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Bengt I Eriksson

Publications and source records attributed to Bengt I Eriksson.

At least 19 recordsLinked to original sources
PubMed2006

The Achilles tendon Total Rupture Score (ATRS): development and validation.

BACKGROUND: There is a need for a patient-relevant instrument to evaluate outcome after treatment in patients with a total Achilles tendon rupture. PURPOSE: To develop and validate a new patient-reported instrument for measuring outcome after treatment for total Achilles tendon rupture. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 1. METHODS: Development of this instrument consisted of item generation and test construction, item reduction, validation, evaluation of structure and internal consistency, test-retest, and test for responsiveness. The final version, the Achilles tendon Total Rupture Score (ATRS), was tested for validity, structure, and internal consistency (Cronbach's alpha) on 82 patients and 52 healthy persons. A correlation analysis was performed of the ATRS with the 2 validated foot/ankle/Achilles tendon scores, the Foot and Ankle Outcome Score (FAOS) and the Swedish version of the Victorian Institute of Sports Assessment-Achilles questionnaire (VISA-A-S). Structure was evaluated with factor analysis. Test-retest reliability was evaluated on 43 patients. The ATRS responsiveness was tested on 43 patients by calculating the effect size. RESULTS: The total score for the patients ranged from 17 to 100 with a mean (median) of 77 (85) and a standard deviation (interquartile range) of 21.4 (23). A significantly (P < .0001) higher total score was found for the healthy subjects, ranging from 94 to 100 with a mean (median) of 99.8 (100) and a standard deviation (interquartile range) of 1.1 (0). The ATRS correlated significantly (P < .01) with all subscales of the FAOS (r = 0.60-0.84) and the VISA-A-S (r = 0.78). The factor analysis gave 1 factor of importance. The internal consistency was 0.96 as measured with Cronbach's alpha. The test-retest produced an intraclass correlation coefficient of 0.98. The tests for responsiveness showed an effect size between 0.87 and 2.21. CONCLUSION: The ATRS is a patient-reported instrument with high reliability, validity, and sensitivity for measuring outcome after treatment in patients with a total Achilles tendon rupture. CLINICAL RELEVANCE: The ATRS is a self-administered instrument with high clinical utility, and we suggest the score for measuring the outcome, related to symptoms and physical activity, after treatment in patients with a total Achilles tendon rupture.

Achilles Tendon↗
PubMed2006

A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement.

BACKGROUND: Rivaroxaban (BAY 59-7939)--an oral, direct Factor Xa inhibitor--could be an alternative to heparins and warfarin for the prevention and treatment of thromboembolic disorders. METHODS AND RESULTS: This randomized, double-blind, double-dummy, active-comparator-controlled, multinational, dose-ranging study assessed the efficacy and safety of once-daily rivaroxaban relative to enoxaparin for prevention of venous thromboembolism in patients undergoing elective total hip replacement. Patients (n=873) were randomized to once-daily oral rivaroxaban doses of 5, 10, 20, 30, or 40 mg (initiated 6 to 8 hours after surgery) or a once-daily subcutaneous enoxaparin dose of 40 mg (given the evening before and > or = 6 hours after surgery). Study drugs were continued for an additional 5 to 9 days; mandatory bilateral venography was performed the following day. The primary end point (composite of any deep vein thrombosis, objectively confirmed pulmonary embolism, and all-cause mortality) was observed in 14.9%, 10.6%, 8.5%, 13.5%, 6.4%, and 25.2% of patients receiving 5, 10, 20, 30, and 40 mg rivaroxaban, and 40 mg enoxaparin, respectively (n=618, per-protocol population). No significant dose-response relationship was found for efficacy (P=0.0852). Major postoperative bleeding was observed in 2.3%, 0.7%, 4.3%, 4.9%, 5.1%, and 1.9% of patients receiving 5, 10, 20, 30, and 40 mg rivaroxaban, and 40 mg enoxaparin, respectively (n=845, safety population), representing a significant dose-response relationship (P=0.0391). CONCLUSIONS: Rivaroxaban showed efficacy and safety similar to enoxaparin for thromboprophylaxis after total hip replacement, with the convenience of once-daily oral dosing and without the need for coagulation monitoring. When both efficacy and safety are considered, these results suggest that 10 mg rivaroxaban once daily should be investigated in phase III studies.

Administration, Oral↗
PubMed2006

Early active extension after anterior cruciate ligament reconstruction does not result in increased laxity of the knee.

If permission of full active and passive extension immediately after an anterior cruciate ligament (ACL) reconstruction will increase the post-operative laxity of the knee has been a subject of discussion. We investigated whether a post-operative rehabilitation protocol including active and passive extension without any restrictions in extension immediately after an ACL reconstruction would increase the post-operative anterior-posterior knee laxity (A-P laxity). Our hypothesis was that full active and passive extension immediately after an ACL reconstruction would have no effect on the A-P laxity and clinical results up to 2 years after the operation. Twenty-two consecutive patients (14 men, 8 women, median age 21 years, range 17-41) were included. All the patients had a unilateral ACL rupture and no other ligament injuries or any other history of previous knee injuries. The surgical procedure was identical in all patients and one experienced surgeon operated on all the patients, using the bone-patellar tendon-bone autograft. The post-operative rehabilitation programme was identical in both groups, except for extension training during the first 4 weeks post-operatively. The patients were randomly allocated to post-operative rehabilitation programmes either allowing (Group A, n=11) or not allowing [Group B (30 to -10 degrees ), n=11] full active and passive extension immediately after the operation. They were evaluated pre-operatively and at 6 months and 2 years after the reconstruction. To evaluate the A-P knee laxity, radiostereometric analysis (RSA) and KT-1000 arthrometer (KT-1000) measurements were used, range of motion, Lysholm score, Tegner activity level, the International Knee Documentation Committee (IKDC) evaluation system and one-leg-hop test quotient were used. Pre-operatively, the RSA measurements revealed side-to-side differences in Group A of 8.6 mm (2.3-15.4), median (range) and in Group B of 7.2 mm (2.2-17.4) (n.s.). The corresponding KT-1000 values were for Group A, 2.0 mm (0-8.0) and Group B, 4.0 mm (0-10.0) (n.s.). At 2 years, the differences between the two groups were minimal, regardless of the method that had been used. The RSA measurements in Group A were 2.7 mm (0-10.7) and in Group B 2.8 (-1.8 to 9.5). The KT-1000 values were for Group A, 1.0 mm (-1.5 to 3.5), and for Group B, 0.5 mm (-1.0 to 4.0), without any significant differences between the groups. Nor did the Lysholm score, Tegner activity level, IKDC or one-leg-hop test differ. Early active and passive extension training, without any restrictions in extension, immediately after an ACL reconstruction using bone-patellar tendon-bone graft did not increase post-operative knee laxity up to 2 years after the ACL reconstruction.

Adolescent↗
PubMed2006

Biodegradable and metallic interference screws in anterior cruciate ligament reconstruction surgery using hamstring tendon grafts: prospective randomized study of radiographic results and clinical outcome.

BACKGROUND: The use of biodegradable screws in anterior cruciate ligament reconstruction has grown in popularity. PURPOSE: To compare the clinical and radiographic results in arthroscopically assisted anterior cruciate ligament reconstruction using 4-strand hamstring tendon grafts and either metallic (metal group) or biodegradable (PLLA group) interference screw fixation. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A randomized series of 77 patients, all with a unilateral anterior cruciate ligament rupture, was included in the study. The preoperative assessments in both groups were similar in gender, Tegner activity level, Lysholm score, KT-1000 arthrometer measurements, and single-legged hop test results. In both groups, interference screw fixation of the graft was used at both ends, and 68 of 77 (88%) patients returned for a radiographic examination at 6 and 24 months, respectively. RESULTS: At follow-up, no significant differences were found between the 2 groups in KT-1000 arthrometer laxity measurements, Tegner activity level, or Lysholm score. The PLLA group had a significantly better outcome in the single-legged hop test and the final International Knee Documentation Committee classification (P = .007 and P = .03, respectively). At 6 and 24 months after the index operation, the PLLA group displayed significantly larger drill holes on the radiographs than did the metal group on both the tibial (8.1 vs 6.6 mm at 6 months [P = .0007]; 6.0 vs 3.2 mm at 24 months [P < .0001]) and femoral sides (7.8 vs 5.6 mm at 6 months [P < .0001]; 6.3 vs 1.9 mm at 24 months [P < .0001]). CONCLUSION: There were significantly larger radiographically visible drill holes on both the tibial and femoral sides in the PLLA group compared with the metal group at 6 and 24 months. Clinical examination at 2 years revealed no major differences between the groups. The larger drill holes in the PLLA group did not correlate with inferior clinical results.

Absorbable Implants↗
PubMed2006

KT-1000 records smaller side-to-side differences than radiostereometric analysis before and after an ACL reconstruction.

The KT-1000 and similar non-invasive arthrometers are used as a complement to clinical examination in the diagnosis of anterior cruciate ligament (ACL) rupture and during the follow-up after surgery. We compared the two methods, KT-1000 and Radiostereometric analysis (RSA), when used to measure anterior-posterior knee laxity (A-P laxity) in patients with ACL rupture, before and after the reconstruction of this ligament, in a prospective, comparative study. Twenty-two consecutive patients (14 men, 8 women) with a median age of 24 years (range 16-41) were studied. All the patients had a unilateral ACL rupture and an intact contralateral knee. The patients were operated on by one experienced surgeon using the bone-patellar tendon-bone (BTB) autograft. Preoperatively and 2 years after the reconstruction, all the patients were evaluated using KT-1000 and RSA measurements of A-P laxity. The side-to-side differences between the injured and the intact knees, that is, total A-P laxity for both knees, are presented. Preoperatively, the median side-to-side differences using the two methods (KT-1000/RSA) were 4.0 (0-10)/7.4 mm (2.2-17.4) (P<0.0001). The total A-P laxity on the injured side was 11.0 (6.0-18.0)/10.9 mm (6.2-19.6) (n.s), while it was 8.0 (6.0-10.0)/3.1 mm (0.2-8.6) on the intact side (P<0.0001). A side-to-side difference of more than 3.0 mm was defined as the cut-off value for indicating ACL rupture. Using the KT-1000, 11 of 22 (50%) patients had a cut-off value above 3.0 mm, while the corresponding figure for RSA was 21/22 (95%) patients. At the 2-year follow-up, the median side-to-side differences using the two methods (KT-1000/RSA) were 0.5 (-1.5 to 4.0)/2.8 mm (-1.8 to 10.7) (P<0.0001). The total A-P laxity on the operated side was 9.5 (7.5-14.0)/6.5 mm (2.4-14.1) (P<0.0001). We conclude that the KT-1000 recorded significantly smaller side-to-side differences than did the RSA, both before and after the reconstruction of the ACL using a BTB autograft. Before it was mainly an effect of larger A-P laxity recordings with KT-1000 on the intact side, and after the reconstruction, the KT-1000 still recorded larger A-P laxity on the intact side and also larger A-P laxity on the reconstructed side than RSA.

Adolescent↗
PubMed2006

Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis.

AIMS: To describe the pharmacokinetic-pharmacodynamic (PK-PD) characteristics of the direct thrombin inhibitor dabigatran in hip replacement patients by assessing coagulation parameters activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT), interindividual variability and factors affecting PD responses. METHODS: BISTRO I patients received oral dabigatran etexilate postsurgery for 6-10 days. Dabigatran plasma concentrations and aPTT/ECT were measured on the day of surgery, on subsequent days and at steady state. PK-PD characteristics of the dabigatran-aPTT/ECT relationships were evaluated using NONMEM V. RESULTS: The dabigatran concentration-aPTT relationship was described combining a linear and an E(max) model. Mean baseline aPTT was 33.4 s and E(max) (maximum increase in aPTT contributed by the E(max) model) was 26.9 s. The dabigatran concentration needed to attain 50% of maximum effect (EC(50)) was 94.7 ng ml(-1) and the mean slope of the linear concentration-response relationship (SLOP) was 0.0509 s ng(-1) ml(-1). Baseline aPTT and E(max) were highest following surgery and declined with time. The dabigatran concentration-ECT relationship fitted a linear model. Mean baseline ECT was 28 s and decreased with time; 50% of the maximum effect was observed after 2.9 days. SLOP decreased from 0.38 to 0.27 s ng(-1) ml(-1) with a half-life of 1.1 day, indicating greater PD effects on the day of surgery. Interindividual and residual variability was low. Covariates could not explain variability of this model. CONCLUSIONS: aPTT and ECT prolongation were directly correlated with dabigatran concentrations. Blood coagulation prolongation was most pronounced following surgery. Data suggest that ECT provides a more precise description of the anticoagulant effect than aPTT.

Aged↗
PubMed2006

Oral anticoagulants in development: focus on thromboprophylaxis in patients undergoing orthopaedic surgery.

Current anticoagulant provision is dominated by parenteral heparin and oral warfarin, which act by inhibiting several steps of the coagulation pathway indirectly. Recent research efforts have focused on the identification of small molecule inhibitors of the coagulation enzymes as novel therapies for thrombotic disorders. There has been particular success in developing nonpeptidic, orally available, small molecules to directly inhibit the key proteases, factor IIa and factor Xa. Of the new oral anticoagulants in development, the two agents in the most advanced stage are dabigatran etexilate (BIBR 1048) and rivaroxaban (BAY 59-7939), which inhibit factor IIa and factor Xa, respectively. Other agents in the early stages of development include several Xa inhibitors (LY-517717, YM150, DU-176b and apixaban [BMS-562247]), a factor IXa inhibitor (TTP889), and an orally active glycosaminoglycan enhancer (odiparcil [SB-424323]), which indirectly enhances thrombin inhibition via heparin cofactor II. Results have been reported from important, phase II dose-finding studies, and a number of registration-track phase III studies have been initiated, reflecting the drive towards potentially more effective, but primarily safer and more convenient therapies for the prevention and treatment of venous and arterial thrombosis. Indeed, two unmet needs for anticoagulation that can be easily identified are safety and ease of use. Safety relates primarily to the incidence of major bleeding and this remains the key concern of orthopaedic surgeons, over and above any efficacy advantage, and convenience of use, which centres on oral administration replacing the need for injections. The clinical development of these new anticoagulants is following the well tested strategy of dose-ranging and registration studies in major orthopaedic surgery, prior to development in arterial indications. There are a number of subtle issues, including the timing of the first perioperative dose, duration of prophylactic treatment and definition/assessment of study endpoints that can influence study outcome and require careful consideration when evaluating study results with new agents and in the comparison with established agents, and which are considered in this review. It is anticipated that over the next 3 years, at least one of these agents will be successfully licensed for the prevention of venous thromboembolism after major orthopaedic surgery, which will act as a springboard for the gradual replacement of current anticoagulants.

Administration, Oral↗
PubMed2005

Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin.

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin. Immunogenicity of heparins differs in that unfractionated heparin (UFH) induces more anti-PF4/heparin antibodies than low-molecular-weight heparin (LMWH) and UFH also causes more HIT. Fondaparinux, a synthetic anticoagulant modeled after the antithrombin-binding pentasaccharide, is believed to be nonimmunogenic. We tested 2726 patients for anti-PF4/heparin antibodies after they were randomized to receive antithrombotic prophylaxis with fondaparinux or LMWH (enoxaparin) following hip or knee surgery. We also evaluated in vitro cross-reactivity of the IgG antibodies generated against PF4 in the presence of UFH, LMWH, danaparoid, or fondaparinux. We found that anti-PF4/heparin antibodies were generated at similar frequencies in patients treated with fondaparinux or enoxaparin. Although antibodies reacted equally well in vitro against PF4/UFH and PF4/LMWH, and sometimes weakly against PF4/danaparoid, none reacted against PF4/fondaparinux, including even those sera obtained from patients who formed antibodies during fondaparinux treatment. At high concentrations, however, fondaparinux inhibited binding of HIT antibodies to PF4/polysaccharide, indicating that PF4/fondaparinux interactions occur. No patient developed HIT. We conclude that despite similar immunogenicity of fondaparinux and LMWH, PF4/fondaparinux, but not PF4/LMWH, is recognized poorly by the antibodies generated, suggesting that the risk of HIT with fondaparinux likely is very low.

Anticoagulants↗
PubMed2005

Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement.

Dabigatran etexilate is an oral low-molecular-weight direct thrombin inhibitor. Following oral administration, dabigatran etexilate is rapidly converted to its active form, dabigatran. The authors investigated the absorption, distribution, and elimination of a single 150-mg dose capsule formulation of dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. In an open-label, 3-way crossover study, dabigatran etexilate was administered to 18 male volunteers in the fasted state, after administration of food and with coadministration of the proton pump inhibitor, pantoprazole. In a subsequent multicenter, open-label study, 59 patients received a single dose of dabigatran etexilate, administered 1 to 3 hours following total hip replacement. In healthy volunteers, food had no effect on the extent of absorption of dabigatran etexilate, although there was reduced interindividual variability for dabigatran maximum plasma concentration and AUC(0-infinity). A decrease in the mean dabigatran AUC(0-infinity) (904 to 705 ng*h/mL) occurred with coadministration of pantoprazole. In patients undergoing total hip replacement, immediate onset of absorption was seen with the maximum plasma concentration of dabigatran occurring after 6 hours. The AUC(0-24) of dabigatran was 88% of the steady-state AUC using a preliminary tablet formulation and 106% of that seen in the healthy volunteer study. Compared with healthy volunteers, the postoperative profile was flattened with delayed peak concentrations. In summary, administration of the dabigatran etexilate capsule with food has no effect on the extent of dabigatran absorption, with a moderate decrease when coadministered with pantoprazole. Adequate plasma concentrations of dabigatran were seen with early postoperative administration of the dabigatran etexilate capsule. These pharmacokinetic characteristics confirm the suitability of this oral solid dosage form for use in future clinical trials.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2004

Efficacy of fondaparinux for thromboprophylaxis in hip fracture patients.

Fondaparinux efficacy for thromboprophylaxis was evaluated in predefined high-risk hip fracture patients. Patients received fondaparinux 2.5 mg for 7 days following surgery; 656 patients were randomized double blind to receive placebo or continue fondaparinux regimen for 21 additional days. Primary efficacy was venous thromboembolism (VTE) based on bilateral venography during the double-blind period. Total VTE was 1.4% (3 of 208 patients) for extended prophylaxis and 35% (77 of 220 patients) for short-term prophylaxis (P = 0.001), relative risk reduction (RRR) of 96%. Major bleeding occurred in 2% (8 of 327 patients) with extended prophylaxis and in 0.6% (2 of 329 patients) with short-term prophylaxis (P =.063). Risk of VTE was continued following short course fondaparinux in hip fracture patients, but was significantly reduced by extending prophylaxis, without significant risk of major bleeding.

Aged↗
PubMed2004

Superiority of fondaparinux over enoxaparin in preventing venous thromboembolism in major orthopedic surgery using different efficacy end points.

STUDY OBJECTIVES: To assess the relevance of various efficacy end points established for thromboprophylaxis trials, we compared the results of the fondaparinux phase III program in major orthopedic surgery using the original primary efficacy end point with those obtained when the efficacy end points recently suggested by the American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy and the European Committee for Proprietary Medicinal Products (CPMP) were used. SETTING AND PATIENTS: Fondaparinux was compared with enoxaparin in four multicenter, randomized, double-blind trials of major orthopedic surgery. The original primary efficacy end point consisted of a composite of deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or pulmonary embolism up to day 11. The efficacy end point established by the ACCP Consensus Conference on Antithrombotic Therapy comprises any proximal deep-vein thrombosis, symptomatic proven deep-vein thrombosis or pulmonary embolism, or fatal pulmonary embolism, and that established by the European CPMP comprises any proximal deep-vein thrombosis, symptomatic proven pulmonary embolism, or death from any cause. INTERVENTIONS: Patients were randomized to receive either subcutaneous fondaparinux (2.5 mg once daily) starting postoperatively or approved enoxaparin regimens. RESULTS: Using the original end point of the fondaparinux studies, the incidence of venous thromboembolism was 13.7% (371 of 2,703 patients) in the enoxaparin group compared with 6.8% (182 of 2,682 patients) in the fondaparinux group, with a common odds reduction of 55.2% (p = 10(-17); 95% confidence interval, 45.8% to 63.1%) in favor of fondaparinux. The respective incidences of efficacy end points with enoxaparin and fondaparinux were 3.3% and 1.7%, respectively, according to the ACCP definition, and 3.9% and 2.1%, respectively, according to the CPMP definition. The common odds reduction in favor of fondaparinux was 49.6% (p < 0.001) and 48.0% (p < 0.001), respectively. CONCLUSIONS: Fondaparinux was consistently more effective than enoxaparin in preventing venous thromboembolism in patients undergoing major orthopedic surgery, irrespective of the established composite outcomes used.

Adolescent↗
PubMed2004

Prevention of venous thromboembolism following orthopaedic surgery: clinical potential of direct thrombin inhibitors.

Patients undergoing total hip or total knee replacement are at high risk of venous thromboembolism (VTE), and are therefore considered to be populations well suited for the evaluation and dose optimisation of new anticoagulants. Deep vein thrombosis may lead to life-threatening pulmonary embolism, disabling morbidity in the form of the post-thrombotic syndrome, and risk of recurrent thrombotic events. There is increasing evidence that anticoagulant treatment for the prevention of VTE should be extended from 1 to at least 4 weeks after surgery. Anticoagulation with vitamin K antagonists (such as warfarin), low molecular weight heparin or unfractionated heparin effectively lowers the risk of VTE, but these anticoagulants have limitations such as the need for coagulation monitoring and subsequent dose adjustment (vitamin K antagonists), difficulty of continuing prophylaxis out of hospital because of the requirement for parenteral administration, and risk of heparin-induced thrombocytopenia. The development of new anticoagulants has been pursued with the aim of finding more effective, safer and/or more convenient therapies. Thrombin is a central regulator in the coagulation and inflammation process and several direct thrombin inhibitors (DTIs) with distinct pharmacological profiles, as well as pharmacological differences from the conventional anticoagulants, are currently in clinical use for certain indications or are under development. Clinical experience with parenterally administered DTIs has accumulated since the mid 1990s, although only desirudin (a recombinant hirudin) is currently approved for use in patients undergoing orthopaedic surgery. Two oral DTIs, ximelagatran and dabigatran etexilate, are in clinical development. Dabigatran etexilate has recently been evaluated in phase II clinical trials in patients undergoing total hip replacement. Several large phase III trials have now demonstrated the efficacy and safety of ximelagatran in the prevention of VTE following total hip or knee replacement. Ximelagatran can be used with an oral fixed dose without the need for coagulation monitoring or dose adjustment. Hence, it offers significant potential to facilitate the management of anticoagulation in or out of hospital.

Animals↗
PubMed2003

Clinical experience of melagatran/ximelagatran in major orthopaedic surgery.

The oral direct thrombin inhibitor (oral DTI) ximelagatran (Exanta, AstraZeneca) is rapidly absorbed and bioconverted to its active form melagatran, which also can be administered subcutaneously (s.c.). Two large-scale clinical trials (MElagatran for THRombin inhibition in Orthopaedic surgery [METHRO] II and III) have evaluated the safety and efficacy of s.c. melagatran followed by oral ximelagatran compared with low-molecular-weight heparins (LMWH) for thromboprophylaxis following total hip (THR) and total knee replacement (TKR) surgery. In METHRO II, patients received either 5000 IU s.c. dalteparin once daily (od) or a combination of one of four doses (from 1 to 3 mg) of s.c. melagatran twice daily (bid) started immediately before surgery, followed by one of four doses (from 8 to 24 mg) of oral ximelagatran bid started 1-3 days after surgery. In METHRO III, patients were randomized to receive either 40 mg s.c. enoxaparin od or 3 mg s.c. melagatran bid started 4-12 h after surgery followed by 24 mg oral ximelagatran. In METHRO II, there was a highly significant dose-response relationship for s.c. melagatran plus oral ximelagatran, with the highest dose combination superior to dalteparin in the prevention of venous thromboembolism (VTE). In METHRO III, a dosing regimen in which s.c. melagatran was started postoperatively and followed by oral ximelagatran was not more effective than enoxaparin started preoperatively. Thus, the time interval between surgery and the first dose of anticoagulant may be important in ensuring optimal efficacy. The METHRO II and III studies demonstrate that s.c. melagatran combined with oral ximelagatran are well tolerated and effective for the prevention of VTE following major orthopaedic surgery.

Azetidines↗
PubMed2003

Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study.

BACKGROUND: The benefit of thromboprophylaxis for 1 month has never been evaluated in patients undergoing hip fracture surgery, a setting in the highest risk category for postoperative venous thromboembolism (VTE). METHODS: In a double-blind multicenter trial, 656 patients undergoing hip fracture surgery were randomly assigned to receive prophylaxis with a once-daily subcutaneous injection of either 2.5 mg of fondaparinux sodium or placebo for 19 to 23 days. Before randomization, all patients had received fondaparinux for 6 to 8 days. The primary efficacy outcome was VTE occurring during the double-blind period (deep vein thrombosis detected by mandatory bilateral venography or documented symptomatic deep vein thrombosis or pulmonary embolism). The main safety outcome was major bleeding. RESULTS: The primary efficacy outcome was assessed in 428 patients. Fondaparinux reduced the incidence of VTE compared with placebo from 35.0% (77/220) to 1.4% (3/208), with a relative reduction in risk of 95.9% (95% confidence interval, 87.2%-99.7%; P<.001). Similarly, the incidence of symptomatic VTE was significantly lower with fondaparinux (1/326; 0.3%) than with placebo (9/330; 2.7%). The relative reduction in risk was 88.8% (P =.02). Although there was a trend toward more major bleeding in the fondaparinux group than in the placebo group (P =.06), there were no differences between the 2 groups in the incidence of clinically relevant bleeding (leading to death, reoperation, or critical organ bleeding). CONCLUSIONS: Extended prophylaxis with fondaparinux for 3 weeks after hip fracture surgery reduced the risk of VTE by 96% and was well tolerated.

Adult↗
PubMed2003

Fondaparinux, the first selective factor Xa inhibitor.

Fondaparinux (Arixtra, Sanofi-Synthelabo, Paris, France) is a pentasaccharide that selectively inhibits factor Xa; it is the first of a new class of synthetic antithrombotic agents. Fondaparinux has a linear pharmacokinetic profile allowing once-daily subcutaneous administration. Absence of metabolism, complete bioavailability, and lack of nonspecific binding in plasma contribute to the predictability of its effect. Fondaparinux has been approved for use in the prophylaxis of venous thromboembolism following orthopedic surgery. In this setting, it was found to reduce VTE risk by more than 50% in comparison with the low molecular weight heparin enoxaparin, with an incidence of clinically important bleeding not significantly different from that of standard low molecular weight heparin regimens. Furthermore, 4 weeks of prophylaxis with fondaparinux after hip fracture surgery was shown to reduce the risk of venous thromboembolism by 96% compared with 1-week prophylaxis. Finally, the efficacy and safety of fondaparinux in the treatment of venous thromboembolism and acute coronary syndromes appears promising.

Acute Disease↗
PubMed2003

Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis.

OBJECTIVE: Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated creatinine clearance was examined. DESIGN AND METHODS: Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model. RESULTS: The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT. CONCLUSIONS: The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.

Administration, Cutaneous↗