26.9.13 antiplatelet how to choose your bride among three sisters

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  • 4 There are a number of therapeutic approaches to acute coronary syndrome (ACS) treatment based on the various pathophysiological steps in the process. 1.  -Blockers and nitrates are symptomatic therapies and exert their action downstream from the thrombus by balancing myocardial oxygen supply and demand. 2. Heparin is used to prevent further clot formation by inhibiting fibrin formation. 3. Antiplatelet agents, such as aspirin, clopidogrel and GP IIb/IIIa inhibitors, reduce platelet adhesion and aggregation, which play a key role in thrombus formation. 4. There is growing interest in agents that may stabilise the plaque and discourage rupture. Statins are currently being studied in this context.
  • 4 There are a number of therapeutic approaches to acute coronary syndrome (ACS) treatment based on the various pathophysiological steps in the process. 1.  -Blockers and nitrates are symptomatic therapies and exert their action downstream from the thrombus by balancing myocardial oxygen supply and demand. 2. Heparin is used to prevent further clot formation by inhibiting fibrin formation. 3. Antiplatelet agents, such as aspirin, clopidogrel and GP IIb/IIIa inhibitors, reduce platelet adhesion and aggregation, which play a key role in thrombus formation. 4. There is growing interest in agents that may stabilise the plaque and discourage rupture. Statins are currently being studied in this context.
  • THIS SLIDE HAS BEEN THROUGH QUALITY REVIEW DOI link website: http://dx.doi.org/10.1056/NEJMoa0706482
  • Source: Q113, Q111, Q331 [Source: Figure 1 on page 19] Reference: Chin CT, Roe MT, Fox KA, Prabhakaran D, Marshall DA, Petitjean H, Lokhnygina Y, Brown E, Armstrong PW, White HD, Ohman EM; TRILOGY ACS Steering Committee. Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial. Am Heart J 2010;160(1):16-22.e1. Pras00045111
  •  –   
  • PAUSE BEFORE DYSPNEA SUMMARY In summary Dyspnea assoc. with T is usually mild to moderate in intensity. IT does not represent a change in pulmonary function AND – There is no evidence to suggest that baseline cardiopulmonary disease should preclude the use of ticagrelor - as patients in this population were not at an increased relative risk of dyspnea. AZ has not identified any risk factors for dyspnea that are different between treatment groups. While We recognized that 9 in1000 T treated patients discontinued therapy due to their dyspnea. The benefit of T was maintained in patients at risk for dyspnea and in those patients who experience dyspnea on treatment. PAUSE Another safety topic evaluated was CLICK Cardiac arrhythmias and conduction abnormalities
  • PLATO hierarchical testing Hierarchical testing is a common statistical method used in clinical trials. PLATO assessed the separate contributions u nder a pre-specified hierarchical testing sequence.The hierarchical analysis only declares statistical significance if the prior endpoint was statistically significant Ticagrelor, compared to clopidogrel, decreases separately the rates of cardiovascular death (RRR 21%; ARR 1.1%; P =0.0013) and MI (RRR 16%; ARR 1.1%; P =0.0045), but not that of stroke (1.5% vs. 1.3%; P =0.2249) Since n o statistically significant difference was observed between ticagrelor and clopidogrel for the efficacy component stroke, further formal testing of secondary endpoints beyond stroke in the hierarchy cease. However, total death (listed last in hierarchy table above) was tested and is reported here because the P value is highly significant and this is clinically meaningful to clinicians. The PLATO trial demonstrated that treatment with ticagrelor as compared to clopidogrel in patients with acute coronary syndromes significantly reduces the rate of death from vascular causes, MI and stroke. A similar benefit was seen for the individual components of death from vascular causes (CV death), and for MI, but not for stroke. Reference: Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
  • Efficacy Across Patient Subgroups In this Forest plot, Blue and yellow cols show individ trt event rates Plot on R compares treatments, with overall cohort at top. 31 different subgroupings were tested: 4 this slide Excellent consistency of effect across age, sex, weight, and hx of prior ischemic stroke/TIA. Also true for many other categories. Reference: Wallentin L, et al. N Engl J Med . 2009;361:1045–1057
  • 26.9.13 antiplatelet how to choose your bride among three sisters

    1. 1. Dr. Rajeev Agarwala Jaswant Rai Speciality Hospital, Meerut. E-mail : rajeev_jrsh@yahoo.co.in HOW TO CHOOSE YOUR BRIDE AMONG THREE SISTERS
    2. 2. 4. Plaque rupture, cholesterol content, inflammation (hs-CRP) (statins) 3. Platelet adhesion/ activation/aggregation (aspirin, clopidogrel, GP IIb/IIIa inhibitors) 2. Activation of clotting cascade – thrombin (heparin/LMWH) 1. Downstream from thrombus myocardial ischaemia/necrosis (β-blockers, nitrates etc) PlateletPlatelet GP IIb/IIIaGP IIb/IIIa receptorreceptor FibrinogenFibrinogen ThrombinThrombin FibrinFibrin clotclot Pathophysiology of ACS and potential pharmacological interventions
    3. 3. Central role of platelets in atherothrombosis and stent thrombosis
    4. 4. Heart 2003;89:1273-1278 Pathways of Platelet Activation
    5. 5. BRIDGING THE GAPBRIDGING THE GAP
    6. 6. BLEEDING ISCHEMIA DILEMMA
    7. 7. Trial Indication Duration CHARISMA CURE CREDO PCI-CURE PCI-CLARITY CLARITY COMMIT Stable CVD MI Stroke PAD ACS UA/NSTEMI PCI Stable CAD UA/NSTEMI STEMI STEMI 28 months 9 months 1-12 months 8-28 days
    8. 8. PIVOTAL TRIALS OF DUAL ORAL ANTIPLATELET THERAPY IN ACS CURE (2001) N=12, 562 11.4% 9.3% P< .001 Primary Endpoint Reached ASA + Placebo ASA + Clopidogrel UA/NSTEMI CLARITY TIMI-28 STEMI < 12 hrs N=3491 21.7% 15.0% P< .001 STEMI COMMIT 93% STEMI or BBB + 24 hrs N=45,852 10.1% 9.2% P= .002
    9. 9. Newer antiplatelet agents
    10. 10. TRITON TIMI-38: Study Design Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 mg MD 1o endpoint: CV death, MI, Stroke 2o endpoints: CV death, MI, UTVR Stent Thrombosis (ARC definite/probable) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies: Pharmacokinetic, Genomic Median duration of therapy - 12 months N= 13,600 Wiviott SD et al. Am Heart J 2006;152:627-35
    11. 11. Net Clinical Benefit Death, MI, Stroke, Major Bleed (non CABG) 0 5 10 15 0 30 60 90 180 270 360 450 Days Endpoint(%) HR 0.87 P=0.004 13.9 12.2 Prasugrel ClopidogrelITT= 13,608ITT= 13,608 -23 6 -25 -20 -15 -10 -5 0 5 10 Events per 1000 ptsEvents per 1000 pts MIMI Major BleedMajor Bleed (non CABG)(non CABG) ++ All CauseAll Cause MortalityMortality Clop 3.2%Clop 3.2% Pras 3.0 %Pras 3.0 % P=0.64P=0.64
    12. 12. 0 2 4 6 8 0 1 2 3 1 0 306090 180 270 360 450 HR 0.82 P=0.01 HR 0.80 P=0.003 5.6 4.7 6.9 5.6 Days PrimaryEndpoint(%) Prasugrel Clopidogrel Prasugrel Clopidogrel Loading Dose Maintenance Dose Timing of BenefitTiming of Benefit
    13. 13. 0 3 6 9 Days CVDeath,MI,Stroke(%) No GP IIb/IIIa Inhibitor Used GP IIb/IIIa Inhibitor Used Benefit Regardless ofBenefit Regardless of GP IIb/IIIa UseGP IIb/IIIa Use O’Donoghue M et al. JACC 2009;54:678-85 0 3015 Days 0 3015 HR 0.76 (0.64-0.90) P=0.001 HR 0.78 (0.63-0.97) P=0.026 Prasugrel Clopidogrel Prasugrel Clopidogrel
    14. 14. Diabetic Subgroup 0 2 4 6 8 10 12 14 16 18 0 30 60 90 180 270 360 450 HR 0.70 P<0.001 Days Endpoint(%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 21 N=3146N=3146 17.0 12.2 Prasugrel Clopidogrel Prasugrel Clopidogrel 2.6 2.5 Wiviott SD et al. NEJM 2007;357:2001-15
    15. 15. Prasugrel, in ACS patients with diabetes undergoing PCI, is associated with significant reduction in primary endpoint compared to clopidogrel without increase in bleeding events.
    16. 16. Prasugrel, in STEMI patients undergoing PCI, is associated with significant reduction in primary endpoint compared to clopidogrel without increase in bleeding events.
    17. 17. TRITON-TIMI 38: Major Efficacy End Points Wiviott SD et al., N Engl J Med 2007 0.5 Prasugrel Better Clopidogrel Better HR 0.4 0.6 0.7 0.8 0.9 1.1 1.2 1.3 1.41.0 1.5 Stent Thrombosis Urgent traget vesell revasc. All Cause Death Nonfatal stroke Nonfatal MI CV Death Primary Endpoint
    18. 18. Safety Significant increase in serious bleeding (32% increase) Avoid in pts with prior CVA/TIA Efficacy 1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis 52% uTVR 34%       MI 24% 2. An early and sustained benefit 3. Across ACS spectrum Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD Conclusions Higher IPA to Support PCI Net clinical benefit significantly favored PrasugrelNet clinical benefit significantly favored Prasugrel Optimization of Prasugrel maintenance dosing in a minority of patients may help improve theOptimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balancebenefit : risk balance
    19. 19. Prasugrel in medically managed ACS patients
    20. 20. TRILOGY ACS Study Design Medically Managed UA/NSTEMI PatientsMedically Managed UA/NSTEMI Patients Clopidogrel1 75 mg MD Clopidogrel1 75 mg MD Prasugrel1 5 or 10 mg MD Prasugrel1 5 or 10 mg MD Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 monthsMinimum Rx Duration: 6 months; Maximum Rx Duration: 30 months Primary Efficacy Endpoint: CV Death, MI, StrokePrimary Efficacy Endpoint: CV Death, MI, Stroke Randomization Stratified by: Age, Country, Prior Clopidogrel Treatment (Primary analysis cohort — Age < 75 years) Randomization Stratified by: Age, Country, Prior Clopidogrel Treatment (Primary analysis cohort — Age < 75 years) Clopidogrel1 300 mg LD + 75 mg MD Clopidogrel1 300 mg LD + 75 mg MD Prasugrel1 30 mg LD + 5 or 10 mg MD Prasugrel1 30 mg LD + 5 or 10 mg MD Medical Management Decision ≤72 hrs (No prior clopidogrel given) — 4% of total Medical Management Decision ≤72 hrs (No prior clopidogrel given) — 4% of total Medical Management Decision ≤ 10 days (Clopidogrel started ≤ 72 hrs in-hospital OR on chronic clopidogrel) — 96% of total Medical Management Decision ≤ 10 days (Clopidogrel started ≤ 72 hrs in-hospital OR on chronic clopidogrel) — 96% of total 1. All patients were on aspirin and low-dose aspirin (< 100 mg) was strongly recommended. For patients <60 kg or ≥75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1. 1. All patients were on aspirin and low-dose aspirin (< 100 mg) was strongly recommended. For patients <60 kg or ≥75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1. Median Time to Enrollment = 4.5 Days
    21. 21. HR (95% CI) ≤ 1 Year: 0.99 (0.84, 1.16) HR (95% CI) > 1 Year: 0.72 (0.54, 0.97) Primary Efficacy Endpoint to 30 Months HR (95% CI): 0.91 (0.79, 1.05) P = 0.21 Interaction P = 0.07 Age<70years
    22. 22. Evaluation of All Ischemic Events Over Time* (Age < 75 years)   Prasugrel Clopidogrel ≥ 1 event 364 397 ≥ 2 events 77 109 3–7 events 18 24  Lower risk multiple recurrent ischemic events suggested withLower risk multiple recurrent ischemic events suggested with prasugrel using the pre-specified Andersen-Gill modelprasugrel using the pre-specified Andersen-Gill model (HR = 0.85, 95% CI: 0.72–1.00, P=0.04)(HR = 0.85, 95% CI: 0.72–1.00, P=0.04)  Significant interaction with treatment and time (HR for > 12 mos =Significant interaction with treatment and time (HR for > 12 mos = 0.64, 95% CI: 0.48–0.86, Interaction P=0.02)0.64, 95% CI: 0.48–0.86, Interaction P=0.02) * Pre-specified evaluation of all CV death, MI, or stroke events by treatment
    23. 23. Evaluation of All Ischemic Events Over Time* (Age < 75 years)   Prasugrel Clopidogrel ≥ 1 event 364 397 ≥ 2 events 77 109 3–7 events 18 24  Lower risk multiple recurrent ischemic events suggested withLower risk multiple recurrent ischemic events suggested with prasugrel using the pre-specified Andersen-Gill modelprasugrel using the pre-specified Andersen-Gill model (HR = 0.85, 95% CI: 0.72–1.00, P=0.04)(HR = 0.85, 95% CI: 0.72–1.00, P=0.04)  Significant interaction with treatment and time (HR for > 12 mos =Significant interaction with treatment and time (HR for > 12 mos = 0.64, 95% CI: 0.48–0.86, Interaction P=0.02)0.64, 95% CI: 0.48–0.86, Interaction P=0.02) * Pre-specified evaluation of all CV death, MI, or stroke events by treatment
    24. 24. Primary Efficacy Endpoint and TIMI Major Bleeding Through 30 Months (Overall population) HR (95% CI): 0.96 (0.86, 1.07) P = 0.45 HR (95% CI): 1.23 (0.84, 1.81) P = 0.29
    25. 25. Conclusions  In the largest trial to date of ACS patients managed medically without revascularization, prasugrel was not statistically different from clopidogrel during 2.5 years of follow-up among patients < 75 years of age  Further analyses of the primary endpoint yielded several important findings favoring prasugrel treatment • Trend for a time-dependent benefit after 1 year • Fewer total recurrent ischemic events, particularly after 1 year  No statistical differences in major, life-threatening, or fatal bleeding with prasugrel vs. clopidogrel
    26. 26. PLATO study design Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding 6–12-month exposure 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) NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack
    27. 27. No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,521 8,628 8,362 8,460 8,124 Days after randomisation 6,743 6,743 5,096 5,161 4,047 4,147 0 60 120 180 240 300 360 12 11 10 9 8 7 6 5 4 3 2 1 0 13 Cumulativeincidence(%) 9.8 11.7 8,219 HR 0.84 (95% CI 0.77–0.92), p=0.0003 Clopidogrel Ticagrelor K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Wallentin L et al. NEJM 2009;361:1045-57.
    28. 28. 0 60 120 180 240 300 360 6 4 3 2 1 0 Clopidogrel Ticagrelor 4.0 5.1 HR 0.79 (95% CI 0.69–0.91) P=0.001 7 5 9,291 9,333 8,865 8,294 8,780 8,822 8,589 Days after randomisation 7079 7119 5,441 5,482 4,364 4,4198,626 Cardiovascular death Cumulativeincidence(%) All-cause mortality 4.5% vs. 5.9% HR 0.78 (0.69-0.89) P<0.001 Wallentin L et al. NEJM 2009;361:1045-57.
    29. 29. 8,688 8,763 0 10 20 30 8 6 4 2 0 Cumulativeincidence(%) Clopidogrel Ticagrelor 4.77 5.43 HR 0.88 (95% CI 0.77–1.00), p=0.045 No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,875 8,942 8,763 8,827 Days after randomisation 31 90 150 210 270 330 8 6 4 2 0 Clopidogrel Ticagrelor 5.28 6.60 8,688 8,673 8,286 8,397 6,379 6,480 Days after randomisation* HR 0.80 (95% CI 0.70–0.91), p<0.001 8,437 8,543 6,945 7,028 4,751 4,822 Cumulativeincidence(%) *Excludes patients with any primary event during the first 30 days Wallentin L et al. NEJM 2009;361:1045-57.
    30. 30. Stent thrombosis  Ticagrelor (n=5,640)     Clopidogrel  (n=5,649)    HR  (95% CI) p value Stent thrombosis, n (%)    Definite     Probable or definite    Possible, probable, definite         71 (1.3) 118 (2.1)           155 (2.8) 106 (1.9) 158 (2.8) 202 (3.6) 0.67 (0.50–0.91) 0.75 (0.59–0.95) 0.77 (0.62–0.95) 0.009 0.02 0.01 (evaluated in patients with any stent during the study) *Time-at-risk is calculated from first stent insertion in the study or date of randomisation
    31. 31. NS NS NS NS NS 0 K-Mestimatedrate(%peryear) PLATO major bleeding 1 2 3 4 5 6 7 8 9 10 12 11 13 TIMI major bleeding Red cell transfusion* PLATO life- threatening/ fatal bleeding Fatal bleeding Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15; * Proportion of patients (%); NS = not significant 11.6 11.2 7.9 7.7 8.9 8.9 5.8 5.8 0.3 0.3 Ticagrelor Clopidogrel Wallentin L et al. NEJM 2009;361:1045-57.
    32. 32. Non-CABG and CABG-related major bleeding p=0.026 p=0.025 NS NS 9K-Mestimatedrate(%peryear) Non-CABG PLATO major bleeding 8 7 6 5 4 3 2 1 0 Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding 4.5 3.8 2.8 2.2 7.4 7.9 5.3 5.8 Ticagrelor Clopidogrel
    33. 33. Conclusions  Reversible, more intense P2Y12 receptor inhibition for one year with ticagrelor in comparison with clopidogrel in a broad population with ST- and non- ST-elevation ACS provides  Reduction in myocardial infarction and stent thrombosis  Reduction in cardiovascular and total mortality  No change in the overall risk of major bleeding Ticagrelor is a more effective alternative than clopidogrel for the continuous prevention of ischaemic events, stent thrombosis and death in the acute and long-term treatment of patients with ACS
    34. 34. Thromb Haemost 2012; 108: 318-327
    35. 35. Efficacy comparison of High dose clopidogrel, prasugrel and ticagrelor strategies vs. standard clopidogrel therapy OASIS-7 PCI (2010) TRITON TIMI-38 (2007) PLATO (2009) High dose clopidogrel Standard clopidogrel Risk reduction Prasugrel Standard clopidogrel Risk reduction Ticagrelor Standard clopidogrel Risk reduction Primary endpoint 3.9% 4.5% 14% 9.9% 12.1% 19% 9.0% 10.7% 16% All Cause Death 1.9% 2.1% 6% 3% 3.2% 5% 3.9% 5% 19% Non-fatal MI 2% 2.6% 21% 7.3% 9.5% 14% 5.3% 6.6% 20% Stent thrombosis 1.6% 2.3% 31% 1.1% 2.4% 52% 2.2% 3% 27%
    36. 36. Bleeding comparison of High dose clopidogrel, prasugrel and ticagrelor strategies vs. standard clopidogrel therapy OASIS-7 PCI (2010) TRITON TIMI-38 (2007) PLATO (2009) High dose clopidogre l Standard clopidogrel HR Prasugrel Standard clopidogre l HR Ticagrelor Standard clopidogrel HR Total Major Bleeding 1% 0.7% 1.36 2.5% 1.7% 1.46 7.9% 7.9% 1.0 Non- CABG related Major bleeding 0.8% 0.6% 1.34 2.4% 1.8% 1.32 2.8% 2.2% 1.23
    37. 37. Study Overview: Prasugrel / Ticagrelor ST-Elevation Myocardial Infarction Non ST-Elevation Acute Coronary Syndromes Medically Managed Pts – NSTE ACS Stable Angina Diabetes mellitus Chronic Kidney Disease Limitations and Contraindications Antiplatelet Therapies – The Dynamics
    38. 38. 0 5 10 15 0 30 60 90 180 270 360 450 Endpoint(%) Days 9.5% 6.5% 12.4% 10.0% Clopidogrel Prasugrel CV death / MI / stroke Efficacy of prasugrel in STEMI Montalescot G et al., Lancet 2009 NNT = 42 P = 0.02
    39. 39. 0 1 2 3 4 5 30 days 15 months P=0.04 P=0.11 Incidence of death from any cause (%) Lower early mortality with prasugrel in STEMI Montalescot G et al., Lancet 2009 Clopidogrel Prasugrel 2.6 1.6 4.3 3.3
    40. 40. 0 5 10 15 0 30 60 90 180 270 360 450 Endpoint(%) Days TIMI major non-CABG bleeds Clopidogrel Prasugrel 2.4% 2.1% Safety of prasugrel in STEMI Montalescot G et al., Lancet 2009 NNH = 333 P = 0.65
    41. 41. Steg PG et al., Circulation 2010 Benefit of ticagrelor in STEMI
    42. 42. 0 2.5 5.0 7.5 8 months P=0.05 Incidence of death from any cause (%) Lower all-cause mortality with ticagrelor in STEMI Clopidogrel Ticagrelor 6.1 5.0 Steg PG et al., Circulation 2010
    43. 43. Steg PG et al., Circulation 2010 Safety of ticagrelor in STEMI
    44. 44. Similar efficacy and safety in STEMI TRITON: Prasugrel 1° efficacy endpoint All cause mortality 1° safety endpoint PLATO: Ticagrelor 1° efficacy endpoint All cause mortality 1° safety endpoint Hazard ratio for 1° endpoint (95 % - confidence limit) 0.5 1 1.5 Study drug better Clopidogrel better Montalescot G et al., Lancet 2009; Steg PG et al., Circulation 2010
    45. 45. Study Overview: Prasugrel / Ticagrelor ST-Elevation Myocardial Infarction Non ST-Elevation Acute Coronary Syndromes Stable Angina Diabetes mellitus Chronic Kidney Disease Limitations and Contraindications Antiplatelet Therapies – The Dynamics
    46. 46. Similar efficacy of prasugrel in STEMI and UA/NSTEMI15-month incidence of death/MI/stroke (%) 0 2 4 6 8 10 12 14 16 12.4 10.0 p=0.02 STEMI NNT = 42 12.0 9.9 p=0.03 UA/NSTEMI NNT = 47 Wiviott SD et al., N Engl J Med 2007 Clopidogrel Prasugrel
    47. 47. Favorable risk-benefit ratio of prasugrel in UA/NSTEMI Clopidogrel Prasugrel Wiviott SD et al., N Engl J Med 2007 15-month incidence (%) 0 2 4 6 8 10 12 14 16 12.0 9.9 p=0.03 death/MI/stroke NNT = 47 1.7 2.4 p=0.01 major non-CABG bleed NNH = 142
    48. 48. TRITON: All cause mortality in NSTE-ACS vs. STEMI Wiviott SD et al., J Am Cardiol 2010 STEMI NSTE-ACS Hazard ratio for all cause mortality (95 % - confidence limit) 0.5 1 1.5 Prasugrel better Clopidogrel better Pint = 0.11
    49. 49. Favorable risk-benefit ratio of ticagrelor in UA/NSTEMI Clopidogrel Ticagrelor Wallentin L et al., N Engl J Med 2009, Steg PG et al., Circulation 2010 15-month incidence (%) 0 2 4 6 8 10 12 14 16 11.5 9.6 P = 0.001 death/MI/stroke NNT = 52 7.8 8.2 P = 0.41 TIMI major bleed NNH = 233
    50. 50. Differential efficacy in NSTE-ACS Wiviott SD et al., J Am Cardiol 2010 & N Engl J Med 2007; Wallentin L et al., N Engl J Med TRITON 1° endpoint All cause mortality PLATO 1° endpoint All cause mortality Hazard ratio for 1° endpoint (95 % - confidence limit) 0.5 1 1.5 Study drug better Clopidogrel better
    51. 51. New P2Y12 inhibitors superior to high-dose clopidogrel Non-selected ACS PLATO (ticagrelor) OASIS-7 (high-dose clopidogrel) ACS undergoing PCI TRITON (prasugrel) OASIS-7 PCI (high-dose clopidogrel) Hazard ratio for 30-day 1° endpoint (95 % - confidence limit) 0.5 1 1.5 study treatment better normal-dose clopidogrel better P = 0.045 P = 0.30 P < 0.001 P = 0.039 Wallentin L et al., N Engl J Med 2009 OASIS-7 investigators, N Engl J Med 2010 Mehta SR et al., Lancet 2010
    52. 52. Study Overview: Prasugrel / Ticagrelor ST-Elevation Myocardial Infarction Non ST-Elevation Acute Coronary Syndromes Medically Managed Pts – NSTE ACS Stable Angina Diabetes mellitus Chronic Kidney Disease Limitations and Contraindications Antiplatelet Therapies – The Dynamics
    53. 53. Study Overview: Prasugrel / Ticagrelor ST-Elevation Myocardial Infarction Non ST-Elevation Acute Coronary Syndromes Medically Managed Pts – NSTE ACS Stable Angina Diabetes mellitus Chronic Kidney Disease Limitations and Contraindications Antiplatelet Therapies – The Dynamics
    54. 54. Superior net clinical benefit of prasugrel in diabetics Days 0 2 4 6 8 10 12 14 16 18 0 30 60 90 180 270 360 450 HR 0.70 P < 0.001 Endpoint(%) CV death / MI / stroke TIMI major non-CABG bleeds NNT = 21 17.0% 12.2% Prasugrel Clopidogrel Prasugrel Clopidogrel 2.6% 2.5% Wiviott SD et al. Circulation 2008
    55. 55. Wiviott SD et al., Circulation 2008 Superior efficacy of prasugrel in diabetics: 1° endpoint
    56. 56. Wiviott SD et al., Circulation 2008 Potent effect of prasugrel in diabetics: Stent thrombosis
    57. 57. Wiviott SD et al., Circulation 2008 Safety of prasugrel in diabetics: TIMI major non CABG bleeding
    58. 58. No interaction with diabetes in PLATO: 1° endpoint Pint = 0.49 James S et al., Eur Heart J 2010
    59. 59. No interaction with diabetes in PLATO: Mortality Pint = 0.66 James S et al., Eur Heart J 2010
    60. 60. Interaction with diabetes mellitus Wiviott SD et al., Circulation 2008; James S et al., Eur Heart J 2010 TRITON No diabetes Diabetes PLATO No diabetes Diabetes Hazard ratio for 1° endpoint (95 % - confidence limit) 0.5 1 1.5 Study drug better Clopidogrel better Pint = 0.49 Pint = 0.09
    61. 61. Study Overview: Prasugrel / Ticagrelor ST-Elevation Myocardial Infarction Non ST-Elevation Acute Coronary Syndromes Stable Angina Diabetes mellitus Chronic Kidney Disease Limitations and Contraindications Antiplatelet Therapies – The Dynamics
    62. 62. Different interaction with renal function Wiviott SD et al., N Engl J Med 2007; James S et al., Circulation 2010 TRITON 1° endpoint CrCl < 60 mL/min CrCl > 60 mL/min Hazard ratio (95 % - confidence limit) 0.5 1 1.5 Study drug better Clopidogrel better Pint n.s.Pint n.s. PLATO 1° endpoint CrCl < 60 mL/min CrCl > 60 mL/min Pint = 0.13
    63. 63. 12.1 % 3.1 % 3.3 % 10.0 % ticagrelor ticagrelor clopidogrel clopidogrel Creatinine clearance > 60 ml/min Creatinine clearance < 60 ml/min Cumulative incidence of all-cause death Days since randomization No survival benefit of ticagrelor in normal creatinine clear James S et al., Circulation 2010
    64. 64. Study Overview: Prasugrel / Ticagrelor ST-Elevation Myocardial Infarction Non ST-Elevation Acute Coronary Syndromes Stable Angina Diabetes mellitus Chronic Kidney Disease Limitations and Contraindications Antiplatelet Therapies – The Dynamics
    65. 65. 0.5 1 2 OVERALL Prasugrel Better Clopidogrel Better No YesPrior Stroke / TIA Pint = 0.006 <75 ≥75 Age Pint = 0.18 ≥60 kg <60 kg Weight Pint = 0.36 www.timi.org – Accessed on July 16, 2008 Contraindication with history of cerebro-vascular event Hazard Ratio for net clinical outcome
    66. 66. Dyspnoea on Ticagrelor Any dyspnoea With discontinuation of study treatment Incidence (%) P < 0.001 7.7 0.1 13.8 0.9 Clopidogrel 0 5 15 10 Ticagrelor P < 0.001 Wallentin L et al., N Engl J Med 2009
    67. 67. Exclusion criterion: Increased risk of bradycardia ≥ 3 sec Incidence of ventricular pauses during 1st week (%) P = 0.01 3.6 1.2 5.8 2.0 Clopidogrel 0 2 6 4 Ticagrelor P = 0.10 Wallentin L et al., N Engl J Med 2009 3 5 1 ≥ 5 sec
    68. 68. P2Y12-Blockers in PCI STEMI ACS - UA Elective PCI Non STEMI Prasugrel Ticagrelor Clopidogrel Diabetes Mellitus Normal Renal Function CKD Ticagrelor over Prasugrel: <60 kg, Over 75 Yrs, Previous Stroke or TIA Prasugrel over Ticagrelor: Bradycardia
    69. 69. TICAGRELOR 180 mg loading dose, then 90 mg bid for 1 year (ASA < 100) PRASUGREL 60 mg loading dose, then 5-10 mg PO daily for 1 year CLOPIDOGREL 600 mg PO loading dose, then 150 mg daily 1-4 weeks, then 75 mg daily for 1 year •R/O Contraindications •PCI ( Clop naïve ) • STEMI • Diabetic • Stent Thrombosis • Clopidogrel NR •Irrespective of strategy • Mod to High Risk ACS/ NSTEMI (On or Off C) • Unknown coronary anatomy; CABG likely •Clopidogrel NR • All others, especially if high-risk for bleeding • Lung and renal disease • Already on Clopidogrel but no ischemic event 10-15% 40-50% 30-40% Choice of Oral Antiplatelet Therapy in ACS/PCI Patients
    70. 70. Antiplatelet Therapy in ACS Placebo APTC CURE TRITON-TIMI 38 Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA ASA ASA + Clopidogrel ASA + Prasugrel - 22% - 20% - 19% + 60% + 38% + 32% Reduction in Ischemic Events - 21% PLATO
    71. 71.  ESC 2011 Antiplatelet guidelines for ACS patients presenting ST segment elevation
    72. 72. Current Research Questions  Head to head comparison of APS.  Short term / reversibility may increase the incidence of stent thrombosis.  Is aspirin still necessary in modern DAPT.
    73. 73. IMPATIENCE CAN BE CUMBERSOME IMPATIENCE CAN BE CUMBERSOME
    74. 74. THANK YOUTHANK YOU
    75. 75. THANK YOU
    76. 76. Results: MACE Non significant 6% reduction in MACE with high dose clopidogrel in overall study population Significant 14% reduction in MACE in PCI subgroup with high dose clopidogrel Significant 19% reduction in MACE with prasugrel after 15 months Significant 22% reduction in MACE with prasugrel after 30 days of FU Significant 16% reduction in MACE with ticagrelor after 12 months of FU Significant 12% reduction in MACE with ticagrelor after 30 days of FU Significant 16% reduction in MACE with ticagrelor in invasive only subgroup
    77. 77. MACE: Clopidogrel high dose vs. standard dose Significant 26% risk reduction in MACE with high dose clopidogrel strategy compared to standard dose clopidogrel therapy
    78. 78. Other Adverse Events Ticagrelor (n=9,235) Clopidogrel (n=9,186) p value Ventricular pauses ≥3 sec on Holter, % In 1st week (n=2866 w/ Holter) At 30 days (n=1991 w/ Holter) 5.8 2.1 3.6 1.7 0.01 0.52 Bradycardia-related event, % Pacemaker Insertion Syncope Bradycardia Heart block 0.9 1.1 4.4 0.7 0.9 0.8 4.0 0.7 0.87 0.08 0.21 1.00 Dyspnea, % Any Leading to d/c of study treatment 13.8 0.9 7.8 0.1 <0.001 <0.001 Wallentin L et al. NEJM 2009;361:1045-57.
    79. 79. Dyspnea Associated with Ticagrelor  Usually mild to moderate  Observed within 1st 7 days, median time 23 days, mostly resolves spontaneously  Patients with baseline cardiopulmonary disease were not at an increased relative risk of dyspnea  No measured changes in pulmonary function/ BNP levels  Benefit of ticagrelor is maintained in patients at risk for dyspnea and those who experience dyspnea  Patient with mild to moderate dyspnea should be encouraged to continue withTicagrelor considering consistency of benefit Wallentin L, et al. N Engl J Med. 2009;361:1045–1057
    80. 80. Key Messages Diabetes  Overall PEP consistent with PLATO Main results  Driven by MI and CVD like PLATO main results  No Increase in PLATO Major, LT, Non-CABG Major Bleeds.  Benefit of PLATO trial design
    81. 81. PLATO hierarchical testing of major efficacy endpoints *The percentages are K-M estimates of the rate of the endpoint at 12 months. Patients could have had more than one type of endpoint. Death from CV causes and fatal bleeding, as only traumatic fatal bleeds were excluded from the CV death category. † By Cox regression analysis using treatment as factor. All Patients*All Patients* TicagrelorTicagrelor (n=9333)(n=9333) ClopidogrelClopidogrel (n=9291)(n=9291) HR forHR for ticagrelorticagrelor (95% CI)(95% CI) PP valuevalue†† Primary objective, n (%/year) CV death + MI + stroke 864 (9.8) 1014 (11.7) 0.84 (0.77–0.92) 0.0003 Secondary objectives, n (%/yr) Total death + MI + stroke 901 (10.2) 1065 (12.3) 0.84 (0.77–0.92) 0.0001 CV death + MI + stroke + severe + recurrent ischemia + TIA + arterial thrombus 1290 (14.6) 1456 (16.7) 0.88 (0.81–0.95) 0.0006 MI 504 (5.8) 593 (6.9) 0.84 (0.75-0–95) 0.0045 CV death 353 (4.0) 442 (5.1) 0.79 (0.69–0.91) 0.0013 Stroke 125 (1.5) 106 (1.3) 1.17 (0.91–1.52) 0.2249 Total death 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) 0.0003 Wallentin L, et al. N Engl J Med. 2009;361:1045–1057
    82. 82. Clop Efficacy Across Patient Subgroups Age Overall Treatment Effect Sex Body Weight Prior Non- hemorrhagic Stroke /TIA Female 13.213.2 Male 11.111.1 ≥ 75 years 18.318.3 < 75 years 10.410.4 < 65 years 8.58.5 11.711.7 < 60 kg 17.317.3 ≥ 60 kg 11.211.2 No 20.820.8 Yes 11.111.1 Diabetes Mellitus Yes 16.216.2 No 10.210.2 Other 14.714.7 STEMI 10.110.1 Final Diagnosis NSTEMI 13.913.9 Uns. Angina 9.19.1 0.5 1.0 2.0 Total Patients Tic HR (95% CI) KM% at Month 12 Characteristic 11.211.2 9.29.2 16.816.8 8.68.6 7.27.2 9.89.8 13.113.1 9.59.5 19.019.0 9.29.2 14.114.1 8.48.4 9.19.1 8.58.5 11.411.4 8.68.6 0.83 (0.71, 0.97) 0.85 (0.76, 0.95) 0.94 (0.78, 1.12) 0.82 (0.74, 0.91) 0.85 (0.74, 0.97) 0.84 (0.77, 0.92) 0.75 (0.56, 0.99) 0.86 (0.78, 0.94) 0.87 (0.66, 1.13) 0.84 (0.76, 0.93) 0.88 (0.76, 1.03) 0.83 (0.74, 0.92) 0.58 (0.34, 1.00) 0.84 (0.72, 0.98) 0.83 (0.73, 0.94) 0.96 (0.75, 1.22) 5288 13336 2878 15744 10643 18624 1312 17256 1152 17462 4662 13962 489 7026 7955 3112 Interaction P-value 0.8182 0.2166 0.3615 0.8351 0.4882 0.4085 Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Tic Better Clop Better

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