Updates on Antiplatelet Therapy Leture slides for M.Pharm Program

1. Balamurugan Tangiisuran, PhD
Discipline of Clinical Pharmacy
School of Pharmaceutical Sciences
Universiti Sains Malaysia
b.tangiisuran@gmail.com
M.PHARM PROGRAMME 2015/16
(FCP 557)

3. Antiplatelet drugs
Antiplatelet drugs
Acetylsalicylic
acid (aspirin)
P2Y12
antagonists
Dipyridamole GPIIb/IIIa
antagonists
Used widely
in patients
at risk of
thromboembolic
disease
Beneficial in the
treatment and
prevention of ACS
and the prevention
of thromboembolic
events
Secondary
prevention in
patients following
stroke, often in
combination with
aspirin
Administered
intravenously, are
effective during
percutaneous
coronary
intervention (PCI)

4. The Most Plausible Mechanism Of Aspirin In
Reducing Risks Of CV Disease
• Aspirin irreversibly acetylates the active site of
cyclooxygenase (COX)-1, which is required for
the production of thromboxane A2, a
powerful promoter of platelet aggregation
Vane JR. Inhibition of prostaglandin synthesis as a mechanism of
action of aspirin like drugs. Nat New Biol. 1971;231:232-5

5. The Most Plausible Mechanism Of Aspirin In
Reducing Risks Of CV Disease
• Rapid absorption of aspirin occurs in the
stomach and upper intestine
• Peak plasma concentration being achieved 15-
20 minutes after administration
• The peak inhibitory effect on platelet
aggregation is apparent approximately one
hour post-administration

6. The Most Plausible Mechanism Of Aspirin In
Reducing Risks Of CV Disease
• Aspirin produces the irreversible inhibition of
the enzyme cyclo-oxygenase and therefore
causes irreversible inhibition of platelets for
the rest of their lifespan (? days)

7. Evolution of Antiplatelet (AP) Therapy Trials
Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71
Year No Of Trials No Of Patients
1988 25 25,000
1997 194 212,000
AP vs control (135,000)
Different AP (77,000)

8. Aspirin in the treatment of CVD
• Pts with prior occlusive, aspirin, prevents ~25%
of serious vascular events, including significant
reductions on MI, stroke, and CVD death
• All these patients have 10-year risks of CHD of
20% or more based on the Framingham risk score
recommended by the US NHLBI
AntiThrombotic Trialists Collaboration. Lancet, 2002

9. Benefit of Aspirin on Risk of Stroke
• 158 trials  total 3,522 nonfatal and 1,424
fatal strokes after randomization
• Aspirin, reduced stroke by about 25%,
regardless of whether the patient entered the
trial with prior MI, stroke, TIA, or other high-
risk conditions
AntiThrombotic Trialists Collaboration. Lancet, 2002

10. Benefit of Aspirin on Risk of Stroke
• Aspirin increases the absolute risk of
hemorrhagic stroke by 3 per 10,000 treated
patients
• The upper bound of the 95% confidence
interval is less than 1 per 1000 treated
patients
AntiThrombotic Trialists Collaboration. Lancet, 2002

11. ISIS-2 Collaborative Group Lancet. 1988 Aug 13;332: 349-60.
Second International Study of Infarct Survival

12. Aspirin
• Debate concerning the optimal dose
• Risk of bleeding is dose-dependent
• CURE Trial – No evidence of greater efficacy at
higher dose but incidence of bleeding
increased with dose, lowest at doses up to
100mg

13. Aspirin
• CURRENT-OASIS 7 Trial
• Randomised 25,087 pts with ACS to low-dose (75-
100mg/day) or high-dose aspirin (300-
325mg/day)
• No difference in the rate of cumulative primary
end point of CV death, MI or stroke or in TIMI
major bleeding
• High-dose aspirin associated with higher risk of
minor bleeding (p=0.04) and GI bleeding (p=0.05)
Mehta et al. NEJM. 2010;363:930-42.

14. Dose-Dependent Side Effects of Aspirin
The 5 Year UK-TIA Trial of about 2400
Warlow C. et al. BMJ, 1988
Side Effects Placebo 300 mg 1200 mg
GI Symptoms 25% 29% 39%
GI bleeding
requiring transfusion 1.6% 2.6% 4.9%

15. Possible Additional Beneficial Mechanisms of
Action of Higher Doses of Aspirin on CVD
• Enhance nitric oxide formation
• Decrease inflammation
• Stabilize endothelial function
Hennekens CH, Sechenova, O, Hollar D, Serebruany VL. Dose of Aspirin in the Treatment and
Prevention of Cardiovascular Disease: Current and Future Directions. JCPT 2006.
Hennekens CH, et al. A randomized trial of aspirin at usual clinical doses and increased nitric oxide
formation in humans. JCPT 2010.

16. P2Y12 ADP - Receptor Antagonists
• Currently available – ticlopidine, clopidogrel,
prasugrel, ticagrelor, cangrelor
• Under investigation
– Elinogrel
• Dual antiplatelet is recommended for all
patients with ACS during acute phase and for
12 months, unless CI
Wright et al. Circulation. 2011;123:2022-60

17. Clopidogrel
• Irreversible thienopyridine inhibitor of the
platelet P2Y12 ADP receptor
• CURE trial – NSTE-ACS
• COMMIT/CCS-2 and CLARITY-TIMI 28 trial –
STEMI patients
– Confirmed the superiority of dual antiplatelet
therapy (A+C vs A alone)
Chen et al. Lancet 2005;366:1607-21
Sabatine et al. NEJM 2005;352:1179-89

18. Clopidogrel
Chen et al. Lancet 2005;366:1607-21
Sabatine et al. NEJM 2005;352:1179-89CURE Trial Investigators NEJM. 2001;345: 494-502

19. Second Chinese Cardiac Study: COMMIT
• Randomized, double-blind, 2x2 factorial trial
of clopidogrel and metoprolol
• 45,852 patients within 24 hours of onset of
symptoms of suspected AMI
• Randomization in clopidogrel arm to daily
75mg clopidogrel + 162mg aspirin (22,960) or
placebo +160mg aspirin(22,891)
COMMIT Collaborative Group. Lancet 2005; 366: 1607-1621.

20. COMMIT Collaborative Group. Lancet 2005; 366: 1607-1621.
COMMIT Clopidogrel Arm:
Primary Outcomes
End point Clopidogrel,
n=22 961 (%)
Placebo,
n=22 891 (%)
Odds ratio
CI)
P value
Death/MI/stroke 9.2 10.1 0.91
(0.86-0.97)
0.002
Death from any
cause
7.5 8.1 0.93
(0.87-0.99)
0.03

21. COMMIT: Major Bleeding
COMMIT Collaborative Group. Lancet 2005; 366: 1607-1621.
Bleeding Clopidogrel (%) Placebo
(%)
Excess per
1000
p
Any major
bleed
0.58 0.55 0.4 0.59

22. Limitation of Clopidogrel
1. Slow onset of action – max platelet
inhibition occurs
–at least 6 h after standard LD (300mg)
–only after 3-5 d at standard daily oral dose
(75mg)
–Pro-drug  two-step biotransformation to
its active metabolite

23. Limitation of Clopidogrel
2. Slow reversal of platelet inhibition
–at least 5 day needed for recovery of
platelet function after drug discontinuation
–Important in patient requiring urgent CABG
or non-cardiac surgery

24. Limitation of Clopidogrel
3. Platelet inhibition is an average 30-40% at
steady state, mainly of poor bioavailability
–Only 15% of the absorbed pro-drug
available for metabolisation by hepatic
CYP450 enzymes to active metabolites

25. Limitation of Clopidogrel
4. There is considerable inter-patient variability
in the response to clopidogrel  increased
risk of the re-occurrence of ischaemic events
5. Clopidogrel and PPI interaction

26. Limitation of Clopidogrel

27. Clopidogrel & PPI
• In several studies, omeprazole decreases
pharmacodynamic effect of clopidogrel on
surrogate markers such as platelet
aggregation
• Studies of the other individual PPIs have not
shown such effects

28. Clopidogrel & PPI
• Observational studies  patients prescribed
clopidogrel have small but significant effects
of all 5 PPIs on increased rates of CV events in
clopidogrel users

29. Clopidogrel & PPI
• RCT - clopidogrel users randomized to
omeprazole have no increased risk of CV
events
• FDA suggests that health care providers avoid
prescribing omeprazole, esomeprazole, or
cimetidine to patients receiving clopidogrel

30. Clopidogrel & PPI
• Can use one of the other PPIs (e.g.,
pantoprazole, rabeprazole) and
• Separate the PPI and clopidogrel by around
14-18 hrs
– prescribing the PPI before breakfast and
clopidogrel at bedtime
– PPI at dinner and clopidogrel at lunchtime

31. Prasugrel
• Oral, irreversible tienopyridine inhibitor of
platelet P2Y12 ADP receptor
• Prodrug – rapidly absorbed and requires in
vivo metabolism to form its active metabolite
• Faster onset of action than clopidogrel and
greater platelet inhibition with less variability
of response
• Genetic plymorphism that limit effectiveness
of clopidogrel do not affect prasugrel
Mega et al. Lancet 2010;376:1312-19

32. Prasugrel
• Biotransformed in liver by rapid hydrolysis
and oxidation mainly by CYP31 and CYP2B6
• Peak conc reached 30 min after oral dosing
and max platelet inhibition occurs about 2h
after LD of 60mg

33. Prasugrel
• Phase III TRITON-TIMI 38 Trial
– Prasugrel > efficious than clopidogrel in
population with STEMI or NSTE-ACS
undergoing PCI
– 13,608 subjects to prasugrel (LD 60mg, MD
10mg/day) or clopidogrel (LD 300mg, MD
75mg/day), with low-dose aspirin for 6-
15mths
Wiviott et al. NEJM 2007;357:2001-15

34. Prasugrel
• Phase III TRITON-TIMI 38 Trial
– Net clinical benefit including efficacy and
safety end point was in favour of prasugrel
– prevented 23 non-fatal MI at the
expense of 5 additional major bleeding
events per 1000 treated patients
Wiviott et al. NEJM 2007;357:2001-15

35. Prasugrel

36. Prasugrel

37. Prasugrel
• Post-hoc subgroup analysis TRITON-TIMI 38
Trial
– Efficacy of Prasugrel was offset by a higher risk of
bleeding in 3 categories of pts:
• Age ≥ 75 years (HR 0.99, 95%CI 0.81-1.21;p=0.92)
• Weight < 60kg (HR 1.03, 0.69-1.53;p=0.89)
• Previous stroke or TIA (HR 1.54, 1.02-2.32;p=0.04)
Wiviott et al. NEJM 2007;357:2001-15
Montalescot et al. Lancet 2009;373:723-31

38. Prasugrel
• Post-hoc subgroup analysis TRITON-TIMI 38
Trial
– Pt with DM and those with STEMI undergoing PCI
obtained considerable clinical benefit with
reduction in rate of ischemic event and non
increase in bleeding risk (10 vs. 12.4%; HR 0.79,
0.65-0.97;p=0.02)
Wiviott et al. NEJM 2007;357:2001-15
Montalescot et al. Lancet 2009;373:723-31

39. Prasugrel

40. Prasugrel
• Prasugrel approved for STEMI and for NSTE-
ACS patients undergoing PCI BUT CI...
• TRILOGY – ACS is an trial comparing the
relative efficacy and safety of prasugrel and
clopidogrel in medically managed patients
with high-risk NSTE-ACS
Chin et al. Am Heart J 2010;160:16-22

41. TRILOGY - ACS
• Prasugrel is not superior to clopidogrel in
NSTE myocardial infarction and unstable
angina in patients without revascularisation
Roe et al. NEJM 2012;367:1297-309.

42. TRILOGY - ACS
Roe et al. NEJM 2012;367:1297-309.

43. TRILOGY - ACS
Roe et al. NEJM 2012;367:1297-309.

44. Ticagrelor
• Oral non-thienopyridine direct and reversible P2Y12
receptor antagonist
• Not a pro-drug
• More rapid onset of action, relatively rapid
reversibility and greater potency and consistency of
platelet inhibition than clopidogrel
Chin et al. Am Heart J 2010;160:16-22

45. Ticagrelor
• Phase III PLATO trial
– 18,624 pts with STEMI or STE-ACS
– Randomised: ticagrelor (LD 180mg and MD
90mg BID), or clopidogrel (LD 300-600mg and
MD 75mg/day)
– Primary end point , composite of CV death, MI
and stroke after 1 year follow up, was reduced
(9.8 vs. 11.7%; HR 0.84. 0.77-0.92; p<0.001)
Wallentin et al. NEJM 2009;361:1045-57

46. Ticagrelor
Wallentin et al. NEJM 2009;361:1045-57

47. Ticagrelor
Wallentin et al. NEJM 2009;361:1045-57

48. Ticagrelor
• Ticagrelor is superior to clopidogrel in NSTE-
ACS patients initially intended for non-invasive
management

49. Ticagrelor
Wallentin et al. NEJM 2009;361:1045-57

50. Ticagrelor
• SE: Dyspnoea and bradyarrhythmias – for few
days of treatment
• Not influenced by genetic polymorphism
• Dec 2010 – European Medicines Agency
approved for patient presenting with ACS
regardless managed medically or undergo PCI
or CABG
Wallentin et al. NEJM 2009;361:1045-57

51. Ticagrelor
• PEGASUS-TIMI 54 Trial – pts with previous
ACS (12-36mths before) randomised to
ticagrelor 60/90mg BID or placebo on top of
aspirin(75-150mg)
• Examine long term efficacy and safety of
ticagrelor after ACS
Wallentin et al. NEJM 2009;361:1045-57

52. Cangrelor
• Non-thienopyridine ADP-receptor antagonist
• Potent, parenteral, reversible and selective
inhibitor of P2Y12 receptor
• Intravenously and does not require any
metabolism
Akers et al. J Clin Pharmacol 2010;50:27-35

53. Cangrelor
• Onset of action is immediate (within
minutes) and platelet function normalises
within 60 mins of the discontinuation of the
infusion
• CHAMPION-PCI and CHAMPION-PLATFORM
– Both Ended prematurely because the
interim analysis did not reveal sufficient
evidence of clinical effectiveness
Akers et al. J Clin Pharmacol 2010;50:27-35

54. Cangrelor
Akers et al. J Clin Pharmacol 2010;50:27-35

55. Summary of antiplatelet
Contractor and Ruparelia. Postgrad Med J 2012

56. New targets for platelet inhibition:
The role of PAR-1 inhibitors
• Despite effective inhibition of the thromboxane-A2
and ADP-Receptor pathway, platelet can still be
activated by thrombin receptor stimulation
• Recurrence of ischemic events in patients with ACS
despite dual antiplatelets
• Blocking platelet thrombin receptor PAR-1
(protease-activated receptor-1) may lead to greater
inhibition
Akers et al. J Clin Pharmacol 2010;50:27-35

57. New targets for platelet inhibition:
The role of PAR-1 inhibitors
• Thrombin receptor antagonists are novel class of
antiplatelet agents that inhibits thrombin-mediated
platelet activation
• Currently under clinical trial : Vorapaxar and
Atopaxar
• Potent, oral competitive and selective PAR-1
antagonists
TRACER. Am Heart J 2009;158:327-34
Morrow et al. Am Heart J 2009;158:335-41

58. New targets for platelet inhibition:
The role of PAR-1 inhibitors
• Safety and efficacy of Vorapaxar in addition
to standard of care therapies two Phase III
trials:
– TRA-CER in the setting of high-risk ACS
– TRA-2P TIMI 50 for secondary prevention
TRACER. Am Heart J 2009;158:327-34
Morrow et al. Am Heart J 2009;158:335-41

59. Thrombolytic drugs – pharmacokinetics
The plasma half-life of the third generation
drugs is 14-45 minutes, allowing
administration as a single or double
intravenous bolus
This is in contrast to second generation t-PA,
which with a half-life of 3-4 minutes, must
be administered an initial bolus followed by
infusion

60.  Thrombolysis in patients with acute MI
 Thrombolysis in patients with ischaemic stroke
 Thrombolysis of (sub)acute peripheral arterial
thrombosis
 Thrombolysis in patients with acute massive
pulmonary embolism
 Thrombolysis of occluded haemodialysis shunts
Thrombolytic drugs – major use

61. Thrombolytic drugs – major drawbacks
Treatment is limited to acute in-hospital
treatment
There is a high risk of bleeding inherent in
this treatment
Patients using anticoagulants are
contraindicated for treatment with
thrombolytics

62. Conclusion
STEMI
Treated with urgent PCI
Has pt a history of CVA
or TIA or cerebral bleed?
Is pt >75 years or <
60kg?
No to
all
Yes to
any
Medically managed – no
PCI procedure
Aspirin 75mg OD long term
with Prasugrel 10mg OD for
12mths
Aspirin 75mg OD long term
with Clopidogrel 75mg daily for
12 mths
Aspirin 75mg OD long term
with Clopidogrel 75mg daily for
28 days

63. Conclusion
NSTE ACS
and
Unstable
angina
Aspirin 75mg daily
long term with
Clopidogrel 75mg
for 12mths
Important:
•Aspirin - prescribe
dispersible aspirin
•The duration of antiplatelet
treatments must be stated
clearly on all discharge
letters

64. Conclusion
PCI with
Drug
Eluting
Stents
(DES)
Elective
Procedures
Aspirin 75mg daily long term
with Clopidogrel 75mg for
12mths
Important:
•Premature D/C of clopidogrel with
aspirin increases risk of stent
thrombosis.PCI with
Drug Bare
Metal
Stents
(BMS)
Elective
Procedures
Aspirin 75mg daily long term
with Clopidogrel 75mg for
28 days

65. Conclusion
Secondary Prevention
Stable Angina
(unless PCI planned)
Aspirin 75mg daily long term
Primary Prevention of
cardiovascular Events
Routine antiplatelet therapy for primary
prevention is not recommended.
Consider aspirin 75mg daily on an individual basis
Type 2 Diabetes
Age 50+ and BP <145/90
Age <50 and CV risk factors
Secondary prevention – Aspirin 75mg daily long
term
Primary prevention - See primary prevention of
cardiovascular Events

66. Conclusion
Secondary Prevention:
Ischaemic Stroke
Aspirin 300mg daily for 14 days
THEN: Clopidogrel 75mg daily long term
• If clopidogrel CI or not tolerated  Aspirin 75mg daily plus
dipyridamole MR 200mg twice daily long term
• If both clopidogrel and aspirin CI or not tolerated 
dipyridamole MR 200mg twice daily long term
Secondary Prevention:
TIA
Aspirin 75mg daily plus dipyridamole MR 200mg twice
daily long term
• If aspirin CI or not tolerated  Dipyridamole MR 200mg twice
daily long term
• If dipyridamole CI or not tolerated  Aspirin 75mg daily
monotherapy long term

67. Conclusion

68. Thank You