INNOVATIONS 2017: Acute Coronary Syndrome Antiplatelet Therapies in Medical and Invasive Strategies.

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1 INNOVATIONS 2017: Acute Coronary Syndrome Antiplatelet Therapies in Medical and Invasive Strategies. José G. Díez, MD, FACC, FSCAI Associate Professor of Medicine, Baylor College of Medicine Hall Garcia Cardiology at Baylor College of Medicine Senior Research Scientist Texas Heart Institute Houston, TX

2 Acute Coronary Syndromes Progression and Stages Opportunities for Treatment Onset of NSTE-ACS -Initial recognition and management in the ED by first responders or ED personnel -Risk stratification -Immediate management Hospital Management -Medication -Conservative versus invasive strategy -Special groups -Preparation for discharge Management Prior to NSTE-ACS Secondary Prevention/ Long-Term Management

3 Acute Coronary Syndromes (stages - scenarios) Presentation Ischemic Discomfort ACS Working Dx ECG No ST Elevation NSTE-ACS ST Elevation Cardiac Biomarker UA NSTEMI* STEMI* Final Dx Unstable Angina Myocardial Infarction NQMI QwMI Noncardiac Etiologies

4 Spectrum of Pathologic and Clinical ST-Segment Elevation Acute Myocardial Infarction (STEMI) and Non-STEMI Acute Coronary Syndromes. Anderson JL, Morrow DA. N Engl J Med 2017;376:

5 TIMI Risk Score TIMI Risk Score* for NSTE-ACS All-Cause Mortality, New or Recurrent MI, or Severe Recurrent Ischemia Requiring Urgent Revascularization Through 14 d After Randomization, % *The TIMI risk score is determined by the sum of the presence of 7 variables at admission; 1 point is given for each of the following variables: 65 y of age; 3 risk factors for CAD; prior coronary stenosis 50%; ST deviation on ECG; 2 anginal events in prior 24 h; use of aspirin in prior 7 d; and elevated cardiac biomarkers.

6 GRACE Risk Model Nomogram To convert serum creatinine level to micromoles per liter, multiply by 88.4.

7 Algorithm for Management of Patients With Definite or Likely NSTE-ACS NSTE-ACS: Definite or Likely Ischemia-Guided Strategy Early Invasive Strategy Initiate DAPT and Anticoagulant Therapy 1. ASA (Class I; LOE: A) 2. P2Y 12 inhibitor (in addition to ASA) (Class I; LOE: B) : Clopidogrel or Ticagrelor 3. Anticoagulant: UFH (Class I; LOE: B) or Enoxaparin (Class I; LOE: A) or Fondaparinux (Class I; LOE: B) Initiate DAPT and Anticoagulant Therapy 1. ASA (Class I; LOE: A) 2. P2Y 12 inhibitor (in addition to ASA) (Class I; LOE: B): Clopidogrel or Ticagrelor 3. Anticoagulant: UFH (Class I; LOE: B) or Enoxaparin (Class I; LOE: A) or Fondaparinux (Class I; LOE: B) or Bivalirudin (Class I; LOE: B) Can consider GPI in addition to ASA and P2Y 12 inhibitor in high-risk (e.g., troponin positive) pts (Class IIb; LOE: B) Eptifibatide Tirofiban Medical therapy chosen based on cath findings Therapy Effective Therapy Ineffective

8 EARLY INVASIVE STRATEGY

9 Factors Associated With Appropriate Selection of Early Invasive Strategy or Ischemia-Guided Strategy in Patients With NSTE-ACS Immediate invasive (within 2 h) Ischemiaguided strategy Early invasive (within 24 h) Delayed invasive (within h) Refractory angina Signs or symptoms of HF or new or worsening mitral regurgitation Hemodynamic instability Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy Sustained VT or VF Low-risk score (e.g., TIMI [0 or 1], GRACE [<109]) Low-risk Tn-negative female patients Patient or clinician preference in the absence of high-risk features None of the above, but GRACE risk score >140 Temporal change in Tn (Section 3.4) New or presumably new ST depression None of the above but diabetes mellitus Renal insufficiency (GFR <60 ml/min/1.73 m²) Reduced LV systolic function (EF <0.40) Early postinfarction angina PCI within 6 mo Prior CABG GRACE risk score ; TIMI score 2

10 Meta-Analysis of Trials Comparing an Early Invasive vs. Conservative Strategy for NSTE-ACS N=8,375 Weighted mean follow-up 23.7 months Bavry AA, et al. JACC 2006;48: P=0.001 P=0.012 P< % 17% 31% INV CONS 5 0 All cause Mort. Nonfatal MI Rehosp UA NNT 62 NNT 66 NNT 11

11 Optimal Strategy for UA/NSTEMI FAST-MI ICTUS VANQWISH Conservative N= TIMACS (Low Risk) MATE TIMI IIIB N=3112 ELISA-3 TIMACS (High Risk) ISAR-COOL VINO Invasive N=10489 RITA-3 TRUCS TACTICS- TIMI 18 FRISC II Modified 2010 from Cannon, C. Cardiology Rounds 2003;7 (4) 1-6.

12 EuroIntervention 2013;9:54-61 Early or late intervention in high-risk non-st-elevation acute coronary syndromes: results of the ELISA-3 trial 2013 EuroIntervention. All rights reserved.

13 EuroIntervention 2015;11-online publish-ahead-of-print November 2015 Invasive strategies and outcomes for non-st-segment elevation acute coronary syndromes: a twelve-year experience from SWEDEHEART 2015 EuroIntervention. All rights reserved.

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15 Wallentin, L. Eur Heart J :ehp296v1-296; doi: /eurheartj/ehp296

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17 The Most Plausible Mechanism Of Aspirin In Reducing Risks Of Cardiovascular Disease Aspirin irreversibly acetylates the active site of cyclooxygenase, which is required for the production of thromboxane A2, a powerful promoter of platelet aggregation Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action of aspirin like drugs. Nat New Biol. 1971;231:232-5.

18 Second International Study of Infarct Survival ISIS-2 Collaborative Croup Lancet Aug 13;332:

19 SUMMARY OF TRIALS OF ANTITHROMBOTIC IN UA/NSTEMI Patients with event (%) Risk ratio (95% CI) P-value Trials N Active Placebo ASA vs placebo % Death or MI 5-day to 2-year endpoint Lewis et al (VA) Cairns et al Theroux et al RISC group All ASA vs placebo UFH + ASA vs ASA Theroux et al week endopoint 0.40 RISC group ATACS group Gurfinkel et al All UFH vs ASA LMWH + ASA vs ASA Gurfinkel et al week endopoint NA FRISC group All hep. or LMWH vs ASA GPIIb/IIIa anta + UFH vs UFH CAPTURE day endopoint PARAGON PRISM-PLUS PRISM* PURSUIT All GPIIb/IIIa vs UFH # Braunwald et al ACC/AHA Practice Guidelines

20 The active metabolite exerts its antiplatelet effect by noncompetitive inhibition of the platelet ADP receptor subtype P2Y 12 CLOPIDOGREL C Clopidogrel: An inactive prodrug requires in vivo conversion in the liver by the cytochrome P450 (CYP) 3A4 enzyme system ADP ADP GPllb/llla (Fibrinogen receptor) Activation Collagen thrombin TXA 2 ASA COX TXA 2 COX (cyclo-oxygenase) ADP (adenosine diphosphate) TXA 2 (thromboxane A 2 ) Jarvis B, Simpson K. Drugs 2000; 60:

21 Cumulative Hazard Rate CURE Study: Primary End Point: MI/Stroke/CV Death Placebo + Aspirin (n=6303) Clopidogrel + Aspirin (n=6259) 20% Relative Risk Reduction P <.001 N=12, Months of Follow-up Yusuf S, et al. N Engl J Med. 2001;345:

22 Cumulative Hazard Rate PCI-CURE Study: CV Death or MI From Randomization Median time to PCI Placebo + Aspirin (n=1345) 12.6% 8.8% 31% Relative Risk Reduction Clopidogrel + Aspirin (n=1313) P= Days of Follow-up Mehta SR, et al. Lancet. 2001;358:

23 CREDO: 1-Year Primary Outcome Death, MI, or stroke (%) RRR=27% P=0.02 Placebo n=1,063 Clopidogrel n=1, % 8.5% Months Steinhubl S et al: JAMA 2002;288:

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25 Percentage with endpoint (%) Clarity TIMI 28: CV Death, MI, RI Urg Revasc (n= 3491) Sabatine MS, et al. N Engl J Med. 2005;352:1179. Placebo 20% Clopidogrel Odds Ratio 0.80 (95% CI ) P= days

26 Schematic of different therapeutic options for inhibition of platelet P2Y12 receptor. José Luis Ferreiro, and Dominick J. Angiolillo Circ Cardiovasc Interv. 2012;5:

27 TRITON TIMI 38 - Main Trial Design ACS (STEMI or UA/NSTEMI) & Planned PCI ASA N= 13,608 Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Duration of therapy: 6-15 months 1 o endpoint: CV death, MI, Stroke 2 o endpoint: Stent Thrombosis Safety endpoints: TIMI major bleeds, Life-threatening bleeds 27 Wiviott SD, Antman EM et al AHJ 2006

28 Endpoint (%) TRITON TIMI 38 Main Trial: Primary Results CV Death / MI / Stroke Clopidogrel Prasugrel HR 0.81 ( ) P= TIMI Major NonCABG Bleeds Days Prasugrel Clopidogrel HR 1.32 ( ) P= Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

29 CV Death, MI, Stroke (%) TRITON-TIMI Clopidogrel clopidogrel prasugrel P=0.002 Prasugrel P< P= HR 0.81 ( ) Days NNT= TIMI major bleed P=0.01 Life threatening Caveats: Warning - Weight < 60 kg, Age > 75, h/o CVA, need for CABG Wiviott et al. New Engl J Med 2007;357: No data long term therapy, uses other than ACS. TIMI major or minor

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32 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 (n=9291) 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 (n=9333) 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 endpoint: Total major bleeding

33 K-M estimated rate (% per year) K-M estimated rate (% per year) PLATO main endpoints 13 Primary efficacy endpoint: D/Mi/CVA 15 Primary safety endpoint: Bleeding Clopidogrel Ticagrelor Ticagrelor Clopidogrel HR 0.84 (95% CI ), p= HR 1.04 (95% CI ), p= No. at risk Ticagrelor Clopidogrel ,333 9,291 Months Months Caveats: Rhythm disorders, dyspnea, 8,628 8,460 8,219 6,743 5,161 4,147 9,235 7,246 6,826 6,545 5,129 8,521 8,362 8,124 6,743 5,096 4,047 9,186 7,305 6,930 6,670 5,209 CrCl, uric acid, not to be used in h/o CVA. 3,783 3,433 3,841 3,479 Wallentin et al., New Eng J Med. 2009;361:

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35 Efficacy in reducing the rates of definite and probable stent thrombosis of new drugs/approaches tested in large-scale clinical trials. José Luis Ferreiro, and Dominick J. Angiolillo Circ

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43 ACC/AHA/SCAI 2005 guideline update for PCI Update No ACS DES - 12, first generation New generation 6, 3 months Class I In patients who have undergone Update PCI: clopidogrel (75 mg daily) should be given for at least 1 month ACS after BMS BMS/DES/ACB/MD implantation (unless the patient 12 is months at increased risk for bleeding); then it should be given for a minimum of 2 weeks), 3 months after sirolimus stent implantation, and Update 2009 and months after paclitaxel stent implantation, and ideally up to 12 ACS-DES months in patients 12 M, who STEMI are not at > high 15 months risk of bleeding. New DES SHORTER? 2016 LONGER - DAPT trial 30 months Smith S et al. Circulation. 2005;113:

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46 Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study Cuisset T, Deharo P, Quilici J, et al. EHJ 2017, May 16 Aims to evaluate the benefit of switching dual antiplatelet therapy (DAPT) from aspirin plus a newer P2Y12 blocker to aspirin plus clopidogrel 1 month after ACS. Methods and results open-label, randomized trial. patients admitted with ACS requiring coronary intervention, on aspirin and a newer P2Y12 blocker and without adverse event at 1 month, were assigned to switch to aspirin and clopidogrel (switched DAPT) or continuation of their drug regimen (unchanged DAPT). The primary outcome was a composite of cardiovascular death, urgent revascularization, stroke and bleeding as defined by the Bleeding Academic Research Consortium (BARC) classification 2 at 1 year post ACS. Six hundred and forty five patients: 322 patients in the switched DAPT and 323 in the unchanged DAPT group. The primary endpoint occurred in 43 (13.4%) patients in the switched DAPT group and in 85 (26.3%) patients in the unchanged DAPT (HR 95%CI 0.48 ( ), P < 0.01). No significant differences were reported on ischaemic endpoints, BARC 2 bleeding occurred in 13 (4.0%) patients in the switched DAPT and in 48 (14.9%) in the unchanged DAPT group (HR 95%CI 0.30 ( ), P < 0.01). Conclusion A switched DAPT is superior to an unchanged DAPT strategy to prevent bleeding complications without increase in ischaemic events following ACS.

47 Balancing Ischemic and Bleeding Risk

48 JACC: Cardiovascular Interventions Volume 10, Issue 11, June 2017 Outcomes in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Via Radial Access Anticoagulated With Bivalirudin Versus Heparin A Report From the National Cardiovascular Data Registry Jovin et al.

49 Six Initial Assessment and Management Decisions Pertaining to Patients Presenting with Chest Pain and a Possible Acute Coronary Syndrome. Anderson JL, Morrow DA. N Engl J Med 2017;376:

50 Oral Chronic Anticoagulation? Choose wisely, choose carefully BMS vs DES Triple combination: 3 6 months INR 2.0 WOEST (Lancet 2013) 50

51 Antiplatelet Strategies in ACS: Conclusions Dual antiplatelet therapy indicated for at least 1 year after ACS and/or PCI CURE, PCI CURE, CREDO Potential benefit beyond 1 year in patients with prior ischemic events CHARISMA High Risk, PEGASUS Potential benefit beyond 1 year in patients with DES registry data, DAPT New Agents: Prasugrel, Ticagrelor, Elinogrel, Vorapaxar

52 Thank you! 52