Hirulog in the treatment of unstable angina. Results of the Thrombin Inhibition in Myocardial Ischemia (TIMI) 7 trial
Fuchs J, Cannon CP (1995) · Circulation · n=410
Studienprofil
- Design
- multicenter, randomized, double-blind, dose-ranging clinical trial of Hirulog (a synthetic peptide derived from leech hirudin) for unstable angina (TIMI-7 trial sites, USA)
- Stichprobengröße (n)
- 410
- Intervention
- Constant 72-hour intravenous infusion of Hirulog with aspirin 325 mg/day at one of four doses: 0.02 mg/kg/h (n=160), 0.25 mg/kg/h (n=81), 0.5 mg/kg/h (n=88), or 1.0 mg/kg/h (n=81)
- Komparator
- Internal dose comparison: lowest dose (0.02 mg/kg/h) compared against pooled three higher doses (0.25, 0.5, 1.0 mg/kg/h) for secondary endpoint of death/MI; aspirin in all arms
- Primärer Endpunkt
- Unsatisfactory outcome composite (death, nonfatal MI, rapid clinical deterioration, recurrent ischemic pain at rest with ECG changes) by 72 hours
- Primäres Ergebnis
- Primary composite: 8.1%, 6.2%, 11.4%, 6.2% across four dose groups (no significant difference); secondary endpoint of death/nonfatal MI through hospital discharge 10.0% in lowest-dose group vs 3.2% in pooled higher doses (p=0.008); major hemorrhage only 0.5% (2/410)
- Follow-up-Dauer
- through hospital discharge
- PMID
- 7641350
Wichtigste Ergebnisse
- Largest PubMed-indexed RCT of a leech-derived therapeutic (n=410) - tests Hirulog, a synthetic peptide directly derived from leech hirudin
- Established proof-of-concept for direct thrombin inhibition without antithrombin III cofactor
- Higher Hirulog doses (≥0.25 mg/kg/h) significantly reduced secondary endpoint of death/MI vs lowest dose (p=0.008)
- Very low major hemorrhage rate (0.5%) compared with heparin in historical comparisons
- Foundational study leading to FDA approval of bivalirudin (Angiomax), the marketed Hirulog formulation for unstable angina and PCI
Einschränkungen
- Tests a leech-derived synthetic peptide, not whole-leech therapy - mechanistic relevance to hirudotherapy clinical practice is indirect
- Primary composite endpoint did not differ across doses - significance came from secondary analysis
- No placebo or heparin direct comparator arm in this dose-ranging design (later trials used heparin comparator)
- Acute coronary syndrome population - generalizability to non-cardiac leech therapy indications limited
- 1995 trial - subsequent guideline and comparator standards have evolved substantially
Klinische Implikationen
TIMI-7 is the most important RCT documenting that a leech-derived thrombin inhibitor (Hirulog, later marketed as bivalirudin) is clinically effective and safe in acute coronary syndrome. The trial does not support whole-leech therapy use in cardiovascular indications, but it does establish that the pharmacological backbone of leech saliva (hirudin) translates to a real, FDA-approved cardiovascular therapeutic. For ASH stakeholders, TIMI-7 is the principal evidence that hirudin-based pharmacotherapy is a successful translation pathway from traditional leech medicine to modern pharmacology - the kind of translational signal also seen with Shakouri 2017's topical leech-saliva gel for knee OA.
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