Antiplatelet drugs in Acute Coronary Syndrome

1.  ANTIPLATELET THERAPY
IN ACUTE CORONARY
SYNDROME
• PRESENTED BY;
DR.ASHOK SHRESTHA
2022/03/03

2.  INTRODUCTION:
• Antiplatelets are the drugs which interfere with platelet function and
are useful in prevention of thromboembolic disorder as principal
function of platelet is to prevent bleeding by thrombus formation.
• Multiple receptor and signaling pathways are involved in the process
leading to arterial thrombosis which may be targeted by antiplatelet
agents.

3. • Currently there are 4 classes of antiplatelet agents that are approved
for treatment and/or secondary prevention of recurrent events with
ACS;
1. Cyclooxygenase-1 (COX-1) inhibitors ; aspirin
2. ADP P2Y12 receptor antagonists ; thienopyridine – ticlopidine,
clopidogrel and prasugrel and non thienopyridines- ticagrelor and
cangrelor
3. GP IIb/IIIa inhibitor; tirofiban, eptifibatide and abciximab
4. PAR-1 receptor antagonist ; vorapaxar

6. 1. CYCLOOXYGENASE-1 (COX-1) INHIBITORS ; ASPIRIN
• Aspirin is the most widely used antiplatelet agent worldwide. Because it is
an inexpensive and effective drug, aspirin serves as the foundation of most
antiplatelet strategies.
• MECHANISM OF ACTION
• Aspirin produces its antithrombotic effect by irreversibly acetylating and inhibiting
platelet COX-1 , a critical enzyme in the biosynthesis of thromboxane A2.
• At high doses (≈ 1 g/day), inhibits COX-2, an inducible COX isoform found in
endothelial cells and inflammatory cells.
• In endothelial cells, COX-2 initiates the synthesis of prostacyclin, a potent
vasodilator and inhibitor of platelet activation that antagonizes the effects of
thromboxane A2.

7. • DOSING AND RECOMMENDATIONS:
• may be effective in inhibiting COX-1 enzymes at doses as low as 30mg/d.
• The antiplatelet trialist’s collaboration showed that daily oral aspirin dose of
75 to 150mg is as effective as higher doses for long-term treatments.
• When given in combination with clopidogrel, dose of aspirin should
generally be lowered to 75 to 100mg (CURE STUDY)
• Particularly in patients with ACS or undergoing PCI, aspirin should be given
as promptly as possible, at initial dose of 162 to 325 mg, followed by 75 to
162mg daily dose.

8. • Aspirin is widely used for secondary prevention in patients with
established coronary, cerebrovascular, or peripheral artery disease. In
such patients, aspirin produces about a 20% reduction in the risk for
cardiovascular death, myocardial infarction, or stroke
• aspirin is no longer recommended for primary cardiac prevention
unless the baseline cardiovascular risk is at least 1% per year and 10%
at 10 years

9. • EVIDENCE OF USE:
• There are 4 randomized trials demonstrating beneficial effects of aspirin in
patient with UA/NSTEMI , showing approximately 50% reduction in risk of
death or MI.(SWEDISH ANGINA PECTORIS ASPIRIN TRIAL)
• In STEMI, aspirin is found to decrease rate of angiographic reocclusion by
more than 50% in meta-analysis of 32 angiographic trials.(ISIS-2)
• Combination of aspirin plus dipyaridamole was shown to reduce incidence
of periprocedural MI during PCI by 77% compared with patients receiving
placebo when administered 24 hours before PCI and continured for 4-7
months.
• In immediate post-op period, aspirin reduces rate of early thrombotic graft
occlusion by approximately 50% and continued aspirin therapy for 1 year
further decrease occulusive events after CABG.

10. • ADVERSE EFFECTS:
• Gastrointestinal, and they range from dyspepsia to erosive
gastritis or peptic ulcers with bleeding and perforation.
• The risk for major bleeding with aspirin is 1% to 3% per year.
• Three types of aspirin sensitivity have been described: respiratory
sensitivity (asthma and/or rhinitis), cutaneous sensitivity (urticaria
and/or angioedema), and systemic sensitivity (anaphylactoid
reaction)

11. 2. P2Y12 receptor antagonists
THIENOPYRIDINES:
- TICLOPIDINE, CLOPIDOGRELAND PRASUGREL
• MECHANISM OF ACTION:
• selectively inhibit ADP-induced platelet aggregation by irreversibly blocking
P2Y12
• These prodrugs require metabolic activation by the hepatic cytochrome P-450
(CYP) enzyme system. Therefore, when given in usual doses, ticlopidine and
clopidogrel have a delayed onset of action.
• The metabolic activation of prasugrel is more efficient than that of clopidogrel.
Consequently, prasugrel acts more rapidly and produces greater and more
predictable inhibition of ADP-induced platelet aggregation than clopidogrel

12. • Clopidogrel, a second-generation thienopyridine approved for clinical use
in 1997, differs structurally from ticlopidine by the addition of a
carboxymethyl group
• Although clopidogrel has a half-life of only 8 hours, it has an irreversible
effect on platelets that lasts from 7 to 10 days.
• The approved loading and maintenance doses of clopidogrel are 300 mg
and 75 mg, respectively.
• Most studies have consistently shown that high (≥ 600 mg) loading dose
regimens are associated with faster and more potent platelet inhibitory
effects as compared with 300 mg

13. • Prasugrel is a third-generation thienopyridine approved for clinical use
in 2009.
• Importantly, prasugrel activation involves fewer steps than
clopidogrel, and it is rapidly converted to an active metabolite that
binds specifically and irreversibly to the P2Y12 receptor
• A 60-mg loading dose of prasugrel achieves 50% platelet inhibition in
30 minutes and 80% to 90% inhibition in 1 to 2 hours.

14. • DOSING AND RECOMMENDATIONS:
• Approved for treatment and prevention of secondary atherothrombotic
events across patients with ACS , irrespective of treatment strategy.
• Clopidogrel is only oral P2Y12 inhibitor approved for stable CAD
undergoing PCI.
• Though recommended loading dose is 300-600mg , 600mg dose is
used in the setting of PCI.
• A 300-mg loading dose of clopidogrel, in addition to aspirin, should
also be given in patients < 75 years old with STEMI treated with
fibrinolytic therapy; patients ≥ 75 years old treated with fibrinolytic
therapy should be treated with clopidogrel 75 mg (without a loading
dose)

15. • Prasugrel is currently approved for patients with ACS undergoing PCI
and should be administered only after coronary anatomy has been
established, with the exception of STEMI patients undergoing primary
PCI .
• Treatment with prasugrel should be initiated with a single 60-mg oral
loading dose and continued at 10 mg orally once daily.
• is contraindicated in patients at high risk of bleeding, with previous
stroke/transient ischemic attack , and with hypersensitivity to the drug.
• Patients pretreated with clopidogrel can switch to prasugrel, leading to
enhanced levels of platelet inhibition that are achieved more promptly
when switching using a 60-mg loading dose rather than a 10-mg
maintenance dose, and without any drug interactions

16. • EVIDENCE OF USE:

17.  NONTHIENOPYRIDINES:
TICAGRELOR:
As an orally active inhibitor of P2Y12, ticagrelor differs from the
thienopyridines in that it does not require metabolic activation and it produces
reversible inhibition of the ADP receptor
MECHANISM OF ACTION:
• Like the thienopyridines, ticagrelor inhibits P2Y12. Because it does not
require metabolic activation, ticagrelor has a more rapid onset and offset of
action than clopidogrel does and it produces greater and more predictable
inhibition of ADP-induced platelet aggregation.
• Half life-7 to 12 hours, thus requiring twice daily dosing

18. • DOSING AND RECOMMENDATIONS:
• Ticagrelor is currently approved for the treatment and prevention of secondary
atherothrombotic events across the spectrum of patients with ACS, irrespective of
the treatment strategy (invasive or noninvasive) and can be administered before
coronary anatomy is known as well as in patients pretreated with clopidogrel
• single 180-mg oral loading dose and continued at 90 mg orally twice daily.
• contraindicated in patients with high risk of bleeding, with prior hemorrhagic
stroke or intracranial bleeding, with severe hepatic dysfunction, and with
hypersensitivity
• should not be used in patients with sick sinus syndrome or high-degree
atrioventricular block without pacemaker protection.
• High doses of aspirin should be avoided in patients treated with ticagrelor; when
aspirin is used in combination with ticagrelor, the dose of aspirin should be < 100
mg daily

20.  CANGRELOR:
• Cangrelor is a rapidly acting reversible inhibitor of P2Y12 that is
administered intravenously.
• It has an immediate onset of action, a half-life of 3 to 5 minutes, and
an offset of action within an hour.
• Cangrelor is licensed for use in patients undergoing PCI and produces
rapid ADP receptor blockade in those who have not received
pretreatment with clopidogrel, prasugrel, or ticagrelor.

21.  DOSING AND RECOMMENDATIONS:
• Cangrelor was approved by the FDA in 2015 as an adjunct to PCI for
reducing the risk of periprocedural MI, repeat coronary
revascularization, and stent thrombosis in patients who have not
been treated with a P2Y12 platelet receptor inhibitor and are not
being given a GP IIb/IIIa inhibitor (GPI).
• Cangrelor should be administered with a 30 μg/kg IV bolus prior to
PCI followed immediately by a 4 μg/kg/min infusion for at least 2
hours or the duration of the procedure, whichever is longer.

25. 3. GP IIb/IIIa inhibitor:

26.  EVIDENCE FOR USE:
• The landmark trial demonstrating efficacy of GP IIb/IIIa inhibition in
the PCI setting was the Evaluation of IIb/ IIIa Platelet Receptor
Antagonist 7E3 in Preventing Ischemic Complications (EPIC) trial.
• In this study, high-risk patients undergoing balloon angioplasty were
randomized to abciximab bolus and infusion versus abciximab bolus
alone versus placebo. The group treated with abciximab bolus and
infusion had a 35% lower rate of death, MI, or unplanned urgent
revascularization at 30 days compared with the placebo group (8.3%
vs 12.8%; P = .008).

27. 4. PAR-1 receptor antagonist
• Two different strategies can be pursued to block thrombin effects:
indirect modulation by blockade of the platelet PAR receptor and
direct inhibition of either thrombin or other upstream coagulation
factors (ie, factor X)
• In humans, four types of PARs have been described; PAR-1 and PAR-
4 are expressed on human platelets, but PAR-1 has the principal role of
mediating platelet activation at low concentrations of thrombin,
whereas PAR-4 reacts only at high concentrations
• Only vorapaxar has completed phase III clinical trial and approved for
clinical use in 2014.

28.  DOSING AND RECOMMENDATION:
• 2.5mg daily in patients with MI or PAD and must be used in addition
to antiplatelet therapy
• Contraindicated in patients with stroke , TIA or ICH and with active
pathologic bleeding.
• Vorapaxar was tested in two large-scale phase III clinical trials:
TRACER (Thrombin Receptor Antagonist for Clinical Event
Reduction in Acute Coronary Syndrome) and TRA 2P-TIMI 50
(Thrombin Receptor Antagonist in Secondary Prevention of
Atherothrombotic Ischemic Events–Thrombolysis in Myocardial
Infarction 50)trial

30. Eur Heart J, Volume 39, Issue 3, 14 January 2018, Pages 213–260, https://doi.org/10.1093/eurheartj/ehx419
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Figure 3 Algorithm for DAPT in patients with coronary artery disease.
ACS = acute coronary syndrome, BMS = bare-metal ...

31. DURATION OF DAPT:
• Current guidelines recommend that DAPT should be continued for up
to 1 year in ACS patients, irrespective of management (invasive or
noninvasive).
• post hoc analysis of the CHARISMA trial showed a benefit of
prolonging DAPT with aspirin (75-162 mg daily maintenance dose)
and clopidogrel (75-mg maintenance dose) up to 3 years among
patients with a prior MI
• the TRILOGY ACS trial showed an ischemic benefit beyond 12
months of therapy, particularly among patients with coronary artery
disease confirmed by angiography

32.  DURATION OF DAPT:

34.  SUMMERY OF ESC
RECOMMENDATION ON USE OF DAPT: