Low dose compared to variable dose Warfarin and to Fondaparinux as prophylaxis for thromboembolism after elective hip or knee replacement surgery; a randomized, prospective study

Abstract

BackgroundDeep vein thrombosis (DVT) and pulmonary emboli (PE), known together as venous thromboembolic (VTE) disease remain major complications following elective hip and knee surgery. This study compares three chemoprophylactic regimens for VTE following elective primary unilateral hip or knee replacement, one of which was designed to minimize risk of post-operative bleeding.MethodsPatients were randomized and stratified for hip vs. knee to receive A: variable dose warfarin (first dose on the night preceding surgery with subsequent target INR 2.0–2.5), B: 2.5 mg fondaparinux daily starting 6–18 h postoperatively, or C: fixed 1.0 mg dose warfarin daily starting 7 days preoperatively. All treatments continued until bilateral leg venous ultrasound day 28 ± 2 or earlier upon a VTE event. The study examined primary endpoints including leg DVT, PE or death due to VTE and secondary endpoints including effects on D-dimer, estimated blood loss (EBL) at surgery and hemorrhagic complications.ResultsThree hundred fifty-five patients were randomized. None was lost to follow-up. Taking 1.0 mg warfarin for seven days preoperatively did not prolong the prothrombin time (PT). Two patients in Arm C had asymptomatic distal DVT. One major bleed occurred in Arm B and one in Arm C (ischemic colitis). Elevated d-dimer did not predict delayed VTE for one year.ConclusionsFixed low dose warfarin started preoperatively is equivalent to two other standards of care under study (95 % CI: -0.0428, 0.0067 for both) as VTE prophylaxis for the patients having elective major joint replacement surgery.Trial registrationClinicalTrials.gov identifier # NCT00767559FDA IND: 103,716

Venous Thromboembolism Prophylaxis After TKA: Aspirin, Warfarin, Enoxaparin, or Factor Xa Inhibitors?

“…This effect may be attributable in part to the mechanism of action, but also ease of administration and compliance in comparison to enoxaparin [9,39]. Data directly comparing factor Xa inhibitors with warfarin after TKA are limited, with a single randomized clinical trial finding no differences between the groups [7]. This contrasts with our study, in which factor Xa inhibitors showed better VTE prophylaxis when compared with warfarin.…”

“…Despite this, we identified lower VTE incidence with comparable bleeding risk with factor Xa inhibitors in the patients who were most medically complex. Our findings regarding VTE prophylaxis do not have a direct correlate in the literature as other studies omit one or more of the two agents, but studies comparing multiple agents do help put our findings into context [3,7,21,22,24,38,40,41]. Aspirin has been found to have a low VTE rate, with no difference when compared with enoxaparin in a couple meta-analyses [3,40].…”

“…As VTE is an uncommon event, it is difficult to acquire sufficient statistical power to discern differences between agents, and as a result the myriad of meta-analyses comparing outcomes continue to reinforce the inadequacy of the retrospective and prospective studies in the area of thromboprophylaxis [3,5,15,40]. Numerous studies are further limited by high variability of study protocols, patient volume, outcome measures, and clinical practice [7,16,22,24,41]. No study to date, to our knowledge, has directly compared aspirin, enoxaparin, warfarin, and factor Xa inhibitors for thromboprophylaxis after TKA because they lacked the power to perform such a comparison.…”

Surgical Technical Evidence Review for Elective Total Joint Replacement Conducted for the AHRQ Safety Program for Improving Surgical Care and Recovery

“…The literature search identified 1942 articles, of which 6 met the inclusion criteria and were specific to total joint replacement: 5 SRs and 1 RCT. A 2016 Cochrane review 112 synthesized a large number of contemporary RCTs (referred to as “trials” below); to this, we added 4 additional SRs 113 – 116 and 1 additional RCT 117 that have been published since the Cochrane literature search concluded.…”

Prophylaxis of Venous Thromboembolism in Knee Replacement Surgery

“…Bern et al [56] randomized 355 patients in three groups A: variable dose warfarin (first dose on the night preceding surgery with subsequent target INR 2.0-2.5), B: 2.5 mg fondaparinux daily starting 6-18 h postoperatively, or C: fixed 1.0 mg dose warfarin daily starting 7 days preoperatively. All treatments continued until bilateral leg venous ultrasound day 28 ± 2 or earlier upon a VTE event.…”