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