new option of antiplatelet and controversies in acs treatment
DESCRIPTION
dr. Isfanuddin N Kaoy, SpJP (K), FIHA. 3rd Pekanbaru Cardiology Update, August 25th 2013. Pangeran Hotel, Pekanbaru. Learn more at PerkiPekanbaru.comTRANSCRIPT
New Option and Controversies
in ACS Treatment
Evolving landscape of antithrombotic treatment in A CS
Aspirin dose
Heparin
LMWH
GP IIb/IIIa timing
Direct thrombin inhib
Clopidogrel dose
Fonda
Prasugrel
Ticagrelor
ANTI PLATELET
ASPIRIN
TICLOPIDINE
Clopidogrel standard Dose
PRASUGREL
TICAGLEROL
CLOPIDOGREL High Dose
PLATO
TRITON
TRILOGI ACS
GRAVITAS
CURRENT
CURE, CALRITY
CREDO, COMMIT
Atherothrombosis: A Generalized and Progressive Disease
Unstable angina MI
Ischemic stroke/TIA
Critical leg ischemiaIntermittentclaudication
CV death
ACS
Atherosclerosis
Stable angina/Intermittent claudication
Atherothrombosis
MI = Myocardial infarctionACS = Acute coronary syndromesCV = Cardiovascular
Adapted from Libby P. Circulation 2001; 104: 365–372
CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of
Optimal Clopidogrel and Aspirin Dosing in Patients with
ACS Undergoing an Early Invasive Strategy with Intent
For PCI
OASIS-7
Shamir R. Mehta on behalf of the CURRENT Investigat ors
Disclosures: CURRENT OASIS 7 was funded by a grant from sanofi-aventis and Bristol Myers Squibb. All data were managed independently of the sponsor at the PHRI, McMaster University and the trial was overseen by an international steering committee of experts.
Study Design, Flow and Compliance25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)
� Planned Early (<24 h) Invasive Management with intended PCI� Ischemic ECG ∆ (80.8%) or ↑cardiac biomarker (42%)
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)� Planned Early (<24 h) Invasive Management with intended PCI� Ischemic ECG ∆ (80.8%) or ↑cardiac biomarker (42%)
PCI 17,232(70%)
Angio 24,769(99%)
Angio 24,769(99%)
No PCI 7,855 (30%)
No Sig. CAD 3,616 CABG 1,809 CAD 2,430
Randomized to receive (2 X 2 factorial):
CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)
ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d)
Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI
Clop in 1st 7d (median) 7d 7 d 2 d 7d
Complete Followup
99.8%
Compliance:
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
Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients
Clopidogrel Standard
Clopidogrel Double
HR 0.8595% CI 0.74-0.99
P=0.036
15% RRR
CV Death, MI or Stroke
Days
Cum
ulat
ive
Haz
ard
0.0
0.00
40.
008
0.01
2
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel Standard Dose
Clopidogrel Double Dose
42% RRR
HR 0.5895% CI 0.42-0.79
P=0.001
Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio confirmed)
CLOPIDOGREL vs. PRASUGREL
TRITON: Primary Efficacy Results in Entire ACS Cohort at 15 Months
Wiviott SD, et al. N Engl J Med 2007;357:2001-15
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)
P<0.001
Prasugrel
Clopidogrel
HR 0.80P=0.0003
HR 0.77P=0.0001
Days
Prim
ary
End
poin
t %
(N
) 12.1%(781)
9.9% (643)
NNT= 46
ITT= 13,608 LTFU = 14 (0.1%)
LTFU = Lost to follow-upITT = Intention to treat
TRITON: Primary Efficacy and Safety Endpoints in Entire ACS Cohort at 15 Months
Wiviott SD, et al. N Engl J Med 2007;357:2001-15
0
5
10
15
0 30 60 90 180 270 360 450
Prasugrel
Clopidogrel
Days
End
poin
t (%
)
12.1
9.9
Prasugrel
Clopidogrel1.82.4
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
HR 0.81(0.73-0.90)
P<0.001
138events
NNT = 46
HR 1.32(1.03-1.68)
P=0.03
35events
NNH = 167
% E
vent
s
TIMI MajorBleeds
ARR 0.6%HR 1.32P=0.03
Clopidogrel
Prasugrel
LifeThreateningARR 0.5%HR 1.52P=0.01
NonfatalARR 0.2%
P=0.23
ICHARR 0%P=0.74
FatalARR 0.3%P=0.002
ICH in Pts w Prior Stroke/TIA
(N=518)
Clop 0 (0) %Pras 6 (2.3)%
(P=0.02)1.8
0.9 0.9
0.10.3
2.4
1.41.1
0.4 0.3
0
2
4
TRITON: Prasugrel increase Significant Major & Life Threatening Bleeding Results in Entire ACS Cohort a t 15 Months
Adapted Wiviott SD, et al. N Engl J Med 2007;357:2001-15
NNH=167
NNH = Number needed to harmARR = Absolute risk reductionHR = hazard ratioICH = intracranial hemorrhage
CURRENT PCI
N=17,232
TRITON
N=13,608
CV Death, MI or Stroke ↓ 15%
↓ 21% (w high dose ASA)
↓ 19%
Definite Stent Thrombosis ↓ 42%
↓ 51% (w high dose ASA)
↓ 58%
TIMI Major Bleed No increase ↑ 32%
CABG-related Bleeding No increase ↑ 4-fold
Fatal bleeding No increase ↑ 4-fold
Comparison of CURRENT and TRITON
CLOPIDOGREL Vs. TICAGLEROL
Primary efficacy endpoint: Death from vascular caus es/MI/strokeSecondary efficacy endpoints: Primary endpoint in patients undergoing PCI; all cause mortality/MI/stroke,vascular death/MI/stroke/severe recurrent ischemia/TIA/arterial thrombotic event; stent thrombosis; all-cause mortalityPrimary safety endpoint: PLATO-defined major bleedi ng
12-month maximum exposure(Min = 6 mo, Max = 12 mo, Mean = 11 mo)
(N>18,000)
ASA* + Clopidogrel300-mg LD/75 mg qd †
Additional 300-mg LD allowed in PCI
ASA* + AZD6140180-mg LD/90 mg bid †
Additional 90 mg LD allowed in PCI >24 h after randomization
ACS patients (UA/NSTEMI/STEMI, PCI,
medically managed, or CABG)
*All patients received ASA 75-100 mg qd unless intolerant.
ASA = acetylsalicylic acid; LD = loading dose; PLATO = PLATelet inhibition and patient Outcomes trial.
James S et al. Am Heart J. 2009;157:599-605.
PLATO Study Design
Dose of study drug assigned as soon as possible ( ≤ 24 h) after index event
4
8
2
6
Primary efficacy endpoint over time (composite of CV death, MI or stroke)
*Excludes patients with any primary event during the first 30 days
0
Clopidogrel
Cum
ulat
ive
inci
denc
e (%
)
Ticagrelor
HR 0.88 (95% CI 0.77–1.00), p=0.045
0 10 20 30
Days after randomisation
5,43
4.77
No. at riskTicagrelor 9,333 8,942 8,827 8,763Clopidogrel 9,291 8,875 8,763 8,688
8
0
Clopidogrel
2
4
6
Cum
ulat
ive
inci
denc
e (%
)
Ticagrelor
0 90 150 330
Days after randomisation
8,673 8,543 8,397 7,028 6,480 4,8228,688 8,437 8,286 6,945 6,379 4,751
210 270
6.60
5.28
HR 0.80 (95% CI 0.70–0.91), p<0.001
Wallentin L et al. New Engl J Med.2009;361:DOI:10.1056/NEJMoa0904327. http://www.clinicaltrialresults.org/
PLATO : No Significant different in Sub Analysis fo r UA
US PLATO: Clopidogrel Better than Ticagrelor
Ticaglerol Better Vs. Clopi Ticaglerol Non Significant and Clopi better
PLATO : Ticaglerol significantly increase Non-CABG Bleeding
7
0
K-M
est
imat
ed r
ate
(% p
er y
ear)
9
8
6
5
4
3
2
1
Non-CABGPLATO major
bleeding
4.5
3.8
P=0.03 HR 1.19 (1.02-
1.38)
2.8
2.2
P=0.03 HR 1.25 (1.03-
1.53)
7.47.9
NS
5.35.8
NS
Ticagrelor
Clopidogrel
Non-CABGTIMI majorbleeding
CABGPLATO major
bleeding
CABGTIMI major bleeding
Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57.
NNH = 143
PLATO : Ticaglerol Increase Intracranial bleeding & Fatal ICH
P=0.06 HR 1.87
P=0.02 HR=5.47
K-M
est
imat
ed r
ate
(%
per
yea
r)
ICH
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0Fatal ICH
0.28
0.15
0.12
0.01
TicagrelorClopidogrel
Ticagrelor (N=9235) 26 11
Clopidogrel (N=9186) 14 1
Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57.FDA website CardiovascularandRenalDrugsAdvisoryCommittee/ucm192863.htm. Accessed on August 23rd, 2010.
Bleeding is a serious event
Moscucci et al, Eur Heart J 2003
*
* p<0.01
Bleeding associated with higher mortality after ACS
Ndrepepa et al, J Am Coll Cardiol 2008
5384 patients from 4 RCT’s, PCI studies, Stable CAD and ACS
Bleeding is a serious event
Same impact on long term mortality than new MI
Verheugt et al, JACC Cardiovasc Interv 2011
Recurrent events and Mortality
17393 PCI patients from 3 RCT’s (REPLACE 2, ACUITY an d HORIZON)
Bleeding is a serious event
Greater impact on prognosis of non access site bleedings
All Access-site bleeding impact mortality ?
Access-site bleeding impact mortality only if associat ed with Ht decrease
Romaguera et al, Am J Cardiol 2012
7718 PCI patients, single center registry, femoral a ccess
Two Types of Bleedings
In Hospital Bleedings (Procedure/Antithrombotic therapy)
Post Discharge Bleedings (Oral Antiplatelet Therapy)
After Discharge
Low dose aspirin
Individualized P2Y12 inhibitors
Use of PPI
Monitoring ?
In Hospital
- Radial Access +++
- Careful use of anticoagulant
- Shorten Duration of Therapy
- Selective use of GPIIbIIIa
How to prevent bleedings in ACS/PCI patients ?
0
108
Placebo APTC CURE
Antiplatelet Therapy in ACS
Single
Antiplatelet Rx
Dual
Antiplatelet RxHigher IPA
ASA
ASA + Clopidogrel ASA +
New P2Y12 blockers
- 22%
- 20%
- 19%
+ 60% + 38%+ 32%
Reduction in
Ischemic Events
Increase in
Major Bleeds
Placebo
0 30 60 90 180 270 360 450 days
5
10
En
dp
oin
t (%
)
0
9.8
11.7
Ticagrelor 90mg x2
HR 0.84 (0.77–0.92) p=0.0003*
12.1
9.9
Prasugrel 10mg
Clopidogrel 75mg
HR 0.81 (0.73-0.90) p=0.0004*
TRITON and PLATO
Primary endpoint = CV Death / MI / Stroke 12-15 months
Wiviott et al, NEJM 2007, Wallentin et al, NEJM 2010
p=0.03* p=0.025*
7
6
5
4
3
2
1
0
2.8
2.2
Safety = Non-CABG related TIMI major bleedings
1.8
2.4
p=0.001*
2.7
3.7
450 days
AS
A o
nly
360 days360 days
+38% +32% +27%
TicagrelorClopidogrel 75
Prasugrel
TRITON PLATOCURE
Same Platelet InhibiCon → Same Bleeding Risk
NNH=167 NNH=167
Wiviott et al, NEJM 2007, Wallentin et al, NEJM 2010
High risk
STEMI
Diabetes mellitus, CKD
High-risk NSTE ACS
(Tn + and/or ST changes)
Recurrent event on clopidogrel
Stent Thrombosis
Low risk
No ST changes
No Troponin elevation
(Patients not in Triton / Plato)
High risk:
Prior stroke/TIA*
Age > 75 y.o
Weight < 60 kg
Chronic OAC, Prior Bleeding
Low risk
No prior stroke/TIA/Bleeding
Age < 75 y.o
Weight > 60 kg
No Chronic OAC
Ischemic Risk
Bleeding Risk
P2Y12 Blockers
Individual Decision Clopidogrel
Clopidogrel
ACS patients
* CI Prasugrel
Prevention of Post discharge Bleedings
STEMI: Oral antiplateletsWhat, when and how?
WHAT?
WHEN?
HOW?
AspirinClopidogrel / Prasugrel* / Ticagrelor*
AspirinClopidogrel
ASAP
Aspirin: started at a dose of 150–300mg per os or 250–500mg bolus iv followed by 75-100mg daily
Prasugrel: 60mg LD followed by 10mg daily, or
Ticagrelor: 180mg LD followed by 90mg twice daily, or
Clopidogrel: 600mg LD followed by 75mg daily
Aspirin: oral dose of 150-325mg or i.v. dose of 250 mg if oral ingestion is not possible.
Clopidogrel: loading dose of 300mg if age ≤75 years; 75mg if age >75 years
1. Wijns W et al Eur Heart J 2010;31:2501-55
2. Van de Werf F et al Eur Heart J 2008;29:2909-45
Primary PCI 1 Thrombolysis 2
Invasive 1,2 Conservative 2
WHAT?
WHEN?
HOW?
AspirinTicagrelor* / Clopidogrel‡
AspirinTicagrelor* / Clopidogrel‡
Loading dose ASAP
Aspirin: started at a dose of 150–300 mg and at a maintenance dose of 75–100 mg, plus
Ticagrelor: 180 mg LD, 90 mg twice daily, or
Clopidogrel: 300 or 600 mg LD, 75 mg daily
Upstream GPIIbIIIa are not recommended in patients with high ischaemic risk
Aspirin: started at 150–300 mg and at a maintenance dose of 75–100 mg, plus
Ticagrelor 180 mg LD, 90 mg twice daily, or
Clopidogrel: an immediate 300 mg LD, 75 mg daily dose
1. Wijns W et al Eur Heart J 2010;31:2501-55
2. Hamm CW et al ESC NSTE-ACS Guidelines EHJ 2011; doi:10.1093/eurheartj/ehr236
3. Anderson JL et al Circulation 2007;116:148-304
‡All patient received clopidogrel LD before PCI in CURRENT* Ticagrelor has limited experience for prePCI load ing
Patients with low-likelihood of ACS, and lowest-risk ACS were excluded from clinical trials=> Recommendations apply to NSTEMI for which the diagnosis is likely or definite 3 and should be adapted
to patient risk level for thrombosis and bleeding 2,3
NSTE-ACS : AntiplateletsWhat, when and how?
New ESC and ACC Guidelines
ESC Guidelines
ACC AHA - PCI
- Loading dose for all P2Y12 inhibitors is recommended (Class I-A)
- 600 mg loading recommended for clopidogrel
- Limitations imposed on prasugrel
- Issue of compliance posed against ticagrelor
Plavix 300 mg = Improve Compliance
Loading Dose 4 tabs 75 mg = 1 tab Plavix 300 mg
Loading Dose 8 tabs 75 mg = 2 tabs Plavix 300 mg
Summary
Clopidogrel Prasugrel TicagrelorMajor study CURE TRITON-TIMI 38 PLATO
Population NSTEACS ACS - PCI ACS
Loading dose 300 mg 60 mg 180 mg
Maintenance dose 75 mg 10 mg 90 mg
Maintenance schedule Daily Daily Twice daily
Treatment arms Clopidogrel vs placebo Prasugrel vs clopidogrel
Ticagrelor vs clopidogrel
Duration of follow-up 9 months 14.5 months 9 months
CV death, MI, stroke9.3 vs 11.4%
RR 0.80, p < 0.0019.9 vs 12.1%
HR 0.81, p < 0.0019.8 vs 11.7%
HR 0.84, p < 0.001
TIMI non-CABG major bleeding1.1 vs 1.2%*
RR 0.94, p = 0.72.4 vs 1.8%
HR 1.32, p = 0.032.8 vs 2.2%
HR 1.25, p = 0.03
Major bleeding per study definition3.7 vs 2.7%
RR 1.38, p = 0.0012.4 vs 1.8%
HR 1.32, p = 0.0311.6 vs 11.2%
HR 1.04, p = 0.43
Yusuf S et al. N Engl J Med. 2001;345:494-502.Wiviott SD et al. N Engl J Med 2007;357:2001-15Wallentin L et al. N Engl J Med. 2009;361(11):1045-57.
*TIMI major bleeding