Top Banner
Translating Evidence into Clinical Practice : Role of More Potent Antiplatelet in Acute Coronary Syndrome Dr. Doni Firman, SpJP(K)
32

Dr. Doni Firman , SpJP (K)

Jan 04, 2016

Download

Documents

Marlie

Translating Evidence into Clinical Practice : Role of More Potent Antiplatelet in Acute Coronary Syndrome. Dr. Doni Firman , SpJP (K). CASE 1. Usia : 63 tahun - PowerPoint PPT Presentation
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Page 1: Dr. Doni  Firman ,  SpJP (K)

Translating Evidence into Clinical Practice : Role of More Potent Antiplatelet in Acute Coronary Syndrome

Dr. Doni Firman, SpJP(K)

Page 2: 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 (-)

Page 3: Dr. Doni  Firman ,  SpJP (K)

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

Page 4: Dr. Doni  Firman ,  SpJP (K)

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

Page 5: Dr. Doni  Firman ,  SpJP (K)

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

Page 6: Dr. Doni  Firman ,  SpJP (K)

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.

Page 7: Dr. Doni  Firman ,  SpJP (K)

ACS with persistent ST segment elevation

ACS without persistent ST segment elevation

Troponin Elevated Troponin Elevated or not

Page 8: Dr. Doni  Firman ,  SpJP (K)

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

Page 9: Dr. Doni  Firman ,  SpJP (K)

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

Page 10: Dr. Doni  Firman ,  SpJP (K)

GRACE RISK SCORE

Khalill R et al. Exp Clin Cardiol.2009; 14(2): e25 – e30

Page 11: Dr. Doni  Firman ,  SpJP (K)

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

Page 12: Dr. Doni  Firman ,  SpJP (K)

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

Page 13: Dr. Doni  Firman ,  SpJP (K)

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

Page 14: Dr. Doni  Firman ,  SpJP (K)

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

Page 15: Dr. Doni  Firman ,  SpJP (K)

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

Page 16: Dr. Doni  Firman ,  SpJP (K)

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

Page 17: Dr. Doni  Firman ,  SpJP (K)

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

Page 18: Dr. Doni  Firman ,  SpJP (K)

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.

Page 19: Dr. Doni  Firman ,  SpJP (K)

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

Page 20: Dr. Doni  Firman ,  SpJP (K)

P2Y12 inhibitor

Hamm CW et al. Eur Heart J 2011;32:2999 – 3054

Page 21: Dr. Doni  Firman ,  SpJP (K)

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

Page 22: Dr. Doni  Firman ,  SpJP (K)

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

Page 23: Dr. Doni  Firman ,  SpJP (K)

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

Page 24: Dr. Doni  Firman ,  SpJP (K)

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 (

%)

Page 25: Dr. Doni  Firman ,  SpJP (K)

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

Page 26: Dr. Doni  Firman ,  SpJP (K)

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

Page 27: Dr. Doni  Firman ,  SpJP (K)

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

Page 28: Dr. Doni  Firman ,  SpJP (K)

Clinical Case

Page 29: Dr. Doni  Firman ,  SpJP (K)

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

Page 30: Dr. Doni  Firman ,  SpJP (K)

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

Page 31: Dr. Doni  Firman ,  SpJP (K)

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

Page 32: Dr. Doni  Firman ,  SpJP (K)

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