Acute Coronary Syndrome: What to do before the specialist arrives
Eduardo Vicente S. Caguioa, M.D., FPCP, FPCC, FACC Assoc. Professor, Dept of Medicine, Section of Cardiology
UST Faculty of Medicine and Surgery Medical Director, University of Santo Tomas Hospital
Hospitalizations in the US Due to ACS
Acute Coronary Syndromes*
1.57 Million Hospital Admissions - ACS
UA/NSTEMI† STEMI
1.24 million Admissions
per year
0.33 million Admissions
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
2011.01
Current Practice in ACS
Acute Coronary Syndrome (ACS)
AGGRESSIVE CONSERVATIVE
CRITERIA
PRE-INVASIVE CARE
AGGRESSIVE / INVASIVE
INTERVENTION
INFRASTRUCTURE / FACILITIES READY OR
NEARBY
YES NO
FACILITATED INVASIVE
Primary Physician
Emergency Room
Setting
= Specialist needed
Area of concern
MEDICAL REPERFUSION and
PREVENTION OF RESTENOSIS
INTENSIVE MEDICAL THERAPY IN ICU/CCU
SETTING
STEP-DOWN THERAPY
CARDIAC REHABILITATION
CRITERIA
Current Practice in ACS Acute Coronary Syndrome (ACS)
AGGRESSIVE INVASIVE THERAPY CRITERIA
•Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy
•Elevated cardiac biomarkers •New or presumably new ST-segment depression
•Signs/Symptoms of HF or worsening MR •High-risk finding from non-invasive test •Hemodynamic instability •Sustained Ventricular tachycardia •PCI within 6 months •Prior CABG •High risk score (TIMI, GRACE) •LVEF <= 40%
CONSERVATIVE THERAPY CRITERIA
• Low risk score (TIMI, GRACE) • Patient or physician
preference in the absence of high risk features
ACC/AHA Guideline Recommendations for Selection of Initial Treatment Strategy: Invasive Versus Conservative; from Braunwald’s Practice Guidelines, 2012, Elsevier Publishing (iPad version)
Acute Coronary Syndrome (ACS) Likelihood that signs/symptoms represent an ACS secondary to coronary
artery disease
Feature High Likelihood Intermediate Likelihood Low Likelihood
Any of the following Absence of high likelihood features and presence of any of the ff:
Absence of high- or Intermediate likelihood features but may have:
History Chest or left arm pain or discomfort as chief symptom reproducing prior angina. Known Hx of CAD including MI
Chest or left arm pain or discomfort as chief symptom; Age > 70; Male; DM
Probable ischemic symptom in absence of any of the intermediate likelihood characteristics; Recent cocaine use
Examination Transient MR murmur; hypotension; diaphoresis; rales; pulmonary edema
Extracardiac vascular disease Chest discomfort reproduced by palpation
ECG New or presumably new transient ST segment deviation (>=1mm) or T wave inversion in multiple precordial leads
Fixed Q waves; ST depression 0.5-1 mm or T wave inversion greater than 1 mm
T wave flatenning or inversion less than 1 mm in leads with dominant R waves; Normal ECG
Cardiac markers
Elevated cardiac TnI, TnT, or CK-MB
Normal Normal
ACC/AHA Guideline Recommendations for Selection of Initial Treatment Strategy: Invasive Versus Conservative; from Braunwald’s Practice Guidelines, 2012, Elsevier Publishing (iPad version)
Acute Coronary Syndrome (ACS) ACC/AHA System for Risk Stratification of Patients with Unstable Angina
Feature High Risk Intermediate Risk Low Risk At least one of the following features: No high Risk features BUT must
have one of the ff: No high- or Intermediate Risk features but may have any of the ff:
History Accelerating tempo of ischemic symptoms in preceding 48 hrs
Prior MI, peripheral or cerebrovascular disease, or CABG; prior Aspirin use
Probable ischemic symptom in absence of any of the intermediate likelihood characteristics; Recent cocaine use
Character of pain
Prolonged ongoing (> 20 mins) rest pain Prolonge rest angina, now resolved, with moderate or high likelihood of CAD; Rest angina < 20 min or relieved by rest or SL NTG
New onset or progressive CCS class III or IV angina the past 2 wks w/o prolonged rest pain but with mod or high likelihood of CAD
Clinical and ECG Findings
Pulmonary edema most likely due to ischemia; New or worsening MR; S3 or new worsening rales; hypotension, brady- or tachycardia; Age > 75; angina at rest with ST segment change > 0.05mm; new BBB; sustained V-tach
Fixed Q waves; Age > 70; T wave inversion > 0.02 mm; pathologic Q waves
Normal or unchanged ECG during an episode of chest discomfort
Cardiac markers
Elevated Slightly elevated Normal
ACC/AHA Guideline Recommendations for Selection of Initial Treatment Strategy: Invasive Versus Conservative; from Braunwald’s Practice Guidelines, 2012, Elsevier Publishing (iPad version)
SYNERGY
LMWH
ESSENCE
1994 1995 1996 1997 1998 1999 2000 2002 2003 2004 2005 2006 2001
CURE
Clopidogrel
Bleeding risk
Ischemic risk
GP IIb/IIIa blockers
PRISM-PLUS
PURSUIT
ACUITY TACTICS TIMI-18
Early invasive
PCI ~ 5% stents ~85% stents Drug-eluting stents
ISAR-REACT 2
Milestones in ACS Management
OASIS-5
[ Fondaparinux ] Anti-Thrombin Rx
Anti-Platelet Rx
Treatment Strategy
Heparin
Aspirin
Conservative
ICTUS
Bivalirudin
REPLACE 2
Adapted from and with the courtesy of Steven Manoukian, MD
Thrombus busters Streptokinase rTPA
TIMI GISSI
Evolution of ACS Therapies
Adapted from White HD et al. Lancet 2008; 372: 570–84
1990 1996 1997 2000 2001 2005 2007 2008
Year
Low molecular weight heparin
IIb/IIIa receptor antagonist
Early invasive management
CLOPIDOGREL Atorvastatin
Fondaparinux
Bivalirudin
Integrated strategy
DABIGATRAN ??
Aspirin
Heparin
Thrombolytics
Beta-Blockers (no ISA)
Evolution of ACS Therapies
Adapted from White HD et al. Lancet 2008; 372: 570–84
1990 1996 1997 2000 2001 2005 2007 2008
Year
Low molecular weight heparin
IIb/IIIa receptor antagonist
Early invasive management
CLOPIDOGREL Atorvastatin
Fondaparinux
Bivalirudin
Integrated strategy
AREA OF INTEREST DABIGATRAN ??
Aspirin
Heparin
Thrombolytics
Beta-Blockers (no ISA)
ASPIRIN in ACS
Accepted necessary accompanying drug in the management of ACS
Proven benefit in secondary prevention of diseases involving the cardio-vascular bed
Doses in trials for acute ACS range from 100 – 325 mg daily dose
Doses in secondary prevention range from low to high dose (30 – 80 – 100 – 325 – 500 mg daily dose)
A must unless contraindicated; Effect better in combination with other anti-platelet
Beta-Blockers
Proven benefit; Mortality and morbidity decreased by at least 25%
ISA property deleterious and not recommended Only 25% are maintained in real life (under usage) Side-effects main problem in utilization
HEPARIN (Unfractionated or low molecular weight)
Accepted as necessary adjunct in the management of ACS especially in cases where time is important
Benefit outweighs the risk of bleeding (ESSENCE and TIMI-11b)
Subcutaneous low molecular weight heparins generally proven to be better than unfractionated heparin probably from smoother anticoagulation
No data on the oral form in ACS
IIb/IIIa RECEPTOR ANTAGONIST in ACS
Accepted adjunct treatment in cases with persistent ischemia or chest pain after initial therapy with thrombolytics and/or PCI
Limited to use in an ICU-CCU setting because of higher bleeding rates
Evolution of ACS Therapies
Adapted from White HD et al. Lancet 2008; 372: 570–84
1990 1996 1997 2000 2001 2005 2007 2008
Year
Low molecular weight heparin
IIb/IIIa receptor antagonist
CLOPIDOGREL Atorvastatin
Fondaparinux
Bivalirudin
Integrated strategy
AREA OF INTEREST
DABIGATRAN ??
Aspirin
Heparin
Thrombolytics
Cornerstone of therapy in preventing adverse vascular events in a spectrum of patients with atherothrombotic disease
Beta-Blockers (no ISA)
Proportional effects of antiplatelet therapy on Vascular events in five main high risk categories
Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
Absolute effects of antiplatelet therapy on vascular events in five main high risk categories
Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
Clopidogrel in NSTE ACS: CURE
CURE. NEJM 2001;345:494-502
12,563 Pts, GP IIb/IIIa & early invasive approach discouraged
RR 0.80, p<0.001
Clopidogrel (9.3%)
Placebo (11.4%)
CV
Dea
th, M
I, St
roke
Months of follow-up
0 3 6 9 12 0.0
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Yusuf S et al. Circulation 2003;107:966-972
CURE: Very Early Efficacy of Clopidogrel in NSTE ACS
Hours After Randomization
0.0
0.005
0.010
0.015
0.020
0.025
0 2 4 6 8 10 12 14 16 18 20 22 24
P=.003
Placebo + Aspirin (n=6303)
Clopidogrel + Aspirin (n=6259)
34% Relative
Risk Reduction
CV Death, MI, Stroke, Severe Ischemia Within First 24 Hours
Cum
ulat
ive
Haz
ard
Rat
e
Fox et al. Circulation. 2004;110:1202-1208
Medical Rx Group
Placebo
Clopidogrel
RR: 0.80 (0.69-0.92)
0.20
4
0.15
0.10
0.05
0.0 100 200 300
Clopidogrel
0.20
4
0.15
0.10
0.05
0.0 100 200 300
PCI Group
Placebo
RR: 0.72 (0.57-0.90)
0.20
4
0.15
0.10
0.05
0.0 100 200 300
CABG Group Placebo
Clopidogrel
RR: 0.89 (0.71-1.11)
CURE: Benefit by Revascularization C
VD/M
I/Str
oke
CVD
/MI/S
trok
e
CVD
/MI/S
trok
e
Clopidogrel in STEMI
Fibrinolytic, ASA, Heparin
Clopidogrel 300 mg + 75 mg qd
Coronary Angiogram (2-8 days)
Primary endpoint: Occluded
artery (TIMI Flow Grade 0/1) or D/MI by time
of angio
randomize
Placebo
Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours
Study Drug
30-day clinical follow-up
Open-label clopidogrel per MD in
both groups
Clopidogrel in STEMI
15.0
21.7
0
5
10
15
20
25
Occ
lud
ed
Art
ery
or
De
ath
/MI (
%)
Placebo Clopidogrel
36% P<0.0001
Sabatine MS et al. NEJM 2005; 352: 1179
days
CV
Dea
th, M
I, or
Urg
Rev
asc
(%)
0 5
10
15
0 5 10 15 20 25 30
Placebo
Clopidogrel
Odds Ratio 0.80 (95% CI 0.65-0.97)
P=0.026
20%
COMMIT: Clopidogrel (75 mg qd) in STEMI
9% relative risk reduction (P=.002)
Placebo (10.1%)
Clopidogrel (9.3%)
Days
Dea
th, M
I, St
roke
(%) 9
8
7
6
5
4
3
2
1
0 0
Mor
talit
y (%
) Days
Placebo (8.1%)
Clopidogrel (7.5%)
7% relative risk reduction (P=.03)
7
6
5
4
3
2
1
0 7 14 21 28 0 7 14 21 28
COMMIT Collaborative Group. Lancet. 2005;366:1607.
45,851 Patients p/w STEMI w/in 24 hrs; ASA; lytic therapy (~1/2)
PCI-CLARITY Design
30-day clinical follow-up
933 underwent PCI during index hosp.
930 underwent PCI during index hosp.
3491 Patients Randomized into CLARITY-TIMI 28
1752 assigned clopidogrel 300 mg 75 mg/d 1739 assigned placebo
Open-label clopidogrel w/ loading dose
recommended
(CLOPIDOGREL PRETREATMENT) (NO PRETREATMENT)
A n g i o g r a p h y
CV Death, MI, or Stroke following PCI
0 2
4 6
8
0 10 20 30 Days post PCI
Perc
enta
ge w
ith o
utco
me
(%)
No Pretreatment – 6.2%
Clopidogrel – 3.6% Pretreatment
46%
Odds Ratio 0.54 (95% CI 0.35-0.85)
P=0.008
Sabatine MS et al. JAMA 2005;294:1224-32
Clopidogrel No Trial Pretreatment Pretreatment PCI-CURE 3.6 5.1 CREDO n/a n/a PCI-CLARITY 4.0 6.1 Overall 3.7 5.5
Clopidogrel No
Trial Pretreatment Pretreatment
PCI-CURE 2.9 4.4 CREDO 6.0 7.1 PCI-CLARITY 3.3 5.4 Overall 3.9 5.5
Meta-Analysis of Clopidogrel Pretreatment
1.0 0.25 2.0 0.5
1.0 0.25 2.0 0.5 OR (95% CI)
OR (95% CI)
CV Death or MI after PCI (%)
MI before PCI (%)
OR 0.67 P=0.005
Favors Pretreatment
Favors No Pretreatment
OR 0.71 P=0.004
Sabatine MS et al. JAMA 2005;294:1224-32
Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA): Study Design
Double-blind treatment up to 1,040 primary efficacy events occur*
Aspirin 75–162 mg once daily
Clopidogrel 75 mg once daily
(n=7600)
Placebo 1 tab once
daily (n=7600)
Aspirin 75-162 mg once daily Patients 45 years or older who are
at high risk of atherothrombotic
events
R = randomization.
N=15,603
R
Bhatt et al. Am Heart J. 2004;148:263
*Event-driven trial: primary efficacy
outcome of vascular death, MI, stroke
Visits every 6 months
(12 m, 18 m…), and intermediate
phone calls in between
(15 m, 21m…)
Overall Population: Primary Efficacy Outcome (CV Death, MI, or Stroke)
Bhatt DL et al. NEJM 2006;354:1706-17
Cum
ulat
ive
even
t rat
e (%
)
0
2
4
6
8
Months since randomization 0 6 12 18 24 30
Placebo + ASA 7.3%
Clopidogrel + ASA
6.8%
RRR: 7.1% [95% CI: -4.5%, 17.5%] p=0.22
Primary Endpoint (CV Death, MI, or Stroke) in Patients with Previous MI, IS, or PAD “CAPRIE-like Cohort”
RRR: 17.1 % [95% CI: 4.4%, 28.1%] p=0.01
Prim
ary
outc
ome
even
t rat
e (%
)
0
2
4
6
8
10
Months since randomization 0 6 12 18 24 30
Clopidogrel + ASA 7.3%
Placebo + ASA 8.8%
N=9,478
Bhatt DL et al. JACC 2007;49:1982
30 Variable and Unpredictable Response to Clopidogrel
24 hrs after 300 mg Clopidogrel
Gurbel PA et al. Circulation 2003; 107: 2908-2913
10
20
≤ -30 (-30,-20)
(-20,-10) (-10,0)
(0,10) (10,20)
(20,30) (30,40)
(40,50) (50,60)
>60
Platelet aggregation before and after Clopidogrel (%)
Pat
ient
s (%
)
“Resistance” = 31% N = 96, Elective PCI
“Resistance” = ≤ 10% platelet aggregation 2015.01
Evolution of ACS Therapies
Adapted from White HD et al. Lancet 2008; 372: 570–84
Aspirin
Heparin
1990 1996 1997 2000 2001 2005 2007 2008
Year
Low molecular weight heparin
IIb/IIIa receptor antagonist
Early invasive management
CLOPIDOGREL Atorvastatin
Fondaparinux
Bivalirudin
Integrated strategy
PRASUGREL
Beta-Blockers (no ISA)
More Efficient and Less Variable Activation of Prasugrel Compared to Clopidogrel
Clopidogrel
CYP1A2, 2B6, 2C19
Intermediate
Active Metabolite
CYP3A, 2B6, 2C9, 2C19 Liver
CYP2C19 variants and inhibitors affect the PK and PD of clopidogrel
Liver
85% Inactive
Metabolite
hCE1
Prasugrel has no clinically relevant interactions with CYP2C19 variants or inhibitors
Prasugrel
Gut hCE2
Intermediate
Active Metabolite
Liver
Gut and CYP3A, 2B6,
2C9, 2C19
Time (Hrs) 0 2 4 6 8
0
100
300
400
500
600 A
ctiv
e M
etab
olite
Con
cent
ratio
n
(ng/
mL)
Clopidogrel 300 mg LD Clopidogrel 600 mg LD Prasugrel 60 mg LD
Higher Active Metabolite Concentrations of Prasugrel After Loading Dose
Cmax and Tmax influence onset of platelet inhibition • Relevant for loading dose but not maintenance dose
AUC influences extent of platelet inhibition • Relevant for loading and maintenance dose
36 Prasugrel 60 mg LD Achieves More Effective Platelet Inhibition than Clopidogrel
*; p < 0.001 vs. clop 300 mg/75 mg 600 mg/75 mg; †; p < 0.05 vs. clop 300 mg/75 mg; ‡; p < 0.001 vs. clop 300 mg/75 mg
Time (Hrs)
Inhi
bitio
n of
Pl
atel
et A
ggre
gatio
n (%
)
-10
0
20
40
60
80
100
24 0.25 0.5 1 2 4 6
*
* * * * *
0.0
Clopidogrel 300 mg LD
Prasugrel 60 mg LD Clopidogrel 600 mg LD
‡
†
‡
‡ ‡
2020
.01
Day 28 (0 hr)
- N
on R
espo
nder
s (%
)
0
10
20
30
40
50
60
Pras 60 mg
Clop 300 mg
Loading dose Maintenance dose
3% 3%
52%
36%
21%
0% 0%
45%
Day 1 (4 hr)
-
Pras 40 mg
Pras 5 mg
Pras 7.5 mg
Pras 10 mg
Pras 15 mg
Clop 75 mg
Prasugrel 60 mg LD with 10 mg MD Demonstrates Superior Response Compared to Clopidogrel
Jernberg et al., Eur Heart J 2006; 27:1166-1173
TRITON-TIMI 38 Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL 60 mg LD/ 10 mg MD
CLOPIDOGREL 300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, stroke 2o endpoints: CV death, MI, stroke, rehosp-Rec Isch CV death, MI, UTVR Stent thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, life-threatening bleeds Key substudies: Pharmacokinetic, genomic
Median duration of therapy - 12 months
N = 13,608
Balance of Efficacy and Safety: All ACS
Wiviott SD et al. NEJM 2007; 357: 2001-2015
HR 1.32 (1.03 - 1.68)
P = 0.03
35 events
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81 (0.73 - 0.90) P = 0.0004
Prasugrel
Clopidogrel
Days
Endp
oint
(%)
12.1%
9.9%
Prasugrel
Clopidogrel 1.8% 2.4%
138 events
CV death / MI / stroke
NNT = 46
NNH = 167
TIMI major Non-CABG bleeds
Antiplatelet Therapy in ACS
Single Antiplatelet Rx
Dual Antiplatelet Rx
Higher IPA
ASA ASA + Clopidogrel ASA +
Prasugrel - 22%
- 20%
- 19%
+ 60% + 38% + 32%
Reduction in
Ischemic Events
Increase in
Major Bleeds
0
100
Placebo APTC CURE TRITON-TIMI 38
Wiviott SD et al. NEJM 2007; 357: 2001-2015
Isch
emic
eve
nts
Net Clinical Benefit in Subgroups: Death / MI / CVA / Major Bleed Post-Hoc Analysis
OVERALL
≥ 60 kg
< 60 kg
< 75 yrs
≥ 75 yrs
No Yes
0.5 1 2
Prior TIA / stroke
Age
Weight
Risk (%)
+ 54
-16
-1
-16
+3
-14
-13
HR
Pint = 0.006
Pint = 0.18
Pint = 0.36
Wiviott SD et al. NEJM 2007; 357: 2001-2015
Favors Prasugrel
Favors Clopidogrel
Modified from Wiviott SD et al. NEJM 2007; 357: 2001-2015
Balance of Efficacy and Safety in Patients < 75 Yrs, ≥ 60 kg, and without Prior TIA/Stroke
0
2
4
6
8
10
12
14
16
0 30 90 180 270 360 450
Endp
oint
(%)
Hazard Ratio, 1.240 (95% CI, 0.91 - 1.69)
P = 0.17
Hazard Ratio, 0.75 (95% CI, 0.66 - 0.84)
P < 0.001
Clopidogrel 11.0%
Prasugrel 8.3%
Clopidogrel 1.50%
Prasugrel 2.0%
Days
CV death, NF MI, or NF stroke
TIMI major bleeding
Therapeutic Considerations
Significant Net Clinical Benefit
with Prasugrel 80%
MD 10 mg
16%
4%
Wiviott SD et al. NEJM 2007; 357: 2001-2015
Kaplan-Meier estimates of the incidence of the primary composite endpoint and of non-CABG related TIMI Major bleeding for All ACS patients with diabetes.
30 90 0 180 270 360 450
Hazard Ratio, 1.06 (95% CI, 0.66-1.69)
p=0.81
All ACS Patients with Diabetes
12.2%
17.0%
2.5%
2.6%
Hazard Ratio, 0.705 (95% CI, 0.58-0.85)
p<0.001
Prasugrel
Clopidogrel
Clopidogrel
TIMI Major Bleeding Prasugrel
CV Death, NF MI , or NF Stroke
Days From Randomization or First Dose
KM
Est
imat
es o
f Eve
nt R
ate
(%)
0
5
10
15
20
Observed incidence and hazard ratios for primary composite endpoint (CV death, Nonfatal MI, or Nonfatal Stroke) and components of the primary and secondary endpoints for All ACS patients with diabetes.
Clopidogrel % (n/N)
Prasugrel % (n/N)
Diabetic Population CV Death, NF MI, or NF Stroke
All ACS 11.4 (180/1576)
15.8 (248/1570)
UA/NSTEMI 10.8 (135/1246)
15.0 (184/1226)
STEMI 13.6 (45/330)
18.6 (64/344)
HR (95% CI)
Subjects receiving Insulin CV Death, NF MI, or NF Stroke
13.7 (52/379)
20.2 (80/397)
10.7 (128/1197)
14.3 (168/1173)
Subjects not receiving Insulin CV Death, NF MI, or NF Stroke
0.5 1.0 2.0
Overall Population CV Death, NF MI, or NF Stroke
Hazard Ratio Observed Incidence
9.4 (643/6813)
11.5 (781/6795)
◄
Outcome Events
◄
Favors Prasugrel
Favors Clopidogrel
Aspirin Clopidogrel Prasugrel ?
August 30, 2009
TICAGRELOR: A New Oral Antiplatelet Agent That Reduces
Cardiovascular Mortality in ACS Patients
TICAGRELOR: First and Only Approved CPTP TICAGRELOR, a new chemical class,
is a cyclo-pentyl-triazolo-pyrimidine (CPTP)
Ticagrelor is direct acting (not a pro-drug and does not require metabolic activation)
It binds directly to P2Y12 receptors and reversibly interacts with the receptor, to prevent platelet activation and aggregation
Thienopyridines bind covalently to P2Y12 ADP binding site for the life of the platelet
P2Y12 receptor
on platelet
Ticagrelor
ADP binding site
Husted S, et al. Eur Heart J. 2006;27:1038–1047.
Gurbel PA, et al. Expert Opin Drug Metab Toxicol. 2009;5(8):989–1004.
Van Giezen JJ, et al. J Thromb Haemost. 2009;7:1556-1565.
Adapted from Schomig A. N Engl J Med. 2009;361:1108–1111.
Ticagrelor: Does NOT require metabolic activation to
become active drug
Clopidogrel: A prodrug; requires metabolism to
become active drug
CYP-dependent oxidation CYP1A2 CYP2B6
CYP2C19
CYP-dependent oxidation CYP2C19 CYP3A4/5 CYP2B6 Active compound
Intermediate metabolite
Prodrug
Ticagrelor
Clopidogrel
Binding
P2Y12
TICAGRELOR: Does Not Require Hepatic Metabolism for Activation
Platelet
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24
Inhibition of Platelet Aggregation: Onset
Ticagrelor (n=54)
Clopidogrel (n=50)
Placebo (n=12)
Time (Hours)
Inhi
bitio
n of
Pla
tele
t Agg
rega
tion
*P<0.0001Ticgrelor vs Clopidogrel
Loading Dose
Ticagrelor 180-mg loading dose in Stable CAD patients Clopidogrel 600-mg loading dose in Stable CAD patients
* * * *
Adapted from Gurbel PA, et al. Circulation. 2009;120:2577–2585.
*
*
PLATO: Study Design Initial treatment approaches 18,624 patients with ACS
(UA, NSTEMI, or STEMI*) randomized within 24
hours of symptom onset
180-mg loading dose 90 mg bid + ASA Maintenance dose
Patients could be taking clopidogrel at time of randomization
• Medically managed (n=5,216 — 28.0%) • Invasively managed (n=13,408 — 72.0%)
Ticagrelor (n=9,333) Clopidogrel (n=9,293)
6–12 months of double-blind treatment
300-mg loading dose† 75 mg qd + ASA Maintenance dose
Primary efficacy endpoint: Composite of CV death, MI
(excluding silent MI), or stroke
Primary safety endpoint: Total PLATO major bleeding‡
*STEMI patients scheduled for primary PCI were randomized; however, they may not have received PCI.
†A loading dose of 300-mg clopidogrel was permitted in patients not previously treated with clopidogrel, with an additional 300 mg allowed at the discretion of the investigator.
‡The PLATO study expanded the definition of major bleeding to be more inclusive compared with previous studies in ACS patients. The primary safety endpoint was the first occurrence of any major bleeding event.
1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. 2. James S, et al. Am Heart J. 2009;157:599–605.
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)
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
4,147 8,219
0 2 4 6 8 10 12
12 11 10 9 8 7 6 5 4 3 2 1 0
13
Cum
ulat
ive
Inci
denc
e (%
) 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
5.4 Clopidogrel
TICAGRELOR
ARR=1.9% RRR=16% NNT=54* P<0.001
HR: 0.84 (95% CI, 0.77–0.92)
0–12 Months
PLATO: Predefined Testing of Primary and Major Secondary Efficacy Endpoints
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
All Patients* TICAGRELOR (n=9,333)
Clopidogrel (n=9,291)
HR for TICAGRELOR (95% CI) P Value**
Primary endpoint, n (%/year)
Death from vascular cause + MI† + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001
Secondary endpoints, n (%/yr)
Death from any cause + MI† + stroke 901 (10.2) 1,065 (12.3) 0.84 (0.77–0.92) <0.001
Death from vascular causes + MI† + stroke + severe recurrent ischemia + recurrent ischemia + TIA + arterial thrombus
1,290 (14.6) 1,456 (16.7) 0.88 (0.81–0.95) <0.001
MI† 504 (5.8) 593 (6.9) 0.84 (0.75–0.95) 0.005
Death from vascular causes 353 (4.0) 442 (5.1) 0.79 (0.69–0.91) 0.001
Stroke 125 (1.5) 106 (1.3) 1.17 (0.91–1.52) 0.22
Death from any cause 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001‡ Nominal
Significance
Both groups included aspirin. The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months.
* Patients could have had more than one type of endpoint. Death from CV causes and fatal bleeding, as only traumatic fatal bleeds were excluded from the CV death category. ** By Cox regression analysis using treatment as factor; †Excluding silent MI; ‡Death from any cause was tested after stroke,
which was non-significant, so the results should be considered nominally significant.
Months After Randomisation 0 2 4 6 8 10 12
6
5
4
3
2
1
0
7
Cum
ulat
ive
Inci
denc
e (%
)
Clopidogrel
TICAGRELOR
5.8
6.9
0 2 4 6 8 10 12
6
4
3
2
1
0
Clopidogrel
TICAGRELOR
4.0
5.1
7
5
Months After Randomisation
Myocardial Infarction Cardiovascular Death
Cum
ulat
ive
Inci
denc
e (%
)
PLATO: Secondary Efficacy Endpoints
Rate of stroke for TICAGRELOR was not different from clopidogrel (1.3% vs 1.1% ), P=0.225.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Supplement.
BRILIQUE: Summary of Product Characteristics, 2010.
ARR=1.1% RRR=16%
Calculated 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)
Both groups included aspirin.
P=0.43 HR: 1.04 (95% CI, 0.95–1.13)
PLATO: Primary Safety Endpoint
PLAT
O-d
efin
ed T
otal
M
ajor
Ble
edin
g (%
)
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Days From First Dose
10
5
0
15
0 60 120 180 240 300 360
Clopidogrel
TICAGRELOR
11.2% 11.6% P=NS
No. at risk
Clopidogrel
TICAGRELOR
9,186
9,235
7,305
7,246
6,930
6,826
6,670 5,209
5,129
3,841
3,783
3,479
3,433 6,545
Both groups included aspirin.
PLATO: Bleeding
11.6
5.8
0.3
16.1
4.5
7.4
11.2
5.8
0.3
14.6
3.8
7.9
0
2
4
6
8
10
12
14
16
18BRILINTA (n=9,235)Clopidogrel (n=9,186)
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
All values presented by PLATO criteria. Both groups included aspirin.
Major Bleeding Non-CABG-Major Bleeding
Major and Minor Bleeding
Life-threatening/ Fatal Bleeding
Fatal Bleeding CABG-Major Bleeding
K-M
Est
imat
ed R
ate
(% P
er Y
ear)
NS
P = 0.03
P = 0.008
NS
NS
NS
PLATO: Dyspnea
Ticagrelor-associated dyspnea 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 Ticagrelor Label precautions and warnings: use with caution in patients with history of asthma
and COPD
Ticagrelor: 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.
Dyspnoea in the PLATO trial Ticagrelor Clopidogrel P Value
Incidence of dyspnea adverse events (%) 13.8 7.8 <0.001
Patients who discontinued treatment due to dyspnoea (%) 0.9 0.1 <0.001
PLATO: Bradycardia-related Events
All Patients Ticagrelor (n=9,235)
Clopidogrel (n=9,186) 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
• Ventricular pauses ≥3 seconds occurred in 5.8% of ticagrelor-treated patients vs 3.6% of clopidogrel-treated patients in the acute phase, and 2.1% and 1.7% after 1 month, respectively
• There were no differences in adverse clinical consequences (ie, pacemaker insertion, syncope, bradycardia, and heart block)
• Label precautions and warnings: Ticagrelor should be used with caution in patients at risk of bradycardic events
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, 2010.
PLATO: Laboratory Parameters
All Patients Ticagrelor (n=9,235)
Clopidogrel (n=9,186) P Value
Mean % increase (± SD) in serum creatinine from baseline
At 1 month 10 ± 22 8 ± 21 <0.001
At 12 months 11 ± 22 9 ± 22 <0.001
1 month after end of treatment 10 ± 22 10 ± 22 0.59
Mean % increase (± SD) in serum uric acid from baseline
At 1 month 14 ± 46 7 ± 44 <0.001
At 12 months 15 ± 52 7 ± 31 <0.001
1 month after end of treatment 7 ± 43 8 ± 48 0.56
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, 2010.
• Creatinine levels may increase during treatment with ticagrelor; renal function should be checked after 1 month and thereafter according to medical practice
• Label precautions and warnings: as a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged
Presented at ESC 2009 as an oral presentation Subsequently published in Lancet, January 2010 A pre-specified objective of PLATO was to compare outcomes of
Ticagrelol versus clopidogrel in patients with planned invasive strategy at randomization
For all patients, the intention for early invasive management had to be indicated by the investigator before patients were randomized
Cannon CP, et al. Lancet. 2010;375:283−293.
Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study Christopher P. Cannon, Robert A. Harrington, Stefan James, et al. for the PLATelet inhibition and patient Outcomes (PLATO) investigators
PLATO Primary Endpoint: Initial Invasive vs Initial Non-Invasive Management
0
2
4
6
8
10
12
14
16
0 60 120 180 240 300 360Days After Randomisation
James S, et al. ESC 2010; Poster #1353.; Cannon C, et al. Lancet. 2010;375:283–293.
10.7%
9%
Clopidogrel
Ticagrelor
6,676
6,732
6,129
6,236
6,034
6,134
5,881 4,815
4,889
3,680
3,735
2,965
3,048 5,972 Ticagrelor
Clopidogrel
Initial Invasive 72% of patients in PLATO
P<0.0025 HR: 0.84 (95% CI, 0.75–0.94)
Initial Non-Invasive 28% of patients in PLATO
2,615
2,601
2,392
2,392
2,328
2,326
2,243 1,835
1,854
1,416
1,426
1,109
1,099 2,247 Ticagrelor
Clopidogrel
P<0.045 HR: 0.85 (95% CI, 0.73–1.00)
14.3%
12% Clopidogrel
Ticagrelor
K-M
Est
imat
ed R
ate
Prim
ary
C
ompo
site
of C
V D
eath
/MI/S
trok
e (%
) No. at risk
Days After Randomisation
K-M
Est
imat
ed R
ate
Prim
ary
C
ompo
site
of C
V D
eath
/MI/S
trok
e (%
)
PLATO: Outcomes of Predefined Efficacy Endpoints A as Described in the EU Label
Ticagrelor % patients with event
(n=9,333)
Clopidogrel % patients with event
(n=9,291)
ARRa
(%/yr) RRRa (%)
(95% CI) P Value
CV Death + Mib + stroke 9.3 10.9 1.9 16 (8,23) 0.0003
Invasive intent 8.5 10.0 1.7 16 (6, 25) 0.0025
Non-Invasive intent 11.3 13.2 2.3 15 (0.3, 27) 0.0444c
CV death 3.8 4.8 1.1 21 (9, 31) 0.0013
MIb 5.4 6.4 1.1 16 (5, 25) 0.0045
Stroke 1.3 1.1 -0.2 -17 (-52, 9) 0.2249
All-cause mortality + MIb + stroke 9.7 11.5 2.1 16 (8, 23) 0.0001
CV Death + Mib + stroke + severe recurrent ischemia + recurrent ischemia + TIA + arterial thrombus
13.8 15.7 2.1 12 (5, 19) 0.0006
All-cause mortality 4.3 5.4 1.4 22 (11, 31) 0.0003c
Definitive stent thrombosis 1.2 1.7 0.6 32 (8, 49) 0.0123c
Both groups included aspirin. The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months.
aARR=absolute risk reduction; RRR=relative risk reduction = (1-Hazard ratio) x 100%. A negative RRR indicates a relative risk increase.; bExcluding silent myocardial infarction.; cNominal significance value; all others are formally statistically significant by pre-defined hierarchical testing.
Ticagrelor: Summary of Product Characteristics, 2010.
TICAGRELOR Indication
Ticagrelor, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndromes (unstable angina, non–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)
Ticagrelor: Summary of Product Characteristics, 2010.
By Diagnosis By Treatment
UA/NSTEMI STEMI Medical management PCI 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
Aspirin
Clopidogrel Prasugrel
Ticagrelor
?
1. The availability, of new treatment alternatives for stroke prevention in patients with nonvalvular atrial fibrillation is a great step forward to further improve outcomes and quality of life.
2. Compared with warfarin, these new alternatives have important advantages, with their lower risk of intracranial bleeding, no clear interactions with food, fewer interactions with medications, and no need for frequent laboratory monitoring and dose adjustments.
3. Dabigatran etexilate is a synthetic low molecular weight peptidomimetic that binds directly and reversibly to the catalytic site of thrombin.
4. Rivaroxaban, apixaban, and endoxaban are selective direct factor Xa inhibitors.
5. Based on the currently available results from the individual trials, it is clear that both the oral direct thrombin inhibitor dabigatran etexilate and the oral factor Xa inhibitors apixaban and rivaroxaban are attractive alternatives to warfarin or aspirin in patients with nonvalvular atrial fibrillation and an increased risk of stroke.
New Anticoagulants in AF and ACS Perspective:
6. Apixaban 5 mg (with dose reduction to 2.5 mg in specific cases) BID is currently the best documented alternative to both warfarin and aspirin for stroke prevention in a broad population with atrial fibrillation and increased risk of stroke, based on two independent large-scale trials. Apixaban is awaiting Food and Drug Administration approval in the United States for atrial fibrillation.
7. Patients already on long-term vitamin K antagonist (VKA) treatment, with well-controlled international normalized ratio and handling VKA treatment and laboratory monitoring without problems, derive uncertain overall advantages from switching to the new oral anticoagulants, and the arguments for changing treatment in such patients appear weak.
8. There is also a need for more information on how to manage patients with bleeding because there are no specific antidotes for any of the new agents.
9. The cost of the drug at the patient level might be an obstacle to their use, although the cost-effectiveness at a societal level might be tolerable in comparison with other recently accepted novel treatments.
10.Additional trials are indicated to determine the utility of these agents in combination with antiplatelet treatments after myocardial infarction and percutaneous coronary intervention.
New Anticoagulants in AF and ACS Perspective:
PCI
Optimal ED Treatment:
Non-ST Elevation ACS, with Cath Lab
Low Molecular Weight Heparin/UFH
Gp IIb/IIIa
ASA + CLOPIDOGREL or PRASUGREL or TICAGRELOL
MM v T
Optimal ED Treatment:
Non-ST Elevation ACS, without Cath Lab
Gp IIb/IIIa
LOW MOLECULAR WEIGHT HEPARIN / UFH
ASA + CLOPIDOGREL or PRASUGREL or TICAGRELOL
ST- ELEVATION ACS Treatment
Emergency physicians should be using optimal therapy for ACS in the ED. In the STE ACS patient, time = muscle. Whether the patient is managed interventionally or medically, the treatment imperative starts in the ED.
In thrombolytic therapy, enoxaparin with TNKase or t-PA appears to be superior to UFH.
In interventional management, enoxaparin was superior to UFH in ENTIRE / TIMI-23.
“Best Practice” Approach to the ACS Patient
Anti-ischemic therapy
Anti-thrombotic therapy
Ongoing risk stratification
Invasive procedures (when appropriate)
ASA + antiplatelet / anticoagulant as
background therapy
LMWH: anticoagulant of choice Enoxaparin:- superior to UFH - recurrent ACS - hospital stay - costs
Therapeutic approach
ASA + anticoagulant + GPIIb/IIIa in high
risk patients
Area of concern
Thank you for your attention!
