Amber Malik Director Cath Lab Services Shaikh Zayed Hospital, Lahore

 Platelet aggregation contributes to atherothrombosis which in turn is associated with Acute Coronary Syndromes  ACS often precipitates cardiovascular death

No ST elevationST elevation Acute coronary syndrome Antiplatelet Rx Antithrombin Rx Complete obstruction Partial flow UA/NSTEMISTEMI

X TF/ VIIa Va Ca ++ FGN IXa XI VIIIa FGN Fibrin Xa Plt Prothrom Thrombin

Collagen fibrils Inactive platelet GP Ia/IIa GP VI Platelet activation: Release of contents, surface receptor expression

ADP Collagen Thrombin Epinephrine Tx A 2 Serotonin  Ca ++ PGG 2 -PGH 2 AA release Tx A 2 COX Tx Syn Tx A 2 RBCs Endothelial cells

ADP Collagen Thrombin Epinephrine Tx A 2 Serotonin GP IIb/IIIa receptor activation IIb/IIIa Shear forces FGN IIb/IIIa inhibitor

 Risk during and after ACS can be reduced by optimal anticoagulation and antiplatelet treatment in conservatively treated as well as revascularised patients  In PCI with stents effective AP inhibition is highly mandatory as the processes themselves are thrombogenic and add to the risk

Prothrombin Thrombin Xa X Va,Ca 2+ Platelet UFH LMWH UFH DTIs GP IIb/IIIa inhibitor ASA Clopidogrel LMWH, pentasaccharide

 DAPT ( aspirin and clopidogrel) for NSTEMI for 1 year (CURE trial )  DAPT for STEMI for at least 30 days (CLARITY- TIMI 28 trial )  DAPT mandatory post PCI with stents BMS at least 1 month DES at least 1 year

 Even though CURE shows a RRR of 20% of composite end point which occurred in 9.3% vs 11.4 % on placebo.  The 9.35 % event rate is still quite high inspite of DAPT, which rose to 16.3% when recurrent ischemia was included.  Hence the desire to improve outcome even further

 Cox inhibitors : Aspirin  ADP receptor antagonist : Ticlopidine Clopidogrel Prasugrel Cangrelor Ticagrelor(AZD6140)

 Phosphodiesterase inhibitors : Cilostazol Dipyridamole  Thrombin inhibitor : Bivalirudin  Glycoprotein IIb/IIIA inhibitors : Abciximab Eptifibatide Tirofiban

Ticlopidine (1 st generation) N S Cl N S COOCH 3 N F O S O O CH 3 Clopidogrel (2 nd generation) Prasugrel (CS-747) (LY640315) (3 rd generation)

 Slow onset: requires prolonged pretreatment for PCI efficacy  Optimal interval from delivery to max drug effect is >15 hrs  Bleeding (especially related to CABG)  Modest levels of platelet inhibition  Variability of response is upto 30% depending on the measure of platelet aggregation used

 ESC guidelines recommend 300mg loading dose > 6 hrs pre PCI  Reality is very different  Common practise CAG is often followed by ad hoc PCI with very little time for optimal dosing etc and exposing patients to an increased risk of bleeding  PRAGUE 8 concluded that non selective treatment of pts with high dose clopidogrel should not be routinely undertaken

Failure of Therapy = Drug Resistance Failure of TherapySuccessful Therapy Lesser Response Greater Response

Prasugrel Sankyo Ann Report 51:1,1999Pro-drugPro-drug Oxidation (Cytochrome P450) Oxidation HOOC * HS N N O O F F Active Metabolite N N S S O O F F O O Sem Vasc Med 3:113, 2003Hydrolysis(Esterases)Hydrolysis(Esterases) N N S S O O C C H H 3 3 C C O O F F O O N N S S O O Cl O O CH 3 CC Clopidogrel 85% Inactive Metabolites Esterases N N S S O O Cl O O CH 3 CC O O N N S S O O Cl O O CH 3 CC Active Metabolite HOOC * HS N N O O Cl OCH 3

Inhibition of Platelet Aggregation (%) Response to Prasugrel Response to Clopidogrel Clopidogrel Responder Clopidogrel Non-responder * Responder =  25% IPA at 4 and 24 h Interpatient Variability Brandt, Payne, Wiviott et al AHJ 2007

 PRASUGREL  Faster and more potent IPA : Less dependent on CYP450 for metabolism More extensively metabolised to its active metabolite Reaches higher concentrations with a 60mg LD and 10mg MD vs 300mgLD and 75mg MD as well as high dose 600mg LD and 150 mg MD clopidogrel  Less variabilty of response  Benefits demonstrated in both healthy volunteers and CAD pts.

TRITON-TIMI 38 AHA 2007 Orlando, Florida Disclosure Statement: The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.

NEJM 357: ,

 Dual antiplatelet Rx (ASA + thienopyridine) is standard of care: Ticlopidine Clopidogrel Ticlopidine Clopidogrel  Clinical need to improve on benefits observed with clopidogrel  Prasugrel Novel thienopyridine Efficient generation of active metabolite High levels of IPA achieved rapidly High levels of IPA achieved rapidly High IPA in clopidogrel “hyporesponders” Encouraging Phase 2 data

1.To test the hypothesis that higher and less variable IPA prevents clinical ischemic events. 2.To evaluate the safety of a regimen that produces higher IPA. These goals were achieved by evaluating the efficacy and safety of prasugrel compared to clopidogrel in mod/high risk patients with ACS undergoing PCI on a background of ASA.

Trial Organization Trial Leadership: TIMI Study Group Eugene Braunwald,Chairman, Elliott M. Antman,PI, Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe, Sabina A. Murphy, Susan McHale Sponsors: Daiichi Sankyo and Eli Lilly J. Anthony Ware, Jeffrey Riesmeyer, William Macias, James Croaning, Govinda Weerakkody, Francis Plat, Tomas Bocanegra J. Anthony Ware, Jeffrey Riesmeyer, William Macias, James Croaning, Govinda Weerakkody, Francis Plat, Tomas Bocanegra Data Center and Site Management: Quintiles Inc Data Safety Monitoring Board David Williams (Chair), Christophe Bode, Spencer King, Ulrich Sigwart, David DeMets David Williams (Chair), Christophe Bode, Spencer King, Ulrich Sigwart, David DeMets

Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 mg MD 1 o endpoint: CV death, MI, Stroke 2 o endpoints:CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies:Pharmacokinetic, Genomic Median duration of therapy - 12 months N= 13,600

Inclusion Criteria Planned PCI for : Mod-High Risk UA/NSTEMI (TRS > 3) STEMI: < 14 days (ischemia or Rx strategy) STEMI: Primary PCI Major Exclusion Criteria: –Severe comorbidity –Increased bleeding risk –Prior hemorrhagic stroke or any stroke < 3 mos –Any thienopyridine within 5 days –No exclusion for advanced age or renal function Known Anatomy

30 Countries707 Sites LTFU = 14 (0.1%) 30 Countries707 Sites LTFU = 14 (0.1%) Argentina (195) Finland (116) New Zealand (49) Australia (217) France (146) Poland (1938) Austria (182) Germany (999) Portugal (67) Belgium (287) Hungary (695) Slovakia (140) Brazil (225) Iceland (10) South Africa (404) Canada (251) Israel (1219) Spain (178) Chile (114) Italy 782) Sweden (154) Czech Rep (340) Latvia (21) Switzerland (136) Denmark (33) Lithuania (54) United Kingdom (73) Estonia 134) Netherlands (390) United States (4059)

Clopidogrel (N=6795) % Prasugrel (N=6813) % UA/NSTEMI74 STEMI26 Age, median (IQR) > 75 y 61 (53,69) y (53, 70) y 13 Wgt, median (IQR) < 60 kg 83 kg (72, 92) kg (73, 93) 4.6 Female2725* Diabetes23 Prior MI18 CrCl (ml/min) >60 < *P<0.05

Clopidogrel (N=6795) % Prasugrel (N=6813) % PCI / CABG99 / 1 Any Stent9594 BMS4748 DES47 Multivessel PCI14 UFH / LMWH / Bival65 / 8 / 366 / 9 / 3 GP IIb/IIIa5554 LD of Study Rx Pre PCI During PCI Post PCI

HR 0.81 ( ) P= Prasugrel Clopidogrel HR 0.80 P= HR 0.77 P= Days Primary Endpoint (%) 12.1 (781) 9.9 (643) Primary Endpoint CV Death,MI,Stroke NNT= 46 ITT= 13,608 LTFU = 14 (0.1%)

 This was primarily driven by a reduction in the rate of non-fatal MI 7.3 vs 9.5%; p< at months  There was no significant difference between the incidence of rates of CV death or nonfatal stroke

 Prasugrel compared to clopidogrel reduces the incidence of recurrent MI  Also reduces the severity of recurrent MI Overall MI RRR – 24% MI followed by deathRRR - 42%

 The rapid onset time of prasugrel upto 30 mins means that the physician can afford to take the time to determine coronary anatomy ( rule out urgent CABG), yet still have time to achieve high levels of IPA for ?proceed PCI LD and day 3 RRR 19 % MD and day 450 RRR 31%

HR 0.82 P=0.01 HR 0.80 P= Days Primary Endpoint (%) Prasugrel Clopidogrel Prasugrel Clopidogrel Loading DoseMaintenance Dose Timing of Benefit (Landmark Analysis)

HR 0.48 P < Prasugrel Clopidogrel 2.4 (142) NNT= (68) Days Endpoint (%) Any Stent at Index PCI N= 12,844

HR 0.81 ( ) P= Prasugrel Clopidogrel Days Endpoint (%) HR 1.32 ( ) P=0.03 Prasugrel Clopidogrel events 35 events Balance of Efficacy and Safety CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH = 167

Bleeding Events Safety Cohort (N=13,457) % Events ARD 0.6% HR 1.32 P=0.03 NNH=167 Clopidogrel Clopidogrel Prasugrel Prasugrel ARD 0.5% HR 1.52 P=0.01 ARD 0.2% P=0.23 ARD 0% P=0.74 ARD 0.3% P=0.002 ICH in Pts w Prior Stroke/TIA (N=518) ICH in Pts w Prior Stroke/TIA (N=518) Clop 0 (0) % Pras 6 (2.3)% (P=0.02)

Days Endpoint (%) HR 0.87 P= Prasugrel Clopidogrel ITT= 13,608 Events per 1000 pts MI Major Bleed (non CABG) + All Cause Mortality Clop 3.2% Pras 3.0 % P=0.64

B OVERALL No GPI GPI DES BMS DM No DM > <65 Female Male STEMI UA/NSTEMI Prasugrel BetterClopidogrel Better HR Age Reduction in risk (%) P inter = NS CV Death, MI, Stroke Major Subgroups CrCl > 60 CrCl <

OVERALL >=60 kg < 60 kg < 75 >=75 No Yes Prior Stroke / TIA Age Wgt Risk (%) Prasugrel BetterClopidogrel Better HR P int = P int = 0.18 P int = 0.36 Post-hoc analysis

Bleeding Risk Subgroups Therapeutic Considerations Significant Net Clinical Benefit with Prasugrel 80% MD 10 mg Reduced MD Guided by PK Age > 75 or Wt < 60 kg 16% Avoid Prasugrel Prior CVA/TIA 4% 4%

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 Thrombosis52% 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 Net clinical benefit significantly favored Prasugrel Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balance

 Prasugrel compared with clopidogrel significantly reduced the incidence of ischemic events, both in the acute and long term  The increased efficacy of prasugrel was associated with an increased risk of bleeding.  The balance of efficacy and safety revealed an early and sustained net clinical benefit over the entire spectrum of ACS investigated  Avoid in pts with prior stroke / TIA  Very old and low body weight may require reduced dose

 Patients with DM and AMI derived the greatest net clincal benefit from prasugrel as compared to clopidogrel

 STEMI 3534 pts  Primary PCI2438(69%)  Secondary PCI1094(31%)  Baseline characteristics well matched  More frequent use of Gp 11b111a inhibitorswith clopidogrel due to bail out

 Benefit of prasugrel across the overall spectrum of ACSs but particularly pronounced in STEMI pts.  Primary end point significant reduction 6.5 vs 9.5%; p=0.002

Antman EM et al. J Am Coll Cardiol. 2008;51: Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction Loading doseMaintenance dose MI (%) Prasugrel HR 0.69 ( ) P < HR 0.81 ( ) P = Prasugrel Clopidogrel Time (days)

 Secondary end point of CV death, MI and UTVR at 30 days was reduced  6.7%vs 8.8% p=0.02  Benefit persisted through 15 months

 Multivariate analyses were performed to identify predictors of CV death, MI and UTVR  Common indicators of high risk remained the same : Gp11b111a use, BMS, multivessel PCI, prior MI >75yrs age.  Only factor that reduced HR was treatment with prasugrel

 Efficacy profile  Reduced rate of : single end points of all cause death, MI and stent thromboses Dual end points of CV death and MI Non significant trend towards a reduced rate of UTVR  Efficacy profile was maintained throughout 15 months

 Safety profile : After 15 months rate of TIMI major non- CABG bleed in prasugrel and clopidogrel was similar 30 day incidence was higher with clopidogrel due to increased Gp2b3a use.

 Net clinical benefit analysis  CV death, MI, non fatal stroke, or TIMI major non CABG bleed after 15 months of treatment with prasugrel vs clopidogrel significant benefit  12.2 vs 14.6% p=0.02

HR 0.70 P<0.001 Days Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 21 N= Prasugrel Clopidogrel Prasugrel Clopidogrel

 The primary end point was again driven by a reduction in the rate of MI in pts treated with Prasugrel 8.2 vs 13.2% p<0.001  A total of 21 pts with DM would need to be treated with prasugrel to avoid one case of the primary end point if the pt was treated with clopidogrel

 In the overall study population the efficacy of prasugrel is at the expense of an increased risk of bleeding.  In this analysis in the DM subset prasugrel did not significantly increase the risk of non CABG bleed

 Multiple sub group analysis showed that the reductions in the rate of stent thrombosis were in favour of prasugrel as compared with clopidogrel in every instance

Randomized 13,608 Stent Placed 12,844 (94%) STENT ANALYSIS BMS Only 6461 (47%) DES Only 5743 (42%) Both BMS/DES 640 (5%) PES Only 2766 (20%) SES Only 2454 (18%) Other/Mixed 523 (4%)

Any Stent (N=12844) 94 % UA/NSTEMI75 STEMI25 Age, median (IQR) > 75 y 60 (53,69) y 13 Female26 Diabetes23 Smoker38 North America32 Prior MI17 CrCl (ml/min) >60 < STENT ANALYSIS

Blinded CEC review of using source documents incl imaging reports: Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of the stent AND a clinical syndrome <48 h. Probable: unexplained death < 30 days or MI in stented territory w/o angiographic confirmation ST AND w/o alternative cause Possible: unexplained death > 30 days following stenting Early: 0 – 30 days after randomization Late > 30 days after randomization (landmark analysis) Based on ARC Definitions Mauri L et al NEJM 2007

Mortality During Follow up (%) Post-Stent Thrombosis STENT ANALYSIS N=210N=12634 HR 13.1 (9.8 – 17.5) P< % of Subjects Stent thrombosis No SAT CLOPIDOGREL

% of Subjects HR 0.48 [ ] P< year: 1.06 vs 2.15% HR 0.48 [ ], P< % 1.13% 52% DAYS CLOPIDOGREL PRASUGREL

% of Subjects HR 0.41 [ ] P< HR 0.60 [ ] P=0.03 DAYS EARLY STLATE ST STENT ANALYSIS 1.56% 0.64% 59% 0.82% 0.49% 40% CLOPIDOGREL PRASUGREL

STENT ANALYSIS DEF/PROB HR 0.48 ( ) P< DEFINITE HR 0.42 ( ) P< DEF/PROB/POSS HR 0.56 ( ) P< CLOPIDOGREL PRASUGREL % of Subjects

PRASUGREL BETTER CLOPIDOGREL BETTER PRASCLO P RISK (%) % % % % % % % % % % % % % % % % % %

% of Subjects HR 0.36 [ ] P< year: 0.74% vs 2.05% HR 0.35 [ ], P< % 0.84% 64% STENT ANALYSIS DAYS CLOPIDOGREL PRASUGREL

% of Subjects HR 0.29 [ ] P= HR 0.46 [ ] P=0.04 DAYS STENT ANALYSIS EARLY STLATE ST 1.44% 0.42% 71% 0.91% 0.42% 54% CLOPIDOGRE L PRASUGREL

2.41% 1.27% % of Subjects HR 0.52 [ ] P= year: 1.22 vs 2.27% HR 0.53 [ ], P= % STENT ANALYSIS DAYS CLOPIDOGREL PRASUGREL

% of Subjects HR 0.45 [ ] P= HR 0.68 [ ] P=0.24 DAYS STENT ANALYSIS EARLY STLATE ST 1.66% 0.75% 55% 0.78% 0.53% 32% CLOPIDOGREL PRASUGREL

Intensive antiplatelet therapy with PRASUGREL in stented patients compared to CLOPIDOGREL: Substantial reduction in ST: Regardless of stent type or ST definition Early and Late A broad range of clinical/procedural characteristics Fewer ischemic events, more major bleeding STENT ANALYSIS

Stent ThrombosisCVD/MI/CVA w/o ST Events per 1000 patients treated TIMI Major Non CABG bleed

Stent Thrombosis is a rare, but devastating complication of PCI associated with a high mortality. Efforts to reduce ST have focused on compliance w/ and duration of ASA/clopidogrel Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a broad array of clinical procedural characteristics STENT ANALYSIS

 In addition to reducing ST prasugrel also reduced the primary end point, in the stented population, the BMS pop, and the DES pop. STENT ANALYSIS

Net Clinical Benefit STENT ANALYSIS HR 0.88 ( ) p=0.07 HR 0.86 ( ) p=0.002 HR 0.84 ( ) p=0.025 N=12844 N=6461 N=5743 % of Subjects Any BMSDES HR 0.84 P=0.025

CVD/MI/CVAMAJOR BLEEDING STENT ANALYSIS HR 0.80 ( ) p=0.003 HR 0.81 ( ) p= HR 0.82 ( ) p=0.02 HR 1.37 ( ) p=0.09 HR 1.27 ( ) p=0.06 HR 1.19 ( ) p=0.34 N=12844 N=6461 N=5743 CLOPIDOGREL PRASUGREL

 Prasugrel as compared to clopidogrel significantly reduced : Incidence of combined end point of CV death, MI and nonfatal stroke NNT 46; p<  This benefit came at the cost of an increase in major non-CABG bleeds NNH 167; p=0.03

 Prasugrel is more effective than clopidogrel for the prevention of ischemic events including stent thrombosis, in ACS pts undergoing PCI esp high risk e.g STEMI, diabetic and stent pop.  The reduction is primarily MI prevention driven  Safety profile is comparable to that of clopidogrel in this high risk subset

Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA ASA ASA + Clopidogrel ASA + Prasugrel - 22% - 20% - 19% + 60%+ 38%+ 32% Reduction in Ischemic Events Increase in Major Bleeds

 ACS can lead to CV death  Post PCI – SAT, death, MI or UTVR  Clopidogrel is not enough  PRASUGREL Pharmacokinetics Pharmacodynamics Good clinical impact as it reduces MI  Prasugrel better  Bleeding risk ????

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