Translating Evidence into Clinical Practice : Role of More Potent Antiplatelet in Acute Coronary Syndrome
Dr. Doni Firman, SpJP(K)
Proprietary and Confidential. © AstraZeneca 2011. Document intended for internal discussion purposes.
CASE 1
• Usia : 63 tahun
• Pasien masuk dengan keluhan nyeri dada sejak 2 jam SMRS, terus menerus seperti ditekan benda berat, tidak menjalar, muntah (-)keringat dingin (+) hingga basah kuyup. Keluhan timbul saat sedang menunggu di bandara ,sesak (-), jantung berdebar (-)
• Pasien baru pertama kali mengalami hal ini, riwayat mudah lelah saat aktivitas
Faktor risiko
• Hipertensi
• Kolesterol tinggi
• Merokok (-)
• DM (-)
• FH (-)
Proprietary and Confidential. © AstraZeneca 2011. Document intended for internal discussion purposes.
Physical Examination and ECG
• KU nyeri dada
• TD 134/78 mmHg
• Nadi 90 x / menit
• RR 16 x / menit
Lab
• Hb 13.6 mg/dl
• Lekosit 11.450
• Hs Trop T 32
• GDS 173
3
Proprietary and Confidential. © AstraZeneca 2011. Document intended for internal discussion purposes.
Case 2
• Laki-laki 73 tahun
• Dikirim dari sejawat dengan riwayat NSTEMI, DM ,CKD
CABG 1996
• EF 63 %
• Diagnostik Angio
RCA distal CTO stent patent, LM stenosis 95%, LAD CTO, LCx CTO. LIMA Patent, SVG-RCA total oklusi, SVG-LCx total oklusi, LIMA patent
Atherothrombosis: A Generalized and Progressive Disease
Unstable angina MI
Ischemic stroke/TIA
Critical leg ischemiaIntermittentclaudication
CV death
ACS
Atherosclerosis
Stable angina/Intermittent claudication
Atherothrombosis
Adapted from Libby P. Circulation 2001; 104: 365–372
Smooth muscleand collagen
From first decade From third decade From fourth decade
Growth mainly by lipid accumulationThrombosis,haematoma
Activated platelets are central to thrombus formation in ACS
Platelets do 3 things that promote thrombus formation :– Adhesion – Activation – Aggregation
Plaque rupture leads to platelet adhesion to the exposed subendothelium
Adherent platelet become activated
Activated platelets aggregate and assemble a critical mass of activated, pro-thrombotic platelet membrane at the site of injury
2
1
3
Vorchheimer DA, et al. Mayo Clin Proc. 2006;81:59-68; Davies MJ. Heart. 2000;83:361-366.
ACS with persistent ST segment elevation
ACS without persistent ST segment elevation
Troponin Elevated Troponin Elevated or not
ACS with persistent ST segment elevation
ACS without persistent ST segment elevation
Management :
1. Primary PCI
2. Fibrinolytic
Management :
1. Risk Stratification
2. Optimal DAPT
3. Early invasive
GRACE RISK SCORENon-ST elevation acute coronary syndrome
Predictor Score
Age, years
< 40 0
40 - 49 18
50 - 59 36
60 - 69 55
70 - 79 73
80 91
Predictor Score
Heart Rate , beats/min
< 70 0
70-89 7
90-109 13
110 - 149 23
150 - 199 36
> 200 46
Predictor Score
Systolic Blood Pressure (mmHg)
< 80 63
80 – 99 58
100 - 119 47
120 - 139 37
140 - 159 26
160 - 199 11
> 200 0
Predictor Score
Creatinine (µmol/L)
0 - 34 2
35 – 70 5
71 – 105 8
106 – 140 11
141 – 176 14
177 – 353 23
≥ 354 31
Predictor Score
Killip class
I 0
II 21
III 43
IV 64
Predictor Score
Cardiac arrest at
admission
43
Elevated cardiac markers
15
ST Segment deviation
30
Khalill R et al. Exp Clin Cardiol.2009; 14(2): e25 – e30
Importance of Primary Care Physician role in ACS management
• Play a major role in the early care of acute myocardial infarction
• Often the first to be contacted by patients• What GP should do
• Can perform and interpret the ECG• Alert EMS• Administer opioids and antithrombotic drugs (including
fibrinolytic)• Undertake defibrillation if needed
Steg PG, et al. European Heart Journal. 2012;33:2569-2619
EARLY DIAGNOSIS AND TREATMENT
10-questions strategy in selecting oral antiplatelet in ACS
Firs
t Med
ical
Con
tact
Cat
h La
bora
tory
ICU
and
Lon
g Te
rm
Q#1:ACS Diagnosis doubtful Q#1:Definite ACS
Admit to ICCUContinue diagnostic tests
No antiplatelet therapy
Q#2 : STEMI ?Q#4 : Invasive strategy for
NSTE-ACS ?
Q#3 : Reperfusion ?
Aspirin : oral 150-300 or IV 80-150 mg
No Reperfusion Reperfusion
Clopidogrel 75 mg
Age ≤ 75 : Clopidogrel 300 mgAge > 75 : Clopidogrel 75 mg
Ticagrelor 180 mg Or Clopidogrel 600 mg if high bleeding risk
Thrombolysis Primary PCI
Probable non Invasive Definite Invasive
Ticagrelor 180 mgOr clopidogrel 75 mg if high bleeding risk
Ticagrelor 180 mgOr Clopidogrel 600 mg if high bleeding risk
Confirmed non invasive
Switch to invasive
Q#5 : Large thrombus burden?
Yes : Thrombectomy
Low Bleeding Risk ?If yes, then GPIIb/IIIa inhibitor according to renal function
If yes, continue Ticagrelor 90 mg/12h if ongoing OR switch from clopidogrel to ticagrelor 90 mg/12h.If no, Clopidogrel 75 mg/d if ongoing OR discuss switch from Prasugrel to Clopidogrel
Confirmed ACS ?If not, stop DAPT
Q#8 : normal coronary arteries?
Q#7 : Adequate antiplatelet Rx for PCI ?
Q#6 : Surgery ?
Q#10 : Stent Thombosis Risk ? Q#9 : Low Bleeding Risk ?
Clopidogrel pre Rx No Clopidogrel
Clopidogrel or switch to Ticagrelor Discuss Tirofiban or Eptifibatide
Ticagrelor or ClopidogrelDiscuss Tirofiban or Eptifibatide
Stop P2Y12 :Clopidogrel or ticagrelor 5 days before. Resume DAPT after CABG
Francois Schiele and Nicolas Meneveau. European Heart Journal: Acute Cardiovascular Care 1(2) 170–176
Dual Antiplatelet Therapy is the STANDARD for ACS
Hamm CW et al. Eur Heart J 2011;32:2999 – 3054
Recommendation Class & level
Aspirin should be given to all patients without contraindications at an initial loading dose of 150–300 mg, and at a maintenance dose of 75–100 mg daily long-term regardless of treatment strategy.
1 A
A P2Y12 inhibitor should be added to aspirin as soon as possible and maintained over 12 months, unless there are contraindications such as excessive risk of bleeding.
1 A
Days
Cum
ulat
ive
Haz
ard
0.0
0.01
0.02
0.03
0.04
0 3 6 9 12 15 18 21 24 27 30
HR 0.96 (0.85-1.08)
P = 0.489
ASA 81-100 mgASA 300-325 mg
Mehta SR et al. N Engl J Med. 2010;10:930-42
ESC STEMI GUIDELINES : P2Y12 Inhibitor
P2Y12 inhibitor is recommended in addition to aspirin :
TicagrelorKelas Level
1 B
Kelas Level
1 C
Steg GS et al. doi:10.1093/eurheartj/ehs215
Aspirin oral or iv (if unable to swallow) is recommendedKelas Level
1 B
Clopidogrel, preferably when prasugrel or ticagrelor are either not available or contraindicated
NSTEMI ACS Guidelines : P2Y12 Inhibitor
Clopidogrel (300-mg loading dose, 75-mg daily dose) is recommended for patients who cannot receive ticagrelor orprasugrel.
A 600-mg loading dose of clopidogrel (or a supplementary 300-mg dose at PCI following an initial 300-mg loadingdose) is recommended for patients scheduled for an invasive strategy when ticagrelor or prasugrel is not an option.
Kelas Level
1 A
Kelas Level
1 B
Hamm CW, et al. European Heart Journal (2011) 32, 2999–3054
Ticagrelor (180-mg loading dose, 90 mg twice daily) is recommended for all patients at moderate-to-high risk of ischaemic events (e.g. elevated troponins) , regardless of initial treatment strategy and including those pre-treated with clopidogrel (which should be discontinued when ticagrelor is commenced).
Kelas Level
1 B
Limitation of clopidogrel
• Dual antiplatelet therapy (DAPT) with aspirin & clopidogrel is the current standard treatment in patients with ACS1
– With or without ST segment elevation1
• Poor platelet inhibition response to clopidogrel is seen in approximately 15% - 40% of patients2
– Contribute to residual high risk of recurrent results• Clopidogrel has slow onset of action1
– Prodrug that requires conversion to active metabolite1
• Variable metabolism results in interindividual variability in inhibition of platelet agregation1
1. Bassand JP . European Heart Journal Supplements (2008) 10 (Supplement D), D3–D11; 2. Gurbel PA, Tantry US. Thrombosis Research. 2007;120: 311–321
GRAVITAS Study (clopidogrel low responders) :No improve in CV outcome with increase dose of clopidogrel
Observed event rates are listed; P value by log rank test.
IPA = inhibition of platelet aggregation; od = once daily; bd = twice daily.Adapted from Husted SE, et al. Presented at: European Society of Cardiology Annual Congress 2005; 3-7 September, 2005; Stockholm, Sweden.
DISPERSE: Greater and more consistent IPA with ticagrelor than with clopidogrel (final extent)
Time, h
Clopidogrel 75 mg od
Mea
n I
nh
ibit
ion
, %
Ticagrelor 100 mg bd
DAY 1
DAY 14
Time, h
Mea
n I
nh
ibit
ion
, %
0
20
40
60
80
100
0 2 4 8 12
0
20
40
60
80
100
0 2 4 8 12
0
20
40
60
80
100
0 2 4 8 12 240
20
40
60
80
100
0 2 4 8 12 24
2nd dose
21APPROVED NOV 2013 FOR USE BY ASTRAZENECA MEDICAL AFFAIRS PERSONNEL. MAY NOT BE USED FOR PRODUCT PROMOTIONAL
PURPOSES. NOT FOR USE BY ASTRAZENECA SALES PERSONNEL.
Ticagrelor is direct acting whereas all thienopyridines are pro-drugs
Figure adapted from Schömig A (2009). CYP, cytochrome P450.Schömig A. N Engl J Med 2009;361:1108–1111.
Binding
P2Y12
Platelet
No in vivobiotransformation
Ticagrelor
Prasugrel
Clopidogrel
CYP-dependentoxidationCYP3A4/5CYP2B6
CYP2C19CYP2C9CYP2D6
Hydrolysisby esterase
CYP-dependentoxidationCYP1A2CYP2B6
CYP2C19
CYP-dependentoxidationCYP2C19CYP3A4/5CYP2B6
Active compoundIntermediate metabolite
Pro-drug
ONSET/OFFSET STUDY :TICAGRELOR FASTER ONSET and FASTER OFFSET VS HIGH DOSE CLOPIDOGREL
Onset
100
90
80
70
60
50
40
30
20
10
0
IP
A %
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
Dose
90 mg bid
75 mg qd
*
*
* P<0.0001† P<0.005‡ P<0.05
Time (Hours)Gurbel PA et al. Circulation 2009;120:2577-2585
All OAP proven to reduce CV event (CV death, MI dan Stroke )
23
n = 12.562 n = 13.608 n = 18.624
1.Yusuf S et al. N Engl J Med 2001;345; Wiviott SD e tal. N Engl J Med 2007;357:2001-15; Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Ra
te o
f c
om
po
sit
e C
V e
ve
nt
(C
V d
ea
th,
MI
ata
u S
tro
ke
)%)
Plasebo Clopidogrel
11.4
9.3
CURE1
Clopidogrel Prasugrel
12.1
9.9
TRITON TIMI 382
Clopidogrel BRILINTA
11.7
9.8
PLATO3
P < 0.001 P < 0.001 P < 0.001
Only ticagrelor proven to have mortality benefit vs clopidogrel
Plasebo Clopidogrel
5.50 5.10
CURE1
Clopidogrel Prasugrel
2.40 2.10
TRITON TIMI 382
Clopidogrel Ticagrelor
5.10
4.00
PLATO3P = N/A
n = 12.562NNT = 250
n = 13.608NNT = 333
n = 18.624NNT = 91
1.Yusuf S et al. N Engl J Med 2001;345; Wiviott SD e tal. N Engl J Med 2007;357:2001-15; Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Ra
te o
f C
V d
ea
th (
%)
Ra
te o
f c
om
po
sit
e C
V d
ea
th (
%)
PLATO: Bleeding No difference in major bleeding as primary safety
endpoint
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
18Ticagrelor (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
ima
ted
Rat
e (%
Per
Yea
r)
NS
P = 0.03
P = 0.008
NS
NS
NS
ESC NSTEMI – Management Bleeding Complication
Interruption and/or neutralization of both anticoagulant and antiplatelet therapies is indicated in case of major bleeding, unless it can be adequately controlled by specific haemostatic measures
Minor bleeding should preferably be managed without interruption of activetreatments.
Co-medication of PPI and antithrombotic agents is recommended in patients at increased risk of GI haemorrhage.
CLASS LEVEL
1 C
CLASS LEVEL
1 C
CLASS LEVEL
1 B
Hamm CW et al. Eur Heart J 2011;32:2999 – 3054
Consistent result of ticagrelor in efficacy primary endpoint despite of PPI treatment
Ticagrelor better Clopidogrel better
0.5 1.0 2.0
Proton Pump Inhibitors (Rand.)
0.2
No
Yesn = 6375
11.0 12.9 0.86 (0.75, 1.00)
n = 12,2499.2 11.0 0.83 (0.74, 0.93)
P value interaction 0.69
Ti. Cl.
KM % atMonth 12 HR (95% CI)
Hazard Ratio(95% CI)
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. + supplement
KM : Kaplan–Meier
CASE 1
Firs
t Med
ical
Con
tact
Cat
h La
bora
tory
ICU
and
Lon
g Te
rm
Q#1:Definite ACS
Q#2 : STEMI ?
Q#3 : Reperfusion ?
Aspirin : oral 150-300 or IV 80-150 mg
Reperfusion
Ticagrelor 180 mg Or Clopidogrel 600 mg if high bleeding risk
Primary PCI
Q#5 : Large thrombus burden?
Yes : Thrombectomy
Low Bleeding Risk ?If yes, then GPIIb/IIIa inhibitor according to renal function
If yes, continue Ticagrelor 90 mg/12h if ongoing OR switch from clopidogrel to ticagrelor 90 mg/12h.If no, Clopidogrel 75 mg/d if ongoing OR discuss switch from Prasugrel to Clopidogrel
Q#10 : Stent Thombosis Risk ? Q#9 : Low Bleeding Risk ?
Francois Schiele and Nicolas Meneveau. European Heart Journal: Acute Cardiovascular Care 1(2) 170–176
Which P2Y12 inhibitor preferred for this case ?
1. Faster onset 2. Low inter individual variability3. No issue with low responders
• Reduced risk of stent thrombosis• Reduced CV mortality
Case 2
Firs
t Med
ical
Con
tact
Cat
h La
bora
tory
ICU
and
Lon
g Te
rm
Q#1:Definite ACS
Q#4 : Invasive strategy for NSTE-ACS ?
Aspirin : oral 150-300 or IV 80-150 mg
Definite Invasive
Ticagrelor 180 mgOr Clopidogrel 600 mg if high bleeding risk
If yes, continue Ticagrelor 90 mg/12h if ongoing OR switch from clopidogrel to ticagrelor 90 mg/12h.If no, Clopidogrel 75 mg/d if ongoing OR discuss switch from Prasugrel to Clopidogrel
Q#7 : Adequate antiplatelet Rx for PCI ?
Q#10 : Stent Thombosis Risk ? Q#9 : Low Bleeding Risk ?
Clopidogrel pre Rx No Clopidogrel
Clopidogrel or switch to Ticagrelor Discuss Tirofiban or Eptifibatide
Ticagrelor or ClopidogrelDiscuss Tirofiban or Eptifibatide
Francois Schiele and Nicolas Meneveau. European Heart Journal: Acute Cardiovascular Care 1(2) 170–176
Check GRACE RISK Score
Age : 73 years oldCKD, Elevated CardiACS maker, ST segment deviation
Moderate – high risk patients
Guidelines Ticagrelor Mod – high risk NSTEMI patientPre treated with clopi or naïvePCI or MM
Clopidogrel If ticagrelor or prasugrel not available
1 B
1 A
Duration of OAP for ACS Patient
DAPT and antithrombotic combination therapies after STEMI• Primary PCI and Fibrinolytic is up to 12 months• No reperfusion at least 1 month up to 12 months
ESC STEMI Guidelines 2012
NTEMI Guidelines 2012
Continue for 12 months (unless at high risk of bleeding)
Cessation of DAPT in Surgery patients
• The risk of bleeding related to surgery must be balanced against the risk of recurrent ischaemic events related to discontinuation of therapy
• it is reasonable to restart DAPT as soon as considered safe in relation to bleeding risk
Steg GS et al. doi:10.1093/eurheartj/ehs215; Hamm CW, et al. European Heart Journal (2011) 32, 2999–3054
Summary• Antiplatelet therapy key to reducing thrombus burden and
plaque stabilisation during ACS • In STEMI patients, a loading dose of P2Y12 receptor
inhibitor should be given as early as possible or at time of primary PCI
• In NSTEMI patients, a strategy of risk stratification, optimal potent dual antiplatelet therapy (including the new oral P2Y12 inhibitors and early invasive approach is appropriate
• Ticagrelor + aspirin has recommended in ESC and AHA guidelines as first line treatment in ACS and proven to reduced CV mortality