cgp-39393 and Venous-Thrombosis

Direct thrombin inhibitors (DTIs) are an emerging class of anticoagulants in routine clinical practice, although they have been under investigation for quite some time. Desirudin (Iprivask®, Canyon Pharmaceuticals™) is a recombinant hirudin derivative that directly inhibits free and fibrin-bound thrombin. Desirudin was the first DTI approved for deep vein thrombosis (DVT) prophylaxis in Europe (Revasc®) and is the newest injectable DTI commercially available in the USA. Desirudin is one of the few nonheparin subcutaneous drugs that has demonstrable efficacy for DVT prophylaxis. Subcutaneous desirudin has been shown to be more effective than both subcutaneous unfractionated heparin and enoxaparin, with comparable bleeding rates in the prevention of DVT in patients undergoing elective hip replacement. Desirudin also offers the advantage of a fixed dosing regimen while being less immunogenic than unfractionated heparin. However, owing to its pharmacokinetic properties, patients with renal dysfunction require dosing modifications. The favorable profile shown with desirudin thus far will allow its clinical use to grow and will promote further investigation into broadening its clinical applications.

Topics: Animals; Anticoagulants; Antithrombins; Dose-Response Relationship, Drug; Hemorrhage; Hirudins; Humans; Recombinant Proteins; Renal Insufficiency; Venous Thrombosis

Native hirudin is the most potent natural direct thrombin inhibitor currently known; it is capable of inhibiting not only fluid phase, but also clot-bound thrombin. Recombinant technology now allows production of recombinant hirudins (r-hirudins), which are available in sufficient purity and quantity with essentially unaltered thrombin-inhibitory potency. As thrombin is known to play a key role in a number of thrombotic disorders, numerous studies focused on the impact of r-hirudins on the clinical course in these diseases. R-hirudins provided significantly more stable anticoagulation than standard heparin, but demonstrated a relatively narrow therapeutic range with relevant bleeding risk even at clinically effective doses. In doses that are not associated with an increased bleeding risk, r-hirudins often failed to demonstrate significant superiority to heparin. To date, r-hirudins have a definite role in the treatment of heparin-induced thrombocytopenia, where they markedly reduce the high risk of thrombosis. For prophylaxis of deep vein thrombosis, r-hirudins have been shown to be superior to both unfractionated and low molecular weight heparin, but are not extensively used in this indication. In acute coronary syndromes, a definite role of r-hirudins has not yet been firmly established. When applied in an appropriate dose as adjunct to thrombolysis in patients with acute myocardial infarction, randomized, controlled trials did not show a consistent benefit of r-hirudins, especially in the long-term. In patients undergoing coronary balloon angioplasty for acute coronary syndromes, promising effects in the early postprocedural phase did not translate to an improved outcome after 6 months. In patients with unstable angina pectoris, efficacy and safety of r-hirudins as primary antithrombotic therapy are still under debate. In the future, r-hirudins are to be compared with alternative or additional potent antithrombotic agents or treatment strategies. This comparison will ultimately lead to their final placement in the management of thrombotic disorders.

Topics: Clinical Trials as Topic; Coronary Disease; Fibrinolytic Agents; Heparin; Hirudins; Humans; Kidney Failure, Chronic; Partial Thromboplastin Time; Recombinant Proteins; Thrombin; Thrombocytopenia; Tissue Distribution; Venous Thrombosis

This prospective pharmacoeconomic study analyses and discusses the cost effectiveness (expressed as cost per life-year gained) of desirudin in comparison with a low molecular weight heparin (LMWH), enoxaparin, as prophylaxis against deep vein thrombosis (DVT) in total hip replacement.. The cost effectiveness was analysed on the basis of results from a clinical trial that compared the recombinant hirudin, desirudin, with the LMWH, enoxaparin. The trial results regarding the incidence of DVT are included together with epidemiological data in a decision tree, simulating long term cost effectiveness of patients undergoing elective hip replacement. The model includes Markov processes simulating patients up to the age of 85 years, including the costs of DVT-related long term complications.. The average total thrombosis-related cost per patient under prophylactic therapy with enoxaparin is 7,022 Swedish kronor (SEK) compared with SEK7,497 when using desirudin (1998 values). The total costs with desirudin are 7% higher. Prophylaxis with desirudin in those patients undergoing elective hip replacement surgery adds, on average, 7 days of life per patient when compared with treatment using enoxaparin. This is equivalent to 1.91 additional years of life per 100 patients treated. The incremental cost-effectiveness ratio of prophylaxis with desirudin in patients undergoing elective hip replacement surgery is SEK24,864 per life-year gained in comparison with enoxaparin.. The present study demonstrates that prophylactic therapy with desirudin is a cost-effective approach for the prevention of DVT in patients undergoing total hip replacement.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Cost-Benefit Analysis; Decision Trees; Economics, Pharmaceutical; Heparin, Low-Molecular-Weight; Hirudin Therapy; Hirudins; Humans; Postoperative Complications; Recombinant Proteins; Venous Thrombosis

In the absence of prophylaxis, elective orthopedic surgery is associated with a high risk of venous thromboembolic events that are responsible for substantial morbidity and mortality. Despite the publication of articles questioning the significance of fatal pulmonary embolism (PE) following elective hip replacement, recent reports support the need for effective thromboprophylaxis in this indication. These reports also provide evidence of a significant reduction in fatal PE and overall mortality provided by treatment with low-molecular-weight heparin (LMWH), compared with unfractionated heparin. Even with the most effective prophylaxis currently available, however, deep vein thrombosis still develops in a minority of high-risk patients, indicating a need for improved therapies. Desirudin, a novel recombinant hirudin and direct thrombin inhibitor, has been shown to provide more effective prophylaxis than the most widely used LMWH, enoxaparin, in orthopedic surgery patients with multiple thromboembolic risk factors. This benefit was not associated with any increase in bleeding. Regional anesthesia and use of graduated compression stockings may provide additional independent reductions in thromboembolic risk in elective orthopedic surgery.

Topics: Anesthesia, Conduction; Anticoagulants; Bandages; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Logistic Models; Postoperative Complications; Pulmonary Embolism; Recombinant Proteins; Risk Factors; Venous Thrombosis

Joint replacement surgery is complicated by a high rate of postoperative venous thromboembolism (VTE). Current thromboprophylactic approaches reduce the rate of VTE, but the incidence remains as high as 20% to 50%. Recombinant hirudins, such as desirudin and lepirudin, function by directly inhibiting thrombin, and are a new development in antithrombotic therapy. In two multicenter studies, desirudin was found to be superior to unfractionated heparin (UFH) in the prevention of deep vein thrombosis (DVT) after total hip alloplasty. A further trial of more than 2,000 patients undergoing elective hip replacement compared the thromboprophylactic efficacy of desirudin versus the low-molecular-weight heparin (LMWH) enoxaparin. Desirudin was more effective than LMWH in providing effective prophylaxis, and maintained superiority in patients with additional risk. Desirudin was shown to be equally safe and did not require laboratory monitoring. Desirudin (15 mg twice daily) is an efficient therapy for DVT prevention in hip alloplasty patients at additional risk.

Topics: Arthroplasty, Replacement, Hip; Cost-Benefit Analysis; Drug Costs; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Venous Thrombosis

This randomized, exploratory study compared the incidence of heparin-dependent antibodies associated with subcutaneous (SC) desirudin or heparin given for deep-vein thrombosis prophylaxis following cardiac and thoracic surgery.. Adult patients scheduled for elective cardiac or thoracic surgery received desirudin 15 mg SC twice daily or unfractionated heparin 5000 units SC thrice daily. Duration of thrombosis prophylaxis was determined by the treating physician. Primary outcome measure was the incidence of new antibody formation directed against platelet factor 4 (PF4)/heparin complex. Secondary outcomes included bleeding and thrombotic complications. Blood was tested for anti-PF4/heparin antibodies at baseline, after surgery prior to study drug administration, postdrug day (PDD) 2, PDD 7, and at 1 month. Doppler studies were done before discharge.. Of 120 patients, 61 received desirudin, 59 received heparin. New PF4/heparin antibodies occurred in 10.2% and 13.6% of desirudin- and heparin-treated patients, respectively. Among desirudin patients with no heparin exposure, none (0/36) developed PF4/heparin antibodies versus 17.1% with heparin exposure. Incidence of deep venous thrombosis was 4.9% and 3.4% in the desirudin and heparin groups, respectively. Two heparin-group patients developed pulmonary embolism. Two patients per group had bleeding events; no patients required re-exploration for bleeding complications. Median chest tube output was similar with desirudin (900 mL) and heparin (692 mL) as was blood transfusion requirements of more than 2 units (5/61, desirudin; 2/59 heparin).. The incidence of thrombotic events was low in both groups. There were no safety concerns, and desirudin was not associated with anti-PF4/heparin antibodies.

Topics: Antibodies; Anticoagulants; Cardiac Surgical Procedures; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Platelet Factor 4; Recombinant Proteins; Thoracic Surgical Procedures; Venous Thrombosis

Topics: Animals; Antithrombins; Arthroplasty, Replacement, Hip; Drug Administration Schedule; Drug Costs; Fibrinolytic Agents; Hirudins; Humans; Injections, Subcutaneous; Recombinant Proteins; Treatment Outcome; Venous Thrombosis

Heparin-induced thrombocytopenia (HIT) is the most common drug-related thrombocytopenia. Thromboembolic complications occur in approximately 50% of patients with HIT and result in limb amputation and death in up to 20% and 30% respectively. Because patients with a history of HIT may require future intravenous anticoagulation but have a high-risk of thromboembolism if re-challenged with heparin, alternative therapies are necessary when further anticoagulation is indicated. The use of direct thrombin inhibitors in HIT patients who also require thrombolytic therapy offers unique challenges to anticoagulant monitoring and safety. We present a case of progressive ileofemoral deep venous thrombosis in a patient with a history of HIT in order to review the combined use of hirudin and thrombolysis in this setting.

Topics: Anticoagulants; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Phlebography; Recombinant Proteins; Thrombocytopenia; Thrombolytic Therapy; Treatment Outcome; Venous Thrombosis

The novel recombinant hirudin analog CX-397 was investigated with respect to its pharmacological activity and antithrombin profiles in vivo and in vitro. In three different types of thrombosis models in rats, including stasis and thrombin-induced venous, glass surface-activated arterio-venous shunt, and ferric chloride-induced arterial thrombosis models, CX-397 and rHV-1 elicited potent antithrombotic effects, where the minimum effective doses of rHV-1 tended to be higher than those of CX-397 in the arterio-venous shunt and arterial thrombosis models. The hemorrhagic risk of CX-397 in template bleeding in rats was not higher than that of rHV-1, indicating that CX-397 is superior to rHV-1 for treating the platelet-dominant type of thrombosis. However, no differences were detected between CX-397 and rHV-1 in their effects on in vitro coagulation times and thrombin-induced platelet aggregation, suggesting the possibility that some unknown mechanisms other than simple thrombin inhibition are also involved in their antithrombotic actions.

Topics: Amino Acid Sequence; Animals; Arginine; Arterial Occlusive Diseases; Arteriovenous Shunt, Surgical; Chlorides; Drug Evaluation, Preclinical; Ferric Compounds; Fibrinolytic Agents; Glass; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Molecular Sequence Data; Pipecolic Acids; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Recombinant Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Serine Proteinase Inhibitors; Sulfonamides; Thrombin; Thrombosis; Vena Cava, Inferior; Venous Thrombosis

Topics: Fibrinolytic Agents; Hematoma; Hemorrhage; Hirudin Therapy; Hirudins; Humans; Pulmonary Embolism; Recombinant Proteins; Venous Thrombosis