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Antiplatelet Therapy in ACS and PCI: current state of the art and future therapies Stephen D Wiviott MD Cardiovascular Division Brigham and Women’s Hospital.

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Presentation on theme: "Antiplatelet Therapy in ACS and PCI: current state of the art and future therapies Stephen D Wiviott MD Cardiovascular Division Brigham and Women’s Hospital."— Presentation transcript:

1 Antiplatelet Therapy in ACS and PCI: current state of the art and future therapies Stephen D Wiviott MD Cardiovascular Division Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School Investigator, TIMI Study Group

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

3 History of Present Illness CC: Chest pain 73 yo F with a h/o HTN, HL, strong FH of CAD admitted with new onset CP. 4 days prior to admission: CP radiating to both arms while walking & relieved with rest 4 days prior to admission: CP radiating to both arms while walking & relieved with rest Sxs continued with minimal exertion over subsequent days Sxs continued with minimal exertion over subsequent days Morning of admission, pt developed CP radiating to both arms at rest. Recurred 3x during am. Morning of admission, pt developed CP radiating to both arms at rest. Recurred 3x during am. Denied SOB, N/V, lightheadedness or diaphoresis Denied SOB, N/V, lightheadedness or diaphoresis

4 Day of presentation Seen in urgent care clinic at PCP’s office Seen in urgent care clinic at PCP’s office Referred to ED. CP-free on arrival. Referred to ED. CP-free on arrival. BP 123/68, P95 regular, O 2 sat 99% RA BP 123/68, P95 regular, O 2 sat 99% RA

5 Past Medical History: CholesterolHTN Breast CA: s/p left breast lumpectomy 12/05, s/p XRT, ER+ on tamoxifen Psoriasis Meds on admission: ASA 81mg PO QD Tamoxifen 20mg PO QD Irbisartan 150mg PO QD Pravastatin 20mg PO QD

6 Data BP 117/73 both arms, P68 reg, R 14, O 2 97%, T97.6 NAD JVP 6 cm H 2 0, nl contours No carotid bruits CV: non-displaced discrete PMI Ext: warm, no edema or tenderness bilaterally 2+ DP bilat Troponin I = 0.12 (ULN = 0.04) CK = 105, CK-MB = 5.2 (ULN =5)

7

8 STRIVE TM 8 No ST elevationST elevation Unstable angina NSTEMISTEMI Spectrum of CAD Stable angina Reprinted with permission from Davies MJ. Heart. 2000;83: American Heart Association. Heart Disease and Stroke Statistics—2007 Update. Circulation. 2007; 115: CAD = coronary artery disease; NSTEMI = non–ST-segment elevation myocardial infarction; STEMI = ST-segment elevation myocardial infarction. ~0.33 Million Discharges Per Year ~1.24 Million Discharges Per Year

9 Decision Making  Diagnosis  Risk Assessment  Early Invasive/Early Conservative Managment?  Antithrombin?  GP IIB/IIIA?  Oral Antiplatelets?

10 10 Risk Assessment Dependent on Contingent Probabilities l Does this patient have symptoms due to acute ischemia from obstructive CAD? l Likelihood of obstructive CAD as cause of symptoms l Dominated by acute findings –Examination –Symptoms –Markers l Traditional risk factors are of limited utility l What is the likelihood of death, MI, heart failure? l Risk of bad outcome l Dominated by acute findings –Older age very important –Hemodynamic abnormalities critical –ECG, markers 2007 ACC/AHA UA/NSTEMI Guideline Revision Anderson JL, et al. Accessed August 8, Reproduced by STRIVE with permission from Cardiosource.com.

11 STRIVE TM 11 TIMI Risk Score for UA/NSTEMI: 7 Independent Predictors 1. Aged ≥65 y 2. ≥3 CAD risk factors (high cholesterol, family history, hypertension, diabetes, smoking) 3. Prior coronary stenosis ≥50% 4. Aspirin in last 7 days 5. ≥2 anginal events ≤24 h 6. ST-segment deviation 7. Elevated cardiac markers (CK- MB or troponin) Antman EM, et al. JAMA. 2000;284: Number of Predictors /123456/7 % Death / MI / Revasc

12 IIIaIIbIII STRIVE ® 12 Our Patient’s GRACE Prediction Score for All-Cause Mortality From Discharge to 6 Months Reprinted with permission from Eagle KA, et al. JAMA. 2004;291(22): NSTEMI 6-Month Postdischarge Mortality Risk GRACE Probability Category Score of Death Low % umassmed.org/grace/grace_ris k_ table.cfm %

13 STRIVE TM Favors Invasive Favors Conservative Odds Ratio Death or MI OR 0.82, P=.001 Trial TIMI 3B VANQWISH MATE FRISC II TACTICS RITA 3 TOTAL Invasive Management of UA/NSTEMI Meta-analysis:  Death/MI at 17-Month F/U 5.1%8.1% 27.2% 28.0% 12.0%8.9% 4.3%11.4% 4.0%5.3% 7.4%10.9% VINO4.8%14.8% InvCons 7.4%11.0% Adapted with permission from Mehta S, et al. JAMA. 2005;293:

14 Anderson JL, et al. J Am Coll Cardiol. 2007;50: ACC/AHA UA/NSTEMI Guidelines: High-risk Indicators for Early Invasive Strategy Coronary angiography needs to be performed within 48 hours ACC = American College of Cardiology; AHA = American Heart Association; CABG = coronary artery bypass graft surgery; GRACE = Global Registry of Acute Coronary Events; HF = heart failure; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; TnI = troponin I; TnT = troponin T Preferred StrategyPatient Characteristics Invasive Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy Elevated cardiac biomarkers (TnT or TnI) New or presumably new ST-segment depression Signs or symptoms of HF or new or worsening mitral regurgitation High-risk findings from noninvasive testing Hemodynamic instability Sustained ventricular tachycardia PCI within 6 months Prior CABG High-risk score (eg, TIMI, GRACE) Reduced left ventricular function (LVEF of <40%) Conservative Low-risk score (eg, TIMI, GRACE) Patient or physician preference in the absence of high-risk features

15 TIMACS: GRACE Score and Primary End Point Death, MI, or Stroke at 6 Months HR=0.65 ( ) P=0.006 HR=1.12 ( ) P=0.48 Low/Intermediate Risk Score ≤140 N=2,070 High Risk Score >140 N=961 GRACE=Global Registry of Acute Coronary Events; HR=hazard ratio; MI=myocardial infarction. Mehta SR, et al. N Engl J Med. 2009;360(21): Delayed Early

16 IIIaIIbIII STRIVE ® 16 It is reasonable for initially stabilized high-risk patients with UA/NSTEMI (GRACE risk score >140) to undergo an early invasive strategy within 12 to 24 hours of admission. For patients not at high risk, an early invasive approach is also reasonable B Kushner FG, et al. J Am Coll Cardiol. 2009;54(23): Timing of Angiography in UA/NSTEMI 2009 ACC/AHA STEMI/PCI Guidelines Focused Updates New Recommendation

17 17 Algorithm for Patients with UA/NSTEMI Managed by an Initial Invasive Strategy Proceed to Diagnostic Angiography ASA (Class I, LOE: A) Clopidogrel if ASA intolerant (Class I, LOE: A) Diagnosis of UA/NSTEMI is Likely or Definite Invasive Strategy Init ACT (Class I, LOE: A) Acceptable options: enoxaparin or UFH (Class I, LOE: A) bivalirudin or fondaparinux (Class I, LOE: B) Select Management Strategy Proceed with an Initial Conservative Strategy Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 7. ACT = anticoagulation therapy; LOE = level of evidence. A B B1 B2 Prior to Angiography Init at least one (Class I, LOE: A) or both (Class IIa, LOE: B) of the following: Clopidogrel IV GP IIb/IIIa inhibitor Factors favoring admin of both clopidogrel and GP IIb/IIIa inhibitor include: Delay to Angiography High Risk Features Early recurrent ischemic discomfort

18 STRIVE ® Initial Invasive Strategy: Antiplatelet, Anticoagulant Therapy  Aspirin  Initiate anticoagulant therapy as soon as possible after presentation (I, A). Regimens with established efficacy: –Enoxaparin or UFH (I, A) –Bivalirudin or fondaparinux (I, B)  Prior to angiography, initiate one (I, A) or both (IIa, B) –Clopidogrel –IV GP IIb/IIIa inhibitor Use both if: Delay to angiography High-risk features Early recurrent ischemic syndromes 2007 ACC/AHA UA/NSTEMI Guideline Revision Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157.

19 STRIVE TM 19 CURE: Primary Outcome by Type of Intervention Adapted with permission from Fox KAA, et al. Circulation. 2004;110: Cumulative Hazard Rates Medical Rx Group Days of Follow-up Placebo Clopidogrel RR:0.80 ( ) Days of Follow-up Cumulative Hazard Rates Any Revascularization Group Placebo Clopidogrel RR:0.82 ( ) Cumulative Hazard Rates PCI Group Days of Follow-up Placebo Clopidogrel RR:0.72 ( ) Cumulative Hazard Rates CABG Group Days of Follow-up Placebo Clopidogrel RR:0.89 ( )

20 IIIaIIbIII STRIVE ® 20 Patients with definite or likely UA/NSTEMI selected for an invasive approach should receive dual antiplatelet therapy. Aspirin should be initiated on presentation. Clopidogrel (before or at the time of PCI) or prasugrel (at the time of PCI) is recommended as a second antiplatelet agent A Kushner FG, et al. J Am Coll Cardiol. 2009;54(23): Timing of Antiplatelet Therapy in UA/NSTEMI 2009 ACC/AHA STEMI/PCI Guidelines Focused Updates New Recommendation B A A

21 STRIVE ® 21 a Use in UA/NSTEMI is off-label. Adapted from Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e ACC/AHA UA/NSTEMI Guideline Revision Bivalirudin0.1 mg/kg bolus, 0.25 mg/kg/h infusion a Enoxaparin30 mg IV bolus may be given a 1 mg/kg SC every 12 h; extend dosing interval to 1 mg/kg every 24 h if estimated creatinine clearance <30 mL/min Fondaparinux2.5 mg SC once daily a Avoid for creatinine clearance <30 mL/min Unfractionated heparin 60 U/kg (max 4000 U) as IV bolus IV infusion of 12 U/kg/h (max 1000 U/h) to maintain aPTT at times control (approx s) Initial Medical Treatment: Anticoagulant Dosing

22 STRIVE ® 22 Moderate- to high- risk ACS ACUITY Study: 30-Day Results Aspirin in all; clopidogrel dosing and timing per local practice UFH or enox + GP IIb/IIIa n=4603 Bivalirudin + GP IIb/IIIa n=4604 Bivalirudin alone n=4612 R* Moderate- to high-risk patients with UA or NSTEMI undergoing an invasive strategy (N=13,819) Stone GW, et al. N Engl J Med. 2006;355(21): *Stratified by preangiography thienopyridine use or administration. Ischemic Composite Bleeding Net Clinical Outcome 7.3%5.7%11.7% 7.7%5.3%11.8% 7.8%3.0%10.1% End points: death, MI, and unplanned revascularization for ischemia (30 days and 1 year); major bleeding (30 days); composite of the above (30 days)

23 23 ACUITY Composite Ischemia & Bleeding Outcomes Absolute Risk Reduction Hazard Ratio % CI0.93– – – –0.65 p (for interaction) < Stone GW, et al. N Engl J Med 2006;355:2203– ACUITY Composite ischemia endpoint at 30 days Ischemia endpoint by thienopyridine loading before angiography or PCI YES Ischemia endpoint by thienopyridine loading before angiography or PCI No ACUITY Major bleeding at 30 days UFH + GP IIb/IIIa Bivalirudin alone

24 STRIVE ® 24 Excess Dosing of Antithrombotic Agents Dose and Major Bleeding Reproduced with permission from Alexander KP, et al. JAMA. 2005;294(24): Unfractionated Heparin UnderdosedRecommended Mild ExcessMajor Excess (n=2074) (n=2063) (n=2073)(n=714) (n=2327) (n=3998) (n=922)(n=237) (n=5879) (n=1955)(n=178) Low-Molecular-Weight Heparin Glycoprotein IIb/IIIa Inhibitors Major Bleeding, % Treatment Group

25 STRIVE ® 25 New ACC/AHA 2008 Test Measures for STEMI and NSTEMI a LDL assessment (formerly a performance measure) Excessive initial UFH, enoxaparin, eptifibatide, tirofiban, or abciximab dose Anticoagulant dosing protocol Anticoagulant error tracking system Clopidogrel prescribed at discharge for medically treated AMI patients a For use in internal quality improvement programs only. Krumholz HM, et al. J Am Coll Cardiol. 2008;52(24):

26 STRIVE TM Day Death or Nonfatal MI Risk Ratio and 95% CI Placebo Better GP IIb/IIIa Inhibitor Better Trial Pooled 11.5% Placebo GP IIb/IIIa Inhibitor 10.7% 29,855 n 0.92 (0.86, 0.995) P=.037 PRISM-PLUS11.9%10.2% 1,915 PURSUIT15.7%14.2% 9,461 PARAGON A11.7%11.3% 2, % PRISM 5.8% 3, PARAGON B11.4%10.5% 5,165 GUSTO-IV ACS 8.0%8.7% 7,800 GP IIb/IIIa Inhibition for Non–ST-Elevation ACS Boersma E, et al. Lancet. 2002;359: CI = confidence interval.

27 STRIVE TM 27 Benefits of GP IIb/IIIa by Troponin Status in Clinical Trials Newby KL, et al. Circulation. 2001;103: TnT-NegativeTnT-Positive PARAGON-B PRISM CAPTURE Combined GP IIb/IIIa Better GP IIb/IIIa Worse GP IIb/IIIa Better GP IIb/IIIa Worse

28 STRIVE TM 28 ISAR-REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR in Subsets With and Without Elevated Troponin levels (>0.03 µg/L) ISAR-REACT 2 = Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2. Adapted with permission from Kastrati A, et al. JAMA. 2006;295: Days After Randomization Cumulative Rate of Primary End Point, % Placebo Group (n=1010) Abciximab Group (n=1012) Troponin >0.03 µg/L Log-Rank P=.02 Troponin ≤0.03 µg/L Log-Rank P=.98

29 Study Design High-risk NSTE ACS n = 10,500 Primary Endpoint: 96-hr Death, MI, Recurrent ischemia requiring urgent revascularization, or Thrombotic bailout Key Secondary Endpoint: 30-d Death or MI Primary Endpoint: 96-hr Death, MI, Recurrent ischemia requiring urgent revascularization, or Thrombotic bailout Key Secondary Endpoint: 30-d Death or MI Placebo / delayed provisional eptifibatide pre-PCI Routine, early eptifibatide (180/2/180) Randomize within 12 hours of presentation Invasive strategy: 12 to 96 hours after randomization Randomize within 12 hours of presentation Invasive strategy: 12 to 96 hours after randomization 2 of 3 high-risk criteria: 1. Age > 60 years 2. + CKMB or TnT/I 3. ST  or transient ST  (Or age 50-59, h/o CVD and + CKMB or TnT/I) 2 of 3 high-risk criteria: 1. Age > 60 years 2. + CKMB or TnT/I 3. ST  or transient ST  (Or age 50-59, h/o CVD and + CKMB or TnT/I) Safety Endpoints at 120 hrs: Bleeding (GUSTO and TIMI scales), Transfusions, Stroke, Non-hemorrhagic SAEs

30 Kaplan-Meier Curves for Primary Endpoint Death, MI, RIUR or TBO (%) Time Since Randomization (Hours) 10.0% 9.3% P = 0.23 (stratified for intended early clopidogrel use) Delayed provisional eptifibatide Routine early eptifibatide

31 Initial Therapies In ED, patient received: ASA 325mg PO x1 5mg IV metoprolol x1 IV unfractionated heparin w/ bolus and infusion (weight based) Clopidogrel 300 mg Referred for cardiac catheterization

32 Cardiac Catheterization Single Vessel CAD 95% Proximal Hazy LAD lesion consistent with acute plaque rupture with thromboisis TIMI 3 (Normal) Flow

33 33 Cardiac cath CADNo Discharge from protocol Yes Left main disease Yes CABG No 1- or 2- Vessel Disease 3- or 2-vessel disease with proximal LAD involvement LV dysfunction or treated diabetes* No PCI or CABG Medial Therapy, PCI or CABG Yes CABG *There is conflicting information about these patients. Most consider CABG to be preferable to PCI. Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 20. Revascularization Strategy in UA/NSTEMI

34 Cardiac Catheterization  Drug Eluting Stent (2.5 x 15) to proximal LAD  Drug Eluting Stent (2.25 x 12) to mid LAD  Both stents post-dilated and fully deployed  Heparin discontinued

35 IIIaIIbIII STRIVE ® In patients receiving a stent (BMS or DES) during PCI for ACS, clopidogrel 75 mg daily or prasugrel 10 mg daily should be given for at least 12 months If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by thienopyridine therapy, earlier discontinuation should be considered B Kushner FG, et al. J Am Coll Cardiol. 2009;54(23): Duration of Thienopyridine Therapy 2009 ACC/AHA STEMI/PCI Guidelines Focused Updates Modified Recommendations C

36 IIIaIIbIII STRIVE ® Continuation of clopidogrel or prasugrel beyond 15 months may be considered in patients undergoing drug-eluting stent placement C Kushner FG, et al. J Am Coll Cardiol. 2009;54(23): Duration of Thienopyridine Therapy 2009 ACC/AHA STEMI/PCI Guidelines Focused Updates Modified Recommendation

37 STRIVE ® 37 Secondary Prevention: Additional Recommendations (cont) Cardiac rehab BP control –<140/90 mm Hg –<130/80 mm Hg with diabetes or CKD Diabetes management: HbA 1c <7% Smoking cessation/no environmental smoke exposure –Education, referral programs, drug therapy Physical activity (30-60 min, 7 d/wk; min 5 d/wk) Weight management –BMI kg/m 2 –Waist circumference: men, <40 in; women, <35 in Discharge education/referral Stepped-care approach to musculoskeletal pain management Annual influenza immunization HRT, antioxidant vitamin supplements (C, E, beta carotene) and folic acid not recommended 2007 ACC/AHA UA/NSTEMI Guideline Revision Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157.

38 Changes from (Post-ACS) Baseline in Median LDL-C Note: Changes in LDL-C may differ from prior trials: 25% of patients on statins prior to ACS event 25% of patients on statins prior to ACS event ACS response lowers LDL-C from true baseline ACS response lowers LDL-C from true baseline LDL- C (mg/ dL) Rand.30 Days4 Mos.8 Mos.16 Mos.Final Pravastatin 40mg Atorvastatin 80mg 49%  21%  P<0.001 Median LDL-C (Q1, Q3) 95 (79, 113) 62 (50, 79) <24h

39 All-Cause Death or Major CV Events in All Randomized Subjects % with Event Months of Follow-up Pravastatin 40mg (26.3%) Atorvastatin 80mg (22.4%) 16% RR (P = 0.005)

40 HD # 3 - Discharge  Patient discharged to home to f/u in cardiology clinic in 2 weeks  Discharge regimen including:  ASA 162 mg PO  Clopidogrel 75mg PO QD  Metoprolol XL 50 mg/d  Lisinopril 10 mg/d  Atorvastatin 80 mg

41 STRIVE ® 41 Secondary Prevention: Additional Recommendations β-blockers ACE inhibitors/ARBs Aldosterone blockade (low EF) Lipid management –Statin regardless of baseline LDL-C initiated prior to discharge –Goal LDL-C <100 mg/dL –LDL <70 mg/dL reasonable Treatment of triglycerides and non–HDL-C useful –If TG mg/dL, non–HDL-C should be <130 mg/dL –TG  500 mg/dL, fibrate or niacin before LDL-C lowering to prevent pancreatitis Encouraging consumption of omega-3 fatty acids for risk reduction reasonable –For treatment of elevated triglycerides, higher doses may be used for risk reduction 2007 ACC/AHA UA/NSTEMI Guideline Revision Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157.

42 Two days after discharge… Recurrent CP while cleaning her basement Recurrent CP while cleaning her basement Returned to ED with 8/10 crushing SSCP Returned to ED with 8/10 crushing SSCP Patient reported compliance with her medications Patient reported compliance with her medications IV UFH started in ED IV UFH started in ED

43

44 Cardiac Catheterization Total Occlusion of LAD in previously stented segment consistent with STENT THROMBOSIS

45 Hospital Course 2 additional stents deployed bridging gap between prior stents 2 additional stents deployed bridging gap between prior stents IVUS showed no evidence of edge dissection, stents fully deployed IVUS showed no evidence of edge dissection, stents fully deployed Reloaded with clopidogrel 600mg x1 Reloaded with clopidogrel 600mg x1 Peak CK 2100, CK-MB 150 Peak CK 2100, CK-MB 150 TTE: LVEF 40%, HK antero-septal wall TTE: LVEF 40%, HK antero-septal wall

46 Patient Antiplatelet noncompliance Response variability Stent Thrombosis Adapted from Kereiakes DJ et al. Rev Cardiovasc Med. 2004;5:9-15. Stent Thrombosis: A Multifactorial Problem Lesion Long lesions Small diameter Multivessel Acute myocardial infarction (AMI) Diabetes Bifurcations Technical Underexpansion Incomplete wall apposition Crush technique Overlapping Stent Material Polymer matrix Antithrombotic agent

47 Early Discontinuation of Antiplatelet Therapy Is an Important Risk Factor for ST UAThrombusDiabetesUnprotected left main artery Bifurcation lesion Renal failure Prior brachytherapy Premature antiplatelet therapy discontinuation Incidence (%) Iakovou I, et al. JAMA. 2005;293: Overall ST-elevation = 1.3% (P =.09, N=2229)

48 Clopidogrel Response Variability: Increase the Dose (300 mg vs. 600 mg) Gurbel PA et al. J Am Coll Cardiol. 2005;45: ≤-30 (-30,-20] (-20,-10] (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] (60,70] > mg Clopidogrel 600 mg Clopidogrel   Aggregation (5 µM ADP-induced Aggregation) at 24 Hr Patients (%) Resistance = 28% (300 mg) Resistance = 8% (600 mg)

49 P < Antoniucci D et al. Presented at ACC The RECLOSE Study: 6-Month Outcomes After DES Implantation Stratified by Post-Clopidogrel ADP-mediated Platelet Reactivity Non-responders defined as >70% aggregation by LTA 12 hours after 600 mg clopidogrel load

50 Platelet Function Test Platelet response assessed on ASA 162mg QD and clopidogrel 75mg BID using Accumetrics™ device Platelet response assessed on ASA 162mg QD and clopidogrel 75mg BID using Accumetrics™ device Appropriate response to aspirin (ARU 410, non-responder >550) Appropriate response to aspirin (ARU 410, non-responder >550) HOWEVER, only 0-3% platelet inhibition to clopidogrel 75mg BID (PRU 253, baseline PRU 260) HOWEVER, only 0-3% platelet inhibition to clopidogrel 75mg BID (PRU 253, baseline PRU 260)

51 Clinical Management No guideline recommendations No guideline recommendations Aspirin increased to 325/d Aspirin increased to 325/d Clopidogrel increased to 150 mg/d (today may switch to prasugrel) Clopidogrel increased to 150 mg/d (today may switch to prasugrel)

52 Study Design, Flow and Compliance 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) PCI 17,232 (70%) Angio 24,769 (99%) Angio 24,769 (99%) No PCI 7,855 (30%) No Sig. CAD 3,616CABG 1,809CAD 2,430 Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d) ASA: High Dose ( mg/d) vs Low dose ( mg/d) Efficacy Outcomes:CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes:Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup: PCI v No PCI Clop in 1st 7d (median) 7d 7 d 2 d 7d Complete Followup 99.8% Compliance:

53 Clopidogrel: Double vs Standard Dose Primary Outcome and Components StandardDoubleHR95% CIPIntn P CV Death/MI/Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) MI PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) CV Death PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087)

54 Clopidogrel Double vs Standard Dose Bleeding Overall Population Clopidogrel Standard N=12579 Double N=12508 Hazard Ratio 95% CIP TIMI Major CURRENT Major CURRENT Severe Fatal ICH RBC transfusion ≥ 2U CABG-related Major ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal 2 Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units 3 Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

55 Days Cumulative Hazard Clopidogrel Standard Dose Clopidogrel Double Dose 42% RRR HR % CI P=0.001 Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio confirmed)

56 Change the Agent? Prasugrel Pro-drug Oxidation (Cytochrome P450) HOOC * HS N O F Active Metabolite N S O F O Hydrolysis(Esterases) N S O CH 3 C O F O N S O ClO CH 3 C Clopidogrel 85% Inactive Metabolites Esterases N S O Cl O CH 3 C O N S O Cl O C Active Metabolite HOOC * HS N O Cl OCH 3 Herbert JM, Savi P. Sem Vasc Med. 2003;3:

57 Inhibition of Platelet Aggregation (IPA) at 24 Hours (Healthy Volunteers) 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 JT et al. Am Heart J. 2007;153:66.e9-e16.

58 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 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 Median duration of therapy - 12 months N= 13,600 Wiviott SD, AHJ 2006

59 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 Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

60 Stent Thrombosis (ARC Definite + Probable) HR 0.48 P < Prasugrel Clopidogrel 2.4 (142) NNT= (68) Days Endpoint (%) Any Stent at Index PCI N= 12,844 Wiviott SD, Braunwald E, McCabe CH et al NEJM2007Antman EM, AHA2007

61 Definite/Probable ST: Any Stent (N=12844) % 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 Wiviott SD, Braunwald E, McCabe CH, Lancet 2008 Antman EM, NYHA 2007

62 Bleeding Events Safety Cohort (N=13,457) % Events ARD 0.6% HR 1.32 P=0.03 NNH=167 Clopidogrel 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) Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

63 Diabetic Subgroup HR 0.70 P<0.001 Days Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 N= Prasugrel Clopidogrel Prasugrel Clopidogrel Wiviott SD, Circulation 2008

64 Percent (%) Days From Randomization 9.5% 6.5% HR 0.68 ( ) P= % 10.0% HR 0.79 ( ) P=0.02 Clopidogrel Prasugrel NNT = 42 CV Death / MI / Stroke TIMI Major NonCABG Bleeds Clopidogrel Prasugrel STEMI Cohort N=3534 Montalescot et al Lancet 2008

65 The first* adequately powered clinical trial to test and confirm the hypothesis: a drug with greater P2Y12 effect and less response variability reduces ischemic events compared to standard clopidogrel *Now corroborated by PLATO and OASIS 7- PCI Lesson

66 Ticagrelor (AZD 6140): an oral reversible P2Y 12 antagonist Ticagrelor is a cyclo-pentyl- triazolo-pyrimidine (CPTP) OH OH O OH N F S N H N N N N F Direct acting – Not a prodrug; does not require metabolic activation – Rapid onset of inhibitory effect on the P2Y 12 receptor – Greater inhibition of platelet aggregation than clopidogrel Reversibly bound – Degree of inhibition reflects plasma concentration – Faster offset of effect than clopidogrel – Functional recovery of all circulating platelets

67  Last Maintenance Dose Loading Dose Time (hours) Onset Maintenance Offset IPA % Ticagrelor (n=54) Clopidogrel (n=50) Placebo (n=12) weeks * * * * * * * * * ‡ † †  20 µM ADP- Final Extent

68 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

69 STRIVE ® 69 PLATO Primary End Point: CV Death, MI, or Stroke Months HR: 0.85 (95% CI, ); P= Clopidogrel Ticagrelor K-M Estimated Rate, % per Year Steg PG. Presented at: the American Heart Association (AHA) Scientific Sessions; November 15, 2009; Orlando, Florida.

70 STRIVE ® 70 PLATO: All-Cause Mortality K-M Estimated Rate, % per Year Months Clopidogrel Ticagrelor HR 0.82 (95% CI, ); P=.04 Steg PG Presented at: the American Heart Association (AHA) Scientific Sessions; November 15, 2009; Orlando, Florida.

71 Time to major bleeding – primary safety event No. at risk Clopidogrel Ticagrelor 9,186 9,235 7,305 7,246 6,930 6,826 6,670 Days from first IP dose 5,209 5,129 3,841 3,783 3,479 3, Clopidogrel Ticagrelor ,545 HR 1.04 (95% CI 0.95–1.13), p=0.434 K-M estimated rate (% per year) Adapted from Wallentin L, et al. N Engl J Med. 2009;361:

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

73 GP IIb/IIIa receptor expression P2Y 12 receptor (irreversible inhibition) Active metabolite Hepatic metabolism Cytochrome P450 pathway Intestinal absorption Variable absorption (Genetics – ABCB1) Drug-drug interactions Genetic polymorphisms CYP enzymes (2C19) Drug-drug interactions (CYP 2C19) Genetic polymorphisms P2Y 12 receptor Alternate pathways of platelet activation ↑ release of circulating ADP Higher baseline platelet reactivity Genetic polymorphisms Poor compliance Inadequate administration (dose, generics?) Potential Sites for Response Variability Adapted from O’Donoghue M and Wiviott SD Circulation 2007

74 log 10 (P Value) GWAS of Platelet Aggregation in Response to Clopidogrel Shuldiner A et al. JAMA 2009; 302: CYP2C18-CYP2C19-CYP2C9-CYP2C8

75 Genetic Effects on PK/PD P value Gene CYP2C19 CYP2C9 CYP2B6 CYP3A5 CYP1A2 -15 PharmacokineticsPharmacodynamics P value Gene CYP2C19 CYP2C9 CYP2B6 CYP3A5 CYP1A Relative percent difference in AUC 0-t (95%CI) in carriers vs non-carriers of a reduced-function allele CLOPIDOGREL PRASUGREL Mega JL et al. N Engl J Med. 2009;360: Absolute difference in  MPA (95% CI) in carriers vs non-carriers of a reduced-function allele % Difference in AUC 0-t Absolute Difference in  MPA Mega JL et al. Circulation 2009

76 Reduction in MPA (%) at 24-hour UMEMIMPM n=47n=43n=27n=3 Clopidogrel 75mg Reduction in MPA (%) at 24-hour UMEMIMPM n=22n=31n=29n=8 Clopidogrel 300mg CYP2C19 Extended Classification

77 CYP2C19 and Stent Thrombosis * Carriers ~30% of the population CYP2C19 Reduced-Function Allele Carriers n=1477 n=1466 Mega JL et al. N Engl J Med. 2009;360:354-62/ Hazard Ratio, 0.58 (95% CI ) P= Number at Risk: Days after randomization Non-Carrier Carriers Hazard Ratio 3.09 (95% CI ) P= Definite or probable stent thrombosis (%) Number at Risk: Days after randomization Non-Carrier Clopidogrel Prasugrel Non-carriers Definite or probable stent thrombosis (%) Mega JL et al. Circulation 2009

78

79 Major Adverse CV Events Carriers vs Non-Carriers Risk Higher with CYP2C19 Variant Risk Lower with CYP2C19 Variant Risk Ratio (95% CI)P Value 1.61 ( )<0.001 Heterozygotes vs Wildtype 1.50 ( )0.016 Homozygotes vs Wildtype 1.81 ( )0.004 Heterozygotes vs Wildtype Homozygotes vs Wildtype 2.51 ( ) 4.78 ( ) < N=9,684 Stent Thrombosis Carriers vs Non-Carriers 2.76 ( )<0.001 N=5,772 CYP2C19 and Treatment with Clopidogrel Mega, J et al AHA 2009

80 Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolite Some PPIs are strong inhibitors of CYP2C19 activity Clopidogrel and PPIs – The OCLA study PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP) Gilard et al. J Am Coll Cardiol 2008;51: p<0.0001

81 Risk of Cardiovascular Events for Patients Taking Clopidogrel in Combination with a PPI Ho PM, et al. JAMA. 2009;301: Days Since Discharge Deaths or recurrent ACS (%) Clopidogrel + PPI Clopidogrel without PPI Adjusted OR 1.25 (95% CI )

82 PPI at baseline (N=374) No PPI at baseline (N=1742) Primary 1-Year Endpoint: Death, MI or Stroke All N=2116 Placebo N=1063 Clopidogrel N=1053 Results – 1 Year Endpoint from CREDO Unadjusted Data P=0.001 P=0.45 Dunn S.P. et al AHA Slide courtesy of Steve Steinhubl MD

83 CV death, MI or stroke Days CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI PPI use at randomization (n= 4529) Clopidogrel Prasugrel PRASUGRELPPI vs no PPI: Adj HR 1.00, 95% CI Observation from an RCT (TRITON-TIMI 38) Conducted for Another Purpose O’Donoghue M, et al Lancet 2009

84 COGENT STUDY CV Events P=0.001 Bhatt TCT 2009

85 Summary  UA/NSTEMI is the most frequent manifestation of ACS  Early risk assessment guides angiography strategy and medication choices  Dynamic evaluation based on angiogram and clinical course guides further therapy  Robust evidence base allows for rational care.  Future therapies in development may offer advantages over current standards


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