cgp-39393 and Thrombophlebitis

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

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

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

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

The in vitro anticoagulant activities of recombinant desulphatohirudin (r-hirudin) were studied in the activated partial thromboplastin time (APTT) and the thrombin generation test systems. In the APTT, at concentrations below 5 micrograms/ml, r-hirudin showed a dose-response curve. At concentrations above 5 micrograms/ml, the plasma became unclottable, but in the thrombin generation test, at least 10 micrograms/ml of r-hirudin was required for full inhibition of thrombin generation. The antithrombotic effect was assessed using a rabbit venous stasis model; 150 micrograms/kg r-hirudin completely prevented thrombus formation at 10 and 20 min stasis. At this full antithrombotic dose, the mean bleeding time ratio measured in a rabbit ear template model, was not prolonged over control values. At higher doses, the bleeding time ratios were higher than those observed for the same dosage of heparin. These data indicate that while r-hirudin is an effective antithrombotic agent, antithrombotic doses have to be carefully titrated to avoid excessive bleeding.

Topics: Animals; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudins; Humans; In Vitro Techniques; Partial Thromboplastin Time; Rabbits; Recombinant Proteins; Thrombin Time; Thrombophlebitis