Balancing Efficacy and Safety of P2Y12 Inhibitors for ACS ... · Balancing Efficacy and Safety of P2Y12 Inhibitors for ACS Patients dr. Hariadi Hariawan, Sp.PD, Sp.JP (K) SYP.CLO-A.16.07.01

Balancing Efficacy and Safety of

P2Y12 Inhibitors for ACS Patients

dr. Hariadi Hariawan, Sp.PD, Sp.JP (K)

SYP.CLO-A.16.07.01

TOPICS

Efficacy – Safety Consideration from Currently

Available Antiplatelet Agents

Dual Antiplatelet Therapy (DAPT), How Long

to Treat ?

Optimizing Risk-Benefit Ratio : Highlights of

Recent Guidelines

Atherothrombosis: A Significant

Cause of Major Ischemic Events

Atherothrombosis is characterized by a sudden, unpredictable atherosclerotic plaque disruption leading to platelet activation and thrombus formation

1. Falk E, et al. Circulation 1995; 92: 657–671. 2. Arbustini E, et al. Heart 1999; 82:

269–272. 3. Aronow WS, et al. Am J Cardiol 1994; 74(1): 64–65.

Plaque rupture1 Plaque erosion2

Atherothrombosis is the underlying condition that results in events leading to myocardial infarction (MI), ischemic stroke or vascular death An atherothrombotic manifestation in one vascular bed results in an increased risk of further events in all vascular beds3

Aggregation

of platelets into

a thrombus

Platelets

Endothelial cells

Platelets adhering to

subendothelial space

Platelet

thrombus

Normal platelets

in flowing blood

Platelets adhering to

damaged endothelium

and undergoing activation

Subendothelial space

Adapted from Ferguson JJ. In: Ferguson JJ, Chronos N, Harrington RA (Eds).

Antiplatelet Therapy in Clinical Practice. London: Martin Dunitz;2000:15–35.

Major role of platelets in atherothrombosis

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

The rationale behind dual antiplatelet therapy

2 indications for DAPT after successful stenting :

1. the stented segment requires protection from

stent thrombosis that occurs as a result of

inflammation during healing.

2. the areas inside and outside the stented section

require protection from the development of

progressive atherosclerosis and plaque rupture

of less concern with drug-eluting stents, especially second- and third-

generation drug-eluting stents.

continues to be important

Colombo A, et al.N Eng J Med.2014;371(23):2225-6.

P = .04 P = .0003 P = .0052

Med

ian

Tim

e o

f L

ate

Ste

nt

Th

rom

bo

sis

(Mo

s)

0

4

8

12

16

20

DES vs BMS Sirolimus Stent

vs BMS

Paclitaxel Stent

vs BMS

Either DES

Sirolimus stent

Paclitaxel stent

BMS

Meta-Analysis: Late Thrombosis in First-

Generation DES vs BMS

Bavry AA, et al. Am J Med. 2006;119:1056-1661.

EXAMINATION: Incidence of Stent Thrombosis

With EES vs BMS in Acute MI

3.0

2.5

2.0

1.5

1.0

0.5

0 0 60 120 180 240 300 360

Stent thrombosis HR: 2.75 (95% CI: 1.15-6.54); P = .0169

Days After Initial Procedure

Cu

mu

lati

ve In

cid

en

ce o

f

Even

ts (

%)

Sabate M, et al. Lancet. 2012;380:1482-1490.

Definite stent thrombosis

Cardiac death

Target-vessel MI

Target-vessel revascularization

Probable stent thrombosis

Cardiac death

Target-vessel MI

Target-vessel revascularization

EES

BMS

Oral Antiplatelet Agents

Antiplatelet Agent Class Binding Dosing

Aspirin[1] Thromboxane inhibitor Irreversible QD

Clopidogrel[2] ADP receptor antagonist Irreversible QD

Prasugrel[3] ADP receptor antagonist

(more potent than clopidogrel) Irreversible QD

Ticagrelor[4] ADP receptor antagonist

(more potent than clopidogrel) Reversible BID

1. Aspirin [package insert]. 2. Clopidogrel [package insert]. 3. Prasugrel [package insert]. 4. Ticagrelor [package insert].

Metabolic Pathway of P2Y12-receptor Inhibitors

Levine GN, et al.Nat Rev Cardiol.2014. doi: 10.1038/nrcardio.2014.104

Major studies of P2Y12 inhibitors in patients with ACS or undergoing PCI


Major studies of P2Y12 inhibitors in patients with ACS or undergoing PCI


Prasugrel is currently not available in Indonesia

CURE: CV Death, MI, or Stroke With 12 Months of

DAPT in NSTEMI

Dual antiplatelet therapy resulted in 20% reduction in relative risk of MI, stroke, or

CV-related death over aspirin alone

Mos of Follow-up

Cu

mu

lati

ve

HR

*

20% RRR

P = .00009

N = 12,562

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 3 6 9 12

Placebo + ASA†

(n = 6303)

Clopidogrel + ASA†

(n = 6259)

*MI, stroke, CV death. †For 3-12 mos.

Yusuf S, et al. N Engl J Med. 2001;345:494-502.

CHARISMA: CV Death, MI, or Stroke in Pts With

Prior MI, Stroke, or PAD

Secondary endpoint of stroke also significantly lower with clopidogrel + ASA (3.0%) vs placebo +

ASA (3.8%), P = 0.048

6

0 6 12 18 24 30

4

2

0

8

10 P

rim

ary O

utc

om

e E

ven

t R

ate

(%

)

Mos Since Randomization

Post Hoc Analysis of “CAPRIE-like” Subgroup

of Pts in CHARISMA Trial

17.1% RRR

(95% CI: 4.4% to 28.1%;

P = .01)

Clopidogrel + ASA

(n = 4745)

Placebo + ASA

(n = 4743)

8.8%

7.3%

Bhatt DL, et al. J Am Coll Cardiol. 2007;49:1982-1988.

CHARISMA: CV Death, MI, or Stroke in Pts

With Prior MI


10

8

6

4

2

0 0 6 12 18 24 30

6.6%

8.3%

HR: 0.774 (95% CI: 0.613-0.978;

P = .031)


Pri

mary

Ou

tco

me E

ven

t

Rate

(%

)

N = 3846

Placebo + ASA

Clopidogrel + ASA

CHARISMA: CV Death, MI, or Stroke in CAD Pts

Without Prior MI

0 6 12 18 24 30

5.7%

6.3%

HR: 1.103 (95% CI: 0.770-1.580;

P = .593)


Pri

mary

Ou

tco

me E

ven

t

Rate

(%

)

N = 1989

Placebo + ASA

Clopidogrel + ASA

10

8

6

4

2

0


810 630 450 270 135 15 0 60

CHARISMA: Timing of Severe or Moderate Bleeding*

In pts tolerating clopidogrel plus ASA, reasonable to continue beyond 12 months if

clinically indicated

*By GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries) criteria, including

fatal bleeding, primary intracranial hemorrhage, and bleeding causing hemodynamic compromise and

requiring blood or fluid replacement, inotropic support, or surgical intervention.

Days Since Randomization

0.00008

0.00006

0.00002

0

0.00004

Hazard

Fu

ncti

on

/d Clopidogrel + ASA

Placebo + ASA


Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From the Prospective,

Randomized PLATO Trial Steg PGB, Harrington RA, Emanuelsson H, et

al.Circulation.2013;128:1055 - 65

Method : multicenter, double-blind, randomized trial, comparing ticagrelor

(180-mg LD 90 mg BID) and clopidogrel (300-to-600-mg LD 75 mg

OD) for the prevention of cardiovascular events

• Results : n=18,624

Efficacy Summary :

• Primary end point was better

for ticagrelor

• Secondary end point was better

for ticagrelor except stroke

• The rate of death from any

cause was also reduced with

ticagrelor

Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From the Prospective, Randomized PLATO Trial

Steg PGB, Harrington RA, Emanuelsson H, et al.Circulation.2013;128:1055 – 65

K-M estimate of time to first primary efficacy

event (composite of CV death, MI or stroke)

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,521

8,628

8,362

8,460

8,124

Days after randomisation

6,743

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 C

um

ula

tive i

ncid

en

ce (

%)

9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

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

Time to major bleeding – primary safety event

No. at risk

Clopidogrel

Ticagrelor

9,186

9,235

7,305

7,246

6,930

6,826

6,670

Days from first IP dose

5,209

5,129

3,841

3,783

3,479

3,433

0 60 120 180 240 300 360

10

5

0

15

Clopidogrel

Ticagrelor

11.20

11.58

6,545

HR 1.04 (95% CI 0.95–1.13), p=0.434

K-M

esti

mate

d r

ate

(%

per

year)

Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From

the Prospective, Randomized PLATO Trial Steg PGB, Harrington RA, Emanuelsson H, et

al.Circulation.2013;128:1055 - 65

Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From the Prospective,

Randomized PLATO Trial Steg PGB, Harrington RA, Emanuelsson H, et

al.Circulation.2013;128:1055 - 65

Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis

From the Prospective, Randomized PLATO Trial Steg PGB, Harrington RA, Emanuelsson H, et

al.Circulation.2013;128:1055 - 65

Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From

the Prospective, Randomized PLATO Trial

Steg PGB, Harrington RA, Emanuelsson H, et al.Circulation.2013;128:1055 - 65

Balance between antiplatelet effect and bleeding risk

“Use of more potent P2Y12 inhibitors (ticagrelor or prasugrel) in place of clopidogrel also results in decreased ischemic risk and increased bleeding

risk” – Levine GN, et al 2016 ACC/AHA Guideline

Randomized Trials Evaluating Duration of DAPT After

Stent Implantation

Capodanno D, et al. Circulation. 2013;128:2785-2798.

*Biolimus A9-eluting stent.

EXCELLENT ITALIC

ISAR SAFE DAPT-STEMI

DAPT ARCTIC

3 months

6 months

24 months

12 months

48 months

30 months

1 month

Meta-analysis of 31,666 pts with DES and DAPT for ≤ 6

mos vs 12 mos vs > 12 mos

Treatment with DAPT for > 12 mos:

Reduced MI and stent

thrombosis

– 25% decrease in MI

(P = .01)

– 41% decrease in stent

thrombosis (P = .06)

Increased bleeding, overall

mortality, and non-cardiac

mortality

– 72% increase in bleeding

(P < .0001)

– 49% increase in noncardiac

mortality (P = .006)

– 22% increase in mortality

(P = .02) Palmerini T, et al. Lancet. 2015;385:2371-2382.

Extended-Duration DAPT After DES

Optimal Duration of DAPT?

Eisen A, et al. Nat Rev Cardiol. 2015;12:445-446..

2016 ACC/AHA Guideline Focused Update on

Duration of Dual Antiplatelet

Therapy in Patients With Coronary Artery

Disease Levine GN, et al.Circulation.2016;133:000-000

Factors Associated With Increased

Ischemic and Bleeding Risk

DAPT Score

• A score of ≥ 2 is associated

with a favorable benefit/risk ratio

for prolonged DAPT;

• A score of < 2 is associated

with an unfavorable benefit/risk

ratio.

CHF: congestive heart failure;

DAPT: dual antiplatelet therapy;

LVEF: left ventricular ejection fraction;

MI: myocardial infarction;

PCI: percutaneous coronary intervention.

2016 ACC/AHA DAPT guideline recommendations:

SIHD and ACS

Treatment Algorithm for DAPT in Recent ACS (NSTE-ACS or STEMI)

CURE COMMIT

CLARITY

CURE

COMMIT

CURE

DAPT

CHARISMA

PEGASUS

Treatment Algorithm for DAPT in SIHD (Without ACS Within the Past Several Years)

• Patients with hx of ACS >1 year prior who have since remained free of recurrent ACS are considered to have transitioned to SIHD;

• Aspirin therapy is

almost always continued indefinitely in patients with CHD.

Treatment Algorithm for Duration of P2Y12 Inhibitor Therapy in Patients Treated With PCI

DAPT

CHARISMA

PEGASUS

Summary of the Guideline (1/2)

Intensification of antiplatelet therapy, with P2Y12 inhibitor + aspirin, as well as prolongation of DAPT, necessitates a fundamental tradeoff between decreasing ischemic risk and increasing bleeding risk;

Shorter-duration DAPT can be considered for patients at lower ischemic risk with high bleeding risk (DAPT score <2), whereas longer-duration DAPT may be reasonable for patients at higher ischemic risk with lower bleeding risk (DAPT score ≥2);

Clopidogrel is recommended for all ACS pts no matter receiving any treatment option (PCI, medical treatment, lytic or CABG), while ticagrelor is recommended for ACS pts receiving PCI, medical treatment or CABG, but not in lytic pts; Prasugrel is recommended only in PCI pts.

Updated recommendations for duration of DAPT are now similar for patients with NSTE-ACS and STEMI, as both are part of the spectrum of acute coronary syndrome.

A Class I recommendation (“should be given”) in most clinical settings is made for at least 6-12 months of DAPT (depending on the setting), and a Class IIb recommendation (“may be reasonable”) is made for prolonged DAPT beyond this initial 6- to 12-month period.

Summary of the Guideline (2/2)

CONCLUSION

Choice and duration of DAPT should be individualized to achieve optimum risk-benefit of the treatment. Evidence and guidelines are available to help the decision.

Use of more potent P2Y12 inhibitors (ticagrelor or prasugrel) in place of clopidogrel also results in decreased ischemic risk and increased bleeding.

Choice of antiplatelet should be based on careful review on the balance between antiplatelet efficacy and risk of bleeding. Tolerability, compliance to treatment, patient’s

preference and cost should also be considered

Balancing Efficacy and Safety of P2Y12 Inhibitors for ACS ... · Balancing Efficacy and Safety of P2Y12 Inhibitors for ACS Patients dr. Hariadi Hariawan, Sp.PD, Sp.JP (K) SYP.CLO-A.16.07.01

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