Oral anticoagulation/antiplatelet therapy in the secondary prevention - PowerPoint PPT Presentation

Oral anticoagulation/antiplatelet therapy in the secondary prevention of ACS patients – the cost of reducing death! Robert C. Welsh, MD, FRCPC Associate Professor of Medicine Director, Adult Cardiac Catheterization and Interventional Cardiology Co-Chair, Vital Heart Response Co-director, U of A Chest Pain Program

Disclosures – past 5 years Research funding: ‐ Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers-Squibb, Eli Lilly, Johnson and Johnson, Pfizer, Portola, Regado, Roche, sanofi aventis Consultant/honorarium: ‐ Astra Zeneca, Bayer, Bristol Myers-Squibb, Edwards Lifesciences, Eli Lilly, Medtronic, Roche, sanofi-aventis

Objectives 1. Review ACS epidemiology 2. Review individual case based risk stratification in ACS patients 3. Review current antiplatelet strategies for ACS patients 4. Review novel agents and evidence regarding ACS management

In-hospital prognosis for patients with ACS has improved in recent years in some countries US National Registry of Myocardial Infarction (NRMI), 1990 – 2006: • ~2 million patients with acute MI admissions in 2157 US hospitals Patient classification and proportion in whom troponin assay was used to diagnose acute MI In-hospital mortality 100 12 STEMI 90 STEMI 11 Troponin assay used Hospital mortality (%) 80 10 All patients 70 Patients (%) 9 60 50 8 40 7 NSTEMI 30 NSTEMI 6 20 5 10 0 4 1990 1994 1998 2002 2006 1994 1996 1998 2000 2002 2004 2006 Year Year MI, myocardial infarction; NRMI, National Registry of Myocardial Infarction; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction; US, United States. Rogers et al. Am Heart J 2008;156:1026 – 34

Residual Risk Six-month mortality rate following an ACS event is high Global Registry of Acute Coronary Events (GRACE): • 43,810 patients with ACS (1999 – 2005) Death from hospital admission Death from hospital discharge to 6 months to 6 months STEMI STEMI 15 10 NSTEMI NSTEMI Hospital mortality (%) Unstable angina Hospital mortality (%) Unstable angina 12 8 9 6 6 4 3 2 0 0 0 30 60 90 120 150 180 0 30 60 90 120 150 180 Days Days ACS, acute coronary syndrome; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction. Fox KA et al. BMJ 2006;333:1091

In vivo arterial thrombosis involves platelet aggregation, tissue factor generation and fibrin formation Real-time in vivo imaging of arterial thrombus formation in the mouse after laser-induced vascular injury The video shows platelet deposition, tissue factor accumulation and subsequent fibrin generation at the injury site in the first minute after injury Falati et al. Nat Med 2002;8:1175 – 80.

Case based risk stratification • 80 year old female presents with 45 minutes of chest heaviness that resolved with pre-hospital NTG and O2 • No prior cardiac events - past history of Hypertension Lab values Troponin =1.2 HCT = 0.34 Creatinine 82 SBS = 7.1

Dilemma Balancing Ischemic and Bleeding Risks Baseline risk estimates 25 20 15 21 10 5 9.2 0 CRUSADE Bleeding Risk Score GRACE Risk Score Bleeding risk Ischemia risk In-hospital major bleeding In-hospital death and re-MI Armstrong & Welsh JACC Int, Dec. 2010.

Dilemma Balancing Ischemic and Bleeding Risks 25 Baseline risk estimates Intervention risk/benefit estimates 20 15 21 10 13 15.5 5 9.2 0 CRUSADE Bleeding Risk Score GRACE Risk Score Bleeding risk Ischemia risk In-hospital major bleeding In-hospital death and re-MI Armstrong & Welsh JACC Int, Dec. 2010.

Major bleeding (non-CABG) in the first month after MI is associated with increased 1-year mortality • ACUITY: randomized trial of bivalirudin versus UFH (+ GPIIb/IIIa inhibitor) in 13,819 patients with NSTE-ACS 1-year estimate 30 28.9% Both MI and major bleeding (N=94) 25 20 Mortality (%) 15 Major bleeding only (no MI) (N=551) 12.5% 10 8.6% MI only (no major bleeding) (N=611) 5 3.4% No MI or major bleeding (N=12,557) 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from randomization CABG, coronary artery bypass graft; GPIIb/IIIa, glycoprotein Iib/IIIa; MI, myocardial infarction; NSTE-ACS, non-ST-elevation acute coronary syndrome. Mehran and Stone. EHJ Supplement 2009;11:C4 – 8.

Ischaemic events result in more deaths than major bleeding • Randomized clinical trials of long-term antithrombotic therapy in patients with ACS CV death OASIS-5* Fatal bleeding Study Patient type Max. CURE duration of PLATO follow-up ATLAS ACS 2 OASIS-5 1 – 3 NSTE-ACS 6 months TIMI 51 Mortality (%) CURE 4 NSTE-ACS 12 months TRITON TIMI-38 TRITON All ACS types 15 months TIMI-38 5 PLATO 6 All ACS types 12 months ATLAS ACS 2- All ACS types 31 months TIMI 51 7 *Unclear if ‘death’ is defined as cardiovascular only or all -cause ACS, acute coronary syndrome; NSTE-ACS, non-ST-elevation acute coronary syndrome. 1. MICHELANGELO OASIS-5 Steering Committee. Am Heart J. 2005; 2. Yusuf et al. N Engl J Med 2006; 3. Budaj et al. Eur Heart J 2009; 4. Yusuf et al. N Engl J Med 2001; 5. Wiviott et al. N Engl J Med 2007; 6. Wallentin et al. N Engl J Med 2009; 7. Mega et al. N Engl J Med 2012.

Currently Available Antiplatelet Agents

METABOLISM OF P2Y12 RECEPTOR ANTAGONISTS Orally active CYP-dependent Ticagrelor Orally active oxidation CYP3A4/5 Binding Hydrolysis by esterase Prasugrel Platelet CYP-dependent oxidation CYP3A4, CYP2B6 CYP2C9, CYP2C19 Clopidogrel CYP-dependent CYP-dependent oxidation oxidation CYP3A4 CYP3A4 CYP2C19 Active compound CYP2C19 CYP1A2 Active metabolite CYP1A2 CYP2B6 CYP2B6 Intermediate metabolite Prodrug Adapted from: Schomig A. NEJM. 2009;361(11):1108-1111.

Inhibition of platelet aggregation P2Y12 Receptor Antagonists Loading Dose Maintenance Doses Inhibition of Platelet Aggregation (Mean ± SEM, 20 µM ADP) 100 * * P <.001 vs * * * * Clop 300 mg 10 mg * * 600 mg and 75 mg * * * * * 80 ‡ Inhibition of Platelet Aggregation (%) ‡ 60 mg ‡ † † P <.05 vs Clop 300 mg/75 ‡ * mg 60 600 mg 75 mg 40 ‡ P <.001 vs † Clop 300 mg/75 300 mg mg 20 Clopidogrel ADP=adenosine diphosphate Clopidogrel Clop=clopidogrel 0 Pras=prasugrel Prasugrel 1 2 3 4 5 6 2 3 4 5 6 7 8 9 Time Day 1, Hours Days Jakubowski et al. Cardiovasc Drug Rev. 2007;25:357-374. Husted SE et al, Clin Pharmacokinet. 2012 Jun 1;51(6):397-409.

Response of novel antiplatelet agents in Clopidogrel resistant patients Alexopoulos et al, JACC, 17 July 2012, Pages 193 – 199

Timing of Randomization and Treatment in Dual Antiplatelet Trials < 24 hrs TRILOGY CURE Prasugrel Clopidogrel PLATO Selective Ticagrelor Medical Management Invasive Medical Symptom Presentation Onset Coronary CABG Early Angiography Invasive PCI TRITON CURRENT Prasugrel Clopidogrel NSTE ACS < 72 hrs STEMI < 12 hrs James SK et al. BMJ 2011;342:d3527. Wiviott SD et al. N Engl J Med 2007;357(20):2001 – 2015. Yusuf S et al. N Engl J Med 2001;345(7):494 – 502.

Prasugrel + ASA: Residual risk of ischaemic events remains 15 TRITON TIMI-38 138 events Clopidogrel HR=0.81 12.1 CV death, (0.73 – 0.90) MI or stroke p =0.001 9.9 10 Endpoint (%) NNT=46 Prasugrel 5 TIMI major 35 events Prasugrel Non-CABG bleeding 2.4 HR=1.32 (1.03 – 1.68) 1.8 Clopidogrel p =0.03 0 0 90 180 270 360 450 Days after randomization ASA, acetylsalicylic acid; CABG, coronary artery bypass graft; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; NNT, number needed to treat; RRR, relative risk reduction; TIMI, Thrombolysis in Myocardial Infarction. Wiviott et al. N Engl J Med 2007;357:2001 – 15.

Ticagrelor + ASA: Residual risk of ischaemic events remains Primary efficacy endpoint – time to first occurrence Time to non-procedural-related major bleeding PLATO Ticag Clopid 13 P value ✝ CV death, (n=9,333) (n=9,291) Clopidogrel 12 MI or stroke 11.7 MI 5.8% 6.9% 0.005 Cumulative incidence (%) 11 10 9.8 CV death 4.0% 5.1 0.001 9 8 Ticagrelor Stroke 1.5% 1.3% 0.22 7 Total 6 K – M estimated rate Death 4.5% 5.9% <0.001 5 4 (% per year) 4 3 Ticagrelor 3 3.06 2 2.31 2 HR=0.84 (95% CI 0.77 – 0.92), p =0.001 1 Clopidogrel 1 0 HR=1.31 (95% CI 1.08 – 1.60), p =0.006 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Months after randomization Months after randomization No. at risk Ticagrelor 9333 8628 8460 8219 6743 5161 4147 9235 7641 7274 6979 5496 4067 3698 Clopidogrel 9291 8521 8362 8124 6650 5096 4047 9186 7718 7371 7134 5597 4147 3764 ASA, acetylsalicylic acid; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Wallentin et al. N Engl J Med 2009;361:1045 – 57.

Antiplatelet Therapy for Secondary Prevention in the First Year Folowing NSTEACS 1. We recommend ASA 81 mg daily indefinitely in all patients with NSTEACS (Strong Recommendation, High Quality Evidence). For patients allergic to or intolerant of ASA, indefinite therapy with clopidogrel 75 mg daily is recommended (Strong Recommendation, High Quality Evidence) (Unchanged) 2. We recommend ticagrelor 90 mg twice daily over clopidogrel 75 mg daily for 12 months in addition to ASA 81 mg daily in patients with moderate to high risk NSTEACS managed with either PCI, CABG surgery or medical therapy alone. (Strong Recommendation, High Quality Evidence) New