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

0

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

Pati

ents

(%

)

STEMI Troponin assay used

NSTEMI

In-hospital mortality

Year

9

10

11

12

8

7

6

5

4

Hosp

ital

mort

ali

ty (

%)

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

0

2

4

6

8

10

Hosp

ita

l m

orta

lity

(%

)

30 90 120 180 60 150 0

Days

STEMI

NSTEMI

Unstable angina

Death from hospital discharge

to 6 months

0 30 90 120 180 60 150

Days

0

3

6

9

12

15

Death from hospital admission

to 6 months

STEMI

NSTEMI

Unstable angina

Hosp

ita

l m

orta

lity

(%

)

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

21

9.2

0

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

0

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.

Morta

lity

(%

)

Days from randomization

0 30 60 90 120 150 180 210 240 270 300 330 360 390

0

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

Mo

rtality

(%

)

Currently Available Antiplatelet Agents

METABOLISM OF P2Y12 RECEPTOR ANTAGONISTS

Ticagrelor

Prasugrel

Clopidogrel

Hydrolysis by esterase

Orally active

CYP-dependent oxidation CYP3A4/5

CYP-dependent oxidation 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

Inh

ibit

ion

of

Pla

tele

t A

gg

reg

atio

n (

%)

0

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

0

5

10

15

0 90 180 270 360 450

HR=0.81

(0.73–0.90)

p=0.001

Prasugrel

Clopidogrel

Days after randomization

En

dp

oin

t (%

)

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

0 2 4 6 8 10 12

12

11

10

9

8

7

6

5

4

3

2

1

0

13

Cu

mu

lati

ve i

ncid

en

ce (

%) 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

esti

mate

d r

ate

(% p

er

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

Cu

mu

lati

ve in

cid

en

ce (

%)

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

Est

ima

ted

cu

mu

lati

ve r

ate

(%

)

Rivaroxaban

Placebo

12

0

0 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

0

Months

NNT=71

0 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

0

5

Months

4.5%

2.9%

24 0

Placebo

Rivaroxaban

2.5 mg bid

HR=0.68

mITT p=0.002

ITT p=0.004

18 12 6

NNT=63

Months

Cu

mu

lati

ve i

ncid

en

ce (

%)

HR=0.84

mITT p=0.02

ITT p=0.007 10.7%

9.1%

Rivaroxaban

2.5 mg bid

Placebo

0

24 0 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-y

ear

Kap

lan–M

eie

r

esti

mate

(%

)

*

#

‡

‡

(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