Does the Risk of Death Within 48 Hours of Hip Hemiarthroplasty Differ Between Patients Treated with Cemented and Cementless Implants? A Meta-analysis of Large, National Registries.

BACKGROUND: Although current recommendations suggest that hip hemiarthroplasties performed for femoral neck fractures be implanted with bone cement, it is known to cause cardiorespiratory and hemodynamic reactions that in some patients can be fatal. Older patients may be at particular risk of this complication, but because of its relative infrequency, large studies-perhaps even larger than can be achieved in the context of single-country national registries-are needed to get reasonably precise estimates as to its frequency. Pooling results from national registries reporting on death within 48 hours of cement exposure in this setting may therefore be helpful. QUESTION/PURPOSE: In a systematic review of studies based on large national registries, we asked: Does the risk of death within 48 hours of hip hemiarthroplasty differ between patients treated with cemented and cementless implants? METHODS: MEDLINE and Embase data sources were searched for cohort studies on patients with hip fractures treated with cement or cementless hip hemiprostheses based on results from national registries that tracked perioperative deaths within 48 hours of surgery, from 2010 or later (to include only studies that used contemporary cement techniques). We excluded registry research on elective THAs for other indications (such as degenerative joint disease), mixed populations (registries that combined patients having arthroplasty for fracture and for other diagnoses like osteoarthritis, such that we could not separate them), and overlapping data from the same registers (to avoid double and triple publications of similar data). Five studies met our inclusion criteria. The cohorts ranged from about 11,000 to about 25,000 patients. About 31% of the patients were in the cementless group. Two studies reported the age ranges of participating patients, and three studies communicated mean ages (which were 82 years for both sexes). Twice as many females as males were present in both the cemented and cementless group. When reported, more than 50% in both groups were in the American Society of Anesthesiologists physical status classification 3 or 4. Study quality was deemed good according to the Newcastle-Ottawa Scale. Publication bias was assessed using a funnel plot and the Egger test, and study heterogeneity was evaluated using the I2 heterogeneity statistic and Cochran Q heterogeneity test. There was some heterogeneity between the studies, with a Cochran Q statistics of 8.13 (degrees of freedom = 4; p = 0.08) and an I2 statistic of 50.8%. There was evidence for a small amount of publication bias (Egger test; p = 0.02). The pooled risk ratio (RR) from a random-effects model is presented with 95% confidence intervals. The primary endpoint was the occurrence of any fatalities within 48 hours of hip fracture treatment with cementless compared with cemented prostheses. We performed a sensitivity analysis to assess the needed association of a potential unmeasured or uncontrolled confounding, and we made an estimate of the amount of unmeasured confounding that would need to be present in order to change the direction of the result. We summarized this using a parameter known as the "E-value." Based on that sensitivity analysis, we found it unlikely that an unmeasured hypothetical confounder could explain the significant association between cemented and cementless implants and risk of death within 48 hours of hip hemiarthroplasty. RESULTS: Compared with the cementless group, mortality was increased in the cemented group (RR 1.63 [95% CI 1.31 to 2.02]; p < 0.001). The number needed to harm from the pooled data was 1 of 183 operated patients; that is, for every 183 patients treated with cemented implants, one death would be expected. CONCLUSION: Bone cement is associated with a higher risk of fatalities within 48 hours of surgery compared with cementless prostheses. However, numerous prior studies have found a higher risk of serious complications resulting in additional surgical procedures associated with cementless devices in this population; those complications, as well, may result in death. Based on our study alone, we cannot recommend cementless implants in this setting. Large, national registries should evaluate fixation choice in older patients with hip fractures, and those studies should consider both early death and the potential for later harms. LEVEL OF EVIDENCE: Level III, therapeutic study.

Low-molecular-weight heparin for hip fracture patients treated with osteosynthesis: should thromboprophylaxis start before or after surgery? An observational study of 45,913 hip fractures reported to the Norwegian Hip Fracture Register.

Background and purpose - Controversies exist regarding thromboprophylaxis in orthopedic surgery. We studied whether the thromboprophylaxis in hip fracture patients treated with osteosynthesis should start preoperatively or postoperatively. Data were extracted from the nationwide Norwegian Hip Fracture Register (NHFR). The risks of postoperative deaths, reoperations, and intraoperative bleeding were studied within 6 months after surgery. Patients and methods - After each operation for hip fracture in Norway the surgeon reports information on the patient, the fracture, and the operation to the NHFR. Cox regression analyses were performed with adjustments for age group, ASA score, sex, duration of surgery, and year of surgery. During the period 2005-2016, 96,599 hip fractures were reported to the register. Only osteosyntheses where low-molecular-weight heparin (LMWH) were given and with known information on preoperative start of the prophylaxis were included in the analyses. Dalteparin and enoxaparin were used in 58% and 42% of the operations respectively (n = 45,913). Results - Mortality (RR =1.01, 95% CI 0.97-1.06) and risk of reoperation (RR =0.99, CI 0.90-1.08) were similar comparing preoperative and postoperative start of LMWH. Postoperative start reduced the risk of intraoperative bleeding complications compared with preoperative start (RR =0.67, CI 0.51-0.90). Interpretation - The initiation of LMWH did not influence the mortality or the risk of reoperation in hip fracture patients treated with osteosynthesis. Postoperative start of LMWH could possibly decrease the risk of intraoperative bleeding.

Similar Clinical Outcomes with Preoperative and Postoperative Start of Thromboprophylaxis in THA: A Register-based Study.

BACKGROUND: Elective THA is associated with a high risk of thromboembolic events. Although these events may be less common now than they were in the past, they can be serious, and most patients undergoing the procedure therefore still receive thromboprophylaxis. However, controversy remains regarding whether to begin thromboprophylaxis before THA or after to best balance the risks of clotting and bleeding. QUESTIONS/PURPOSES: We asked the following questions: (1) Is there a difference in bleeding events with pre- versus postoperative thromboprophylaxis? (2) Is there a difference in thromboembolic episodes after THA between the two regimens? (3) How do the two approaches of thromboprophylaxis influence mortality, readmissions, and other complications? METHODS: We used a population-based followup design with predefined data based on international health codification to assess clinical effects of LMWH prophylaxis initiated before or after THA. We took data limited to primary THAs done in Norway between January 1, 2008, and December 31, 2011, from the Norwegian Arthroplasty Register and the National Patient Register to have necessary data elements to complete the study. The two registers were merged after identifying patients with their 11-digit personal identification number (Social Security number). We obtained data regarding demographics, administrative and surgical details, and episode histories for prophylaxis-related events within 180 days of surgery. A total of 25,163 patients undergoing THA were included for analysis, and 9977(40%) versus 15,186 (60%) patients received pre- and postoperative LMWH, respectively. We performed statistical adjustment for differences in baseline characteristics using multivariate logistic regression. RESULTS: After adjustment for age, sex, operation time, year of surgery, and American Society of Anesthesiologists class, we could not show major differences in bleeding events; (odds ratio [OR], 1.04; 95% CI, 0.88-1.22; p = 0.660), thromboembolic episodes; (OR, 1.03; 95% CI, 0.84-1.27; p = 0.786), or other postoperative clinical complications; (OR, 0.86; 95% CI, 0.76-0.99; p = 0.034), with the two regimens. Six-month mortality was similar, (OR, 0.76; 95% CI, 0.56-1.05; p = 0.093), and the readmission rate was higher in the preoperative group; (OR, 0.92; 95% CI, 0.85-0.97; p = 0.016). CONCLUSIONS: The risk for postoperative complications seems to be comparable whether LMWH prophylaxis is initiated before or after THA. The postoperative approach reduces costs, decreases risks related to neuraxial anesthesia, and facilitates same-day admissions. Methods for individual risk assessment including laboratory tests would be feasible. LEVEL OF EVIDENCE: Level III, therapeutic study.

Postoperative start compared to preoperative start of low-molecular-weight heparin increases mortality in patients with femoral neck fractures.

Background and purpose - Controversies exist regarding thromboprophylaxis in orthopedic surgery. Using data in the nationwide Norwegian Hip Fracture Register (NHFR) with postoperative death and reoperation in the first 6 months after surgery as endpoints in the analyses, we determined whether the thromboprophylaxis in patients who undergo hemiarthroplasty for femoral neck fracture should start preoperatively or postoperatively. Patients and methods - After each operation for hip fracture in Norway, the surgeon reports information on the patient, the fracture, and the operation to the NHFR. Cox regression analyses were performed with adjustments for age, ASA score, gender, type of implant, length of surgery, and year of surgery. Results - During the period 2005-2014, 25,019 hemiarthroplasties as treatment for femoral neck fractures were reported to the registry. Antithrombotic medication was given to 99% of the patients. Low-molecular-weight heparin predominated with dalteparin in 57% of the operations and enoxaparin in 41%. Only operations with these 2 drugs and with known information on preoperative or postoperative start of the prophylaxis were included in the analyses (n = 20,241). Compared to preoperative start of thromboprophylaxis, postoperative start of thromboprophylaxis gave a higher risk of death (risk ratio (RR) = 1.13, 95% CI: 1.06-1.21; p < 0.001) and a higher risk of reoperation for any reason (RR =1.19, 95% CI: 1.01-1.40; p = 0.04), whereas we found no effect on reported intraoperative bleeding complication or on the risk of postoperative reoperation due to hematoma. The results did not depend on whether the initial dose of prophylaxis was the full dosage or half of the standard dosage. Interpretation - Postoperative start of thromboprophylaxis increased the mortality and risk of reoperation compared to preoperative start in femoral neck fracture patients operated with hemiprosthesis. The risks of bleeding and of reoperation due to hematoma were similar in patients who received low-molecular-weight heparin preoperatively and in those who received it postoperatively.

Arterial and venous thrombosis following trauma and major orthopedic surgery: molecular mechanisms and strategies for intervention.

A variety of harmful effects can be triggered by trauma and major orthopedic surgery. One of the key players involved in this process is thrombin. The clinical consequence of this process has, for several decades, been considered to be formation of deep vein thrombosis and pulmonary embolism. Controlling thrombin generation and activation has therefore been the goal of thromboprophylaxis regimens administered to patients suffering from trauma or undergoing major surgery. Protecting patients from venous thromboembolism has, for many years, been the main goal of preventive strategies. However, our knowledge of cell destruction and release of substances that may cause organ damage has expanded in recent years. Release of molecules such as RNA and histones from destroyed tissues may cause cell destruction and organ damage at distal sites if released in huge amounts and disseminated systemically. This new knowledge points toward an unmet need for therapies that prevent both vascular events and organ deterioration. This article briefly reviews molecular mechanisms associated with the occurrence of vascular events and cellular destruction in patients with major bone damage caused by trauma.

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.

Perioperative mortality in hip fracture patients treated with cemented and uncemented hemiprosthesis: a register study of 11,210 patients.

PURPOSE: Adverse events associated with the use of bone cement for fixation of prostheses is a known complication. Due to inconclusive results in studies of hip fracture patients treated with cemented and uncemented hemiprostheses, this study was initiated. METHODS: Our study is based on data reported to the Norwegian Hip Fracture Register on 11,210 cervical hip fractures treated with hemiprostheses (8,674 cemented and 2,536 uncemented). RESULTS: Significantly increased mortality within the first day of surgery was found in the cemented group (relative risk 2.9, 95 % confidence interval 1.6-5.1, p=0.001). The finding was robust giving the same results after adjusting for independent risk factors such as age, sex, cognitive impairment and comorbidity [American Society of Anesthesiologists (ASA) score]. For the first post-operative day the number needed to harm was 116 (one death for every 116 cemented prosthesis). However, in the most comorbid group (ASA worse than 3), the number needed to harm was only 33. CONCLUSIONS: We found increased mortality for the cemented hemiprosthesis the first post-operative day compared to uncemented procedures. This increased risk is closely related to patient comorbidity estimated by the patient's ASA score.

The Bone Cement Hypercoagulation Syndrome: Pathophysiology, Mortality, and Prevention.

Since Charnley introduced acrylic cement to seal metallic hip prostheses in the 1950s, reports of perioperative fatal cardiorespiratory and vascular dysfunctions have been published. Studies on humans and animals have shown neurogenic stimulation and substantial local and systemic activation of coagulation are caused by surgical bone marrow damage and chemical cell destruction by toxic monomeric methyl methacrylate from the implanted cement and other tissue-released substances. Venous blood-borne cell fragments and conjugates of activated cells from the surgical site are sequestered and trapped in the pulmonary microcirculation. A substantial hypercoagulation occurs in the lung circulation. Hypercoagulable blood is passed over to the arterial side and may cause vessel obliteration and organ damage. This process may affect the brain, heart, and kidneys and, through the release of vasoactive substances, introduce hemodynamic imbalances that can lead to fatal outcomes in susceptible populations such as elderly patients with hip fractures. The main underlying pathophysiologic processes leading to these occasionally devastating outcomes are a substantial activation of coagulation and cell destruction caused by the toxic substance released by curing bone cement and several vasoactive substances.

Blood loss in cemented THA is not reduced with postoperative versus preoperative start of thromboprophylaxis.

BACKGROUND: Thrombin formation commences perioperatively in orthopaedic surgery and therefore some surgeons prefer preoperative initiation of pharmacologic thromboprophylaxis. However, because of the potential for increased surgical bleeding, the postoperative initiation of thromboprophylaxis has been advocated to reduce blood loss, need for transfusion, and bleeding complications. Trials on timing of thromboprophylaxis have been designed primarily to detect thrombotic events, and it has been difficult to interpret the magnitude of blood loss and bleeding events owing to lack of information for bleeding volume and underpowered bleeding end points. QUESTIONS/PURPOSES: We therefore asked whether there are differences in blood loss, transfusion requirements, and other postoperative clinical complications with preoperative versus postoperative start of thromboprophylaxis with dalteparin. METHODS: In a double-blind, randomized controlled trial, 80 patients undergoing primary cemented THA were allocated to dalteparin injections starting 12 hours before or 6 hours after surgery. Blood loss was measured by weighing sponges and drapes, volume in suction drains during surgery, and wound drains until removal 24 hours postoperatively. Hemoglobin and hematocrit were recorded at predefined times during and after surgery. RESULTS: We found no differences in blood loss (1081 mL ± 424 mL versus 1023 mL ± 238 mL), bleeding-related events (10% versus 17%), or number of patients who had transfusions (12 versus five) with preoperative and postoperative thromboprophylaxis, respectively. Other complications were few in both groups. CONCLUSIONS: Our data suggest blood loss is similar with preoperative and postoperative initiation of dalteparin thromboprophylaxis, but indicate a trend toward fewer transfusion requirements which might favor postoperative start of thromboprophylaxis.

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.

Biochemical lung, liver and kidney markers and early death among elderly following hip fracture.

INTRODUCTION: In the elderly, hip fracture is a common injury associated with high early mortality dominated by cardiorespiratory and thromboembolic events. Identification of risk factors that can be modified by treatment has caught attention over the last years. This study was conducted to assess biological markers on perioperative organ dysfunction and its association with early mortality within 3 months after surgery. METHOD: Blood samples were collected before, during and until 4 days after surgery. Analyses on PaO(2), alanine aminotransaminase (ALAT), gamma-glutamyl transpeptidase (g-GT) and creatinine were performed and used as markers on lung, liver and kidney functions. PATIENTS: Three hundred and two patients over 75 years of age with acute dislocated hip fracture were consecutively enrolled from two hospitals in Norway. RESULTS: We found a positive correlation between the plasma levels of ALAT, creatinine and death, and an inverse relationship between PaO(2) and death. After controlling for confounding factors such as sex, age and comorbidity, ALAT and creatinine levels were shown to be significantly and independently related to risk for fatal outcome. CONCLUSION: Our results provide data on clinically important biomarkers in patients undergoing hip fracture surgery. We suggest a stronger emphasis on monitoring and correcting these biomarkers when possible.

Clinical and biochemical prediction of early fatal outcome following hip fracture in the elderly.

Hip fracture, a moderate musculoskeletal trauma, is associated with a high postoperative mortality. Most patients are elderly, with comorbid conditions and often with heart disease. The objective of this study was to find out if clinical parameters and analyses of specific muscle enzymes could predict three month postoperative mortality. A total of 302 patients above 75 years of age with hip fracture were consecutively enrolled. Baseline information on age, sex and comorbidity assessed with the American Society of Anesthesiologists (ASA) score was obtained before surgery. Creatine kinase (CK), myocardium-specific creatine kinase (CK-MB) and troponin T (TnT) were analysed from venous blood, collected the day before surgery (-1) and postoperatively, within 24 hours (0) and on days one (+1) and four (+4). The overall three month mortality was 19.5%. Multivariate analyses showed that age, male sex and comorbidity (ASA) correlated with mortality (p = 0.027, p = 0.002, p < 0.001, respectively). Surgery induced a two- to threefold increase of CK and CK-MB but without any correlation with mortality. However, high TnT levels >0.04 µg/l correlated significantly with death (days -1, +1 and +4, p = 0.003, p = 0.005 and p = 0.003, respectively). Multivariate analyses, adjusted for age, sex and ASA category, confirmed this correlation (day +4, p = 0.008). Thus, in elderly patients with comorbidities undergoing hip fracture surgery information on sex, age, ASA category and postoperative laboratory analyses on TnT provide the clinicians with useful information on patients at risk of fatal outcome.

Correction to: Do direct oral anticoagulants (DOACs) cause delayed surgery, longer length of hospital stay, and poorer outcome for hip fracture patients?

The original version of this article unfortunately contained a mistake.

Do direct oral anticoagulants (DOACs) cause delayed surgery, longer length of hospital stay, and poorer outcome for hip fracture patients?

PURPOSE: The perioperative consequences of direct oral anticoagulants (DOACs) in hip fracture patients are not sufficiently investigated. The primary aim of this study was to determine whether DOAC-users have delayed surgery compared to non-users. Secondarily, we studied whether length of hospital stay, mortality, reoperations and bleeding complications were influenced by the use of DOAC. METHODS: The medical records of 314 patients operated for a hip fracture between 2016 and 2017 in a single trauma center were assessed. Patients aged < 60 and patients using other forms of anticoagulation than DOACs were excluded. Patients were followed from admission to 6 months postoperatively. Surgical delay was defined as time from admission to surgery. Secondary outcomes included length of hospital stay, transfusion rates, perioperative bleeding loss, postoperative wound ooze, mortality and risk of reoperation. The use of general versus neuraxial anaesthesia was registered. Continuous outcomes were analysed using Students t test, while categorical outcomes were expressed by Odds ratios. RESULTS: 47 hip fracture patients (15%) were using DOACs. No difference in surgical delay (29 vs 26 h, p = 0.26) or length of hospital stay (6.6 vs 6.1 days, p = 0.34) were found between DOAC-users and non-users. DOAC-users operated with neuraxial anaesthesia had longer surgical delay compared to DOAC-users operated with general anaesthesia (35 h vs 22 h, p < 0.001). Perioperative blood loss, transfusion rate, risk of bleeding complications and mortality were similar between groups. CONCLUSION: Hip fracture patients using DOAC did not have increased surgical delay, length of stay or risk of reported bleeding complications than patients without anticoagulation prior to surgery. The increased surgical delay found for DOAC-users operated with neuraxial anaesthesia should be interpreted with caution.

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.

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.

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.