Translating updated ACS guidelines into clinical practice : Right Patient for The Right

OAP

37,5

14.0

22 /

Sept

201

4

The spectrum of ACS

Hamm CW, et al. European Heart Journal . 2011; 32: 2999–3054

Updated Guidelines ACS

2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With UA/NSTEMI 3

2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction 4

2011 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation 1

2012 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation 2

1. Hamm CW, et al. European Heart Journal . 2011; 32: 2999–3054 ; 2. Steg PG et al. Eur Heart J 2012;33:2569-619; 3. Jneid H et al. Circulation 2012; 126: 875 – 910; 4. O’Gara PT et al. Circulation 2013;127:529-555

Platelet play a “ pivotal role” in ACS

•  Platelets do 3 things that promote thrombus formaton

–  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.

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

Profile of P2Y12 inhibitor

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

Metabolism of P2Y12 inhibitor

Adapted from Schomig A. N Engl J Med 2009;361:1108–1111

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

–  Irreversible binds to platelet P2Y12 reseptors

1. Bassand JP . European Heart Journal Supplements (2008) 10 (Supplement D), D3–D11; 2. Gurbel PA, Tantry US. Thrombosis Research. 2007;120: 311–321

Ticagrelor in reducing CV death in ACS patient Trial & population

Primary endpoint CV DEATH Safety endpoint (bleeding)

CURE (2001) NSTE-ACS patients n = 12,562

Clopidogrel vs plasebo : 9.3 % vs 11.4% P < 0.001

Clopidogrel vs plasebo : 5.1% vs 5.5% ; NNT = 250 P value : N/A

Major bleeding* Clopidogrel 3.7% Placebo 2.7% (P = 0.001) NNH: 100

TRITON (2007) Undergoing PCI NSTE-ACS 74% STEMI 26% n = 13 608

Prasugrel vs Clopidogrel : 9.9% vs 12.1% ; P value < 0.001

Prasugrel vs Clopidogrel : 2.1% vs 2.4% ; NNT = 333 P value = 0.31 (NS)

Non–CABG-related major bleeding**: Prasugrel 2.4%; Clopidogrel 1.8% ; (P = 0.03) ; NNH: 167 CABG-related major bleeding** Prasugrel 13.4% vs Clopidogrel 3.2% (P < 0.001) NNH: 10

PLATO (2009) All ACS both invasive and non invasive n = 18.624

Ticagrelor vs clopidogrel : 9.8% vs 11.7% P value < 0.001

Ticagrelor vs clopidogrel : 4.0% vs 5.1%; NNT = 91, P value =0.001

Major bleeding : PLATO definition*** : Ticagrelor 11.6% vs clopidogrel 11.2% ; NNH 250; , p = 0.43 (NS) TIMI definition** : Ticagrelor 7.9% vs clopidogrel 7.7% ; NNH 500; p = 0.57 (NS)

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.

* CURE Definition; **TIMI definition ; ***PLATO definition

PLATO study design

6–12-month exposure

Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose,

then 75 mg qd maintenance; (additional 300 mg allowed pre PCI)

Ticagrelor 180 mg loading dose, then

90 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)

ü  Pretreated with clopidogrel ü  Invasive and non invasive management (except fibrinolytic ≤ 24 hours) ü  Additional dose up to 600 mg for clopidogrel and 90 mg for ticagrelor

prior to PCI Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

James S, et al. Am Heart J. 2009;157:599–605.

In combination with aspirin

Composite CV event Ticagrelor vs Clopidogrel

No. at risk

Clopidogrel Ticagrelor

9,291 9,333

8,521 8,628

8,362 8,460

8,124

Days after randomisation

6,650 6,743

5,096 5,161

4,047 4,147

0 60 120 180 240 300 360

12 11 10 9 8 7 6 5 4 3 2 1 0

13

Cum

ulat

ive

inci

denc

e (%

)

9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p < 0.001

Clopidogrel

Ticagrelor

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

RRR

16%

Primary Safety Endpoint : No increase in major bleeding

Days from first IP dose

0 60 120 180 240 300 360

10

5

0

15

Clopidogrel

Ticagrelor 11.2 11.6

HR 1.04 (95% CI 0.95–1.13), p=0.43 K-M

est

imat

ed ra

te (%

per

yea

r)

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

Case Study

•  57 years old male, retired technician

Coronary Risk Factors •  Hypertension •  Dyslipidaemia •  Smoker (30 pack years history) Present History •  Three days history of on and off

chest pain initially thought to be ‘indigestion’

•  Severe chest pain at 10 am on the day of presentation

•  Associated breathlessness worse on exertion

1st ECG •  Sinus rhythm •  T wave inversion in lead V5 and

V6 •  Tall R wave in V1 to 3 • Q waves in II & AVF 2nd ECG (10 mins apart) •  Sinus rhythm •  T wave inversion in lead V6 and

I, dynamic T wave on V5 Lab •  Troponin T 3.830 ug/l (Elevated

consistent with myocardial damage)

Which P2Y12 Inhibitor ?

How to choose the right OAP ?

1.  Clinical setting ? 2.  Patient related factor ? •  ischemic risk •  bleeding risk •  other baseline characteristic – age, weight, history of

stroke/TIA

Damman P et al. J Thromb Thrombolysis (2012) 33:143 - 153

STEMI patient

• The preferred treatment for patients with STEMI is mechanical reperfusion by primary PCI

• Fast acting P2Y12 inhibitors are of paramount importance in these high-risk patients who require urgent intervention

Damman P et al. J Thromb Thrombolysis (2012) 33:143–153; Steg PG et al. Eur Heart J 2012;33:2569-619

An ADP-receptor blocker is recommended in addition to aspirin. Options are:

Prasugrel in clopidogrel-naive patients, if no history of prior stroke/TIA, age <75 years.

Ticagrelor.

Clopidogrel, preferably when prasugrel or ticagrelor are either not available or contraindicated.

1 A

1 B

1 B

1 C

NSTEMI patient

•  The choice of P2Y12 inhibition in patients presenting with NSTE-ACS depends on the chosen treatment strategy

•  Current guidelines recommend a routine invasive strategy, consisting of routine coronary angiography and PCI if suitable, in high-risk NSTE-ACS patients

•  High risk of ischemic heart disease is associated with ST-segment changes, elevated troponin, diabetes, and a GRACE risk score of more than 140

•  Regardless of the intended treatment strategy in NSTEACS, a large proportion of the patients do not undergo revascularization during initial hospitalization

Damman P et al. J Thromb Thrombolysis (2012) 33:143–153;

MORE potent Oral Antiplatelet is the preferred options NSTEMI

Hamm CW et al. Eur Heart J 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)  

Class Level 1 B

Prasugrel (60-mg loading dose, 10-mg daily dose) is recommended for P2Y12-inhibitor-naïve patients (especially diabetics) in whom coronary anatomy is known and who are proceeding to PCI unless there is a high risk of lifethreatening bleeding or other contraindications  

Class Level 1 B

Clopidogrel (300-mg loading dose, 75-mg daily dose) is recommended for patients who cannot receive ticagrelor or prasugrel.  

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.  

Class Level 1 A

Class Level 1 B

GRACE risk score

Hamm CW, et al. European Heart Journal . 2011; 32: 2999–3054

Guidelines recommendation P2Y12 Inhibitor based on treatment approach

1. Hamm CW et al. Eur Heart J 2011;32:2999 – 3054; 2 Jneid H et al. Circulation 2012; 126: 875 – 910; 3. Steg PG et al. Eur Heart J 2012;33:2569-619; 4. O’Gara PT et al. Circulation 2013;127:529-555

Conservative strategy

ESC Ticagrelor (1B) or Clopidogrel (1A) or AHA Clopidogrel (1B) or ticagrelor (1B)

PCI Strategy

ESC • Ticagrelor (1 B) • Prasugrel (1 B) – no prior stroke/TIA , age < 75 years old • Clopidogrel 600 mg (1 C) AHA (1 B) • Clopidogrel (600 mg/ 75 mg BID) • Prasugrel (60 mg/10 mg BID) • Ticagrelor (180 mg/90 mg BID

Fibrinolytic ESC dan AHA Clopidogrel I A

Other clinical consideration in the choice of P2Y12 inhibitor

A.  High risk for (recurrent) ischemic events •  Diabetic patients

B.  High risk subgroup for bleeding events •  Impaired renal function

Damman P et al. J Thromb Thrombolysis (2012) 33:143–153

Platelet Dysfunction in DM: The “Diabetic” Platelet

Ferreiro JL , Angiolillo DJ. Circulation. 2011;123:798-813

Platelet Response to Clopidogrel Is Attenuated in Diabetic Patients Undergoing Coronary Stent

Implantation

Geisler T et al. Diabetes Care. 2007;30 (2): 372 - 374

ADP aggregation after a 600-mg clopidogrel loading dose

Increased risk of ischaemic events in diabetic patients

Increased risk for diabetics

CV death, MI or stroke

All-cause mortality

MI

HR (95% CI)

Decreased risk for diabetics

1.0

CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Adapted from James S, et al. Eur Heart J 2010;31:3006–3016.

Days after randomisation

CV

deat

h, M

I, or

str

oke

(%)

14.1%

16.2%

8.4% 10.2%

PLATO diabetes: Primary composite endpoint

CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Adapted from James S, et al. Eur Heart J 2010;31:3006–3016.

Diabetes Ticagrelor (n=2326) Clopidogrel (n=2336) HR (95% CI) = 0.88(0.76–1.03)

No diabetes Ticagrelor (n=6999) Clopidogrel (n=6952) HR (95% CI) = 0.83(0.74–0.93)

0 60 120 180 240 300 360

20

15

10

5

0

Primary endpoint benefit with ticagrelor was consistent with the overall PLATO trial results

No interaction between diabetes status and treatment was observed (p=0.49)

p for interaction = 0.49

PLATO diabetes: Major bleeding

14.1% 14.8%

10.8% 10.0%

Diabetes Ticagrelor (n=2305) Clopidogrel (n=2316) HR (95% CI) = 0.95(0.81–1.12)

No diabetes Ticagrelor (n=6928) Clopidogrel (n=6870) HR (95% CI) = 1.08(0.97–1.20)

CI, confidence interval; HR, hazard ratio. Adapted from James S, et al. Eur Heart J 2010;31:3006–3016.

Days after randomisation

0 60 120 180 240 300 360

15

10

5

0

Maj

or b

leed

ing

(%)

Bleeding occurred with similar frequency in the ticagrelor and clopidogrel groups, independent of diabetes status

No interaction between diabetes status and treatment was observed (p=0.21)

p for interaction = 0.21

Disorders of Hemostasis in CKD

1.  Prothrombotic tendency à excessive cardiovascular events

2.  Platelet dysfunction à increased bleeding tendency

Jalal DI et al. Semin Thromb Hemost 2010;36:34–40

Responsiveness of clopidogrel and CV event in patient with CKD

Htun P et al. J Am Soc Nephrol. 2011 April; 22(4): 627–633

Response of clopidogrel in CKD patients

CV event in clopidogrel response vs low response

Percentage of low responders to clopidogrel increase according to deterioration of renal

function Clopidogrel low responders significantly increases risk

for CV events in patients with poor renal function

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 MI HR (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 1.2 0.4

Incr

easi

ng re

nal i

mpa

irmen

t

p for interaction = 0.92

Renal function and outcomes in PLATO: Major bleeding

15.1% 14.3%

NB: Figure labeled ‘Non-CABG TIMI bleeding’ in manuscript. CABG, coronary artery bypass graft; CI, confidence interval; CKD, chronic kidney disease HR, hazard ratio; TIMI, Thrombolysis in Myocardial Infarction. Adapted from James S, et al. Circulation 2010;122:1056–1067.

Days after randomisation 0 60 120 180 240 300 360

Maj

or b

leed

ing

(%)

25

20

15

10

5

0

CKD Ticagrelor Clopidogrel HR (95% CI) = 1.07(0.88–1.30)

Normal renal function Ticagrelor Clopidogrel HR (95% CI) = 1.08(0.96–1.22)

9.8% 10.6%

Bleeding occurred with similar frequency in the ticagrelor and clopidogrel groups

Summary

• Updated ACS guidelines has recommended new P2Y12 inhibitor as a first line treatment

• Evidence Based Medicine provide guidance to translate guidelines into clinical practice

• Right OAP for the right ACS patient will help patient to achieve better CV outcomes

• Ticagrelor has recommended as first line therapy in ACS Guidelines both ESC and AHA