A patient with an acute coronary syndrome one year ago. Options for antiplatelet treatment

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1 A patient with an acute coronary syndrome one year ago. Options for antiplatelet treatment Ronen Durst, MD Cardiology Department Hadassah, Hebrew University Medical Center. Chairman, Israeli society for treatment and prevention of atherosclerosis.

2 Case presentation 67 year old man. PMH: PUD at 40 treated with PPI and antibiotics DM HbA1c 7.5, HTN Smoking 12 months ago had MI. Primary PCI on the LAD with DES. NOA of the RCA and M2 Treatment: Atorvastain 80mg Aspirin 100mg Prasugrel 10mg Ramipril 10mg Januet (sitagliptin and metformin 50/1000)*2 Wants to stop some of the medication Should we stop Prasugrel?

3 Platelet activation pathways Sangkuhl Katrin, Shuldiner Alan R, Klein Teri E, Altman Russ B. "Platelet aggregation pathway" Pharmacogenetics and genomics (2010).

4 Coronary stents: historical development Time Person(s) Landmark events 1964 Dotter and Judkins Conceptual description of coronary angioplasty using an implantable prosthetic device May 1977 Gruntzig and Myler First coronary angioplasty during coronary artery bypass graft surgery September 1977 Andreas Gruntzig First coronary angioplasty in an awake patient; a revolution in interventional cardiology 1979 Geoffrey Hartzler First balloon angioplasty to treat AMI 1986 Sigwart and Puel The first implantation of a stent in human coronary arteries; second revolution in interventional cardiology 1991 Cannon and Roubin First coronary stenting to treat AMI 1994 Serruys et al. and Fischman et al. Publication of first two landmark (Benestent and STRESS) trials 1994 FDA 1999 Eduardo Sousa FDA-approved use of stents to treat acute and threatened vessel closure after failed balloon angioplasty The first drug (sirolimus) eluting stent implanted in human coronary artery; third revolution in interventional cardiology EME and FDA Approvals of Cypher and Taxus stents in Europe and USA 2011 EME British Medical Bulletin Volume 106, Pp Approval of Absorb BVS (bioresorbable vascular scaffold) in Europe; fourth revolution in interventional cardiology

5 Stent complications These initial stents had high metallic density: sub-acute stent thrombosis Intimal proliferation and restenosis Exposed metal struts acts as a nidus for platelet aggregation and thrombosis This potentially devastating complication is associated with a 50% incidence of AMI and a 20% mortality rate

6 Stent antiplatelets Initially, stent thrombosis was tackled by the use of complex anticoagulation regimens using aspirin, heparin and warfarin Combination led to high rates of major bleeding, vascular complications and prolonged hospital stays. The development of new anti-platelet agents led to a breakthrough with the adoption of a dual anti-platelet treatment (DAPT) combining aspirin with a thienopyridine Aspirin and ticlopidine Aspirin and clopidogrel

7 Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI- CURE study Figure 3. Kaplan-Meler cumulative hazard rates for cardiovascular death or myocardial infarction from randomisation to end of follow-upa=median time from randomisation to percutaneous coronary intervention. B=30 days after median time of PCI. Shamir R Mehta, Salim Yusuf, Ron JG Peters, Michel E Bertrand, Basil S Lewis, Madhu K Natarajan, Klas Malmberg, Hans- Jürgen Rupprecht, Feng Zhao, Susan Chrolavicius, Ingrid Copland, Keith AA Fox null, Volume 358, Issue 9281, 2001,

8 Cumulative Hazard Rates for the First Primary Outcome (Death from Cardiovascular Causes, Nonfatal Myocardial Infarction, or Stroke) during the 12 Months of the Study. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. N Engl J Med 2001;345:

9 The Rates and Relative Risks of the First Primary Outcome (Death from Cardiovascular Causes, Nonfatal Myocardial Infarction, or Stroke) in Various Subgroups. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. N Engl J Med 2001;345:

10 Clopidogrel Pathway Sangkuhl Katrin, Klein Teri E, Altman Russ B. "Clopidogrel pathway" Pharmacogenetics and genomics (2010).

11 From: Association of Cytochrome P450 2C19 Genotype With the Antiplatelet Effect and Clinical Efficacy of Clopidogrel Therapy JAMA. 2009;302(8): doi: /jama Date of download: 6/12/2016 Copyright 2016 American Medical Association. All rights reserved.

12 Estimated Rates of Death from Any Cause, Nonfatal Myocardial Infarction, or Stroke, According to Characteristics of Variant-Allele Polymorphisms. Simon T et al. N Engl J Med 2009;360:

13 Association between Status as a Carrier of a CYP2C19 Reduced- Function Allele and the Primary Efficacy Outcome or Stent Thrombosis in Subjects Receiving Clopidogrel. Mega JL et al. N Engl J Med 2009;360:

14 Biotransformation and Mode of Action of Clopidogrel, Prasugrel, and Ticagrelor. Schömig A. N Engl J Med 2009;361:

15 CV Death/MI/Stroke (%) TRITON-TIMI 38: Primary End Point All ACS Population HR 0.77 ( ) P<0.001 Clopidogrel 12.1 (n=781) HR 0.80 ( ) P< Days Prasugrel Intent To Treat: n=13,608; Lost to Follow-Up: n=14 (0.1%) (n=643) HR 0.81 ( ) P<0.001 ARR=2.2 NNT=46 ACS=Acute Coronary Syndrome; ARR=Absolute Risk Reduction; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT=Number Needed to Treat Wiviott SD et al. New Engl J Med 2007;357:

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17 Cumulative incidence (%) Primary efficacy endpoint over time (composite of CV death, MI or stroke) Cumulative incidence (%) Clopidogrel Ticagrelor Clopidogrel Ticagrelor HR 0.88 (95% CI ), p= HR 0.80 (95% CI ), p< No. at risk Days after randomisation Days after randomisation * Ticagrelor 9,333 8,942 8,827 8,763 8,673 8,543 8,397 7,028 6,480 4,822 Clopidogrel 9,291 8,875 8,763 8,688 8,688 8,437 8,286 6,945 6,379 4,751 *Excludes patients with any primary event during the first 30 days

18 K-M estimated rate (% per year) Non-CABG and CABG-related major bleeding NS 7.9 Ticagrelor Clopidogrel p= NS p= Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding

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20 DAPT trial Enrollment, Randomization, and Follow-up. Multicenter, randomized, placebo-controlled trial Continued therapy (prsugrel clopidogrel) (n=5,020) Aspirin (n=4,941) Inclusion Criteria At time of PCI: Age >18 years Undergoing PCI with stent, or had PCI with stent in prior 3 days No contraindications for DAPT for the next 30 months At month 12 randomization: Event free in prior 12 months (death, MI, stroke, repeat coronary revascularization, stent thrombosis, or moderate or severe GUSTO bleeding) Compliant with medical therapy in prior 12 months Mauri L et al. N Engl J Med 2014;371:

21 Cumulative Incidence of Major Adverse Cardiovascular and Cerebrovascular Events, According to Study Group. Mauri L et al. N Engl J Med 2014;371:

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23 PEGASUS-TIMI 54 Trial design: Subjects with a history of MI (1-3 years prior) on aspirin therapy were randomized to ticagrelor 90 mg bid (n = 7,050) or ticagrelor 60 mg bid (n = 7,045) vs. placebo (n = 7,067). 10 % 5 0 (ticagrelor 90 mg vs. placebo p = 0.008; ticagrelor 60 mg vs. placebo p = 0.004) CV death, MI, or stroke Results CV death, MI, or stroke: 7.8% of the ticagrelor 90 mg bid group (hazard ratio [HR] vs. placebo = 0.85, p = 0.008), 7.8% of the ticagrelor 60 mg bid group (HR vs. placebo = 0.84, p = 0.004), and 9.0% of the placebo group TIMI major bleeding: 2.6% with ticagrelor 90 mg (HR vs. placebo = 2.7, p < 0.001), 2.3% with ticagrelor 60 mg (HR vs. placebo = 2.3, p < 0.001), and 1.1% with placebo Conclusions Among patients with prior MI on aspirin therapy, the addition of ticagrelor was beneficial ticagrelor 90 mg bid ticagrelor 60 mg bid Placebo Ticagrelor compared with placebo reduced the risk of cardiovascular death, MI, or stroke, but was associated with increased major bleeding Bonaca MP, et al. N Engl J Med 2015;Mar 14:[Epub]

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25 Case presentation 67 year old man. PMH: PUD at 40 treated with PPI and antibiotics DM HbA1c 7.5, HTN Smoking 12 months ago had MI. Primary PCI on the LAD with DES. NOA of the RCA and M2 Treatment: Atorvastain 80mg Aspirin 100mg Prasugrel 10mg Ramipril 10mg Januet (sitagliptin and metformin 50/1000)*2 Wants to stop some of the medication Should we stop Prasugrel?

26 Pro and cons Pros Significant residual risk Cons History of peptic disease Reduces compliance

27 Would you continue DAPT treatment? 1. Yes 2. No

28 Figure 2. Treatment Algorithm for Duration of P2Y 12 Inhibitor Therapy in Patients Treated With PCI

29 DAPT score A new risk score (the DAPT score ), derived from the Dual Antiplatelet Therapy study Analysis of study data suggest that in patients treated for 1 year with DAPT without significant bleeding or ischemic events, the benefit/risk ratio with prolonged DAPT may be favorable for those with a high DAPT score ( 2)

30 Factors Used to Calculate a DAPT Score Variable Age 75 y Age 65 to <75 y Age <65 y Current cigarette smoker Diabetes mellitus MI at presentation Prior PCI or prior MI Stent diameter <3 mm Paclitaxel-eluting stent CHF or LVEF <30% Saphenous vein graft PCI Points

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