Ximelagatran for the prevention of venous thromboembolism following elective hip or knee replacement surgery

Patients undergoing major lower-extremity orthopedic surgery such as total hip replacement (THR) and total knee replacement (TKR) are at an increased risk of venous thromboembolism (VTE). Routine prophylaxis is necessary to reduce the risk of deep vein thrombosis (DVT), which may progress to potentially fatal pulmonary embolism and secondary complications such as postthrombotic syndrome, recurrent DVT, and chronic pulmonary hypertension. Prophylaxis in patients undergoing TKR, THR, and hip fracture surgery is now standard practice and generally involves anticoagulant treatment with either low-molecular-weight heparin (LMWH) or warfarin for a period of 7 to 10 days, with extended prophylaxis in those with ongoing risk factors such as obesity, cancer, or previous VTE. Data from clinical practice suggest that there is a general trend toward longer postsurgical prophylaxis and shorter hospital stays, making practicality of treatment an important consideration. LMWH is effective for the prophylaxis of VTE, but the parenteral route of administration is not convenient for use in the outpatient setting. Warfarin, on the other hand, can be administered orally but requires the infrastructure for careful patient monitoring and dose adjustments because of its unpredictable dose-response relationship. The development of new anticoagulants has been pursued with the aim of improving efficacy, predictability, consistency of response, safety, and convenience. A recently approved anticoagulant, fondaparinux, has been proven to provide superior efficacy for the prevention of VTE compared with LMWH, but this agent requires parenteral administration and does not overcome the convenience issue. Ximelagatran is the oral form of the direct thrombin inhibitor melagatran, which is available for subcutaneous administration. Ximelagatran has a consistent anticoagulant response allowing fixed oral dosing without the need for coagulation monitoring. The efficacy and safety profile of melagatran/ximelagatran prophylaxis for VTE following THR and TKR has compared favorably with standard LMWH prophylaxis, as seen in the European METHRO II and III trials and EXPRESS trial, and with warfarin prophylaxis, as seen in the North American EXULT A and B trials. Several prophylactic treatment regimens have been evaluated in the European trials to determine the optimal dosing and timing of first dose of melagatran to achieve the best balance of efficacy and safety. Preoperative initiation of melagatran was more effective than when prophylactic treatment was initiated postoperatively, and the lowest rates of bleeding were associated with a postoperative initiation of prophylaxis. Early administration of the first postoperative melagatran dose (4 to 8 hours) was also associated with better prophylactic efficacy relative to a later postoperative start (8 to 12 hours). The results of the comprehensive international clinical trial program and in particular the optimal balance of efficacy/safety data provided by the METHRO III study have led to approval of melagatran/ximelagatran in 2004 in the European Union for the prevention of VTE in patients undergoing elective hip or knee replacement surgery. Ximelagatran has the potential to maximize the use of anticoagulation in patients discharged following major lower-extremity orthopedic surgery.     

Variation in age and physical status prior to total knee and hip replacement surgery: A comparison of centers in Australia and Europe

Objective

To investigate whether variation exists in the preoperative age, pain, stiffness, and physical function of people undergoing total knee replacement (TKR) and total hip replacement (THR) at several centers in Australia and Europe.

Methods

Individual Western Ontario and McMaster Universities Osteoarthritis Index data (range 0–100, where 0 = best and 100 = worst) collected within 6 weeks prior to primary TKR and THR were extracted from 16 centers (n = 2,835) according to specified eligibility criteria. Analysis of covariance was used to evaluate differences in pain, stiffness, and physical function between centers, with adjustment for age and sex.

Results

There was marked variation in the age of people undergoing surgery between the centers (TKR mean age 67–73 years; F[6,1004] = 4.21, P < 0.01, and THR mean age 63–72 years; F[14,1807] = 7.27, P < 0.01). Large differences in preoperative status were observed between centers, most notably for pain (TKR adjusted mean pain 52.5–61.1; F[6,1002] = 4.26, P < 0.01, and THR adjusted mean pain 49.2–65.7; F[14,1802] = 8.44, P < 0.01) and physical function (TKR adjusted mean function 52.7–61.4; F[6,1002] = 5.27, P < 0.01, and THR adjusted mean function 53.3–71.0; F[14,1802] = 6.71, P < 0.01). Large effect sizes (up to 0.98) reflect the magnitude of variation between centers and highlight the clinical relevance of these findings.

Conclusion

The large variations in age and preoperative status indicate substantial differences in the timing of joint replacement across the centers studied, with potential for compromised surgical outcomes due to premature or delayed surgery. Possible contributing factors include patient preferences, the absence of concrete indications for surgery, and the capacity of the health care systems.     

Perioperative coagulation assessment of patients undergoing major elective orthopedic surgery

Traditional coagulative parameters are of limited use in identifying perioperative coagulopathy occurring in patients undergoing major elective orthopedic surgery (MEOS). The aim of our study was to evaluate the coagulation changes in patients undergoing MEOS and to facilitate an early detection of perioperative coagulopathy in patients experiencing major intraoperative bleeding. We enrolled 40 consecutive patients (M/F 10/30, age range 34–90 years) who underwent MEOS at the Orthopedic Unit of the Padua University Hospital, Italy, between January 2014 and January 2015. Blood samples were obtained at the following time points: T0-pre: 30 min before surgery; T0-post: 30 min after the end of the procedure; T1: morning of the first postoperative day; T2: 7 ± 2 days after surgery. Patients who experienced an intraoperative blood loss ≥250 mL/h were considered as cases. Routine coagulative parameters, thromboelastometry and thrombin generation (TG) profiles were evaluated. At baseline, a significantly lower platelet count and FIBTEM MCF/AUC were observed in patents with excessive bleeding (p < 0.05 and 0.02/0.01, respectively). At T0-post and T1 intervals, cases showed hypocoagulation characterized by a significantly low platelet count (p = 0.001), prolonged CFT INTEM/EXTEM, reduction of alpha-angle and MaxV INTEM/EXTEM, MCF and AUC INTEM/EXTEM/FIBTEM (p < 0.05 in all comparisons). The only TG parameter standing out between study groups was time to peak at T0-pre. A low platelet count and fibrinogen activity were associated with significant intraoperative bleeding in patients undergoing MEOS. Thromboelastometry performed by ROTEM^® identifies patients with coagulopathy.     

Trajectories in functional recovery for patients receiving inpatient rehabilitation for unilateral hip or knee replacement

The purpose of this study was to explore trajectories of recovery in patients with lower extremity joint replacements receiving post-acute rehabilitation. A retrospective cohort design was used to examine data from the Uniform Data System for Medical Rehabilitation (UDSMR^®) for 7434 patients with total knee replacement (TKR) and 4765 patients with total hip replacement (THR) who received rehabilitation from 2008 to 2010. Functional Independence Measure (FIM)™ instrument ratings were obtained at admission, discharge, and 80–180 days after discharge. Random coefficient regression analyses using linear mixed models were used to estimate mean ratings for items within the four motor subscales (self-care, sphincter control, transfers, and locomotion) and the cognitive domain of the FIM instrument. Mean improvements at discharge for motor items ranged from 1.16 (95% confidence interval [CI]: 1.14, 1.19) to 2.69 (95% CI: 2.66, 2.71) points for sphincter control and locomotion, respectively. At follow-up mean motor improvements ranged from 2.17 (95% CI: 2.15, 2.20) to 4.06 (95% CI: 4.03, 4.06) points for sphincter control and locomotion, respectively. FIM cognition yielded smaller improvements: discharge = 0.47 (95% CI: 0.46, 0.48); follow-up = 0.83 (95% CI: 0.81, 0.84). Persons who were younger, female, non-Hispanic white, unmarried, with fewer comorbid conditions, and who received a TKR demonstrated slightly higher functional motor ratings. Overall, patients with unilateral knee or hip replacement experienced substantial improvement in motor functioning both during and up to six months following inpatient rehabilitation.     

Antibiotic prophylaxis for dental or urological procedures following hip or knee replacement

OBJECTIVES: Reports of prosthetic joint infection associated with urological or dental procedures have prompted suggestions that these patients require antibiotic prophylaxis, but no guidelines have been agreed. We have polled orthopaedic surgeons, urologists, and dentists on this issue. METHODS: The questions asked were: could infection of a joint prosthesis result from a dental or urological procedure; does the risk of infection warrant patients informing their dentist or urologist about their joint replacement; should these patients have prophylactic antibiotics for (a) routine procedures and (b) lengthy procedures. RESULTS: Urologists and orthopaedic surgeons agreed that infection could probably result from urological procedures and that patients should definitely inform their urologist about their prosthesis. Orthopaedic surgeons thought that antibiotics were definitely indicated for routine and lengthy urological procedures while urologists thought antibiotics were probably indicated. Orthopaedic surgeons thought that infection probably could result from dental procedures, while dentists answered "don't know". Both groups agreed that patients should definitely inform their dentist about their prosthesis. Orthopaedic surgeons thought that antibiotics probably were necessary for routine and lengthy dental procedures, whereas dentists answered "probably not" and "don't know", respectively. CONCLUSIONS: These results could provide the basis for a consensus regarding prophylactic antibiotic use in this growing patient population.     

Determinants of willingness to pay for hip and knee joint replacement surgery for osteoarthritis

OBJECTIVES: To determine whether patients with osteoarthritis (OA) would be willing to pay for joint replacement and whether patient characteristics or health outcomes, including pain, physical function and health-related quality of life, were related to willingness to pay (WTP). METHODS: Patients who had undergone primary total hip replacement (THR) or total knee replacement (TKR) for OA completed a disease-specific questionnaire (Western Ontario and McMaster: WOMAC index), a generic measure of health status (Medical Outcome Study Short Form-36: SF-36) and an Evaluation Questionnaire to measure WTP and satisfaction with the replacement. RESULTS: Responses were obtained from 109 (77%) THR patients and 129 (72%) TKR patients. Mean age of respondents was 67 yr for THR (47% female) and 73 yr for TKR (60% female). Overall, 85% of patients responded to the WTP question. Of the THR patients, 71% were willing to pay something, 11% were not willing to pay anything and 18% did not answer the question. For TKR patients these figures were 70, 16 and 14% respectively. However, of those who responded to the WTP question, only 25% of the THR patients and 18% of the TKR patients indicated they would be willing to pay the actual current average cost of the operation in Australia (>/= A$15 000). A lower postoperative pain score (as measured by the WOMAC index) was a significant predictor of WTP for both THR and TKR patients. Income also significantly predicted WTP in THR patients but not in TKR patients. The other significant predictors for TKR patients were older age, having private health insurance and willingness to recommend joint replacement to others. CONCLUSIONS: Willingness to pay was a measure that was understandable and acceptable to patients, most of whom were willing to pay something. There was a high correlation between WTP, good health outcomes and patient satisfaction, pain relief being the dominant determinant.     

Preoperative education for total hip and knee replacement patients

Objective. Psychoeducational preparation is known to improve postoperative outcome. We tested two common psychoeducational procedures in elderly orthopedic patients, examining how best to match interventions to patients by psychological type. Methods. Two hundred twenty-two elderly patients undergoing total hip or knee replacement were randomly assigned to (1) a slide-tape with information on the postoperative, in-hospital rehabilitation experience, or (2) training in Benson's Relaxation Response with a bedside audiotape, in a 2 × 2 factorial design. Results. The relaxation response did not influence postoperative outcomes. The educational intervention reduced length of stay and pain medication use for patients who exhibited most denial (tendency to avoid thinking about unpleasant events), and reduced postoperative anxiety and cognitive errors on the Mini-Mental State Exam for patients with most baseline anxiety. There was no effect on postoperative pain. Conclusions. The importance of attending to the patient's psychological state and level of preparation before orthopedic surgery is reinforced. Patients who exhibit most denial and highest anxiety may benefit from educational interventions, but patients' directly expressing desire for information may be a poor guide in deciding which patients would benefit, compared with more formal psychological testing for denial and anxiety.     

Platelet aggregation and coagulation factors in orthopedic surgery

Hemostasis is a major concern during the perioperative period. Changes in platelet aggregation and coagulation factors may contribute to the delicate balance between thrombosis and bleeding. We sought to better understand perioperative hemostasis by investigating the changes in platelet aggregation and coagulation factors during the perioperative period. We performed a prospective cohort analysis of 70 subjects undergoing non-emergent orthopedic surgery of the knee (n = 28), hip (n = 35), or spine (n = 7) between August 2011 and November 2011. Plasma was collected preoperatively (T1), 1-h intraoperatively (T2), 1-h (T3), 24-h (T4) and 48-h (T5) postoperatively. Platelet function testing was performed using whole blood impedance aggregometry. Coagulation assays were performed for factor VII, factor VIII, von Willebrand Factor (vWF), and fibrinogen. Of the 70 patients, mean age was 64.1 ± 9.8 years, 61 % were female, and 74 % were Caucasian. Platelet activity decreased until 1 h postoperatively and then significantly increased above baseline at 24- and 48-h postoperatively. Compared to baseline, coagulation factors decreased intraoperatively. Factor VII activity continued to decrease, while FVIII, vWF, and fibrinogen all increased above baseline postoperatively. The results of our study indicate significant changes in platelet activity and coagulation factors during the perioperative period. Both platelet activity and markers of coagulation decrease during the intraoperative period and then some increase postoperatively. These changes may contribute to the hypercoagulabity and/or bleeding risk that occurs in the perioperative period. Future prospective studies aimed at correlating hemostatic changes with perioperative outcomes are warranted.     

The impact of elective knee/hip replacement surgery and thromboprophylaxis with rivaroxaban or dalteparin on thrombin generation

Total hip/knee replacement surgeries are associated with an increased risk of venous thromboembolism and post‐operative thromboprophylaxis has become standard treatment. This study aimed to: (i) assess the impact of hip/knee replacement surgery on ex vivo thrombin generation (TG), prothrombin fragments 1 + 2 (F1 + 2), thrombin‐antithrombin complexes (TAT) and D‐dimer; (ii) compare the anticoagulant effects of dalteparin and rivaroxaban on TG 24 h after surgery. Haemostatic variables were assessed in plasma samples of 51 patients taken pre‐operatively, peri‐operatively, and 24 h post‐operatively. Prophylaxis, once a day, with dalteparin or rivaroxaban, starting 6–8 h post‐operatively, was administered in 25 (14 knee/11 hip) and 26 patients (13 knee/13 hip) respectively. TG, F1 + 2, TAT and D‐dimer increased during surgery. Dalteparin patients showed a variable TG response 24 h after surgery: conversely, the effect of rivaroxaban on TG was consistent across individuals. Good correlation was seen between rivaroxaban levels and TG‐lag‐time (rs = 0·46, P = 0·01); TG‐time‐to‐Peak (rs = 0·53, P = 0·005); TG‐peak‐thrombin (rs = ?0·59, P = 0·001); and TG‐velocity‐index‐rate (rs = ?0·61, P = 0·0009). Patients who received rivaroxaban showed a greater decrease of TG, F1 + 2 and TAT (but not D‐dimer) than those on dalteparin. TG increases during hip/knee replacement surgery. Rivaroxaban inhibits TG more than dalteparin at 24 h after surgery.     

Health-related quality of life and appropriateness of knee or hip joint replacement

BACKGROUND: We studied the association between explicit appropriateness criteria for total hip joint replacement (THR) and total knee replacement (TKR) with changes in health-related quality of life of patients undergoing these procedures. METHODS: Prospective observational study of 1576 consecutive patients with diagnoses of osteoarthritis on waiting lists to undergo THR or TKR. Explicit appropriateness criteria using the RAND appropriateness method were applied. Patients completed 2 questionnaires that measured health-related quality of life, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), before the procedure and 6 months afterward. RESULTS: Patients who were considered appropriate candidates for these procedures had greater improvements than those who were considered inappropriate candidates in all 3 WOMAC domains (pain, functional limitation, and stiffness; THR: 43.0, 40.6, and 40.4 vs 14.7, 19.1, and 15.9; TKR: 34.9, 32.5, and 30.2 vs 23.2, 18.9, and 17.1; P<.001 for all comparisons). Patients who underwent THR and were judged to be appropriate candidates had greater improvements in the physical function, role-physical, bodily pain, and social function domains of the SF-36 than those judged to be inappropriate candidates (34.4, 35.1, 33.1, and 26.6 vs 19.6, 9.2, 5.7, and 7.0; P = .04, P = .03, P < .001, and P < .001, respectively). Appropriate candidates for TKR demonstrated greater improvement in the social function domain of the SF-36 after the procedure than those deemed inappropriate candidates (19.9 vs 7.9; P = .004) but not in the other domains of functional status. CONCLUSIONS: These results suggest a direct relationship between explicit appropriateness criteria and better health-related quality-of-life outcomes after THR and TKR surgery. Our results support the use of these criteria for clinical guidelines or evaluation purposes.     

Risk factors for venous thromboembolism after total hip and knee replacement surgery

Elective total hip and total knee arthroplasty surgeries are associated with an extraordinarily high incidence of asymptomatic venous thromboembolism (VTE). Symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) is diagnosed in only 2%-4% of these patients. A number of studies have defined the incidence and time course of symptomatic thromboembolism after these procedures. Knee arthroplasty is associated with a very high incidence of asymptomatic calf vein thrombosis, with almost all symptomatic VTE events diagnosed in the first 21 days after surgery. Hip arthroplasty, however, is associated with a higher incidence of asymptomatic proximal thrombi and a modestly higher incidence of symptomatic VTE events, many diagnosed up to 6 or 8 weeks after hospital discharge. Extended medical thromboprophylaxis has been shown to reduce the incidence of symptomatic and asymptomatic VTE among hip arthroplasty patients but not among knee arthroplasty patients. Risk factors for VTE after knee arthroplasty are not well defined. Important risk factors that have been shown to be associated with the development of VTE after hip surgery include (1) a history of prior VTE, (2) obesity (body mass index > 25), (3) delay in ambulation after surgery, and (4) female sex. Factors associated with lower risk include (1) Asian/Pacific Islander ethnicity, (2) use of pneumatic compression among non-obese patients after surgery, and (3) extended thromboprophylaxis after hospital discharge.     

Living with severe osteoarthritis while awaiting hip and knee joint replacement surgery

Objectives: To explore the lived experiences of patients with severe osteoarthritis (OA) of the hip or knee joint while awaiting joint replacement surgery. Methods: An exploratory qualitative approach using phenomenology was adopted for the purpose of the study. Unstructured interviews were carried out on a sample of six patients who had been referred to the National Health Service waiting list for a primary hip or knee replacement. The participants were invited to share their experiences and concerns relating to how they were coping with end‐stage OA of their hip or knee joint. Interviews were digitally recorded and transcribed verbatim. Narrative data were analysed using Giorgi's (1985) procedural steps to reveal themes which recurred in the participants' stories. Results: Six themes emerged from the data, central to the experience of living with severe OA. They were: coping and living with pain; not being able to walk; coping with everyday activities; body image; advice and support available; and the effect of their disease upon family, friends and helpers. There were also a number of sub‐themes associated with each major theme. Conclusions: This study suggests that there is an absence of generic support, guidance and information relating to the management of symptoms of OA for individuals awaiting hip and knee replacement surgery. Patients awaiting hip and knee joint replacement surgery often have difficulty in managing their symptoms. Support in general appears to be dependent on the availability of resources in the primary care setting. Potential patients who are fortunate to know or meet someone who has undergone a similar procedure learn from the experience of exchanging information between themselves, along with coping strategies in the management of their symptoms. Copyright © 2008 John Wiley & Sons, Ltd.