Q2i / 25B20: Describe the following pharmacology of both unfractionated heparin and bivalirudin

25B20: Exam Report

Describe the following pharmacology of both unfractionated heparin and bivalirudin:

  1. Indications for use (10% of marks)
  2. Mechanism of action (30% of marks)
  3. Monitoring and reversal (10% of marks)
  4. Important pharmacokinetic differences and considerations when using in the
    intensive care unit (ICU) (30% of marks)
  5. Adverse effects (20% of marks).

35% of candidates passed this question.

Given that heparin is the more commonly used drug and a level 1 drug, compared with bivalirudin which is level 2, a suggested way to answer this was to provide details on heparin for each subsection and then note the similarities and differences of bivalirudin.

The low pass rate for this question largely reflected a limited knowledge of heparin not just bivalirudin.

Q2i / 25B20: Describe the following pharmacology of both unfractionated heparin and bivalirudin

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Heparin

Bivalirudin

Comparisons / Notes

Indications for use

  1. Therapeutic anticoagulation (continuous IV infusion) – mechanical valves, AF, extracorporeal circuits, thrombus treatment (VTE, LV thrombus, ACS, etc)
  2. VTE Prophylaxis (subcutaneous intermittent bolus)

Therapeutic anticoagulation (continuous IV infusion) – AF, extracorporeal circuits, thrombus treatment (VTE, LV thrombus, ACS, etc)

Bivalirudin not indicated for mechanical valves, nor VTE prophylaxis

 

HITS = major indication for Bivalirudin

MoA

Indirect inhibition of thrombin and factor Xa

  • Binds to anti-thrombin III resulting in conformational change and increase in its activity
  • Binds & inactivates (free) thrombin and factor Xa (1:1 activity ratio)
  • Prevents clot propagation and formation, and platelet activation

Direct thrombin inhibitor

  • Binds to thrombin (free and in clot) preventing fibrin formation and platelet activation
  • Direct vs. indirect effect
  • Heparin having multiple targets, bivalirudin only affecting thrombin
  • Bivalirudin binds to both free and in-clot thrombin

Monitoring & reversal

Less predictable titration, requires close monitoring   APTT Measure of extrinsic pathway clotting time
  • Specific baseline values & therapeutic target dependent on local lab assay and heparin protocols
  • Baseline 25-40sec, Therapeutic ~60-80sec
  • Check and titration of infusion Q4-8H
ACT
Test of whole clotting cascade
  • Used as point-of-care rapid test, particularly for large dose anticoagulation & intraoperative use
  • Normal 110-130sec, target variable depending on indication (e.g. 150-200 for ECMO, >300 interventional cardiology/vascular, ~400 CPB)
Anti-Xa Levels
  • Not commonly utilised first-line monitoring for UFH, but can be used if concerns around lab-accuracy/availability of APTT
  • Also used if suspecting heparin resistance (to rule-out erroneous APTT measurements, & to help confirm diagnosis)
  • Specific population groups (lupus anticoagulant positive, antiphospholipid syndrome, factor deficiencies (VIII, IX, XI, XII)
  • Normal level 0-0.2u/mL, Therapeutic 0.3-0.7
  • Check and titration of infusion Q4-8H
  Reversal  – Protamine sulphate
  • Dosing dependent on time since heparin administration, bolus vs. infusion, and reversal target (e.g. full vs. partial)
  • 1mg Protamine for every 100 IU of Heparin administered to achieve full reversal after bolus given within last 15 minutes

More predictable titration, however still requires serial monitoring

APTT

  • As with heparin

 

ACT

  • As with heparin

 

Reversal – Nil direct

Bivalirudin cannot be monitored by Anti-Xa level

Bivalirudin has no reversal agent

Important PK differences and considerations

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Heparin

Bivalirudin

Comparisons / Notes

A

Some minor subcutaneous BA – use for VTE prophylaxis as intermittent s/c bolus dosing

IV only

Both drugs have minimal PO BA

D

High plasma protein binding (including antithrombin III)

Vd = Extracellular Fluid (40-100ml/kg)

Vd = Extracellular fluid

Similar Vd

Heparin has high PPB – yields some of the initial unpredictability & patient variability in initial titration.

M

Heparinases – degrade heparins into inactive compounds

  • Reticuloendothelial system, renal, and liver
  • 80%: Plasma proteases degradation to inactive metabolites
  • 20%: Excreted renally unchanged

Bivalirudin solely organ- independent metabolism, though not fully metabolised.

Organ clearance variability (saturatable vs. non saturatable pathways) lead to some of the unpredictability in heparin titration.

E

Inactive metabolites excreted renally

T ½ = 0.5-25 hrs

Renally cleared

  • Unmetabolised drug that is renally cleared → requires dose adjustment in renal impairment

T ½

Heparin does not require renal adjustment

Other Considerations

  • Pregnancy and breastfeeding safe
  • Cheaper
  • Higher cost
  • Restricted availability/supply

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Adverse Effects

  • Unexpected / occult bleeding
  • Thrombocytopenia
  • Osteopenia
  • Transaminitis
  • Skin necrosis
  • Alopecia
  • Anaphylaxis
  • HITTS
    • 1-5% patients on UFH
    • Type I – benign, non-immune
      • 10-30% patients within 4 days of exposure to heparin
      • Heparin binds to PF4 → mild platelet aggregation → thrombocytopenia
      • PF4 also supresses thrombopoiesis

 

  • Type II
    • PF4-Heparin complex triggers IgG mediated immune response → binding & clustering of PF4-Heparin complexes → platelet activation and thrombus formation
    • Endothelial damage → vWF release → thrombosis
  • Unexpected/occult bleeding
  • Nausea
  • Thrombocytopenia
  • Rash
  • Anaphylaxis

Bivalirudin used in patients with previous history, or acute suspicion of HITTS (where other non-heparin-based anticoagulation is inappropriate or otherwise contraindicated)

Author: Nathan Abraham