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PAR-1 (Protease-Activated Receptor-1) Antagonist — Secondary Prevention in PAD / MI Pregnancy: Avoid — insufficient data; theoretical fetal bleeding risk

Vorapaxar

Brand names: Zontivity

Adult dose

Dose: 2.08 mg once daily (with aspirin ± clopidogrel)
Route: Oral
Frequency: Once daily
Max: 2.08 mg/day
Used on top of standard antiplatelet therapy (aspirin ± thienopyridine). TRA 2P-TIMI 50 trial: reduced CV death/MI/stroke but increased GUSTO moderate/severe bleeding. Contraindicated in prior stroke/TIA — significantly increased intracranial haemorrhage. Licensed in US; MHRA approved for PAD and post-MI (without prior stroke/TIA) in UK.

Paediatric dose

Route:
Seek specialist opinion — not licensed in paediatrics

Dose adjustments

Renal

No dose adjustment required

Hepatic

Avoid in severe hepatic impairment — hepatically metabolised

Clinical pearls

  • Unique mechanism: PAR-1 antagonist — blocks thrombin-mediated platelet activation; completely different from ADP antagonists (clopidogrel/ticagrelor) or TXA2 inhibitors (aspirin); additive antiplatelet effect
  • TRA 2P-TIMI 50 trial: in PAD patients, vorapaxar reduced acute limb ischaemia and peripheral arterial revascularisation events — specific PAD benefit
  • Absolute contraindication in prior stroke/TIA — ICH risk increase was the main safety signal driving the label restriction
  • Long half-life (5–13 days) and irreversible-like PAR-1 binding — no antidote; effects persist for weeks after stopping
  • Niche agent — used in selected high-risk PAD patients on aspirin who cannot tolerate or have failed thienopyridines

Contraindications

  • Prior stroke or TIA (absolute — intracranial haemorrhage risk increased)
  • Active pathological bleeding
  • Severe hepatic impairment

Side effects

  • Bleeding (major risk — especially intracranial in stroke/TIA history)
  • Anaemia
  • Epistaxis
  • Bruising
  • Depression
  • Rash

Interactions

  • Strong CYP3A4 inducers (rifampicin, carbamazepine) — reduce vorapaxar levels significantly — avoid
  • Strong CYP3A4 inhibitors (ketoconazole, ritonavir) — increase levels — avoid
  • Other antiplatelets and anticoagulants — additive bleeding risk

Monitoring

  • Signs of bleeding (especially CNS — headache, neurological symptoms)
  • FBC
  • Renal and hepatic function
  • Concurrent antiplatelet/anticoagulant review

Reference: BNFc; BNF 90; TRA 2P-TIMI 50 Trial 2012; MHRA Vorapaxar SPC; ESC/ESVS PAD Guidelines 2017. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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