Complete mid-portion rupture of the rat achilles tendon leads to remote and time-mismatched changes in uninjured regions.

PURPOSE: To examine healing adaptations over 17 weeks post Achilles tendon (AT) rupture in the injured region (IR) compared to an uninjured region (UIR) of the AT. METHODS: Twenty-four rats were subjected to a complete right-sided AT rupture, while the left side served as a control. ATs were harvested at 1, 2, 8 and 17 weeks post-rupture and stained with antibodies specific to Collagen type I (Col I) and II (Col II) as well as Alcian Blue and Picrosirius Red staining techniques. Histopathological changes, proteoglycan content, collagen alignment and immunoexpression were assessed. RESULTS: Both regions examined, IR and UIR, exhibited over weeks 1-17 similar healing adaptations of increasing collagen alignment, decreasing Col I immunoexpression, as well as increasing proteoglycan content and Col II occurrence. Increased proteoglycan content was found already at week 2 in the UIR, while it first increased at week 8 in the IR. The area positive to Col II was increased compared to controls at week 8 in the UIR, whereas it first raised at week 17 in the IR. Collagen disorganization successively declined to reach control levels at week 17 in the UIR, but was still higher in the IR. CONCLUSION: This study demonstrated that uninjured areas of the AT remote from the rupture site also undergo pronounced remodeling, although with time-span differences relative to injured AT portions. These changes including the pathologic heterotopic mineralization and chondrogenic differentiation observed in both regions may have implications in the choice of rehabilitation regimes in order to prevent secondary rupture.

Postoperative Thromboprophylaxis With New Oral Anticoagulants is Superior to LMWH in Hip Arthroplasty Surgery: Findings from the Swedish Registry.

BACKGROUND: Although the use of thromboprophylaxis is well established, there is no consensus on the preferred thromboprophylaxis regimen after THA; large, population-based studies offer an opportunity to examine this problem in a robust way that can complement results from randomized trials. QUESTIONS/PURPOSES: Using data from a large national registry, we asked: (1) Is there any difference between low-molecular weight heparin (LMWH) and new oral anticoagulants in preventing symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), after THA? (2) Are there any differences in safety parameters, such as bleeding, reoperations and mortality, between LMWH and new oral anticoagulants? METHODS: Between 2008 and 2012, 78,066 THAs were performed in Sweden. This study evaluated 32,663 (42%) of them, selected through the merger of several national registries. These patients underwent unilateral THA due to primary osteoarthritis. They had not experienced any venous thromboembolic events 5 years before the index operation and were not prescribed potent antithrombotic agents, of any type, in the 6 months before the index operation. Additionally, their postoperative thromboprophylaxis was confirmed in a national registry by purchase of prescribed medications. We divided the cohort into two groups: those patients who received new oral anticoagulants (5752, 18%) and those who received LMWH (26,881, 82%) as postoperative thromboprophylaxis. Our primary endpoints were the frequencies of symptomatic DVT and symptomatic PE within 3 months of surgery. Our secondary comparison was a between-group comparison of bleeding (by way of diagnostic coding), reoperation, and mortality within 3 months of surgery. Odds ratios (OR) are presented with 95% confidence intervals (CIs) as pooled results for the two groups after adjustment for duration of thromboprophylaxis (short or extended for at least 28 days), year of the index operation, Elixhauser comorbidity index, sex, age and previous treatment with platelet aggregation inhibitors. RESULTS: The risk of symptomatic DVT was lower in the group that received new oral anticoagulants than the group that received LMWH (0.3% versus 0.6%, OR, 0.47; 95% CI, 0.27-0.76; p = 0.026). The risk of symptomatic PE was lower in the group that received new oral anticoagulants than the group that received LMWH (0.1% versus 0.4%, OR, 0.36; 95% CI, 0.16-0.69; p = 0.005). There was no difference in the risk of bleeding (by way of diagnostic coding) (OR, 1.03; 95% CI, 0.82-1.28; p = 0.688), reoperation (OR, 1.02; 95% CI, 0.71-1.44; p = 0.860) or mortality (OR, 0.83; 95% CI, 0.31-1.88; p = 0.883) between groups. CONCLUSIONS: New oral anticoagulants were associated with a lower risk of symptomatic DVT and symptomatic PE in this large, registry study, and we observed no differences in the risk of bleeding, reoperation, or death between the groups. Although we were able to control for a number of potential confounding variables, we cannot ascertain the indications that drove the prescription decisions in this setting, and there were important between-group differences in terms of duration of thromboprophylaxis (new oral anticoagulants generally were used for a longer period of time after surgery). Future studies, preferably large randomized trials with pragmatic inclusion criteria, to analyze symptomatic DVT, symptomatic PE and death are needed to confirm or refute our findings. LEVEL OF EVIDENCE: Level III, therapeutic study.

Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.

BACKGROUND: Two phase 3 trials compared 28-35 days of treatment with oral dabigatran 220 mg or 150 mg (RE-NOVATE) or 220 mg (RE-NOVATE II) once daily with subcutaneous enoxaparin 40 mg once daily for prevention of venous thromboembolism (VTE) after elective total hip arthroplasty. METHODS: This prespecified pooled analysis compared the outcomes for the dabigatran 220 mg dose with enoxaparin, which included 4,374 patients. Total VTE (venographic and symptomatic) plus all-cause mortality (primary efficacy), major VTE (proximal deep vein thrombosis [DVT] or non-fatal pulmonary embolism) plus VTE-related death, and bleeding events were evaluated. Efficacy analysis was based on the modified intention-to-treat (ITT) population and safety analysis was based on all treated patients. The common risk difference (RD) for dabigatran versus enoxaparin was estimated using a fixed effects model. RESULTS: Total VTE and all-cause mortality occurred in 6.8 % (114/1,672) and 7.7 % (129/1,682) (RD:-0.8 %, 95 % confidence interval [CI] -2.6 to 0.9) for dabigatran and enoxaparin, respectively. Major VTE plus VTE-related mortality occurred in 2.7 % (46/1,714) and 4.0 % (69/1,711) (RD: -1.4 %, 95 % CI -2.6 to -0.2) of patients receiving dabigatran 220 mg and enoxaparin, respectively. Major bleeding occurred in 1.7 % (37/2,156) and 1.3 % (27/2,157) (RD: 0.5 %, 95 % CI -0.2 to 1.2), for dabigatran and enoxaparin respectively. CONCLUSIONS: Extended prophylaxis with oral dabigatran 220 mg once daily was as effective as enoxaparin 40 mg once daily in reducing the risk of total VTE and all-cause mortality after total hip arthroplasty, with a similar bleeding profile. The clinically relevant outcome of major VTE and VTE-related death was significantly reduced with dabigatran versus enoxaparin. TRIAL REGISTRATION: NCT00657150 and NCT00168818.

Nucleostemin- and Oct 3/4-positive stem/progenitor cells exhibit disparate anatomical and temporal expression during rat Achilles tendon healing.

BACKGROUND: The recent discovery of residing tendon stem/progenitor cells has triggered a growing interest in stem cells as a useful tool in tendon repair. Our knowledge of their involvement in naturally healing tendons is, however, sparse. The aim of this study was to identify and determine stem/progenitor cells in relation to different healing phases and regions in a rat model of Achilles tendon rupture. METHODS: Surgery was performed to create a mid-tendon rupture on the right Achilles tendon of 24 rats, whereas the left tendon was used as a control. Tendons were harvested at one, two, eight and 17 weeks post-rupture and stained with antibodies specific to stem/progenitor cells (Octamer-binding transcription factor 3/4 (Oct 3/4) and nucleostemin), migrating cells (Dynamin 2 (Dyn 2)) and leukocytes (CD45). A histological examination was performed on sections stained with Alcian blue. RESULTS: At one and two weeks post-rupture, a large number of stem/progenitor cells were discovered throughout the tendon. Most of these cells were nucleostemin positive, whereas only a few Oct 3/4-positive cells were found, mainly situated inside the injury region (I region). At eight and 17 weeks, the increment in stem/progenitor cells had diminished to equal that in the control tendons. At all time points, Oct 3/4-positive cells were also found in the connective tissue surrounding the tendon and at the muscle-tendon junction in both ruptured and control tendons and were often seen at the same location as the migration marker, Dyn 2. CONCLUSIONS: The whole length of the Achilles tendon is infiltrated by stem/progenitor cells at early time points after a mid-tendon rupture. However, different stem/progenitor cell populations exhibit varying anatomical and temporal expressions during Achilles tendon healing, suggesting distinct reparative implications. Oct 3/4 may thus act as a more local, migrating stem/progenitor cell involved in injury-site-specific regenerative effects, as compared to the more general proliferative role of nucleostemin-positive stem/progenitor cells.

Ilizarov external fixation or locked intramedullary nailing in diaphyseal tibial fractures: a randomized, prospective study of 58 consecutive patients.

PURPOSE: The aim of this study was to compare the Ilizarov circular fixator (IL) and locked intramedullary nailing (IM). PATIENTS AND METHODS: Patients with isolated tibia shaft fractures were randomly allocated to either the IL (n = 31) or IM (n = 27) method. Conventional radiographs, postoperative pain assessment, self-appraisal scores and complications were evaluated. At the clinical 1-year follow-up, the patients were also evaluated by an independent observer. RESULTS: The minority of patients had open fractures, two and nine patients in the IM and IL groups, respectively. Eight patients in the IM group and four in the IL group sustained major complications (p = 0.107). In the IM group, two patients developed compartment syndrome, one deep infection, one hardware failure, one delayed union, one pseudarthrosis and two had a malunion. In the IL group, two patients developed pseudarthrosis and two had a malunion. Superficial pin-site infections were observed in 16 patients in the IL group. The fractures had healed radiographically at 12 weeks in both groups. At the 1-year follow-up, there were differences in pain (VAS) and satisfaction (VAS) scores in favor of IL treatment (VAS, p = 0.03 and p = 0.02, respectively). There were no differences between the groups with regard to range of motion (ROM) in the knee and ankle joints. The registration of local tenderness and pain revealed that there were 19 patients with anterior knee pain in the IM group and one in the IL group at the 1-year follow-up (p < 0.001). CONCLUSION: The IL is a safe and reliable alternative to IM for the treatment of tibial shaft fractures, with a low complication rate and good clinical outcome. Both treatments were well tolerated, but at the 1-year follow-up the patients in the IM group had more pain and were less satisfied. Finally, there was a high frequency of anterior knee pain in the IM group.

Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism.

The last decade has seen the evaluation of several new oral anticoagulants that directly target thrombin or activated factor X (FXa). All demonstrate a rapid onset of action, a low potential for food and drug interactions, and a predictable anticoagulant effect that obviates the need for routine coagulation monitoring. Those agents at the most advanced stages of clinical development are a direct thrombin inhibitor, dabigatran, and direct FXa inhibitors, rivaroxaban and apixaban. Dabigatran and rivaroxaban are approved in more than 70 countries for prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty, and apixaban is being considered for approval by regulatory agencies for this indication. Dabigatran was shown in a large phase III trial to be more effective and safer than warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and has recently been approved for this indication. Edoxaban, an oral FXa inhibitor, is also being evaluated in phase III clinical trials. This review summarizes the pharmacology, clinical trial results, and future role of the new oral anticoagulants in clinical practice.

Treatment of distal tibial fractures with the Ilizarov external fixator--a prospective observational study in 39 consecutive patients.

BACKGROUND: The management of displaced distal tibial fractures is still controversial. The different internal fixation techniques are often burdened by relatively high complication rates. Minimally invasive techniques with ring fixators have been introduced as an alternative allowing immediate reduction and stabilization, avoiding a staged protocol. The aim of this prospective study was to analyze the clinical and radiographic outcome the Ilizarov technique in patients with distal metaphyseal tibial fractures, with or without intra-articular involvement. METHODS: Thirty-nine consecutive patients with isolated fractures treated with the Ilizarov technique were followed prospectively for one year. Depending on the type of fracture, 4 or 5 rings were used, in some cases with additional foot extension. Unrestricted weight-bearing was allowed in all cases. Pre- and post-operatively conventional radiographs, post-operative pain assessment and complications were evaluated. The function was evaluated clinically and with self-appraisal protocols: EQ-5D, NHP and FAOS. RESULTS: No patient developed compartment syndrome or deep venous thrombosis. Pin infections were frequent, but they were mostly superficial and were treated with antibiotics and/or the removal of isolated pins. Two patients required debridement. One of them had a deep infection and developed a residual deformity which was corrected and healed after re-operation. Another patient had a severe residual deformity. The fixator was removed after a median period of 16 weeks (range 11-30). The radiological results were poor in 5 patients but the overall self-appraisal showed satisfactory results in 36 patients. CONCLUSIONS: The Ilizarov method allowed early definitive treatment with a low complication rate and a good clinical outcome.

The Ilizarov external fixator--a useful alternative for the treatment of proximal tibial fractures. A prospective observational study of 30 consecutive patients.

BACKGROUND: In dislocated proximal tibial fractures, the most frequently used treatment is ORIF with screws and plates. Minimally-invasive techniques using external fixation are an alternative. The aim of this study was to analyse the clinical and radiological results using the Ilizarov technique in both uni- and bicondylar tibial fractures. METHODS: Thirty consecutive patients with isolated fractures of the proximal tibia were treated with the Ilizarov technique, 11 Schatzker I-IV with 2-3 rings and 19 Schatzker V-VI with 3-4 tibial rings and a femoral, hinged, two-ring extension. Unrestricted weight-bearing was allowed. Pre and post-operatively, conventional radiographs, computerized tomography scans, post-operative pain assessments and complications were evaluated. The knee function was evaluated with the EQ-5D, NHP and KOOS scores, as well as self-appraisal. RESULTS: All the fractures healed. Twenty-five patients achieved a range of motion better than 10-100º. The type I-IV fractures had a shorter operating time and hospital stay, as well as better knee flexion, and the self-appraisal indicated that they tolerated the treatment better. Pin infections occurred in 4% of the pin sites, but only two patients required debridement. Two patients developed compartment syndrome and underwent fasciotomy. No patient complained of functional knee instability. Two patients underwent a total knee arthroplasty because of residual pain. The overall result was judged as satisfactory in twenty-seven patients. CONCLUSIONS: The Ilizarov method produces a good clinical outcome and is a valuable treatment alternative in proximal tibial fractures of all types.

Detection of slow-cycling and stem/progenitor cells in different regions of rat Achilles tendon: response to treadmill exercise.

PURPOSE: Tendons generally exhibit poor healing capacity, probably due to slow cell regeneration potential and low vascularization. The potential to regenerate may partly be due to activation of stem/progenitor cells localized in the tendon or its vicinity. In the present study, we attempted to determine where in the rat Achilles tendon stem/progenitor cells reside and to investigate the effect of exercise on cell proliferation in the in vivo situation. METHOD: We used bromodeoxyuridine (BrdU) labelling to investigate proliferation and label-retaining cells (i.e. slow-cycling cells) in non-exercised and exercised rats, in combination with immunostaining of the stem cell marker nucleostemin. Rat Achilles tendons were harvested 14, 28, 56 and 105 days after BrdU administration. RESULTS: We found the proportion of stem/progenitor cells to be twice as high in the distal tendon (DT) compared with the mid/proximal tendon (MPT) and that paratenon/endotenon regions appear to host a pool of existing stem/progenitor cells. Exercise increased the BrdU-stained cell population after 14 days only (DT region p = 0.032, MPT p = 0.065), indicating effect mainly on more differentiated cells, since the nucleostemin-positive cells (i.e. stem/progenitor cells) remained unaffected in the intact Achilles tendon. CONCLUSION: Stem/progenitor cells exist in several areas of the rat Achilles tendon which implies a possible stem cell regeneration pool of different origins. The distal region has twice the amount of stem/progenitor cells compared with the mid/proximal region, indicating a potentially higher stem cell activity in this tissue. Daily moderate exercise (treadmill running) mainly improves in vivo cell proliferation in rapidly proliferating cells, whereas the stem/progenitor pool remains constant.

Type of anaesthesia and the safety and efficacy of thromboprophylaxis with enoxaparin or dabigatran etexilate in major orthopaedic surgery: pooled analysis of three randomized controlled trials.

BACKGROUND: There has been a shift towards greater use of neuraxial over general anaesthesia for patients undergoing total hip or knee arthroplasty. Furthermore, suggestions that peripheral nerve block may reduce adverse effects have recently been put forward. Although older studies showed a reduction in venous thromboembolism (VTE) with neuraxial compared with general anaesthesia, this difference has not been confirmed in studies using effective current thromboprophylaxis. We used a large data set to investigate the pattern of anaesthesia usage, and whether anaesthesia type affects efficacy and bleeding outcomes of thromboprophylaxis overall, within each treatment group, or for the novel oral anticoagulant dabigatran etexilate versus enoxaparin. METHODS: Three previously reported trials compared 220 mg and 150 mg dabigatran etexilate once daily with enoxaparin after knee or hip arthroplasty. A pooled analysis was performed in patients receiving general or neuraxial anaesthesia, or the combination of either with peripheral nerve block (n = 8062). Outcome measures were major VTE plus VTE-related mortality, major bleeding and major plus clinically relevant bleeding events. RESULTS: General, neuraxial and combination anaesthesia were used in 29%, 52% and 19% of patients, respectively. Differences in efficacy and safety between anaesthesia subgroups were small and not significant, except for a slightly higher rate of major VTE and VTE-related mortality with general versus neuraxial anaesthesia (odds ratio: 1.40; 95% confidence interval: 1.03-1.90; p = 0.035) in the overall population. There were no significant effects of anaesthesia type on efficacy or safety of dabigatran etexilate versus enoxaparin. CONCLUSIONS: Anaesthesia type did not greatly affect efficacy and safety outcomes in the pooled population of all three treatment groups. The efficacy and safety of dabigatran etexilate was comparable with enoxaparin, regardless of type of anaesthesia. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00168805, NCT00168818, NCT00152971.

Thromboprophylaxis in patients older than 75 years or with moderate renal impairment undergoing knee or hip replacement surgery [corrected].

PURPOSE: Prospective, double-blind studies in orthopaedic patients have been conducted using the direct thrombin inhibitor dabigatran etexilate (hereafter referred to as dabigatran), with two doses investigated and approved for adults (220 mg and 150 mg once daily) to prevent venous thromboembolism (VTE). The European Medicines Agency decided that in major joint orthopaedic surgery, the lower dose should be used in elderly patients (aged over 75 years) and those with reduced renal function (creatinine clearance between 30 and 50 ml/min). Our objective was to understand the efficacy and bleeding data for the lower dose in this subpopulation. METHODS: We extracted and analysed data from the elderly or from moderately renally impaired patients (n 632 of = 5,539) from the orthopaedic clinical development programme of dabigatran. RESULTS: Dabigatran 150 mg once daily was as effective as the standard European enoxaparin regimen, with numerically fewer major bleeding events. Rates of major VTE were 4.3% vs 6.4% of patients, respectively. Major bleeding events occurred in four (1.3%) vs 11 (3.3%), which shows a trend towards lower bleeding with dabigatran 150 mg [odds ratio (OR) 0.40; 95% confidence interval (CI) 0.13-1.25; p = 0.110]. Mean volume of blood loss was 395 vs 417 ml, and transfused units were 2.4 vs 2.5, respectively. Other safety parameters, including the incidence of wound infections and complications, were similar for 150 mg once daily dabigatran and enoxaparin. CONCLUSION: For patients at higher risk of bleeding, dabigatran 150 mg once daily is as effective as enoxaparin following major orthopaedic surgery and is associated with a favourable bleeding rate.

Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.

BACKGROUND: This phase 3 trial compared the efficacy and safety of rivaroxaban, an oral direct inhibitor of factor Xa, with those of enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. METHODS: In this randomized, double-blind study, we assigned 4541 patients to receive either 10 mg of oral rivaroxaban once daily, beginning after surgery, or 40 mg of enoxaparin subcutaneously once daily, beginning the evening before surgery, plus a placebo tablet or injection. The primary efficacy outcome was the composite of deep-vein thrombosis (either symptomatic or detected by bilateral venography if the patient was asymptomatic), nonfatal pulmonary embolism, or death from any cause at 36 days (range, 30 to 42). The main secondary efficacy outcome was major venous thromboembolism (proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death from venous thromboembolism). The primary safety outcome was major bleeding. RESULTS: A total of 3153 patients were included in the superiority analysis (after 1388 exclusions), and 4433 were included in the safety analysis (after 108 exclusions). The primary efficacy outcome occurred in 18 of 1595 patients (1.1%) in the rivaroxaban group and in 58 of 1558 patients (3.7%) in the enoxaparin group (absolute risk reduction, 2.6%; 95% confidence interval [CI], 1.5 to 3.7; P<0.001). Major venous thromboembolism occurred in 4 of 1686 patients (0.2%) in the rivaroxaban group and in 33 of 1678 patients (2.0%) in the enoxaparin group (absolute risk reduction, 1.7%; 95% CI, 1.0 to 2.5; P<0.001). Major bleeding occurred in 6 of 2209 patients (0.3%) in the rivaroxaban group and in 2 of 2224 patients (0.1%) in the enoxaparin group (P=0.18). CONCLUSIONS: A once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. The two drugs had similar safety profiles. (ClinicalTrials.gov number, NCT00329628.)

Will early reconstruction prevent abnormal kinematics after ACL injury? Two-year follow-up using dynamic radiostereometry in 14 patients operated with hamstring autografts.

PURPOSE: Previous studies have reported that Anterior Cruciate Ligament (ACL) reconstruction does not restore normal tibial rotation in patients with chronic instability and repeated episodes of giving way. We hypothesised that early ACL reconstruction, using quadruple hamstring autografts, before the pivoting episodes had occurred, would protect the knee joint from developing abnormal kinematics with increased external tibial rotation during flexion. METHODS: Fourteen consecutive patients (8 men, 6 women) with a median age of 24 years (18-43), with a complete, isolated unilateral ACL rupture and an intact contralateral knee, were studied. The operations were performed by one experienced surgeon, using quadruple hamstring autografts. We used dynamic radiostereometry (RSA) with tantalum markers inserted in both the injured and the intact contralateral knee to study the pattern of knee motion during active and weight-bearing knee extension. The patients were evaluated pre-operatively and followed for 2 years after the ACL reconstruction. The anterior-posterior laxity was measured using the KT-1000. RESULTS: Before surgical repair of the ACL, the internal/external tibial rotation or abduction/adduction did not differ significantly between the injured and intact knees (P = 0.27-0.91). Separate studies of the anterior-posterior translation of the medial and lateral femoral flexion facet centres (MFC and LFC) relative to a fixed tibia did not reveal any significant differences between the injured and intact knees (P = 0.21-0.59). Pre-operatively, the KT-1000 laxity measurements showed a side-to-side difference of 2.5 (1.0-5.5) mm. At 2 years, the laxity side-to-side difference was 0.5 (0-3.0) mm (P = 0.001), and there were still no significant differences between the injured and intact knees in terms of internal/external tibial rotation and abduction/adduction (P = 0.13-0.60). Nor did the anterior-posterior translation of the flexion facet centres differs (P = 0.27-0.97). CONCLUSION: During the first 6-8 weeks after the ACL injury, before pivoting episodes had occurred, the kinematics of the injured knee were normal and did not differ from those of the intact contralateral knee. Reconstruction of the ACL within 10 weeks after injury using quadruple hamstring autografts resulted in unchanged knee kinematics for 2 years and no difference compared with the intact contralateral knee. Surgical repair during the early phase after the injury appears to protect the knee from developing abnormal knee motion after an ACL rupture. LEVEL OF EVIDENCE: III.

Major functional deficits persist 2 years after acute Achilles tendon rupture.

PURPOSE: The purpose of this prospective randomized controlled study was to evaluate the long-term results after an acute Achilles tendon rupture in patients treated surgically or non-surgically. The focus was to evaluate whether any improvements occurred between the one and 2-year evaluation. METHOD: Eighty-one patients (67 men, 14 women) with a mean (SD) age of 42 (9.1) were included in this study. Forty-two patients were treated surgically, and 39 treated non-surgically otherwise the treatment was identical for the two groups. All patients were evaluated using the Achilles tendon Total Rupture Score (ATRS), the Physical Activity Scale (PAS) and validated functional tests one and 2 years after injury. RESULTS: There were significant functional deficits on the injured side compared with the contralateral side 2 years after Achilles tendon rupture, regardless of treatment. Only minor improvements, even though statistically significant, occurred between the 1- and 2-year evaluations. The physical activity level remained significantly reduced as compared with prior to injury, but the ATRS mean was relatively high in both groups (89 and 90). CONCLUSION: This long-term follow-up indicates that the majority of patients with an Achilles tendon rupture have not fully recovered (in regards to symptoms, physical activity level and function) 2 years after injury regardless of surgical or non-surgical treatment. Furthermore, only minor improvements occur between the 1- and 2-year evaluations. This indicates that to enhance the final outcome the focus should be on improvements in treatment within the first year. The patients appear to have adjusted to their impairments since the patient-reported outcome is relatively high in spite of functional deficits and lower activity level compared with pre-injury. LEVEL OF EVIDENCE: Prospective randomized study, Level I.

A new measurement of heel-rise endurance with the ability to detect functional deficits in patients with Achilles tendon rupture.

Studies evaluating treatment effects on muscle function after an Achilles tendon rupture often use various tests for evaluating calf muscle strength. However, these tests rarely demonstrate the difference between treatment groups; therefore, new tests with a higher ability to detect possible differences in outcome are needed. The purpose of this study was to evaluate the validity and ability to detect differences in outcome of a heel-rise work test that would measure both the height of each heel-rise and the number of repetitions. Seventy-eight patients (65 men and 13 women) at a mean (standard deviation) age of 42 (9) years with Achilles tendon ruptures were included. The patients were evaluated with the new heel-rise test at 6 and 12 months after injury. The limb symmetry index (LSI = involved/uninvolved x 100) was calculated to determine the size of the difference in function between the injured and the uninjured side. The heel-rise height differed significantly between the injured and uninjured sides at the 6- and 12-month evaluations (P < 0.001). At the 6-month evaluation, the patients had achieved a mean LSI of 84% on the number of repetitions parameter but only a mean LSI of 61% on the work parameter. At the 12-month evaluation the mean, LSI of the heel-rise repetition parameter was 95%, indicating that the patients had fully recovered function, but on the work parameter the mean LSI was only 76%. The heel-rise work test in the present study has good validity and greater ability to detect differences between the injured and the uninjured sides than a test that measures only the number of heel-rise repetitions in patients with Achilles tendon rupture.

Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.

BACKGROUND: The risk of venous thromboembolism is high after total hip arthroplasty and could persist after hospital discharge. Our aim was to compare the use of rivaroxaban for extended thromboprophylaxis with short-term thromboprophylaxis with enoxaparin. METHODS: 2509 patients scheduled to undergo elective total hip arthroplasty were randomly assigned, stratified according to centre, with a computer-generated randomisation code, to receive oral rivaroxaban 10 mg once daily for 31-39 days (with placebo injection for 10-14 days; n=1252), or enoxaparin 40 mg once daily subcutaneously for 10-14 days (with placebo tablet for 31-39 days; n=1257). The primary efficacy outcome was the composite of deep-vein thrombosis (symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism, and all-cause mortality up to day 30-42. Analyses were done in the modified intention-to-treat population, which consisted of all patients who had received at least one dose of study medication, had undergone planned surgery, and had adequate assessment of thromboembolism. This study is registered at ClinicalTrials.gov, number NCT00332020. FINDINGS: The modified intention-to-treat population for the analysis of the primary efficacy outcome consisted of 864 patients in the rivaroxaban group and 869 in the enoxaparin group. The primary outcome occurred in 17 (2.0%) patients in the rivaroxaban group, compared with 81 (9.3%) in the enoxaparin group (absolute risk reduction 7.3%, 95% CI 5.2-9.4; p<0.0001). The incidence of any on-treatment bleeding was much the same in both groups (81 [6.6%] events in 1228 patients in the rivaroxaban safety population vs 68 [5.5%] of 1229 patients in the enoxaparin safety population; p=0.25). INTERPRETATION: Extended thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin plus placebo for the prevention of venous thromboembolism, including symptomatic events, in patients undergoing total hip arthroplasty.

Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis.

Dabigatran etexilate has been investigated in three phase III trials for the prevention of venous thromboembolism (VTE). Health technology assessment agencies increasingly require meta-analyses of all relevant evidence for an intervention, if appropriate. The objective of this study was to perform a meta-analysis of efficacy and safety data for the recommended dose of dabigatran etexilate, 220 mg once daily (od), for VTE prophylaxis after total knee arthroplasty (TKA) and total hip arthroplasty (THA), and discuss the appropriateness of combining the data. Risk ratios (RR) for VTE and bleed end-points were estimated using fixed and random effects meta-analysis. Analyses were performed combining RE-MODEL and RE-NOVATE, which compared dabigatran etexilate with enoxaparin 40 mg od after TKA and THA, respectively, and also including RE-MOBILIZE, which compared dabigatran etexilate with enoxaparin 30 mg twice daily after TKA. Tests for statistical heterogeneity were performed using the Chi-squared statistic. No significant differences were detected between dabigatran etexilate and enoxaparin in any of the end-points analysed, either in the two trial analysis (all p > 0.15), or when all three trials were combined ( all p > 0.30). RRs (random effects) for the composite end-point total VTE and all-cause mortality were 0.95 [95% confidence intervals 0.82 - 1.10] and 1.05 [0.87 - 1.26] in the two and three trial analyses, respectively. Meta-analysis of RE-MODEL and RE-NOVATE supported the conclusions of the individual trials that dabigatran etexilate is non-inferior to enoxaparin 40 mg od, with a similar safety profile. Meta-analysis of all three trials found no significant differences between treatments in any of the end-points analysed. Heterogeneity between the trials cannot be ruled out.

Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development.

For the past five decades, there has been little progress in the development of oral anticoagulants, with the choices being limited to the vitamin K antagonists (VKAs). The situation is changing with the development of orally active small molecules that directly target thrombin or activated factor X (FXa). The two agents in the most advanced stages of development are dabigatran etexilate and rivaroxaban, which inhibit thrombin and FXa, respectively. Both are approved in the EU and Canada for venous thromboprophylaxis in patients undergoing elective hip- or knee-replacement surgery. Other agents in the early stages of development include several FXa inhibitors (apixaban, DU 176b, LY 517717, YM 150, betrixaban, eribaxaban [PD 0348292] and TAK 442) and one thrombin inhibitor (AZD 0837). With a predictable anticoagulant response and low potential for drug-drug interactions, these new agents can be given in fixed doses without coagulation monitoring. This renders them more convenient than VKAs. While the anticoagulant effect of the new thrombin and FXa inhibitors is similar, differences in the pharmacokinetic and pharmacodynamic parameters may influence their use in clinical practice. Here, we compare the pharmacokinetic and pharmacodynamic features of these new oral agents.

High incidence of deep venous thrombosis after Achilles tendon rupture: a prospective study.

Deep venous thrombosis (DVT) is common after lower limb injury, but the effect of prophylactic treatment has not been documented in large randomised trials or meta-analyses. As a result, evidence-based recommendations have not been established. The purpose of this study was to evaluate the incidence of venous thromboembolism in patients with Achilles tendon rupture. A total of 100 consecutive patients with an acute Achilles tendon rupture were included in a prospective study and randomised to either surgical or non-surgical treatment. At 8 weeks after the initiation of treatment, 95/100 patients were screened for DVT using colour duplex sonography (CDS) with blinded interpretation by two experienced examiners and adjudication in cases of disagreement by a third person. A total of 95 patients (79 male and 16 female) with a median (range) age of 41 (24-63) years were screened for CDS at 8 weeks. Of the 95 patients, 32 had a CDS-verified thrombosis, 5 proximal and 27 distal, whereas 3 had non-fatal pulmonary embolism. Surgical treatment was performed in 49 patients, non-surgical in 46. There were no significant differences in DVT frequency between the two treatment groups. The incidence of asymptomatic and symptomatic deep venous thrombosis is high after Achilles tendon rupture and there is a need to define the possible benefit of thromboprophylaxis.

Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.

BACKGROUND: After hip replacement surgery, prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism. Our aim was to assess the oral, direct thrombin inhibitor dabigatran etexilate for such prophylaxis. METHODS: In this double-blind study, we randomised 3494 patients undergoing total hip replacement to treatment for 28-35 days with dabigatran etexilate 220 mg (n=1157) or 150 mg (1174) once daily, starting with a half-dose 1-4 h after surgery, or subcutaneous enoxaparin 40 mg once daily (1162), starting the evening before surgery. The primary efficacy outcome was the composite of total venous thromboembolism (venographic or symptomatic) and death from all causes during treatment. On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo, the non-inferiority margin for the difference in rates of thromboembolism was defined as 7.7%. Efficacy analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00168818. FINDINGS: Median treatment duration was 33 days. 880 patients in the dabigatran etexilate 220 mg group, 874 in the dabigatran etexilate 150 mg group, and 897 in the enoxaparin group were available for the primary efficacy outcome analysis; the main reasons for exclusion in all three groups were the lack of adequate venographic data. The primary efficacy outcome occurred in 60 (6.7%) of 897 individuals in the enoxaparin group versus 53 (6.0%) of 880 patients in the dabigatran etexilate 220 mg group (absolute difference -0.7%, 95% CI -2.9 to 1.6%) and 75 (8.6%) of 874 people in the 150 mg group (1.9%, -0.6 to 4.4%). Both doses were thus non-inferior to enoxaparin. There was no significant difference in major bleeding rates with either dose of dabigatran etexilate compared with enoxaparin (p=0.44 for 220 mg, p=0.60 for 150 mg). The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups. INTERPRETATION: Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile.