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

NSTEMI

100 10 20 30 40 50 60 70 80 90

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

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

Patient classification and proportion in whom troponin assay was used to diagnose acute MI

2006 1990 1994 1998 2002 Year

Patients (%)

STEMI Troponin assay used NSTEMI

In-hospital mortality

Year 9 10 11 12 8 7 6 5 4

Hospital mortality (%)

1994 1996 1998 2002 2006 2000 2004

STEMI All patients

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)

ACS, acute coronary syndrome; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction. Fox KA et al. BMJ 2006;333:1091 2 4 6 8 10

Hospital mortality (%)

30 90 120 180 60 150

Days

STEMI NSTEMI Unstable angina

Death from hospital discharge to 6 months

30 90 120 180 60 150

Days

3 6 9 12 15

Death from hospital admission to 6 months

STEMI NSTEMI Unstable angina

Hospital mortality (%)

In vivo arterial thrombosis involves platelet aggregation, tissue factor generation and fibrin formation

Real-time in vivo imaging

• f 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

21 9.2 5 10 15 20 25

Ischemia risk

In-hospital death and re-MI

Bleeding risk

In-hospital major bleeding

Baseline risk estimates

Dilemma Balancing Ischemic and Bleeding Risks

Armstrong & Welsh JACC Int, Dec. 2010. GRACE Risk Score CRUSADE Bleeding Risk Score

21 9.2 13 15.5

5 10 15 20 25

Ischemia risk

In-hospital death and re-MI

Bleeding risk

In-hospital major bleeding

Baseline risk estimates Intervention risk/benefit estimates Armstrong & Welsh JACC Int, Dec. 2010.

Dilemma Balancing Ischemic and Bleeding Risks

GRACE Risk Score CRUSADE Bleeding Risk Score

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

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.

Mortality (%) Days from randomization 30 60 90 120 150 180 210 240 270 300 330 360 390 5 15 30 10 25 20

Major bleeding only (no MI) (N=551) Both MI and major bleeding (N=94) No MI or major bleeding (N=12,557) MI only (no major bleeding) (N=611)

28.9% 12.5% 8.6% 3.4% 1-year estimate

Ischaemic events result in more deaths than major bleeding

*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.

Study Patient type Max. duration of follow-up OASIS-51–3 NSTE-ACS 6 months CURE4 NSTE-ACS 12 months TRITON TIMI-385 All ACS types 15 months PLATO6 All ACS types 12 months ATLAS ACS 2- TIMI 517 All ACS types 31 months

• Randomized clinical trials of long-term antithrombotic therapy in patients with ACS

OASIS-5* CURE TRITON TIMI-38 PLATO ATLAS ACS 2 TIMI 51 CV death Fatal bleeding Mortality (%)

Currently Available Antiplatelet Agents

METABOLISM OF P2Y12 RECEPTOR ANTAGONISTS

Ticagrelor Prasugrel Clopidogrel

Hydrolysis by esterase Orally active CYP-dependent

• xidation

CYP3A4/5 CYP-dependent

• xidation

CYP3A4 CYP2C19 CYP1A2 CYP2B6 CYP-dependent oxidation CYP3A4 CYP2C19 CYP1A2 CYP2B6 Binding Platelet Active compound Active metabolite Prodrug Intermediate metabolite CYP-dependent oxidation CYP3A4, CYP2B6 CYP2C9, CYP2C19 Orally active

Adapted from: Schomig A. NEJM. 2009;361(11):1108-1111.

Inhibition of Platelet Aggregation (Mean ± SEM, 20 µM ADP)

ADP=adenosine diphosphate Clop=clopidogrel Pras=prasugrel Inhibition of Platelet Aggregation (%) 20 40 60 80 100 Loading Dose Maintenance Doses 2 3 4 5 6 7 8 9 1 2 3 4 5 6 ‡ * * * * * * * * * * * * † † ‡ ‡ ‡ * Days Time Day 1, Hours Clopidogrel Clopidogrel Prasugrel 10 mg 300 mg 600 mg 75 mg Jakubowski et al. Cardiovasc Drug Rev. 2007;25:357-374. 60 mg *P<.001 vs Clop 300 mg 600 mg and 75 mg †P <.05 vs Clop 300 mg/75 mg ‡P <.001 vs Clop 300 mg/75 mg

Inhibition of platelet aggregation P2Y12 Receptor Antagonists

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 NSTE ACS < 72 hrs STEMI < 12 hrs

CURE

Clopidogrel

PLATO

Ticagrelor

Presentation Selective Invasive Early Invasive Coronary Angiography CABG PCI Medical Management

TRITON

Prasugrel

Symptom Onset

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.

CURRENT

Clopidogrel

Medical

TRILOGY

Prasugrel

5 10 15 90 180 270 360 450 HR=0.81 (0.73–0.90) p=0.001 Prasugrel Clopidogrel

Days after randomization Endpoint (%)

12.1 9.9 HR=1.32 (1.03–1.68) p=0.03 Prasugrel Clopidogrel 1.8 2.4

138 events 35 events

TIMI major Non-CABG bleeding NNT=46

Prasugrel + ASA: Residual risk of ischaemic events remains

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.

TRITON TIMI-38

CV death, MI or stroke

Ticagrelor + ASA: Residual risk of ischaemic events remains

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.

• No. at risk

Ticagrelor 9333 8628 8460 8219 6743 5161 4147 Clopidogrel 9291 8521 8362 8124 6650 5096 4047

Primary efficacy endpoint – time to first occurrence Time to non-procedural-related major bleeding

PLATO

9.8 Months after randomization

2 4 6 8 10 12 12 11 10 9 8 7 6 5 4 3 2 1 13

Cumulative incidence (%) 11.7

HR=0.84 (95% CI 0.77–0.92), p=0.001

Clopidogrel Ticagrelor CV death, MI or stroke

9235 7641 7274 6979 5496 4067 3698 9186 7718 7371 7134 5597 4147 3764

2.31 3.06 Ticagrelor Clopidogrel

4 3 2 1 0 0 2 4 6 8 10 12

Months after randomization

HR=1.31 (95% CI 1.08–1.60), p=0.006

K–M estimated rate (% per year) Ticag (n=9,333) Clopid (n=9,291) P value✝ MI 5.8% 6.9% 0.005 CV death 4.0% 5.1 0.001 Stroke 1.5% 1.3% 0.22 Total Death 4.5% 5.9% <0.001

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

Antiplatelet Therapy for Secondary Prevention in the First Year Following NSTEACS

• 3. We recommend prasugrel 10 mg daily over clopidogrel 75 mg daily for 12 months

in addition to ASA 81 mg daily in P2Y12 inhibitor-naive patients with NSTEACS after their coronary anatomy has been defined and PCI planned (Strong Recommendation, High Quality Evidence)

• 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 New

Bleeding in Perspective (Danish Registry – 82, 000)

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

ASA, acetylsalicylic acid; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction; VKA, vitamin K antagonist. Dewilde et al. Lancet 2013, Epub Feb 12

Primary endpoint: bleeding events

VKA + clopidogrel VKA + clopidogrel + ASA

Cumulative incidence (%)

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 2013, Epub Feb 12

ATLAS ACS 2-TIMI 51: a randomized, double-blind, event-driven Phase III trial in patients hospitalized with ACS

*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 2011;161:815–21.e6; 2. Mega et al. N Engl J Med 2012;366:9–19.

ASA dose: 75–100 mg

Event-driven study – 983 events

Physician's decision whether or not to add thienopyridine

N=15,526*

Rivaroxaban 2.5 mg bid (n=349)

Stratum 1: ASA alone (7%)

Stratum 2: ASA + thienopyridine (93%)

Placebo (n=355) Rivaroxaban 5 mg bid (n=349) Rivaroxaban 2.5 mg bid (n=4825) Rivaroxaban 5 mg bid (n=4827) Placebo (n=4821)

YES NO

ATLAS ACS 2-TIMI 51: Rivaroxaban (combined doses) reduced the primary efficacy endpoint vs placebo

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 2012;366:9–19.

Months after randomization HR=0.84 (0.74–0.96) ARR=1.7% mITT p=0.008 ITT p=0.002 NNT=56 10.7% 8.9% 2-year Kaplan–Meier estimate Estimated cumulative rate (%) Rivaroxaban Placebo 12 15 10 8 6 4 2 21 12 9 3 24 Primary efficacy endpoint (CV death/MI/stroke) Combined rivaroxaban doses, both strata 6 18

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

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 2012;366:9–19; 2. Gibson et al. AHA 2011 (www.clinicaltrialresults.org).

Cardiovascular death All-cause death CV death/MI/stroke (primary efficacy endpoint) 5 13 Months NNT=71 24 4.1% 2.7% Placebo Rivaroxaban 2.5 mg bid HR=0.66 mITT p=0.002 ITT p=0.005 18 12 6 5 Months 4.5% 2.9% 24 Placebo Rivaroxaban 2.5 mg bid HR=0.68 mITT p=0.002 ITT p=0.004 18 12 6 NNT=63 Months

Cumulative incidence (%)

HR=0.84 mITT p=0.02 ITT p=0.007 10.7% 9.1% Rivaroxaban 2.5 mg bid Placebo 24 18 12 6 NNT=63

ATLAS ACS 2-TIMI 51: Rivaroxaban did not increase fatal bleeding or fatal ICH versus placebo

*p=0.04 vs placebo; #p=0.005 vs placebo; ‡p<0.001 vs placebo. bid, twice daily; CABG, coronary artery bypass graft; ICH, intracranial haemorrhage; NS, not significant.

• 1. Mega et al. N Engl J Med 2012;366:9–19; 2. Gibson et al. AHA 2011 (www.clinicaltrialresults.org).

Rivaroxaban vs placebo p=NS Rivaroxaban vs placebo p=NS

2-year Kaplan–Meier estimate (%)

*

# ‡ ‡

(principal safety outcome)

Adoption of novel therapies in Canada

• Prasugrel - TRITON-TIMI 38 – published in 2007

– Health Canada approval – April 16, 2010

• Selected clinical usage
• Ticagrelor - PLATO – published in 2009

– Health Canada approval – May 30, 2011

• Regional variation in Coverage
• Significant issues with provincial and regional

formulary coverage and reimbursement

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