Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial
Mehran R, Lansky AJ, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Wong SC, Nikolsky E, Gambone L, Vandertie L, Parise H, Dangas GD, Stone GW (2009) · The Lancet · n=3602
Study Profile
- Design
- multicenter, open-label, prospective 1:1 randomized controlled trial (HORIZONS-AMI) of bivalirudin monotherapy versus unfractionated heparin plus glycoprotein IIb/IIIa inhibitor (GPI) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (PCI); 1-year prespecified follow-up analysis; ClinicalTrials.gov NCT00433966
- Sample size (n)
- 3602
- Intervention
- Bivalirudin monotherapy (recombinant hirudin-derived direct thrombin inhibitor; 0.75 mg/kg IV bolus followed by 1.75 mg/kg/h infusion) during primary PCI for STEMI (n=1800)
- Comparator
- Unfractionated heparin (60 IU/kg IV bolus, target ACT 200-250 s) plus a glycoprotein IIb/IIIa inhibitor (control arm, n=1802)
- Primary endpoint
- Co-primary endpoints (originally specified at 30 days and maintained through 1 year): (1) major bleeding and (2) net adverse clinical events (NACE = major bleeding + major adverse cardiovascular events [MACE: death, reinfarction, target vessel revascularisation for ischaemia, or stroke])
- Primary result
- At 1 year, NACE was lower in the bivalirudin arm (15.6% vs 18.3%; HR 0.83, 95% CI 0.71-0.97, p=0.022), driven by lower major bleeding (5.8% vs 9.2%; HR 0.61, 95% CI 0.48-0.78, p<0.0001); MACE was similar between groups (11.9% vs 11.9%); 1-year cardiac mortality (2.1% vs 3.8%; HR 0.57, 95% CI 0.38-0.84, p=0.005) and all-cause mortality (3.5% vs 4.8%; HR 0.71, 95% CI 0.51-0.98, p=0.037) favored bivalirudin
- Follow-up duration
- 1 year (prespecified follow-up analysis; subsequent reports extended to 3 years)
- PMID
- 19717185
Key Findings
- Largest contemporary RCT of a hirudin-derived direct thrombin inhibitor in primary PCI for STEMI (n=3602)
- Bivalirudin monotherapy reduced 1-year major bleeding by 39% (HR 0.61) versus heparin + GPI
- 1-year cardiac and all-cause mortality were both significantly lower with bivalirudin (HR 0.57 and 0.71, respectively)
- Findings led to ACC/AHA and ESC guideline incorporation of bivalirudin for STEMI PCI
- Mechanistic continuity from Hirudo medicinalis natural hirudin to recombinant hirudins (lepirudin, desirudin) to synthetic analog bivalirudin is documented in the ASH compound registry
Limitations
- Open-label design — outcome ascertainment partially unblinded (mitigated by adjudication committee)
- Comparator includes GPI in all patients — modern practice may use heparin alone or with different antiplatelet regimens
- Industry-funded with Boston Scientific and The Medicines Company unrestricted grants — bias risk addressed in CSR
- Bivalirudin is a synthetic analog, not whole-leech therapy — relevance to K040187-cleared device indication is indirect
- Subsequent trials (MATRIX, VALIDATE-SWEDEHEART, BRIGHT-4) have refined the modern positioning of bivalirudin; HORIZONS-AMI represents the original landmark signal
Clinical Implications
Mehran 2009 (HORIZONS-AMI) is the most important translational reference connecting Hirudo medicinalis biochemistry to mainstream cardiology practice. The trial established bivalirudin — a synthetic 20-amino-acid analog of the leech's natural hirudin — as a guideline-recommended alternative to heparin + GPI in primary PCI for STEMI, with a robust 1-year bleeding and mortality benefit. For US clinicians, the trial illustrates that leech-derived molecular pharmacology has produced an evidence-based therapeutic now used in tens of thousands of US heart attack procedures annually. The trial is cited in the ASH registry to demonstrate that the leech bioactive class has clinical impact far beyond the K040187 device indication and underpins the rationale for ongoing leech-compound discovery research.