Disclosures. Research consulting with: Sanofi-Regeneron Pfizer The Medicines Company Astra Zeneca

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1 Antiplatelet Therapy in Coronary Artery Disease What are the roles for newer therapies? How do you decide what to cover? R. Scott Wright, MD, FACC, FESC, FAHA Professor of Medicine, Mayo Clinic College of Medicine Consultant, Division of Cardiology and the Coronary Care Unit Orlando 2015 Disclosures Research consulting with: Sanofi-Regeneron Pfizer The Medicines Company Astra Zeneca Follow me on

2 Clinical Pearls 1. Anti-platelet and Anti-coagulant therapies are critically important in the management of patients with ACS Anti-platelet therapy Platelet activation remains a major pathophysiological issue in ACS. Platelet aggregation is the leading mechanism for ACS Platelets upregulate the expression of receptors promoting aggregation and thrombosis 1 million fold during ACS 2

3 Platelets and thrombus are activated in the patient with ACS 3

4 Libby NEJM May

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6 Management of AMI Patients Inhibit Aspirin Platelet Aggregation IV GP2b3a Rx P2Y12 Inhibitor Ace Inhibitors Reduce Sheer Stress Nitrates Beta Blockers Heparin Endothelial Statins function Statins Ace Inhibitors Nitrates Stabilize the Plaque Statins Heparin Passivate the Plaque Statins Aspirin Suppress Inflammation Stent the Vessel LDL-C Statins Fibrates HDL-C TG Niacin Others 6

7 Clinical Pearls 1. Anti-platelet and Anti-coagulant therapies are critically important in the management of patients with ACS. 2. The American and European guidelines stress the critical importance of these therapies with initial stabilization and long-term management of ACS patients. Class I and Class IIa Recommendations for Initial Management of UA/NSTEMI Diagnosis of UA/NSTEMI is likely or definite ASA (class I, LOE: A) Clopidogrel if ASA intolerant (class I, LOE: A) Select management strategy Initial conservative strategy or unknown Invasive strategy Initiate anticoagulant therapy (class I, LOE: A) Acceptable options include Enoxaparin or UFH (class I, LOE: A) Fondaparinux (class I, LOE: B)* Enoxaparin or fondaparinux preferred over other GP IIb/IIIa inhibitors (class IIa, LOE: B) Initiate clopidogrel (class I, LOE: B) Or Initiate Ticagrelor (Class I, LOE:C) Initiate anticoagulant therapy (class I, LOE: A) Acceptable options include Enoxaparin or UFH (class I, LOE: A) Bivalirudin (class I, LOE: B) PCI: add 2 nd antiplatelet agent (class I, LOE: A) P2Y12 (class I, LOE: B) or GP IIb/IIIa inhibitor (class I, LOE: A) (IV eptifibatide or tirofiban preferred) Next step per triage decision at angiography Wright et al: Circ 123, 2011 CABG: maintenance ASA (class I, LOE: A) PCI: class I: Clopidogrel (if not begun precath) (LOE: A) or Prasurgrel (LOE: B) or Selectively, GP IIb/IIIa inhibitor (if not begun precath) (LOE: A) Rx: D/C GP IIb/IIIa inhibitors if begun and give clopidogrel per conservative strategy

8 Oral Anti-platelet therapy in ACS The role of aspirin in the acute and longterm management of patients with ACS is well understood and established. The ACC/AHA and ESC Guidelines for management of ACS (STEMI and Non- STEMI) are unified in their recommendation that all patients should receive a second oral anti-platelet agent a P2Y12 inhibitor DAPT is now a Class I indication (LOE:B) Issues in AMI Management What data support the use of two oral anti-platelet agents in patients with acute cardiovascular disease? Are the newer, more expensive antiplatelet P2Y12 inhibitors superior? What is the appropriate duration of therapy for dual anti-platelet therapy? Are the $$$ being spent worth the ROI? 8

9 Oral Anti-platelet therapy in ACS Acute ST elevation MI aspirin has been the mainstay of therapy but clopidogrel has been approved as a second agent for use following fibrinolysis and/or PCI The use of a P2Y12 inhibitor at the time of initiation of fibrinolytic therapy is established and currently limited to clopidogrel in the USA (FDA Approval) Cumulative Incidence of the End Point of Death from CV Causes, Recurrent MI, or Recurrent Ischemia Leading to the Need for Urgent Revascularization 15 Placebo End point (%) 10 5 Clopidogrel P= No. at risk Days 1,739 1,529 1,504 1,494 1,752 1,569 1,555 1,550 NEJM 352(12):1184, 2005 CLARITY Trial CP

10 Efficacy Outcomes Clopidogrel Placebo Odds ratio Outcome n=1,752 n=1,739 (95% CI) P Primary efficacy end point, 262 (15.0) 377 (21.7) 0.64 (0.53 to 0.76) <0.001 no. (%) TIMI flow grade 0 or (11.7) 301 (18.4) 0.59 (0.48 to 0.72) <0.001 Death 45 (2.6) 38 (2.2) 1.17 (0.75 to 1.82) 0.49 Recurrent MI 44 (2.5) 62 (3.6) 0.70 (0.47 to 1.04) 0.08 Other angiographic measurement, no. (%) TIMI flow grade 3 1,112 (67.8) 993 (60.8) 1.36 (1.18 to 1.57) <0.001 TIMI myocardial-perfusion 885 (55.8) 817 (51.2) 1.21 (1.05 to 1.40) grade 3 Intracoronary thrombus 697 (43.0) 822 (50.8) 0.73 (0.64 to 0.84) <0.001 Mean stenosis (%) (-3.8 to -0.9) Mean minimal luminal (0.03 to 0.11) diameter (mm) NEJM 352(12):1182, 2005 CLARITY Trial CP NEJM 352(12):1184, 2005 CLARITY Trial 10

11 NEJM 352(12):1184, 2005 CLARITY Trial Anti-Platelet Therapy in STEMI Use of clopidogrel prejunctively with fibrinolysis is strongly supported in STEMI for those < 75 years of age Clarity TIMI 28 demonstrated a clear superiority to aspirin alone Multiple studies have demonstrated a benefit prior to PCI 11

12 Incidence of Cardiovascular End Points Before and After PCI % with outcome Recurrent MI or Stroke Before PCI P=0.023 No pretreatment Clopidogrel pretreatment CV Death, Recurrent MI, or Stroke After PCI to 30 Days After Randomization P=0.008 No pretreatment Clopidogrel pretreatment No. at risk Days after randomization JAMA 294(10):1228, Days after PCI CP Safety Outcomes Clopidogrel No pretreatment pretreatment n=923 n=918 Outcomes No. % No. % P Major or minor >0.99 bleeding Major bleeding Minor bleeding JAMA 294(10):1230, 2005 CP

13 Thrombus Burden is Associated with ST Resolution % with > 70% ST Resolution % N = 293 Thrombus P < % N = 306 No Thrombus These data provide a pathophysiologic link between platelet inhibition, reduced thrombus burden & improvements in both epicardial and microvascular perfusion Circulation 2001; 103: The good news The tough news Clopidogrel is generic and is the only P2Y12 approved for post- Lytic treated STEMI patients The other P2Y12 agents have tested superior in post-pci populations with STEMI and represent decisiondilemmas for formulary committees 13

14 The newer P2Y12 agents Clopidogrel has several weaknesses or qualities that have led to the development of alternative P2Y12 agents 1. Onset of action is 3 to 6 to 9 hours depending on loading dose this makes acute loading a bit tricky as there is a window of SAPT coverage 2. Some patients demonstrate clopidogrel resistance Response Distribution to Clopidogrel Pt (%) NR Kereiakes and Gurbel: JACC 1:111, mg clopidogrel 600 mg clopidogrel -30 (-20, -10) (0, 10) (20, 30) (40, 50) (60, 70) (80, 90) (-30, -20) (-10, 0) (10, 20) (30, 40) (50, 60) (70, 80) (90, 100) Absolute change in platelet aggregation ( A) (20 M ADP) CP

15 Issues in anti-platelet therapy Can we do better than clopidogrel? Prasugrel Ticagrelor Mechanisms of Platelet Activation and Inhibition Activated platelet Clopidogrel Ticlopidine Prasugrel To neighboring platelet GP IIb/IIIa Inhibitors Fibrinogren Adhesive proteins Thrombospondin Fibrinogen P-selectin vwf Prothrombotic factors Factor V Factor XI PAI-1 Kereiakes and Gurbel: JACC 1:111, 2008 Activation Degranulation COX1 Proinflammatory factors Platelet factor 4 CD 154 (CD40L) PDGF Aspirin Thrombin Serotonin Epinephrine Collagen Platelet agonists ADP ATP Serotonin Calcium Magnesium CP

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18 Ticagrelor (AZD 6140): an oral reversible P2Y 12 antagonist HO HO O N N N S N N H N F F Ticagrelor is a cyclo-pentyltriazolo-pyrimidine (CPTP) OH 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 18

19 NEJM 2009;361: PLATO study design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) 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) 6 12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack 19

20 Cumulative Kaplan-Meier Estimates of the Time to the First Adjudicated Occurrence of the Primary Efficacy End Point Cumulative incidence of primary end point (%) P< Clopidogrel 10 8 Ticagrelor Months PLATO Results No. at risk 9,333 8,628 8,460 8,219 6,743 5,161 4,147 9,291 8,521 8,362 8,124 6,650 5,096 4,047 Wallentin et al: NEJM, Cumulative Kaplan-Meier Estimates of the Time to the First Major Bleeding End Point, According to the Study Criteria Cumulative incidence of major bleeding (%) P= Months Ticagrelor Clopidogrel No. at risk 9,235 7,246 6,826 6,545 5,129 3,783 3,433 9,186 7,305 6,930 6,670 5,209 3,841 3,479 Wallentin et al: NEJM,

21 Dual Anti-platelet therapy in Medically managed subjects Are all P2Y12 agents ok to use in medically managed patients with non- STEMI? No, only clopidogrel and prasugrel are FDA approved for this sub-set Why is that? TRITON TIMI 38 tested a PCI strategy only What about use of Prasugrel in those without PCI? Trilogy Trial Population tested Non-STEMI not undergoing PCI Head to head comparison for efficacy and safety in patients being managed medicaly

22 Study Design 9326 patients in 8 regions, 52 countries (Primary: 7243 patients < 75 years old) Medically Managed UA/NSTEMI Patients Randomization Stratified by: Age, Country, Prior Clopidogrel Treatment (Primary analysis cohort Age < 75 years) Median Time to Enrollment = 4.5 Days 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 Clopidogrel mg LD + 75 mg MD Prasugrel 1 30 mg LD + 5 or 10 mg MD Clopidogrel 1 75 mg MD Prasugrel 1 5 or 10 mg MD Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months Primary Efficacy Endpoint: CV Death, MI, Stroke 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. Roe Mt et al NEJM 2012 Primary Efficacy Endpoint and TIMI Major Bleeding Through 30 Months (Age < 75 years; 7243) Endpoint (%) HR (95% CI): 0.91 (0.79, 1.05) P = 0.21 HR (95% CI): 1.31 (0.81, 2.11) P = 0.27 Roe MT et al NEJM

23 Dual anti-platelet therapy in NSTEMI There are many reasons why NSTEMI patients are not referred for PCI Some NSTEMI patients may have type II infarcts rather than type I Co-morbidities like renal failure may influence a decision for PCI. What about enriching the analyzed cohort for CAD using prerandomization coronary angiography? Primary Efficacy Endpoint to 30 Months (Age < 75 years) Angio N=3085 No Angio N= % vs 14.9% P = HR (95% CI): 0.77 (0.61, 0.98) 16.3% vs 16.7% P = HR (95% CI): 1.01 (0.84, 1.20) P interaction =

24 TIMI Major Bleeding Angio No Angio 2.7% vs 1.4% P = HR (95% CI): 1.84 (0.93, 3.63) TIMI Major or Minor Bleeding Angio: No Angio: HR (95% CI): HR (95% CI): 1.68 (1.00, 2.83) 1.42 (0.83, 2.41) P interaction = % vs 1.5% P = HR (95% CI): 0.92 (0.47, 1.83) P interaction = 0.16 What have we learned with Prasugrel? It is effective and superior to clopidogrel in patients undergoing PCI The data do not support extending its label to the medically managed ACS patient Prasugrel may have superior efficacy in diabetic patients 24

25 DAPT benefit without PCI CURE was enriched for subjects not undergoing urgent or early PCI Selection bias clearly impacts who is referred for angiography vs who is not referred for angiography The diagnosis of MI was based upon CK-MB elevation in CURE Small changes in ctnt or I in recent trials thus enriching these trials with Type II infarcts (infarcts likely not due to plaque rupture) Mechanisms of Platelet Activation and Inhibition Activated platelet Clopidogrel Ticlopidine Prasugrel Ticagrelor To neighboring platelet GP IIb/IIIa Inhibitors Fibrinogren Adhesive proteins Thrombospondin Fibrinogen P-selectin vwf Prothrombotic factors Factor V Factor XI PAI-1 Kereiakes and Gurbel: JACC 1:111, 2008 Activation Degranulation COX1 Proinflammatory factors Platelet factor 4 CD 154 (CD40L) PDGF Aspirin Thrombin Serotonin Epinephrine Collagen Platelet agonists ADP ATP Serotonin Calcium Magnesium CP

26 Anti-platelet and Anti-coagulant therapies How long should dual anti-platelet therapy be continued? Are there data suggesting longer-term DAPT is effective? 2014 MFMER NEJM March 2015 on line ahead of print 26

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28 NEJM March 2015 on line ahead of print NEJM March 2015 on line ahead of print 28

29 Duration of Anti Platelet therapy TRITON TIMI 38 suggested 15 months with Prasugrel is appropriate PEGASUS TIMI 54 suggests that 3 years of additional therapy with lower dose Ticagrelor (60 mg bid) confers additional risk reduction but the FDA needs to approve this before we can recommend it. P2Y 12 Inhibitor Therapy Clopidogrel Prasugrel Ticagrelor Post PCI Yes Yes Yes Med Rx Yes No Yes Loading 600 mg 60 mg 180 mg Dose Daily 75 mg 10 mg 90 mg Dose % Platelet inhib 50-60% 60-70% 85-90% Aspirin Dose mg mg < 100 mg (Daily) Cost (daily) $0.33 $6.50 $5.00 Optimal duration ? (Months)

30 Therapy for Acute MI: Effect on Mortality Therapy Pt (no.) Aspirin 18,773 Thrombolysis 58,600 blocker 28,970 blocker (post) 24,298 ACE-I 100,963 ACE-I, EF 5,986 Statins (post MI) 13,673 Statins (ACS) 3,086 P <0.001 < < <0.001 <0.001 <0.05 Hennekens: NEJM, 1996 Other Data CP Mean Effect of Sequential Application of Each Guideline and/or for 6-Month Mortality in Patients with an ACS Heart 96:1201,

31 Relationship Between Evidence-Based Recommendations and 6-Month Survival in Overall Population Overall population OR 95% CI P CABG surgery PCI <0.001 Statin therapy <0.001 Clopidogrel Intravenous glycoprotein IIb/IIIa inhibitor -blocker Referral to cardiac rehab ACE inhibitor Aspirin Cardiac catheterization Heart 96:1201, 2010 AF of 6-Month Mortality Associated with Incomplete Application of Evidence-Based Recommendations Guideline recommendation* AF (%) 95% CI Revascularization to 42.4 Thienopyridine to 9.8 Statin therapy to 15.0 Rehabilitation referral to 21.5 ACE inhibitor to 9.4 Glycoprotein IIb/IIIa inhibitation to blocker to 4.6 *Effect of aspirin not estimatable Heart 96:1201,

32 Pearls - P2Y 12 Inhibitor Therapy Clopidogrel is established therapy with proven efficacy and is approved for: Medical management Invasive management Prasugrel is proven and approved for: Invasive management Stent thrombosis Ticagrelor is proven and approved for: Medical Invasive management Value of particular second agents for DAPT What is the most cost effective choice? Cloidogrel What are the data for whether the $$ are justified with the newer P2Y12 agents? CURE 2% ARR vs aspirin alone TRITON Trial 2.2% ARR vs Clopidogrel PLATO Trial 1.9% ARR vs clopidogrel

33 P2Y 12 Inhibitor Therapy Clopidogrel Prasugrel Ticagrelor Post PCI Yes Yes Yes Med Rx Yes No Yes Loading 600 mg 60 mg 180 mg Dose Daily 75 mg 10 mg 90 mg Dose % Platelet inhib 50-60% 60-70% 85-90% Aspirin Dose mg mg < 100 mg (Daily) Cost (daily) $ 0.33 $ 6.50 $ 5.00 Cost (1 Year) $ $ 2373 $ Anti-platelet therapy Practical thoughts Dual anti-platelet therapy for one year in post-acs patients is the gold standard -- Evidence suggests that clopidogrel works well and that the others are slightly better with higher bleeding risks -- Some centers use Ticagrelor for one month, then switch to clopidogrel not FDA Approved or established by trial evidence but driven by insurance co-pays

34 Anti-platelet therapy Practical thoughts Patient adherence to DAPT for the first year after ACS is critical -- More efforts must be given to promote adherence -- Discontinuation of DAPT triggers some recurrent ACS events Use of aspirin after year-1 is usually adequate and is the Guideline based expectation Anti-platelet therapy Practical thoughts Guidelines are just that Guidelines The science evolves be prepare to alter strategy Decisions often need to be tailored to individual patient needs Remain vigilant for safety concerns

35 Vorapaxar is a thrombin receptor (PAR 1) antagonist Derived from himbacine Tested in TRAP2, TIMI 50 in PVD patients Functions by inhibiting thrombin related platelet aggregation Considered an anti platelet agent that works independently of the aspirin (COX 2) and ADPmediated (P2Y12) pathways 35

36 NEJM 2012;366: NEJM 2012;366:

37 NEJM 2012;366: NEJM 2012;366:

38 NEJM 2012;366: Impact of Voraxepar on Events 42% RRR 38

39 Impact of Voraxepar on Events Impact of Voraxepar on Events Vorapaxar reduced: Urgent peripheral revascularization by 35% Urgent hospitalizations by 28% Tested in TRAP2, TIMI 50 in PVD patients Benefit offset by an increase in modeate or severe bleeding. 39

40 Summary of Anti platelet therapy Parameter Aspirin Clopidogrel Prasugrel Ticagrelor Vorapaxar 30 Day cost $ 5 $ 10 $ $ $ Day Cost $ 12 $ 19 $ $ 800 $962 Bleeding risks 3 5%/year 1 2% above aspirin Efficacy Modest 2% ARR above aspirin 2% AR above Clopid in subgroups 2% ARR beyond Clopidogrel No significant difference c/w clopid 2% ARR beyond clopidogrel + 4% AR increase 1% on top of aspirin + clopidogrel Source: GoodRX.com, April 2015 Discount Drug Coupon Your Prescription: Brilinta 90mg 60 tablets Discounted price with this coupon: $ $ If your prescription is for 60 tablets to be taken over 84+ days. If your prescription is for 60 tablets to be taken over 30 to 84 days. Pharmacist Info: Member ID GN RxGroup GRXGN083 RxBin RxPCN NVT This is your estimated price at Target. Questions? Call (M-F 8:30AM - 5:00PM CST) Print this free coupon and hand it to your pharmacist. 40

41 Discount coupons Discount Drug Coupon Your Prescription: atorvastatin 20mg 90 tablets Discounted price with this coupon: $ If your prescription is for 90 tablets to be taken over 84+ days. Pharmacist Info: Member ID GN RxGroup GRXGN083 RxBin $ If your prescription is for 90 tablets to be taken over 31+ days. RxPCN NVT This is your estimated price at Walgreens. The pharmacy will provide the exact pricing. Questions? Call (M-F 8:30AM - 5:00PM CST) Print this free coupon and hand it to your pharmacist. Anti-platelet therapy the Future? What are the future directions new therapies will take? Is it reasonable to develop new antiplatelet agents? Current therapies are very effective Can we afford new therapies? Bleeding risks less or more?