Surveying the Landscape of Therapy in NSTE‐ACS
Yanina Purim-Shem-Tov, MD, MS, FACEPAssociate Professor
Medical Director, Chest Pain Center
Medical Director of Clinical Practice, Emergency Department
Rush University Medical Center
Chicago, IL
Disclosure
• No financial conflicts of interest
2
Goals and Objectives
• Epidemiology/ pathophysiology (brief)
• Recognize the clinical features of low, intermediate and high risk ACS
• Discuss pharmacological treatments (focus on antiplatelet therapy)
• Be able to identify and treat patients appropriate for a conservative or invasive strategy
3
Overview of ACS
Acute Coronary Syndromes*
1.57 Million Hospital Admissions - ACS
UA/NSTEMI† STEMI
1.24 millionAdmissions per year
0.33 millionAdmissions per year
*Primary and secondary diagnoses. †About 0.57 million NSTEMI and 0.67 million UA.Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007; 115:69–171.
4
Pathophysiology of ACSEvolution of Coronary Thrombosis
Davies MJ. Circulation. 1996;94:2013
Pathogenesis of Acute Coronary Syndromes: The “Ruptured” Plaque
Fissures inthe fibrous cap
6
Distal embolization in the setting of a ruptured plaque is the most likely cause of troponin elevation
Greater troponin elevation is associated with a more extensive plaque rupture event and more associated thrombus
Distal Embolization:Pathogenesis of Troponin Elevation in
NSTEMI
7
Evidence for Distal EmbolizationArteriole 100% occluded by a platelet thrombus
8
Unstable Angina STEMINSTEMI
Non occlusive thrombus
Non specific ECG
Normal cardiac enzymes
Non-occlusive thrombus sufficient to cause tissue damage & mild myocardial necrosis
ST depression +/-T wave inversion on ECG
Elevated cardiac enzymes
Complete thrombus occlusion
ST elevations on ECG or new LBBB
Elevated cardiac enzymes
More severe symptoms
Initial Evaluation and management of Non ST‐elevation ACS
Initial Evaluation and Management
•History and Physical•ECG•Cardiac Biomarkers
Establish the Likelihood thatClinical PresentationRepresents an ACSSecondary to CAD
Risk Stratify for Short-termAdverse Outcomes
10
Clinical Features of NSTEMI
11
12
Likelihood of ACS by Hx/PE
• History/Examination – Pain in Chest or Left Arm
– CP Radiation
• Right Shoulder
• Left Arm
• Both Left & Right Arm
– Diaphoresis
– 3rd Heart Sound
– SBP < 80 mm Hg
– Pulmonary Crackles
Panju AA. JAMA. 1998;280:1256.
Suggesting AMILR 2.7
LR 2.9 (1.4‐6.0)
LR 2.3 (1.7‐3.1)
LR 7.1 (3.6‐14.2)
LR 2.0 (1.9‐2.2)
LR 3.2 (1.6‐6.5)
LR 3.1 (1.8‐5.2)
LR 2.1 (1.4‐3.1)
13
Likelihood of ACS by Hx/PE
• Clinical Examination –– Pleuritic Chest Pain– Sharp or Stabbing Pain– Positional Chest Pain– Reproducible Chest Pain
Against AMI
LR 0.2 (0.2-0.3)
LR 0.3 (0.2-0.5)
LR 0.3 (0.2-0.4)
LR 0.2-0.4
Panju AA. JAMA. 1998;280:1256.
Risk Stratification by ECG
• ECG Findings and Associated LR for AMI
– New ST‐E > 1mm LR 5.7‐53.9
– New Q waves LR 5.3‐24.8
– Any ST‐E LR 11.2 (7.1‐17.8)
– New Conduction Defect LR 6.3 ( 2.5‐15.7)
– New ST‐D LR 3.0‐5.2
– NORMAL ECG LR 0.1‐0.4Panju AA. JAMA. 1998;280:1256.
CAVEATS 1‐8% AMI have a normal ECGOnly Approx 50% of AMI patients have diagnostic changes on their initial ECG1 ECG cannot exclude AMIBrief sample of a dynamic processSmall regions of ischemia or infarction may be missed
Peter J. Zimetbaum, M.D., N Engl J Med 2003;348:933‐40.
Risk Stratification by Troponin
17
18
Incremental Sensitivity for Detecting ACS within 30 days
Ann Emerg Med 2002; 40: 584-594
Early Invasive
Conservative
19
Medical Therapy
20
Antiplatelet Therapy
Mechanism of Action of Antiplatelet Agents
21
Bhatt D. N Engl J Med 2007;10.1056
Role of Platelet Activation and Aggregation in Acute Coronary Syndromes
22
Role of Platelet Activation and Aggregation in Acute Coronary Syndromes
Adhesion, Activation
Amplification Aggregation
Bhatt D. N Engl J Med 2007;10.105623
Mechanism of Action of Antiplatelet Therapies
Schafer AI: Am J Med 1996:101;199
Clopidogrel, Prasugrel (irreversible)
Ticagrelor (reversible)
GPIIb/IIIa Antagonists:Abciximab (irreversible)Eptifibatide, Tirofiban
(reversible)
Collagen, Thrombin
TXA2
GPIIbIIIa Receptor
24
25
Level or Treatment Recommendations
Antiplatelet Therapy
Aspirin
26
Mechanism of Action of Antiplatelet Therapies
Schafer AI: Am J Med 1996:101;199
Clopidogrel, Prasugrel (irreversible)
Ticagrelor (reversible)
GPIIb/IIIa Antagonists:Abciximab (irreversible)Eptifibatide, Tirofiban
(reversible)
Collagen, Thrombin
TXA2
GPIIbIIIa Receptor
27
UA/NSTEMI – Antiplatelet Therapy
ASA as soon as possible after presentation and continued indefinitely in patients who tolerate it
If ASA intolerant, clopidogrel, prasugrel (PCI) or ticagrelor(loading and maintenance dose)
28Jneid H et al. J Am Coll Cardiol 2012;60:645-81.
2012 ACCF/AHA UA/NSTEMI Focused Update
For both early invasive and conservative strategy
II IIaIIa
IIbIIb
IIIIII
A
B
ESC NSTEMI 2011:Recommendations for antiplatelet agents
Recommandations Class Level
Aspirin should be given to all patients without contraindications at an initial loading dose of 150-300 mg, and at a maintenance dose of 75-100 mg dailylong-term regardless of treatment strategy.
I A
European Heart Journal (2011) 32:2999–3054; doi:10.1093/eurheartj/ehr23630
NEJM and Lancet 2010 31
ASA 75‐100 mg
ASA300‐325 mg HR 95% CI P
CV Death/MI/Stroke
Overall (2N=25,087) 4.4 4.2 0.97 0.86‐1.09 .61
PCI (2N=17,232) 4.2 4.1 0.98 0.84‐1.13 .76
No PCI (2N=7855) 4.7 4.4 0.92 0.75‐1.14 .44
Stent thrombosis 2.1 1.9 0.91 0.73‐1.12 .37
TIMI major bleed 1.4 1.6 1.09 0.89‐1.34 .39
CURRENT major bleed 2.3 2.3 0.99 0.84‐1.17 .90
CURRENT severe bleed 1.7 1.7 1.01 0.84‐1.22 1.00
GI Bleeds: 19 (0.2%) vs. 47 (0.4%), P=.04
CURRENT–OASIS 7 Investigators. N Engl J Med. 2010;363(10):930‐942.
Results: ASA Dose ComparisonPrimary Outcome and Bleeding
32
Antiplatelet Therapy
Clopidogrel
33
Mechanism of Action of Antiplatelet Therapies
Schafer AI: Am J Med 1996:101;199
Clopidogrel, Prasugrel (irreversible)
Ticagrelor (reversible)
GPIIb/IIIa Antagonists:Abciximab (irreversible)Eptifibatide, Tirofiban
(reversible)
Collagen, Thrombin
TXA2
GPIIbIIIa Receptor
Thienopyridines and ticagrelor block the P2Y12 receptor and inhibit ADP-induced
platelet activation
34
Months of Follow‐up
Yusuf S et al. N Engl J Med. 2001;345:494‐502.
CURE Study Primary end point: MI/stroke/CV death
Clopidogrel + Aspirin(n=6259)
Placebo + Aspirin(n=6303)
P<0.001n=12,562
3 6 90 12
20%Relative RiskReduction
0.12
0.14
0.10
0.06
0.08
0.00
0.04
0.02Cumulative Hazard Rate
35
36
UA/NSTEMI – Antiplatelet Therapy
Before PCI, clopidogrel (300‐600 mg)
At the time of PCI, clopidogrel (if not begun earlier)
Duration of maintenance doseClopidogrel for at least 1yr
If risk of morbidity (bleeding) outweighs anticipated benefits, earlier discontinuation should be considered
Wright RS, et al. J Am Coll Cardiol 2011;57:1920–59.
2011 ACC/AHA UA/NSTEMI Focused Update Class I Recommendations (should be given, benefit >>> risk)
Early invasive strategy and conservative Rx with PCI
B
A
B
C
II IIaIIa IIIIIIII
IIbIIb
NEJM and Lancet 2010 37
Total population
PCI population
HR 0.86; P=0.039
CURRENT‐OASIS 7
38
High dose:600 mg load, 150 mg/day x 6d, then 75/dvs. Standard dose: 300 mg load, 75mg/d
NEJM and Lancet 2010
39
UA/NSTEMI – Antiplatelet Therapy
Clopidogrel 600 mg followed by a higher maintenance dose of 150 mg daily for 6 days, then 75 mg daily may be reasonable in patients not considered at high risk for bleeding
Wright RS, et al. J Am Coll Cardiol 2011;57:1920–59.
2011 ACC/AHA UA/NSTEMI Focused Update Class IIb Recommendations (may be considered, benefit > risk)EARLY INVASIVE STRATEGY
40
FDA Boxed Warning on ClopidogrelWARNING: DIMINISHED EFFECTIVENESS IN POOR
METABOLIZERS Effectiveness of clopidogrel depends on activation to an
active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19
Poor metabolizers treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function
Tests are available to identify a patient’s CYP2C19 genotype, and can be used as an aid in determining therapeutic strategy
Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers
FDA Drug Safety Communication. March 12, 2010. http://www.fda.gov/drugs/drugsafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm
Roles in Clopidogrel Activity of Proteins with Known Genetic Polymorphisms
Cytochrome P450 enzymes, especially CYP2C19, play an important role in the conversion of clopidogrel to its active metabolite1
Patients carrying reduced function CYP2C19 alleles2
Reduced level active metabolite
Less platelet inhibition Observed increased risk of
ischemic events
1. Reprinted from Simon T, et al. N Engl J Med. 2009;360(4): 363‐375.
2. Storey RF. Lancet. 2009;373(9660):276‐278.41
Mega J, et al. N Engl J Med. 2009;360(4):354‐362.
CV Risk with Clopidogrel CYP2C19 Reduced‐function Allele: TRITON‐TIMI 38
Days since randomization
HR, 1.53; 95% CI, 1.07‐2.19Incidence of CV death,
MI, or stroke (%)
Carriers
Noncarriers
12.112
10
0
2
4
6
8
0 30 90 180 270 360 450
8.0
42
Antiplatelet Therapy
Prasugrel
43
Active Metabolite Formation:Prasugrel and Clopidogrel
5. Kurihara et al. Drug Metab Rev. 2005;37(S2):99.6. Lagorce et al. J Chromatogr B Biomed Sci Appl. 1998;720:107‐117.7. Tang et al. J Pharmacol Exp Ther. 2006;319:1467‐1476.8. Plavix Full Prescribing Information.
1. Rehmel et al. Drug Metab Dispos. 2006;34:600‐607.2. Williams et al. Drug Metab Dispos. 2008;36:1227‐1232.3. Farid et al. J Clin Pharmacol. 2009 Nov 30. [Epub ahead of print].4. Savi et al. Thromb Haemost. 2000;84:891‐896.
Clopidogrel4–8Prasugrel1–3
Genetic variation in CYP2C19 can impair metabolism
No relevant effect of genetic variation in CYP2C19
GutHydrolysis
hCE2
Intermediate
Active metabolite
Gut & Liver Oxidation
CYP3A, 2B6,2C9, 2C19
1st Oxidation
CYP1A2, 2B6, 2C19
Intermediate
2nd Oxidation
CYP3A, 2B6,2C9, 2C19
Liver
LiverHydrolysishCE1
85% Inactive Metabolite8
Active Metabolite
44
Prasugrel Compared with Higher-dose Clopidogrel
Wiviott SD, et al; PRINCIPLE-TIMI 44 Investigators. Circulation. 2007;116(15):2923-2932.
P<.0001 for each
IPA (%; 20 μM ADP)
Hours
N=201
Prasugrel 60 mg
Clopidogrel 600 mg30.8
64.5
74.8
69.3
4.9
20.3
31.8
32.6
0
20
40
60
80
100
0 4 8 12 16 20 24 28
14 Days
IPA (%; 20 μM ADP)
P<.0001
Prasugrel 10 mg
Clopidogrel 150 mg
46.1
61.3
0
20
40
60
80
100
45
TRITON‐TIMI 38 Study Design
Wiviott SD et al. Am Heart J. 2006;152:627‐635.
UTVR = urgent target vessel revascularization
NSTEMI = non‐ST segment elevation MI
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL60 mg LD/ 10 mg MD
CLOPIDOGREL300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, stroke2o endpoints: CV death, MI, stroke, rehosp‐rec isch CV death, MI, UTVR
n=13,600
Median duration of therapy ‐ 12 months
Double‐blind
46
47
TRITON TIMI‐38
Days
35events
HR 0.81(0.73‐0.90)P=0.0004
HR 1.32(1.03‐1.68)P=0.03
138events
NNT=46
NNH=167
Wiviott SD et al. N Engl J Med. 2007;357:2001‐2015.
End Point (%
)
12.1
9.9
1.8
2.4
0
5
10
15
0 30 60 90 180 270 360 450
CV Death/MI/stroke
TIMI Major Non‐CABG bleeds
Clopidogrel
Prasugrel
Prasugrel
Clopidogrel
HR = hazard ratioNNT = number needed to treatNNH = number needed to harm
Balance of efficacy and safety
48
TRITON TIMI‐38: Stent Thrombosis
Days
0
1
2
3
0 30 60 90 180 270 360 450
HR 0.48P<0.0001
Prasugrel
Clopidogrel 2.4(142)
74 events
NNT=77
1.1 (68)En
d Point (%
)
Any Stent at Index PCIn=12,844
Wiviott SD et al. N Engl J Med. 2007;357:2001‐2015.
ARC definite + probable
ARC = Academic Research Consortium PCI = Percutaneous Coronary Intervention
49
TRITON TIMI‐38 Net Clinical Benefit
Post‐hoc analysisWiviott SD et al. N Engl J Med. 2007;357:2001‐2015.
Overall
≥60 kg
<60 kg
<75
No
Yes
0.5 1 2
PriorStroke / TIA
Age
Weight
Risk (%)
+ 37
‐16
‐1
‐16
+3
‐14
‐13
Prasugrel better Clopidogrel betterHazard ratio
Pint = 0.006
Pint = 0.18
Pint = 0.36
≥75
Bleeding risk subgroups
50
CYP2C19 Reduced‐function Allele Carrier Status and Clinical Outcomes in Prasugrel Patients
Number at risk
Carriers*Non-carriers
407 383 376 320 276 1883641048 982991 951 849 750 541
Days after randomization
Mega et al. Circulation. 2009;119:2553‐2560.
0
2
4
6
8
10
12
14
CV
dea
th, n
onfa
tal M
I,
or n
onfa
tal s
trok
e (%
)
A Subanalysis from the TRITON-TIMI 38 trial
HR 0.89P=0.27
9.88.5
0 30 90 180 270 360 450
Non-carriers
Carriers
*Represents a mixture of intermediate and poor metabolizers
Days after randomization
CV
dea
th, n
onfa
tal M
I,or
non
fata
l str
oke
(%)
51
CYP2C19 Reduced‐function Allele Carrier Status and Clinical Outcomes in Clopidogrel Patients
Number at riskCarriers* 395 364 360 306 270 181348Non-carriers 1064 9991009 980 870 755 542
A Subanalysis from the TRITON-TIMI 38 trial
0
2
4
6
8
10
12
14
30 90 180 270 360 450
12.1
8.0
HR 1.53P=0.01
Non-carriers
Carriers
0
Mega et al. N Engl J Med. 2009;360:354‐362.*Represents a mixture of intermediate and poor metabolizers
52
UA/NSTEMI – Antiplatelet Therapy
At the time of PCIClopidogrel (if not begun earlier), or
Prasugrel, or
GP IIb/IIIa inhibitor
For patients with a prior history of stroke and/or TIA for whom PCI is planned, prasugrel is potentially harmful as part of a dual‐antiplatelet therapy regimen
Wright RS, et al. J Am Coll Cardiol 2011;57:1920–59.
2011 ACC/AHA UA/NSTEMI Focused Update Class I Recommendations (should be given, benefit >>> risk)
Early invasive strategy
II IIaIIa IIIIIIII
IIbIIb
BA
A
A
ESC NSTEMI 2011:Recommendations for antiplatelet agents
Recommendations Class Level
A P2Y12 inhibitor should be added to aspirin as soon as possible and maintained over 12 months, unless there are contraindications such as excessive risk of bleeding.
I A
Prasugrel (60 mg loading dose, 10 mg daily dose) is recommended forP2Y12-inhibitor-naïve patients (especially diabetics) in whom coronary anatomyis known and who are proceeding to PCI unless there is a high risk of life-threatening bleeding or other contraindications.
I B
European Heart Journal (2011) 32:2999–3054; doi:10.1093/eurheartj/ehr236 53
TRILOGY ACS Study Design
Medically Managed UA/NSTEMI Patients
Clopidogrel1
75 mg MD
Prasugrel1
5 or 10 mg MD
Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months
Primary Efficacy Endpoint: CV Death, MI, Stroke
Randomization Stratified by:Age, Country, Prior Clopidogrel Treatment(Primary analysis cohort — Age < 75 years)
Clopidogrel1300 mg LD
+75 mg MD
Prasugrel130 mg LD
+5 or 10 mg MD
Medical Management Decision ≤72 hrs(No prior clopidogrel given) — 4% of total
Medical Management Decision ≤ 10 days(Clopidogrel started ≤ 72 hrs in-hospital OR
on chronic clopidogrel) — 96% of total
1. All patients were on aspirin and low-dose aspirin (< 100 mg) was strongly recommended. For patients <60 kg or ≥75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1.
Median Time to Enrollment = 4.5 Days
Roe MT, et al. NEJM 2012;367:1297. 54
HR (95% CI) ≤ 1 Year:0.99 (0.84, 1.16)
HR (95% CI) > 1 Year:0.72 (0.54, 0.97)
Primary Efficacy Endpoint to 30 Months(Age < 75 years)
HR (95% CI):0.91 (0.79, 1.05)
P = 0.21
Interaction P = 0.07
Roe MT, et al. NEJM 2012;367:1297.
TIMI Major Bleeding to 30 Months(Age < 75 years)
HR (95% CI):1.31 (0.81, 2.11)
P = 0.27
Roe MT, et al. NEJM 2012;367:1297.
Antiplatelet Therapy
Ticagrelor
57
58
Ticagrelor – Pharmacology
Non‐thienopyridine platelet P2Y12 antagonistDirect acting (not a pro‐drug), does not require cytochrome P450 metabolic activation to exert its antiplatelet effect
Faster, greater and more consistent inhibition of platelet function than clopidogrel
Reversibly binds to the P2Y12 receptorPotential advantage if needing to discontinue therapy due to surgery
Adapted from: Owen RT et al. AZD6140. Drugs of the Future. 2007;32 :845‐853.
TIME (hours)Gurbel PA, et al. Circulation. 2009;120(25):2577‐2585.
59
Wallentin L, et al. N Engl J Med. 2009;361(11):1045‐1057. 60
Wallentin L, et al. N Engl J Med. 2009;361(11):1045‐1057.
UA/NSTEMI (moderate‐high risk)STEMI (if primary PCI)
All receiving ASAClopidogrel‐treated or naïve
Clopidogrel (n=6676)If pretreated, no additional load;if naïve, standard 300 mg load,then 75 mg daily maintenance
(additional 300 mg allowed pre‐PCI)
1 end point: CV death/MI/stroke2 end point: CV death/MI/stroke/revascularization with PCI;
CV death/MI/stroke; severe recurrent ischemia1 safety end point: total major bleeding
12‐month maximum exposure(min, 6 mo; max, 12 mo; mean, 11 mo)
N=18,624 patients
Ticagrelor (n=6732)180 mg load, then
90 mg bid maintenance(additional 90 mg pre‐PCI)
PLATO PLATelet Inhibition and Patient Outcomes
61
Early Randomization: ACS Patient
Admission Initial Management Angiography PCI
Hospital Course
PLATO TRITON
PLATO Key Feature #1
In ER, irrespective of Clopi Pre-Rx
In Cath Lab, with no Clopi Pre-Rx
James S, et al. Am Heart J. 2009;157:599-605; Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015; Wiviott SD, et al. Am Heart J 2006;152:627235 62
Irrespective of Management Strategy
Start Antiplatelet therapy
(PLATO randomization)
StopAntiplatelet
Therapy
Emergency Room – Initial ECG
Invasive/CatheterizationLaboratory
Determine CV anatomy and clinical strategy
Manage Medically PCI
Continue antiplatelet therapy When medically
appropriate
CABG
STE (40%), NSTEMI (40%), UA (20%)
PLATO Key Feature #2
Irrespective of Management Sx
James S, et al. Am Heart J. 2009;157:599-605.
63
ACS Patient
STEMI
NSTEMI
Primary PCI
Fibrinolytic Rx
No Reperf
Early Invasive Rx
Early Conservative Rx
PCI
Medical Rx
CABG
PCI
Medical Rx
CABG
Fibrinolytic excluded within24 hours
PLATO Key Feature #3
James S, et al. Am Heart J. 2009;157:599-605.
Broad ACS Population
64
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Both groups included aspirin.*NNT at one year.
PLATO: Primary Efficacy Endpoint(Composite of CV Death, MI, or Stroke)
65
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
Months After Randomization
8,521
8,628
8,362
8,460
8,124 6,650
6,743
5,096
5,161
4,047
4,1478,219
0 2 4 6 8 10 12
12111098765432
10
13
Cu
mu
lati
ve
In
cid
en
ce
(%
) 11.7 Clopidogrel
9.8 Ticagrelor
ARR=0.6%
RRR=12%
P=0.045
HR: 0.88 (95% CI, 0.77−1.00)
0–30 Days
4.8
5.4Clopidogrel
Ticagrelor
ARR=1.9%
RRR=16%
NNT=54*
P<0.001
HR: 0.84 (95% CI, 0.77–0.92)
0–12 Months
Secondary Efficacy EndpointsMI and CVD follows PEP
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
ARR=1.1%
RRR=16%
NNT=91
P=0.005
HR: 0.84 (95% CI, 0.75–0.95)
ARR=1.1%
RRR=21%
NNT=91
P=0.001
HR: 0.79 (95% CI, 0.69–0.91)
66
67
68
PLATO: Time to major bleeding: primary safety endpoint
K-M
est
ima
ted
ra
te (
% a
t 1
ye
ar)
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
Days from first IP dose
10
5
0
15
0 60 120 180 240 300 360
Clopidogrel
Ticagrelor
11.2%11.6%
(HR 1.04; 95% CI, 0.95-1.13; P=0.43)
P=NS
#Both groups included aspirin
No. at risk
Ticagrelor 9235 7246 6826 6545 5129 3783 3433
Clopidogrel 9186 7305 6930 6670 5209 3841 3479
NS=non-significant
PLATO: bradycardia-related events and Holter monitoring programAll Patients
Ticagrelor (n=9235)
Clopidogrel (n=9186)
P value
Bradycardia-related event, n (%)
Pacemaker insertion 82 (0.9) 79 (0.9) 0.87*
Syncope 100 (1.1) 76(0.8) 0.08*
Bradycardia 409 (4.4) 372 (4.0) 0.21*
Heart Block 67 (0.7) 66 (0.7) 1.00*
Holter monitor first week, n (%) Ticagrelor (n=1451)
Clopidogrel (n=1415)
P value
Ventricular pauses ≥3 seconds 84 (5.8) 51 (3.6) 0.01
Ventricular pauses ≥5 seconds 29 (2.0) 17 (1.2) 0.10*
Holter monitor at 30 days, n (%) Ticagrelor (n=985)
Clopidogrel (n=1006)
P value
Ventricular pauses ≥3 seconds 21 (2.1) 17 (1.7) 0.52*
Ventricular pauses ≥5 seconds 8 (0.8) 6 (0.6) 0.60*
Wallentin L, et al. New Engl J Med. 2009;361:1045–1057.
* * Not significant*69
Dyspnoea in PLATO• Dyspnoea was reported more frequently by patients on
ticagrelor than clopidogrel (13.8% vs 7.8%; P<0.001)– More patients on ticagrelor discontinued study drug because of
dyspnoea, but numbers were small (0.9% vs 0.1%, P<0.001)
• The higher frequency of dyspnoea with ticagrelor was not associated with any detectable detrimental effect on pulmonary function compared with clopidogrel– Most episodes lasted less than a week
– Ticagrelor-associated dyspnoea was mostly mild to moderate and did not affect efficacy
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057; Storey R, et al. JACC. 2010;55(Suppl 1):A108.E1007. 70
71
Mahaffey, Circ 2011;124:544 72
73
Patient disposition
18,624 patients randomized
CABG in 1899 patients during the course of the
study
CABG in 1261 patients with last intake of study drug ≤7 days
prior to surgery
632 patients treated with ticagrelor
629 patients treated with clopidogrel
CABG
Held C, et al. J Am Coll Cardiol 2011;57:000–00
74
75
Risk of the primary endpoint -CV death, MI, or stroke - after CABG
Months from CABG procedureNo. at risk
Clopidogrel
Ticagrelor
629
629
541
543
516
519
448 386
386
255
268
125
108458
0 1 2 3 4 5 6 7 8 9 10 11 12
14
13
12
11
10
9
8
7
6
5
4
3
2
1
Hazard ratio (HR): 0.84 (95% CI=0.60-1.16), P=0.29
13.1
10.6
Clopidogrel
Ticagrelor
Kap
lan
-Mei
er e
stim
ated
rat
e (%
)
ARR = 2.5%RRR = 16%
CABG
Held C, et al. J Am Coll Cardiol 2011;57:000–00
76
Risk of CV death after CABG
No. at risk
Clopidogrel
Ticagrelor629
629
565
583
539
557
472 404
415
269
291130
119491
0 1 2 3 4 5 6 7 8 9 10 11 12
8
7
6
5
4
3
2
1
0
Months from CABG procedure
HR: 0.52 (95% CI = 0.32-0.85), P<0.01
7.9
4.1
Clopidogrel
Ticagrelor
Kap
lan
-Mei
er e
stim
ated
rat
e (%
)
P=0.009
ARR = 3.8%RRR = 48%
CABG
Held C, et al. J Am Coll Cardiol 2011;57:000–00
ESC 2012 STEMI: Antiplatelet Recommendations
European Heart Journal (2011) 32:2999–3054; doi:10.1093/eurheartj/ehr23677
Comparison of Antiplatelet Agents
Loadingmaintenance
Clopidogrel300‐600 mg75 mg qday
Prasugrel60 mg
10 mg qday
Ticagrelor180 mg90 mg bid
UAP, NSTEMI, STEMI indication
Yes Yes Yes
Potency ++ +++ +++
Rapidity of onset + +++ ++++
Variable response Very variable No No
CYP2C19 carrier –clinical impact?
Yes No No
Reversibility Not reversible Not reversible Reversible
Hold before CABG 5 days 7 days 3‐5 days
Clinical experience ++++ +++ ++
Bleeding risk + ++ +
Side effects Rare Rare More common79
Antiplatelet Therapy
GP IIBIIIA Inhibitors
80
Mechanism of Action of Antiplatelet Therapies
Schafer AI: Am J Med 1996:101;199
Clopidogrel, Prasugrel (irreversible)
Ticagrelor (reversible)
GPIIb/IIIa Antagonists:Abciximab (irreversible)Eptifibatide, Tirofiban
(reversible)
Collagen, Thrombin
TXA2
GPIIbIIIa Receptor
81
82
The FRISC II and TACTICS TIMI-18 trials demonstrated an additional benefit when a GP IIb/IIIa inhibitor was combined with an early invasive strategy. The largest benefit from early use of GP IIb/IIIa inhibitors is seen in patients at high risk, particularly those with significant elevations in troponin levels.
83
Recommendations for GP IIB-IIIA Inhibitor
Antiplatelet and Anticoagulation Treatments
84
85
86
Early Hospital CareAnti‐Ischemic Therapy• Class I
– Bed/Chair rest and Telemetry– Oxygen (maintain saturation >90%)– Nitrates (SLx3 Oral/topical. IV for ongoing ischemia, heart failure, hypertension)
– Oral B‐blockers in First 24‐hours if no contraindications. (IV B‐blockers class IIa indication)
– Non‐dihydropyridine Ca‐channel blockers for those with contraindication for B‐blockers
– ACE inhibitors in first 24‐hours for heart failure or EF<40% (Class IIa for all other pts) (ARBs for those intolerant)
– Statins
Early Hospital CareAnti‐Platelet Therapy
• Class I
– Aspirin (162‐325 mg), non enteric coated
– Clopidogrel for those with Aspirin allergy/intolerance (300‐600 mg load and 75 mg/d) (or Prasugrel or Ticagrelor)
– GI prophylaxis if a Hx of GI bleed
– GP IIb/IIIa inhibitors should be evaluated based on whether an invasive or conservative strategy is used
– GP IIb/IIIa inhibitors recommended for all diabetics and all patient in early invasive arm
Early Hospital CareAnticoagulant Therapy
• Class I
– Unfractionated Heparin
– Enoxaparin
– Bivalarudin
– Fondaparinux
– Relative choice depends on invasive vs conservative strategy and bleeding risk
Early Hospital CareStatin Therapy
• MIRACL TrialInclusion Criteria
– 3086 patients with Non ST ACS
– Total cholesterol <270 mg/dl
– No planned PCI
– Randomized to Atorvastatin vs Placebo
– Drug started at 24‐96 hours
Statin Evidence: MIRACL Study
Relative risk = 0.84P = .04895% CI 0.701-0.999
Atorvastatin
Placebo
0
5
10
15
0 4 8 12 16
Time Since Randomization (weeks)
Cu
mu
lativ
e I
nci
de
nce
(%
)
Time to first occurrence of:• Death (any cause)• Nonfatal MI• Resuscitated cardiac arrest• Worsening angina with new
objective evidence and urgent rehospitalization
17.4%
14.8%
Primary Efficacy Measure
Schwartz GG, et al. JAMA. 2001;285:1711-1718.
All-Cause Death or Major CV Events in All Randomized Subjects
0 3 18 21 24 27 306 9 12 15
% with Event
Months of Follow-up
Pravastatin 40mg(26.3%)
Atorvastatin 80mg(22.4%)
16% RR
(P = 0.005)
30
25
20
15
10
5
0
PROVE‐IT Trial
Invasive vs Conservative Strategies
Invasive vs Conservative Strategy Clinical Trials
TIMI IIIB (94)
ConservativeStrategy Favored
N=920
InvasiveStrategy Favored
N=7,018
VANQWISH (98)
MATE
FRISC II (99)
TACTICS-TIMI 18 (01)
VINO
RITA-3 (02)
TRUCS
ISAR-COOL
ICTUS (05)
No differenceN=2,874
Weight ofthe evidence
95
TIMI Risk Score
T: Troponin elevation (or CK-MB elevation)
H: History or CAD (>50% Stenosis)
R: Risk Factors: > 3 (HTN, Hyperlipidemia, Family Hx, DM II, Active Smoker)
E: EKG changes: ST elevation or depression 0.5 mm concordant leads
A2:Aspirin use within the past 7 days; Age over 65
T: Two or more episodes of CP within 2 hours
TIMI Risk ScorePredicts risk of death, new/recurrent MI, need for urgent revascularization within 14 days
98
99
How Early is Early?
100
Early Invasive vs Conservative Strategies
Definitive/Possible ACSInitiate ASA, BB, Nitrates, Anticoagulants, Telemetry
Early Invasive Strategy
• TIMI Risk Score >3• New ST segment
deviation• Positive biomarkers
Conservative Strategy
•TIMI Risk Score <3 (Esp. Women)•No ST segment deviation•Negative Biomarkers
Coronary angiography(24-48 hours)
Recurrent Signs/SymptomsHeart failureArrhythmias
Remains Stable↓
Assess EF and/or Stress Testing↓
EF<40% OR Positive stressGo to Angiography
•Hemodynamic instability•Elecrical instability•Refractory angina•PCI in past 6 months•CABG•EF <40%
Secondary PreventionClass I Indications• Aspirin• Beta‐blockers: (all pts, slow titration with moderate to severe failure
• ACE‐Inhibitors: CHF, EF<40%, HTN, DM(All pts‐Class IIa) ARB when intolerant to ACE. (Class IIa as alternative to ACEI)
• Aldosterone blockade: An ACEI, CHF with either EF<40% or DM and if CrCl>30 ml/min and K<5.0 mEq/L
• Statins• Standard Risk Factor Management
102
2012 Key Updates to UA/NSTEMI Guidelines
103
2012 Key Updates to UA/NSTEMI Guidelines
104
NSTEMI/Unstable Angina
*Ticagrelor is also considered
*
Summary
• Management guideline focus– Risk stratification
– Conservative vs Invasive therapy for UA/NSTEMI
• Aggressive attention to secondary prevention initiatives for ACS patients
• Beta blocker, ASA, ACE‐I, Statin
• Gear appropriate therapy towards the stratified pathway
106
Thank You
Questions?
107