1. Antiplatelet Agents in
Acute Coronary Syndrome
LHH Cardiology Grand Rounds
January 27th 2014
Salaheldin Abusin
Interventional Cardiology Fellow

2. Outline
• 3 FDA approved Oral Agents
– Clopidogrel
– Prasugrel
– Ticagrelor
• IV Agents
– Cangrelor
• Evidence
• Discerning the differences

3. Vorapaxar
TRACER, NEJM 2012
Apixaban, APPRAISE-2
Rivoraxaban, ATLAS ACS TIMI 51, 2012
Warfarin,
CHAMP,Circulaation 2002
ACCSAP8
Acquity trial, NEJM 2006

4. Oral P2Y12 Agents
Schomig, NEJM 2009

5. Clopidogrel
• Oral thienopyridine
• Irreversible ADP P2Y12 receptor blocker
• Is a prodrug that is converted to active
metabolites through oxidation by the hepatic
cytochrome P-450 system

6. Clopidogrel
• CURE 2001
– Patients with non STE ACS who had presented within 24
hours after the onset of symptoms.
– Clopidogrel vs Placebo
– ~ 6000 in each arm
– Primary outcome a composite endpoint of death, non
fatal MI, Stroke
– 21% PCI rate (conservative therapy)
CURE investigators NEJM 2001

10. • ARR 2.1% in the composite endpoint
• Reduction in non fatal MI, with a favorable trend
towards benefit with Clopidogrel in death from
cardiovascular causes and stroke
• More major bleeding in the Clopidogrel group ARI 1%
• Predominantly in patients who underwent CABG less
than 5 days after stopping Clopidogrel

11. AHA/ACC 2007
• All patients with ACS should receive
Clopidogrel, loading dose followed by
maintenance, regardless of choice selective
invasive or invasive (Class I)
• For a duration of 1 month minimum, ideally
one year (Class I)
• Stop Clopidogrel 5-7 days before CABG

12. Benefit from Clopidogrel and Timing of PCI
300mg dose
Steinhubl et al. JAMA 2002 ; CREDO trial

13. Non responders to clopidogrel
Carriers of CYP2C19 loss of function
Hulot et al. Circ: Cardiovasc Interv 2011; CLOVIS trial

14. Platelet Reactivity Testing
Hulot et al. Circ: Cardiovasc Interv 2011; Gravitas trial

15. CABG in ACS with clopidogrel on board
• 30% of patients undergoing CABG have
received clopidogrel
• 90% of them get CABG in less than 5 days
• Operating in less than 5 days with clopidogrel
on board
– More blood transfusion rates, and more blood given
– 1% additional risk of MI while waiting for CABG
Mehta et al JACC 2006 ; CRUSADE Registry

16. Emergency Reversal of Clopidogrel
• No antidote
• Platelet transfusion
– Invitro studies of healthy volunteers
• Recombinant Factor VII
– Invitro studies of healthy volunteers
– Renal transplant patients improved bleeding time
• DDAVP ( n=1)
– Severe epistaxis
Beshay et al Journal of Neurosurgery 2010: Review

17. Clopidogrel a good drug with
drawbacks
•
•
Proven benefit
Drawbacks
1. Slow onset ;can be minimized by administering
600mg loading dose
2. Slow offset; (5 days wait before CABG can be
safe to perform)
3. Variability in response up to 21% non
responders, who will have higher risk of MI and
stent thrombosis
4. No antidote

18. May 17th 2012
Clopidogrel goes off patent
Medication
Price per day
Clopidogrel
Generic
Clopidogrel
Brand
Prasugrel
$0.37
Ticagrelor
$7.11
$4.00
$5.78

19. Is Generic Clopidogrel as good as Plavix?
Caldiera et al. Journal of Cardiovascular Pharmacology 2013

20. Prasugrel
• Oral thienopyridine
• Irreversible ADP P2Y12 receptor blocker
• 2 step activation process without significant
genetic polymorphism
• Faster onset of action
• More potent Higher rates of platelet
aggregation

21. LD and repeated pre-dose at days 14 and 29.
Results: There was no significant difference in clinical characteristics o
level at baseline. 106 patients completed the study (54 on prasugrel and
clopidogrel). Treatment was well tolerated in both groups. As illustrated
figure the mean MPA levels were significantly (p< 0.0001) lower with prasu
all time-points after start of treatment.
Faster, more potent
Varenhorst et al. ESC 2007 Congress Abstract

22. Prasugrel more reliable
Proven efficacy in carriers of CYP2C19
Trenk et al. JACC 2012. Trigger PCI

23. TRITON TIMI 38
• 13,608 patients with moderate-to-high-risk ACS planned for
PCI (99% underwent PCI)
• Prasugrel 60mg loading dose followed by 10mg maintenance
• Clopidogrel 300 mg loading dose followed by 75mg
maintenance dose for 6 to 15 months.
• Difference from CURE population
–
–
–
–
–
25% STEMIs compared to none
50% GPIIbIIIa compared to none
Higher use of statins 92% vs. 25% at time of randomization
Higher use of BBs 88% vs. 58%
Higher use of ACEI 76% vs. 37%
Wiviott et al. NEJM 2007

27. •
•
•
•
•
•
•
•
ARR in composite endpoint 2.2% with Prasugrel
ARR 2.3% in MI with Prasugrel
ARR in Death from cardiovascular cause 0.3% NS
Major bleeding ARI 0.6%
Fatal bleeding ARI 0.3%
So Prasugrel use contraindicated in PH of TIA/Stroke
Caution in > 75, and low BMI
Discontinue 7 days before CABG

29. Timing of Prasugrel administration
• On the table administration after diagnostic
angiography and decision of PCI taken in
TRITON TIMI 38
• FDA Package Insert/ Class IIb Recommendation
– “it is reasonable to consider selective use of
prasugrel before catheterization in subgroups of
patients for whom a decision to proceed to
angiography and PCI has already been established
for any reason. “

30. ACCOAST
•
•
•
•
•
N ~4000
NSTE ACS with +ve troponin
PCI planned in 2-48 hours
30mg upfront then 30mg in Cath Lab vs
60mg in Cath Lab
Montalescot et al. NEJM 2013

32. More bleeding with pretreatment

33. TRILOGY ACS
•
•
•
•
Role of Prasugrel beyond PCI patients
NSTE ACS, USA did not undergo PCI (< 75 yrs)
Clopidogrel vs Prasugrel
No difference in composite primary endpoint
(Death, non fatal MI, Revasc)
• Trend towards less ischemic events and more
minor bleeding with prasugrel
Roe et al. NEJM 2012

34. Prasugrel
• More reliable than clopidogrel
• Higher efficacy
• More bleeding
– Avoid in bleeders
• Initiate in Cath Lab
• If CABG needed  7 day wait

35. Ticagrelor
• Ticagrelor, a reversible and direct-acting oral ADP
receptor blocker (P2Y12)
• faster, greater, and more consistent
P2Y12 inhibition than Clopidogrel (possibly more
than Prasugrel)
• 90mg twice daily is the dose used in PLATO, higher
doses were associated with more side effects
(dyspnea, ventricular pauses)

36. OFFSET/ONSET trial
Gurbel et al. Circulation 2009

37. Efficacy in clopidogrel non responders
Gurbel et al. Circulation 2010: RESPOND study

38. PLATO
• Multicenter, randomized, double blind
, double dummy clinical trial
• 18,624 patients from 862 centers in 43
countries from October 2006 through July
2008
• The follow-up period ended in February 2009
Wallentin et al. NEJM 2009

39. Study Design
• Ticagrelor group
– given in a loading dose of 180 mg followed by a
dose of 90 mg twice daily.
• Clopidogrel group
– 300-mg loading dose followed by a dose of 75 mg
– OR maintenance dose of 75 mg if already on
Clopidogrel

42. Results

44. Safety

46. What does PLATO brings to the table?
1. More platelet inhibition not necessarily
more overall harm
– CURE, TRITON TIMI 18 showed that more
platelet inhibition equaled less MI, less urgent
revascularization,
– more bleeding, and in case of Prasugrel more
life threatening, and fatal bleeding
– Ticagrelor patients bled more (albeit not
significantly) than Clopidogrel, but less during
CABG

47. 2. Ticagrelor saves lives
 No significant mortality benefit in CURE with
Clopidogrel in non ST ACS, or TRITON TIMI 38 with
Prasugrel in all ACS, or the GPIIb/IIIa trials.
 PLATO shows mortality benefit like aspirin in all ACS
 ?play of chance as the trial not powered to detect
difference in mortality,
 but consistent benefit across MACE with less
bleeding might be a possibility

48. 3. New side effects with Ticagrelor

Dyspnea
•
•


Mild, early, transient with no changes on
PFTs, Imaging
Similar to adenosine reaction in non invasive stress
testing
Bradycardia
Pauses

49. ³75 Years
Sex
Male
Female
Weight Group
<60 kg
³60 kg
<80 kg
³80 kg
Medical History of DM
No
Yes
Region
Asia/Australia
Central/South America
Europe/Middle East/Africa
North America
2878
16.8
18.3
0.94 (0.78, 1.12)
0.82
13336
5288
9.2
11.2
1312
17256
9055
9513
13.1
9.5
11.4
8.3
11.1
13.2
0.85 (0.76, 0.95)
0.83 (0.71, 0.97)
17.3
11.2
12.8
10.5
0.75 (0.60, 0.99)
0.86 (0.78, 0.94)
0.90 (0.79, 1.01)
0.79 (0.69, 0.90)
Subgroup
analysis
0.36
0.17
0.49
• Benefits of Ticagrelor were
8.4
10.2
0.83 (0.74, 0.92)
14.1
16.2
0.88 (0.76, 1.03)
seen across 62/66 subgroups
0.05
1714• 11.4
14.8
0.80 (0.61, 1.04)
Trend towards harm in those
1237
15.2
17.9
0.86 (0.65, 1.13)
enrolled in North America
13859
8.8
11.0
0.80 (0.72, 0.90)
13962
4662
1814
11.9
9.6
1.25 (0.93, 1.67)
Antiplatelet Therapy Prior to Index Event
0.43
Clopidogrel ± ASA
1397
15.8
17.8
0.95 (0.73, 1.24)
ASA
5024
11.8
14.0
0.84 (0.71, 0.98)
None
12147
8.2
10.0
0.82 (0.73, 0.93)
ASA on Day of Rand.
No
Yes
0.86
927
11.6
13.8
0.87 (0.60, 1.27)
17697
9.7
11.6
0.84 (0.77, 0.93)
GPIIb/IIIa (IE to End of Index Hosp.)
0.41
No
13562
9.7
11.9
0.82 (0.74, 0.92)
Yes
5062
10.0
11.1
0.90 (0.76, 1.07)
Race
Caucasian
0.66
17077
9.5
11.2
0.85 (0.77, 0.94)

51. • 2 independent statistical analyses reached:
Aspirin dose >300 in US (53.6%) compared to
rest of the world (1.7%) may explain the
geographic variation in outcomes

54. Devil in the detail OR
paranoid conspiracy theory

56. Ticagrelor
•
•
•
•
•
More reliable than clopidogrel
Superior to clopidogrel (?maybe)
Less bleeding (?maybe)
BID dosing issue
Still 5 day wait for CABG

57. Cangrelor
•
•
•
•
•
•
Direct acting
Parenteral
Reversible P2Y12
very rapid onset half life 3-6 minutes
Very rapid offset 30-60 minutes
High efficacy similar to Abiciximab

58. CHAMPION trials
• Champion PCI – (Harrington, NEJM 2009)
– Cangrelor vs clopidogrel 600mg (before PCI)
– Negative trial
• Champion Platform – (Bhatt, NEJM 2009)
– Cangrelor vs clopidogrel 600mg (at end of PCI)
– Negative Trial (less ST, less death trend)
• Champion Phoenix (Bhatt, NEJM 2013)
– Cangrelor vs clopidogrel 600mg or 300mg (start or end of
PCI)
– Changed periprocedural MI to include (ECG changes, new
angio changes)
– Positive trial
– ARR 1.2 % driven by reduction in MI, also less ST

59. Pooled Analysis of the Champion Trials
Stegg et al. Lancet 2013

60. Stegg et al. Lancet 2013

61. Cangrelor
• Patient cannot take orally
• Superior onset (but does that matter?)
• Comparison with newer agents

62. Thanks