Ticagrelor - Cardiology Update FK UNAND

Report
CASE 1
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Usia : 63 tahun
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Pasien baru pertama kali mengalami hal ini, riwayat mudah lelah saat
aktivitas
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 (-)
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
•
•
•
•
3
Hb 13.6 mg/dl
Lekosit 11.450
Hs Trop T 32
GDS 173
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
Proprietary and Confidential. © AstraZeneca 2011. Document intended for internal discussion purposes.
Atherothrombosis: A Generalized and Progressive
Disease
Atherothrombosis
Unstable angina
MI
Ischemic
stroke/TIA
Critical leg
ischemia
Intermittent
claudication
Atherosclerosis
CV death
Stable angina/Intermittent claudication
From first decade
From third decade
Growth mainly by lipid accumulation
Adapted from Libby P. Circulation 2001; 104: 365–372
From fourth decade
Smooth muscle
and collagen
Thrombosis,
haematoma
ACS
– Adhesion
– Activation
– Aggregation
2
3
Adherent platelet become activated
1
Plaque rupture leads
to platelet adhesion
to the exposed
subendothelium
Vorchheimer DA, et al. Mayo Clin Proc. 2006;81:59-68; Davies MJ. Heart. 2000;83:361-366.
Activated platelets aggregate
and assemble a critical mass
of activated, pro-thrombotic
platelet membrane at the site
of injury
ACS with persistent
ST segment elevation
Troponin Elevated
ACS without persistent
ST segment elevation
Troponin Elevated or not
ACS with persistent
ST segment elevation
ACS without persistent
ST segment elevation
Management :
Management :
1. Primary PCI
1. Risk Stratification
2. Fibrinolytic
2. Optimal DAPT
3. Early invasive
Predictor
Score
Age, years
Predictor
Score
Predictor
Score
Killip class
Systolic Blood Pressure (mmHg)
< 40
0
< 80
63
I
0
40 - 49
18
80 – 99
58
II
21
50 - 59
36
100 - 119
47
III
43
60 - 69
55
120 - 139
37
IV
64
70 - 79
73
140 - 159
26
80
91
160 - 199
11
> 200
0
Predictor
Score
Heart Rate , beats/min
Predictor
Score
Creatinine (µmol/L)
< 70
0
0 - 34
2
70-89
7
35 – 70
5
90-109
13
71 – 105
8
110 - 149
23
106 – 140
11
150 - 199
36
141 – 176
14
> 200
46
177 – 353
23
≥ 354
31
Khalill R et al. Exp Clin Cardiol.2009; 14(2): e25 – e30
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
• 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
10-questions strategy in selecting oral antiplatelet in ACS
Admit to ICCU
Continue diagnostic tests
No antiplatelet therapy
Q#1:Definite ACS
Q#2 : STEMI ?
Aspirin : oral 150-300 or
IV 80-150 mg
Q#4 : Invasive strategy for
NSTE-ACS ?
Q#3 : Reperfusion ?
Probable non Invasive
No Reperfusion
Reperfusion
Clopidogrel 75 mg
Thrombolysis
Age ≤ 75 : Clopidogrel 300 mg
Age > 75 : Clopidogrel 75 mg
Primary PCI
Ticagrelor 180 mg Or
Clopidogrel 600 mg if
high bleeding risk
Ticagrelor 180 mg
Or clopidogrel 75 mg if
high bleeding risk
Confirmed
non invasive
Definite Invasive
Ticagrelor 180 mg
Or Clopidogrel 600 mg if
high bleeding risk
Switch to
invasive
Q#8 : normal
coronary arteries?
Q#5 : Large thrombus
burden?
Q#7 : Adequate antiplatelet
Rx for PCI ?
Clopidogrel pre Rx
No Clopidogrel
Yes : Thrombectomy
ICU and Long
Term
Cath Laboratory
First Medical Contact
Q#1:ACS Diagnosis doubtful
Low Bleeding Risk ?
If yes, then GPIIb/IIIa
inhibitor according to
renal function
Confirmed
ACS ?
If not, stop
DAPT
Q#10 : Stent Thombosis Risk ?
Clopidogrel or
switch to
Ticagrelor
Discuss
Tirofiban or
Eptifibatide
Ticagrelor or
Clopidogrel
Discuss
Tirofiban or
Eptifibatide
Q#6 : Surgery ?
Stop P2Y12 :
Clopidogrel or
ticagrelor 5
days before.
Resume DAPT
after CABG
Q#9 : Low 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
Francois Schiele and Nicolas Meneveau. European Heart Journal: Acute Cardiovascular Care 1(2) 170–176
Dual Antiplatelet Therapy is the STANDARD for ACS
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.
1A
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.
1A
Hamm CW et al. Eur Heart J 2011;32:2999 – 3054
0.04
0.03
0.02
0.01
Cumulative Hazard
HR 0.96 (0.851.08)
P = 0.489
0.0
ASA 81-100 mg
ASA 300-325 mg
0
3
6
9
12
15
Days
18
Mehta SR et al. N Engl J Med. 2010;10:930-42
21
24
27
30
ESC STEMI GUIDELINES : P2Y12 Inhibitor
Aspirin oral or iv (if unable to swallow) is recommended
Kelas
Level
1
B
Kelas
Level
1
B
Kelas
Level
1
C
P2Y12 inhibitor is recommended in addition to aspirin :
Ticagrelor
Clopidogrel, preferably when prasugrel
or ticagrelor are either not available or
contraindicated
Steg GS et al. doi:10.1093/eurheartj/ehs215
NSTEMI ACS Guidelines : P2Y12 Inhibitor
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
Clopidogrel (300-mg loading dose, 75-mg daily dose) is
recommended for patients who cannot receive ticagrelor or
prasugrel.
Kelas
Level
1
A
Kelas
Level
1
B
A 600-mg loading dose of clopidogrel (or a supplementary 300-mg
dose at PCI following an initial 300-mg loading
dose) is recommended for patients scheduled for an invasive strategy
when ticagrelor or prasugrel is not an option.
Hamm CW, et al. European Heart Journal (2011) 32, 2999–3054
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.
DISPERSE: Greater and more consistent IPA with ticagrelor
than with clopidogrel (final extent)
Clopidogrel 75 mg od
100
100
80
80
DAY 1
60
40
20
0
0
2
4
8
60
Mean Inhibition, %
Mean Inhibition, %
Ticagrelor 100 mg bd
12
100
80
40
20
0
0
2
4
8
12
100
80
60
60
DAY 14
40
20
40
20
 2nd dose
0
0
0 2 4
8
12
Time, h
24
0 2 4
8
12
Time, h
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.
24
P2Y12 inhibitor
Hamm CW et al. Eur Heart J 2011;32:2999 – 3054
Ticagrelor is direct acting whereas all thienopyridines
are pro-drugs
Active compound
Intermediate metabolite
Pro-drug
Ticagrelor
No in vivo
biotransformation
CYP-dependent
oxidation
CYP3A4/5
CYP2B6
CYP2C19
CYP2C9
Hydrolysis
CYP2D6
by esterase
Binding
Platelet
Prasugrel
P2Y12
Clopidogrel
CYP-dependent
oxidation
CYP1A2
CYP2B6
CYP2C19
Figure adapted from Schömig A (2009). CYP, cytochrome P450.
Schömig A. N Engl J Med 2009;361:1108–1111.
CYP-dependent
oxidation
CYP2C19
CYP3A4/5
CYP2B6
21
APPROVED NOV 2013 FOR USE BY ASTRAZENECA MEDICAL AFFAIRS PERSONNEL. MAY NOT BE USED FOR PRODUCT
PROMOTIONAL PURPOSES. NOT FOR USE BY ASTRAZENECA SALES PERSONNEL.
ONSET/OFFSET STUDY :
TICAGRELOR FASTER ONSET and FASTER OFFSET VS
Last
HIGH DOSE CLOPIDOGREL Maintenance
100
90
80
Dose
90 mg bid
75 mg qd
Loading
Dose
*
180 mg
*
*
*
*
*
600 mg
70
IPA %
Ticagrelor (n=54)
*
†
Clopidogrel (n=50)

*
*
P<0.0001
P<0.005
‡ P<0.05
†
60
50

*
40
‡
30
†
20
10

0
0
0.5
1
2
4
Onset
Time (Hours)
Gurbel PA et al. Circulation 2009;120:2577-2585
8
24
6 weeks
Maintenance
0
2
4
8
24
48
Offset
Time (Hours)
72
120
168
240
All OAP proven to reduce CV event
(CV death, MI dan Stroke )
Rate of composite CV event
(CV death, MI atau Stroke)%)
CURE1
TRITON TIMI 382
12.1
11.4
11.7
9.9
9.3
P < 0.001
Plasebo
Clopidogrel
n = 12.562
PLATO3
P < 0.001
Clopidogrel
Prasugrel
n = 13.608
9.8
P < 0.001
Clopidogrel
BRILINTA
n = 18.624
23
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.
Only ticagrelor proven to have mortality benefit vs
clopidogrel
composite
of of
Rate
(%)death (%)
CV deathCV
Rate
CURE1
TRITON TIMI 382
PLATO3
P = N/A
5.50
5.10
5.10
4.00
2.40
Plasebo
Clopidogrel
n = 12.562
NNT = 250
Clopidogrel
2.10
Prasugrel
n = 13.608
NNT = 333
Clopidogrel
Ticagrelor
n = 18.624
NNT = 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.
K-M Estimated Rate (% Per Year)
P = 0.008
Ticagrelor (n=9,235)
18
16
Clopidogrel (n=9,186)
16.1
NS
14.6
14
12
11.6
10
11.2
NS
NS
P = 0.03
8
6
5.8
5.8
4.5
4
7.4
3.8
NS
2
0.3
0.3
0
Major Bleeding
Life-threatening/
Fatal Bleeding
All values presented by PLATO criteria.
Both groups included aspirin.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Fatal Bleeding
Major and Minor
Bleeding
Non-CABGMajor Bleeding
CABG-Major
Bleeding
7.9
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 active
treatments.
Co-medication of PPI and antithrombotic
agents is recommended in patients at
increased risk of GI haemorrhage.
Hamm CW et al. Eur Heart J 2011;32:2999 – 3054
CLASS
LEVEL
1
C
CLASS
LEVEL
1
C
CLASS
LEVEL
1
B
Consistent result of ticagrelor in efficacy primary
endpoint despite of PPI treatment
Proton Pump Inhibitors (Rand.)
P value interaction 0.69
KM % at
Month 12
Hazard Ratio
(95% CI)
HR (95% CI)
Ti. Cl.
No
n = 12,249
9.2 11.0 0.83 (0.74, 0.93)
Yes
n = 6375
11.0 12.9 0.86 (0.75, 1.00)
0.2
0.5
Ticagrelor better
1.0
2.0
Clopidogrel better
KM : Kaplan–Meier
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. + supplement
CASE 1
Q#1:Definite ACS
ICU and Long
Term
Cath Laboratory
First Medical Contact
Q#2 : STEMI ?
Aspirin : oral 150-300 or
IV 80-150 mg
Q#3 : Reperfusion ?
Reperfusion
Primary PCI
Ticagrelor 180 mg Or
Clopidogrel 600 mg if
high bleeding risk
Which P2Y12 inhibitor preferred for
this case ?
1. Faster onset
2. Low inter individual variability
3. No issue with low responders
Q#5 : Large thrombus
burden?
Yes : Thrombectomy
Low Bleeding Risk ?
If yes, then GPIIb/IIIa
inhibitor according to
renal function
•Reduced risk of stent thrombosis
•Reduced CV mortality
Q#10 : Stent Thombosis Risk ?
Q#9 : Low 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
Francois Schiele and Nicolas Meneveau. European Heart Journal: Acute Cardiovascular Care 1(2) 170–176
Case 2
First Medical Contact
Q#1:Definite ACS
Aspirin : oral 150-300 or
IV 80-150 mg
Check GRACE RISK Score
Q#4 : Invasive strategy for
NSTE-ACS ?
Definite Invasive
Age : 73 years old
CKD, Elevated CardiACS maker, ST
segment deviation
Ticagrelor 180 mg
Or Clopidogrel 600 mg if
high bleeding risk
ICU and Long
Term
Cath Laboratory
Moderate – high risk patients
Guidelines
Ticagrelor
Mod – high risk NSTEMI patient
Pre treated with clopi or naïve
PCI or MM
Q#7 : Adequate antiplatelet
Rx for PCI ?
1B
Clopidogrel
If ticagrelor or prasugrel not available
Clopidogrel pre Rx
1A
Q#10 : Stent Thombosis Risk ?
Clopidogrel or
switch to
Ticagrelor
Discuss
Tirofiban or
Eptifibatide
No Clopidogrel
Ticagrelor or
Clopidogrel
Discuss
Tirofiban or
Eptifibatide
Q#9 : Low 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
Francois Schiele and Nicolas Meneveau. European Heart Journal: Acute Cardiovascular Care 1(2) 170–176
ESC STEMI Guidelines 2012
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
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
• 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

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