CardiologyTier 2Topic

Pharmacology of major drug classes used - anticoagulant drugs

Classes and targets

Class	Agents	Target
Vitamin K antagonist	Warfarin	II, VII, IX, X (+ protein C, S)
Direct thrombin inhibitor	Dabigatran; bivalirudin, argatroban (IV)	Factor IIa
Direct factor Xa inhibitor	Apixaban, rivaroxaban	Factor Xa
Antithrombin-mediated	UFH, enoxaparin, fondaparinux	Xa +/- IIa

DOACs are first line for AF and VTE
Warfarin remains mandatory for mechanical valves and moderate-severe mitral stenosis

Use

DOACs have displaced warfarin for most non-valvular indications
Warfarin persists where DOACs are contraindicated, unaffordable, or where INR monitoring is already established
Anticoagulant-related bleeding is a leading cause of medication-related hospital admission in Australia

Warfarin

Inhibits VKOR
- -> dec reduced vitamin K
- -> dec gamma-carboxylation of II, VII, IX, X
Protein C and S have the shortest half-lives and fall first
- -> transient procoagulant state
- -> warfarin without heparin cover -> skin necrosis
Full effect 5-7 days (factor II half-life ~60-72 h - the INR rises before the patient is anticoagulated)

Heparins

UFH binds antithrombin -> inc inactivation of IIa and Xa
LMWH - predominantly anti-Xa
Fondaparinux - pure synthetic pentasaccharide, anti-Xa only

DOACs

Direct active-site inhibition, antithrombin-independent
Rapid onset, peak 1-4 h; renally cleared to varying degrees (dabigatran ~80%)

Monitoring

Warfarin - INR
UFH - APTT or anti-Xa
LMWH - anti-Xa only in renal impairment, extremes of weight, pregnancy
DOACs need no routine monitoring
- But check renal function, weight and age at least annually - they set the dose
- A normal INR or APTT does not exclude a DOAC effect
- Dabigatran: thrombin time / dilute TT. Apixaban and rivaroxaban: drug-calibrated anti-Xa

DOAC dose reduction - the examinable table

Agent	Standard	Reduced	Criteria
Apixaban	5 mg BD	2.5 mg BD	>=2 of: age >80, weight <=60 kg, creatinine >=133 micromol/L
Rivaroxaban	20 mg daily	15 mg daily	CrCl 30-49 mL/min
Dabigatran	150 mg BD	110 mg BD	Age >75, CrCl 30-50, or high bleeding risk

Contraindications to DOACs

Mechanical heart valve; moderate-severe mitral stenosis
Pregnancy and breastfeeding
Severe renal impairment - dabigatran CrCl <30, rivaroxaban <30, apixaban <25
Active clinically significant bleeding, coagulopathic liver disease
Indwelling spinal or epidural catheter (and 6 h after removal)

Reversal

Warfarin - vitamin K; Prothrombinex-VF +/- FFP for major bleeding
Dabigatran - idarucizumab
Apixaban / rivaroxaban - andexanet alfa (limited Australian availability); otherwise PCC
Heparin - protamine (complete for UFH, partial for LMWH; ineffective for fondaparinux)

Periprocedural

Withhold DOAC 24-48 h before, by bleeding risk and CrCl
Bridging is rarely needed for DOACs - the short half-life is the bridge

Interactions

Warfarin - CYP2C9: amiodarone, metronidazole, fluconazole, SSRIs, many antibiotics
- Dietary vitamin K, alcohol, intercurrent illness
DOACs - P-glycoprotein +/- CYP3A4
- Avoid strong inducers: rifampicin, carbamazepine, phenytoin, St John's wort
- Caution with strong inhibitors: azoles, ritonavir
- Dabigatran is P-gp only, not CYP3A4
All - NSAIDs and antiplatelets multiply bleeding risk

Bleeding risk

Major bleeding ~1.3%/yr on warfarin with INR 2.0-3.9
DOACs cause less intracranial haemorrhage than warfarin
- But dabigatran 150 mg BD and rivaroxaban 20 mg cause more GI bleeding

Agent-specific harms

Warfarin - skin necrosis, purple toe syndrome, teratogenic
Heparin - HIT (UFH >> LMWH), osteoporosis with prolonged use, hyperkalaemia
Dabigatran - dyspepsia, limiting adherence

Monitor

Renal function, weight, age - reassess the dose
Haemoglobin
Concomitant NSAIDs and antiplatelets
Adherence - no INR means no adherence check

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