Which Antiplatelet Therapy for PCI? Stephen D Wiviott MD Cardiovascular Division Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School Investigator, TIMI Study Group

Disclosures CME Honoraria: Eli Lilly, Daiichi Sankyo; Accumetrics, Astra-Zeneca, Pfizer, Merck, Bayer. Consultancies: Sanofi-Aventis, BMS, Portola, Astra-Zeneca , Medco, ARENA Research Funding: Eli Lilly, Daiichi Sankyo, Merck-Schering Plough TIMI Study Group Receives Research Funding From: Eli Lilly, Daiichi Sankyo, Merck, Schering Plough, Sanofi-Aventis, AstraZeneca, Accumetrics

What antiplatelet therapy should we use for PCI? It depends… …but, mostly 3rd generation agents: prasugrel and ticagrelor

Goals of Antiplatelet Therapy for PCI? Potent Antiplatelet Effect Consistent Antiplatelet Effect SAFETY !!! – choice of patients Speed if rapid to cath lab High risk NSTEACS STEMI

Prasugrel: PRINCIPLE – TIMI 44 Results Wiviott_ACC Platelet_Dr Wiviott's comments included_021910 Prasugrel: PRINCIPLE – TIMI 44 Results Wiviott/p 2927/Figure 4 Loading Dose Maintenance Dose 100 Wiviott/p 2926/col 2/para 3 100 Clopidogrel Prasugrel 150 mg 10 mg 80 Prasugrel 60 mg * 80 * * 61.3* 60 60 IPA (20 mmol/L ADP, %) IPA (20 mmol/L ADP, %) PRINCIPLE-TIMI 44: Inhibition of platelet aggregation with loading and maintenance doses 46.1 At 6 hours, the extent of inhibition was 74.8% and 31.8% with prasugrel and clopidogrel loading doses, respectively (P < 0.0001). Significantly greater inhibition was also observed at 30 minutes and up to 24 hours (P < 0.0001 for both comparisons). . Wiviott SD, Trenk D, Frelinger AL, et al; PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116(25):2923-2932. Clopidogrel 600 mg 40 40 * 20 20 4 8 12 16 20 24 14 Days Time (h) *P<0.0001 vs clopidogrel. IPA=inhibition of platelet aggregation; PRINCIPLE TIMI=Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction. Reprinted with permission from Wiviott S, et al. Circulation. 2007;116(25):2923-2932.

Prasugrel vs Clopiodogrel 15 138 events Clopidogrel 12.1 HR 0.81 (0.73-0.90) P=0.0004 CV Death / MI / Stroke 9.9 10 NNT = 46 Prasugrel Endpoint (%) This slide depicts the balance of efficacy and safety observed in the trial. At the top is shown the significant reduction in the primary endpoint as presented a few moments ago. The number needed to treat to prevent one event was 46 At the bottom is the rate of TIMI major non CABG bleeds--a key safety endpoint-- which was 2.4% with prasugrel and 1.8% with clopidogrel—a 0.6% Absolute risk increase. The excess of 35 major bleeds with prasugrel corresponded to an HR of 1.32 and P value of 0.03 . The number of subjects who would need to be treated to result in one excess major bleed (NNH) was 167. 5 35 events TIMI Major NonCABG Bleeds Prasugrel 2.4 HR 1.32 (1.03-1.68) P=0.03 1.8 Clopidogrel NNH = 167 30 60 90 180 270 360 450 Days Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

TRITON-TIMI 38—Bleeding Events Safety Cohort (N=13,457) Wiviott_ACC Platelet_Dr Wiviott's comments included_021910 TRITON-TIMI 38—Bleeding Events Safety Cohort (N=13,457) Wiviott/p 2005/col 2/para 3; p 2007/col 1/para 1; p 2011/Table 3 4 2 Clopidogrel ICH in patients with prior stroke/TIA (N=518) Prasugrel Clopidogrel: 0 (0%) Prasugrel: 6 (2.3%) P=0.02 Events (%) More details of the bleeding events are shown on this slide. The TIMI major non CABG bleed data are shown in the pair of bar graphs on the left, showing the increase in events with prasugrel Life threatening bleeding--another key safety EP ( defined as requiring a 4 unit txn, fluid or inotropic support, surgical intervention, or an ICH) occurred in 0.9 % of clopidogrel and 1.4% of prasugrel subjects—a 0.5% ARI with prasugrel, associated with a P value of 0.01 Subcategories of life threatening bleeding are shown to the right. Fatal bleeding occurred in 0.1% of pts with clopidogrel and was increased to 0.4% of patients with prasugrel—a 0.3% Absolute risk increase associated with a P value of 0.002. There was no difference in ICH overall in the trial—occurring in 0.3% of pts in both groups. Of note, in the subgroup of 518 patients with a history of prior stroke or TIA, no ICH’s occurred with clopidogrel while 6 occurred with prasugrel—a significant difference at the 0.02 level. ARD 0.6% HR 1.32 P=0.03 NNH=167 ARD 0.5% HR 1.52 P=0.01 ARD 0.2% HR=1.25 P=0.23 ARD 0.3% HR=4.19 P=0.002 ARD 0% HR=1.12 P=0.74 ARD=absolute risk difference; HR=hazard ratio; ICH=intracranial hemorrhage; TIA=transient ischemic attack; TIMI=Thrombolysis in Myocardial Infarction. Wiviott SD, et al. N Engl J Med. 2007;357(20):2001-2015. 7 7

Summary: Prasugrel Beyond Standard Clopidogrel Speed of Onset ++ Extent of Inhibition ++ Poor Responders - - Genetic Effects - - Ischemic Events/Stent Thrombus - - Bleeding Risk + + Indications ACS with PCI, w/o known Stroke or TIA Guidelines PCI/STEMI 2009; UA/NSTEMI 2011

20 µM ADP- Final Extent     * * IPA % † ‡ 100 Last Maintenance Dose Loading Dose Ticagrelor (n=54) Clopidogrel (n=50) Placebo (n=12) * * ‡ † 90 80  70 60 IPA %  50  40 30 20 10  0 .5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240 Onset Maintenance Offset Time (hours) 9

K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) 13 12 Clopidogrel 11.7 11 10 9.8 9 Ticagrelor 8 7 Cumulative incidence (%) 6 5 4 3 2 1 HR 0.84 (95% CI 0.77–0.92), p=0.0003 60 120 180 240 300 360 Days after randomisation No. at risk 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 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Adapted from Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.

Secondary efficacy endpoints over time Myocardial infarction Cardiovascular death 7 6.9 7 Clopidogrel 6 6 5.8 Clopidogrel 5.1 5 Ticagrelor 5 4 4 4.0 Ticagrelor Cumulative incidence (%) Cumulative incidence (%) 3 3 2 2 1 1 HR 0.84 (95% CI 0.75–0.95), p=0.005 HR 0.79 (95% CI 0.69–0.91), p=0.001 60 120 180 240 300 360 60 120 180 240 300 360 Days after randomisation Days after randomisation No. at risk Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,333 8,294 8,822 8,626 7119 5,482 4,419 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109 9,291 8,865 8,780 8,589 7079 5,441 4,364 Adapted from Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.

Time to non-procedure-related PLATO major bleeding Completeness of follow-up 99.97% = five patients lost to follow-up 4 Ticagrelor 3 3.06 2.31 2 K-M estimated rate (% per year) Clopidogrel 1 HR 1.31 (95% CI 1.08–1.60), p=0.006 60 120 180 240 300 360 Days from first IP dose No. at risk Ticagrelor 9,235 7,641 7,247 6,979 5,496 4,067 3,698 Clopidogrel 9,186 7,718 7,371 7,134 5,597 4,147 3,764

Summary: Ticagrelor Beyond Standard Clopidogrel Speed of Onset ++ Extent of Inhibition ++ Poor Responders - - Genetic Effects - - Ischemic Events/Stent Thrombus - - Bleeding Risk + Indications ACS with or without PCI Guidelines Pending

Clinical Considerations: Summary Clopidogrel Prasugrel Ticagrelor Anti-thrombotic ++ +++ +++ Bleeding Risk ++ ++++ +++ Indications ACS, PCI ACS with PCI ACS Black Boxed Warnings Genetic Bleeding, Stroke/TIA Bleeding, ASA >100 Cautions 2C19/DDI Age >75, Wt < 60 Dyspnea Cost $$ (▼) $$$ $$$ Convenience/Compliance QD QD BID CABG 5 days 7 days 5 days

Clinical Considerations: Summary Clopidogrel Prasugrel Ticagrelor Anti-thrombotic ++ +++ +++ Bleeding Risk ++ ++++ +++ Indications ACS, PCI ACS with PCI ACS Black Boxed Warnings Genetic Bleeding, Stroke/TIA Bleeding, ASA >100 Cautions 2C19/DDI Age >75, Wt < 60 Dyspnea Cost $$ (▼) $$$ $$$ Convenience/Compliance QD QD BID CABG 5 days 7 days 5 days

Clinical Considerations: Summary Clopidogrel Prasugrel Ticagrelor Anti-thrombotic ++ +++ +++ Bleeding Risk ++ ++++ +++ Indications ACS, PCI ACS with PCI ACS Black Boxed Warnings Genetic Bleeding, Stroke/TIA Bleeding, ASA >100 Cautions 2C19/DDI Age >75, Wt < 60 Dyspnea Cost $$ (▼) $$$ $$$ Convenience/Compliance QD QD BID CABG 5 days 7 days 5 days

Clinical Considerations: Summary Clopidogrel Prasugrel Ticagrelor Anti-thrombotic ++ +++ +++ Bleeding Risk ++ ++++ +++ Indications ACS, PCI ACS with PCI ACS Black Boxed Warnings Genetic Bleeding, Stroke/TIA Bleeding, ASA >100 Cautions 2C19/DDI Age >75, Wt < 60 Dyspnea Cost $$ (▼) $$$ $$$ Convenience/Compliance QD QD BID CABG 5 days 7 days 5 days

Choice of APT ACS? STEMI vs. NSTEMI? Bleeding Risk Prior APT Rapid PCI? Patient choice/cost/compliance

Rapid /No DAPT Delayed/Prior DAPT CABG PCI CABG PCI Med Rx Med Rx ACS High Bleeding Risk Standard Clopidogrel Pathway Yes Yes N o N o Standard Clopidogrel Pathway Timing of Dx Catheterization And Prior APT Rapid /No DAPT Delayed/Prior DAPT Load Clopidogrel or Ticagrelor if Appropriate Dx Catheterization Dx Catheterization CABG PCI Med Rx CABG PCI Med Rx No DAPT Prasugrel* Ticagrelor Clopidogrel Ticagrelor Stop DAPT Ticagrelor Prasugrel* if no load Clopidogrel Ticagrelor * Without Contraindication (STROKE/TIA)

Standard Clopidogrel Pathway Standard Clopidogrel Pathway ACS High Bleeding Risk Standard Clopidogrel Pathway Yes Yes N o Bleeding Risks: Active Bleeding Major Surgery Thrombolytic Therapy Oral anticoagulants Prior ICH or Previous Severe Bleeding Severe Liver Disease Any history of STROKE/TIA for Prasugrel Other (mostly long term): Cost Coverage Compliance Concerns Standard Clopidogrel Pathway

Timing of Dx Catheterization * Without Contraindication (STROKE/TIA) ACS High Bleeding Risk Yes N o Timing of Dx Catheterization Rapid /No DAPT Delayed/Prior DAPT Dx Catheterization CABG PCI Med Rx No DAPT Prasugrel* Ticagrelor Clopidogrel Ticagrelor * Without Contraindication (STROKE/TIA)

Rapid /No DAPT Delayed/Prior DAPT CABG PCI Med Rx ACS High Bleeding Risk Yes N o Timing of Dx Catheterization Rapid /No DAPT Delayed/Prior DAPT Load Clopidogrel or Ticagrelor if Appropriate Dx Catheterization CABG PCI Med Rx Stop DAPT Ticagrelor Prasugrel* if no load Clopidogrel Ticagrelor * Without Contraindication (STROKE/TIA)

Rapid /No DAPT Delayed/Prior DAPT CABG PCI CABG PCI Med Rx Med Rx ACS High Bleeding Risk Standard Clopidogrel Pathway Yes Yes N o N o Standard Clopidogrel Pathway Timing of Dx Catheterization Rapid /No DAPT Delayed/Prior DAPT Load Clopidogrel or Ticagrelor if Appropriate Dx Catheterization Dx Catheterization CABG PCI Med Rx CABG PCI Med Rx No DAPT Prasugrel* Ticagrelor Clopidogrel Ticagrelor Stop DAPT Ticagrelor Prasugrel* if no load Clopidogrel Ticagrelor * Without Contraindication (STROKE/TIA)

Stent Thrombosis in STEMI Pts by PCI Timing at 15 mo P-interaction=0.78 **We could present this slide as a Forest/Tornado plot instead** Stent thrombosis and TIMI major bleeding events were infrequent, however bleeding associated with prasugrel as compared to clopidogrel was consistent in the STEMI cohort, and either PCI subgroup, with the overall trial result (PPCI 15m HR 1.52 [0.87-2.65]; SecPCI 15m HR 0.39 [0.14-1.11]). HR 0.55 (0.30-1.00) p=0.048 HR 0.63 (0.28-1.39) p=0.25 Stent Thrombosis (ARC Definite/Probable)

PLATO STE-ACS: Stent thrombosis Stent thrombosis,* %[Steg 2010:K] Ticagrelor (n=3752) Clopidogrel (n=3792) p value Definite† 1.6 2.4 0.03 Probable or definite† 2.6 3.4 0.05 Possible, probable, or definite† 3.3 4.3 0.04 HR (95% CI) A lower percentage of patients treated with ticagrelor experienced stent thrombosis compared with those treated with clopidogrel, regardless of how stent thrombosis was defined[Steg 2010:K,M] There was also a 1.0% absolute reduction (25% relative) in the risk of all stent thromboses and a 0.8% absolute (34% relative) reduction in definite stent thrombosis[Steg 2010:K] These results are broadly consistent with those observed in the overall PLATO population[Wallentin 2009:J] Definite: 1.3 vs. 1.9% (HR [95% CI] = 0.67[0.50–0.91]; p=0.009) Probable or definite: 2.2 vs. 2.9% (HR [95% CI] = 0.75[0.59–0.95]; p=0.02) Possible, probable or definite: 2.9 vs. 3.8% (HR [95% CI] = 0.77[0.62–0.95]; p=0.01] Academic Research Consortium definitions of stent thrombosis (also see back-up slide 23)[Cutlip 2007:A] Definite stent thrombosis* Angiographic confirmation of stent thrombosis† The presence of a thrombus‡ that originates in the stent or in the segment 5 mm proximal or distal to the stent and presence of at least 1 of the following criteria within a 48-hour time window: Acute onset of ischaemic symptoms at rest New ischaemic ECG changes that suggest acute ischaemia Typical rise and fall in cardiac biomarkers (refer to definition of spontaneous MI) Nonocclusive thrombus Intracoronary thrombus is defined as a (spheric, ovoid, or irregular) non-calcified filling defect or lucency surrounded by contrast material (on three sides or within a coronary stenosis) seen in multiple projections, or persistence of contrast material within the lumen, or a visible embolisation of intraluminal material downstream Occlusive thrombus TIMI 0 or TIMI 1 intrastent or proximal to a stent up to the most adjacent proximal side branch or main branch (if originates from the side branch) Pathological confirmation of stent thrombosis Evidence of recent thrombus within the stent determined at autopsy or via examination of tissue retrieved following thrombectomy Probable stent thrombosis Clinical definition of probable stent thrombosis is considered to have occurred after intracoronary stenting in the following cases: Any unexplained death within the first 30 days§ Irrespective of the time after the index procedure, any MI that is related to documented acute ischaemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause Possible stent thrombosis Clinical definition of possible stent thrombosis is considered to have occurred with any unexplained death from 30 days after intracoronary stenting until end of trial follow-up *Definite stent thrombosis is considered to have occurred by either angiographic or pathological confirmation †The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not considered a confirmed stent thrombosis (silent occlusion) ‡Intracoronary thrombus §For studies with ST-elevation MI population, one may consider the exclusion of unexplained death within 30 days as evidence of probable stent thrombosis Cutlip DE, et al. Circulation 2007;155:2344–2351. Steg PG, et al. Circulation 2010;122:2131–2141. Wallentin L, et al. N Engl J Med 2009;361:1045–1057. 1.0 *As per Academic Research Consortium definitions.[Cutlip 2007:A] †Denominator is number of patients receiving at least one stent. ACS, acute coronary syndromes; CI, confidence interval; HR, hazard ratio; STE, ST-segment elevation. Cutlip DE, et al. Circulation 2007;155:2344–2351; Steg PG, et al. Circulation 2010;122:2131–2141. Ticagrelor better Clopidogrel better

STEMI PCI PCI Planned No DAPT PPCI Prior DAPT CABG CABG Med Rx Med Rx High Bleeding Risk Or Other Concerns Standard Clopidogrel Pathway Yes N o Planned PPCI No DAPT Prior DAPT Load Prasugrel or Ticagrelor if Rapidly Available Load Ticagrelor If Rapidly Available Dx Catheterization Dx Catheterization CABG PCI Med Rx CABG PCI Med Rx No DAPT Prasugrel* Ticagrelor Clopidogrel Ticagrelor Stop DAPT Ticagrelor Prasugrel* if no load Clopidogrel Ticagrelor * Without Contraindication (STROKE/TIA)

Summary Platelet P2Y12 inhibitors act by inhibiting platelet activation and aggregation This results in reduction of myocardial infarction, stent thrombosis and increased bleeding More intensive inhibition of P2Y12 intensifies these outcomes regardless of mechanism Appropriate choice of patients allows for optimized clinical outcomes

Summary Patients undergoing PRIMARY PCI for STEMI are a special population: Rapid Care requiring rapid onset therapy High Thrombotic Risk Generally Lower Risk for Bleeding (Demographics) These patients are well-suited for newer, more intensive, consistent therapies.

GO PATS!