Anti Platelets Agents

Dr. Sachana KC
1st year Resident
Department Of Anesthesia
Anti platelets agents

 Drugs or agents which antagonize or impair any mechanism leading

to blood platelet aggregation, whether during the phases of
activation and shape change or following the dense-granule release
reaction and stimulation of the prostaglandin-thromboxane system.
Role of Platelets
Aspirin (Acetylsalicylic acid )
Pharmacology
 ASA is an anti-inflammatory and antiplatelet agent whose effect is
mediated through irreversible inhibition of cyclooxygenase 1 and 2
(COX1 and COX2).
 Its antithrombotic effect : inhibition of COX1, which is responsible for
inhibiting PGH2 formation from arachidonic acid.
 PGH2 is the precursor for TxA2 formation by platelets (platelet
aggregant and vascular vasoconstrictor), and PGI2 by endothelial cells
(vascular vasodilator and antithrombotic).
 The doses required for its anti-inflammatory effects (mediated by
COX2inhibition) are much higher than the ones required for its
antiplatelet effect (75–150 mg day).
Figure: Therapies targeted at inhibiting various platelet receptors. These include the thromboxane inhibitors, ADP
receptor antagonists, and GPIIb/
IIIa inhibitors. Adapted fromMeadowsand Bhatt,4 with permission. TxA2, thromboxane A2; GPIa/IIa, glycoprotein
Ia/IIa;GPVI, glycoprotein VI;GP
Ib-IX-V, glycoprotein Ib-IX-V; ADP, adenosine diphosphate; GP IIb/IIIa, glycoprotein IIb/IIIa.
Contd…

 ASA is rapidly absorbed through the enteric mucosa, with peak

plasma level attained within 30–40 min for regular preparations and
a half-life of 20 min14
 While antiplatelet effects can usually be detected within an hour,
enteric-coated preparations slow the rate of absorption that can lead
to suboptimal antiplatelet effects in obese patients.
 The irreversible inhibition of COX1 maintains the antithrombotic
effects of ASA for the lifespan of the platelet (7–10 days),with slow
recovery of overall platelet function 10%per day due to new platelet
formation.
Indications and efficacy

Coronary artery disease

 Primary prevention. In several trials, ASA therapy in doses of 75–
325 mg daily demonstrated a 36–44% reduction in the rates of
subsequent myocardial infarction (MI) with no increase in mortality
 Secondary prevention. Patients with stable or unstable angina
receiving ASA 75–1200 mg daily derive a survival benefit up to 1
yr.
 For patients with acute coronary syndromes (ACS), current
guidelines recommend ASA 162–325 mg given before primary
percutaneous coronary intervention (PCI) or thrombolysis and
continued indefinitely (class I).
Contd…

 As part of a dual antiplatelet therapy (DAPT) regimen, ASA doses

of 75–100 mg daily are considered as effective as higher doses in
reducing major adverse cardiac events (MACE) but are associated
with less bleeding.
 After coronary artery bypass grafting (CABG) surgery, ASA
decreases saphenous venous graft occlusion and significantly
decreases in-hospital mortality, MI, stroke, and renal failure rates.
Cerebrovascular disease

 While it is unclear if there is benefit derived from ASA therapy for

primary prevention of stroke, earlier data showed a 25% reduction
in recurrent cerebrovascular ischaemic events when used for
secondary prevention.
 The indications for ASA therapy for secondary prevention of stroke
are the same as for CAD.
 In patients undergoing carotid endarterectomy, current guidelines
recommend ASA 81–325 mg before the procedure and continued
indefinitely if no contraindications exist.
Atrial fibrillation

 Compared with warfarin, ASA is less effective in preventing stroke

in patients with non-valvular atrial fibrillation (AF), but can be
considered an option in patients who cannot receive anticoagulation
Side effects
Gastrointestinal
 Common (1% to 10%): Dyspepsia,
 GI bleeding, ulceration, perforation, nausea, vomiting, pancreatitis, gastric
irritation, GI erosions, gastritis, melena, hematemesis, gingival bleeding
Renal
 Interstitial nephritis, papillary necrosis, renal insufficiency and failure
Hematologic
 Common (1% to 10%): Increased bleeding tendencies
 Rare (0.01% to 0.1%): Aplastic anemia, agranulocytosis, thrombocytopenia
 Prolongation of prothrombin time, disseminated intravascular
coagulation, coagulopathy, antepartum and postpartum bleeding, anemia
P2Y12 receptor antagonists

 P2Y12 receptors are adenosine diphosphate (ADP) receptors expressed

on the surface of thrombocytes, which can be blocked chemically
 The ADP receptor blockers inhibit platelet aggregation by preventing the
binding of ADP to its specific platelet receptor.
 While the first ADP receptor blocker, ticlopidine, is rarely used now, due
to side-effects such as thrombocytopenia, newer agents
 Clopidogrel,
 Prasugrel , and
 Ticagrelor are routinely prescribed as part of a DAPT regimen in
patients with ischaemic heart disease.
Pharmacology

 Clopidogrel is a thienopyridine that requires conversion to an active

metabolite that irreversibly binds the ADP receptor.
 Recommended in doses of 150–600 mg for loading and 75 mg daily
for maintenance.
 Eliminated both in faeces and urine.
 The dose does not have to be adjusted for patients with moderate
renal and hepatic disease.
 At regular doses (75 mg daily), clopidogrel achieves a peak plasma
level 2 h after oral ingestion and a plateau of inhibition of platelet
aggregation (IPA) of 40–60% after 3–7 days.
Contd…

 A prodrug, of which 85% is hydrolysed to an inactive metabolite.

The remaining part is activated via cytochromes P3A4/3A5 and
P2B6/1A2/2C9/2C.
 The active metabolite binds irreversibly to P2Y12.
 For rapid onset of platelet inhibition, an initial loading dose is
necessary.
 The pharmacological effect lasts for the lifespan of the affected
thrombocytes
Contd…

Interactions
 The CYP450 dependency makes clopidogrel susceptible to drug
interactions.
 Proton -pump inhibitors can also reduce its effect.
 No studies have been published proving sufficient evidence that any
other drug interactions have any impact on its therapeutic effect.
Contd…

 30 % f patients treated with clopidogrel do not show adequate

platelet inhibition.
 Genetic polymorphisms (CYP2C19, P2Y12 receptor) or altered intracellular
signal pathways seem to be causative.
 Diabetic may show high platelet reactivity even when receiving
dual antiplatelet therapy.
 However, non-compliance, discontinuation of drug intake, or lack of
access to clopidogrel are more frequent causes of inadequate
platelet inhibition than pharmacological high platelet reactivity
Prasugrel

 A third-generation oral thienopyridine, is a prodrug, converted by

CYP450 enzymes to its active metabolite.
 Binds irreversibly to P2Y12, inhibiting platelet function for the
lifespan of the affected platelets.
 It shows a more reliable conversion to the active drug and more
rapid onset of action than clopidogrel.
 It produces more effective platelet inhibition than clopidogrel.
 Genetic polymorphisms (CYP2C9, CYP2C19) do not influence the
metabolism of prasugrel.
 Drug interactions attributable to CYP-dependent conversion have
not been described.
Contd…

 Prasugrel’s active metabolite reaches a peak plasma concentration in

30 min, and has a 7 h elimination half-life.
 As with clopidogrel, dose adjustment is not required for moderate
hepatic or renal impairment.
 The maximum IPA (75–85%) occurs 2–4 h after a loading dose.
 Prasugrel is more effective and faster than clopidogrel in
achievingplatelet inhibition.
 The recommended dose of prasugrel is 60 mg for loading and 10 mg
daily for maintenance.
Ticagrelor

 Is an non-thienopyridine, reversible,non-competitive antagonistof

the ADP receptor.
 Compared with clopidogrel and prasugrel, it has a more rapid onset
of action and is more potent, achieving80%IPA at 2 h after oral
ingestion.
 Eliminated in the faeces.
 Unlike its predecessors, it needs a dose adjustment in patients with
liver dysfunction, but not with renal disease.
 Half -life of 7–8.5 h.
Contd…

 The recommended loading dose is 180 mg, with 90 mg twice a day

recommended for maintenance.
 Unlike clopidogrel, ticagrelor’s effect is independent of genetic
polymorphism, making it less prone to response variability.
 It also has a better safety profile than prasugrel.
 These two considerations, including its efficacy, led to ticagrelor
virtually replacing clopidogrel as the preferred ADP receptor
antagonist in patients with ACS.
Cangrelor

 Cangrelor is the most recently (June 2015) approved i.v. non-

thienopyridine, reversible P2Y12-blocking agent.
 It has a fast onset of action, and infusion rates of 2–4 mg kg/min
result in 80% IPA.
 Its major advantage is its short half-life (2.6 min).
 Clearance is not affected by renal disease.
 Platelet functions begins to recovers within 5 min of infusion
discontinuation.
Contd…

 Platelet inhibition is >90%.

 Is inactivated by plasma enzymes, and within 60 min of stopping
the infusion the platelet function has recovered to normal.
 These favourable pharmacokinetic properties make cangrelor a
promising agent for bridging of high-risk patients in the
perioperative setting.
Side Effects

 Bleeding is the most significant side-effect associated with ADP

receptor-blocker therapy.
 When compared with patients receiving ASA therapy alone for
ACS, patients receiving DAPT with clopidogrel and ASA had an
increase in major, minor, and GI bleeding.
 However, no increase in the incidence of fatal bleeding was noted.A
high loading dose of clopidogrel (600 mg) leads to increased rates
of major bleeding events when compared with doses of 300 mg.
Glycoprotein IIb/IIIa inhibitors

 Glycoprotein IIb/IIIa (GpIIb/IIIa) receptors are the most numerous

proteins on the platelet surface.
 Block the adhesion of fibrinogen to the activated platelet,
preventing the building of interplatelet bridges.
 Adhesion of fibronectin, von Willebrand factor, and vitronectin are
inhibited.
Contd…

 The activation of the GpIIb/IIIa receptor is one of the final steps in

platelet activation, building cross-linked platelet–fibrinogen
complexes.
 Also contribute to a positive feedback mechanism with thrombin
and collagen, producing a sustained prothrombotic effect.
 Abciximab, Triofiban, and Eptifibatide are i.v. GpIIb/IIIa
inhibitors that are currently in use.
Abciximab

 Abciximab is a humanized monoclonal mouse antibody.

 It reversibly binds to thrombocytes within 1 min of adminstration.
 A loading dose is necessary to achieve a >80% receptor blockage.
(A bolus dose of 0.25mgkg/1 or as an infusion of 0.125 mg kg/1
min/1)
 It shows the highest affinity to the GpIIb/IIIa receptor of the three
licensed drugs.
Contd…

 It has a plasma half-life of 10min and platelet function recovers

over48h, although inhibition of platelet, GP IIb/IIIa receptors can be
documented up to 15 days after drug discontinuation
 It has a short plasma half-life, but a long biological activity.
Tirofiban

 Has an onset of action within 5 min after the initiation of infusion.

 The ACS dosage of tirofiban includes a 30 min loading dose of 0.4
mg kg/1 min21 followed by an infusion of 0.1–0.15 mg kg/min/.
 Return of platelet aggregation to 80% of pre-treatment value occurs
at 4 h after stopping drug infusion.
 It has a plasma half-life of 1.5–2 h.
 It is removed by both renal and biliary excretion.
 Patients with renal insufficiency require dose adjustment of
tirofiban
Eptifibatide

 Given as a single 180 mg kg/min bolus and 2mg kg/min, infusion

produces rapid and sustained highgrade IPA (80% within 15 min).
 It is renally excreted (75%) and, unlike abciximab, there is unbound
drug available in the plasma.
 Therefore, platelet transfusions are unlikely to reverse its
antiplatelet effects since circulating drug would most likely rapidly
inhibit newly transfused platelets.
 Thus reversal relies primarily on stopping the medication, requiring
4 h to achieve 50% of normal platelet aggregation
Contd…

 The main difference between abciximab and the smaller molecules

tirofiban and eptifibatide is the rate at which they dissociate from
GP IIb/IIIa receptors (hours for abciximab vs seconds for tirofiban
and eptifibatate).
 In addition, the lower affinity of eptifibatide for GP IIb/IIIa
receptors compared with tirofiban means that a greater
concentration of the former is required to achieve the same degree
of IPA.
Indications

 Unstable Angina/Non-STElevation Myocardial Infarction :

recommend the use of i.v. GP IIb/IIIa inhibitors in combination
with ASA and heparin, both in patients treated medically and
interventionally.
 For the Management of ST-Elevation Myocardial Infarction :
initiation of therapy with heparin and an i.v. GP IIb/IIIa receptor
antagonist such as abciximab (Level of Evidence: A), high-
bolusdose tirofiban (Level of Evidence:B), or double-bolus
eptifibatide (Level of Evidence: B) at the time of PCI
O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline
for the management of ST-elevation myocardial infarction:
executive summary: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice
Guidelines. J Am Coll Cardiol 2013; 61: 485–510
Other antiplatelet agents

 Cilostazol and dipyridamole are phosphodiesterase inhibitors that

interfere with degradation of cyclic adenosine monophosphate and cyclic
guanosine monophosphate.
 In addition to their antiplatelet action, they cause vasodilation because of an
effect on vascular smooth muscle.
 The protease-activated receptor-1 antagonists, agents such as vorapaxar
and atopaxar, inhibit platelet activation through alternative routes,
including thrombin-mediated platelet aggregation.
Newer antiplatelet agents

There are several antiplatelet drugs currently under various stages of

development.
 (i) Terutuban, a thromboxane receptor antagonist.
 (ii) Elinogrel, a P2Y12 receptor blocker, it can be administered both
orally and i.v.
 (iii) Atoxapar, PAR-1 antagonist.
Figure : Major characteristics of traditional and newer antiplatelet medications
Figure : Treatment recommendations for antiplatelet agents.
BMS, bare metal stent; DES, drug-eluting stent; PCI,
percutaneous coronary intervention; PVD, peripheral vascular
disease
Perioperative management of antiplatelet
agents
 Several factors need to be considered before a decision to continue
or stop antiplatelet agents peri-operatively.
 An important factor is the initial indication for antiplatelet therapy
and, most importantly, the consequences of stopping the drug before
the operation.
 Keep in mind
 Estimate thromboembolic risk
 Estimate bleeding risk
 Determine the timing of anticoagulant interruption
 Determine whether to use bridging anticoagulation
Cardiac risk

 Mechanical valve in the mitral position

 High risk prostheses
 Starr Edward, Lillehei Kaster, Omniscience
 Atrial fibrillation
 LVEF < 30%
 Prior thromboembolism
 Hyper-coagulable state
 Surgery for malignancy or infection
Contd…

 Premature discontinuation of antiplatelet agents including GP

IIb/IIIa inhibitors is associated with an increase in thrombotic
events due to a rebound effect on platelet activation.
 Dual antiplatelet therapy is known to reduce significantly the
number of arterial thrombotic events in the perioperative period.
 The other important factor to consider is the inherent bleeding risk
of certain procedures and the impact of bleeding on overall patient
outcome
Figure : Bleeding risk in non-cardiac surgery
Contd…

 Antiplatelet therapy and treatment for other co-morbidities should

be optimized.
 The relative risks of a thromboembolic event and of bleeding should
be weighed.
 Postoperative restarting of antiplatelet therapy depends on the
individual patient’s cardiovascular risk profile, the bleeding risks
associated with the particular operation, and the pharmacokinetics
of each drug.
 The aim should be to re-establish the antiplatelet regimen as early as
is reasonably possible.
Contd…

 For operations with a low bleeding risk, antiplatelet therapy does

not need to be interrupted.
 In procedures with a high risk of bleeding, aspirin should be
maintained and other antiplatelet substances discontinued long
enough before surgery to allow the antiplatelet effect to have waned.
 The continuous evaluation of the bleeding should guide intra- and
postoperative therapeutic strategies
Bridging therapies

When???
 where there is a high chance of bleeding and withdrawal of
antiplatelet therapy carries a high risk of cardiovascular events,
bridging of antiplatelet therapy can be considered.
What is Bridging therapy???
 Bridging therapies involve replacing antiplatelet therapy using long-
acting P2Y12 antagonists with a short-acting anticoagulant or
antiplatelet agent that can be discontinued shortly before surgery.
Contd…

 In the situation of bridging, treatment with aspirin should be

continued and the other oral agent stopped 5–7 days before surgery.
 A short-acting i.v. agent should be started no more than 72 h after
the discontinuation of DAPT. Four to six hours (or 1 h for
cangrelor ) before surgery, the i.v. drug is discontinued and is
restarted 6 h after surgery.
 The patient’s usual DAPT is restarted as soon as the risk of
perioperative haemorrhage is negligible.
Contd…

 Heparinoids are sometimes used for bridging. This is based on their

known effect in unstable angina and Non-ST-elevation myocardial
infarction (NSTEMI); they do not have any protective effect against
coronary or stent thrombosis.
 Heparin is not an appropriate substitute for antiplatelet agents.
 Non-steroidal anti-inflammatory agents and, in particular, reversible
COX1 inhibitors can be considered as short-term substitutes.
Management of bleeding

 Antiplatelet drugs have haemorrhage as a common side-effect.

 Management of significant haemorrhage is based on the
administration of tranexamic acid, fibrinogen, factor XIII,
desmopressin, platelets, and activated factor VIIa.
(prothrombotic properties of these agents may pose a risk of major
thrombotic complications)
 No antagonists for antiplatelet agents are available.
Regional anaesthesia and antiplatelet agents

 There is no evidence that aspirin needs to be stopped for performing

regional anaesthetic techniques.
 For all other antiplatelet agents, sufficient time should be allowed
for the platelet function to recover.
 This time duration depends upon the elimination half-life and
mechanism of action of the antiplatelet agents.
Summary

 In general, antiplatelet agents used for primary prevention or for AF can

be safely discontinued before surgery.
 Recent data suggest that, with few exceptions, proceeding with surgery
on DAPT is a relatively safe alternative.
 In situations of life-threatening bleeding, anaesthesiologists can consider
platelet transfusions.
 The more challenging cases are those patients at high risk of
cardiovascular events who are undergoing procedures with a high
risk of bleeding, and thus are required to completely stop their
antiplatelet medications.
 In these situations, the perioperative team can consider using bridging
therapies.
References

 New antiplatelet drugs and new oral anticoagulants; British Journal

of Anaesthesia, 117 (S2): ii74–ii84 (2016)
 Perioperative management of antiplatelet therapy; British Journal of
Anaesthesia 111 (S1): i3–i17 (2013)
 Platelets for anaesthetists—Part 2: pharmacology; BJA Education,
16 (4): 140–145 (2016)
 Stoelting’s Pharmacology and Physiology in Anesthetic Practice 5th
Edition (2015)
Aspirin

 With the exception of high-risk bleeding procedures (intracranial and

medullary canal surgery, posterior chamber of the eye surgery, and
transurethral prostate resection), ASA continuation peri operatively is not
associated with significant bleeding events or with increased mortality.
 The 2012 ACCP guidelines on Perioperative Management of
Antithrombotic Therapy recommend continuing ASA in the perioperative
period for patients at high cardiovascular risk.
 In patients undergoing cardiac surgery, preoperative ASA administration
increases postoperative bleeding and red blood cell requirements with no
effect on mortality, re-exploration rate, and perioperative MI.
ADP receptor inhibitors

 As with ASA, when the ADP receptor inhibitors are recommended

for treatment of AF or primary prevention of cardiac or
cerebrovascular events, these agents can be stopped before
operation without major consequences.
 ADP receptor inhibitors are a major component of the DAPT
recommended pre- and post-PCI with stenting.
 Several aspects need to be considered in patients with stents
undergoing surgery: the appropriate time frame after stent
placement before surgery can be safely performed, the potential
consequences of stopping DAPT, the urgency of the intervention,
and the bleeding risk associated with the intervention.