Dr. Rajeev Agarwala Jaswant Rai Speciality Hospital, Meerut. E-mail : [email protected] HOW TO CHOOSE YOUR BRIDE AMONG THREE SISTERS
Dec 18, 2014
Dr. Rajeev AgarwalaJaswant Rai Speciality Hospital, Meerut.
E-mail : [email protected]
HOW TO CHOOSE YOUR BRIDEAMONG 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 (-blockers, nitrates etc)
PlateletPlatelet
GP IIb/IIIaGP IIb/IIIareceptor receptor
FibrinogenFibrinogenThrombinThrombin
Fibrin Fibrin 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
BLEEDING
ISC
HEM
IADILEMMA
Trial
Indication
Duration
CHARISMA CURE CREDOPCI-CUREPCI-CLARITY
CLARITY COMMIT
Stable CVDMI Stroke PAD
ACSUA/NSTEMI
PCIStable CADUA/NSTEMISTEMI
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
COMMIT93% STEMI or BBB + 24
hrs
N=45,852
10.1% 9.2% P= .002
Newer antiplatelet agents
TRITON TIMI-38: Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCIASA
PRASUGREL60 mg LD/ 10 mg
MD
CLOPIDOGREL300 mg LD/ 75 mg
MD
1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, UTVR Stent Thrombosis (ARC definite/probable) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey 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 BenefitDeath, MI, Stroke, Major Bleed (non CABG)
0
5
10
15
0 30 60 90 180 270 360 450Days
En
dp
oin
t (%
)
HR 0.87P=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 CauseMortalityMortalityClop 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
3060 90 180 270 360 450
HR 0.82P=0.01
HR 0.80P=0.003
5.6
4.7
6.9
5.6
Days
Pri
mary
En
dp
oin
t (%
)
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel
Loading Dose Maintenance Dose
Timing of BenefitTiming of Benefit
0
3
6
9
Days
CV
Death
, M
I, S
troke (
%)
No GP IIb/IIIa Inhibitor Used
GP IIb/IIIa Inhibitor Used
Benefit Benefit Regardless of GP Regardless of GP
IIb/IIIa UseIIb/IIIa Use
O’Donoghue M et al. JACC 2009;54:678-85
0 3015
Days0 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 0.70P<0.001
Days
En
dp
oin
t (%
) 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 BetterHR
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
ConclusionsHigher 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 the Optimization 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, Stroke Primary 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 Lower risk multiple recurrent ischemic events suggested with prasugrel using the pre-specified suggested with prasugrel using the pre-specified Andersen-Gill model 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 Significant interaction with treatment and time (HR for > 12 mos = 0.64, 95% CI: 0.48–0.86, Interaction > 12 mos = 0.64, 95% CI: 0.48–0.86, Interaction P=0.02) P=0.02)
* Pre-specified evaluation of all CV death, MI, or stroke events by treatment
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 Lower risk multiple recurrent ischemic events suggested with prasugrel using the pre-specified suggested with prasugrel using the pre-specified Andersen-Gill model 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 Significant interaction with treatment and time (HR for > 12 mos = 0.64, 95% CI: 0.48–0.86, Interaction > 12 mos = 0.64, 95% CI: 0.48–0.86, Interaction P=0.02) 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
ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)
Ticagrelor180 mg loading dose, then90 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
1211109876543210
13
Cu
mu
lati
ve in
cid
en
ce (
%)
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
Days after randomisation
7079
7119
5,441
5,482
4,364
4,4198,626
Cardiovascular deathC
um
ula
tive in
cid
en
ce (
%)
All-cause mortality4.5% vs. 5.9%
HR 0.78(0.69-0.89)
P<0.001
Wallentin L et al. NEJM 2009;361:1045-57.
8,688
8,763
0 10 20 30
8
6
4
2
0
Cu
mu
lati
ve in
cid
en
ce
(%)
Clopidogrel
Ticagrelor
4.775.43
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
Days after randomisation
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
Cu
mu
lati
ve in
cid
en
ce
(%)
*Excludes patients with any primary event during the first 30 daysWallentin L et al. NEJM 2009;361:1045-57.
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-M
esti
mate
d r
ate
(%
per
year)
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
11.611.2
7.9 7.7
8.9 8.9
5.8 5.8
0.3 0.3
TicagrelorClopidogrel
Wallentin L et al. NEJM 2009;361:1045-57.
Non-CABG and CABG-related major bleeding
p=0.026
p=0.025
NS
NS
9K
-M e
stim
ate
d r
ate
(%
per
year)
Non-CABGPLATO majorbleeding
8
7
6
5
4
3
2
1
0Non-CABGTIMI major bleeding
CABGPLATO major bleeding
CABG TIMI major bleeding
4.5
3.8
2.8
2.2
7.4
7.9
5.3
5.8
TicagrelorClopidogrel
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 clopidogrel
Standard clopidogrel
HR Prasugrel Standard clopidogrel
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
End
poin
t (%
)
Days
9.5%
6.5%
12.4%
10.0%
Clopidogrel
Prasugrel
CV death / MI / stroke
Efficacy of prasugrel in STEMIEfficacy 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 STEMILower early mortality with prasugrel in STEMI
Montalescot G et al., Lancet 2009
Clopidogrel
Prasugrel
2.62.6
1.61.6
4.34.3
3.33.3
0
5
10
15
0 30 60 90 180 270 360 450
End
poin
t (%
)
Days
TIMI major non-CABG bleeds
Clopidogrel
Prasugrel 2.4%
2.1%
Safety of prasugrel in STEMISafety of prasugrel in STEMI
Montalescot G et al., Lancet 2009
NNH = 333
P = 0.65
Steg PG et al., Circulation 2010
Benefit of ticagrelor in STEMIBenefit 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 STEMILower all-cause mortality with ticagrelor in STEMI
Clopidogrel
Ticagrelor6.16.1
5.05.0
Steg PG et al., Circulation 2010
Steg PG et al., Circulation 2010
Safety of ticagrelor in STEMISafety of ticagrelor in STEMI
Similar efficacy and safety in STEMI
TRITON: Prasugrel1° efficacy endpointAll cause mortality 1° safety endpoint
PLATO: Ticagrelor1° efficacy endpointAll 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/NSTEMI
15-month incidence of death/MI/stroke (%)
0
2
4
6
8
10
12
14
16
12.4
10.0
p=0.02
STEMINNT = 42
12.0
9.9
p=0.03
UA/NSTEMINNT = 47
Wiviott SD et al., N Engl J Med 2007
Clopidogrel
Prasugrel
Favorable risk-benefit ratio of prasugrel in UA/NSTEMI
Clopidogrel
Prasugrel
Wiviott SD et al., N Engl J Med 2007
15-month incidence (%)
0
2
4
6
8
10
12
14
16
12.0
9.9
p=0.03
death/MI/stroke
NNT = 47
1.72.4
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(95 % - confidence limit)
0.5 1 1.5
Prasugrel better Clopidogrel better
Pint = 0.11Pint = 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 2009
TRITON1° endpoint All cause mortality
PLATO1° endpoint
All cause mortality
Hazard ratio for 1° endpoint(95 % - confidence limit)
0.5 1 1.5
Study drug better Clopidogrel better
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(95 % - confidence limit)
0.5 1 1.5
study treatment better
normal-dose clopidogrelbetter
P = 0.045
P = 0.30
P < 0.001
P = 0.039
Wallentin L et al., N Engl J Med 2009OASIS-7 investigators, N Engl J Med 2010Mehta SR et al., Lancet 2010
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
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
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 0.70P < 0.001
En
dpo
int (
%)
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
Wiviott SD et al., Circulation 2008
Potent effect of prasugrel in diabetics:Stent thrombosis
Wiviott SD et al., Circulation 2008
Safety of prasugrel in diabetics:TIMI major non CABG bleeding
No interaction with diabetes in PLATO: 1° endpoint
Pint = 0.49Pint = 0.49
James S et al., Eur Heart J 2010
No interaction with diabetes in PLATO: Mortality
Pint = 0.66Pint = 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
TRITONNo diabetesDiabetes
PLATONo diabetes
Diabetes
Hazard ratio for 1° endpoint(95 % - confidence limit)
0.5 1 1.5
Study drug better Clopidogrel better
Pint = 0.49Pint = 0.49
Pint = 0.09Pint = 0.09
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
Different interaction with renal function
Wiviott SD et al., N Engl J Med 2007; James S et al., Circulation 2010
TRITON 1° endpointCrCl < 60 mL/min CrCl > 60 mL/min
Hazard ratio(95 % - confidence limit)
0.5 1 1.5
Study drug better Clopidogrel better
Pint n.s.Pint n.s.Pint n.s.Pint n.s.
PLATO 1° endpointCrCl < 60 mL/min CrCl > 60 mL/min
Pint = 0.13Pint = 0.13
12.1 %
3.1 %3.3 %
10.0 %
ticagrelor
ticagrelor
clopidogrel
clopidogrel
Creatinine clearance > 60 ml/minCreatinine clearance > 60 ml/min
Creatinine clearance < 60 ml/minCreatinine clearance < 60 ml/min
Cumulative incidence of all-cause deathCumulative incidence of all-cause death
Days since randomization
No survival benefit of ticagrelor in normal creatinine clearanceNo survival benefit of ticagrelor in normal creatinine clearance
James S 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
0.5 1 2
OVERALL
Prasugrel Better Clopidogrel Better
No
YesPrior Stroke / TIA Pint = 0.006
<75
≥75Age
Pint = 0.18
≥60 kg
<60 kgWeight
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
10Ticagrelor
P < 0.001
Wallentin L et al., N Engl J Med 2009
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
4Ticagrelor
P = 0.10
Wallentin L et al., N Engl J Med 2009
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 TIAPrasugrel over Ticagrelor: Bradycardia
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 TIAPrasugrel over Ticagrelor: Bradycardia
TICAGRELOR180 mg loading dose,
then 90 mg bid for
1 year (ASA < 100)
PRASUGREL60 mg loading dose,
then 5-10 mg PO daily
for 1 year
CLOPIDOGREL600 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 38Single Antiplatelet Rx
Dual Antiplatelet Rx
Higher IPA
ASAASA + Clopidogrel ASA +
Prasugrel
- 22%
- 20%
- 19%
+ 60% + 38% + 32%
Reduction inIschemicEvents
- 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 CUMBERSOMEIMPATIENCE CAN BE CUMBERSOME
THANK YOUTHANK YOU
THANK YOU
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% reduction in MACE
with prasugrel after 15 months
Significant 22% reduction in MACE
with prasugrel after 30 days of
FU
Significant 16% reduction in MACE
with ticagrelor after 12 months of
FU
Significant 12% reduction in MACE
with ticagrelor after 30 days of
FU
Significant 16% reduction in MACE with 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 EventsTicagrelor
(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
Wallentin L et al. NEJM 2009;361:1045-57.
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 with Ticagrelor 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* Ticagrelor Ticagrelor (n=9333)(n=9333)
Clopidogrel Clopidogrel (n=9291)(n=9291)
HR for HR for ticagrelor ticagrelor (95% CI)(95% CI)
PP value value††
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
AgeAge
Overall Treatment Effect
SexSex
Body WeightBody Weight
Prior Non-hemorrhagic Stroke /TIA
Prior Non-hemorrhagic Stroke /TIA
FemaleFemale 13.213.213.213.2
MaleMale 11.111.111.111.1
≥ 75 years≥ 75 years 18.318.318.318.3
< 75 years< 75 years 10.410.410.410.4
< 65 years< 65 years 8.58.58.58.5
11.711.711.711.7
< 60 kg< 60 kg 17.317.317.317.3
≥ 60 kg≥ 60 kg 11.211.211.211.2
NoNo 20.820.820.820.8
YesYes 11.111.111.111.1
Diabetes MellitusDiabetes MellitusYesYes 16.216.216.216.2NoNo 10.210.210.210.2
OtherOther 14.714.714.714.7
STEMISTEMI 10.110.110.110.1Final DiagnosisFinal Diagnosis NSTEMINSTEMI 13.913.913.913.9
Uns. AnginaUns. Angina 9.19.19.19.1
0.5 1.0 2.0
TotalPatients Tic HR (95% CI)
KM% at Month 12
Characteristic
11.211.211.211.2
9.29.29.29.2
16.816.816.816.8
8.68.68.68.6
7.27.27.27.2
9.89.89.89.8
13.113.113.113.1
9.59.59.59.5
19.019.019.019.0
9.29.29.29.2
14.114.114.114.18.48.48.48.4
9.19.19.19.18.58.58.58.5
11.411.411.411.48.68.68.68.6
0.83 (0.71, 0.97)0.83 (0.71, 0.97)
0.85 (0.76, 0.95)0.85 (0.76, 0.95)
0.94 (0.78, 1.12)0.94 (0.78, 1.12)
0.82 (0.74, 0.91)0.82 (0.74, 0.91)
0.85 (0.74, 0.97)0.85 (0.74, 0.97)
0.84 (0.77, 0.92)0.84 (0.77, 0.92)
0.75 (0.56, 0.99)0.75 (0.56, 0.99)
0.86 (0.78, 0.94)0.86 (0.78, 0.94)
0.87 (0.66, 1.13)0.87 (0.66, 1.13)
0.84 (0.76, 0.93)0.84 (0.76, 0.93)
0.88 (0.76, 1.03)0.88 (0.76, 1.03)0.83 (0.74, 0.92)0.83 (0.74, 0.92)
0.58 (0.34, 1.00)0.58 (0.34, 1.00)
0.84 (0.72, 0.98)0.84 (0.72, 0.98)
0.83 (0.73, 0.94)0.83 (0.73, 0.94)
0.96 (0.75, 1.22)0.96 (0.75, 1.22)
52885288
1333613336
28782878
1574415744
1064310643
1862418624
13121312
1725617256
11521152
1746217462
466246621396213962
489489
70267026
79557955
31123112
InteractionP-value
0.81820.8182
0.21660.2166
0.36150.3615
0.83510.8351
0.48820.4882
0.40850.4085
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Tic Better
Clop Better