Biomedical subjects

Bengt I Eriksson

Publications and source records attributed to Bengt I Eriksson.

33 records · Page 2Linked to original sources

PubMed2003

Improvements in the prevention of postoperative venous thromboembolism in hip fracture patients.

Hip fracture surgery carries a high risk of venous thromboembolism and, until recently, was poorly investigated. The efficacy and safety of fondaparinux, a new synthetic antithrombotic, were investigated in two large, thromboprophylaxis studies. Results of the Penthifra study, which was a randomized, double-blind phase III trial, showed that 1 week of fondaparinux, compared with enoxaparin, significantly reduced venous thromboembolic events from 19.1% to 8.3% (relative risk reduction: 56.4%; P<.001) without increasing bleeding risk. Penthifra Plus results showed that extending fondaparinux prophylaxis from 1 to 4 weeks was well tolerated and, compared to placebo, significantly reduced delayed venous thromboembolism events from 35% to 1.4% (relative risk reduction: 95.9%; P<.001). Based on these findings, 4-week fondaparinux treatment may become the standard thromboprophylaxis after hip fracture surgery.

Adolescent↗

PubMed2003

Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement.

We evaluated whether a postoperative regimen with melagatran followed by oral ximelagatran, two new direct thrombin inhibitors, was an optimal regimen for thromboprophylaxis in major orthopaedic surgery. In a double-blind study, 2788 patients undergoing total hip or knee replacement were randomly assigned to receive for 8 to 11 days either 3 mg of subcutaneous melagatran started 4-12 h postoperatively, followed by 24 mg of oral ximelagatran twice-daily or 40 mg of subcutaneous enoxaparin once-daily, started 12 h preoperatively. Ximelagatran was to be initiated within the first two postoperative days. The primary efficacy endpoint was venous thromboembolism (deep-vein thrombosis detected by mandatory venography, pulmonary embolism or unexplained death). The main safety endpoint was bleeding. Venous thromboembolism occurred in 355/1146 (31.0%) and 306/1122 (27.3%) patients in the ximelagatran and enoxaparin group, respectively, a difference in risk of 3.7% in favour of enoxaparin (p = 0.053). Bleeding was comparable between the two groups.

Administration, Oral↗

PubMed2003

New pentasaccharides for the prophylaxis of venous thromboembolism: clinical studies.

Fondaparinux, a selective inhibitor of factor Xa, is the first of a new class of antithrombotic compounds, the synthetic pentasaccharides. Its benefit-to-risk ratio in preventing venous thromboembolism after major orthopedic surgery was investigated in four randomized, double-blind international phase III trials in patients undergoing surgery for hip fracture, elective hip replacement, and major knee surgery. Compared to enoxaparin, fondaparinux administered at a subcutaneous dose of 2.5 mg qd, starting postoperatively, reduced the overall incidence of venous thromboembolism up to day 11 by 55.2% (p < 0.001). The incidence of clinically relevant bleeding was low and did not differ between the two groups. Overall, fondaparinux achieved optimal efficacy and safety when treatment was initiated > or =6 h after the surgical procedure. In a further randomized double-blind trial, 4 weeks of prophylaxis with fondaparinux after hip fracture surgery reduced the risk of venous thromboembolism by 96% as compared to 1 week of prophylaxis, and was well tolerated. Fondaparinux has been recently approved for use in thromboprophylaxis after major orthopedic surgery. The clinical development of fondaparinux in other thromboprophylactic indications is ongoing.

Anticoagulants↗

PubMed2002

Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial.

BACKGROUND: Heparins substantially reduce the risk of thromboembolic complications after total hip or knee replacement. However, they can be given only by injection and have several other drawbacks. We did a multicentre, randomised, double-blind study to examine the dose-response relation of subcutaneous melagatran, a direct thrombin inhibitor, followed by oral ximelagatran as thromboprophylaxis after total hip or knee replacement. We aimed to compare the efficacy and safety with that of dalteparin. METHODS: Of 1900 patients, 1495 were assigned to four dose categories of subcutaneous melagatran from just before surgery (1.00 mg, 1.50 mg, 2.25 mg, or 3.00 mg twice daily) followed from the day after surgery by oral ximelagatran (8 mg, 12 mg, 18 mg, or 24 mg twice daily). 381 patients were assigned subcutaneous dalteparin 5000 IU once daily, from the evening before surgery. Bilateral venography was done at 7-10 days, and clinically suspected venous thromboembolism (VTE) was confirmed radiologically. The primary endpoint was the rate of deep-vein thrombosis and pulmonary embolism (PE). Analyses were by intention to treat. FINDINGS: 1876 patients underwent total replacement of hip (n=1270) or knee (n=606); evaluable venograms were obtained in 1473 (79%). Four patients without evaluable venograms had PE. Overall, a significant dose-dependent decrease in VTE was seen with melagatran/ximelagatran (lowest to highest group: 111 [37.8%], 70 [24.1%], 71 [23.7%], and 43 [15.1%]; p=0.0001); there were also significant relations for both total hip and total knee replacement individually. The frequency of VTE was significantly lower with the highest dose of melagatran/ximelagatran than with dalteparin (15.1% vs 28.2%, p<0.0001). There were no reoperations due to bleeding and no critical organ bleeding. Excessive surgical bleeding was uncommon but more frequent in the highest dose group. INTERPRETATION: This sequential therapy was effective and safe in patients undergoing major joint replacement surgery. The findings should be confirmed in a large phase III trial.

Adult↗

PubMed2002

Antihirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance.

Recombinant hirudin has been found to be immunogenic in patients treated with lepirudin following heparin-induced thrombocytopenia (HIT). We assessed the incidence of immunoglobulin G (IgG) antihirudin antibodies by enzyme-linked immunosorbent assay in 112 patients enrolled in a dose-finding study with desirudin. Patients received desirudin subcutaneously following orthopedic hip surgery at 10 mg twice a day (n = 17), 15 mg twice a day (n = 75), and 20 mg twice a day (n = 20). Of 112 patients, 11 (9.8%) developed antihirudin antibodies independently of the dose. The rate of immunization did not differ from that observed in HIT patients treated with lepirudin (P =.113). Plasma concentrations of desirudin did not differ between antihirudin antibody-positive and -negative patients. Antihirudin antibodies had no impact on incidences of deep vein thrombosis and/or pulmonary embolism, allergic reactions, and hemorrhage. However, the total number of immunized patients observed was low and so infrequent (but severe) effects of antihirudin antibodies cannot be excluded.

Antibodies↗

PubMed2002

Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies.

BACKGROUND: Orthopedic surgery remains a condition at high risk of venous thromboembolism (VTE). Fondaparinux, the first of a new class of synthetic selective factor Xa inhibitors, may further reduce this risk compared with currently available thromboprophylactic treatments. METHODS: A meta-analysis of 4 multicenter, randomized, double-blind trials in patients undergoing elective hip replacement, elective major knee surgery, and surgery for hip fracture (N = 7344) was performed to determine whether a subcutaneous 2.5-mg, once-daily regimen of fondaparinux sodium starting 6 hours after surgery was more effective and as safe as approved enoxaparin regimens in preventing VTE. The primary efficacy outcome was VTE up to day 11, defined as deep vein thrombosis detected by mandatory bilateral venography or documented symptomatic deep vein thrombosis or pulmonary embolism. The primary safety outcome was major bleeding. RESULTS: Fondaparinux significantly reduced the incidence of VTE by day 11 (182 [6.8%] of 2682 patients) compared with enoxaparin (371 [13.7%] of 2703 patients), with a common odds reduction of 55.2% (95% confidence interval, 45.8% to 63.1%; P<.001); this beneficial effect was consistent across all types of surgery and all subgroups. Although major bleeding occurred more frequently in the fondaparinux-treated group (P =.008), the incidence of clinically relevant bleeding (leading to death or reoperation or occurring in a critical organ) did not differ between groups. CONCLUSION: In patients undergoing orthopedic surgery, 2.5 mg of fondaparinux sodium once daily, starting 6 hours postoperatively, showed a major benefit over enoxaparin, achieving an overall risk reduction of VTE greater than 50% without increasing the risk of clinically relevant bleeding.

Aged↗

PubMed2002

Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial.

BACKGROUND: Elective hip-replacement surgery carries significant risk of venous thromboembolism, despite use of thromboprophylaxis. We aimed to see whether the pentasaccharide fondaparinux, the first drug of a new class of synthetic antithrombotic agents, could reduce this risk to a greater extent than other available treatments. METHODS: In a double-blind study, we randomly assigned 2275 consecutive patients aged 18 years or older who were undergoing elective hip-replacement surgery to receive postoperative subcutaneous injections of either 2.5 mg fondaparinux once daily or 30 mg enoxaparin twice daily. The primary efficacy outcome was venous thromboembolism to day 11. The main safety outcomes were bleeding and death. Patients were followed up for 6 weeks. FINDINGS: We assessed venous thromboembolism to day 11 in 1584 (70%) of 2275 patients. By day 11, venous thromboembolisms were recorded in 48 (6%) of 787 patients on fondaparinux and in 66 (8%) of 797 patients on enoxaparin. The relative reduction in risk was 26.3% (95% CI -10.8 to 52.8, p=0.099). The two groups did not differ in the number of patients who died or in the number who had clinically relevant bleeding. INTERPRETATION: In patients undergoing elective hip-replacement surgery, 2.5 mg fondaparinux once daily was not significantly more effective than 30 mg enoxaparin twice daily in reducing risk of venous thromboembolism. However, the lower risk recorded with fondaparinux than enoxaparin was clinically important, with no increase in clinically relevant bleeding.

Adult↗

PubMed2002

Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison.

BACKGROUND: Despite use of thromboprophylaxis, elective hip-replacement surgery carries a high risk of venous thromboembolic complications. We aimed to assess the ability of the pentasaccharide fondaparinux, the first of a new class of synthetic antithrombotic agents, to further reduce this risk. METHODS: In a double-blind study, we randomly assigned 2309 consecutive patients aged 18 years or older who were undergoing elective hip-replacement surgery to once daily, subcutaneous injections of either 2.5 mg fondaparinux, starting postoperatively, or 40 mg enoxaparin, starting preoperatively. The primary efficacy outcome was venous thromboembolism up to day 11, defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The main safety outcomes were bleeding and death. The duration of follow-up was 6 weeks. Analysis was per protocol. FINDINGS: We assessed the primary efficacy outcome in 1827 (79%) of 2309 patients. By day 11, venous thromboembolisms were recorded in 37 (4%) of 908 patients assigned to fondaparinux and in 85 (9%) of 919 assigned to enoxaparin (difference -5.2% [95% CI -8.1 to -2.7], p<0.0001). The relative reduction in risk was 55.9% (95% CI 33.1-72.8). The two groups did not differ in frequency of death or clinically relevant bleeding. INTERPRETATION: Drugs that act through specific inhibition of factor Xa, such as fondaparinux, could be more effective than low molecular weight heparins in prevention of venous thromboembolism in patients undergoing hip-replacement surgery.

Adult↗

PubMed2002

Prophylaxis of venous thromboembolism with subcutaneous melagatran in total hip or total knee replacement: results from Phase II studies.

The first clinical studies evaluating the safety and efficacy of melagatran, a novel, direct thrombin inhibitor, given subcutaneously as prophylaxis for venous thromboembolism (VTE) following total hip (THR) or total knee replacement (TKR) are reported. In Study I, 66 patients received subcutaneous melagatran (1.5-6 mg bid) in a poloxamer depot formulation, and in Study II, 104 patients received subcutaneous melagatran (2-4 mg bid) in saline or as a depot formulation in cyclodextrin. Treatment was given for 8-11 days, with the first dose administered immediately before surgery. Deep vein thrombosis (DVT) was assessed using mandatory bilateral venography on the last day of treatment, and pulmonary scintigraphy was performed if required. Bleeding complications occurred in the only patient who received melagatran 6 mg, and this dose-arm was discontinued. The frequency of VTE was low (12/129=9%, 95% confidence interval [CI]: 5-16%). Eight patients (6%) had distal DVT, three (2%) had proximal DVT, and in one patient (1%) pulmonary embolism (PE) was verified. In conclusion, subcutaneous melagatran 1.5-4.5 mg bid in saline or depot formulation was well tolerated and resulted in a low frequency of VTE.

Adolescent↗

PubMed2002

Factor Xa inhibition in the prevention of venous thromboembolism and treatment of patients with venous thromboembolism.

Venous thromboembolism (VTE) is a life-threatening complication following orthopedic surgery. Selective factor Xa inhibition is a new antithrombotic approach designed to avoid difficulties associated with heparins and other current anticoagulants. Several antifactor Xa compounds are in early investigation, but fondaparinux (Arixtra; NV Organon, Oss, The Netherlands; Sanofi-Synthelabo, Paris, France) is the first and most advanced compound in the development of a new class of synthetic antithrombotic agents--the selective factor Xa inhibitors. Fondaparinux has a highly favorable pharmacokinetic profile; four large phase 3 trials comparing subcutaneous fondaparinux 2.5 mg once daily with the low molecular weight heparin (LMWH) enoxaparin in doses approved by regulatory bodies showed that fondaparinux reduced the overall risk of VTE in major orthopedic surgery by > 50% without increasing clinically relevant bleeding. Fondaparinux also appears to be a very promising candidate for the treatment of patients with existing VTE.

Animals↗

PubMed2002

A dose-ranging study of the oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I. MElagatran for THRombin inhibition in Orthopaedic surgery.

The novel, oral direct thrombin inhibitor, ximelagatran (formerly H 376/95), represents an advance in antithrombotic therapy through its oral availability. After oral administration, ximelagatran is converted to its active form, melagatran. Melagatran can also be administered subcutaneously (s.c.). The results from the first clinical study with ximelagatran are reported. In this randomized, parallel-group, controlled study, 103 patients scheduled for elective total hip or total knee replacement received s.c. melagatran (1, 2 or 4 mg bid) for 2 days commencing immediately before surgery, followed by oral ximelagatran (6, 12 or 24 mg bid) for 6-9 days. Another 33 patients received dalteparin 5000 IU s.c. once daily, started the evening before surgery, for 8-11 days. At bilateral venography, deep vein thrombosis was found in 20.5% (16/78) of patients who had received s.c. melagatran and oral ximelagatran and in 18.5% (5/27) of patients in the dalteparin group. The study did not evaluate a dose-response for efficacy, and no differences between the three dose levels of melagatran and ximelagatran were shown. No pulmonary embolism was diagnosed during treatment. Total bleeding in the s.c. melagatran plus oral ximelagatran groups showed no dose-response and was similar to that seen in the dalteparin group. The pharmacokinetic properties of melagatran in the surgery patients were consistent with those observed for healthy subjects, and the APTT ratio, which increased non-linearly with plasma melagatran concentration, showed a consistent concentration-effect relationship during the treatment period. Ximelagatran and melagatran were well tolerated. In conclusion, ximelagatran and its active form melagatran appear to be promising agents for the prevention of venous thromboembolism following orthopaedic surgery.

Administration, Oral↗

PubMed2002

A meta-analysis of fondaparinux versus enoxaparin in the prevention of venous thromboembolism after major orthopaedic surgery.

A worldwide phase III program, consisting of four randomized, double-blind trials in patients undergoing surgery for hip fracture, in elective hip replacement surgery patients and in elective major knee surgery patients, was conducted to compare the benefit-to-risk ratio of a subcutaneous 2.5-mg once-daily regimen of fondaparinux, a synthetic selective factor Xa inhibitor, starting postoperatively with enoxaparin in preventing venous thromboembolism. The overall incidence of venous thromboembolism up to day 11 was reduced from 13.7% in the enoxaparin group to 6.8% in the fondaparinux group with a common odds reduction of 55.2% in favor of fondaparinux (95% confidence interval: 45.8-63.1%, p = 10(-17)). This superior efficacy of fondaparinux was also demonstrated for proximal deep vein thrombosis with a reduction of 57.4%. The overall incidence of clinically relevant bleeding was low and did not differ between the two groups. The benefit of fondaparinux was consistent across all types of surgery and all subgroups.

Adolescent↗

PubMed2002

A new antithrombotic strategy, the selective inhibition of coagulation factors, and its importance to the orthopedic specialist.

Traditional anticoagulant drugs including vitamin K antagonists and heparins have several limitations. Despite their use, the burden of venous thromboembolism remains high, particularly in patients undergoing major orthopedic surgery. A new strategy for the design of new antithrombotic drugs is based on selective inhibition of a specific coagulation factor. Fondaparinux is a synthetic selective inhibitor of factor Xa, which is critically positioned at the start of the common pathway of the coagulation system. Its pharmacokinetic profile allows for once-daily administration without the need for laboratory monitoring or dose adjustment. Fondaparinux has demonstrated its efficacy compared to a widely used low-molecular-weight heparin in a number of thromboprophylaxis trials after major orthopedic surgery and is approved for use in this setting.

Anticoagulants↗

PubMedDate not supplied

Kinematics and laxity of the knee joint after anterior cruciate ligament reconstruction: pre- and postoperative radiostereometric studies.

BACKGROUND: Injury of the anterior cruciate ligament changes the kinematics of the knee joint. In studies of cadaveric knees, investigators have examined the effect of anterior cruciate ligament reconstruction on knee kinematics, but the effect on dynamic knee motion is not known. HYPOTHESIS: Reconstruction of the anterior cruciate ligament restores knee kinematics to normal. STUDY DESIGN: Prospective cohort study. METHODS: Nine patients were examined preoperatively and 1 year after reconstruction. Continuous radiostereometric exposures were performed at a speed of two to four exposures per second while the patients ascended an 8-cm high platform. Tibial rotation and tibial and femoral translation were measured with radiostereometric analysis. RESULTS: Tibial rotation and tibial and femoral translation were not significantly different after anterior cruciate ligament reconstruction compared with preoperative measurements. A radiostereometric evaluation of anterior knee laxity revealed restoration to within 1 mm of that on the uninjured side. Further evaluation of knee function using the Lysholm score, the Tegner activity level score, the International Knee Documentation Committee evaluation system score, and measurements of laxity using the KT-1000 arthrometer revealed significant improvements after reconstruction. CONCLUSION: Kinematics of the anterior cruciate ligament injured knee did not change significantly after ligament reconstruction, but the functional results were satisfactory and knee laxity was diminished.

Adolescent↗

PubMedDate not supplied

Fondaparinux.

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Biological Availability↗