105/03/11 急性冠心症的治療趨勢

急性冠心症治療新趨勢 國軍高雄總醫院左營分院 心臟內科劉開璽醫師 高雄市醫師公會 105-3-11

Early risk stratification for NSTE-ACS 2014 ACC/AHA NSTE-ACS

JACC 2014 doi: 10.1016/j.jacc.2014.09.017

2012 ESC NSTE-ACS

Eur Heart J. 2011; 32: 2999-3054 3

Troponin I levels to predict the risk of mortality in ACS

4

N Engl J Med 1996;335:1342

GRACE risk score vs. TIMI risk score

6

Comparison of TIMI and GRACE risk scores The GRACE scores provided superior discrimination as compared with the TIMI scores

In-hospital mortality

7

6-month mortality

PLoS One 2009; 4: e7947

Regardless of How ACS Presents, Post-discharge Mortality Remains High 7

GRACE REGISTRY ST depression

Cumulative Mortality (%)

6 5

ST elevation

4 Neither

3 2

≈ 15% Overall mortality at 1 year

1 0

16 26 36 46 56 66 76 86 96 106 116 126 136 146 156 166 176 186

Days From Admission Post-discharge mortality (GRACE registry).

Fox KAA, et al. Nat Clin Pract Cardiovasc Med. 2008;5:580–589.

Tang EW, et al. Am Heart J. 2007;153:29–35.

Benefit of routine early invasive angiography

Patient level metaanalysis of routine vs selective angiography in NSTEACS JACC 2010; 55(22): 2435– 2445

Benefit of early angiography: TIMACS trial Mehta SR et al. N Engl J Med 2009;360:2165-2175.

Impact of Delay to Angioplasty : Analysis From the ACUITY Trial JACC 55(14) 2010 1416 - 1424

2015 ESC NSTEACS Guidelines Invasive Management

European Heart Journal 2015

2015 ESC NSTEACS Guidelines Invasive Management

European Heart Journal 2015

2015 ESC NSTEACS Guidelines Invasive Management

European Heart Journal 2015

Classifying ACS

ACS NSTEACS

STEMI

STEMI: Acutely blocked artery, rapidly dying heart muscle

STEMI: Acutely blocked artery, rapidly dying heart muscle

Treatment aim: • Prevent death • Limit extent of myocardial damage • Minimise patient discomfort and stress

Treatment strategy: Re-establish myocardial reperfusion before irreversible damage occurs

Potential Myocardial Salvage, (%)

STEMI is a TIME CRITICAL event 100 80 Gersh BJ, et al. JAMA . 2005;293:979986.

60 40 20 0

0

4 8 12 16 20 24 Time From Symptom Onset to Reperfusion Therapy (hours)

Time Delay to Treatment & Mortality Risk Zwolle AMI Study Group 1994-2001 n = 1791 G.De Luca Circulation. 2004

Early recognition, rapid transport and treatment is absolutely vital 1. Every minute delay in Rx affects mortality in both Thrombolytic & 1o PCI groups.

2. Every 300 min delay = Relative

in 1 year mortality by 7.5%.

Treatment Delayed is Treatment Denied

Symptom Recognition

Call to Medical System

PreHospital

ED

Cath Lab

Increasing Loss of Myocytes Delay in Initiation of Reperfusion Therapy

Traditional AMI Communication Strategy: Patient with CP

Ambulance

Transports Patient to ED

Patient Triaged in ED

12 Lead ECG Performed by ED Staff

Diagnosis Made

ED Resident/Registrar or Consultant

Calls Cardiology Registrar

Cardiology Registrar sights ECG & calls

CCU Ward Service Consultant

Interventional Cardiologist Contact

Infarct Team Activated

ESC STEMI Reperfusion Guidelines

European Heart Journal 2014

Pre-Hospital Cath Lab Activation Strategy: Patient with CP

ED notified

Ambulance Attends & Performs 12 Lead ECG On Site

Interventional Cardiologist Contacted

Ambulance administers heparin, aspirin and ticagrelor, Transports Patient directly to Cath Lab

Infarct Team Ready & Waiting in Cath Lab

Reasons for pretreatment  Early administration of antiplatelet and antithrombotic agents can lead to reperfusion prior to PCI in some patients  Optimal inhibition of platelets at the time of PCI desirable to avoid ischemic complications; however, in STEMI there is delayed absorption / onset of action of ADPreceptor antagonists  Optimal platelet inhibition at PCI might improve longterm outcome

The ATLANTIC Study STE –ACS planned for PCI

N = 1770

RANDOMIZE DOUBLE BLIND

Ticagrelor 180mg loading dose Loading dose placebo

•Written informed consent in mobile care unit •Symptoms of acute MI of more than 30 min but less than 6 hours •New persistent ST-segment elevation ≥ 1 mm in two or more contiguous ECG leads

Pre-Hospital

Loading dose placebo

In-Hospital

Ticagrelor 180mg loading dose

- -TIMI TIMIflow flowgrade grade33of ofMI MIculprit culpritvessel vesselatatinitial initialangiography angiographyor or - -≥70% ≥70%ST-segment ST-segmentelevation elevationresolution resolutionpre-PCI pre-PCI

Ticagrelor 90mg/bid Ticagrelor 90mg/bid

Primary PrimaryObjective: Objective:

30d

Median times to pre- and in-hospital steps Randomization Onset of Symptoms

EKG Pre-hospital

LD1

LD2

EKG Pre-PCI

Angiography

PCI

Co-primary efficacy endpoints (mITT) Absence of ST-segment elevation ≥70% AND/OR

Absence of TIMI flow grade 3 in infarct-related artery Pre-hospital In-hospital

p=NS

p=NS

• •

Pre-PCI† – Pre-hospital n=719 – In-hospital n=751 Post-PCI‡ – Pre-hospital n=684 – In-hospital n=703

Pre-PCI

Post-PCI

ATLANTIC VASP-Substudy

Definite stent thrombosis up to 30 days P=0.0078

P=0.0225

Ticagrelor pre-hospital 2/906 (0.2%) versus Ticagrelor in-hospital 11/952 (1.2%) OR 0.19 (95% CI 0.04, 0.86), P=0.0225

24 hrs

30

days

2014 ESC Revascularisation Guidelines

European Heart Journal (2014) Online 29 August 2014

ESC STEMI Reperfusion Guidelines

European Heart Journal 2014

ESC STEMI Reperfusion Guidelines

European Heart Journal 2014

Rapid Transfer Strategy: QAS Patient with CP

diagnoses STEMI Thrombolysis

Regional DEM (Thrombolysis)

Triage on arrival at Tertiary Hospital: Direct to lab if failed reperfusion.

Otherwise to lab within 24 hours

Transport services and Tertiary Hospital notified, ‘immediate’ transfer arranged

Ongoing treatment for all ACS patients

~1 in 5 patients with ACS will have died within 5 years of their index event •

GRACE study: Analysis of UK and Belgian patients with ACS

Fox KA, et al. Eur Heart J 2010;31:2755–2764.

STEMI: The highest risk of recurrent MI occurs in the first 6 months post STEMI, but the risk is continuous and linear up to Year 5 •

Investigation of clinical outcomes after recurrent MI in STEMI patients who underwent PCI with up to 5 years of follow-up (n=1700)

Cumulative incidence of recurrent MI (%)

20 15 10 5 0 0

Kikkert WJ, et al. Am J Cardiol 2014;113:229–235.

1

2 3 4 Time from initial PCI (years)

5

Much of the ongoing risk is due to new plaque rupture and thrombotic occlusion of the artery

Current ACS strategies target the activated platelet

– Adhesion – Activation

3

– Aggregation 2 1

Activated platelets lead to thrombus formation

Activated platelets aggregate covering the thrombus surface

Plaque rupture leads to platelet adhesion to the exposed subendothelium [Adapted from Davies 2000: A]

Vorchheimer DA, et al. Mayo Clin Proc. 2006;81:59-68; Davies MJ. Heart. 2000;83:361-366.

Platelet Activation

Platelet Pathway

ADP

Platelet activation

Platelet aggregation

Collagen TXA2

THROMBUS

Event rate of CV death, MI or stroke in the first year post event remains ~12% on best treatment 25

CV death, MI or stroke Major bleeding

Event rate (%)

20 –25%

15

–20%

10 5 0

20.0

0.8

None

15.0

1.3

ASA1,2

11.7

2.2*

ASA + clopidogrel3

ASA + ticagrelor3

*Major bleeding: non-CABG-related TIMI major bleeding 1. Antiplatelet Trialists' Collaboration, 1994; 2. Antithrombotic Trialists' Collaboration, 2002; 3. Wallentin et al, 2009

Limitations of Clopidogrel

 Moderate overall levels of platelet inhibition – Average IPA ~55%

 Highly variable individual response – 25-30% with very low levels of platelet inhibition

 Slow onset of antiplatelet effect – Takes 4-6 hours from loading to reach peak inhibition

Variability in Inter-Individual Clopidogrel Response

Hochholzer, et al. Circulation. 2005;111:2560-2564.

Clopidogrel has major limitation in terms of CYP2C19 genetic polymorphism CYP2C19 表現型和基因型頻率 黃種人 (n= 573)

白種人 (n= 1356)

緩和代謝 : CYP2C19*2/*2, *2/*3 or *3/*3

14%

2%

中等代謝 : CYP2C19*1/*2 or *1/*3

50%

26%

快速代謝 : CYP2C19*1/*1

38%

74%

FDA WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS

1.

2.

保栓通衛生署核准仿單 Highlights of prescribing information, PLAVIX

BRILINTA: Does Not Require Hepatic Metabolism for Activation BRILINTA: Does NOT require metabolic activation to become active drug

BRILINTA Binding

Platelet

P2Y12

Clopidogrel

Active compound

CYP-dependent oxidation CYP1A2 CYP2B6 CYP2C19

CYP-dependent oxidation CYP2C19 CYP3A4/5 CYP2B6

Intermediate metabolite Prodrug

Clopidogrel: A prodrug; requires metabolism to become active drug

Adapted from Schomig A. N Engl J Med. 2009;361:1108–1111.

2011 ESC NSTE ACS Guideline

ONSET/OFFSET: Pharmacodynamics in Stable CAD Patients 100

Loading Dose

90

180 mg 600 mg

80

*

*

*

*

Last Maintenance Dose 90 mg bid 75 mg qd

*

IPA %

70

*

//

*

BRILINTA (n=54)

†

Clopidogrel (n=50)

*

60 50

//

*

40

‡

30

†

20 10 0 0 P<0.0001 P<0.005 ‡ P<0.05 *

†

0.5

1

2

Onset

4

Time (Hours)

8

24

//

6 weeks

Maintenance

0

2

4

8

24

48 72 120 168 240

Offset Time (Hours)

PLATO Study PLATO study tested the hypothesis that… ticagrelor will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS as compared to clopidogrel and this would be achieved with a clinically acceptable bleeding rate and overall safety profile

PLATO Study: • 43 countries • 862 sites • 18,624 patients

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

Ticagrelor â&#x20AC;&#x201C; MI and mortality benefit over Clopidogrel Myocardial infarction 7

Clopidogrel

Ticagrelor

5 4 3 2 1

HR 0.84 (95% CI, 0.75-0.95) P=0.005

0 0

2

4

6

8

10

Months after randomisation

6.9

7

5.8

6

Cumulative incidence (%)

Cumulative incidence (%)

6

Cardiovascular death

12

Clopidogrel

5.1

5

4.0

4 Ticagrelor 3 2 1 0

HR 0.79 (95% CI, 0.69-0.91) P=0.001 0

2

4

6

8

10

Months after randomisation

12

*The rate of stroke did not differ significantly between the two treatment groups PLATO NEJM 2009

PLATO Substudies Ticagrelor Clopidogrel Group Group

HR for (95% CI)

p

p*

MI / CV Death / Stroke, K-M % PLATO (n=18,624)

9.8

11.7

0.84 (0.74-0.92) <0.001

PLATO-INVASIVE (n=13,408) PLATO-MEDICAL (n=5,216) PLATO-STEMI (n=8,430) PLATO-CABG (n=1,261) PLATO-DIABETES No Diabetes (n=13,951) Diabetes (n=4,662) PLATO-GENETICS No CYP2C19 loss of function allele (n=3554) Any CYP2C19 loss of function allele (n=1384)

9.0 12.0 9.3 10.5

10.7 14.5 11.0 12.6

0.84 (0.75-0.97) 0.85 (0.73-1.00) 0.85 (0.74-0.97) 0.84 (0.60-1.16)

<0.01 0.04 0.02 0.29

8.4 14.1

10.2 16.2

0.83 (0.74-0.93) 0.88 (0.76-1.03)

<0.05 >0.05

0.49

8.8 8.6

10.0 11.2

0.86 (0.74-1.01) 0.77 (0.60-0.99)

>0.05 <0.05

0.46

* p for interaction

Plato: Results in Asia

PLATO Asian Substudy: AHJ 2015;169:899-905

Ticagrelor reduces mortality in medically treated patients just as much as in PCI treated All-cause mortality (%)

Non-invasive HR, 0.75, 95% CI: (0.61â&#x20AC;&#x201C;0.93)

Number at risk Invasive Ticagrelor Clopidogrel Non-invasive Ticagrelor Clopidogrel

Invasive HR, 0.81, 95% CI: (0.68â&#x20AC;&#x201C;0.95)

Days after randomization 6732 6676

6439 6376

6375 6331

6241 6209

5141 5114

3951 3917

3233 3164

2601 2615

2485 2488

2447 2448

2385 2380

1978 1965

1531 1524

1186 1200

James S et al. , BMJ 2011;342

No Increased bleeding in medically treated patients Total major bleeding (%)

20 Non-invasive HR, 1.17, 95% CI: (0.98â&#x20AC;&#x201C;1.39)

15 10 5

Invasive HR, 0.99, 95% CI: (0.89â&#x20AC;&#x201C;1.39)

0 0 Number at risk Invasive Ticagrelor Clopidogrel Non-invasive Ticagrelor Clopidogrel

60

120

180

240

300

360

Days after randomization 6651 6585

5238 5220

4948 4985

4766 4798

3730 3756

2748 2760

2521 2507

2584 2601

2008 2085

1878 1945

1779 1872

1399 1453

1035 1081

912 972

James S et al. , BMJ 2011;342

Ticagrelor Indication

â&#x20AC;˘

Ticagrelor, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndromes (unstable angina, nonâ&#x20AC;&#x201C;ST-elevation myocardial infarction [NSTEMI] or ST-elevation myocardial infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)

If clinically indicated, ticagrelor should be used with caution in the following patient groups: Patients with concomitant administration of medicinal products that may increase the risk of bleeding (eg, non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing

BRILIQUE: Summary of Product Characteristics, 2010.

Event rate of CV death, MI or stroke in the first year post event can now be <10% on best treatment 25

CV death, MI or stroke Major bleeding

Event rate (%)

20 –25%

15

–20% –16%

10 5 0

20.0

0.8

None

15.0

1.3

ASA1,2

11.7

2.2*

ASA + clopidogrel3

9.8

2.8*

ASA + ticagrelor3

*Major bleeding: non-CABG-related TIMI major bleeding 1. Antiplatelet Trialists' Collaboration, 1994; 2. Antithrombotic Trialists' Collaboration, 2002; 3. Wallentin et al, 2009

The Adenosine effect

ď Ź Does ticagrelor do more than just inhibit platelets?

Ticagrelor increases adenosine plasma concentrations

61 J Am Coll Cardiol 2014; 63(9): 872-877

Confidential for AstraZeneca Discussion Purposes Only

Ticagrelor Increases Serum Adenosine Levels •

Plasma adenosine levels are increased in patients on ticagrelor

•

Adenosine has a number of physiological effects: – – – –

Coronary microvascular dilation / hyperaemia Bradycardia Dyspnoea Anti-inflammatory?

•

Adenosine is used clinically to cardiovert SVT, and to induce coronary vasodilation for perfusion studies and FFR

•

Dyspnoea often occurs in patients administered intravenous adenosine 62 Confidential for AstraZeneca Discussion Purposes Only

PLATO: Dyspnoea

• • • • •

BRILINTA-associated dyspnoea was mostly mild to moderate in severity and did not reduce efficacy Most events were reported as single episode occurring early after starting treatment Not associated with new or worsening heart or lung disease In 2.2% of patients, investigators considered dyspnoea causally related to treatment with BRILINTA Label precautions and warnings: use with caution in patients with history of asthma and COPD

BRILIQUE: Summary of Product Characteristics, 2010.

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

Storey R, et al. J Am Coll Cardio. 2010;55(Suppl 1):A108.E1007.

How does Ticagrelor increase Adenosine Levels?

?

?

?

ADP, adenosine diphosphate; AMP, adenosine monophosphate; AMPD, adenosine monophosphate deaminase; ATP, adenosine triphosphate; ENT-1, equilibrative nucleoside transporter-1; IMP, inosine monophosphate.

64 King AE, et al. Trends Pharmacol Sci 2006;27:416â&#x20AC;&#x201C;425; Van Giezen JJ, et al. J Cardiovasc Pharmacol Ther 2012;17:164â&#x20AC;&#x201C;172.

Confidential for AstraZeneca Discussion Purposes Only

Ticagrelor inhibits adenosine uptake via the nucleoside transporter ENT-1

?

?

?

*Ticagrelor bound to ENT-1.

ADP, adenosine diphosphate; AMP, adenosine monophosphate; AMPD, adenosine monophosphate deaminase; ATP, adenosine triphosphate; ENT-1, equilibrative nucleoside transporter-1; IMP, inosine monophosphate.

65 King AE, et al. Trends Pharmacol Sci 2006;27:416â&#x20AC;&#x201C;425; Van Giezen JJ, et al. J Cardiovasc Pharmacol Ther 2012;17:164â&#x20AC;&#x201C;172.

Confidential for AstraZeneca Discussion Purposes Only

Ticagrelor improves peripheral endothelial function in stable ACS patients [Torngren 2013]

No P2Y12 inhibitor (n=35) Ticagrelor 90 mg BID (n=25) Clopidogrel 75 mg QD (n=35) Prasugrel 10 mg QD (n=32)

*

*p<0.05 versus control; â&#x20AC; Endothelial dysfunction defined as RHI <1.67.

68 ACS, acute coronary syndromes; ASA, acetylsalicylic acid; BID, twice daily; QD, once daily; RHI, reactive hyperaemia index.

Torngren K, et al. Cardiol 2013;124:252â&#x20AC;&#x201C;258.

Confidential for AstraZeneca Discussion Purposes Only

ESC STEMI Guidelines 2012 STEMI treated with Primary PCI

European Heart Journal (2012) 33, 2569â&#x20AC;&#x201C;2619

2015 ESC NSTEACS Guidelines Antiplatelet Treatment

European Heart Journal 2015

How long should DAPT continue? ď Ź Keys considerations: clinical context (stable disease vs ACS, atheroma burden), risk of further events, risk of bleeding ď Ź Modern generation DES have low risk of stent thrombosis, and for patients undergoing PCI for stable disease, shorter periods of DAPT (as little as 1-3 months) appears safe

Ischemic Endpoints By DAPT Duration In (Small) Randomized Trials EXCELLENT t 6 mos (n=957) 12 mos (n=970)

*Cardiac death / MI / TVR **Death / MI, CVA, Revasc ***Death/MI/Revasc

PRODIGY tt 6 mos (n=1546) 24 mos (n=1500)

REAL-LATE/ ZEST-LATE ttt 12 mos (n=1344) 24 mos (n=1357)

Adapted from

OPTIMIZE tttt 3 mos (n=1563) 12 mos (n=1556)

t Gwon et al. ACC 2011 tt Valgimigli et al. ESC 2011 ttt Park et al. NEJM 2010;362:1374 tttt Feres et al. TCT 2013 LBCT

How long should DAPT continue?

Cumulative Incidence (%)

PLATO: Primary Efficacy Endpoint (Composite of CV Death, MI, or Stroke) 13 12 11 10 9 8 7 6 5 4 3 2 1 0

0–30 Days

11.7 Clopidogrel 9.8

RRR=16% NNT=54* P<0.001 HR: 0.84 (95% CI, 0.77–0.92)

2

4

6

8

10

12

Months After Randomization

No. at risk

Clopidogrel

Ticagrelor

ARR=1.9%

0 BRILINTA

0–12 Months

9,333

8,628

8,460

8,219

6,743

5,161

4,147

9,291

8,521

8,362

8,124

6,650

5,096

4,047

Both groups included aspirin. *NNT at one year.

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

How long should DAPT continue?

9,961 PCI patients: 12 vs 30 months DAPT In the DAPT Study, 30 months of dual antiplatelet therapy reduced ischemic complications after coronary stenting compared to 12 months.

Cumulative Incidence of Stent Thrombosis

10%

Thienopyridine Placebo

8%

6%

Stent StentThrombosis Thrombosis HR HR0.29 0.29(0.17-0.48) (0.17-0.48) 0.4% 0.4%vs. vs.1.4%, 1.4%, P<0.001 P<0.001

10% Cumulative Incidence of Death, Myocardial Infarction or Stroke

•

4%

2%

0% 12

15

18

21

24

27

30

MACCE MACCE HR HR0.71 0.71(0.59-0.85) (0.59-0.85) 4.3% 4.3%vs. vs.5.9%, 5.9%, P<0.001 P<0.001

Thienopyridine Placebo

8%

6%

4%

2%

0% 33 12

Months After Enrollment

15

18

21

24

27

30

33

Months After Enrollment

•

Continuing DAPT beyond 12 months reduced both stent thrombosis and MACE (death, MI, stroke)

•

Moderate or Severe Bleeding was increased 2.5% vs. 1.6%, p = 0.001 Mauri, Kereiakes, Yeh et al. NEJM. 2014 Dec 4:371:2155-66.

76

77

PEGASUS-TIMI 54: Study Design Patients aged ≥50 years with a history of spontaneous MI 1–3 years prior to enrolment AND at least one additional atherothrombosis risk factor* (N=21,162)

Ticagrelor 90 mg bid + ASA 75–150 mg/day

Ticagrelor 60 mg bid + ASA 75–150 mg/day

Placebo + ASA 75–150 mg/day

Minimum of 12 months’ follow up: Every 4 months in Year 1, then semi-annually Primary efficacy endpoint: CV death, MI or stroke Primary safety endpoint: TIMI-defined major bleeding *Age ≥65 years, diabetes mellitus, second prior MI, multivessel CAD or chronic non-end stage renal disease bid, twice daily; CAD, coronary artery disease; TIMI, Thrombolysis in Myocardial Infarction Bonaca MP et al. Am Heart J 2014;167:437–444 Bonaca MP et al. N Engl J Med 2015 [Epub ahead of print]

78

78

Confidential for AstraZeneca Discussion Purposes Only

PEGASUS-TIMI 54: Primary Endpoint 10

Placebo Ticagrelor 90 mg bid Ticagrelor 60 mg bid

Event rate (%)

9

9.04% Placebo

8

7.85% 90 mg bid

7

7.77% 60 mg bid

6 5 4 3

Ticagrelor 90 mg vs placebo HR 0.85 (95% CI 0.75–0.96) P=0.008

2

Ticagrelor 60 mg vs placebo HR 0.84 (95% CI 0.74–0.95) P=0.004

1 0 0 No. at risk Placebo 90 mg bid 60 mg bid

3

6

9

12

15

18

21

24

27

30

33

36

5876 5921 5904

5157 5243 5222

4343 4401 4424

3360 3368 3392

2028 2038 2055

Months from randomisation 7067 7050 7045

6979 6973 6969

6892 6899 6905

6823 6827 6842

6761 6769 6784

6681 6719 6733

6508 6550 6557

6236 6272 6270

CI, confidence interval; HR, hazard ratio Bonaca MP et al. N Engl J Med 2015 [Epub ahead of print]

79

79

Confidential for AstraZeneca Discussion Purposes Only

PEGASUS-TIMI 54: Efficacy Endpoints 3-year KM event rates (%)

Endpoint

Ticagrelor

Primary (CV death, MI or stroke) CV death

MI

Stroke

0.4

0.6

0.8

Ticagrelor better

1

1.25

Placebo

HR (95% CI)

P value

7.85

9.04

0.85 (0.75–0.96)

0.008

7.77

9.04

0.84 (0.74–0.95)

0.004

7.81

9.04

0.84 (0.76–0.94)

0.001

2.94

3.39

0.87 (0.71–1.06)

0.15

2.86

3.39

0.83 (0.68–1.01)

0.07

2.90

3.39

0.85 (0.71–1.00)

0.06

4.40

5.25

0.81 (0.69–0.95)

0.01*

4.53

5.25

0.84 (0.72–0.98)

0.03*

4.47

5.25

0.83 (0.72–0.95)

0.005*

1.61

1.94

0.82 (0.63–1.07)

0.14*

1.47

1.94

0.75 (0.57–0.98)

0.03*

1.54

1.94

0.78 (0.62–0.98)

0.03*

1.67

Placebo better

Ticagrelor 90 mg bid Ticagrelor 60 mg bid Ticagrelor pooled

*Indicates nominal P value; P<0.026 indicates statistical significance Bonaca MP et al. N Engl J Med 2015 [Epub ahead of print]

80

80

Confidential for AstraZeneca Discussion Purposes Only

3-year KM event rate

PEGASUS-TIMI 54: Bleeding

P<0.001 2.6 2.3

P<0.001 1.1

1.3

P=NS

P=NS

0.6 0.7 0.6

0.6 0.6 0.5

P=NS

1.2

0.4

0.1

0.3 0.3

Rates are presented as 3-year Kaplan-Meier estimates P<0.026 indicates statistical significance Bonaca MP et al. N Engl J Med 2015 [Epub ahead of print]

81

81

Confidential for AstraZeneca Discussion Purposes Only

Benefit is greater in those at higher risk

82 PEGASUS Renal Sub-study EHJ 2015; (online Oct 5)Only Confidential for AstraZeneca Discussion Purposes

Benefit is greater if DAPT is continued without interruption

83 Presented atfor ESC Congress, London, UK September 2015Only Confidential AstraZeneca Discussion Purposes

Need to consider patientâ&#x20AC;&#x2122;s ischaemia and bleeding risk to decide DAPT duration

84 Montalescot and Sabatine, EHJ 2015Only Confidential for AstraZeneca Discussion Purposes

Patients with prior MI have the greatest benefit from long-term DAPT

85 Montalescot and Sabatine, EHJ 2015Only Confidential for AstraZeneca Discussion Purposes

Need to consider patientâ&#x20AC;&#x2122;s ischaemia and bleeding risk to decide DAPT duration

86 Montalescot and Sabatine, EHJ 2015Only Confidential for AstraZeneca Discussion Purposes

The Future…?

…Now we have ticagrelor, do we still need aspirin?

Global Leaders â&#x20AC;&#x201C; Ticagrelor alone vs. standard DAPT

GEMINI-ACS â&#x20AC;&#x201C;

Dual Pathway Therapy (DPT) vs DAPT Recent ACS

Stabilized >48 hours & <10 days from hospitalization for index event

ASA Stratify by MD decision to use either Clopidogrel or Ticagrelor

Clopidogrel (n=1500)

Ticagrelor (n=1500) R

R

Clopidogrel 75 mg qd + ASA 100 mg qd

Clopidogrel 75 mg qd + Rivaroxaban 2.5 mg bid

Ticagrelor 90 mg bid + ASA 100 mg qd

Ticagrelor 90 mg bid + Rivaroxaban 2.5 mg bid

Minimum 180; Maximum 360, Day F/U PRIMARY ENDPOINT: TIMI clinically significant bleeding EXPLORATORY EFFICACY ENDPOINT: Composite of CV death, MI, ischemic stroke, or stent thrombosis

Summary ď Ź Following an MI, there is a high ongoing risk â&#x20AC;&#x201C; 1 in 5 patients die or have another MI within one year

Summary

Summary

Summary

Summary

Summary  There is ongoing protection with continuing ticagrelor treatment – in the PLATO study, the magnitude of benefit continued to increase throughout the first year post-ACS – The Pegasus trial confirmed that continuing therapy beyond 1 year leads to ongoing benefit, especially in patients with high ischaemic risk (eg large atheroma burden, extensive stenting, renal impairment)

 Ticagrelor has proven to be such a highly effective antiplatelet agent, ongoing research is now focused on whether we still need aspirin

感謝聆聽

Thank You