26.9.13 antiplatelet how to choose your bride among three sisters

Dr. Rajeev Agarwala
Jaswant Rai Speciality Hospital, Meerut.
E-mail : rajeev_jrsh@yahoo.co.in
HOW TO CHOOSE YOUR BRIDE
AMONG THREE SISTERS

4. Plaque rupture,
cholesterol content,
inflammation (hs-CRP)
(statins)
3. Platelet adhesion/
activation/aggregation
(aspirin, clopidogrel,
GP IIb/IIIa inhibitors)
2. Activation of clotting
cascade – thrombin
(heparin/LMWH)
1. Downstream from thrombus
myocardial ischaemia/necrosis
(β-blockers, nitrates etc)
PlateletPlatelet
GP IIb/IIIaGP IIb/IIIa
receptorreceptor
FibrinogenFibrinogen
ThrombinThrombin
FibrinFibrin
clotclot
Pathophysiology of ACS and potential
pharmacological interventions

Central role of platelets in
atherothrombosis and stent
thrombosis

Heart 2003;89:1273-1278
Pathways of Platelet Activation

BRIDGING THE GAPBRIDGING THE GAP

Trial
Indication
Duration
CHARISMA CURE CREDO
PCI-CURE
PCI-CLARITY
CLARITY
COMMIT
Stable CVD
MI
Stroke
PAD
ACS
UA/NSTEMI
PCI
Stable CAD
UA/NSTEMI
STEMI
STEMI
28 months 9 months 1-12 months 8-28 days

PIVOTAL TRIALS OF DUAL ORAL
ANTIPLATELET THERAPY IN ACS
CURE (2001) N=12, 562 11.4% 9.3% P< .001
Primary Endpoint Reached
ASA + Placebo ASA + Clopidogrel
UA/NSTEMI
CLARITY TIMI-28
STEMI < 12 hrs
N=3491 21.7% 15.0% P< .001
STEMI
COMMIT
93% STEMI or BBB + 24 hrs
N=45,852 10.1% 9.2% P= .002

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, UTVR
Stent Thrombosis (ARC definite/probable)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
Median duration of therapy - 12 months
N= 13,600
Wiviott SD et al. Am Heart J 2006;152:627-35

Net Clinical Benefit
Death, MI, Stroke,
Major Bleed (non CABG)
0
5
10
15
0 30 60 90 180 270 360 450
Days
Endpoint(%)
HR 0.87
P=0.004
13.9
12.2
Prasugrel
ClopidogrelITT= 13,608ITT= 13,608
-23
6
-25
-20
-15
-10
-5
0
5
10
Events per 1000 ptsEvents per 1000 pts
MIMI
Major BleedMajor Bleed
(non CABG)(non CABG)
++
All CauseAll Cause
MortalityMortality
Clop 3.2%Clop 3.2%
Pras 3.0 %Pras 3.0 %
P=0.64P=0.64

0
2
4
6
8
0 1 2 3
1
0
306090 180 270 360 450
HR 0.82
P=0.01
HR 0.80
P=0.003
5.6
4.7
6.9
5.6
Days
PrimaryEndpoint(%)
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel
Loading Dose Maintenance Dose
Timing of BenefitTiming of Benefit

0
3
6
9
Days
CVDeath,MI,Stroke(%)
No GP IIb/IIIa Inhibitor Used
GP IIb/IIIa Inhibitor Used
Benefit Regardless ofBenefit Regardless of
GP IIb/IIIa UseGP IIb/IIIa Use
O’Donoghue M et al. JACC 2009;54:678-85
0 3015
Days
0 3015
HR 0.76
(0.64-0.90)
P=0.001
HR 0.78
(0.63-0.97)
P=0.026
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel

Diabetic Subgroup
0
2
4
6
8
10
12
14
16
18
0 30 60 90 180 270 360 450
HR 0.70
P<0.001
Days
Endpoint(%)
CV Death / MI / Stroke
TIMI Major
NonCABG Bleeds
NNT = 21
N=3146N=3146
17.0
12.2
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel 2.6
2.5
Wiviott SD et al. NEJM 2007;357:2001-15

Prasugrel, in ACS patients with diabetes
undergoing PCI, is associated with significant
reduction in primary endpoint compared to
clopidogrel without increase in bleeding events.

Prasugrel, in STEMI patients undergoing PCI, is
associated with significant reduction in primary
endpoint compared to clopidogrel without
increase in bleeding events.

TRITON-TIMI 38: Major
Efficacy End Points
Wiviott SD et al., N Engl J Med 2007
0.5
Prasugrel Better Clopidogrel Better
HR
0.4 0.6 0.7 0.8 0.9 1.1 1.2 1.3 1.41.0 1.5
Stent Thrombosis
Urgent traget vesell revasc.
All Cause Death
Nonfatal stroke
Nonfatal MI
CV Death
Primary Endpoint

Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke 19%
Stent Thrombosis 52%
uTVR 34%
MI 24%
2. An early and sustained benefit
3. Across ACS spectrum
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Conclusions
Higher IPA to Support PCI
Net clinical benefit significantly favored PrasugrelNet clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve theOptimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balancebenefit : risk balance

Prasugrel in medically managed ACS
patients

TRILOGY ACS Study Design
Medically Managed UA/NSTEMI PatientsMedically Managed UA/NSTEMI Patients
Clopidogrel1
75 mg MD
Clopidogrel1
75 mg MD
Prasugrel1
5 or 10 mg MD
Prasugrel1
5 or 10 mg MD
Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 monthsMinimum Rx Duration: 6 months; Maximum Rx Duration: 30 months
Primary Efficacy Endpoint: CV Death, MI, StrokePrimary Efficacy Endpoint: CV Death, MI, Stroke
Randomization Stratified by:
Age, Country, Prior Clopidogrel Treatment
(Primary analysis cohort — Age < 75 years)
Randomization Stratified by:
Age, Country, Prior Clopidogrel Treatment
(Primary analysis cohort — Age < 75 years)
Clopidogrel1
300 mg LD
+
75 mg MD
Clopidogrel1
300 mg LD
+
75 mg MD
Prasugrel1
30 mg LD
+
5 or 10 mg MD
Prasugrel1
30 mg LD
+
5 or 10 mg MD
Medical Management Decision ≤72 hrs
(No prior clopidogrel given) — 4% of total
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
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.
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

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
HR (95% CI):
0.91 (0.79, 1.05)
P = 0.21
Interaction P =
0.07
Age<70years

Evaluation of All Ischemic Events Over
Time*
(Age < 75 years)
Prasugrel Clopidogrel
≥ 1 event 364 397
≥ 2 events 77 109
3–7 events 18 24
 Lower risk multiple recurrent ischemic events suggested withLower risk multiple recurrent ischemic events suggested with
prasugrel using the pre-specified Andersen-Gill modelprasugrel using the pre-specified Andersen-Gill model
(HR = 0.85, 95% CI: 0.72–1.00, P=0.04)(HR = 0.85, 95% CI: 0.72–1.00, P=0.04)
 Significant interaction with treatment and time (HR for > 12 mos =Significant interaction with treatment and time (HR for > 12 mos =
0.64, 95% CI: 0.48–0.86, Interaction P=0.02)0.64, 95% CI: 0.48–0.86, Interaction P=0.02)
* Pre-specified evaluation of all CV death, MI, or stroke events by treatment

Primary Efficacy Endpoint and
TIMI Major Bleeding Through 30
Months
(Overall population)
HR (95% CI):
0.96 (0.86,
1.07)
P = 0.45
HR (95% CI):
1.23 (0.84,
1.81)
P = 0.29

Conclusions
 In the largest trial to date of ACS patients managed medically
without revascularization, prasugrel was not statistically
different from clopidogrel during 2.5 years of follow-up
among patients < 75 years of age
 Further analyses of the primary endpoint yielded several
important findings favoring prasugrel treatment
• Trend for a time-dependent benefit after 1 year
• Fewer total recurrent ischemic events, particularly after 1
year
 No statistical differences in major, life-threatening, or fatal
bleeding with prasugrel vs. clopidogrel

PLATO study design
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
6–12-month exposure
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;
CV = cardiovascular; TIA = transient ischaemic attack

No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,521
8,628
8,362
8,460
8,124
Days after randomisation
6,743
6,743
5,096
5,161
4,047
4,147
0 60 120 180 240 300 360
12
11
10
9
8
7
6
5
4
3
2
1
0
13
Cumulativeincidence(%)
9.8
11.7
8,219
HR 0.84 (95% CI 0.77–0.92), p=0.0003
Clopidogrel
Ticagrelor
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
Wallentin L et al. NEJM 2009;361:1045-57.

0 60 120 180 240 300 360
6
4
3
2
1
0
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79
(95% CI 0.69–0.91) P=0.001
7
5
9,291
9,333
8,865
8,294
8,780
8,822
8,589
7079
7119
5,441
5,482
4,364
4,4198,626
Cardiovascular death
All-cause mortality
4.5% vs. 5.9%
HR 0.78
(0.69-0.89)
P<0.001

8,688
8,763
0 10 20 30
8
6
4
2
0
Clopidogrel
Ticagrelor
4.77
5.43
HR 0.88 (95% CI 0.77–1.00), p=0.045
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,875
8,942
8,763
8,827
31 90 150 210 270 330
8
6
4
2
0
Clopidogrel
Ticagrelor
5.28
6.60
8,688
8,673
8,286
8,397
6,379
6,480
Days after randomisation*
HR 0.80 (95% CI 0.70–0.91), p<0.001
8,437
8,543
6,945
7,028
4,751
4,822
*Excludes patients with any primary event during the first 30 days

Stent thrombosis
Ticagrelor
(n=5,640)

Clopidogrel
(n=5,649)
   HR
(95% CI) p value
Stent thrombosis, n (%)
   Definite
   Probable or definite
   Possible, probable, definite

71 (1.3)
118 (2.1)
   155 (2.8)
106 (1.9)
158 (2.8)
202 (3.6)
0.67 (0.50–0.91)
0.75 (0.59–0.95)
0.77 (0.62–0.95)
0.009
0.02
0.01
(evaluated in patients with any stent during the study)
*Time-at-risk is calculated from first stent insertion in the study or date of randomisation

NS
NS
NS
NS
NS
0
K-Mestimatedrate(%peryear)
PLATO major
bleeding
1
2
3
4
5
6
7
8
9
10
12
11
13
TIMI major
bleeding
Red cell
transfusion*
PLATO life-
threatening/
fatal bleeding
Fatal bleeding
Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use
of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15;
*
Proportion of patients (%); NS = not significant
11.6
11.2
7.9 7.7
8.9 8.9
5.8 5.8
0.3 0.3
Ticagrelor
Clopidogrel

Non-CABG and CABG-related major
bleeding
p=0.026
p=0.025
NS
NS
9K-Mestimatedrate(%peryear)
Non-CABG
PLATO major
bleeding
8
7
6
5
4
3
2
1
0
Non-CABG
TIMI major
bleeding
CABG
PLATO major
bleeding
CABG
TIMI major
bleeding
4.5
3.8
2.8
2.2
7.4
7.9
5.3
5.8
Ticagrelor
Clopidogrel

Conclusions
 Reversible, more intense P2Y12 receptor inhibition for
one year with ticagrelor in comparison with
clopidogrel in a broad population with ST- and non-
ST-elevation ACS provides
 Reduction in myocardial infarction and stent thrombosis
 Reduction in cardiovascular and total mortality
 No change in the overall risk of major bleeding
Ticagrelor is a more effective alternative than clopidogrel
for the continuous prevention of ischaemic events, stent thrombosis
and death in the acute and long-term treatment
of patients with ACS

Thromb Haemost 2012; 108: 318-327

Efficacy comparison of High dose
clopidogrel, prasugrel and
ticagrelor strategies vs.
standard clopidogrel therapy
OASIS-7 PCI (2010) TRITON TIMI-38 (2007) PLATO (2009)
High dose
clopidogrel
Standard
clopidogrel
Risk
reduction
Prasugrel Standard
clopidogrel
Risk
reduction
Ticagrelor Standard
clopidogrel
Risk
reduction
Primary
endpoint
3.9% 4.5% 14% 9.9% 12.1% 19% 9.0% 10.7% 16%
All Cause
Death
1.9% 2.1% 6% 3% 3.2% 5% 3.9% 5% 19%
Non-fatal MI 2% 2.6% 21% 7.3% 9.5% 14% 5.3% 6.6% 20%
Stent
thrombosis
1.6% 2.3% 31% 1.1% 2.4% 52% 2.2% 3% 27%

Bleeding comparison of High dose
clopidogrel, prasugrel and
ticagrelor strategies vs.
standard clopidogrel therapy
OASIS-7 PCI (2010) TRITON TIMI-38 (2007) PLATO (2009)
High dose
clopidogre
l
Standard
clopidogrel
HR Prasugrel Standard
clopidogre
l
HR Ticagrelor Standard
clopidogrel
HR
Total
Major
Bleeding
1% 0.7% 1.36 2.5% 1.7% 1.46 7.9% 7.9% 1.0
Non-
CABG
related
Major
bleeding
0.8% 0.6% 1.34 2.4% 1.8% 1.32 2.8% 2.2% 1.23

Study Overview: Prasugrel / Ticagrelor
ST-Elevation Myocardial Infarction
Non ST-Elevation Acute Coronary Syndromes
Medically Managed Pts – NSTE ACS
Stable Angina
Diabetes mellitus
Chronic Kidney Disease
Limitations and Contraindications
Antiplatelet Therapies – The Dynamics

0
5
10
15
0 30 60 90 180 270 360 450
Endpoint(%)
Days
9.5%
6.5%
12.4%
10.0%
Clopidogrel
Prasugrel
CV death / MI / stroke
Efficacy of prasugrel in STEMI
Montalescot G et al., Lancet 2009
NNT = 42
P = 0.02

0
1
2
3
4
5
30 days 15 months
P=0.04 P=0.11
Incidence of death from any cause (%)
Lower early mortality with prasugrel in
STEMI
Clopidogrel
Prasugrel
2.6
1.6
4.3
3.3

0
5
10
15
0 30 60 90 180 270 360 450
Endpoint(%)
Days
TIMI major
non-CABG bleeds
Clopidogrel
Prasugrel 2.4%
2.1%
Safety of prasugrel in STEMI
NNH = 333
P = 0.65

Steg PG et al., Circulation 2010
Benefit of ticagrelor in STEMI

0
2.5
5.0
7.5
8 months
P=0.05
Incidence of death from any cause (%)
Lower all-cause mortality with ticagrelor in STEMI
Clopidogrel
Ticagrelor
6.1
5.0

Safety of ticagrelor in STEMI

Similar efficacy and safety in STEMI
TRITON: Prasugrel
1° efficacy endpoint
All cause mortality
1° safety endpoint
PLATO: Ticagrelor
1° efficacy endpoint
All cause mortality
1° safety endpoint
Hazard ratio for 1° endpoint
(95 % - confidence limit)
0.5 1 1.5
Study drug better Clopidogrel better
Montalescot G et al., Lancet 2009; Steg PG et al., Circulation 2010

Study Overview: Prasugrel / Ticagrelor
ST-Elevation Myocardial Infarction
Non ST-Elevation Acute Coronary Syndromes
Stable Angina
Diabetes mellitus
Chronic Kidney Disease
Limitations and Contraindications
Antiplatelet Therapies – The Dynamics

Similar efficacy of prasugrel in
STEMI and UA/NSTEMI15-month incidence of death/MI/stroke (%)
0
2
4
6
8
10
12
14
16
12.4
10.0
p=0.02
STEMI
NNT = 42
12.0
9.9
p=0.03
UA/NSTEMI
NNT = 47
Clopidogrel
Prasugrel

Favorable risk-benefit ratio of
prasugrel in UA/NSTEMI
Clopidogrel
Prasugrel
15-month incidence (%)
0
2
4
6
8
10
12
14
16
12.0
9.9
p=0.03
death/MI/stroke
NNT = 47
1.7
2.4
p=0.01
major non-CABG bleed
NNH = 142

TRITON: All cause mortality in NSTE-ACS vs.
STEMI
Wiviott SD et al., J Am Cardiol 2010
STEMI
NSTE-ACS
Hazard ratio for all cause mortality
0.5 1 1.5
Prasugrel better Clopidogrel better
Pint = 0.11

Favorable risk-benefit ratio of
ticagrelor in UA/NSTEMI
Clopidogrel
Ticagrelor
Wallentin L et al., N Engl J Med 2009, Steg PG et al., Circulation 2010
15-month incidence (%)
0
2
4
6
8
10
12
14
16
11.5
9.6
P = 0.001
death/MI/stroke
NNT = 52
7.8
8.2
P = 0.41
TIMI major bleed
NNH = 233

Differential efficacy in NSTE-ACS
Wiviott SD et al., J Am Cardiol 2010 & N Engl J Med 2007; Wallentin L et al., N Engl J Med
TRITON
1° endpoint
All cause mortality
PLATO
1° endpoint
All cause mortality
0.5 1 1.5

New P2Y12 inhibitors superior to
high-dose clopidogrel
Non-selected ACS
PLATO (ticagrelor)
OASIS-7 (high-dose clopidogrel)
ACS undergoing PCI
TRITON (prasugrel)
OASIS-7 PCI (high-dose clopidogrel)
Hazard ratio for 30-day 1° endpoint
0.5 1 1.5
study treatment
better
normal-dose clopidogrel
better
P = 0.045
P = 0.30
P < 0.001
P = 0.039
Wallentin L et al., N Engl J Med 2009
OASIS-7 investigators, N Engl J Med 2010
Mehta SR et al., Lancet 2010

Superior net clinical
benefit of prasugrel in
diabetics
Days
0
2
4
6
8
10
12
14
16
18
0 30 60 90 180 270 360 450
HR 0.70
P < 0.001
Endpoint(%)
CV death / MI / stroke
TIMI major
non-CABG bleeds
NNT = 21
17.0%
12.2%
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel 2.6%
2.5%
Wiviott SD et al. Circulation 2008

Wiviott SD et al., Circulation 2008
Superior efficacy of prasugrel in diabetics:
1° endpoint

Potent effect of prasugrel in diabetics:
Stent thrombosis

Safety of prasugrel in diabetics:
TIMI major non CABG bleeding

No interaction with diabetes in
PLATO: 1° endpoint
Pint = 0.49
James S et al., Eur Heart J 2010

No interaction with diabetes in
PLATO: Mortality
Pint = 0.66
James S et al., Eur Heart J 2010

Interaction with diabetes mellitus
Wiviott SD et al., Circulation 2008; James S et al., Eur Heart J 2010
TRITON
No diabetes
Diabetes
PLATO
No diabetes
Diabetes
0.5 1 1.5
Pint = 0.49
Pint = 0.09

Different interaction with renal function
Wiviott SD et al., N Engl J Med 2007; James S et al., Circulation 2010
TRITON 1° endpoint
CrCl < 60 mL/min
CrCl > 60 mL/min
Hazard ratio
0.5 1 1.5
Pint n.s.Pint n.s.
PLATO 1° endpoint
CrCl < 60 mL/min
CrCl > 60 mL/min
Pint = 0.13

12.1 %
3.1 %
3.3 %
10.0 %
ticagrelor
ticagrelor
clopidogrel
clopidogrel
Creatinine clearance > 60 ml/min
Creatinine clearance < 60 ml/min
Cumulative incidence of all-cause death
Days since randomization
No survival benefit of ticagrelor in normal creatinine clear
James S et al., Circulation 2010

0.5 1 2
OVERALL
Prasugrel Better Clopidogrel Better
No
YesPrior
Stroke / TIA Pint = 0.006
<75
≥75
Age
Pint = 0.18
≥60 kg
<60 kg
Weight
Pint = 0.36
www.timi.org – Accessed on July 16, 2008
Contraindication with history of cerebro-vascular
event
Hazard Ratio for net clinical outcome

Dyspnoea on Ticagrelor
Any dyspnoea With discontinuation
of study treatment
Incidence (%)
P < 0.001
7.7
0.1
13.8
0.9
Clopidogrel
0
5
15
10
Ticagrelor
P < 0.001

Exclusion criterion: Increased
risk of bradycardia
≥ 3 sec
Incidence of ventricular pauses during 1st week (%)
P = 0.01
3.6
1.2
5.8
2.0
Clopidogrel
0
2
6
4
Ticagrelor
P = 0.10
3
5
1
≥ 5 sec

P2Y12-Blockers in PCI
STEMI ACS - UA
Elective PCI
Non STEMI
Prasugrel Ticagrelor
Clopidogrel
Diabetes Mellitus
Normal Renal Function CKD
Ticagrelor over Prasugrel: <60 kg, Over 75 Yrs, Previous Stroke or TIA
Prasugrel over Ticagrelor: Bradycardia

TICAGRELOR
180 mg loading dose,
then 90 mg bid for
1 year (ASA < 100)
PRASUGREL
60 mg loading dose,
then 5-10 mg PO daily
for 1 year
CLOPIDOGREL
600 mg PO loading dose,
then 150 mg daily 1-4
weeks,
then 75 mg daily for
1 year
•R/O Contraindications
•PCI ( Clop naïve )
• STEMI
• Diabetic
• Stent Thrombosis
• Clopidogrel NR
•Irrespective of strategy
• Mod to High Risk
ACS/ NSTEMI (On or Off C)
• Unknown coronary
anatomy; CABG likely
•Clopidogrel NR
• All others, especially if
high-risk for bleeding
• Lung and renal disease
• Already on Clopidogrel
but no ischemic event
10-15% 40-50% 30-40%
Choice of Oral Antiplatelet
Therapy in ACS/PCI Patients

Antiplatelet Therapy in ACS
Placebo APTC CURE TRITON-TIMI 38
Single
Antiplatelet Rx
Dual
Antiplatelet Rx
Higher
IPA
ASA
ASA +
Clopidogrel ASA +
Prasugrel
- 22%
- 20%
- 19%
+ 60% + 38% + 32%
Reduction
in
Ischemic
Events
- 21%
PLATO

 ESC 2011 Antiplatelet guidelines for ACS
patients presenting ST segment
elevation

Current Research Questions
 Head to head comparison of APS.
 Short term / reversibility may increase the
incidence of stent thrombosis.
 Is aspirin still necessary in modern DAPT.

IMPATIENCE CAN BE CUMBERSOME
IMPATIENCE CAN BE CUMBERSOME

Results: MACE
Non significant 6%
reduction in MACE with
high dose clopidogrel in
overall study population
Significant 14%
reduction in MACE in
PCI subgroup with
high dose clopidogrel
Significant 19%
prasugrel after 15
months
Significant 22%
prasugrel after 30 days
of FU
Significant 16%
ticagrelor after 12
months of FU
Significant 12%
ticagrelor after 30 days
of FU
Significant 16%
ticagrelor in invasive
only subgroup

MACE: Clopidogrel high dose
vs. standard dose
Significant 26% risk reduction in
MACE with high dose
clopidogrel strategy compared
to standard dose clopidogrel
therapy

Other Adverse Events
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186) p value
Ventricular pauses ≥3 sec on Holter, %
In 1st
week (n=2866 w/ Holter)
At 30 days (n=1991 w/ Holter)
5.8
2.1
3.6
1.7
0.01
0.52
Bradycardia-related event, %
Pacemaker Insertion
Syncope
Bradycardia
Heart block
0.9
1.1
4.4
0.7
0.9
0.8
4.0
0.7
0.87
0.08
0.21
1.00
Dyspnea, %
Any
Leading to d/c of study treatment
13.8
0.9
7.8
0.1
<0.001
<0.001

Dyspnea Associated with
Ticagrelor
 Usually mild to moderate
 Observed within 1st
7 days, median time 23 days, mostly resolves
spontaneously
 Patients with baseline cardiopulmonary disease were not at an
increased relative risk of dyspnea
 No measured changes in pulmonary function/ BNP levels
 Benefit of ticagrelor is maintained in patients at risk
for dyspnea and those who experience dyspnea
 Patient with mild to moderate dyspnea should be encouraged
to continue withTicagrelor considering consistency of benefit
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057

Key Messages Diabetes
 Overall PEP consistent with PLATO Main results
 Driven by MI and CVD like PLATO main results
 No Increase in PLATO Major, LT, Non-CABG Major
Bleeds.
 Benefit of PLATO trial design

PLATO hierarchical
testing of major efficacy
endpoints
*The percentages are K-M 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.
All Patients*All Patients*
TicagrelorTicagrelor
(n=9333)(n=9333)
ClopidogrelClopidogrel
(n=9291)(n=9291)
HR forHR for
ticagrelorticagrelor
(95% CI)(95% CI)
PP valuevalue††
Primary objective, n
(%/year)
CV death + MI + stroke 864 (9.8) 1014 (11.7) 0.84 (0.77–0.92) 0.0003
Secondary objectives,
n (%/yr)
Total death + MI + stroke 901 (10.2) 1065 (12.3) 0.84 (0.77–0.92) 0.0001
CV death + MI + stroke +
severe + recurrent
ischemia + TIA + arterial
thrombus
1290 (14.6) 1456 (16.7) 0.88 (0.81–0.95) 0.0006
MI 504 (5.8) 593 (6.9) 0.84 (0.75-0–95) 0.0045
CV death 353 (4.0) 442 (5.1) 0.79 (0.69–0.91) 0.0013
Stroke 125 (1.5) 106 (1.3) 1.17 (0.91–1.52) 0.2249
Total death 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) 0.0003
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057

Clop
Efficacy Across Patient
Subgroups
Age
Overall Treatment Effect
Sex
Body Weight
Prior Non-
hemorrhagic
Stroke /TIA
Female 13.213.2
Male 11.111.1
≥ 75 years 18.318.3
< 75 years 10.410.4
< 65 years 8.58.5
11.711.7
< 60 kg 17.317.3
≥ 60 kg 11.211.2
No 20.820.8
Yes 11.111.1
Diabetes Mellitus
Yes 16.216.2
No 10.210.2
Other 14.714.7
STEMI 10.110.1
Final Diagnosis NSTEMI 13.913.9
Uns. Angina 9.19.1
0.5 1.0 2.0
Total
Patients Tic HR (95% CI)
KM% at Month 12
Characteristic
11.211.2
9.29.2
16.816.8
8.68.6
7.27.2
9.89.8
13.113.1
9.59.5
19.019.0
9.29.2
14.114.1
8.48.4
9.19.1
8.58.5
11.411.4
8.68.6
0.83 (0.71, 0.97)
0.85 (0.76, 0.95)
0.94 (0.78, 1.12)
0.82 (0.74, 0.91)
0.85 (0.74, 0.97)
0.84 (0.77, 0.92)
0.75 (0.56, 0.99)
0.86 (0.78, 0.94)
0.87 (0.66, 1.13)
0.84 (0.76, 0.93)
0.88 (0.76, 1.03)
0.83 (0.74, 0.92)
0.58 (0.34, 1.00)
0.84 (0.72, 0.98)
0.83 (0.73, 0.94)
0.96 (0.75, 1.22)
5288
13336
2878
15744
10643
18624
1312
17256
1152
17462
4662
13962
489
7026
7955
3112
Interaction
P-value
0.8182
0.2166
0.3615
0.8351
0.4882
0.4085
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Tic
Better
Clop
Better

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