Farmaci antiaggreganti                Marco Cattaneo                 Clinica MedicaOspedale San Paolo – Università degli S...
PLATELET                                 GP IIb/IIIa                                Antagonists                           ...
Characteristics of the ideal                antithrombotic agent•Potent antithrombotic effect•Low risk•Predictable pharmak...
Kaplan-Meier estimates of mortality during the first 30 days among patients who         developed and those who did not de...
Reletionship between inhibition of platelet aggregation        and the risk of thrombosis or bleeding      Inhibition of h...
Characteristics of the ideal                antithrombotic agent•Potent antithrombotic effect•Low risk•Predictable pharmak...
Reletionship between inhibition of platelet aggregation        and the risk of thrombosis or bleeding      Inhibition of h...
Reletionship between inhibition of platelet aggregation        and the risk of thrombosis or bleeding      Inhibition of h...
INR-Specific Incidence of All Adverse Events (All Episodes of Thromboembolism, All Major                       Bleeding Ep...
Reletionship between inhibition of platelet aggregation        and the risk of thrombosis or bleeding      Inhibition of h...
“Evolution” of antithrombotic treatment ANTICOAGULANT Need for laboratory    monitoringNo Need for laboratory     monitoring
“Evolution” of antithrombotic treatment ANTICOAGULANT               ANTIPLATELET Need for laboratory        Need for labor...
ASPIRIN
Prevalence of “Aspirin resistance”But:Hillarp et al, 2003         122          Arachidonic acid-induced WB aggregation    ...
THIENOPYRIDINES
agonist                        ADP                               ADP             prostacyclin  specific                   ...
THIENOPYRIDINES               ACTIVE METABOLITES            N                 HOOC      N      S         Cl               ...
O                                         CH3                    HOOC        Nagonist                  S          Cl      ...
Prevalence of resistance to             antiplatelet agents• Aspirin (serum TxB2)                  ≈ 0-5% (*)• Clopidogrel...
Schematic representation of the metabolism              of clopidogrel                        Mega, J. L. et al. Circulati...
ORs for MACE, according to CYP2C19*2 allele (n=11,959),               and PPI use (n=46,037)                              ...
Risk for cardiovascular death, myocardial infarction, or stroke for subtypes of PPIs.Time-        dependent, propensity sc...
Kaplan–Meier Estimates of the Probability of Remaining Free of Primary Cardiovascular                        Events, Accor...
Other factors affecting the response to               clopidogrel                               Higher response   Lower re...
Response variability (“resistance”) to Clopidogrel                  The solution?                “Tailored treatment”: inc...
Who would dare arguing against?“Responders”“Non Responders”
Laboratory monitoring of clopidogrel therapy        Questions that need to be answered•   Which test of platelet function?...
Studio GRAVITAS
GRAVITAS Trial - Profile                      Price, M. J. et al. JAMA 2011;305:1097-1105
Cumulative Kaplan-Meier Estimates of the Time to the FirstAdjudicated Occurrence of the Primary Efficacy End Point        ...
Response variability (“resistance”) to Clopidogrel              Another solution?                Change the drug!
THIENOPYRIDINES                  ACTIVE METABOLITES               N                 HOOC      N         S         Cl      ...
Schematic representation of the metabolism      of clopidogrel and prasugrel                        Mega, J. L. et al. Cir...
Inhibition of ADP (20µM)-induced platelet aggregation                               Prasugrel 60+10                       ...
Reletionship between IPA by Clopidogrel 300 mg orPrasugrel 60 mg in response to 20 µM ADP 24 h after the loading dose     ...
Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points            during the Follow-up Period, in TRITON-T...
Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points            during the Follow-up Period, in TRITON-T...
Effects of Prasugrel and Clopidogrel active metabolites (AM)  on human platelet aggregation induced by ADP (10 µM)        ...
Reletionship between drug-induced inhibition of hemostasis           and the risk of thrombosis or bleeding         Inhibi...
Reletionship between IPA by Clopidogrel 300 mg orPrasugrel 60 mg in response to 20 µM ADP 24 h after the loading dose     ...
Short-acting, direct P2Y12 antagonists       (Cangrelor)       (Ticagrelor)
DISPERSE Study: Faster and More Consistent IPA With AZD6140 Than With Clopidogrel (Final Extent)        Clopidogrel 75 mg ...
IPA (%; 20 {micro}mol/L ADP, final extent) by protocol time and treatment                                          Gurbel,...
Cumulative Kaplan-Meier Estimates of the Time to the First Adjudicated            Occurrence of the Primary Efficacy End P...
Incidence of the primary end-point and non-CABG relatedTIMI-major bleeding events in patients who received ticagrelor vs p...
Major Efficacy End Points at 12 Months                 Wallentin L et al. N Engl J Med 2009;361:1045-1057
Held et al, JACC 2011
Short-acting, direct P2Y12 antagonists       (Cangrelor)       (Ticagrelor)
ELINOGREL• Elinogrel is direct-acting, competitive, reversible P2Y12 non-  nucleotide antagonist• IC50 ~2-3 µM in ADP aggr...
INNOVATE PCI - Adverse Events                                            Clopidogrel         Pooled elinogrel         Pool...
Dyspnea in PLATO trial                                           Ticagrelor ClopidogrelAll patients                       ...
Cangrelor and dyspnoea• CHAMPION PCI: a dyspnoea adverse event  was reported in 1.0% of patients receiving  cangrelor and ...
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Cattaneo le urgenze in ematologia 21 maggio 2011

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Cattaneo le urgenze in ematologia 21 maggio 2011

  1. 1. Farmaci antiaggreganti Marco Cattaneo Clinica MedicaOspedale San Paolo – Università degli Studi di Milano
  2. 2. PLATELET GP IIb/IIIa Antagonists GPIIb/IIIa Adhesive TxA2 protein ADP GPIIb/IIIa TxA2-R P2Y12 Arachidonic Acid ThienopirydinesCOX-1 ASPIRIN delta granule PGH2 TxA2 Tx synthase PLATELET
  3. 3. Characteristics of the ideal antithrombotic agent•Potent antithrombotic effect•Low risk•Predictable pharmakodynamic profile, making monitoringunnecessary•Rapid onset•Rapid offset*•Availability of an antidote•No interaction with food or adjunctive medicines commonlyused•Low cost* For safety reasons, a drug with rapid offset is generally preferable to a drug withlong-lasting effects, although the use of the latter might minimize the negative effectsof poor compliance.
  4. 4. Kaplan-Meier estimates of mortality during the first 30 days among patients who developed and those who did not develop major bleeding Eikelboom, J. W. et al. Circulation 2006;114:774-782
  5. 5. Reletionship between inhibition of platelet aggregation and the risk of thrombosis or bleeding Inhibition of hemostasis (%) “Responders” Thrombosis Bleeding “Non Responders”
  6. 6. Characteristics of the ideal antithrombotic agent•Potent antithrombotic effect•Low risk•Predictable pharmakodynamic profile, making monitoringunnecessary•Rapid onset•Rapid offset*•Availability of an antidote•No interaction with food or adjunctive medicines commonlyused•Low cost* For safety reasons, a drug with rapid offset is generally preferable to a drug withlong-lasting effects, although the use of the latter might minimize the negative effectsof poor compliance.
  7. 7. Reletionship between inhibition of platelet aggregation and the risk of thrombosis or bleeding Inhibition of hemostasis (%) “Responders” Thrombosis Bleeding “Non Responders” Time of treatment
  8. 8. Reletionship between inhibition of platelet aggregation and the risk of thrombosis or bleeding Inhibition of hemostasis (%) “Responders” Thrombosis Bleeding “Non Responders” Time of treatment
  9. 9. INR-Specific Incidence of All Adverse Events (All Episodes of Thromboembolism, All Major Bleeding Episodes, and Unclassified Stroke) Thrombosis Bleeding Cannegieter S et al. N Engl J Med 1995;333:11-17
  10. 10. Reletionship between inhibition of platelet aggregation and the risk of thrombosis or bleeding Inhibition of hemostasis (%) “Responders” Thrombosis Bleeding “Non Responders” Time of treatment
  11. 11. “Evolution” of antithrombotic treatment ANTICOAGULANT Need for laboratory monitoringNo Need for laboratory monitoring
  12. 12. “Evolution” of antithrombotic treatment ANTICOAGULANT ANTIPLATELET Need for laboratory Need for laboratory monitoring monitoringNo Need for laboratory No need for laboratory monitoring monitoring
  13. 13. ASPIRIN
  14. 14. Prevalence of “Aspirin resistance”But:Hillarp et al, 2003 122 Arachidonic acid-induced WB aggregation 0.8%Tantry et al, 2005 223 Arachidonic acid-induced PRP aggregation 0.4%Fontana et al, 2006 96 Serum TxB2 1.0%Frelinger et al, 2006 680 Serum TxB2 1.0% (uncompliant or under-dosed) Campbell & Steinhubl, 2005
  15. 15. THIENOPYRIDINES
  16. 16. agonist ADP ADP prostacyclin specific P2Y12 IP receptor receptor Gq Gi Gs PI3K AC δ cAMP stabilization Platelet aggregation
  17. 17. THIENOPYRIDINES ACTIVE METABOLITES N HOOC N S Cl HS Cl Ticlopidine O O CH3 CH3 N HOOC N S Cl HS Cl Clopidogrel
  18. 18. O CH3 HOOC Nagonist S Cl prostacyclin S ADP specific P2Y12 IP receptor receptor Gq Gi Gs AC δ cAMP Platelet aggregation
  19. 19. Prevalence of resistance to antiplatelet agents• Aspirin (serum TxB2) ≈ 0-5% (*)• Clopidogrel (P2Y12-specific assays) ≈ 30%(*) mostly due to non-compliance
  20. 20. Schematic representation of the metabolism of clopidogrel Mega, J. L. et al. Circulation 2009;119:2553-2560
  21. 21. ORs for MACE, according to CYP2C19*2 allele (n=11,959), and PPI use (n=46,037) Hulot et al, JACC 2010
  22. 22. Risk for cardiovascular death, myocardial infarction, or stroke for subtypes of PPIs.Time- dependent, propensity score–matched Cox proportional hazards analysis. Charlot M et al. Ann Intern Med 2010;153:378-386
  23. 23. Kaplan–Meier Estimates of the Probability of Remaining Free of Primary Cardiovascular Events, According to Study Group. Bhatt DL et al. N Engl J Med 2010. DOI: 10.1056/NEJMoa1007964
  24. 24. Other factors affecting the response to clopidogrel Higher response Lower responseAge √Body weight √Diabetes mellitus √Renal failure in diabetes m. √Smoking √
  25. 25. Response variability (“resistance”) to Clopidogrel The solution? “Tailored treatment”: increase the dose of Clopidogrel in poor responders (based on the results of platelet function tests) tests) Is it the right approach? approach?
  26. 26. Who would dare arguing against?“Responders”“Non Responders”
  27. 27. Laboratory monitoring of clopidogrel therapy Questions that need to be answered• Which test of platelet function?• Is it really effective?• Is it the solution for all patients?• Is it safe?• Is it cost-effective?
  28. 28. Studio GRAVITAS
  29. 29. GRAVITAS Trial - Profile Price, M. J. et al. JAMA 2011;305:1097-1105
  30. 30. Cumulative Kaplan-Meier Estimates of the Time to the FirstAdjudicated Occurrence of the Primary Efficacy End Point Price, M. J. et al. JAMA 2011;305:1097-1105
  31. 31. Response variability (“resistance”) to Clopidogrel Another solution? Change the drug!
  32. 32. THIENOPYRIDINES ACTIVE METABOLITES N HOOC N S Cl HS Cl Ticlopidine O O CH3 CH3 N HOOC N S Cl HS Cl Clopidogrel O O O CH3 O N HOOC N S F HS F Prasugrel
  33. 33. Schematic representation of the metabolism of clopidogrel and prasugrel Mega, J. L. et al. Circulation 2009;119:2553-2560
  34. 34. Inhibition of ADP (20µM)-induced platelet aggregation Prasugrel 60+10 Clopidogrel 600+75 Clopidogrel 300+75 Payne et al, J Cardiovasc Pharmacol 2007
  35. 35. Reletionship between IPA by Clopidogrel 300 mg orPrasugrel 60 mg in response to 20 µM ADP 24 h after the loading dose “Responders” “Non Responders” Brandt et al, Am Heart J 2007
  36. 36. Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points during the Follow-up Period, in TRITON-TIMI 38 Wiviott S et al. N Engl J Med 2007
  37. 37. Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points during the Follow-up Period, in TRITON-TIMI 38 Wiviott S et al. N Engl J Med 2007
  38. 38. Effects of Prasugrel and Clopidogrel active metabolites (AM) on human platelet aggregation induced by ADP (10 µM) Sugidachi et al, JTH 2007
  39. 39. Reletionship between drug-induced inhibition of hemostasis and the risk of thrombosis or bleeding Inhibition of hemostasis (%) “Responders” Thrombosis Bleeding “Non Responders”
  40. 40. Reletionship between IPA by Clopidogrel 300 mg orPrasugrel 60 mg in response to 20 µM ADP 24 h after the loading dose “Responders” Thrombosis Bleeding “Non Responders” Brandt et al, Am Heart J 2007
  41. 41. Short-acting, direct P2Y12 antagonists (Cangrelor) (Ticagrelor)
  42. 42. DISPERSE Study: Faster and More Consistent IPA With AZD6140 Than With Clopidogrel (Final Extent) Clopidogrel 75 mg qd AZD6140 100 mg bid Day 1 Day 14 Day 1 Day 14100 10080 8060 6040 4020 20 2 4 8 12 2 4 8 12 24 2 4 8 12 2 4 8 12 24 Time, h Time, h Husted S. Presented at ESC 2005.
  43. 43. IPA (%; 20 {micro}mol/L ADP, final extent) by protocol time and treatment Gurbel, P. A. et al. Circulation 2009;120:2577-2585
  44. 44. Cumulative Kaplan-Meier Estimates of the Time to the First Adjudicated Occurrence of the Primary Efficacy End Point Wallentin L et al. N Engl J Med 2009;361:1045-1057
  45. 45. Incidence of the primary end-point and non-CABG relatedTIMI-major bleeding events in patients who received ticagrelor vs patients who received clopidogrel in the PLATO trial. Events Ticagrelor Clopidogre Hazard p no/total lno/total Ratio (%) (%) (95% C.I.) Primary end point 864/9333 1014/9291 0.84 <0.001 (composite of vascular (9.8) (11.7) (0.77-0.92)death, myocardial infarction or stroke) Non-CABG-related major 221/9235 177/9186 1.25 0.03 bleedings, TIMI criteria (2.8) (2.2) (1.03-1.53) Wallentin and PLATO Investigators, NEJM 2009
  46. 46. Major Efficacy End Points at 12 Months Wallentin L et al. N Engl J Med 2009;361:1045-1057
  47. 47. Held et al, JACC 2011
  48. 48. Short-acting, direct P2Y12 antagonists (Cangrelor) (Ticagrelor)
  49. 49. ELINOGREL• Elinogrel is direct-acting, competitive, reversible P2Y12 non- nucleotide antagonist• IC50 ~2-3 µM in ADP aggregation (PRP)• Highly selective for P2Y12 (does not inhibit P2Y1 or other purinergic receptors)• Oral bioavailability ~50%• T1/2 ~12 h (BID drug) (Elimination: 50% renal, 50% hepatic)• Tmax 2-6 h
  50. 50. INNOVATE PCI - Adverse Events Clopidogrel Pooled elinogrel Pooled elinogrel N=208 100 mg 150 mg N=201 N=207Any SAE 11.1% 14.9% 12.6%Drug d/c due to AE or SAE 7.2% 7.5% 10.1%Dyspnea* 4.3% 15.4% 12.1%Bradycardia 0.5% 1.0% 0.5%Syncope 0.5% 1.5% 0.5%ALT/AST > 3x^ 1.0% 4.0% 4.8% ALT/AST > 5x 0.5% 2.0% 3.4%* Dyspnea was generally mild, transient, and infrequently led to discontinuation^ Most cases occurred within first 60 days and were asymptomatic; All cases resolved, even when treatmentwas continued; No Hy’s Law cases.
  51. 51. Dyspnea in PLATO trial Ticagrelor ClopidogrelAll patients (n=9,235) (n=9,186) p value*Dyspnea, % Any 13.8 7.8 <0.001 With discontinuation of study treatment 0.9 0.1 <0.001
  52. 52. Cangrelor and dyspnoea• CHAMPION PCI: a dyspnoea adverse event was reported in 1.0% of patients receiving cangrelor and 0.4% of patients receiving only clopidogrel (P = 0.001)• CHAMPION PLATFORM: a dyspnoea adverse event was reported in 1.4% of patients receiving cangrelor and 0.5% of patients receiving placebo (P = 0.002)

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