Oral anticoagulation/antiplatelet therapy in the secondary prevention of ACS patients the cost of reducing death!

Transcription

1 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

2 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

3 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

4 Patients (%) Hospital mortality (%) In-hospital prognosis for patients with ACS has improved in recent years in some countries US National Registry of Myocardial Infarction (NRMI), : ~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 STEMI Troponin assay used STEMI All patients NSTEMI Year NSTEMI 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 28;156:126 34

5 Hospital mortality (%) Hospital mortality (%) Residual Risk Six-month mortality rate following an ACS event is high Global Registry of Acute Coronary Events (GRACE): 43,81 patients with ACS ( ) 15 Death from hospital admission to 6 months STEMI NSTEMI 1 Death from hospital discharge to 6 months STEMI NSTEMI 12 Unstable angina 8 Unstable angina Days ACS, acute coronary syndrome; NSTEMI, non-st-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction. Fox KA et al. BMJ 26;333: Days

6 In vivo arterial thrombosis involves platelet aggregation, tissue factor generation and fibrin formation Falati et al. Nat Med 22;8: 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

7 Case based risk stratification 8 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 =.34 Creatinine 82 SBS = 7.1

8 Dilemma Balancing Ischemic and Bleeding Risks 25 Baseline risk estimates GRACE Risk Score Ischemia risk In-hospital death and re-mi CRUSADE Bleeding Risk Score Bleeding risk In-hospital major bleeding Armstrong & Welsh JACC Int, Dec. 21.

9 Dilemma Balancing Ischemic and Bleeding Risks 25 2 Baseline risk estimates Intervention risk/benefit estimates GRACE Risk Score Ischemia risk In-hospital death and re-mi CRUSADE Bleeding Risk Score Bleeding risk In-hospital major bleeding Armstrong & Welsh JACC Int, Dec. 21.

10 Mortality (%) 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 3 25 Both MI and major bleeding (N=94) 1-year estimate 28.9% 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 29;11:C4 8. Major bleeding only (no MI) (N=551) MI only (no major bleeding) (N=611) No MI or major bleeding (N=12,557) 12.5% 8.6% 3.4%

11 Mortality (%) Ischaemic events result in more deaths Study Patient type Max. duration of follow-up OASIS NSTE-ACS 6 months than major bleeding Randomized clinical trials of long-term antithrombotic therapy in patients with ACS OASIS-5* CURE PLATO CV death Fatal bleeding ATLAS ACS 2 TIMI 51 CURE 4 NSTE-ACS 12 months TRITON All ACS types 15 months TIMI-38 5 PLATO 6 All ACS types 12 months TRITON TIMI-38 ATLAS ACS 2- TIMI 51 7 All ACS types 31 months *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. 25; 2. Yusuf et al. N Engl J Med 26; 3. Budaj et al. Eur Heart J 29; 4. Yusuf et al. N Engl J Med 21; 5. Wiviott et al. N Engl J Med 27; 6. Wallentin et al. N Engl J Med 29; 7. Mega et al. N Engl J Med 212.

12 Currently Available Antiplatelet Agents

13 METABOLISM OF P2Y12 RECEPTOR ANTAGONISTS Orally active Ticagrelor Prasugrel Hydrolysis by esterase Orally active CYP-dependent oxidation CYP3A4/5 Binding Platelet Clopidogrel Active compound Active metabolite Intermediate metabolite CYP-dependent oxidation CYP3A4 CYP2C19 CYP1A2 CYP2B6 CYP-dependent oxidation CYP3A4, CYP2B6 CYP2C9, CYP2C19 CYP-dependent oxidation CYP3A4 CYP2C19 CYP1A2 CYP2B6 Prodrug Adapted from: Schomig A. NEJM. 29;361(11):

14 Inhibition of Platelet Aggregation (%) * Loading Dose * 6 mg Maintenance Doses Inhibition of Platelet Aggregation (Mean ± SEM, 2 µm ADP) * * * * 6 mg Inhibition of platelet aggregation P2Y12 Receptor Antagonists *P<.1 vs * Clop 3 1 mg mg 6 mg * and * 75 mg * * P <.5 vs Clop 3 mg/75 mg * * 4 3 mg 75 mg P <.1 vs Clop 3 mg/75 mg 2 Clopidogrel ADP=adenosine diphosphate Clop=clopidogrel Clopidogrel Pras=prasugrel Prasugrel Time Day 1, Hours Days Jakubowski et al. Cardiovasc Drug Rev. 27;25: Husted SE et al, Clin Pharmacokinet. 212 Jun 1;51(6):

15 Response of novel antiplatelet agents in Clopidogrel resistant patients Alexopoulos et al, JACC, 17 July 212, Pages

16 Timing of Randomization and Treatment in Dual Antiplatelet Trials < 24 hrs CURE Clopidogrel PLATO Ticagrelor Selective Invasive TRILOGY Prasugrel Medical Management Symptom Onset Presentation Early Invasive Coronary Angiography Medical CABG PCI CURRENT Clopidogrel TRITON Prasugrel NSTE ACS < 72 hrs STEMI < 12 hrs James SK et al. BMJ 211;342:d3527. Wiviott SD et al. N Engl J Med 27;357(2): Yusuf S et al. N Engl J Med 21;345(7):

17 Endpoint (%) 15 1 Prasugrel + ASA: Residual risk of ischaemic events remains TRITON TIMI-38 CV death, MI or stroke Clopidogrel Prasugrel events HR=.81 (.73.9) p=.1 NNT=46 5 TIMI major Non-CABG bleeding Days after randomization Prasugrel Clopidogrel 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 27;357: events HR=1.32 ( ) p=.3

18 Cumulative incidence (%) K M estimated rate (% per year) Ticagrelor + ASA: Residual risk of ischaemic events remains Primary efficacy endpoint time to first occurrence No. at risk CV death, MI or stroke Clopidogrel Ticagrelor Months after randomization PLATO HR=.84 (95% CI.77.92), p=.1 Time to non-procedural-related major bleeding Ticag Clopid (n=9,333) (n=9,291) P value MI 5.8% 6.9%.5 CV death 4.% Stroke 1.5% 1.3%.22 Total Death 4.5% 5.9% <.1 Ticagrelor Clopidogrel Months after randomization HR=1.31 (95% CI ), p=.6 Ticagrelor Clopidogrel ASA, acetylsalicylic acid; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Wallentin et al. N Engl J Med 29;361:

19 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 9 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

20 Antiplatelet Therapy for Secondary Prevention in the First Year Following NSTEACS 3. We recommend prasugrel 1 mg daily over clopidogrel 75 mg daily for 12 months in addition to ASA 81 mg daily in P2Y 12 inhibitor-naive patients with NSTEACS after their coronary anatomy has been defined and PCI planned (Strong Recommendation, High Quality Evidence) New 4. We recommend avoiding prasugrel in patients with prior TIA or stroke or in patients who are not treated with PCI. Except in patients with a high probability of undergoing PCI, we recommend avoiding prasugrel before the coronary anatomy has been defined. (Strong Recommendation, Moderate Quality Evidence) New

21 Bleeding in Perspective (Danish Registry 82, )

22 Cumulative incidence (%) WOEST: randomized trial comparing single versus dual antiplatelet therapy in patients on oral anticoagulant therapy undergoing PCI One-year follow-up: All TIMI bleeding (minimal, minor and major) significantly reduced in the VKA + clopidogrel arm Major bleeding also numerically lower No difference in intracranial bleeding Clinical ischaemic events were not increased in the VKA + clopidogrel arm Most efficacy endpoints showed numerically lower rates in the VKA + clopidogrel arm Primary endpoint: bleeding events VKA + clopidogrel VKA + clopidogrel + ASA ASA, acetylsalicylic acid; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction; VKA, vitamin K antagonist. Dewilde et al. Lancet 213, Epub Feb 12

23 WOEST Trial Dual vs. Triple therapy following stenting ASA, acetylsalicylic acid; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction; VKA, vitamin K antagonist. Dewilde et al. Lancet 213, Epub Feb 12

24 ATLAS ACS 2-TIMI 51: a randomized, double-blind, event-driven Phase III trial in patients hospitalized with ACS NO Stratum 1: ASA alone (7%) N=15,526* Physician's decision whether or not to add thienopyridine YES Stratum 2: ASA + thienopyridine (93%) Placebo (n=355) Rivaroxaban 2.5 mg bid (n=349) Rivaroxaban 5 mg bid (n=349) Placebo (n=4821) Rivaroxaban 2.5 mg bid (n=4825) Rivaroxaban 5 mg bid (n=4827) Event-driven study 983 events ASA dose: 75 1 mg *184 patients were excluded from the efficacy analyses prior to unblinding because of trial misconduct at three sites. ACS, acute coronary syndrome; ASA, acetylsalicylic acid; ATLAS ACS, Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome; bid, twice daily; od, once daily; TIMI, Thrombolysis In Myocardial Infarction. 1. Gibson et al. Am Heart J 211;161: e6; 2. Mega et al. N Engl J Med 212;366:9 19.

25 Estimated cumulative rate (%) ATLAS ACS 2-TIMI 51: Rivaroxaban (combined doses) reduced the primary efficacy endpoint vs placebo Primary efficacy endpoint (CV death/mi/stroke) Combined rivaroxaban doses, both strata Placebo Months after randomization Rivaroxaban year Kaplan Meier estimate 1.7% 8.9% HR=.84 (.74.96) ARR=1.7% mitt p=.8 ITT p=.2 NNT=56 ARR, absolute risk reduction; CV, cardiovascular; HR, hazard ratio; ITT, intention to treat; MI, myocardial infarction; mitt, modified intention to treat; NNT, number needed to treat. Mega et al. N Engl J Med 212;366:9 19.

26 Cumulative incidence (%) ATLAS ACS 2-TIMI 51: Rivaroxaban 2.5 mg bid significantly reduced CV events and death The primary efficacy endpoint reduction was driven by reduced mortality 13 CV death/mi/stroke (primary efficacy endpoint) HR=.84 mitt p=.2 Placebo ITT p=.7 1.7% 5 Cardiovascular death HR=.66 mitt p=.2 ITT p=.5 Placebo 4.1% 5 All-cause death HR=.68 mitt p=.2 ITT p=.4 Placebo 4.5% 9.1% 2.7% 2.9% Rivaroxaban 2.5 mg bid Rivaroxaban 2.5 mg bid Rivaroxaban 2.5 mg bid NNT= Months NNT= Months 6 12 Months NNT= Both strata. bid, twice daily; CV, cardiovascular; HR, hazard ratio; ITT, intention to treat; MI, myocardial infarction; mitt, modified intention to treat; NNT, number needed to treat 1. Mega et al. N Engl J Med 212;366:9 19; 2. Gibson et al. AHA 211 (

27 2-year Kaplan Meier estimate (%) ATLAS ACS 2-TIMI 51: Rivaroxaban did not increase fatal bleeding or fatal ICH versus placebo Rivaroxaban vs placebo p=ns * # Rivaroxaban vs placebo p=ns (principal safety outcome) *p=.4 vs placebo; # p=.5 vs placebo; p<.1 vs placebo. bid, twice daily; CABG, coronary artery bypass graft; ICH, intracranial haemorrhage; NS, not significant. 1. Mega et al. N Engl J Med 212;366:9 19; 2. Gibson et al. AHA 211 (

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29 Adoption of novel therapies in Canada Prasugrel - TRITON-TIMI 38 published in 27 Health Canada approval April 16, 21 Selected clinical usage Ticagrelor - PLATO published in 29 Health Canada approval May 3, 211 Regional variation in Coverage Significant issues with provincial and regional formulary coverage and reimbursement

30 Summary 1. Guidelines support ticagrelor and ASA as first line DAPT for the majority of ACS patients 2. In patients that have indication for triple therapy with anticipated increased bleeding risk VKA and clopidogrel may be considered (no ASA) 3. Very low dose rivaroxaban (2.5 mg bid) in combination with ASA and clopidogrel reduces CV death and all cause death but is associated with increased risk of major bleeding 4. Investigation with rivaroxaban and novel antiplatelet agents/strategies may facilitate clinical application