Ola Einar Dahl

12.06.2018: Kommentar - Takk for kommentar til vår artikkel.

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. 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. 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. 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. NCT00657150 and NCT00168818

We describe annual incidences and 6-month postoperative patterns of clinical venous thromboembolism (VTE) in 9078 patients undergoing major joint surgery in a Scandinavian hospital. In cohort I (1989-1999), low-molecular-weight heparin thromboprophylaxis for 7 to 10 days was uniformly introduced, 5-week thromboprophylaxis becoming routine after total hip replacement (THR), partially applied after hip fracture surgery (HFS), but not used after total knee replacement (TKR) thereafter (2003-2011; cohort II). Mean annual VTE incidence was lower in cohort II than in cohort I after THR and HFS but not after TKR. In cohort I, the cumulative VTE incidence increased sharply during the first 5 postoperative weeks in all groups, subsequently plateauing up to 6 months postsurgery. In cohort II, this incidence remained low and stable during 5 weeks post-THR, rising gradually up to 6 months, with a comparable but less pronounced pattern following HFS but not TKR. In conclusion, the VTE risk after major joint surgery seems to persist after 5- and 1-week prophylaxis in patients undergoing hip surgery and TKR, respectively.

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. 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. 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. 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.

Dabigatran etexilate is an oral reversible direct thrombin inhibitor that offers potential practical advantages over existing anticoagulants for the prevention of venous thromboembolism after major joint replacement surgery. These include oral administration, rapid onset of action, and a predictable anticoagulant effect that obviates the need for laboratory monitoring. Evidence from 3 phase II dose-finding trials showed that dabigatran etexilate, 100 to 300 mg daily, had similar efficacy, risk of bleeding, and tolerability compared with enoxaparin. Using pharmacokinetic modeling and taking into account efficacy/safety considerations, dabigatran etexilate 150 mg and 220 mg once daily, with a half-dose on the day of surgery, were selected for further evaluation in phase III trials. These doses were selected to ensure that the risk of bleeding did not exceed that of enoxaparin. This review discusses the rationale for selection of these dose regimens based on results from phase II trials.

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.