dr. Isfanuddin N Kaoy, SpJP (K), FIHA. 3rd Pekanbaru Cardiology Update, August 25th 2013. Pangeran Hotel, Pekanbaru. Learn more at PerkiPekanbaru.com

1. New Option and Controversies
in ACS Treatment

2. Evolving landscape of antithrombotic treatment in ACS
Aspirin dose
Heparin
LMWH
GP IIb/IIIa timing
Direct thrombin inhib
Clopidogrel dose
Fonda
Prasugrel
Ticagrelor

3. ANTI PLATELET
ASPIRIN
TICLOPIDINE
Clopidogrel standard Dose
PRASUGREL
TICAGLEROL
CLOPIDOGREL High Dose
PLATO
TRITON
TRILOGI ACS
GRAVITAS
CURRENT
CURE, CALRITY
CREDO, COMMIT

4. Atherothrombosis: A Generalized and
Progressive Disease
Unstable angina
MI
Ischemic
stroke/TIA
Critical leg
ischemia
Intermittent
claudication
CV death
ACS
Atherosclerosis
Stable angina/Intermittent claudication
Atherothrombosis
MI = Myocardial infarction
ACS = Acute coronary syndromes
CV = Cardiovascular
Adapted from Libby P. Circulation 2001; 104: 365–372

5. 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 Investigators
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.

6. Study Design, Flow and Compliance
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%)
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 30
Stent 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:

7. Days
CumulativeHazard
0.00.010.020.030.04
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 0.85
95% CI 0.74-0.99
P=0.036
15% RRR
CV Death, MI or Stroke

8. Days
CumulativeHazard
0.00.0040.0080.012
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel Standard Dose
Clopidogrel Double Dose
42%
RRR
HR 0.58
95% CI 0.42-0.79
P=0.001
Clopidogrel: Double vs Standard Dose
Definite Stent Thrombosis (Angio confirmed)

9. CLOPIDOGREL vs. PRASUGREL

10. 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 0.80
P=0.0003
HR 0.77
P=0.0001
Days
PrimaryEndpoint%(N)
12.1%
(781)
9.9% (643)
NNT= 46
ITT= 13,608 LTFU = 14 (0.1%)
LTFU = Lost to follow-up
ITT = Intention to treat

11. 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
Endpoint(%)
12.1
9.9
Prasugrel
Clopidogrel
1.8
2.4
CV Death / MI / Stroke
TIMI Major
NonCABG Bleeds
HR 0.81
(0.73-0.90)
P<0.001
138
events
NNT = 46
HR 1.32
(1.03-1.68)
P=0.03
35
events
NNH = 167

12. %Events
TIMI Major
Bleeds
ARR 0.6%
HR 1.32
P=0.03
Clopidogrel
Prasugrel
Life
Threatening
ARR 0.5%
HR 1.52
P=0.01
Nonfatal
ARR 0.2%
P=0.23
ICH
ARR 0%
P=0.74
Fatal
ARR 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
0.1
0.3
2.4
1.4
1.1
0.4 0.3
0
2
4
TRITON: Prasugrel increase Significant Major & Life
Threatening Bleeding Results in Entire ACS Cohort at
15 Months
Adapted Wiviott SD, et al. N Engl J Med 2007;357:2001-15
NNH=167
NNH = Number needed to harm
ARR = Absolute risk reduction
HR = hazard ratio
ICH = intracranial hemorrhage

13. 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

14. CLOPIDOGREL Vs. TICAGLEROL

15. Primary efficacy endpoint: Death from vascular causes/MI/stroke
Secondary 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 mortality
Primary safety endpoint: PLATO-defined major bleeding
12-month maximum exposure
(Min = 6 mo, Max = 12 mo, Mean = 11 mo)
(N>18,000)
ASA* + Clopidogrel
300-mg LD/75 mg qd†
Additional 300-mg LD allowed in PCI
ASA* + AZD6140
180-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

16. 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
Cumulativeincidence(%)
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 risk
Ticagrelor 9,333 8,942 8,827 8,763
Clopidogrel 9,291 8,875 8,763 8,688
8
0
Clopidogrel
2
4
6
Cumulativeincidence(%)
Ticagrelor
0 90 150 330
Days after randomisation
8,673 8,543 8,397 7,028 6,480 4,822
8,688 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/

17. PLATO : No Significant different in Sub Analysis for UA

18. US PLATO: Clopidogrel Better than Ticagrelor

19. Ticaglerol Better Vs. Clopi Ticaglerol Non Significant and Clopi better

20. PLATO : Ticaglerol significantly increase Non-
CABG Bleeding
7
0
K-Mestimatedrate(%peryear)
9
8
6
5
4
3
2
1
Non-CABG
PLATO 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)
7.4
7.9
NS
5.3
5.8
NS
Ticagrelor
Clopidogrel
Non-CABG
TIMI major
bleeding
CABG
PLATO major
bleeding
CABG
TIMI major
bleeding
Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57.
NNH = 143

21. PLATO : Ticaglerol Increase Intracranial
bleeding & Fatal ICH
P=0.06 HR
1.87
P=0.02
HR=5.47
K-Mestimatedrate(%peryear)
ICH
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
Fatal ICH
0.28
0.15
0.12
0.01
Ticagrelor
Clopidogrel
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.

22. Bleeding is a serious event
Moscucci et al, Eur Heart J 2003
*
* p<0.01
Bleeding associated with higher mortality after ACS

23. 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

24. Verheugt et al, JACC Cardiovasc Interv 2011
Recurrent events and Mortality
17393 PCI patients from 3 RCT’s (REPLACE 2, ACUITY and
HORIZON)
Bleeding is a serious event
Greater impact on prognosis of non access site
bleedings

25. All Access-site bleeding impact mortality ?
Access-site bleeding impact mortality only if associated with Ht decrease
Romaguera et al, Am J Cardiol 2012
7718 PCI patients, single center registry, femoral access

26. Two Types of Bleedings
In Hospital Bleedings (Procedure/Antithrombotic therapy)
Post Discharge Bleedings (Oral Antiplatelet Therapy)

27. 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 ?

28. 0
108
Placebo APTC CURE
Antiplatelet Therapy in ACS
Single
Antiplatelet Rx
Dual
Antiplatelet Rx
Higher IPA
ASA
ASA + Clopidogrel ASA +
New P2Y12 blockers
- 22%
- 20%
- 19%
+ 60% + 38%
+ 32%
Reduction in
Ischemic Events
Increase in
Major Bleeds
Placebo

29. 0 30 60 90 180 270 360 450 days
5
10
Endpoint(%)
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

30. 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
ASAonly
360 days360 days
+38% +32% +27%
Ticagrelor
Clopidogrel 75
Prasugrel
TRITON PLATOCURE
Same Platelet InhibiƟon → Same Bleeding Risk
NNH=167 NNH=167
Wiviott et al, NEJM 2007, Wallentin et al, NEJM 2010

31. 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

32. STEMI: Oral antiplatelets
What, when and how?
WHAT?
WHEN?
HOW?
Aspirin
Clopidogrel / Prasugrel* / Ticagrelor*
Aspirin
Clopidogrel
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 250mg
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 PCI1 Thrombolysis2

33. Invasive 1,2 Conservative 2
WHAT?
WHEN?
HOW?
Aspirin
Ticagrelor* / Clopidogrel‡
Aspirin
Ticagrelor* / 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 loading
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 : Antiplatelets
What, when and how?

34. New ESC and ACC Guidelines

35. ESC Guidelines

36. 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

37. 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

39. Summary
Clopidogrel Prasugrel Ticagrelor
Major 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, stroke
9.3 vs 11.4%
RR 0.80, p < 0.001
9.9 vs 12.1%
HR 0.81, p < 0.001
9.8 vs 11.7%
HR 0.84, p < 0.001
TIMI non-CABG major bleeding
1.1 vs 1.2%*
RR 0.94, p = 0.7
2.4 vs 1.8%
HR 1.32, p = 0.03
2.8 vs 2.2%
HR 1.25, p = 0.03
Major bleeding per study definition
3.7 vs 2.7%
RR 1.38, p = 0.001
2.4 vs 1.8%
HR 1.32, p = 0.03
11.6 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;357:2001-15
Wallentin L et al. N Engl J Med. 2009;361(11):1045-57.
*TIMI major bleeding