A Comparison of Liver MRI and Contrast-Enhanced CT as Standard Workup Before Treatment for Rectal Cancer in Usual Care - A Retrospective Study.

BACKGROUND: The liver is the most common site for rectal cancer metastases. Recommended standard pre-treatment workups have involved Computed Tomography (CT) for abdominal metastases, however, few hospitals have replaced this with Magnetic Resonance Imaging (MRI). INTRODUCTION: The aim of this study was to compare MRI with CT as an index examination of the liver in the pre-treatment workup in usual care. The primary endpoint was the need for supplementary liver investigations. METHODS: Consecutive patients from two hospitals during 2013-2015 were identified in the Regional Swedish Colorectal Cancer Register and included in this retrospective study. Hospital records and radiology reports were reviewed. Inconclusive reports were re-evaluated by two radiologists. RESULTS: A total of 320 patients were included, and 293 were available for analysis. Some 175 and 118 patients had undergone CT and MRI respectively, as their index pre-treatment liver examination. Thirty-four (19.4%) in the CT group and 6 (5.1%) patients in the MRI group underwent supplementary liver investigation due to inconclusive index examination (RR 3.82, 95% CI: 1.66; 8.81, p=0.0017). Median time (q1; q3) from index examination to start of treatment was 50 (36; 68) days in the CT group and 34 (27; 45) days in the MRI group. CONCLUSION: This retrospective study of two modalities within usual care found that MRI of the liver as index radiological workup before treatment for rectal cancer was associated with fewer supplementary liver investigations and a shorter time to start of treatment. Based on these findings, a prospective trial should be undertaken before implementing MRI as a standard. Clinicaltrials.gov Registration Number: NCT03463616.

Signs of neuroaxonal injury in preeclampsia-A case control study.

BACKGROUND: Cerebral injury is a common cause of maternal mortality due to preeclampsia and is challenging to predict and diagnose. In addition, there are associations between previous preeclampsia and stroke, dementia and epilepsy later in life. The cerebral biomarkers S100B, neuron specific enolase, (NSE), tau protein and neurofilament light chain (NfL) have proven useful as predictors and diagnostic tools in other neurological disorders. This case-control study sought to determine whether cerebral biomarkers were increased in cerebrospinal fluid (CSF) as a marker of cerebral origin and potential cerebral injury in preeclampsia and if concentrations in CSF correlated to concentrations in plasma. METHODS: CSF and blood at delivery from 15 women with preeclampsia and 15 women with normal pregnancies were analysed for the cerebral biomarkers S100B, NSE, tau protein and NfL by Simoa and ELISA based methods. MRI brain was performed after delivery and for women with preeclampsia also at six months postpartum. RESULTS: Women with preeclampsia demonstrated increased CSF- and plasma concentrations of NfL and these concentrations correlated to each other. CSF concentrations of NSE and tau were decreased in preeclampsia and there were no differences in plasma concentrations of NSE and tau between groups. For S100B, serum concentrations in preeclampsia were increased but there was no difference in CSF concentrations of S100B between women with preeclampsia and normal pregnancy. CONCLUSION: NfL emerges as a promising circulating cerebral biomarker in preeclampsia and increased CSF concentrations point to a neuroaxonal injury in preeclampsia, even in the absence of clinically evident neurological complications.

Stoma-related complications: a report from the Stoma-Const randomized controlled trial.

AIM: The impact of construction techniques on the development of stoma complications is partly undiscovered. The aim of this paper was to report and analyse the impact of the three surgical techniques in a randomized controlled trial Stoma-Const on stoma-related complications as well as identifying risk factors and patient-reported stoma function as a planned secondary analysis. METHODS: This was a randomized, multicenter trial where all patients scheduled to receive an end colostomy were invited to participate. Patients were randomized to one of three techniques for stoma construction; cruciate fascial incision, circular incision or prophylactic mesh. Stoma complications were assessed by a surgeon and stoma care nurses within 1 year postoperatively. RESULTS: Two hundred and nine patients were randomized. Patient demographics were similar in all three groups. Data on stoma-related complications were available for analysis in 201 patients. A total of 127 patients (63%) developed some type of stoma complication within 1 year after surgery. The risk ratio (95% CI) for stoma complications was 0.93 (0.73; 1.2) between cruciate vs. circular incision groups and 1.02 (0.78; 1.34) between cruciate vs. mesh groups. There were no statistically significant differences between the groups regarding parastomal hernia rate and no risk factors could be identified. CONCLUSION: This randomized trial confirmed a high prevalence of stoma-related complications but could not identify an impact of surgical technique or identify modifiable risk factors for stoma-related complications.

Methods of Colostomy Construction: No Effect on Parastomal Hernia Rate: Results from Stoma-const-A Randomized Controlled Trial.

OBJECTIVE: The primary objective of this trial was to compare the parastomal hernia rates 1 year after the construction of an end colostomy by 3 surgical techniques: cruciate incision, circular incision in the fascia and using prophylactic mesh. Secondary objectives were evaluation of postoperative complications, readmissions/reoperations, and risk factors for parastomal hernia. SUMMARY OF BACKGROUND DATA: Colostomy construction techniques have been explored with the aim to improve function and reduce stoma complications, but parastomal herniation is frequent with an incidence of approximately 50%. METHODS: A randomized, multicenter trial was performed in 3 hospitals in Sweden and Denmark; all patients scheduled to receive an end colostomy were asked to participate. Parastomal hernia within 12 months was determined by computed tomography of the abdomen in prone position and by clinical assessment. Complications, readmissions, reoperations, and risk factors were also assessed. RESULTS: Two hundred nine patients were randomized to 1 of the 3 arms of the study. Patient demographics were similar in all 3 groups. Assessment of parastomal hernia was possible in 185 patients. The risk ratio (95% confidence interval) for parastomal hernia was 1.25 (0.83; 1.88), and 1.22 (0.81; 1.84) between cruciate versus circular and cruciate versus mesh groups, respectively. There were no statistically significant differences between the groups with regard to parastomal hernia rate. Age and body mass index were found to be associated with development of a parastomal hernia. CONCLUSION: We found no significant differences in the rates of parastomal hernia within 12 months of index surgery between the 3 surgical techniques of colostomy construction.

Acute Ultrasonography Investigation to Predict Reruptures and Outcomes in Patients With an Achilles Tendon Rupture.

BACKGROUND: The optimal treatment for acute Achilles tendon ruptures is still an ongoing debate. Acute ultrasonography (US) investigation to measure the diastasis between the tendon ends has previously been used to classify acute Achilles tendon ruptures; however, no study has used US to predict reruptures and functional outcomes. PURPOSE: To investigate whether acute US can be used to predict the risk of reruptures and outcomes after treatment of an acute Achilles tendon rupture. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Forty-five patients (37 men, 8 women) with a mean age of 39 ± 9.2 years (range, 23-59 years) from a cohort of 97 patients participating in a randomized controlled study comparing surgical and nonsurgical treatment were included. US was performed within 72 hours from the index injury. Diastasis between the tendon ends was documented. Reruptures were documented, and the patients' functional outcomes were measured 12 months after injury. RESULTS: Patients with a diastasis of >10 mm treated nonsurgically had a higher degree of rerupture. In the nonsurgically treated group, 3 of 4 patients with a diastasis of >10 mm suffered from rerupture (P < .001). Moreover, in the nonsurgical group, there was significantly worse outcomes in patients with a diastasis of >5 mm in terms of patient-reported outcomes using the Achilles tendon Total Rupture Score (ATRS) (P = .004) and heel-rise height at 12 months (P = .048) compared with the group with a lesser degree of tendon separation. CONCLUSION: US may be a useful tool to predict the risk of rerupture and greater degree of functional deficit. It may be an important measure in a clinical treatment algorithm for deciding whether a patient will benefit from surgical intervention after an acute Achilles tendon rupture.

Stage and size using magnetic resonance imaging and endosonography in neoadjuvantly-treated rectal cancer.

AIM: To assess the stage and size of rectal tumours using 1.5 Tesla (1.5T) magnetic resonance imaging (MRI) and three-dimensional (3D) endosonography (ERUS). METHODS: In this study, patients were recruited in a phase I/II trial of neoadjuvant chemotherapy for biopsy-proven rectal cancer planned for surgical resection with or without preoperative radiotherapy. The feasibility and accuracy of 1.5T MRI and 3D ERUS were compared with the histopathology of the fixed surgical specimen (pathology) to determine the stage and size of the rectal cancer before and after neoadjuvant chemotherapy. A Philips Intera 1.5T with a cardiac 5-channel synergy surface coil was used for the MRI, and a B-K Medical Falcon 2101 EXL 3D-Probe was used at 13 MHz for the ERUS. Our hypothesis was that the staging accuracy would be the same when using MRI, ERUS and a combination of MRI and ERUS. For the combination, MRI was chosen for the assessment of the lymph nodes, and ERUS was chosen for the assessment of perirectal tissue penetration. The stage was dichotomised into stage I and stage II or greater. The size was measured as the supero-inferior length and the maximal transaxial area of the tumour. RESULTS: The staging feasibility was 37 of 37 for the MRI and 29 of 36 for the ERUS, with stenosis as a limiting factor. Complete sets of investigations were available in 18 patients for size and 23 patients for stage. The stage accuracy by MRI, ERUS and the combination of MRI and ERUS was 0.65, 0.70 and 0.74, respectively, before chemotherapy and 0.65, 0.78 and 0.83, respectively, after chemotherapy. The improvement of the post-chemotherapy staging using the combination of MRI and ERUS compared with the staging using MRI alone was significant (P = 0.046). The post-chemotherapy understaging frequency by MRI, ERUS and the combination of MRI and ERUS was 0.18, 0.14 and 0.045, respectively, and these differences were non-significant. The measurements of the supero-inferior length by ERUS compared with MRI were within 1.96 standard deviations of the difference between the methods (18 mm) for tumours smaller than 50 mm. The agreement with pathology was within 1.96 standard deviations of the difference between imaging and pathology for all tumours with MRI (15 mm) and for tumours that did not exceed 50 mm with ERUS (22 mm). Tumours exceeding 50 mm in length could not be reliably measured by ERUS due to the limit in the length of each recording. CONCLUSION: MRI is preferable to use when assessing the size of large or stenotic rectal tumours. However, staging accuracy is improved by combining MRI with ERUS.

Magnetic resonance imaging and ultrasonography in diagnosis of pelvic vein thrombosis during pregnancy.

INTRODUCTION: Pelvic deep vein thrombosis (DVT) is difficult to diagnose during pregnancy. In a two-center trial, we evaluated the agreement between ultrasonography and magnetic resonance imaging (MRI) in diagnosing the extent of DVT into the pelvic veins during pregnancy. MATERIALS AND METHODS: Pregnant women with proximal DVT were examined both with ultrasound and MRI as part of a study designed for treatment of DVT during pregnancy. Ultrasound was performed using color flow by specialist in vascular ultrasound with Doppler and compression techniques. The MRI sequences consisted of a 2D Time of Flight angiography with arterial flow suppression and maximum intensity projection reconstructions; a 3D, T1-w-prepared gradient echo sequence with fat saturation for thrombus imaging; a steady-state free precession sequence; and a Turbo-Spin-Echo. No contrast agent was used. Proportion of agreement (kappa) for detection of DVT in individual veins was measured for different ipsilateral veins and inferior vena cava. RESULTS: All 27 patients were imaged with both techniques at an average gestational age of 29 weeks (range 23-39). Three cases (11.5%) of DVT in the pelvic veins were missed on ultrasound but detected by MRI. The upper limit of the DVT was always depicted at a higher (20 cases, 65.4%) or the same level (seven cases, 34.6%) on MRI than on ultrasound. Agreement expressed as kappa was 0.33 (95% CI 0.27-0.40) demonstrating only fair agreement. In one woman the thrombus had propagated into the inferior vena cava, shown only on MRI. CONCLUSION: Our study suggests that in pregnant women there is only fair agreement between ultrasound and MRI for determination of extent of DVT into pelvic veins, with MRI showing consistently more detailed depiction of extension. Our results indicate that MRI has an important role as a complementary technique in the diagnosis of DVT during pregnancy.

Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement.

Rivaroxaban (Xarelto) is an oral, direct factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim was to compare the population pharmacokinetics (PK) and pharmacodynamics (PD) of twice-daily (bid) and once-daily (od) rivaroxaban in patients undergoing total hip replacement (THR). Blood samples were collected from patients enrolled in two phase IIb, dose-ranging studies undertaken to investigate rivaroxaban for thromboprophylaxis after THR. A sparse sampling technique was used and the samples were pooled for PK and PD analysis, which used non-linear mixed effect modelling. Rivaroxaban PK (samples from 758 patients) were well described by an oral, one-compartment model; age and renal function influenced clearance, and body surface area affected volume of distribution. When comparing the same total daily doses, maximum plasma concentrations of rivaroxaban were higher and minimum plasma concentrations were lower with od dosing, compared with bid dosing; however, the 90% intervals overlapped. The area under the plasma concentration-time curve was 18-30% higher in the od than in the bid study. Prothrombin time in seconds (samples from 1181 patients) correlated with rivaroxaban plasma concentrations in a linear fashion in both studies. In conclusion, the PK and PD of rivaroxaban were predictable when given either bid or od. These findings, along with the suggested efficacy and safety of rivaroxaban in the phase II studies, relative to enoxaparin, supported the selection of a convenient, once-daily 10 mg rivaroxaban dose for investigation in phase III studies.

Population pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct factor Xa inhibitor--in patients undergoing major orthopaedic surgery.

BACKGROUND: There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and pharmacodynamics of rivaroxaban in patients participating in two phase II, double-blind, randomized, active-comparator-controlled studies of twice-daily rivaroxaban for the prevention of venous thromboembolism after total hip- or knee-replacement surgery. METHODS: Sparse blood samples were taken from all patients participating in the studies (n = 1009). In addition, a subset of patients in the hip study (n = 36) underwent full profiling. Rivaroxaban plasma concentrations, FXa activity and the prothrombin time were determined. Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of rivaroxaban. RESULTS: An oral one-compartment model described the population pharmacokinetics of rivaroxaban well. On the first postoperative day only, categorization of patients as slow or fast absorbers as a tool to address variability in absorption improved the fit of the model. Clearance of rivaroxaban was lower and more variable on the first postoperative day, and so time was factored into the model. Overall, the only major difference between the models for the hip study and the knee study was that clearance was 26% lower in the knee study, resulting in approximately 30% higher exposure. Residual variability in the models was moderate (37% and 34% in the hip and knee studies, respectively). Plasma concentrations of rivaroxaban increased dose dependently. Pharmacokinetic parameters that were estimated using the models agreed closely with results from full-profile patients in the hip study, demonstrating that rivaroxaban pharmacokinetics are predictable. The pharmacokinetics of rivaroxaban were affected by expected covariates: age affected clearance in the hip study only, haematocrit (on the first postoperative day only) and gender affected clearance in the knee study only, and renal function affected clearance in both studies. Bodyweight affected the volume of distribution in both studies. However, the effects of covariates on the pharmacokinetics of rivaroxaban were generally small, and predictions of 'extreme' case scenarios suggested that fixed dosing of rivaroxaban was likely to be possible. FXa activity and the prothrombin time were both affected by surgery, probably because of perioperative bleeding and intravenous administration of fluids; therefore, time was included in the pharmacodynamic models. In both studies, FXa activity correlated with rivaroxaban plasma concentrations following a maximum effect model, whereas prothrombin time prolongation correlated following a linear model with intercept. The slope of the prothrombin time prolongation correlation was 3.2 seconds/(100 microg/L) in the hip study and 4.2 seconds/(100 microg/L) in the knee study. Both pharmacodynamic models in both studies demonstrated low residual variability of approximately 10%. CONCLUSION: This population analysis in patients undergoing major orthopaedic surgery demonstrated that rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of rivaroxaban may be possible in patients undergoing major orthopaedic surgery.

Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies.

Rivaroxaban (BAY 59-7939) is an oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of venous thromboembolism (VTE). This analysis of pooled results from two phase II studies of rivaroxaban for VTE prevention after major orthopaedic surgery aimed to strengthen the conclusions of the individual studies. One study was conducted in patients undergoing total hip replacement (THR; N = 722), and one in patients undergoing total knee replacement (TKR; N = 621). In both studies, patients were randomized, doubleblind, to oral, twice-daily (bid) rivaroxaban beginning after surgery, or subcutaneous enoxaparin (40 mg once daily beginning before THR, and 30 mg bid beginning after TKR). Treatment continued until mandatory bilateral venography was performed 5-9 days after surgery. Total VTE (deep vein thrombosis, pulmonary embolism, and all-cause mortality) occurred in 16.1-24.4% of per-protocol patients receiving rivaroxaban 5-60 mg, and 27.8% receiving enoxaparin (n = 914). There was a flat dose response relationship between rivaroxaban and total VTE (p = 0.39). Major bleeding (safety population, n = 1,317) increased dose-dependently with rivaroxaban (p < 0.001), occurring in 0.9%, 1.3%, 2.1%, 3.9%, and 7.0% of patients receiving rivaroxaban total daily doses of 5, 10, 20, 40, and 60 mg, respectively, versus 1.7% of patients receiving enoxaparin. No routine coagulation monitoring was performed, and there were no significant differences between dose response relationships with rivaroxaban after THR and TKR. Overall, rivaroxaban total daily doses of 5-20 mg had the most favorable balance of efficacy and safety, relative to enoxaparin, for the prevention of VTE after major orthopaedic surgery.

Dose-escalation study of rivaroxaban (BAY 59-7939)--an oral, direct Factor Xa inhibitor--for the prevention of venous thromboembolism in patients undergoing total hip replacement.

INTRODUCTION: Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention of thromboembolic disorders. The aim of this study was to demonstrate proof-of-principle for rivaroxaban. MATERIALS AND METHODS: This was an open-label, dose-escalation study to assess the efficacy and safety of rivaroxaban, relative to enoxaparin, for the prevention of venous thromboembolism (VTE) after total hip replacement surgery. Patients were randomized in a 3:1 ratio to rivaroxaban (2.5, 5, 10, 20 and 30 mg twice daily [bid] or 30 mg once daily [od] starting 6-8 h after surgery) or enoxaparin (40 mg od starting the evening before surgery). Therapy continued until mandatory bilateral venography was performed 5-9 days after surgery. RESULTS: A total of 625 patients received therapy, of whom 466 patients were eligible for the per-protocol efficacy analysis. The primary efficacy endpoint - deep vein thrombosis (DVT), pulmonary embolism (PE) or all-cause mortality - occurred in 22.2%, 23.8%, 20.0%, 10.2%, 17.4%, 15.1% and 16.8% of patients receiving rivaroxaban 2.5, 5, 10, 20, 30 mg bid, 30 mg od and enoxaparin, respectively. The dose-response relationship with rivaroxaban for the primary efficacy endpoint was not statistically significant (p=0.0504), although major VTE (proximal DVT, PE and VTE-related death) decreased dose dependently with rivaroxaban (p=0.0108). Major, post-operative bleeding increased dose dependently with rivaroxaban (p=0.0008), occurring in 0-10.8% of patients, compared with 0% in patients receiving enoxaparin. CONCLUSIONS: This study demonstrated proof-of-principle for rivaroxaban for the prevention of VTE after total hip replacement surgery.

The value of ultrasonography in the preoperative diagnostic evaluation of patients with recurrent anterior shoulder dislocation: a prospective study of 44 patients.

The purpose of this study was to investigate the value of ultrasonography in the pre-operative assessment of patients with recurrent post-traumatic, anterior shoulder instability. Forty-four consecutive patients, 44 men and 12 women, with unilateral, post-traumatic, recurrent instability of the shoulder were included in the study. One experienced radiologist examined all patients, using a 5.0 or 7.5 MHz linear-array transducer, with the arm in different positions, one of which was used to provoke apprehension of the shoulder. Special attention was paid to the evaluation of the joint capsule, the anterior labrum, especially in terms of the presence of a Bankart lesion. All patients were subsequently treated surgically. After a diagnostic arthroscopy either an open or arthroscopic stabilisation of the shoulder was performed. Ultrasonography disclosed an unstable anterior labrum (equivalent to a Bankart lesion) in 36 shoulders; the lesion was verified in all 36 shoulders during arthroscopy. In three shoulders, arthroscopy disclosed an injured labrum, which had healed in an anterio-medial position on the scapular neck. In these three shoulders, ultrasonography failed to show any lesion. In five shoulders no Bankart lesion was found at arthroscopy. All these patients had increased shoulder laxity, and ultrasonography did not show any Bankart lesion. Furthermore a judgement of the joint capsule was not possible either. A bony Bankart lesion was found in four shoulders, using both arthroscopy and ultrasonography. The sensitivity of the ultrasonographic evaluation was 92%, and the specificity 100%. The positive predictive value was 100%, and the negative predictive value 63%. Ultrasonography showed a high correlation with the arthroscopic findings, with a high sensitivity and specificity. Therefore, we conclude that US can give important pre-operative information in patients with recurrent, unilateral, post-traumatic, anterior shoulder instability.

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.

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.

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.

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.

The ultrasonographic appearance of the ruptured Achilles tendon during healing: a longitudinal evaluation of surgical and nonsurgical treatment, with comparisons to MRI appearance.

This prospective, randomized trial compared healing characteristics of the Achilles tendon after surgical and nonsurgical treatment for complete rupture of the Achilles tendon. Fifty-eight patients were examined by ultrasonography after 6, 12, and 24 months and by magnetic resonance imaging after 12 months. A standardized protocol was used, and the outcome was correlated with clinical findings. Common findings 1 year after the injury were tendon thickening and moderate heterogeneity of the tendon. Peritendinous reactions, edema, and defects were present only in a minority of patients. There were no significant differences between the treatment groups in any of the evaluated parameters apart from the gliding function of the tendon, which was significantly less in the surgically treated group than in the nonsurgically treated group. No correlations were found between the radiological findings and the clinical parameters, such as muscle strength, endurance, and range of motion. We conclude that the roles of ultrasonography and magnetic resonance imaging during the healing process after Achilles tendon rupture are limited, due to a weak correlation with clinical findings.