Α ΚΑΡΔΙΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ ΚΑΙ ΟΜΩΝΥΜΟ ΕΡΓΑΣΤΗΡΙΟ ΙΑΤΡΙΚΗ ΣΧΟΛΗ ΠΑΝΕΠΙΣΤΗΜΙΟΥ ΑΘΗΝΩΝ ΙΠΠΟΚΡΑΤΕΙΟ ΓΕΝΙΚΟ ΝΟΣΟΚΟΜΕΙΟ ΑΘΗΝΩΝ Διευθυντής: Καθηγητής ΔΗΜΗΤΡΙΟΣ ΤΟΥΣΟΥΛΗΣ Προβληματισμοι στην χρηση αντιαιμοπεταλιακων στα οξέα ισχαιμικά σύνδρομα Δημήτριος Τούσουλης Καθηγητης Καρδιολογίας Α Πανεπιστημιακή Καρδιολογική Κλινική Ιπποκράτειο Γ.Ν.Α.
Ho orarium from Me ari i, Phizer, MSD Via ex E pe, Bayer, Amje, Boerger I ge heim
ΘΕΡΑΠΕΙΑ
Αντιαιμοπεταλιακή αγωγη μετα απο ΟΣΣ χρειαζεται?
Aspirin after myocardial infarction ISIS-2 Trial Aspirin reduces CV death in the first 5 weeks post MI Lancet 1988
Aspirin after myocardial infarction BMJ 2011
Διπλη αντιαιμοπεταλιακή αγωγη μετα απο ΟΣΣ Ειναι αναγκαία?
DAPT in STEMI CLARITY-TIMI 28 STEMI receiving fibrinolysis clopidogrel 300 loading + 75 thereafter vs placebo Sabatine MS et al, NEJM 2005
Cumulative Hazard Rate DAPT in NSTEMI / ACS Primary End Point - MI/Stroke/CV Death 0.14 0.12 0.10 CURE Placebo + ASA* 11.4% 9.3% 0.08 0.06 Clopidogrel + ASA* 0.04 0.02 0.00 * In combination with standard therapy 0 3 6 9 12 Months of Follow-Up The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. 20% RRR P < 0.001 N = 12,562
DAPT in STEMI / NSTEMI-ACS
Prasugrel in STEMI / non-ste ACS TRITON-TIMI 38 Efficacy and Safety endpoints Wiviott SD et al, NEJM 2007
Prasugrel in STEMI / non-ste ACS TRITON-TIMI 38 Safety endpoint: bleeding Wiviott SD et al, NEJM 2007
Cumulative incidence (%) Cumulative incidence (%) PLATO: primary efficacy endpoint over time (composite of CV death, MI or stroke) 8 6 4 Clopidogrel Ticagrelor 5.4 4.8 8 0-30 days 31-360 days 6 4 Clopidogrel Ticagrelor 6.6 5.3 2 2 0 (HR, 0.88; 95% CI, 0.77-1.00; P=0.045) 0 (HR, 0.80; 95% CI, 0.70-0.91; P<0.001) 0 10 20 30 Days after randomization No. at risk Ticagrelor 9333 8942 8827 8763 Clopidogrel 9291 8875 8763 8688 31 90 150 210 270 330 Days after randomization * 8673 8543 8397 7028 6480 4822 8688 8437 8286 6945 6379 4751 *Excludes patients with any primary event during the first 30 days Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
K-M estimated rate (% per year) PLATO: Time to major bleeding: primary safety endpoint* 15 10 Ticagrelor Clopidogrel 11.6% 11.2% P=NS 5 (HR 1.04; 95% CI, 0.95-1.13; P=0.43) 0 No. at risk 0 60 120 180 240 300 360 Days from first IP dose Ticagrelor 9235 7246 6826 6545 5129 3783 3433 Clopidogrel 9186 7305 6930 6670 5209 3841 3479 *Both groups included aspirin Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
Διπλη Αντιαιμοπεταλιακή αγωγη μετα απο stent
Prasugrel in STEMI / non-ste ACS TRITON-TIMI 38 Efficacy endpoints: stent thrombosis Wiviott SD et al, NEJM 2007
Ticagrelor in STEMI / non-ste ACS PLATO Trial Efficacy endpoints: stent thrombosis Wallentin L et al, NEJM 2009
Predictors of stent thrombosis Tada T et al. JACC: Cardiovasc Interv 2013;5:1267-74
Διπλη Αντιαιμοπεταλιακή αγωγη Διάρκεια<12 μηνες?
Mehran R et al. J Am Coll Cardio 2015;65:1103-6
Palmerini T et al. Eur Heart J 2017; e-pub ahead of print
An OPen-label, Randomized, Controlled, Multicenter Study ExplorIng TwO TreatmeNt StratEgiEs of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention PIONEER AF-PCI
Patients With Atrial Fibrillation Undergoing Coronary Stent Placement: PIONEER AF-PCI End of treatment 12 months 2100 patients with NVAF Coronary stenting No prior stroke/tia, GI bleeding, Hb<10, CrCl<30 72 hours After Sheath removal R A N D O M I Z E 1,6, or 12 months Pre randomization MD Choice Rivaroxaban 2.5 mg bid Clopidogrel 75 mg qd Aspirin 75-100 mg qd 1,6, or 12 months Pre randomization MD Choice VKA (target INR 2.0-3.0) Clopidogrel 75 mg qd Aspirin 75-100 mg qd Rivaroxaban 15 mg qd* Clopidogrel 75 mg qd Rivaroxaban 15mg QD Aspirin 75-100 mg qd VKA (target INR 2.0-3.0) Aspirin 75-100 mg qd WOEST Like ATLAS Like Triple Therapy Primary endpoint: TIMI major + minor + bleeding requiring medical attention Secondary endpoint: CV death, MI, and stroke (Ischemic, Hemorrhagic, or Uncertain Origin) *Rivaroxaban dosed at 10 mg once daily in patients with CrCl of 30 to <50 ml/min. Alternative P2Y 12 inhibitors: 10 mg once-daily prasugrel or 90 mg twice-daily ticagrelor. Low-dose aspirin (75-100 mg/d). Open label VKA
Cardiovascular Death, Myocardial Infarction, or Stroke (%) Kaplan-Meier Estimates of First Occurrence of CV Death, MI or Stroke Riva + P2Y 12 6.5% 6.0% 5.6% Riva + DAPT VKA + DAPT Riva + P2Y 12 v. VKA + DAPT HR=1.08 (95% CI: 0.69-1.68) p=0.750 Riva + DAPT v. VKA + DAPT HR=0.93 (95% CI: 0.59-1.48) p=0.765 No. at risk Riva + P2Y 12 Riva + DAPT VKA + DAPT 694 704 695 648 662 635 633 640 607 621 628 579 Days Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Composite of adverse CV events is composite of CV death, MI, and stroke. Hazard ratios as compared to VKA group are based on the (stratified, only for the Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank P-values as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/115 mg QD comparing VKA) two-sided log rank test. 6 Subjects were excluded from all efficacy analyses because of violations in Good Clinical Practice guidelines 590 596 543 562 570 514 430 457 408
All Cause Rehospitalization (%) All Cause Hospitalization for an Adverse Event 41.5% VKA + DAPT Riva + P2Y 12 Riva + DAPT 34.1% 31.2% Riva + P2Y 12 v. VKA + DAPT HR=0.77 (95% CI: 0.65-0.92) p=0.005 ARR=7.4 NNT=14 Riva + DAPT v. VKA + DAPT HR=0.74 (95% CI: 0.61-0.88) p=0.001 ARR=10.3 NNT=10 No. at risk Riva + P2Y 12 Riva + DAPT VKA + DAPT 696 706 697 609 607 592 582 570 540 559 548 490 Days Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Rehospitalizations do not include the index event and include the first rehospitalization after the index event. Hazard ratios as compared to the VKA group are based on the Cox proportional hazards model. Log-Rank P-values as compared to VKA group are based on the two-sided log rank test. 496 493 422 437 454 369 322 367 272
Διπλη Αντιαιμοπεταλιακή αγωγη μετα απο ΟΣΣ >12 μηνες?
MI is the tip of the atherothrombotic iceberg ACUTE PLAQUE RUPTURE ACS (UA/NSTEMI/STEMI) ACS, acute coronary syndrome; NSTEMI, non-st segment elevation myocardial infarction; STEMI, ST segment elevation myocardial infarction; UA, unstable angina. Goldstein JA. J Am Coll Cardiol 2002;39:1464 1467.
Features of conculprit lesion vulnurability across the same artery Toutouzas K,.Tousoulis D, EHJ 2015
Platelets may be involved in all stages of atherothrombosis Initiation and progression Plaque rupture Acute thrombus formation Platelet adhesion & activation Release of inflammatory mediators, cell recruitment Platelet activation Release of inflammatory mediators, plaque instability Platelet aggregation Fuentes QE et al. Platelets 2013;24(4):255 262; Gawaz M. Eur Heart J Suppl 2008:10(Suppl 1);14 17.
Recurrent events are as likely to originate from a new atherosclerotic plaque as they are from the initial culprit lesion PROSPECT study: Prospective study of the natural history of atherosclerosis over 3 years in patients with ACS who underwent PCI (n=697)[stone 2011] All events 20.4% ACS, acute coronary syndrome; MACE, major adverse cardiac events; PCI, percutaneous coronary intervention; PROSPECT, Providing Regional Observations to Study Predictors of Events in the Coronary Tree. Stone GW et al. N Engl J Med 2011;364:226 235.
Impact of bleeding on prognosis Rao et al, JAMA 2004
CHARISMA Study MI subgroup Bhatt DL et al, J Am Coll Cardiol 2007;49:1982 8.
DAPT Study - Design
DAPT Study Primary safety end point
DAPT Study Endpoints
DAPT Study MI vs non-mi patients
DAPT Study MI All MIs No-stent thrombosis MIs
Event rate (%) PEGASUS-TIMI 54: Primary Endpoint 10 9 8 Placebo Ticagrelor 90 mg bid Ticagrelor 60 mg bid 9.04% Placebo 7.85% 90 mg bid 7 7.77% 60 mg bid 6 5 4 3 2 1 0 Ticagrelor 90 mg vs placebo HR 0.85 (95% CI 0.75 0.96) P=0.008 Ticagrelor 60 mg vs placebo HR 0.84 (95% CI 0.74 0.95) P=0.004 0 3 6 9 12 15 18 21 24 27 30 33 36 No. at risk Placebo 90 mg bid 60 mg bid 7067 7050 7045 6979 6973 6969 6892 6899 6905 6823 6827 6842 6761 6769 6784 P<0.026 indicates statistical significance; CI, confidence interval; HR, hazard ratio Months from randomisation 6681 6719 6733 6508 6550 6557 6236 6272 6270 5876 5921 5904 5157 5243 5222 4343 4401 4424 3360 3368 3392 2028 2038 2055 Bonaca MP et al. N Engl J Med 2015;372:1791 1800
PEGASUS-TIMI 54: Efficacy Endpoints Endpoint 3-year KM event rates (%) Ticagrelor Placebo HR (95% CI) P value Primary CV death, MI or stroke (1558 events) CV death (566 events) MI (898 events) Stroke (313 events) 7.85 9.04 0.85 (0.75 0.96) 0.008 7.77 9.04 0.84 (0.74 0.95) 0.004 7.81 9.04 0.84 (0.76 0.94) 0.001 2.94 3.39 0.87 (0.71 1.06) 0.15 2.86 3.39 0.83 (0.68 1.01) 0.07 2.90 3.39 0.85 (0.71 1.00) 0.06 4.40 5.25 0.81 (0.69 0.95) 0.01* 4.53 5.25 0.84 (0.72 0.98) 0.03* 4.47 5.25 0.83 (0.72 0.95) 0.005* 1.61 1.94 0.82 (0.63 1.07) 0.14* 1.47 1.94 0.75 (0.57 0.98) 0.03* 1.54 1.94 0.78 (0.62 0.98) 0.03* 0.4 0.6 0.8 1 1.25 1.67 Ticagrelor better Placebo better Ticagrelor 90 mg bid Ticagrelor 60 mg bid Ticagrelor pooled *Indicates nominal P value; P<0.026 indicates statistical significance Bonaca MP et al. N Engl J Med 2015;372:1791 1800
3-year KM event rate PEGASUS-TIMI 54: Bleeding 5 4 3 2 P<0.001 2.6 2.3 P<0.001 Ticagrelor 90 mg bid Ticagrelor 60 mg bid Placebo P=NS P=NS P=NS 1 0 1.1 TIMI major bleeding 1.3 1.2 0.4 TIMI minor bleeding 0.6 0.7 0.6 0.6 0.6 0.5 Fatal bleeding or ICH ICH 0.1 0.3 0.3 Fatal bleeding Rates are presented as 3-year Kaplan-Meier estimates Bonaca MP et al. N Engl J Med 2015;372:1791 1800
PEGASUS-TIMI 54: Numbers Needed to Treat and Numbers Needed to Harm (ITT Population) Efficacy endpoint Primary endpoint: CV death, MI or stroke Ticagrelor 90 mg bid Estimated risk difference NNT Ticagrelor 60 mg bid Estimated risk difference NNT 1.19% 85 1.27% 79 CV death 0.45% 221 0.53% 189 MI 0.85% 119 0.72% 139 Stroke 0.33% 304 0.47% 213 Safety endpoint Primary safety endpoint: TIMI major bleeding Estimated risk difference NNH Estimated risk difference NNH 1.22% 82 0.94% 107 ICH 0.08% 1309-0.01% -8005 Fatal bleeding -0.06% -1753-0.05% -2182 Estimated risk difference is the difference in 3-year Kaplan-Meier percent between ticagrelor and placebo based on intention-to-treat analyses NNH, number needed to harm; NNT, number needed to treat Data on file: ATLAS approval ID 773,116.011 59
Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials Major adverse cardiovascular events Udell JA et al. Eur Heart J. 2015;37(4):390-399.
Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials Efficacy & safety end points Udell JA et al. Eur Heart J. 2016;37(4):390-399.
Διπλη Αντιαιμοπεταλιακή αγωγη μετα απο ΟΣΣ >12 μηνες? Πιοος ο υποψηφιος?
Predictors of combined treatment effect Yeh RW et al. JAMA 2016;315:1735-49 63
Cumulative Incidence of ST/MI Continued Thienopyridine vs. Placebo DAPT Score <2 (Low); N=5731 Cumulative Incidence of GUSTO Moderate/ Severe Bleed Cumulative Incidence of MACCE 10 % 8 % 6 % 4 % 2 % 0 % 1 2 Continued Thienopyridine Placebo 1.7% vs. 2.3% P=0.07 1 5 1 8 GUSTO Moderate/ Severe Bleeding 2 1 Months After Enrollment 10 % 8 % 6 % 4 % 2 % 0 % 1 Yeh RW et al. JAMA 2016;315:1735-49 2 Stent Thrombosis or MI 2 4 2 7 3.0% vs. 1.4% P<0.001 3 0 Continued Thienopyridine Placebo 1 5 1 8 10 % 8 % 6 % 4 % 2 % 0 % 1 2 2 1 Months After Enrollment 2 4 Continued Thienopyridine Placebo 3.7% vs. 3.8% P=0.73 1 5 2 7 1 8 2 1 Months After Enrollment 3 0 MACCE 2 4 2 7 3 0 64
Cumulative Incidence of ST/MI Continued Thienopyridine vs. Placebo DAPT Score 2 (High); N=5917 Cumulative Incidence of GUSTO Moderate/ Severe Bleed Cumulative Incidence of MACCE 10 % 8 % 6 % 4 % 2 % 0 % 1 2 Continued Thienopyridine Placebo 2.7% vs. 5.7% P<0.001 1 5 1 8 GUSTO Moderate/ Severe Bleeding Stent Thrombosis or MI 2 Months 1 After Enrollment 10 % 8 % 6 % 4 % 2 % 0 % 1 Yeh RW et al. JAMA 2016;315:1735-49 2 2 4 2 7 1.8% vs. 1.4% P=0.26 3 0 Continued Thienopyridine Placebo 1 5 1 8 10 % 8 % 6 % 4 % 2 % 0 % 1 2 2 Months 1 After Enrollment 2 4 Continued Thienopyridine Placebo 4.9% vs. 7.6% P<0.001 1 5 2 7 1 8 2 Months 1 After Enrollment 3 0 MACCE 2 4 2 7 3 0 65
Treatment effect by DAPT Score The DAPT Score accurately identifies patients with the greatest anticipated benefit vs. harm from continuing dual antiplatelet therapy beyond 12 months among randomized patients in the DAPT Study Low DAPT Score (< 2) NNT to prevent ischemia = 153 NNH to cause bleeding 64 High DAPT Score 2 NNT to prevent ischemia = 34 NNH to cause bleeding = 272 Yeh RW et al. JAMA 2016;315:1735-49 66
Διπλη Αντιαιμοπεταλιακή αγωγη μετα απο ΟΣΣ >12 μηνες? Ποσο ενωρις?
Effect of ticagrelor on the composite of CV death, MI and stroke at 3 years by time from P2Y 12 withdrawal PEGASUS TIMI 54 P trend <0.001 Time from P2Y 12 inhibitor withdrawal to randomization 30 days n=7181 >30 days to 1 year n=6501 >1 year n=5079 3-year Kaplan-Meier rate (%) Ticagrelor Placebo HR (95% CI) P value 7.4 0.70 (0.57, 0.87) 8.0 0.75 (0.61, 0.92) 7.7 9.9 0.73 (0.61, 0.87) <0.001 8.1 0.90 (0.72, 1.12) 7.2 0.82 (0.65, 1.02) 7.6 8.7 0.86 (0.71, 1.04) 0.11 6.3 0.96 (0.73, 1,26) 6.9 1.06 (0.81, 1.38) 6.6 6.9 1.01 (0.80, 1.27) 0.96 Ticagrelor 90 mg Ticagrelor better 1.0 Placebo better Ticagrelor 60 mg Pooled Bonaca MP et al. Eur Heart J 2015:doi:10.1093/eurheartj/ehv531
Summary Post-MI patients are at high risk for recurrent ischaemic events One year of DAPT is essential in all patients after MI, unless contraindicated due to high bleeding risk Withdrawal from P2Y 12 inhibition in high-risk post MI patients is associated with heightened CV risk Longer event-free survival on ASA monotherapy is associated with lower future CV risk Prolonged and more intensive antiplatelet therapy reduces CV death and ischaemic complications in high-risk patients with prior MI Recognising the patient who will benefit from prolonged DAPT after assessing the ischaemic and bleeding risk is a matter of clinical judgement and an important aspect of the management of post-mi patients
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