About uses of antiplatlet

1. ANTIPLATELETS
MO!Z

2. Platelet
ADP receptor - P2Y12
Irreversible – Ticlopidine,
Clopidogrel,
Prasugrel
Reversible - Cangrelol, Ticagrelol
GP IIb/IIIa
↓
Most abundant receptor
Activated by binding of fibrinogen and vVF
This binding blocked by - Abciximab, Eptifibatide,
Tirofiabn
Thrombin mediated platelet activation – inhibited by
VORAPAXER
↑
Protease activated receptor ( PAR-1 )
Thrombin receptor

3. ASPIRIN
Most extensively tested agent.
Prevention of platelet aggregation
Irreversibly acetylating and inhibiting platelet COX-1
COX1 - blocks the synthesis of thromboxane A2 (TxA2), a vasoconstriction - promotes platelet aggregation
At high doses (≈ 1 g/day) - also inhibits COX-2
COX 2 - 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
Relatively weak antiplatelet agent - Since it inhibits only one pathway of platelet activation and aggregation
( other agonists can directly stimulate the glycoprotein IIb/IIIa receptor, for example, thereby bypassing the
arachidonic acid–thromboxane pathway )

4. ASPIRIN
• The inhibitory effect - within 30 to 60 minutes,
• Effect on platelets lasts for up to 7 days after discontinuation.
• All STEMI should receive aspirin asap after an initial encounter in the absence of C/I
• Because low doses take several days to achieve a full antiplatelet effect, 162 to 325 mg should be administered at
the first opportunity after initial medical contact.
• To achieve therapeutic blood levels rapidly, the patient should chew a non–enteric-coated tablet to promote
buccal absorption bypassing the gastric mucosa.

5. • The minimum effective aspirin dosage in the setting of PCI – uncertain
• On a regimen of daily chronic aspirin therapy should receive 81 to 325 mg before PCI.
• Not already taking daily long-term aspirin - should be given 325 mg - at least 2 hours and preferably 24 hours
before PCI
• After PCI - continued indefinitely in patients without allergy, and
- a lower dose (e.g., 81 mg) may be preferable to decrease the risk for GI bleeding risk
• When combined with warfarin or other oral anticoagulants, use of low-dose aspirin (75 to 100 mg daily) is best.
• Eradication of Helicobacter pylori infection and administration of proton pump inhibitors may reduce the risk for
aspirin-
induced upper gastrointestinal bleeding in patients with peptic ulcer disease.

6. • Recent trials such as TWILIGHT suggest that stopping aspirin after a short duration of dual antiplatelet therapy
(for instance,
3 months in TWILIGHT) may be feasible post-CI
• The ISIS-2 study - largest trial of aspirin in STEMI, provided the single strongest piece of evidence that aspirin
reduces mortality in patients treated with or without fibrinolytic
• CURRENT-OASIS 7 trial did not find differences in terms of efficacy or safety in STEMI patients randomly
assigned to 81 versus 325 mg of aspirin

7. • Aspirin allergy - in ~ 0.3% of the general population
- characterized by bronchospasm - should not receive aspirin.
- more common in patients with chronic urticaria or asthma
( particularly those with coexisting nasal polyps or chronic rhinitis )
Patients with true aspirin allergy can receive clopidogrel (75 mg once daily).
• Aspirin overdose - a/w hepatic & renal toxicity.

8. Aspirin Resistance describe both clinical and laboratory phenomena.
Clinical aspirin resistance – failure of aspirin to protect patients from ischemic vascular events
- can be made only after such an event occurs.
- retrospective diagnosis
- provides no opportunity to modify therapy
The biochemical definition - failure to inhibit TXA2 synthesis and/or arachidonic acid–induced platelet
aggregation.
Potential mechanisms - poor adherence,
- reduced or delayed absorption of aspirin due to its enteric coating,
- TXA2 generation via pathways distinct from COX-1,
- increased activity of TXA2–independent pathways of platelet activation,
- use of concomitant medications that interfere action of aspirin, and pharmacogenetic
factors.

9. Testing for aspirin resistance remains a research tool
Tests used for the diagnosis of biochemical aspirin resistance
- measurements of thromboxane B2, the stable metabolite of thromboxane A2, in serum or in urine
- assessment of arachidonic acid–induced platelet aggregation.
These tests have not been standardized,
& there is no evidence that they identify patients at risk for recurrent vascular events or that resistance can be
reversed
either by giving higher doses of aspirin or by adding other antiplatelet drugs.

10. Adenosine diphosphate (ADP) receptor antagonists
- thienopyridines (ticlopidine, clopidogrel, prasugrel) - irreversible platelet inhibition
- non-thienopyridines (ticagrelor, cangrelor) – Reversible platelet inhibition.
Both clopidogrel and prasugrel are pro-drugs - require metabolic conversion to their active metabolites in the liver.
Prasugrel - more predictable conversion of pro-drug to active metabolite - requiring a single cytochrome p450
metabolic step
- contrasted with clopidogrel requiring two sequential steps.

11. CLOPIDOGREL :
• Maximal inhibition of ADP-induced platelet aggregation occurs 3 to 5 days after initiation of a standard dose (75
mg OD)
• A loading dose of 600 mg of clopidogrel rather than 300 mg results in more rapid (<2 hours) platelet inhibition &
improved
clinical outcomes, including lower rates of stent thrombosis.
• For patients receiving clopidogrel, current guidelines recommend that a 600-mg loading dose of clopidogrel be
administered before or during PCI, followed by 75 mg daily
• Interpatient variability in the response to clopidogrel can occur
In TRITON-TIMI 38 trial
Among patients treated with clopidogrel, carriers of reduced-function CYP2C19 alleles had
- high rates of “non-responsiveness”,
- with significantly lower levels of active metabolite,
- diminished platelet inhibition, and
- higher rates of adverse cardiovascular events

12. CLARITY-TIMI 28
- provided insight into the mechanism of the benefit of clopidogrel in STEMI
- did not increase the rate of complete opening of occluded infarct arteries when fibrinolysis was administered
but was effective in preventing reocclusion of an initially reperfused infarct artery.
Meta-analysis of –
PCI-CLARITY (PCI-Clopidogrel as Adjunctive Reperfusion Therapy)
PCI-CURE (PCI-Clopidogrel in Unstable angina to prevent Recurrent Events), and
CREDO (Clopidogrel for the Reduction of Events During Observation)
-- found that pretreatment with clopidogrel significantly reduced the risk for 30-day CV death or MI in a population
that
included both patients with STEMI and non-ST elevation ACS.

13. PRASUGREL
- a more potent P2Y12 ADP receptor inhibitor
- a more rapid onset of action and higher levels of platelet inhibition than higher-dose clopidogrel.
- 60-mg loading dose and 10-mg daily maintenance dose.
- Patients older than 75 years or weighing less than 60 kg should receive a daily prasugrel dose of
5 mg.
- Duration of effect 7 to 10 days
- withdraw 7 days before surgery.
• Prasugrel does not however appear to have a role in the treatment of medically managed patients with ACS
and may increase bleeding risk without an ischemic benefit. (TRITON-TIMI 38 trial )

14. • TRITON-TIMI 38 trial
13,608 patients with moderate-to high-risk ACS undergoing scheduled PCI randomly assigned to receive
- prasugrel (60-mg loading dose and 10-mg daily maintenance dose)
- or clopidogrel (300-mg loading dose and 75-mg daily maintenance dose) for 6 to 15 months.
The primary efficacy endpoint—a composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.
occurred - in 12.1% of patients receiving clopidogrel &
- in 9.9% of those receiving prasugrel (P < 0.001).
Prasugrel was a/w - significant reductions in - rates of MI (9.7% for clopidogrel versus 7.4% for prasugrel; P <
0.001),
- urgent target-vessel revascularization (3.7% versus 2.5%; P <
0.001), and
- stent thrombosis (2.4% vs. 1.1%; P < 0.001).
Major bleeding - in 2.4% of patients receiving prasugrel and
- in 1.8% of patients receiving clopidogrel (P = 0.03),
with more frequent rates of life-threatening bleeding occurring in the prasugrel group

15. TICAGRELOR
- orally active - non-thienopyridine - the cyclopentyltriazolopyrimidine class.
- reversible P2Y12 receptor antagonist,
- Active drug with active metabolite ( not prodrug ), metabolized in the liver via CYP3A4
- provides faster, greater, and more consistent ADP receptor inhibition than clopidogrel
( Because it does not require metabolic activation )
- Active drug with active metabolite ( not prodrug )
- 180 mg loading followed by 90 mg bd
- Duration of effect 3 – 5 days
- to withdraw 5 days before surgery
- Not recommended in eGFR < 15 ml/min/1.73m2, No dose adjustment for > 15 15
ml/min/1.73m2

16. Side Effects - may be adenosine-mediated because ticagrelor inhibits its reuptake
- bleeding,
- dyspnea, in up to 15% of patients, tends to occur soon after initiating ticagrelor, usually self-limited & mild
but can be persistent and may necessitate drug discontinuation in some patients
- bradyarrhythmias.
. to treat serious bleeding complications –
platelet transfusions may be useful in patients taking clopidogrel or prasugrel, which bind irreversibly to P2Y12,
platelet transfusions they are not effective for ticagrelor reversal because ticagrelor will bind to the transfused
platelets.
Bentracimab -
- under development for ticagrelor reversal prior to urgent surgery or intervention or for patients with serious bleeding
- an antibody fragment that binds ticagrelor and its metabolite with high affinity and rapidly reverses its inhibitory
effects,

17. PLATO (Platelet Inhibition and Patient Outcomes) trial
- 18,624 patients with ACS, with or without ST-segment elevation.
- randomly assigned to treatment with ticagrelor (180-mg loading dose, then 90 mg twice daily)
or clopidogrel (300-to 600-mg loading dose, then 75 mg daily) for 12 months.
The primary endpoint—a composite of death from vascular causes, MI, or stroke at 12 months
- occurred in 9.8% of ticagrelor and in 11.7% of clopidogrel (hazard ratio, 0.84; P < 0.001).
- also a/w significant reductions in MI alone (5.8% vs. 6.9% in clopidogrel group; P = 0.005) and
- in death from vascular causes (4.0% vs. 5.1%, respectively; P = 0.001).
- No significant difference in overall rates of major bleeding (11.6% and 11.2%, respectively; P = 0.43),
but ticagrelor was a/w a higher rate of major bleeding not related to CABG (4.5% vs. 3.8%; P = 0.03).
- there was a 26% reduction in definite or probable stent thrombosis and an 18% reduction in all-cause mortality

18. ATLANTIC trial (Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial
Infarction to
Open the Coronary Artery)
- Prehospital administration of ticagrelor did not improve the primary endpoint of coronary reperfusion
- but did reduce the secondary endpoint of stent thrombosis without any additional bleeding compared to in-hospital
administration in patients with STEMI undergoing primary PCI

19. CANGRELOR
• potent, fast-acting, reversible binding
• IV adenosine triphosphate (ATP) analogue, P2Y12 inhibitor,
• has a short plasma half-life (<10 minutes)
• highly effective inhibition of ADP-induced platelet aggregation, immediately after bolus administration
• and allows for restoration of platelet function within 1 to 2 hours of infusion discontinuation in NSTE-ACS
patients.

20. • can be used during PCI in patients who have not received a P2Y12 inhibitor before PCI based on CHAMPION-
PHOENIX
findings demonstrating a lower rate of death, MI, revascularization, or stent thrombosis, compared with
clopidogrel in
patients undergoing PCI, including primary PCI for STEMI
THE CHAMPION studies (69% of patients with PCI for ACS)
- 19% relative risk reduction (RRR) in periprocedural death, MI, ischemia-driven revascularization & stent
thrombosis
- 39% RRR in stent thrombosis alone (cangrelor vs. clopidogrel 0.5% vs. 0.8%; p = 0.008).

22. ABCIXIMAB
• a chimeric human-murine monoclonal antibody
• irreversibly binds to the platelet GP IIb/IIIa receptor on human platelets.
• abciximab persists on the surface of platelets for up to 2 weeks.
• also binds to the vitronectin (αvβ3) receptor found on platelets and to vessel wall endothelial and smooth
muscle cells.
• The recommended dosage of abciximab is a 0.25 mg/kg by IV bolus,
followed by a continuous IV infusion of 0.125 μg/kg/min (to a maximum of 10 μg/ min) for 12 hours.
• Abciximab can be administered safely in patients with renal insufficiency,
• platelet infusions can reverse the effect of this agent (although repeated transfusions may be necessary).

23. EPTIFIBATIDE
• a cyclic heptapeptide
• reversibly binds GP IIb/ IIIa,
• The double eptifibatide bolus (180-μg/kg boluses 10 minutes apart) and
infusion dose (2.0 μg/kg/min for 18 to 24 hours)
( must be reduced to 1 μg/kg/min in patients with a creatinine clearance lower than 50 mL/min )
- result in sufficient platelet inhibition to prevent ischemic events in patients undergoing PCI.
Addition of eptifibatide to a 600-mg loading dose of clopidogrel also causes incremental platelet inhibition.
Platelet transfusions do not reverse the platelet inhibition with eptifibatide,
although by 4 hours after cessation of the infusion, patients have safely undergone CABG.

24. TIROFIBAN
• Small peptidomimetic molecule,
• found to be inferior to abciximab for prevention of ischemic events during PCI.
• The recommended dosage of tirofiban is an initial rate of 25 μg/ kg administered over ≤5 minutes and
then continued at 0.15 μg/kg/ min for 18-24 hours.
• Patients with severe renal insufficiency (creatinine clearance <30 mL/min) should receive half the usual rate of
infusion.
• The tirofiban bolus dose given in the initial PCI studies may not have produced an optimal antiplatelet effect
during PCI,
but larger bolus doses can improve the inhibition of platelet aggregation

26. • Vorapaxar - inhibits PAR-1, the major thrombin receptor on human platelets.
• TRA- 2P trial – vorapaxar must be used in addition to standard of care antiplatelet therapy – include aspirin and
P2Y12 inhibitors ( to date clopidogrel only )
• 2.08 mg PO OD
• The drug is now licensed for
-- patients younger than 75 years with myocardial infarction
-- who have no history of stroke, transient ischemic attack, or intracranial bleeding and
-- who weigh more than 60 kg.

27. DIPYRIDAMOLE

28. DIPYRIDAMOLE
• This fixed combination is given twice daily.
• Each capsule contains 200 mg of extended-release dipyridamole and 25 mg of aspirin.
• Although dipyridamole/aspirin can replace aspirin for stroke prevention
• Because of the vasodilatory effects of dipyridamole and the paucity of data supporting the usefulness of this drug
in patients with symptomatic coronary artery disease, dipyridamole/aspirin is contraindicated in such patients;
• S/E - Gastrointestinal complaints, headache, facial flushing, dizziness, and hypotension can also occur. These
symptoms often subside with continued use of the drug

29. DAPT

30. DAPT
Distinct mechanisms of action - combination inhibits platelet aggregation to a greater extent than either agent
alone.
Dual therapy - (aspirin, P2Y12 inhibitor )
Triple therapy - (aspirin, P2Y12 inhibitor, and oral anticoagulant)
The combination of aspirin and clopidogrel was also found to reduce
- Death,
- MI, and
- Urgent revascularization within 12 months
( in patients undergoing PCI in the setting of NSTEMI and UA and in those undergoing elective PCI )

31. • Aspirin therapy - almost always continued indefinitely in patients with CAD
• Daily aspirin doses as low as 30 mg to 50 mg inactivate the platelet COX 1 enzyme and inhibit thromboxane
production
• In patients treated with DAPT - The optimal range of aspirin dose - that provides maximal protection from
ischemic events
and minimizes bleeding risk appears to be 75 mg to 100 mg
• For practical purposes, because the relevant aspirin dose available in the United States is 81 mg, this
maintenance dose is
recommended in patients with CAD treated with DAPT

32. • All STEMI should receive a platelet inhibitor in addition to aspirin for 12 months
• one of the following regimens:
clopidogrel (75 mg/day) in patients with STEMI treated with medical therapy alone, lytic therapy, or PCI;
prasugrel (10 mg/day) in patients treated with PCI;
or ticagrelor (90 mg twice daily) in patients treated with medical therapy alone or PCI.
• Ticagrelor is usually administered in conjunction with aspirin; the daily aspirin dose should not exceed 100 mg
• When using ticagrelor, the recommended maintenance dose of aspirin is 81 mg daily
• For secondary prevention at least 1 year after myocardial infarction, the dose of ticagrelor is reduced to 60 mg
twice daily

34. • Either clopidogrel or ticagrelor are recommended for all patients with NSTE-ACS without
contraindications who
are treated with either an early invasive or ischemia-guided strategy
(ticagrelor preferred over clopidogrel as a class IIa recommendation);
• In patients treated with PCI, prasugrel and ticagrelor have proved superior to clopidogrel and are
recommended as preferred in some guidelines.
• prasugrel is only indicated for ACS patients undergoing PCI .

35. LARITY-TIMI 28 trial –
addition of the P2Y12 inhibitor clopidogrel to background treatment with aspirin in patients with STEMI who were
younger
than 75 years and received fibrinolytic therapy
- reduced the risk for clinical events (death, reinfarction, stroke) and reocclusion of a successfully reperfused
infarct artery
COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial)
- 45,852 patients with suspected MI
- randomly assigned to clopidogrel, 75 mg/day (without a loading dose), or placebo in addition to aspirin, 162
mg/day
- clopidogrel group had a lower rate of the composite endpoint of death, reinfarction, or stroke
(9.2% versus 10.1%; P = 0.002).
- They also had a significantly lower rate of death (7.5% versus 8.1%; P = 0.03).
- No excessive bleeding with clopidogrel occurred in this trial

36. PLATO (Platelet Inhibition and Patient Outcomes) trial: -
- 53 patients with ACS were treated with either medical therapy alone or medical therapy plus PCI.
- Treatment with ticagrelor 90 mg twice daily, compared with clopidogrel 75 mg once daily,
- Resulted in fewer ischemic complications and stent thromboses but more frequent non–CABG-related
bleeding.
PEGASUS-TIMI 54 - study of post-MI patients
- both 60-mg and 90-mg twice-daily doses of ticagrelor were evaluated.
- The benefit/risk ratio appears to be numerically more favorable for the 60-mg dose,
- Although no formal statistical comparison was made between results of the 2 dosing regimens.
( The 60-mg twice-daily dose has now been approved by the US Food and Drug Administration for reduction in
ischemic
events in patients with ACS or a history of MI )

37. • TRITON-TIMI 38
(Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction
38)study
Patients with ACS - undergoing planned PCI
- treated with prasugrel 10 mg daily, compared with clopidogrel 75 mg daily.
Prasugrel treatment resulted in fewer ischemic complications and stent thromboses
- but more frequent bleeding, including life-threatening and fatal bleeding.
Because of increased rates of major bleeding with prasugrel (compared with clopidogrel), there was no net
benefit of
prasugrel therapy in those ≥75 years of age and those <60 kg, and there was net harm (including increased risk
of
intracranial hemorrhage) in those with prior stroke or transient ischemic attack (TIA).

38. PATIENTS WITH PCI ALSO NEEDING ANTICOAGULATION FOR AF OR
VTE.
- historically treated with an AC and dual antiplatelet therapy (aspirin, P2Y12 inhibitor ) —“triple therapy.”
- significantly increases the risk of bleeding.
Recent data from RCT suggests - patients requiring both an AC and APT, the default strategy after recent PCI
should be dual antithrombotic therapy consisting of an AC and a P2Y12i.
If high risk for coronary thrombosis and bleeding risk is judged to be low, aspirin may be added to a P2Y12i and an
AC for up to 30 days following PCI.
In such scenarios, clopidogrel is the preferred P2Y12i of choice, and a DOAC is the preferred AC of choice

41. • PPIs should be used in patients with a history of prior gastrointestinal bleeding treated with DAPT
(Class I).
• In patients with increased risk of gastrointestinal bleeding ( those with advanced age, concomitant use
of warfarin/ steroids or NSAID )
- use of PPIs is reasonable (Class IIa).
• Routine use of PPIs is not recommended for patients at low risk of gastrointestinal bleeding (Class III:
No Benefit).

42. • Patients with a h/o ACS >1 year prior, who have since remained free of recurrent ACS - stable ischemic heart
disease (SIHD)
• DAPT is not recommended in patients with SIHD without prior stent implantation and no history of ACS or MI.
• Decisions about treatment with and duration of DAPT in patients with SIHD with a history of MI or coronary stent
implantation require - a thoughtful assessment of the benefit/ risk ratio,
- integration of study data, and
- consideration of patient preference.

43. DURATION FOR
DAPT

44. • Current US guidelines recommend DAPT for at least 12 months after DES PCI for an ACS indication.
• The PRECISE-DAPT score to refine individualized treatment by determining which patients are most likely to
benefit from
or be harmed by continuation of DAPT beyond 12 months
• Indefinite aspirin and clopidogrel therapy is recommended in patients undergoing brachytherapy,
• Long-term higher doses (150 mg daily) of clopidogrel, or alternatively, prasugrel or ticagrelor, may be considered
in
patients in whom stent thrombosis may be catastrophic, such as –
- those with unprotected left main coronary artery stenting or
- with stenting of the last remaining vessel

45. Patients treated with a bare metal stent (BMS)
- The risk of stent thrombosis in is greatest in the first days to weeks after implantation.
- Cessation of DAPT during this period, particularly in cases of patients undergoing surgery, is a/w an
unacceptable rate of
often catastrophic stent thrombosis.
For post-PCI patients receiving a BMS, current guidelines recommend clopidogrel
- for a minimum of 1 month
- ideally up to 12 months
(unless the patient has an increased risk for bleeding, in whom it should be given for a minimum of 2 weeks).
In current practice, BMS are generally reserved for patients
- who cannot receive DAPT for more than ≈1 month for reasons of active bleeding,
- nonadherence to medical therapy, or
- planned surgery

46. The recommended minimum duration of DAPT in patients treated with first-generation DES
( based primarily on observational data and one subgroup analysis ) - 12 months
• For SIHD patients undergoing DES PCI, clopidogrel - the preferred P2Y12 inhibitor,
and DAPT (with low-dose aspirin) should be continued for at least 6 months if not have a high risk for bleeding.
( the minimum recommended duration of DAPT has been decreased from 12 to 6 months. )

48. The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and
Avoidance) trial-
- randomized patients with established atherosclerosis or at high risk of clinical atherosclerotic disease to either
DAPT (with
clopidogrel) or aspirin monotherapy;
- with DAPT, no significant reduction was found in ischemic effects at a median follow-up of 28 months, but there
was a 0.4%
absolute increase in severe bleeding
Dual Antiplatelet Therapy study-
- the benefit/risk ratio for prolonged DAPT was more favorable for those presenting with MI than those with SIHD
Studies of longer-duration (“prolonged” or “extended”) DAPT for an additional 18 to 36 months after DES -
- found an absolute decrease in late stent thrombosis and ischemic complications of ≈1% to 2% and
- an absolute increase in bleeding complications of ≈1%

49. • PEGASUS-TIMI 54
(Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a
Background of Aspirin—Thrombolysis In Myocardial Infarction 54) trial –
- were randomized 1 to 3 years after MI with additional high-risk features to either DAPT (with ticagrelor 60 mg or
90 mg
twice daily) or continued aspirin monotherapy.
After a mean of 33 months of therapy, DAPT, when compared with aspirin monotherapy resulted in
- 1.2% to 1.3% absolute reduction in the primary composite endpoint of cardiovascular death, MI, or stroke
and
- 1.2% to 1.5% absolute increase in major bleeding, with no excess in fatal bleeding or intracranial
hemorrhage.
In the absence of significant overt bleeding or risk factors for bleeding
- reasonable to continue DAPT for more than 12 months based on DAPT and PEGASUS-TIMI 54 trials

60. Thank you