Antiplatelet Agents

 

Aspirin

Mechanism:

  • Irreversible binding to cyclooxygenase (COX1)

  • --> prevents thromboxane A2 generation and so prevents plt aggregation

  • As platelets are non-nucleated they cannot produce new COX1

  • --> drug effect 7-10 days (lifespan of platelets)

Perioperative

  • Associated with 1.5-fold increase in post-op bleeding but not in the severity of the bleed

  • Continue through most surgery – exceptions: neuro and prostate surgeries

  • Management of Emergency surgery with high bleed risk:

    • Consider 2 units platelets >2 hours since last dose (4-5 hours if enteric coated)

    • (aspirin-inactivated platelets can still be recruited by thromboxane generated in the transfused platelets)

Half-life: 3 hours

Onset of action: 1 hour

Time from drug admin during which platelet transfusion will have reduced efficacy: 2 hours

Time to normal platelet function after discontinuation: 5-7 days

 

Clopidogrel

Mechanism:

  • Binds to P2Y12 --> preventing ADP-induced plt aggregation

  • (Normal action of ADP is to bind to P2Y12 and P2Y1, in turn activating Gp IIb/IIIa)

Metabolised by CYP2C19

  • Defective genotypes vary by ethnicity and can cause clopidogrel refractoriness

Perioperative

  • Emergency surgery with high bleed risk

    • Consider 2-4 units platelets >12-24 hours since last dose (based on little evidence)

  • Stop day -7 prior to neuroaxial procedures

Half-life: 6 hours

Onset of action: 3-4 hours

Time from drug admin during which platelet transfusion will have reduced efficacy: 12-24 hours

Time to normal platelet function after discontinuation: 5-7 days

 

Dual Antiplatelet Therapy (ESC 2017)

Typical DAPT treatment durations

  • Minimum 4 weeks post bare metal

  • Minimum 12 months post drug-eluting

  • <12 months for newer bioabsorbable drug-eluting

  • May differ for high bleeding risk patients (e.g. NEJM 2021 - no difference 1 vs 3 months DAPT following drug eluting stent)

Thrombotic risk categories for patients on DAPT

  • Very high: ACS <8 days, drug eluting stent <8 days

  • High: ACS 8-30 days, drug eluting stent 8-30 days

  • Moderate: ACS 1-12 months, drug eluting stent 1-12 months

  • Low: Cerebrovascular and peripheral vascular disease, ACS >12 months, drug eluting stent >12 months

Perioperative

  • 4-8% of patients need surgery within 12 months of starting DAPT

  • Hold clopidogrel from day -5, continue aspirin for most low risk procedures, inc neuroaxial ones

  • High bleeding risk, also omit aspirin day -3 to day +7

  • If high risk surgery cannot be deferred in a patient with recent ACS

    • Continue aspirin, stop clopidogrel/ticagrelor day -5 or prasugrel day -7

  • For high thrombotic + high bleed risk CABG patients

    • Stop antiplatelets, consider parenteral GpIIb/IIIa inhibitor day -3 to 4-6 hours post op

Peri-Procedure

  • Lumbar puncture: Do not perform whilst on DAPT. If clinically justified then performing LP can be considered whilst on aspirin alone.

  • Gastro procedures: BSG 2021 guideline

Bleeding (see pages 246-248 ESC guideline for flowchart):

  • Weigh bleeding severity against thrombotic risk (above)

  • Trivial bleeding: Continue DAPT

  • Mild bleeding (No hospitalisation): Consider reducing duration of DAPT

  • Moderate bleeding (hospitalisation, no CVS compromise): Stop DAPT, continue single agent

  • Severe (Major blood loss): Stop DAPT, treat source of bleeding, continue single agent unless bleeding source cannot be controlled

  • Life-threatening: Stop anti-platelets, treat source of bleeding

  • Trial data to consider:

    • ATACAS 2017: TXA vs placebo in cardiac surgery. No increase in thrombotic complications

    • PATCH 2016: Non-traumatic ICH on anti-platelets, not fit for urgent surgery. Platelet transfusion vs standard of care. Primary outcome: increased mortality/disability at 3 months in platelet arm. Surprising finding, lead to further analysis in 2020 but still no evidence for platelet benefit.

    • Zakko et al 2017: case-control trial. Platelets for GI bleeding on anti-platelets. No benefit but also no harm.

    • RESTART 2019: Re-starting anti-platelets after ICH. Small trial. Larger trials in progress.

 

Prasugrel

Thienopyridine drug class (same as clopidogrel)

Mechanism:

  • Binds to P2Y12 preventing ADP-induced platelet aggregation

  • Prodrug. Converted to active drug by CYP450. Metabolised more efficiently than clopidogrel resulting in a greater antiplatelet effect.

Perioperative

  • Emergency surgery with high bleed risk

    • Consider 2-4 units platelets >12-24 hours since last dose (based on little evidence)

Half-life: 7 hours

Onset of action: 2-4 hours

Time from drug admin during which platelet transfusion will have reduced efficacy: 16-18 hours

Time to normal platelet function after discontinuation: 5-7 days

 

Dipyridamole

Mechanism:

  • Inhibits phosphodiesterase --> accumulation of cAMP --> Intracellular Ca2+ falls --> blocks response to ADP --> reduced thromboxane A2 production preventing plt aggregation.

  • Also prevents cellular uptake of adenosine

Alpha half-life: 40 min, Beta half-life: 10 hours

Onset of action: 1 hour

Time from drug admin during which platelet transfusion will have reduced efficacy: 5-7 hours

Time to normal platelet function after discontinuation: 24 hours

 

GPIIb/IIIa Inhibitors

 

Abciximab

Mechanism

  • Human-murine antibody to GpIIb/IIIa, close to FGN binding site

SE: Thrombocytopenia in 0.5%. Onset in hours to days. Risk increases with repeated exposure

Half-life: 30 minutes

Time from drug admin during which platelet transfusion will have reduced efficacy: 1-2 hours

Time to normal platelet function after discontinuation: 24-48 hours

 

Tirofibran

SE: Thrombocytopenia in 0.5%

Half-life 2 hours

Time from drug admin during which platelet transfusion will have reduced efficacy: 4 hours

Time to normal platelet function after discontinuation: 4-8 hours

 

Eptifibatide

Half-life 2.5 hours

Time from drug admin during which platelet transfusion will have reduced efficacy: 4 hours

Time to normal platelet function after discontinuation: 4-8 hours

 

Significant Others

 

Ticagrelor

Mechanism

  • Reversible binding of ADP receptors

  • 50-60% inhibition of ADP-induced plt aggregation (>clopidogrel)

Perioperative

  • Emergency surgery with high bleed risk

    • Consider 4 units platelets >24 hours since last dose (based on little evidence)

Half-life: 6-13 hours

Onset of action: 1-2 hours

Time from drug admin during which platelet transfusion will have reduced efficacy: 18-26 hours

Time to normal platelet function after discontinuation: 3-5 days

 

Cangrelor

IV reversible ADP P2Y12 inhibitor

Continuous infusion

Half-life 90 min

Plt return to normal after 60 minutes

 

Vorapaxar & Atopaxar

Reversible PAR-1 inhibitors

PAR1 and PAR4 receptors are activated by thrombin leading to plt aggregation.