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Dr. Jajang Sinardja, SpJP, FIHA. 3rd Pekanbaru Cardiology Update, August 24th 2013. Pangeran Hotel Pekanbaru. Learn more at PerkiPekanbaru.com
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Jajang Sinardja
The Standard Dual Antiplatelet
Therapy for ACS
� Clopidogrel : loading dose 300 mg, followed
by 75 mg daily
� ASA: 160 mg non-enteric chewed tablet,
followed by 80 mg daily
Trial & population Comparison Primary Endpoint Bleedin g
CURE (2001)NSTE-ACS patientsn = 12,562
Clopidogrel 75 mg(300 mg loading)vs. placebo
CV death, MI, CVAClopidogrel 9.3%Placebo 11.4%(P < 0.001)ARR 2.1%;RRR 20%; NNT 48
Major bleeding*Clopidogrel 3.7%Placebo 2.7%(P = 0.001)NNH: 100
PCI Cure (2001)NSTE-ACS undergoing PCIn = 2,658
Like CURE (after PCIclopidogrel in both groups for 1 month)
CV death, MI, orurgent TVR in30 daysClopidogrel 4.5%Placebo 6.4%ARR 1.9%;RRR 30%; NNT 53
Major bleeding*Clopidogrel 2.7%Placebo 2.5%(P = 0.69
CURRENT OASIS 7 (2010)NSTE-ACS - 63%STEMI - 37%n = 25,086
Clopidogrel double dose(600 mg loading, 150 mg day 2–7, then 75 mg) vs. standard dose75 mg (150 mg loading)
CV death, MI, CVA(at 30 days)Double 4.2%Standard 4.4%(P = 0.30)
Major bleedingDouble 2.5%Standard 2.0%(P = 0.01)NNH: 200
Clopidogrel Trials
Hamm CW et al. Eur Heart J 2011;32:2999 – 3054
* CURE Definition
Potential Limitations of
Clopidogrel
� Moderate overall levels of platelet inhibition
� Average IPA ~50%
� High variability response within a population
� 4-34% with very low levels of platelet inhibition
� Slow onset of antiplatelet effect
� Requiring 300 – 600 mg loading doses in acute
phase
Gurbel et al. Circulation 2009;120:2577-2585
O’ Donoghue M. Wiviott SD . Circulation 2006;114:e600-e606
Inhibition of ADP-Induced Platelet Function Following 600mg Clopidogrel in 1,001 patients
Hochholzer W. Circulation 2005;111: 2560-2564
Variability in Clopidogrel
Responsiveness
Angiolillo DJ & Ueno M. JACC: Cardiology Interventions 2011;4 (4):411–414
Trial & population Comparison Primary Endpoint Bleedin g
TRITON (2007)Undergoing PCINSTE-ACS 74%STEMI 26%n = 13 608
Prasugrel 10 mg(60 mg loading)vs. clopidogrel75 mg(300 loading)
CV death, MI, CVAPrasugrel 9.9%Clopidogrel 12.1%(P < 0.001)ARR 2.2%;RRR 27%;NNT 45
Non–CABG-relatedmajor bleeding:#Prasugrel 2.4%Clopidogrel 1.8%(P = 0.03)NNH: 167CABG-related majorbleeding Prasugrel13.4%Clopidogrel 3.2%(P < 0.001)NNH: 10 (CABG
Prasugrel Trial
Hamm CW et al. Eur Heart J 2011;32:2999 – 3054
* TIMI Criteria
Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)
OH
OH
O
OH
N
F
S
NH
NN
NN
F
• Direct-acting
– Not a pro drug: does not require metabolic activation
– Rapid onset of inhibitory effect on the P2Y12 receptor than clopidogrel
• Reversibly bound
– Faster offset than clopidogrel
– Functional recovery of circulating platelets within ~ 48 hours
Ticagrelor
Deeks ED. Drugs 2011;71(7):909-933Husted S. Van Giezen JJJ. Cardiovascular Therapeutics 2009;27:259-274
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-dependentoxidationCYP1A2CYP2B6
CYP2C19
CYP-dependentoxidationCYP2C19 CYP3A4/5 CYP2B6
Active compound
Intermediate metabolite
Prodrug
Ticagrelor
Clopidogrel
Binding
P2Y12
Ticagrelor: Does Not Require Hepatic Metabolism for Activation
Platelet
Ticagrelor P2Y12 receptor
binding
ADP, adenosine diphosphateAdapted from Husted S. Van Giezen JJJ. Cardiovascular Therapeutics 2009;27:259-274
ADP
P2Y12 receptor ADP binds and activates the receptor
Conformational change and signalling
Ticagrelor binds away from ADP pocket
ADP can bind reversibly but no conformational change or signalling
Receptor remains intact upon dissociation
ONSET/OFFSET: Pharmacodynamics in
Stable CAD Patients
Onset
100
90
80
70
60
50
40
30
20
10
0
IPA
%
//
Ticagrelor (n=54)
Clopidogrel (n=50)
0 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240
Maintenance Offset
Time (Hours)
Loading Dose
180 mg
600 mg
*
*
* * *
‡
†
** †
LastMaintenance
Dose90 mg bid75 mg qd
//*
*
//
* P<0.0001† P<0.005‡ P<0.05
Time (Hours)
Gurbel PA et al. Circulation 2009;120:2577-2585
PLATO Study
PLATO Study2: • 43 countries• 862 sites• 18,624 patients
43 countries862 sites
PLATO study tested the hypothesis that…ticagrelor will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS as compared to clopidog rel and this would be
achieved with a clinically acceptable bleeding rate and overall safety profile 1
18,624 patients
1. James S et al. Am Heart J 2009;157: 599 – 6052. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
PLATO: Study Population
ACS Patient
STEMI
Primary PCI
No Reperf
Fibrinolytic Rx
UA/NSTEMI
Initial Invasive Management
PCI
No revascularisation
CABG
Initial Non-Invasive Management
PCI
CABG
No revascularisationOnly STEMI patients
intended for primary PCI included
Adapted from James S, et al. Am Heart J. 2009;157:599–605.
180-mg loading dose
Ticagrelor (n=9,333)
*STEMI patients scheduled for primary PCI were randomised; 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.
90 mg bid + ASA maintenance dose
300-mg loading dose † 75 mg qd + ASA maintenance dose
Clopidogrel (n=9,291)
Primary efficacy endpoint:Composite of CV death, MI (excluding silent MI), or stroke
Primary safety endpoint:Total PLATO major bleeding‡
N=18,624Patients with ACS(UA, NSTEMI, or
STEMI*)
<24h Month 1 Month 3 Month 6 Month 9 Month 12Screening
Visit 2 Visit 3 Visit 4 Visit 5 Visit 6
Initial Treatment approaches• Medically managed (n=5,216 — 28.0%)
• Invasively managed (n=13,408 — 72.0%)
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.James S, et al. Am Heart J. 2009;157:599–605.
Randomisation
• All patients were hospitalised with symptom onset <24 hours• Patients could be taking clopidogrel at time of randomisation
PLATO: Study Design
PLATO Main: Inclusion Criteria
• Hospitalisation for STEMI or NSTEMI/UA ACS, with onset during previous 24 hours
• With STEMI, the following 2 inclusion criteria were required
– Persistent ST elevation of at least 0.1 mV in ≥2 contiguous leads or new LBBB
– Primary PCI planned
James S, et al. Am Heart J. 2009;157:599–605.
PLATO Main: Inclusion Criteria
• With NSTEMI, at least 2 of the following 3 were required
– ST changes on ECG indicating ischaemia
– Positive biomarker indicating myocardial necrosis
– One of the following risk indicators
• ≥60 years of age
• Previous MI or CABG
• CAD with ≥50% stenosis in ≥2 vessels
• Previous ischaemic stroke, TIA, carotid stenosis (≥50%), or cerebral revascularisation
• Diabetes mellitus
• Peripheral artery disease
• Chronic renal dysfunction (creatinine clearance <60 mL/min)
James S, et al. Am Heart J. 2009;157:599–605.
PLATO Main: Key Exclusion Criteria
• Contraindication to clopidogrel
• Fibrinolytic therapy within 24 hours
• Oral anticoagulation therapy that cannot be stopped
• ACS event was a complication of previous PCI
• PCI after index event (initial clinical signs and symptoms) and before first study dose
• Increased risk for bradycardic events
• Concomitant therapy with strong CYP3A inhibitors/inducers
• Patients requiring dialysis
James S, et al. Am Heart J. 2009;157:599–605.
Efficacy Results
PLATO: Baseline Characteristics
CharacteristicTicagrelor(n=9,333)
Clopidogrel (n=9,291)
Median age, years 62.0 62.0
Age ≥75 years, n (%) 1,396 (15.0) 1,482 (16.0)
Women, n (%) 2,655 (28.4) 2,633 (28.3)
CV risk factors, n (%)
Habitual smoker 3,360 (36.0) 3,318 (35.7)
Hypertension 6,139 (65.8) 6,044 (65.1)
Dyslipidemia 4,347 (46.6) 4,342 (46.7)
Diabetes mellitus 2,326 (24.9) 2,336 (25.1)
History, n (%)
MI 1,900 (20.4) 1,924 (20.7)
PCI 1,272 (13.6) 1,220 (13.1)
CABG 532 (5.7) 574 (6.2)
ECG at study entry, n (%)
ST-segment elevation, persistent 3,497 (37.5) 3,511 (37.8)
ST-depression 4,730 (50.7) 4,756 (51.2)
T-wave inversion 2,970 (31.8) 2,975 (32.0)
Troponin-I positive, n (%) 7,965 (85.3) 7,999 (86.0)
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
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
4,1478,219
0 2 4 6 8 10 12
1211109876543210
13C
umul
ativ
e In
cide
nce
(%)
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
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 Randomisation0 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 fro m 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.
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.
PLATO Primary Endpoint: Initial Invasive vsInitial Non-Invasive Management
James S, et al. ESC. 2010; Poster #1353.Cannon CP, et al. Lancet. 2010;375:283–293.
Stent Thrombosis ticagrelor vs clopidogrel
0,6%ARR
33%RRR
P = 0.009
Ticagrelorn= 5640
Clopidogreln = 5649
Wallentin L, et al. N Engl J Med 2009;361:1045-57
* Definition by Academic Research Consortium criteria
PLATO Efficacy Results
Summary
� Ticagrelor significantly reduced the composite of
CV death, MI or stroke vs clopidogrel at 1 year
(1.9% ARR, 16% RRR, P<0.001, NNT=54)
� Ticagrelor significantly reduced CV mortality vs
clopidogrel
(1.1% ARR, 21% RRR, P=0.001)� Risk of CV death and MI were both significantly reduced
� Risk of stroke was not significantly different
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
PLATO Efficacy Results
Summary
� The absolute risk reduction with ticagrelor vs
clopidogrel starts early and continues to build
over the full 1 year treatment period
� For every 91 ACS patients treated with
ticagrelor for 1 year, instead of clopidogrel, 1
CV death was prevented (NNT=91)
� The effect of ticagrelor over clopidogrel
appears consistent across many subgroups
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
Safety Results
P=0.43
HR: 1.04 (95% CI, 0.95–1.13)
PLATO: Primary Safety Endpoint
PLA
TO-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
3,4336,545
Both groups included aspirin.
PLATO: Safety Endpoints - bleeding
*Both groups included aspirin; **Proportion of patients (%)
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
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: Dyspnoea
• Ticagrelor-associated dyspnoea was mostly mild to moderate in severity and did not reduce efficacy
• Most events were reported as single episode occurring early after starting treatment
• Not associated with new or worsening heart or lung disease
BRILINTA. Indonesia Prescribing Information 2012.Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.Storey R, et al. Eur Heart J 2011;32:2945-2953
Dyspnoea in the PLATO trial Ticagrelor Clopidogrel P Value
Incidence of dyspnoea 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 PatientsTicagrelor(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)
1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.2. Scirica BM et al. J Am Coll Cardiol 2011;57:1908-19163. BRILINTA Indonesia Prescribing Information 2012.
PLATO: Laboratory Parameters
All PatientsTicagrelor(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.
CI, confidence interval; CrCl, creatinine clearance; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.James S, et al. Circulation 2010;122:1056–1067.
Renal function and outcomes in PLATO : Primary composite endpoint by CrCl
Ticagrelor better
Clopidogrel better
Risk of CV death, stroke or MIHR (95% CI)
30
40
50
60
70
80
90
100
CrCl(mL/min)
0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.20.4
Incr
easi
ng r
enal
impa
irmen
t
PLATO Safety Results
Summary
� No increase in overall major bleeding with
Ticagrelor vs clopidogrel
� Non-CABG major bleeding and major + minor
bleeding were more frequent with Ticagrelor
vs clopidogrel
� No increase in overall fatal/life-threatening
bleeding with Ticagrelor vs clopidogrel
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
PLATO Safety Results
Summary
� There are more dyspnoea-related events
associated with Ticagrelor vs clopidogrel,
however most events were mild to moderate
in intensity and often resolved without a need
for treatment
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
Implicating New Guidelines into ACS Management
ESC Guidelines for the management of ACS in patient s presenting without persistent ST-segment elevation
Hamm CW et al. Eur Heart J 2011;32:2999 – 3054
LevelClass
Steg PG, et al. European Heart Journal. 2012;33:2569-2619
Oral antiplatelet in ESC
2012 STEMI Guideline
ACCF/AHA 2013 STEMI
Guideline
Anderson JL, et al. Circulation. 2007;116:e148-e304.
Summary
� Ticagrelor is an active drug with reversible
binding to P2Y12 receptor
� Ticagrelor provide fast onset and fast offset
� Ticagrelor significantly reduces the combined
risk of CV death, MI, or stroke as compared to
clopidogrel in patients with ACS
Summary
� Ticagrelor is effective in a broad spectrum of
ACS patients
� There is no increase of overall major bleeding
with Ticagrelor as compared to clopidogrel
� Ticagrelor has been recommended in ACS
guidelines both in initial management ,
before PCI procedure and at discharge