Antiplatelets in ACS/ CAD/CCS patients

1. Antiplatelet drugs

2. Intended learning objectives
• Definition of antiplatelet drugs, and it’s different classes.
• Mechanism of action of different antiplatelet drugs.
• Role of antiplatelet in different diseases.
• Major trials that studied antiplatelet drugs in coronary diseases.

3. Drugs used in thrombosis
Drug Action
Antiplatelets Prevent and inhibit platelet activation and
aggregation.
Anticoagulants Prevent clotting by inhibiting clotting factors
(coagulation process)
Thrombolytics / Fibrinolytics Dissolve existing thrombi or emboli, and used
in acute treatment of thrombosis

4. Antiplatelets drugs

5. What are the antiplatelet drugs?
• The principal function of platelets is to prevent bleeding by thrombus formation.
• Antiplatelet drugs interfere with this function and are useful in prophylaxis of
thromboembolic events.

6. Mechanism of action

7. Role of Platelets in Thrombosis
 After vascular injury, platelets are bound to exposed collagen and von Willebrand
factor (vWF) and activated.
vWF: von Willebrand Factor; ADP: Adenosine Di-Phosphate; TXA2: Thromboxane A2

8. Role of Platelets in Thrombosis
 Activated platelets then secrete thromboxane A2 (TXA2) and adenosine diphosphate
(ADP), which leads to platelet aggregation and recruitment of more platelets.

9. Role of Platelets in Thrombosis
 The final common pathway of platelet aggregation is mediated by glycoprotein (GP)
IIb & IIIa receptors that bind to fibrinogen and vWF, leading to platelet plug and clot
formation.

10. Vorapaxar and
Atopaxar
Antiplatelet agents targets

11. Cyclooxygenase Inhibitor: Aspirin Arachidonic acid
pathway inhibitor MOA
PG: Prostaglandin
TXA2 Prostacyclin

12. Cyclooxygenase Inhibitor: Aspirin Arachidonic acid
pathway inhibitor MOA
Aspirin in low doses irreversibly inhibits
COX-1, which is required for synthesis of
TXA2 a vasoconstrictor required for
platelet aggregation.
At higher doses, ASA also inhibits COX-
2, which is required for prostacyclin
production; prostacyclin are inhibitors
of platelet aggregation and vasodilators.
Optimum dose must be adjusted

13. Aspirin Uses
• Acute coronary syndromes
• Chronic stable angina
• Peripheral arterial disease
• Primary prevention In men aged 45–79 years (for reduction of MIs) and women
aged 55–79 years (for reduction of ischemic strokes), if their potential benefit exceeds the risk
of GI bleed.

14. Vorapaxar and
Atopaxar
Antiplatelet agents targets

15. P2Y12 Receptor Blockers, ADP pathway inhibitors
MOA
Irreversible inhibition Reversible inhibition
ADP
Irreversible inhibition

16. P2Y12 Receptor Blockers, ADP pathway
inhibitors
Clopidogrel
• Clopidogrel has replaced ticlopidine.
• Longer duration of action ( once daily ).
• Less neutropenia.
• Not affected by food.
• Used to reduce the risk of thrombotic
cardiovascular events
• A prodrug has to be activated in liver,
has a slow onset of action.
Prasugrel and Ticagrelor
• New ADP pathway inhibitors.
• Faster onset of action than clopidogrel.
• Don’t need hepatic activation
• Used to reduce the risk of thrombotic
cardiovascular events
• Both increase bleeding risk.
• Ticagrelor cause dyspnea.

17. Intended learning objectives
• Definition of antiplatelet drugs, and it’s different classes.
• Mechanism of action of different antiplatelet drugs.
• Role of antiplatelet in different diseases.
• Major trials that studied antiplatelet drugs.

18. CAPRIE: Clopidogrel
versus Aspirin in Patients
at risk of Ischemic Events
Purpose
To assess the relative efficacy of the
antiplatelet drugs clopidogrel and aspirin
in reducing the risk of thrombotic events
in patients with atherosclerotic disease.
Design
Multicenter, multinational, randomized,
double-blind, parallel group Patients
19,185 patients with atherosclerotic
vascular disease (either recent ischemic
stroke, recent MI or symptomatic
peripheral arterial disease)
Reference CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–39.
,P<0.043
RRR = 9%
There were no major differences in terms of safety

19. Results
Reference
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–39.

20. Conclusion
Reference
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–39.
Long-term administration of clopidogrel to patients
with atherosclerotic vascular disease is more effective
than aspirin in reducing the combined risk of ischemic
stroke, myocardial infarction, or vascular death. The
overall safety profile of clopidogrel is at least as good as
that of medium-dose aspirin.

21. Comparison of different regimens
Endpoint ASA VS Placebo Clopidogrel VS ASA
MACE -19% -9%
Mortality -10% -2% (NS)

22. CHARISMA:
Clopidogrel + ASPIRIN
VS ASPIRIN alone in
high risk patients
Reference
Bhatt DL et al. Am Heart J. 2004;148:263-8. Bhatt DL et al. N Engl J Med. 2006;354:1706-17. Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events
(CAPRIE). Lancet 1996;348:1329–39.
Purpose
Does long-term treatment with clopidogrel
plus aspirin provide greater vascular
protection than aspirin alone in a broad
population of high-risk patients?
Design
Randomly assigned 15,603 patients with
either clinically evident cardiovascular
disease or multiple risk factors to receive
clopidogrel (75 mg per day) plus low-dose
aspirin (75 to 162 mg per day) or placebo
plus low-dose aspirin and followed them
for a median of 28 months.
RRR = 7%,
NS
0.93 (0.83-1.05), P=0.22

23. CHARISMA: Secondary endpoint
UA: Unstable Angina
Reference
Bhatt DL et al. Am Heart J. 2004;148:263-8. Bhatt DL et al. N Engl J Med. 2006;354:1706-17. Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events
(CAPRIE). Lancet 1996;348:1329–39.

24. CHARISMA: Safety endpoints
Clopidogrel +
ASA (% of
patients)
Placebo + ASA
(% of patients)
P-Value
Severe bleeding 1.7 1.3 0.09
Fatal bleeding 0.3 0.2 0.17
Intracranial
hemorrhage
0.3 0.3 0.89
Moderate
bleeding
2.1 1.3 <0.001
GUSTO: Global utilization of streptokinase and t-PA for occluded coronary arteries.
Reference
Bhatt DL et al. Am Heart J. 2004;148:263-8. Bhatt DL et al. N Engl J Med. 2006;354:1706-17. Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events
(CAPRIE). Lancet 1996;348:1329–39.

25. Results Summary
1ry efficacy endpoint Non-significant reduction
Principal 2ry efficacy endpoint Significant reduction
Severe bleeding Non-significant Increase but a trend
noted
Moderate bleeding Significant Increase

26. Comparison of different regimens
Endpoint ASA VS
Placebo
Clopidogrel VS
ASA
ASA +
Clopidogrel VS
ASA
MACE -19% -9% -7% (NS)
Mortality -10% -2% (NS) -1% (NS)

27. Prevention of Cardiovascular Events in
Patients With Prior Heart Attack Using
Ticagrelor Compared to Placebo on a
Background of Aspirin (2015)
RRR
=
15%
RRR
=
16%

28. Components of Primary Endpoint

29. Bleeding

30. Reduced the risk
of CV death, MI or
stroke
The benefit of
ticagrelor was
consistent
Increased the risk
of TIMI major
bleeding, but not
fatal bleeding or
ICH

31. Comparison of different regimens
Endpoint ASA Clopidogrel
VS ASA
ASA +
Clopidogrel
VS ASA
ASA +
Ticagrelor
VS ASA
MACE -19% -9% -7% (NS) -16%
Mortality -10% -2% (NS) -1% (NS) -11% (NS)

32. Trial TWILIGHT (2019) THEMIS PCI (2019)
Intervention VS Control (Ticag. + Aspirin) VS Aspirin Ticag. alone VS (Ticag. + Aspirin)
Patients 50 years or older, with type 2
diabetes, with stable coronary
artery disease, a history of
previous PCI.
Previous PCI with high risk for
bleeding or an ischemic event and
completed 3 months of dual
antiplatelet therapy.
Conclusion • Ticagrelor added to aspirin
reduced cardiovascular death,
myocardial infarction, and
stroke, although with increased
major bleeding.
• Ticagrelor provided a favorable
net clinical benefit (more than
in patients without history of
PCI).
• Ticagrelor monotherapy was
associated with a lower
incidence of clinically relevant
bleeding than ticagrelor plus
aspirin.
• No higher risk of death,
myocardial infarction, or
stroke.

33. EUCLID: Ticagrelor versus Clopidogrel in Symptomatic PAD

34. Medical Treatment VS
Intervention

35. COURAGE:
Optimal Medical
Therapy with or without
PCI for Stable Coronary
Disease (2007)
Design
Randomized trial involving 2287
patients who had objective evidence of
myocardial ischemia and significant
coronary artery disease. Assigned 1149
patients to undergo PCI with optimal
medical therapy (PCI group) and 1138 to
receive optimal medical therapy alone
(medical-therapy group).
The primary outcome was death from
any cause and nonfatal myocardial
infarction during a follow-up period of
2.5 to 7.0 years
Death from any cause and MI
Incidence of ACS

36. COURAGE:
Optimal Medical
Therapy with or without
PCI for Stable Coronary
Disease
Conclusion.
As an initial management
strategy in patients with stable
coronary artery disease, PCI did
not reduce the risk of death,
myocardial infarction, or other
major cardiovascular events
when added to optimal medical
therapy..
Overall Survival
Incidence of MI

37. Design
OMT: Optimum Medical Treatment
The primary outcome was the rate of death from any cause
The STICH Trial
Coronary-Artery Bypass
Surgery in Patients with Left
Ventricular Dysfunction
(2011)
1212
MT+
CABG
MT 610
602
EF≤ 35% +
CAD
Death from any cause

38. OMT: Optimum Medical Treatment
The STICH Trial
Coronary-Artery Bypass
Surgery in Patients with Left
Ventricular Dysfunction
(2011)
Conclusion
no significant difference between
medical therapy alone and medical
therapy plus CABG with respect to
the primary end point of death from
any cause.
CABG patients had lower rates of
death from cardiovascular causes and
of death from any cause or
hospitalization for cardiovascular
causes.
Death from CV causes
Death from any cause + Hosp. for CV causes

39. The ISCHEMIA Trial
Impact of Completeness of
Revascularization on Clinical
Outcomes in Patients With
Stable Ischemic Heart Disease
Treated With an Invasive Versus
Conservative Strategy (2020)
Design
OMT: Optimum Medical Treatment
Primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or
hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest.
1ry outcome
HR =
0.93 [CI], 0.80 to
1.08; P=0.34)
Death from any
cause
HR =
1.05 [CI], 0.83 to
1.32; P=0.34)

40. The ISCHEMIA Trial
Impact of Completeness of
Revascularization on Clinical
Outcomes in Patients With
Stable Ischemic Heart Disease
Treated With an Invasive Versus
Conservative Strategy (2020)
Conclusion
In patients with coronary disease and
moderate or severe ischemia. We did
not find evidence that the initial
invasive strategy reduced the risk of
ischemic cardiovascular events or
death from any cause.
OMT: Optimum Medical Treatment
Death from CV
causes or MI
HR = NA
MI
HR = NA

41. REVIVED-BCIS2
Revascularization for
Ischemic Ventricular
Dysfunction (2022)
700 Patients with LVEF ≤35% and extensive CAD
OMT: Optimum Medical Treatment
The primary composite outcome was death from any
cause or hospitalization for heart failure.

42. REVIVED-BCIS2
Revascularization for
Ischemic Ventricular
Dysfunction (2022)
Conclusion
• Multivessel PCI did not improve all-cause
mortality or LV systolic function.
• It remains possible that patients with the
most severe CAD were referred for CABG as
The STICH trial found an association
between CABG and improved survival
among patients with LV systolic dysfunction
and extensive CAD.
• Lack of benefit from PCI may have been due
to less extensive CAD, fewer patients, and
shorter follow-up.
OMT: Optimum Medical Treatment

43. “
”
Thank You!