points Time is muscle: open artery by PCI wins over drugs if done <90 minutes Platelets are extremely important in the prothrombotic state with inflammation and LDL Newer anti-platelet drugs block better than clopidogrel..but more bleeding Besure to use low dose ASA with ticagrelor Thank you