1. 广东省人民医院 广东省心血管病研究所 谭宁 何鹏程
抗血小板治疗进展
广东省人民医院
广东省心血管病研究所
谭宁 何鹏程

2. Antiplatelet Therapy
What to use?
How to use?

3. Route of Administration
Comparison of P2Y12 Receptor Antagonists: Ticagrelor vs Thienopyridines
Name
Type of Molecule
Route of Administration
Mode of Action
Ticagrelor
Cyclo-pentyl-triazolo-pyrimidine
Oral
Direct, Reversible
Clopidogrel
Thienopyridine
Prodrug, Irreversible
Prasugrel 3

4. TIMI Major Non-CABG Bleeds Days After Randomization
TRITON-TIMI 38: Prasugrel vs Clopidogrel in ACS Patients Treated With PCI 15
Clopidogrel
HR 0.81 (95% CI, 0.73–0.90) P<0.001)
12.1
CV Death/MI/Stroke 10
9.9
Prasugrel*
Endpoint (%)
NNT=46 5
TIMI Major Non-CABG Bleeds
HR 1.32 (95% CI, 1.03–1.68) P=0.03
Prasugrel
TRITON-TIMI 38: Balance of Efficacy and Safety
In addition to the efficacy data, shown here are the safety data for prasugrel. The key safety endpoint, TIMI major non-coronary artery bypass graft bleeding, occurred in 2.4% of prasugrel patients versus 1.8% of clopidogrel patients.
Thus, for every patient treated with prasugrel, there were 35 additional bleeding events, but 138 fewer cardiac deaths, nonfatal myocardial infarctions, and nonfatal strokes.
Wiviott SD, Braunwald E, McCabe CH, et al; for the TRITON-TIMI 38 Investigators. Prasugrel versus
clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):
2.4
1.8
Clopidogrel 30 60 90
180
270
360
450
NNH=167
Days After Randomization
Wiviott SD et al. N Engl J Med. 2007;357(20):

5. PLATO: KM estimate of time to first primary efficacy event (CV death, MI or stroke)13 12
Clopidogrel
11.7 11 10
9.8 9
Ticagrelor 8 7
Cumulative incidence (%) 6 5 4
HR 0.84 (95% CI 0.77–0.92), p=0.0003 3 2 1 60
120
180
240
300
360
Days after randomisation
No. at risk
Ticagrelor
9,333
8,628
8,460
8,219
6,743
5,161
4,147
Clopidogrel
9,291
8,521
8,362
8,124
6,743
5,096
4,047
Wallentin L et al, N Engl J Med. 2009;361(11):

6. PLATO: Non-CABG and CABG-related major bleeding9 NS
Ticagrelor
Clopidogrel
7.9 8
7.4 7 NS
5.8 6
5.3
p=0.026 5
K-M estimated rate (% per year)
4.5 4
3.8
p=0.025
2.8 3
2.2 2 1
Non-CABG PLATO major bleeding
Non-CABG TIMI major bleeding
CABG PLATO major bleeding
CABG TIMI major bleeding

7. Antiplatelet Therapy
What to use?
How to use?

8. Prasugrel vs. Clopidogrel for Acute Coronary Syndromes Patients Managed without Revascularization — the TRILOGY ACS trial On behalf of the TRILOGY ACS Investigators
NEJM 2012:on-line
Identifier: NCT

9. TRILOGY ACS Study Design
With or w/o prior angiography; if with (42%), required CAD with DS ≥30%
Medically managed UA or NSTEMI (68%)
(n=9,326)
Randomization Stratified by:
Age, Country, Prior Clopidogrel Treatment
(Primary analysis cohort — Age < 75 years; n=7,243)
Median Time to Enrollment = 4.5 Days
Clopidogrel1 300 mg LD +
75 mg MD
Prasugrel1 30 mg LD
5 or 10 mg MD
Medical Management Decision ≤72 hrs
(No prior clopidogrel given) — 4% of total
Medical Management Decision ≤ 10 days
(Clopidogrel started ≤ 72 hrs in-hospital OR
on chronic clopidogrel) — 96% of total
Source: Q113, Q111, Q331
[Source: Figure 1 on page 19]
Reference:
Chin CT, Roe MT, Fox KA, Prabhakaran D, Marshall DA, Petitjean H, Lokhnygina Y, Brown E, Armstrong PW, White HD, Ohman EM; TRILOGY ACS Steering Committee. Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial. Am Heart J 2010;160(1):16-22.e1.
Clopidogrel1
75 mg MD
Prasugrel1 5 or 10 mg MD
Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months
Primary Efficacy Endpoint: CV Death, MI, Stroke
All patients were on aspirin and low-dose aspirin (< 100 mg) was strongly recommended. For patients <60 kg or ≥75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1.
Among pts <75 years, 7.9% underwent revascularization (median 113 [40-334] days)
Pras

10. Primary Efficacy Endpoint to 30 Months (Age < 75 years)
HR (95% CI) ≤ 1 Year:
0.99 (0.84, 1.16)
HR (95% CI) > 1 Year:
0.72 (0.54, 0.97)
HR (95% CI):
0.91 (0.79, 1.05)
P = 0.21
Interaction P = 0.07
Median study FU 17 months

11. Efficacy Component Endpoints to 30 Months (Age < 75 years)
CV Death
All MI
HR: 0.93 ( )
HR: 0.89 ( )
All Stroke
HR (95% CI) ≤ 1 Year
HR (95% CI) > 1 Year
CV Death
1.00 (0.78, 1.28)
0.75 (0.49, 1.14)
All MI
0.97 (0.78, 1.19)
0.68 (0.46, 0.99)
All Stroke
0.86 (0.50, 1.47)
0.35 (0.14, 0.88)
HR: 0.67 ( )

12. Primary Endpoint - Pre-Specified Sub-Groups (Age < 75 years)

13. TIMI Major Bleeding to 30 Months (Age < 75 years)
HR (95% CI):
1.31 (0.81, 2.11)
P = 0.27

14. Incidence of Bleeding Outcomes (Age < 75 years)
P = 0.87
P = 0.06
TIMI Criteria
P = 0.02
P = 0.39
P = 0.99
P = 0.88
P = 0.27 70 8 4 16 39 46 12 17 30 13 14 52 35
GUSTO Criteria

15. TRILOGY ACS: Need to be answered
Currently, prasugrel is indicated only for pts with NSTE-ACS managed by PCI. What are the implications of TRILOGY ACS, if any, for pts with NSTE-ACS treated medically after angiography?

16. CURRENT OASIS-7: Low vs. High-Dose Clopidogrel And Aspirin in ACS Patients Managed Invasively
Intended PCI < 24 hrs
No restriction on GP IIb/IIIa inhibitors
Clopidogrel 600 mg
150 mg from Day 2 to Day 7
75mg from Day 8 to 30
Clopidogrel 300 mg
75 mg from Day 2 to 30
CURRENT/OASIS-7 is a Phase III, multinational, multicenter, randomized, factorial design, parallel-group study comparing 2 regimens of clopidogrel (high vs. standard dose) in a double-blind fashion and 2 regimens of ASA (high vs. low dose) in an open-label fashion in patients with non-ST-segment elevation ACS managed with an early invasive strategy with intent for PCI as early as possible within 24 hours.
Each patient will be treated and followed for 30 days.
ASA 300 mg Day 1
75–100 mg from Day 2 to 30
ASA 300 mg Day 1
300 mg–325 mg from Day 2 to 30
ASA 300 mg Day 1
75–100 mg from Day 2 to 30
ASA 300 mg Day 1
300 mg–325 mg from Day 2 to 30
1o Outcome: Death / MI /stroke, 30 Days; 2o outcome: CURRENT bleeding
Mehta SR et al. N Engl J Med. 2010;363(10):

17. Clopidogrel: Double vs Standard Dose Primary Outcome and ComponentsHR
95% CI P
Intn P
CV Death/MI/Stroke
PCI (2N=17,232)
4.5
3.9
0.85
0.036
0.016
No PCI (2N=7855)
4.2
4.9
1.17
0.14
Overall (2N=25,087)
4.4
0.95
0.370 MI
2.6
2.0
0.78
0.012
0.025
1.4
1.7
1.25
0.23
2.2
1.9
0.86
0.097
CV Death
0.96
0.68
1.0
2.8
2.7
0.77
2.1
0.628
Stroke
0.4
0.88
0.59
0.50
0.8
0.9
1.11
0.67
0.5
0.99
0.950

18. Clopidogrel: Double vs Standard Dose
Definite Stent Thrombosis (Angio confirmed)
Clopidogrel Standard Dose
0.012
42%
RRR
0.008
Cumulative Hazard
Clopidogrel Double Dose
0.004
HR 0.58
95% CI
P=0.001
0.0 3 6 9 12 15 18 21 24 27 30
Days

19. ACCF/AHA Recommendations Regarding Thienopyridine Use to Support PCI in Patients with NSTEMI
During PCI
Drug
Patient Received Initial Medical Treatment (with a thienopyridine)
Patient Did Not Receive Initial Medical Treatment (with a thienopyridine)
Comments
All Patients to Receive ASA ( mg)
Clopidogrel*
If 600 mg given orally, then no additional treatment.
A second LD of 300 mg may be given orally to supplement a prior LD of 300 mg (Class I, LOE: C)
LD of mg (Class I, LOE; A)
MD of 75 mg orally QD (Class I, LOE: A)
An MD of 150 mg orally QD for initial 6 days may be considered (Class IIb, LOE: B)
Optimum LD requires clinical consideration.
Dose for patient >75 years of age has not been established
There is a recommended duration of therapy for all post-PCI patients receiving a BMS or DES
Period of withdrawal before surgery should be at least 5 days. (For full explanations, see footnote)
Prasugrel**
No data are available to guide decision making
LD of 60 mg orally
MD of 10 mg orally QD (Class I, LOE: B)
There is no clear need for treatment with prasugrel before PCI
MD of 5 mg orally QD in special circumstances
Special dosing for patients >60 kg
There is a recommended duration of therapy for all post-PCI patients receiving a DES
Prasugrel is generally not recommended for patients ≥75 years of age because of increased bleeding risk and uncertain benefit compared with clopidogrel
Contraindicated for use in patients with prior history of TIA or stroke (For full explanations, see footnote)
Wright RS et al. J Am Coll Cardiol. 2011;57:

21. Time Relative to PCI Recommendation COR LOE
Pre-PCI
Aspirin mg before PCI if already on aspirin therapy I B
Nonenteric-coated aspirin 325 mg before PCI if not on aspirin therapy
PCI
Aspirin administered at time of PCI
Post-PCI
After PCI, aspirin continued indefinitely. A
After PCI, use of 81 mg/d of aspirin in preference to higher maintenance doses.
IIa

22. Recommendation COR LOE
Administration of a loading dose** of a P2Y12 receptor to patients undergoing PCI with stenting I A
Patients counseling on the need for and risks of DAPT before placement of intracoronary stents, especially a DES C
P2Y12 inhibitor therapy for at least 12 months in patients receiving a stent (BMS or DES) during PCI for ACS B
Clopidogrel for at least 12 months in patients treated with a DES for a non–ACS indication, if patients are not at high risk of bleeding
Clopidogrel for a minimum of 1 month and ideally up to 12 months in patients receiving a BMS for a non-ACS indication (unless the patient is at increased risk of bleeding; then it should be given for a minimum of 2 weeks)
Earlier discontinuation (e.g., <12 months) of P2Y12 inhibitor therapy after stent implantation if the risk of morbidity from bleeding outweighs the anticipated benefit afforded by a recommended duration of P2Y12 inhibitor therapy
IIa
Continuation of DAPT beyond 12 months in patients undergoing DES implantation
IIb
Prasugrel administration in patients with a prior history of stroke or transient ischemic attack
III – Harm

23. 对于最佳DAPT时长，已有RCTs尝试进行分析
REAL-LATE&ZEST-LATE :Zotarolimus-Eluting Stent versus Sirolimus-Eluting Stent and Paclitaxel-Eluting Stent for Coronary Lesions
Excellent 研究：比较Xience/promus和 Cypher支架植入后减少晚期失败的疗效的随机、多中心研究
PRODIGY:bare-metal, zotarolimus-eluting, paclitaxel-eluting,or everolimus-eluting stent
三个研究的结果并无统计学差异
Park SJ, Park DW, Kim YH, et al. N Engl J Med. 2010;362(15): Gwon HC, Hahn JY, Park KW, et al. Circulation. 2012;125(3): Valgimigli M, Campo G, Monti M, et al. Circulation. 2012;125(16):

24. EXCELLENT Trial DAT 6 months N=722 DAT 12 months N=721
1443 Patients Matching Enrollment Criteria
EES N=540
SES N=182
EES N=539
SES
N=182
Percutaneous Coronary Intervention
2x2 factorial design
1mo
3mo
9mo
12mo
Clinical
Angiographic
3yr
2yr
4yr
5yr
Primary clinical endpoint evaluation
Co-primary angiographic
endpoint evaluation
Am Heart J 2009 May;157: e1
Gwon HC et al ACC 2011

25. Cumulative incidence rate (%) Months after initial procedure
EXCELLENT Trial
Target Vessel Failure
6-mo DAT
12-mo DAT
P=0.507
HR = 1.17 (95% CI )
Non-inferiority
p=0.0031
4.7%
Cumulative incidence rate (%)
4.4%
Months after initial procedure
Patient Number at Risks
6-month
722
707
701
697
681
12-month
721
710
699
698
680
Am Heart J 2009 May;157: e1
Gwon HC et al ACC 2011

26. PRODIGY Trial : DAPT 6 versus 24 month
1970 Pts
DES: 75%
ACS: 75%
Valgimigli M et al, ESC 2011

27. PRODIGY Trial : DAPT 6 versus 24 month
Valgimigli M et al, ESC 2011

29. Ongoing Trials Dual Antiplatelet Therapy(DAPT) DES/BMS，12m vs. 30m
 Stenting and Antithrombotic Regimen: Safety And EFficacy of Six Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE)
DES，6m vs. 12m

30. COGENT TRIAL ACS – PCI 3627 PATIENTS CLOPIDOGREL + ASPIRIN +
OMEPRAZOLE
CLOPIDOGREL + ASPIRIN +
PLACEBO
GI EVENTS TREATMENT GROUP
67 PLACEBO ARM P=0.007
NO DIFFERENCE CLINICAL CARDIOVASCULAR
END POINTS DEATH IN MI

32. The only available randomized trial showed no significant association of omeprazole with CV events
A significant association between PPI use and increased CV events has been inconsistently demonstrated in observational studies, with the majority of studies show-ing no association
Evidence remains weak for diminished antiplatelet activity associated with PPIs and thienopyridine coprescription.

33. Thank you for your attention!