A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial.

BACKGROUND: Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following orthopedic surgery. METHODS: In a multicenter, parallel-group, double-blind study, 1973 patients undergoing total hip or knee replacement were randomized to 6-10 days of oral dabigatran etexilate (50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily), starting 1-4 h after surgery, or subcutaneous enoxaparin (40 mg once daily) starting 12 h prior to surgery. The primary efficacy outcome was the incidence of VTE (detected by bilateral venography or symptomatic events) during treatment. RESULTS: Of the 1949 treated patients, 1464 (75%) patients were evaluable for the efficacy analysis. VTE occurred in 28.5%, 17.4%, 16.6%, 13.1% and 24% of patients assigned to dabigatran etexilate 50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily and enoxaparin, respectively. A significant dose-dependent decrease in VTE occurred with increasing doses of dabigatran etexilate (P < 0.0001). Compared with enoxaparin, VTE was significantly lower in patients receiving 150 mg twice daily [odds ratio (OR) 0.65, P = 0.04], 300 mg once daily (OR 0.61, P = 0.02) and 225 mg twice daily (OR 0.47, P = 0.0007). Compared with enoxaparin, major bleeding was significantly lower with 50 mg twice daily (0.3% vs. 2.0%, P = 0.047) but elevated with higher doses, nearly reaching statistical significance with the 300 mg once-daily dose (4.7%, P = 0.051). CONCLUSIONS: Oral administration of dabigatran etexilate, commenced early in the postoperative period, was effective and safe across a range of doses. Further optimization of the efficacy/safety balance will be addressed in future studies.

Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I.

BACKGROUND: Dabigatran etexilate (BIBR 1048) is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following total hip replacement. Following oral administration, dabigatran etexilate is rapidly converted to its active form dabigatran (BIBR 953 ZW). OBJECTIVES: To determine the safe therapeutic range of dabigatran etexilate following total hip replacement. METHODS: In a multicenter, open-label, dose-escalating study, 314 patients received oral doses of dabigatran etexilate (12.5, 25, 50, 100, 150, 200 and 300 mg twice daily or 150 and 300 mg once daily) administered 4-8 h after surgery, for 6-10 days. Dose escalation was based on clinical and pharmacokinetic data. The primary safety outcome was major bleeding. The primary efficacy outcome included venographic deep vein thrombosis (DVT), symptomatic DVT and pulmonary embolism, during the treatment period. RESULTS: No major bleeding event was observed in any group, but two patients at the highest dose (300 mg twice daily) suffered bleeding from multiple sites associated with reduced renal clearance and prolonged pharmacodynamic (PD) parameters. A dose-response was demonstrated for minor bleeding events. Of the 289 treated patients, 225 patients had evaluable venograms. The overall incidence of DVT was 12.4% (28/225 patients). There was no consistent relationship between the dose and incidence of DVT, the highest incidence in any group being 20.8% (5/24 patients). The lowest dose (12.5 mg twice daily) showed a high rate of proximal DVT [12.5% (3/24)] and no increase in PD parameters. Peak and trough plasma concentrations, area under the dabigatran plasma concentration-time curve and PD parameters also increased in proportion with the dose. Higher dabigatran plasma concentrations were associated with lower DVT rates. Approximately 20% of the patients had low plasma concentrations after the first dose suggesting further optimization of the preliminary tablet formulation is required. CONCLUSIONS: Dabigatran etexilate demonstrates an acceptable safety profile, with a therapeutic window above 12.5 mg and below 300 mg twice daily. The low number of VTE events within each treatment group indicates a satisfactory antithrombotic potential, although the study was not powered for an efficacy analysis. Additional studies are ongoing to optimize oral absorption and the efficacy/safety balance.

Dislocations and the femoral head size in primary total hip arthroplasty.

The dislocation rate of 3197 Charnley prostheses with 22 mm head in which the surgery was done between 1979 and 1991 in 2 orthopaedic centers was compared with that of 2875 Lubinus prostheses with 32 mm head in which the surgery was done between 1980 to 1991 in 3 other centers. A 1-year followup showed an equal rate of dislocation (2.4%-2.5%) in the 2 groups and included 75% of the 201 dislocated hips. Almost all of the late dislocations occurred with the Charnley prosthesis, resulting in a total dislocation rate of 3.7% compared with 2.9% with the Lubinus prosthesis. Regardless of the type of prosthesis used, there was a higher risk of dislocation in patients with nonhealed hip fractures and in arthroplasties performed by less experienced surgeons. When these 2 variables were removed, the small femoral head was not associated with an increased risk of dislocation. However, there were 77 of 118 (65%) recurrent dislocations in the Charnley group, compared with 37 of 83 (45%) in the Lubinus group, and the relative risk of a dislocated hip arthroplasty becoming recurrent increased by 2.3 times if the small femoral head was used. The number of reoperations also were doubled in this group. Almost 4 times as many dislocations were documented within 2 weeks after surgery after any type of prosthesis inserted through a posterior approach compared with the transtrochanteric approach, but there was no increase in rate of recurrence or revision.

Surgical experience related to dislocations after total hip arthroplasty.

We studied the effect of surgical experience on the dislocation rate after 4230 primary total hip arthroplasties (THAs) all performed using the posterior approach at three orthopaedic centres at major county hospitals. There were 129 postoperative (3%) dislocations. Twice the number of dislocations were registered for inexperienced surgeons as for their more experienced colleagues. This frequency of dislocation levelled off with increasing numbers of operations and remained constant after approximately 30. For every ten primary THAs performed annually, the risk of dislocation decreased by 50%.

Prognosis of total hip replacement in Sweden. Follow-up of 92,675 operations performed 1978-1990.

A prospective, national multi-center study of all reoperations after total hip replacement (THR) was started by the Swedish Orthopedic Association in 1979. The material comprises all THR performed in Sweden, presently more than 10,000 yearly or 130 THR per 100,000 inhabitants; uncemented implants have been used in less than 2 percent. The main reasons for revision have been aseptic loosening 79 percent, infection 10 percent, technical error 6 percent, and dislocation 2 percent. The cumulative rate of revision for deep infection has dropped from 0.9 percent to < 0.5 percent for implants inserted 1979 and 1983, respectively. With the Charnley prosthesis as the gold, standard the performance of other prostheses was analyzed. Improved cementation techniques and anti-infection measures have continuously reduced the revision risk. The register demonstrates that the average orthopedic surgeon cannot match the results achieved by experts. However, the vast majority of THR, worldwide, are not performed by experts. Quality-assurance in this sector of orthopedics demands a continuous analysis of the outcome of these operations.

Incidence of dislocation after hip arthroplasty. Comparison of different registration methods in 408 cases.

We studied four different methods of registration of dislocations after total hip arthroplasty (THA) carried out at Malmö General Hospital during 1979-1988. Established registers failed to incorporate more than half of the dislocations and approximately one third of the patients, compared with a manual retrospective review of the original operating cords and the patient files. In 22 percent of the cases the first dislocation occurred more than one year postoperatively. Therefore different studies must use similar methods of registration concerning all details about dislocations in order to allow an adequate comparison of THA dislocation parameters.

Multicenter clinical trials and their value in assessing total joint arthroplasty.

Multicenter clinical trials (MCT) have an important role in the assessment of total joint arthroplasty. The primary reason for such MCT is the need to have access to a large number of patients. In Sweden, failure after total hip arthroplasty has been recorded prospectively since 1979. Medical records from every reoperation are documented and computer analyzed. This MCT has shown that patient-related, surgical, and implant-related parameters are of importance to rates of failure. There were an increasing number of revisions after total hip arthroplasty in Sweden between 1979 and 1986. Male gender and young age increase the risk of revision. The primary diagnosis is very important for type of failure. The risk of deep infection is small but increases with the number of previous operations. Aseptic loosening has emerged as the main problem and is the cause for 74% of all revisions. Prosthetic design is of utmost importance for the rate of failure, and significant differences exist among different prosthesis types with respect to long-term survival. Finally, this MCT has shown that revisions for total hip arthroplasty in patients younger than 70 years of age eventually have failed in Sweden whenever the cemented technique has been used.

Revision total hip arthroplasty in patients younger than 55 years old. Clinical and radiologic results after 4 years.

Since 1979, all revision total hip arthroplasties performed in Sweden have been entered into a prospective multicenter study. Between 1979 and 1982, 65 patients (67 hips) younger than 55 years old required revision arthroplasty because of aseptic loosening. These patients were followed clinically and radiographically for 2-6 years (mean, 4 years). Thirteen patients requiring a second revision because of a recurrent aseptic loosening and one because of subluxations were classified as failures and were not included in the final follow-up study. In the remaining 52 hips (50 patients), the results, rated by the Harris hip score, were good or excellent in 15 hips (29%), fair in 9 hips (17%), and poor in 28 hips (54%). Early complications were rare. Ten hips in 10 patients had radiographic signs of gross loosening of the acetabular or femoral component. mechanical failure, defined as gross loosening or a second revision, was identified in 36% of hips included in the study (n = 67). Revision hip arthroplasty using cement in young and middle-aged patients with cemented primary arthroplasty gave a high rate of failure, because of aseptic loosening. The use of alternative methods and techniques must be explored for revision surgery in younger patients.

How far does prophylaxis against infection in total joint replacement offset its cost?

Selection of a cost effective method of prophylaxis against infection for patients undergoing total joint replacement was shown to depend on the number of arthroplasties performed each year at individual hospitals. When 100 arthroplasties were performed each year the prophylactic use of systemic antibiotics minimised the total costs of the department--that is, the combined costs of prophylaxis and reoperation for deep sepsis. Some departments also used local antibiotic prophylaxis in the form of polymethylmethacrylate cement impregnated with gentamicin or a combination of systemic and local prophylaxis at almost as low a total cost and with comparable effect. Selection of a method of prophylaxis should not be determined solely on the basis of reducing costs. When a value was assigned to the effects of loss of health an economic optimum was established that allowed selection of a more costly method of prophylaxis together with further reductions in the incidence of infection and the need for reoperation.