Bivalirudin

A synthetic 20-residue hirudin-derived direct thrombin inhibitor (Hirulog) that reversibly blocks both the active site and exosite I of thrombin; FDA-approved as Angiomax (2000) for intravenous anticoagulation during percutaneous coronary intervention.

Also referenced as: Angiomax, Angiomax RTU, Hirulog, Hirulog-1, BG8967, bivalirudin trifluoroacetate, Angiox

Also appears in: Other

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What is Bivalirudin?

Bivalirudin is a synthetic 20-amino-acid peptide (molecular weight about 2,180 Da) built from two fragments of hirudin, the natural thrombin inhibitor of the medicinal leech: an N-terminal D-Phe-Pro-Arg-Pro active-site motif joined through a tetraglycine spacer to a 12-residue sequence copied from the hirudin C-terminus. Originally designated Hirulog-1 (and, as a development compound, BG8967), it was designed at Biogen and brought through clinical development by The Medicines Company; the FDA approved it on December 15, 2000 as Angiomax, an intravenous anticoagulant for patients undergoing percutaneous coronary intervention (PCI), including those with heparin-induced thrombocytopenia. Bivalirudin is a hospital catheterization-laboratory drug with no self-administration, compounding, or research-market footprint; it appears here as one of the few peptide drugs that reached broad cardiovascular use and because its two decades of large randomized trials make it an unusually well-characterized peptide pharmacologically.

How it works

• Bivalent, direct thrombin inhibition — bivalirudin binds thrombin at two sites simultaneously: the D-Phe-Pro-Arg-Pro segment occupies the catalytic (active) site while the hirudin-derived C-terminal tail binds anion-binding exosite I, the fibrinogen-recognition surface. The design of these “hirulogs,” which inhibited thrombin but lacked measurable activity against factor Xa, plasmin, or trypsin even at a thousand-fold higher inhibitor-to-enzyme ratio, was described by Maraganore et al., Biochemistry, 1990
• Reversible, self-limiting inhibition — thrombin slowly cleaves the Arg3-Pro4 bond of bound bivalirudin, after which the active-site fragment dissociates and thrombin recovers its activity; this cleavage underlies the drug’s short duration of effect, with a plasma half-life of roughly 25 minutes in patients with normal renal function (Witting et al., Biochemical Journal, 1992; FDA label)
• Activity against clot-bound as well as free thrombin — heparin works through antithrombin and cannot efficiently reach fibrin-bound thrombin, whereas antithrombin-independent inhibitors acting at the active site or exosite I can (Weitz et al., Journal of Clinical Investigation, 1990, using the hirudin dodecapeptide and an active-site inhibitor that correspond to bivalirudin’s two halves). Bivalirudin binds no plasma proteins other than thrombin and is structurally unrelated to heparin, so it neither induces nor cross-reacts with heparin-induced thrombocytopenia antibodies, which is the basis of its labeled use in HIT (FDA label)
• Downstream effects on platelets and coagulation tests — by blocking thrombin, bivalirudin suppresses thrombin-mediated platelet activation and fibrin formation, prolonging the activated clotting time, aPTT, PT, and INR in a dose-dependent manner; elimination is by proteolysis and glomerular filtration, so clearance falls by about 70% in dialysis-dependent patients, with the half-life extending to about 3.5 hours (FDA label, clinical pharmacology section)

Research status

Bivalirudin is an approved drug with one of the largest randomized evidence bases of any peptide therapeutic, though the comparative question that drove most of that research, bivalirudin versus heparin during PCI, has shifted repeatedly as background therapy changed.

• Early angioplasty trials — Bittl et al. (1995), N Engl J Med 333(12):764–769, randomized 4,098 patients with unstable or post-infarction angina to Hirulog or heparin during balloon angioplasty; the overall primary endpoint was not significantly different (11.4% versus 12.2%), but bleeding was lower (3.8% versus 9.8%) and the post-infarction subgroup had fewer ischemic events.
• REPLACE-2 — Lincoff et al. (2003), JAMA 289(7):853–863: 6,010 PCI patients randomized to bivalirudin with provisional glycoprotein IIb/IIIa inhibition versus heparin plus planned GP IIb/IIIa blockade. Bivalirudin was non-inferior on the 30-day ischemic composite (7.6% versus 7.1%) with less in-hospital major bleeding (2.4% versus 4.1%, P < 0.001). This trial established bivalirudin as a standard PCI anticoagulant in the United States.
• ATBAT (HIT indication) — Mahaffey et al. (2003), J Invasive Cardiol 15(11):611–616: an open-label study of 52 patients with heparin-induced thrombocytopenia undergoing PCI; procedural success was 98% with one major bleed. This small study, together with the broader PCI experience, supports the labeled use in HIT/HITTS.
• HORIZONS-AMI — Stone et al. (2008), N Engl J Med 358(21):2218–2230: 3,602 STEMI patients undergoing primary PCI randomized to bivalirudin alone or heparin plus a GP IIb/IIIa inhibitor. Bivalirudin reduced 30-day net adverse clinical events (9.2% versus 12.1%) and major bleeding (4.9% versus 8.3%), and cardiac mortality was lower (1.8% versus 2.9%), but acute stent thrombosis within 24 hours was higher (1.3% versus 0.3%). The three-year follow-up (Stone et al., Lancet, 2011; 377(9784):2193–2204) maintained the mortality and bleeding advantages.
• ISAR-REACT 4 — Kastrati et al. (2011), N Engl J Med 365(21):1980–1989: in 1,721 NSTEMI patients, bivalirudin and abciximab-plus-heparin produced similar 30-day ischemic outcomes (10.9% versus 11.0% on the primary composite), with less major bleeding on bivalirudin (2.6% versus 4.6%).
• HEAT-PPCI — Shahzad et al. (2014), Lancet 384(9957):1849–1858: a single-center UK trial of 1,829 primary PCI patients with mostly radial access and potent oral P2Y12 inhibitors; the primary ischemic composite was higher with bivalirudin than heparin (8.7% versus 5.7%, RR 1.52) with no bleeding difference (3.5% versus 3.1%), a result that challenged the earlier bleeding-benefit narrative.
• BRIGHT and MATRIX — Han et al. (2015), JAMA 313(13):1336–1346 (2,194 Chinese AMI patients) found bivalirudin with a post-PCI infusion reduced 30-day net adverse events (8.8%) versus heparin alone (13.2%) or heparin plus tirofiban (17.0%). Valgimigli et al. (2015), N Engl J Med 373(11):997–1009 (MATRIX, 7,213 ACS patients) found no significant reduction in the co-primary composites of MACE (10.3% versus 10.9%) or net adverse clinical events (11.2% versus 12.4%), though bleeding and mortality analyses favored bivalirudin.
• VALIDATE-SWEDEHEART — Erlinge et al. (2017), N Engl J Med 377(12):1132–1142: a registry-based trial of 6,006 Swedish MI patients treated mostly transradially with ticagrelor; the 180-day composite of death, MI, or major bleeding was 12.3% with bivalirudin versus 12.8% with heparin (HR 0.96, P = 0.54), with identical major bleeding rates (8.6%). This result, together with HEAT-PPCI, shifted guideline language toward heparin as the default in contemporary practice.
• BRIGHT-4 — Li et al. (2022), Lancet 400(10366):1847–1857: 6,016 Chinese STEMI patients randomized to bivalirudin with a 2–4 hour high-dose post-PCI infusion or heparin monotherapy. The 30-day composite of all-cause death or BARC 3–5 bleeding was lower with bivalirudin (3.06% versus 4.39%, HR 0.69), and stent thrombosis was also lower (0.37% versus 1.10%), suggesting the post-procedure infusion addresses the early stent-thrombosis signal seen in HORIZONS-AMI.
• Active research — as of November 2026, registered trials include Chinese multicenter studies of bivalirudin versus heparin in high-bleeding-risk ACS patients (NCT07383155, phase 4, planned 5,270 patients, not yet recruiting) and in STEMI patients undergoing PCI after fibrinolysis (NCT06861374, BRIGHT-FIT, planned 2,400 patients, not yet recruiting), randomized trials of bivalirudin as an alternative to heparin for extracorporeal membrane oxygenation anticoagulation in adults (NCT06275555 in Beijing; NCT05959252, a phase 2 feasibility trial in Sydney), and an observational pediatric pharmacokinetic study spanning catheterization, bypass, and extracorporeal life support (NCT03532399, Boston Children’s Hospital). None of these seek a new US indication; the ECMO and pediatric uses remain off-label.
• Regulatory history — Angiomax (NDA 020873) was approved December 15, 2000. The acute stent thrombosis warning was added in the March 2016 labeling supplement, and the label was most recently revised in June 2019 (supplement 39). A ready-to-use solution, Angiomax RTU (NDA 211215, MAIA Pharmaceuticals), was approved July 25, 2019. Generic lyophilized bivalirudin has been approved since July 2015 (Hospira first), with more than a dozen ANDAs since and routine labeling updates continuing through 2025–2026. In Europe, the originator brand Angiox (authorized 2004) had its EU marketing authorization withdrawn in June 2018 at the holder’s request for commercial reasons; generic bivalirudin remains available there. No new US indications, complete response letters, or withdrawals were identified for 2025–2026.

Common dosage forms

Bivalirudin is supplied only as a sterile product for intravenous administration in a hospital setting. The reference product and its generics are lyophilized powder in single-dose glass vials containing 250 mg of bivalirudin (as the trifluoroacetate salt). Ready-to-use 5 mg/mL liquid presentations in vials also exist (Angiomax RTU and a generic solution equivalent). A frozen premixed bag in 0.9% sodium chloride (250 mg/50 mL and 500 mg/100 mL, Baxter, NDA 208374) was approved in December 2017 but is now listed as discontinued. There is no oral, subcutaneous, or nasal form, and bivalirudin is not offered as a research-market peptide.

Key considerations

• Approved, hospital-only anticoagulant — the FDA Approved status reflects Angiomax’s December 2000 approval for intravenous anticoagulation during PCI, including in patients with heparin-induced thrombocytopenia; bivalirudin has no compounding, self-administration, or research-vendor pathway.
• Comparative benefit depends on background therapy — the bleeding advantage over heparin seen in REPLACE-2 and HORIZONS-AMI was measured against heparin plus routine GP IIb/IIIa inhibitors and femoral access; with radial access and potent P2Y12 inhibitors (HEAT-PPCI, VALIDATE-SWEDEHEART) the difference largely disappeared. BRIGHT-4 reopened the question with a prolonged post-PCI infusion, but it was open-label and enrolled only Chinese patients.
• Acute stent thrombosis signal — the label carries a warning, added in March 2016, that acute stent thrombosis within four hours occurred more often with bivalirudin than heparin in primary PCI (1.2% versus 0.2% in pooled trials); the label advises that patients remain at least 24 hours in a facility able to manage ischemic complications, and a post-procedure infusion is the usual mitigation.
• Bleeding, renal clearance, and lab interference — the only contraindications are active major bleeding and hypersensitivity (anaphylaxis has been reported post-marketing); infusion rates are reduced in severe renal impairment and dialysis, and because bivalirudin raises INR, INR values measured during therapy cannot guide warfarin dosing. There is no reversal agent, but the roughly 25-minute half-life limits the duration of effect.
• Naming — “bivalirudin,” “Hirulog,” “Hirulog-1,” “BG8967,” “Angiomax,” and the former European brand “Angiox” all refer to the same molecule. It should not be confused with hirudin itself or the recombinant hirudins lepirudin (Refludan, withdrawn) and desirudin (Iprivask), which are 65-residue proteins, nor with the small-molecule direct thrombin inhibitors argatroban and dabigatran.