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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
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
Levine GN, et al.Nat Rev Cardiol.2014. doi: 10.1038/nrcardio.2014.104
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
Bhatt DL, et al. J Am Coll Cardiol. 2007;49:1982-1988.
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)
Mos Since Randomization
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)
Mos Since Randomization
Pri
mary
Ou
tco
me E
ven
t
Rate
(%
)
N = 1989
Placebo + ASA
Clopidogrel + ASA
10
8
6
4
2
0
Bhatt DL, et al. J Am Coll Cardiol. 2007;49:1982-1988.
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
Bhatt DL, et al. J Am Coll Cardiol. 2007;49:1982-1988.
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
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
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.
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