cgp-39393 and Postoperative-Complications

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

Leeches have been in medical use for many years. Hirudin, the anticoagulant obtained from the medicinal leech has been purified, characterized and can now be produced by recombinant (r) technology. R-hirudin is a potent inhibitor of thrombin and is therefore a potentially valuable anticoagulant and antithrombotic drug. This article reviews the current status of r-hirudin in this role and compares the pharmacokinetics, mechanism of action and clinical efficacy of this agent with heparin. The methods available for laboratory assessment and clinical monitoring of r-hirudin and the possible ways of antagonizing its effects are also discussed. Finally, the potential clinical applications of r-hirudin are outlined, although further laboratory and clinical studies, together with a fall in the cost of this compound are required before r-hirudin can be more widely accepted as an anticoagulant and antithrombotic agent.

Topics: Amino Acid Sequence; Animals; Blood Coagulation; Blood Platelets; Drug Evaluation; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Molecular Sequence Data; Postoperative Complications; Recombinant Proteins; Thrombin; Thrombosis

Because of an extreme risk for thromboemboli, patients with suspected heparin-induced thrombocytopenia (HIT) require immediate initiation of an alternative anticoagulant. The only therapies approved by the Food and Drug Administration require intravenous infusion of expensive direct thrombin inhibitors. This prospective, randomized, open-label, exploratory study compared the clinical and economic utility of subcutaneous desirudin vs argatroban, the most frequently used agent for suspected or immunologically confirmed HIT, with or without thrombosis. Sixteen patients were randomized to treatment with fixed-dose desirudin (15 or 30 mg) every 12 hours or activated partial thromboplastin time-adjusted argatroban by intravenous infusion. Arm A included 8 patients naive to direct thrombin inhibitor therapy, whereas Arm B included 8 patients on argatroban for at least 24 hours before randomization. The primary efficacy measure was the composite of new or worsening thrombosis (objectively documented), amputation, or death. Other end points included major and minor bleeding while on drug therapy, time to platelet count recovery, and pharmacoeconomics. No amputations or deaths occurred. One patient randomized to argatroban had worsening of an existing thrombosis. Major bleeding occurred in 2 patients on argatroban and in none during desirudin treatment. There was 1 minor bleed in each treatment group. The average medication cost per course of treatment was $1688 for desirudin and $8250 for argatroban. Desirudin warrants further study as a potentially cost-effective alternative to argatroban in patients with suspected HIT.

Topics: Adolescent; Adult; Aged; Anticoagulants; Arginine; Disease Progression; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Pilot Projects; Pipecolic Acids; Platelet Count; Postoperative Complications; Postoperative Period; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Thrombosis; Treatment Outcome; Young Adult

Measurements of prothrombin fragment 1+2 (F1+2), thrombin antithrombin III complexes (TAT) and D-dimer plasma levels have been proposed as non-invasive screening tests to exclude postoperative deep venous thrombosis (DVT). We investigated the diagnostic efficacy of these coagulation activation markers to rule out postoperative DVT in patients undergoing hip surgery under antithrombotic prophylaxis.. In this substudy of a randomized double-blind thrombosis prophylaxis trial comparing three doses of desirudin (10, 15 or 20 mg b.i.d.) with unfractionated heparin (5000 IU t.i.d.) we used ELISA procedures to measure F1+2, TAT and D-dimer in 159 patients undergoing total hip replacement at baseline (day 0) and on postoperative days 1, 3 and 6. Bilateral venography was performed in all cases 8-11 days after surgery.. For the F1+2 assay sensitivity ranged from 73 to 83% in the three postoperative days investigated, and negative predictive value (NPV) from 68 to 74%. For TAT and D-dimer sensitivity ranged from 71 to 73% and from 71 to 83% and NPV from 61 to 65% and from 61 to 74% respectively.. In terms of sensitivity and NPV F1+2 and D-dimer are equivalent and are superior to TAT. However, their accuracy is too low to rule out the presence of DVT after hip surgery under antithrombotic prophylaxis.

Topics: Anticoagulants; Antithrombin III; Arthroplasty, Replacement, Hip; Biomarkers; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Heparin; Hirudins; Humans; Peptide Fragments; Peptide Hydrolases; Postoperative Complications; Prothrombin; Recombinant Proteins; Thrombophlebitis

Specific inhibition of thrombin is a new method for the prevention of postoperative deep-vein thrombosis. The objective of this multicenter, randomized, double-blind study was to compare the efficacy and safety of desirudin (Revasc, CGP 39393; fifteen milligrams two times a day) with that of unfractionated heparin (5000 international units three times a day) in patients having a primary elective total hip replacement. The medications were administered subcutaneously, starting preoperatively and continuing for eight to eleven days. The primary end point was a confirmed thromboembolic event during the treatment period. The presence of deep-vein thrombosis was evaluated with bilateral venograms, which were centrally assessed by two independent radiologists. A total of 445 eligible patients were randomized: 220, to management with heparin, and 225, to management with desirudin. A per-protocol analysis of efficacy was performed for the 351 patients (79 per cent) for whom an adequate bilateral venogram had been made within eight to eleven days after the operation or who had had a proved thromboembolic event. The prevalence of confirmed deep-vein thrombosis was thirteen (7 per cent) of 174 patients who had received desirudin and forty-one (23 per cent) of 177 patients who had received heparin, a significant difference (p < 0.0001). The prevalence of proximal deep-vein thrombosis was also significantly reduced (p < 0.0001), by 79 per cent, in the group that had received desirudin (six [3 per cent] of 174 patients) compared with in the group that had received heparin (twenty-nine [16 per cent] of 177). There were no confirmed pulmonary embolisms or deaths during the period of prophylaxis. During a six-week follow-up period, pulmonary embolism was confirmed in four patients, all of whom had received heparin. There was no significant difference between the treatment groups with respect to bleeding variables or bleeding complications. These data demonstrate that a fixed dose of fifteen milligrams of desirudin, started preoperatively and administered subcutaneously twice daily for at least eight days, provided effective, safe prevention of thromboembolic complications, with no specific requirements for laboratory monitoring, in patients who had a total hip replacement.

Topics: Aged; Anticoagulants; Double-Blind Method; Female; Heparin; Hip Prosthesis; Hirudin Therapy; Hirudins; Humans; Injections, Subcutaneous; Male; Postoperative Complications; Pulmonary Embolism; Recombinant Proteins; Thromboembolism; Thrombophlebitis

Despite prophylaxis, deep vein thrombosis (DVT) after hip surgery continues to occur frequently. Thus it would be helpful if before surgery patients at higher risk of DVT could be identified and more adequate prophylaxis given. As part of an international study on the prevention of DVT after total hip replacement, we investigated whether preoperative levels of three coagulation activation markers, prothrombin fragment F1 + 2 (F1 + 2), thrombin-antithrombin III complexes (TAT) and D-dimer, correlate with results of postoperative venography.. 159 patients undergoing total hip replacement were randomized to receive 10, 15 or 20 mg desirudin bid or 5000 IU unfractionated heparin tid immediately before surgery and then for 11 days, until bilateral venography was performed. Preoperative F1 + 2, TAT and D-dimer plasma levels were measured using ELISA procedures. As no difference among anticoagulant treatments or in the interaction between treatments and DVT was detected for any of the three variables, results are reported as pooled data.. The frequency of DVT was 18.8% in the low (0.75-1.33 nM) vs 65.7% in the high third of distribution (1.77-3.47 nM) of F1 + 2 (p < .001), 27.3% in the low (2.00-2.50 micrograms/l) vs 57% in the high third (5.10-61.00 micrograms/l) of TAT (p = .042), and 29.4% in the low (39-59 micrograms/l) vs 57.1% in the high third (129-651 micrograms/l) of D-dimer (p = .051).. Preoperative F1 + 2, TAT and D-dimer levels are associated with the risk of development of DVT after total hip replacement.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombin III; Biomarkers; Blood Coagulation Tests; Double-Blind Method; Female; Fibrin Fibrinogen Degradation Products; Heparin; Hip Prosthesis; Hirudin Therapy; Hirudins; Humans; Incidence; Male; Middle Aged; Peptide Fragments; Peptide Hydrolases; Phlebography; Postoperative Complications; Predictive Value of Tests; Prothrombin; Recombinant Proteins; Risk; Sensitivity and Specificity; Thrombophlebitis

Patients who undergo total hip replacement have a high risk of thromboembolic complications. Recombinant hirudin (desirudin), a specific inhibitor of thrombin, represents a new development in antithrombotic therapy. We compared the efficacy and safety of desirudin with those of a low-molecular-weight heparin (enoxaparin) for the prevention of thromboembolic complications in patients undergoing primary total hip replacement.. Both treatments, which were assigned in a randomized, double-blind manner, were started preoperatively: enoxaparin on the evening before surgery, and desirudin within 30 minutes before the start of surgery. The dose of desirudin was 15 mg subcutaneously twice daily, and the dose of enoxaparin was 40 mg subcutaneously once daily. The duration of treatment was 8 to 12 days. Deep-vein thrombosis was verified by bilateral venography performed at the end of the treatment period or earlier, if there were clinical signs of deep-vein thrombosis.. At 31 centers in 10 European countries, 2079 eligible patients were randomly assigned to receive desirudin or enoxaparin. A total of 1587 patients were included in the primary analysis of efficacy. In the desirudin group, as compared with the enoxaparin group, there was a significantly lower rate of proximal deep-vein thrombosis (4.5 vs. 7.5 percent, P=0.01; relative reduction in risk, 40.3 percent) and a lower overall rate of deep-vein thrombosis (18.4 vs. 25.5 percent, P=0.001; relative reduction in risk, 28.0 percent). The safety profiles were similar in the two treatment groups.. When administered 30 minutes before total hip replacement surgery, desirudin is more effective than enoxaparin in preventing deep-vein thrombosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Double-Blind Method; Enoxaparin; Female; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Postoperative Complications; Recombinant Proteins; Thrombophlebitis; Treatment Outcome

The frequency of thromboembolism after major orthopaedic surgery continues to be high despite prophylaxis. New agents such as CGP 39393, a recombinant form of hirudin, may be more effective than existing therapies.. In this double-blind, multicentre, European study the efficacy of three doses of CGP 39393, in comparison with unfractionated heparin, were examined in 1119 patients undergoing elective hip surgery. Patients were randomly allocated to receive by subcutaneous injection either 10, 15, or 20 mg of CGP 39393 twice daily or 5000 IU of heparin three times daily. All treatments were started just before surgery and continued for 8-11 days, until bilateral venography was performed.. The occurrence of thromboembolism was significantly reduced in patients treated with CGP 39393 compared to heparin. The frequency of deep-vein thrombosis was 34.2% in the heparin group as compared to 23.9% (p=0.0113), 18.4% (p=0.0003), and 17.7% (p=0.0001) in the 10 mg, 15 mg, and 20 mg CGP 39393 groups, respectively. At all dose levels, CGP 39393 was more effective than heparin in preventing proximal deep-vein thrombosis. The frequency of proximal thrombosis was 19.6% in the heparin group as compared to 8.5% (p<0.001), 3.1% (p<0.001), and 2.4% (p<0.001) in the 10 mg, 15 mg, and 20 mg CGP 39393 groups, respectively. All treatments were well tolerated.. This study indicates that specific inhibition of thrombin by prophylactic CGP 39393 significantly reduces thromboembolic complications in patients undergoing total hip replacement.

Topics: Aged; Anticoagulants; Confounding Factors, Epidemiologic; Double-Blind Method; Female; Follow-Up Studies; Heparin; Hip Prosthesis; Hirudin Therapy; Hirudins; Humans; Male; Partial Thromboplastin Time; Postoperative Complications; Recombinant Proteins; Thromboembolism; Thrombophlebitis

Hirudin is an anticoagulant originally extracted from the leech Hirudo medicinalis. Using recombinant DNA technology a new compound, recombinant desulphato hirudin CGP 39393 has now been produced. The aim of this study was to determine the maximum tolerated dose in patients undergoing elective hip replacement. This open safety trial represents, to our knowledge, the first experience of recombinant hirudin in orthopedic patients. In this study 48 patients undergoing primary total hip replacement were included and the safety of subcutaneous injections of 10, 15, 20 and 40 mg CGP 39393 twice daily, was evaluated. Prophylaxis was started immediately pre-operatively and continued for 8-10 days. A mandatory bilateral phlebography was performed at the end of the prophylactic treatment period and a clinical follow-up was done 6 weeks after surgery. A major bleeding event occurred in the first 3 patients receiving 40 mg CGP 39393 b.i.d. and the prophylaxis regimen at this dosage level was therefore discontinued. Median values of total blood loss and requirements of blood transfusion in the patients receiving 10-20 mg CGP 39393 were similar to those reported in previous studies on total hip replacement performed at the same centre, using other prophylactic drugs. Deep vein thrombosis (DVT) was confirmed by phlebography in 5 out of 12 patients in the 10 mg group (41.7%, 95% confidence limits [CL]: 15.2-72.3%), 1 out of 11 patients in the 15 mg group (9.1%, CL: 0.23-41.3%) and 2 out of 20 patients in the 20 mg group (10.0%, CL: 1.2-31.7%) during the prophylaxis period. CGP 39393 was safe and well tolerated, when administered as subcutaneous injections of 10-20 mg twice daily. The dose level of 40 mg CGP 39393 twice daily resulted in serious disturbance of the hemostasis in patients after hip prosthesis surgery.

Topics: Adult; Aged; Aged, 80 and over; Blood Loss, Surgical; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Hemorrhage; Hip Prosthesis; Hirudin Therapy; Hirudins; Humans; Injections, Subcutaneous; Male; Middle Aged; Partial Thromboplastin Time; Postoperative Complications; Recombinant Proteins; Risk Factors; Safety; Thrombin; Thromboembolism

Topics: Anticoagulants; Drug Approval; Hirudins; Humans; Kidney Diseases; Postoperative Complications; Recombinant Proteins; Thrombin; United States; United States Food and Drug Administration

Desirudin, a recombinant hirudin used in the prevention and management of thromboembolic disease, is a thrombin inhibitor which binds directly and with high affinity to clot-bound and fluid phase thrombin. As a prophylaxis in patients undergoing hip replacement surgery, desirudin was significantly more effective in reducing the incidence of deep vein thrombosis (DVT) than either unfractionated or low molecular weight heparin. However, results in patients with acute coronary syndromes are less conclusive. A significant reduction with desirudin compared with heparin in the incidence of death or non-fatal (re)infarction at 24 hours in patients with acute myocardial infarction (MI) was reported in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial but not in the TIMI (Thrombolysis and Thrombin Inhibition in Myocardial Infarction) 9B trial. Despite the early reduction shown in GUSTO IIb, desirudin was not associated with an improved long term clinical benefit at 30 days compared with heparin. Similar results were seen in patients with unstable angina/non-Q-wave MI enrolled in the GUSTO IIb trial. In addition, desirudin and heparin showed similar efficacy in preventing restenosis 30 weeks after coronary angioplasty for unstable angina, despite desirudin being associated with a significant reduction in the rate of cardiac events within the first 96 hours. Desirudin is as well tolerated as heparin with a similar incidence of moderate and severe bleeding, intracranial haemorrhage or stroke reported when trialled in the prevention of DVT associated with hip replacement surgery or the treatment of acute coronary syndromes. However, in the GUSTO IIb trial a significantly higher incidence of transfusions was observed in patients with unstable angina/non-Q-wave MI.. Desirudin is clearly more effective than heparin in the prevention of DVT in patients undergoing elective hip replacement, although cost factors may influence its ultimate place in therapy. In the treatment of acute coronary syndromes the role of desirudin is less certain; however, it may be useful for patients in whom heparin therapy is not a viable option.

Topics: Angina Pectoris; Anticoagulants; Arthroplasty, Replacement, Hip; Drug Administration Schedule; Hirudins; Humans; Myocardial Infarction; Postoperative Complications; Recombinant Proteins; Thromboembolism

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Enoxaparin; Hirudin Therapy; Hirudins; Humans; Postoperative Complications; Recombinant Proteins; Thrombophlebitis

To test the efficacy of a single intraocular injection of various doses of recombinant desulphatohirudin variant 1 (Revasc) in a rabbit model after lensectomy-vitrectomy surgery.. Standard fragmatome lensectomies and core vitrectomies were performed on Dutch Belted rabbits. In a masked fashion, 17 control eyes received single intraocular injections of lactated Ringer's solution, and the treated eyes, with eight eyes per treatment group, received single intraocular injections of hirudin at doses of 0.02 microgram, 2 micrograms, 10 micrograms, 50 micrograms, or 200 micrograms.. Intraocular injections of hirudin were effective in preventing postoperative fibrin formation at doses of 2 micrograms. There was no notable intraoperative bleeding. With an injection of 2.0 micrograms hirudin there was no hemorrhage at any time after surgery; with an injection of 200 micrograms hirudin, however, there was notable bleeding.. Hirudin is effective in the prevention of postoperative fibrin formation with a single intraocular injection of 2.0 micrograms after lensectomy-vitrectomy surgery in the rabbit model. There was no bleeding at the effective dose of 2.0 micrograms; at 100 times the effective dose, however, there was significant postoperative bleeding.

Topics: Animals; Fibrin; Fibrinolysis; Fibrinolytic Agents; Hirudins; Injections; Lens, Crystalline; Postoperative Complications; Rabbits; Recombinant Proteins; Thrombolytic Therapy; Vitrectomy; Vitreous Body

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Enoxaparin; Fibrinolytic Agents; Hirudin Therapy; Hirudins; Humans; Postoperative Complications; Recombinant Proteins; Thrombophlebitis

Topics: Anticoagulants; Antithrombin III; Antithrombins; Clinical Trials as Topic; Hemorrhage; Heparin, Low-Molecular-Weight; Hip Prosthesis; Hirudin Therapy; Hirudins; Humans; Postoperative Complications; Recombinant Proteins; Thrombophlebitis; Thrombosis

Topics: Anticoagulants; Heparin; Hip Prosthesis; Hirudin Therapy; Hirudins; Humans; Postoperative Complications; Recombinant Proteins; Research Design; Thromboembolism

Patients under going orthopedic surgery are at high risk of developing deep vein thrombosis. One hundred and thirty-eight consecutive patients undergoing total hip replacement or hip fracture surgery were included in this study. They were surveilled with colour Doppler ultrasound (CDU) and bilateral ascending contrast phlebography. The prevalence of proximal and distal DVT in this study was 5.8% and 20.3% respectively. CDU has a satisfactory sensitivity in patients with symptomatic deep vein thrombosis, especially in the proximal region. These results could not be confirmed in the present study of asymptomatic patients. The sensitivity was 62.5% (95% confidence interval: C.I. 24-91%) and the specificity 99.6% (C.I. 98-100%) for proximal DVT; 53.6% (C.I. 34-73%) and 98% (C.I. 96-99%) respectively for distal thrombi. the overall sensitivity was 58.1% (C.I. 39-75%) and the specificity 98% (C.I. 96-99%). The positive predictive value was 83.3% (C.I. 36-99%) and 75% (C.I. 51-91%) for proximal and distal DVT respectively. The negative predictive value was 98.9% (C.I. 98-100%) and 94.9% (C.I. 92-98%) for proximal and distal DVT respectively. The results of this study showed that even with a highly specialised and experienced investigator the sensitivity of CDU was too low to make it suitable for screening purposes in a high risk surgical population.

Topics: Anticoagulants; Dalteparin; Dextrans; Hip Fractures; Hip Prosthesis; Hirudin Therapy; Hirudins; Humans; Incidence; Phlebography; Postoperative Care; Postoperative Complications; Predictive Value of Tests; Recombinant Proteins; Risk; Sensitivity and Specificity; Thrombophlebitis; Ultrasonography, Doppler, Color