Desirudin
desulfatohirudin, recombinant hirudin variant 1, CGP 39393, 63-desulfohirudin
Desirudin is a recombinant version of hirudin, the anticoagulant protein that medicinal leeches use to keep blood flowing. It is a 65-residue direct thrombin inhibitor that was licensed to prevent deep vein thrombosis after elective hip replacement. It worked (it beat both heparin and enoxaparin in randomised trials), but it was withdrawn from both the EU and US markets for commercial reasons and is no longer available.
Mechanism
Desirudin is recombinant hirudin variant 1 produced in yeast, differing from the natural leech protein only in that tyrosine 63 is not sulfated (hence the name desulfatohirudin). Like all hirudins it is a bivalent direct thrombin inhibitor, and it is one of the most potent inhibitors known for any enzyme: the dissociation constant for the thrombin complex is in the sub-picomolar range, making the interaction effectively irreversible on a clinically relevant timescale.
The binding geometry is the template on which bivalirudin was later designed. The compact, disulfide-stabilised N-terminal domain (three disulfide bridges: Cys6-Cys14, Cys16-Cys28, Cys22-Cys39) inserts into the thrombin active site, while the highly acidic, glutamate-rich C-terminal tail wraps around exosite 1, the anion-binding site that thrombin normally uses to recognise fibrinogen. Because inhibition does not depend on antithrombin, desirudin inactivates clot-bound thrombin that heparin cannot reach, and because it has no affinity for platelet factor 4 it neither causes nor worsens heparin-induced thrombocytopenia. Elimination is almost entirely renal, so exposure rises steeply as glomerular filtration falls, the practical constraint that limited its use.
What the research shows
Two double-blind multicentre randomised trials by Eriksson and colleagues established efficacy, both using bilateral venography as the objective endpoint rather than clinical events alone. In the first, against unfractionated heparin in total hip replacement, 445 patients were randomised (225 desirudin, 220 heparin) and 351 were evaluable: confirmed deep vein thrombosis occurred in 7% of desirudin patients versus 23% of heparin patients. Proximal deep vein thrombosis (the clinically important subset) fell by 79%, from 16% to 3%. There was no significant difference between groups in bleeding variables or bleeding complications.
The second trial raised the bar by using a low-molecular-weight heparin as the comparator. Against enoxaparin in total hip replacement, with 2,079 patients randomised and 1,587 in the primary efficacy analysis, desirudin again came out ahead: proximal deep vein thrombosis 4.5% versus 7.5% (p=0.01) and overall deep vein thrombosis 18.4% versus 25.5%, with comparable safety. Beating enoxaparin on an objective venographic endpoint is a genuinely demanding result and few agents have achieved it.
A separate line of work examined immunogenicity. In 112 orthopaedic patients receiving subcutaneous desirudin for thromboprophylaxis, 11 (9.8%) developed antihirudin antibodies, independently of dose. Their presence had no measurable impact on rates of deep vein thrombosis or pulmonary embolism, allergic reactions or haemorrhage, although the authors were explicit that the number of immunised patients was too small to exclude infrequent but severe effects. Recombinant leech proteins are foreign antigens and can provoke a humoral response; the clinical consequences were far more prominent with lepirudin than in this desirudin setting.
Evidence assessment
High-quality evidence
Desirudin held marketing authorisations in both the EU (1997) and the US (2003), granted on the basis of two large, double-blind, multicentre randomised trials in hip replacement in which it was superior to unfractionated heparin and superior to enoxaparin for venographically confirmed deep vein thrombosis. Both trials were verified against PubMed. Titles, PMIDs, DOIs, journals, years, sample sizes and effect estimates all match. That is replicated randomised evidence plus regulator-approved labelling, so the tier is strong. The important qualification is commercial, not scientific: the product was never marketed in any European country, the EU authorisation was withdrawn in 2014 at the holder's request, and it has been discontinued in the United States. The evidence stands; the medicine does not.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Prevention of thromboembolism with use of recombinant hirudin. Results of a double-blind, multicenter trial comparing the efficacy of desirudin with that of unfractionated heparin in patients having a total hip replacement Preclinical only
Confirmed deep vein thrombosis occurred in 7% of desirudin patients versus 23% on heparin. Proximal deep vein thrombosis fell 79% (3% versus 16%). There was no significant difference between groups in bleeding variables or bleeding complications.
A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement Preclinical only
Desirudin was superior to enoxaparin: proximal deep vein thrombosis 4.5% versus 7.5% (p=0.01) and overall deep vein thrombosis 18.4% versus 25.5%. Safety profiles, including bleeding, were comparable.
Antihirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance Preclinical only
Antihirudin antibodies developed in 11 of 112 patients (9.8%), independently of dose. Their presence had no impact on the incidence of deep vein thrombosis or pulmonary embolism, allergic reactions or haemorrhage. The authors noted the number of immunised patients was low, so infrequent but severe antibody effects could not be excluded.
Safety
Bleeding is the main risk and there is no specific antidote; the fully renal elimination means that in impaired kidney function the drug accumulates and the anticoagulant effect is prolonged and difficult to manage. Monitoring by activated partial thromboplastin time was recommended in patients with reduced creatinine clearance.
Spinal and epidural haematoma is the safety issue that dominates the labelling for any parenteral anticoagulant used around hip surgery, where neuraxial anaesthesia is common; this carried a boxed warning in the US. Antihirudin antibodies form in around one in ten treated patients. Anaphylaxis has been described with recombinant hirudins as a class. The problem was far more prominent with lepirudin, where it was sometimes fatal on re-exposure, but the class signal applies. Injection-site reactions, wound haematoma and anaemia were reported in the trials. Since the product is no longer marketed anywhere, any material sold as desirudin outside a regulated pharmaceutical supply chain should be treated as unverified in identity and purity.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Not available. Desirudin held a centralised EU marketing authorisation granted in 1997, but it was never marketed in any European country and the European Commission withdrew the authorisation in July 2014 at the marketing authorisation holder's request, for commercial reasons. There is no current MHRA-licensed desirudin product in Great Britain. |
| United States | Formerly FDA-approved (2003) for prophylaxis of deep vein thrombosis in patients undergoing elective hip replacement surgery. The originator product and all generics have been discontinued and desirudin is no longer marketed in the United States. |
| WADA (sport) | Not listed on the WADA Prohibited List. Anticoagulants are not prohibited in or out of competition. |
Questions
Hirudin is the anticoagulant protein secreted by the salivary glands of the medicinal leech, Hirudo medicinalis, which the animal uses to stop its host's blood clotting while it feeds. It is one of the most potent thrombin inhibitors known. Desirudin is a recombinant version made in yeast, identical to natural hirudin variant 1 except that tyrosine 63 lacks its sulfate group.
For commercial rather than safety or efficacy reasons. It beat both unfractionated heparin and enoxaparin on objective venographic endpoints, but it required twice-daily subcutaneous injection, accumulated dangerously in renal impairment, had no reversal agent, and arrived just as low-molecular-weight heparins and then oral direct factor Xa inhibitors captured the orthopaedic thromboprophylaxis market. It was never actually marketed in any European country, and the EU authorisation was formally withdrawn in 2014 at the company's request.
Desirudin is the full 65-residue recombinant protein and binds thrombin essentially irreversibly, with a half-life of a few hours and entirely renal clearance. Bivalirudin is a 20-residue synthetic peptide that reproduces only the two essential binding domains of hirudin, joined by a short glycine linker, and is deliberately designed so that thrombin slowly cleaves it, giving a 25-minute half-life. Bivalirudin was, in effect, hirudin engineered to be shorter-acting and safer to use during a procedure.
No. The European marketing authorisation was withdrawn in July 2014 and the product was never marketed in Europe. In the United States the originator product and all generics have been discontinued. Any material offered for sale under this name today is outside the regulated pharmaceutical supply chain and its identity, purity and sterility cannot be assumed.