Lowering Mortality ofACS with Optimal Therapy:

Doing It Right from the Start

dr. Berlian Idriansyah Idris, SpJP(K), FIHA, MPH, DSc

RSUD Kota Tangerang

ACUTE CORONARY SYNDROME

Spectrum of clinical syndromes due to sudden, significantly compromised coronary circulation due to thrombosis, ranging from unstable angina to NSTEMI and STEMI.

Topol EJ, ed. Textbook of cardiovascular medicine 2007.

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

Acute thrombosis induced by a ruptured or eroded atherosclerotic coronary plaque, causing a sudden and critical reduction in blood flow

Normal

vessel

Minimal

CAD

Severe

CAD

Moderate

CAD

Progression

Pathophysiology

Autopsy

Stable plaque

Davies MJ. Heart 2000;83;361-366.

Thrombosis caused by erosion

Thrombosis caused by disruption

Thrombosis caused

by disruption

Cardiovascular

disease

Cerebrovascular

disease

PAD

24.7%

3.8% 11.8%

29.9%

3.3%

7.4%

19.2% A total of ~26% of patients

had manifestations of

atherothrombosis in

more than one arterial bed

26.2%†

Coccheri S. Eur Heart J 1998;19(Suppl):227.

Atherothrombosis is often found in more than one

arterial bed*

*Data from the Clopidogrel versus Aspirin in Patients

at Risk of Ischemic Events (CAPRIE) study (n=19,185)

†Total does not add up because of rounding

Atherogenesis and Atherothrombosis: A Progressive Process

NormalFatty

StreakFibrousPlaque

Athero-scleroticPlaque

PlaqueRupture/Fissure &

Thrombosis

Acute

coronary

syndrome

Ischemic

Stroke

Critical Leg

Ischemia

Clinically Silent

Cardiovascular Death

Increasing Age

Angina

Transient Ischemic Attack

Claudication/PAD

~1 IN 5 mortality in 5 years from index event:

2010 Global Registry

GRACE study: Analysis of UK and Belgian patients with ACS (n=3721)

Of the patients who died, death occurred post-discharge in 68%, 86% and 97% of STEMI, NSTEMI and UA patients, respectively. ACS, acute coronary

syndromes; GRACE, Global Registry of Acute Coronary Events; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI,

ST-segment elevation myocardial infarction; UA, unstable angina.

Fox KA et al. Eur Heart J 2010;31:2755–2764.

Activated platelets are central to

thrombus formation 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.

Spectrum of ACS

9Reference: 1. Adapted from Hamm CW et al. Eur Heart J 2011;32:2999 – 3054

Admission

ECG

Bio-chemistry

Diagnosis STEMI NSTEMI

ST segment

ST depression

ST elevation

UA

Typical Angina

Troponin

rise/fall

Troponin

normal

Clinical classification of chest pain

Typical angina (definite)

• Substernal chest discomfort with a characteristic quality and duration that is

• provoked by exertion or emotional stress and

• relieved by rest or nitroglycerin

Atypical angina (probable)

• meets 2 of the above characteristics

Noncardiac chest pain

• meets <=1 of the typical angina characteristics

10Diamond GA. J Am Coll Cardiol 1983;1:574

Management

• Monitor and support ABCs

• Check vital signs, including oxygen saturation

• Establish IV access

• Administer

– Oxygen 4L/min

– Aspirin 160-325 mg chewed

– Clopidogrel loading dose 300 mg or ticagrelor 180 mg

– NTG (ISDN) sublingual and intravenous if needed

– Morphine if pain not relieved with NTG

– Anticoagulant: UFH/enoxaparine/fondaparinux

• Urgent reperfusion as indicated in STEMI: fibrinolytic or primary PCI

11

Antiplatelet Agent

Metabolism P2Y12 inhibitor

(Pro drug vs active drug)

*Prasugrel is not yet approved and available in Indonesia Figure adapted from Schömig A (2009). CYP, cytochrome P450.

Schömig A. N Engl J Med 2009;361:1108–1111.

Binding

P2Y12

Platelet

No in vivo

biotransformation

Ticagrelor

(Active Drug)

Prasugrel*

(Prodrug)

Clopidogrel

(Prodrug)

CYP-dependent

oxidation

CYP3A4/5

CYP2B6

CYP2C19

CYP2C9

CYP2D6Hydrolysis

by esterase

CYP-dependent

oxidation

CYP1A2

CYP2B6

CYP2C19

CYP-dependent

oxidation

CYP2C19

CYP3A4/5

CYP2B6

Active compound

Intermediate metabolite

Pro-drug

CYP2C19 Polymorphisms

Ultrarapidmetabolizer

Intermediate Metabolizer

Poor Metabolizer

Reduced response of “pro drug” agent

Prevalence of Poor Metabolizer is higher in Asian 2 – 5% in Caucasian 4 – 8 % of african 11 - 12% of Asian

Sukasem C et al. Pharmacogenomics and

Personalized Medicine 2013:6 85–91

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

Me

an

In

hib

itio

n, %

Ticagrelor 100 mg bd

DAY 1

DAY 14

Time, h

Me

an

In

hib

itio

n, %

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 24

0

20

40

60

80

100

0 2 4 8 12 24

2nd dose

Onset P2Y12 inhibitor

Ticagrelor provide Faster Onset and offset vs high dose clopidogrel

IPA : Inhibition of Platelet Aggregation

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 OffsetTime (hours))

Loading Dose

TICA 180 mg

CLO 600 mg

*

** * *

‡

†

** †

Last maintenance dose

TICA 90 mg bid

CLOPI 75 mg qd

** * P<0,0001

† P<0,005‡ P<0,05

Time (hours)

Catatan : penelitian ini dilakukan pada pasien CAD yang

mengkonsumsi aspirin tanpa riwayat ACS <1 tahun

Ticagrelor belum mendapatkan persetujuan untuk populasi

pasien ini.

18

Referensi Adapted from Gurbel PA, et al. Circulation. 2009;120:2577–2585.

41% ticagrelorVs.

8% clopidogrel

At 30 minutes

88% ticagrelorVs.

38% clopidogrel

At 2 hours

8

Balance between antiplatelet effect and bleeding risk

Balancing risk and benefit

INHIBITION OF PLATELET AGGREGATION

RIS

K O

F A

NY

EV

ENT

RIS

K O

F A

NY

EV

ENT

High Risk of Ischemic Event High Risk of Bleeding Event“Sweet Spot”

Ischemic risk Bleeding risk

Ferreiro Jl, Sibbing D, Angiolillo DJ. Thromb Haemost 2010; 103: 1128–1135

Factors Associated with Increased Ischemic and Bleeding Risk

PLATO Study

PLATO Study:

• 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 clopidogrel and this would be

achieved with a clinically acceptable bleeding rate and overall safety profile

18,624 patients

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

PLATO Trial: Reduction CV event of ticagrelor starts early and

continue until 12 months in ACS Patients vs. clopidogrel1

Reference: 1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

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

12

11

10

9

8

7

6

5

4

3

2

1

0

13

Cu

mu

lati

ve

In

cid

en

ce

of

(Co

mp

osit

e o

f

CV

De

ath

, M

I, o

r S

tro

ke

) %

11.7 Clopidogrel

9.8 Ticagrelor

HR: 0.88 (95% CI, 0.77−1.00); P=0.045

0–30 Days

4.8

5.4

Clopidogrel

Ticagrelor

0–12 Months

at 1 month

ARR=0.6%

RRR=12%

HR: 0.84 (95% CI, 0.77–0.92); P<0.001

at 12 months

ARR=1.9%

RRR=16%

Benefit CV Mortality P2Y12 Inhibitor

5.50 5.10

Plasebo Clopidogrel

CURE1

2.40 2.10

Clopidogrel Prasugrel *

TRITON TIMI 382

5.10

4.00

Clopidogrel Ticagrelor

PLATO3

P = NS

n = 12.562

NNT = 250

n = 13.608

NNT = 333

n = 18.624

NNT = 91

1.Yusuf S et al. N Engl J Med 2001;345; 2.Wiviott SD e tal. N Engl J Med 2007;357:2001-15; 3.Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

* Prasugrel is not yet approved and available in Indonesia

Rate

of C

V d

ea

th (

%)

Rate

of co

mp

osite C

V d

ea

th (

%) P = N/A P = 0.001

Real World Evidence DAPT in ACS

• Outcomes in Patients Treated With Ticagrelor

or Clopidogrel After Acute Myocardial

Infarction: Experiences From SWEDEHEART

Registry (The PRACTICAL study) Anders Sahlén, Christoph Varenhorst, Bo Lagerqvist, Henrik Renlund,

Elmir Omerovic, David Erlinge, Lars Wallentin, Stefan James, Tomas Jernberg

Referensi: 1. Salhén A et al. Eur Heart J 2016; 37; 3335 - 3342 14

PRACTICAL Study :Consistent effectiveness Ticagrelor in ACS showed in real-world setting1

Reduce

15%vs.

Clopidogrel

Cu

mu

lati

ve

in

cid

en

ce

Time (days)

0 100 200 300 365

0.00

0.02

0.04

0.06

0.08

0.10Clopidogrel

Ticagrelor 90 mg

Ticagrelor

90 mgClopidogrel

HR adjusted

(complete cases)*

95% confidence

interval

4.43% 3.85%1.178

(0.994–1.396)

All-cause death, MI or strokeBleeding requiring

hospitalization at 12 months

(sensitivity analysis)3

HR 0.85. 95% CI (0.77-0.94)

Referensi: 1. Salhén A et al. Eur Heart J 2016; 37; 3335 - 3342

45,073 consecutive patients who survived an acute MI

15

ESC STEMI 2017

Ticagrelor is preferred OAP before clopidogrel

28

ESC NSTEACS 2015:

Ticagrelor is preferred OAP before clopidogrel

A P2Y12 inhibitor is recommended, in addition to aspirin, for 12 months

unless there are contraindications such as excessive risk of bleeds.

Ticagrelor is recommended, in the absence of contraindications,

for all patients at moderate-to-high risk of ischaemic events (e.g.

elevated cardiac troponins), regardless of initial treatment strategy

and including those pretreated with clopidogrel (which should be

discontinued when ticagrelor is started).

Prasugrel is recommended in patients who are proceeding to PCI if

no contraindication).

Clopidogrel is recommended for patients who cannot receive

ticagrelor or prasugrel or who require oral anticoagulation.

1B

1B

1B

1A

Roffi M et al. Eur Heart J 2016;37(3):267-315

29

Summary

•ACS is a fatal condition, mortality is still high

•Platelet plays important role in

atherothrombosis pathophysiology of ACS

•Agressively treating atherothrombosis from

the start is the hallmark of therapy, while

taking into account bleeding bleeding risk

•Recent guidelines prefer ticagrelor for ACS

patients with better efficacy and similar safety

profile

THANK YOU…

30

31

• Thank you

Key Question

32

Switching DAPT in ACS, how ?

Bleeding with OAP, how to prevent and manage ?

How long DAPT ?

SWITCHING RECOMMENDATION BASED ON STEMI 2017

Valgimigli Marco et al. Europan Heart Journal . 2017;0: 1-48

PLATO Study : Switch in Acute from Ticagrelor to

Clopidogrel is allowed

Characteristic Ticagrelor

(n=9333)

Clopidogrel

(n=9291)

P value

Start of randomized treatment , %

Time after start of chest pain (hours) median 11.3 11.3 0.89

Time after start of hospitalization (hours), median 4.9 5.3 0.75

Clopidogrel start-up

Clopidogrel in hospital before randomization, n (%) 4293 (46.0) 4282 (46.1) 0.91

Clopidogrel dose given within 24 h before or after randomization, n (%) 0.65

No loading dose or missing information 4937 (52.9) 94 (1.0)

300-375 mg 1921 (20.6) 5528 (59.5)

600-675 mg 1282 (13.7) 1822 (19.6)

Other dose 697 (7.5) 1339 (14.4)

Same dose as before index event 496 (5.3) 508 (5.5)

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

35

Greater IPA will achieved when switching from clopidogrel to ticagrelor

despite of patient respond or no respond to clopidogrel

Non Responders Responders

*p<0.0001, †p<0.001, ‡p<0.05.

Gurbel PA, et al. Circulation 2010;121:1188–1199.

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.

CLASS LEVEL

1 C

CLASS LEVEL

1 C

CLASS LEVEL

1 B

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

Bleeding Management

37

The proton pump inhibitor treatment algorithm in

patients with acute coronary syndrome

Agewall S et al. Eur Heart J 2013; 34, 1708–1715

ACS treated with DAPT in patients with a history of GI

hemorrhage or peptic ulcer, and/or high CRUSADE score or

multiple other risk factor for GI Bleeding

( Helicobacter Pylori infection, age ≥ 65 years , concurrent use

of anticoagulants or steroids)

Prasugrel

Ticagrelor

Clopidogrel Warfarin

Any PPI PPI with less CYP2C19 inhibitory

capacity (pantoprazole) rather

than a PPI with high inhibitory

capacity (omperazole

Any PPI,

With carefull

INR monitoring

How Long DAPT

Referensi: 1. Valgimigli M et al. European Heart Journal 2017; 0; 1–48