Journal of Clinical & Experimental Orthopaedics

DIRECT ORAL ANTI-COAGULANTS IN THE PREVENTION OF VENOUS THROMBOEMBOLISM FOLLOWING SURGERY FOR HIP FRACTURE IN THE ELDERLY

Venous thromboembolism (VTE), which comprises pulmonaryembolism (PE) and deep vein thrombosis (DVT), is a signifi-cant cause of morbidity and mortality following hip fracture.1The elderly hip fracture population in particular is at the high-est risk of developing VTE.2In the absence of prophylacticmeasures, the postoperative incidence of VTE following hipfracture is estimated to range between 40%and 60%.3Thisis reduced to 1.4%to 3.5%with the use of effective anticoagulation strategies, which typically utilize anticoagu-lants such as low-molecularweight heparin (LMWH), fonda-parinux, or warfarin.4- 6In recent years, the role of direct oral anticoagulants(DOACs) in major orthopedic surgery has grown exten-sively.7,8The DOACs are advantageous as they are adminis-tered orally, have a predictable pharmacological profile, and donot require monitoring.9Furthermore, several studies havedemonstrated that DOACs are associated with lower rates ofVTE without increased risk of hemorrhage compared to conven-tional anticoagulants for lower limb orthopedic surgery.10-15However, there is limited evidence regarding the use ofDOACs as VTE prophylaxis following surgery for hip frac-ture, with LMWH the preferred form of anticoagulation.16This study aims to evaluate the efficacy and safety of DOACsin older adults undergoing surgery for hip fracture.MethodsPopulationThis is a single-center, retrospective, population-based cohortstudy of patients receiving either a DOAC (apixaban, rivarox-aban, and dabigatran) or LMWH (dalteparin) for VTE prophy-laxis following surgery for hip fracture from January 1, 2017,to December 31, 2018. Patients with any of the following wereexcluded: missing data, age <65 years, previous PE or DVT,previous major hemorrhage, underlying malignancy, or inher-ited disorder of coagulation. All patients were followed up for30 days postoperatively.Clinical ParametersThe following data were obtained: patient demographics,comorbidities, fracture classification, American Society ofAnesthesiologists (ASA) classification, time to surgery, proce-dure performed, and length of stay. The outcomes assessedwere incidence of PE and DVT, incidence of major hemor-rhage, blood transfusion, and death within 30 days of surgery.Both PE and DVT were diagnosed using computed tomographypulmonary angiography and duplex ultrasound scanning,respectively. Major hemorrhage was defined in accordancewith the International Association of Thrombosis and Hemos-tasis Scientific Committee and included hemorrhage from thegastrointestinal, urinary, and cerebrovascular systems.17In theevent of death, the coroner’s report, hospital, and general prac-tice records were reviewed to establish the cause of death.Administration RegimeThe administration regime for all medications were based onguidelines from the British National Formulary. Apixaban wasadministered 2.5 mg twice daily to be started 12 to 24 hoursafter surgery. Rivaroxaban was administered 10 mg once dailyto be started 6 to 10 hours after surgery. Dabigatran was admi-nistered at 75 mg, to be taken 1 to 4 hours after surgery, fol-lowed by 150 mg once daily for 10 days, to be taken on the firstday after surgery. Dalteparin was administered initially at 5000units for 1 dose, to be given on the evening before surgery,followed by 5000 units after 24 hours, and then 5000 unitsevery 24 hours. The duration for treatment across both groupswas standardized at 6 weeks (42 days).Statistical AnalysisMultivariate analysis was performed using IBM SPSS Statis-tics (Armonk, New York). Summary statistics are presented aspercentages, means, and standard deviations. The Student ttestwas used to analyze parametric data, while the w2test was usedto analyze categorical data. Relative risk (RR) is presented with95%confidence interval (CI) and Pvalue and calculated usingthe method described by Altman.18Ethics ApprovalThis was a retrospective study and only anonymized data pre-viously acquired as part of the patient workup or for serviceevaluation purposes were used. Ethical approval was waivedfollowing review of the study proposal by the local ethicscommittee.ResultsThere were 379 patients who underwent surgery for hip frac-ture during the 2-year study period. Of these, 321 patients wereincluded in this study, with 54 patients in the DOAC group and267 patients in the LMWH group. In the DOAC group, 79.6%of patients received apixaban, 16.7%received rivaroxaban, and3.7%received dabigatran. All patients included in the finalanalysis were followed up for a duration of 30 days.The mean age of the study cohort was 85.5 +11.0 years,and the male–female ratio was 104:217 (Tables 1 and 2). Theright hip was involved in 43.0%of cases and the left in theremaining 57.0%. The cohort comprised intracapsular fracturesin 59.2%, intertrochanteric fractures in 38.0%, and subtrochan-teric fractures in the remaining 2.8%. Hemiarthroplasty wasperformed in 40.2%of cases, followed by dynamic hip screwin 44.9%, total hip arthroplasty in 11.2%, and intramedullarynailing in 3.7%. The mean time to surgery was 0.9 +0.6 daysand length of hospital stay was 17.9 +13.3 days. Pre- andpostoperative hemoglobin levels were 122.6 +15.3 g/L and102.8 +16.3 g/L, respectively.The DOAC group had a VTE incidence of 0%compared tothe LMWH group, which was 3.4%(RR: 0.26, 95%CI: 0.02- Journal of Clinical & Experimental Orthopaedics ISSN 2471-8416 4.34, P¼.35; Table 3). Pulmonary embolism occurred in 0%of patients in the DOAC group and in 3.0%in the LMWHgroup (RR: 0.29, 95%CI: 0.02-4.89, P¼.39), while DVToccurred in 0%of patients in the DOAC group and 0.3%ofpatients in the LMWH group (RR: 1.62, 95%CI: 0.07-39.35, P¼.77). Hemorrhage occurred in 7.4%of patients in the DOACgroup and 3.0%of patients in the LMWH group (RR: 2.47,95%CI: 0.77-7.91, P¼.13). The incidence of blood transfu-sion was 20.4%in the DOAC group and 23.6%in the LMWH group (RR: 0.86, 95%CI: 0.48-1.53, P¼.61). Wound hema-toma occurred in 1.9%of patients treated with a DOAC and1.1%of patients treated with LMWH (RR: 1.65, 95%CI: 0.17-15.55, P¼.66).All-cause mortality in the DOAC group was 7.4%. Com-paratively, all-cause mortality in the LMWH group was 3.4%(RR: 2.20, 95%CI: 0.70-6.88, P¼.18). Mortality from VTEwas 0%in the DOAC group and 0.7%in the LMWH group(RR: 0.97, 95%CI: 0.05-20.02, P¼.99). Mortality fromhemorrhage was 1.9%in the DOAC group and 0.7%in theLMWH group (RR: 2.47, 95%CI: 0.23-26.78, P¼.46).Hemorrhage leading to death in the DOAC and LMWH groupswas due to gastrointestinal and intracranial hemorrhagesources, respectively.DiscussionIn the present study, the use of DOACs for VTE prophylaxisfollowing surgery in older adults with hip fracture was associ-ated with a similar rate of VTE compared to LMWH. Thesefindings are comparable to previous studies evaluating the effi-cacy of DOAC therapy for prevention of VTE in lower limborthopedic surgery.10-15,19,20Although nonsignificant, therewasatrendtowardanelevatedriskofhemorrhage,which was not reported in earlier studies of elective orthopedicsurgery.10-15,19,20The elderly hip fracture population are frail,have multiple comorbidities, and are at high risk of falls, whichpredispose them to lifethreatening hemorrhage.2As such, thisfinding warrants further investigation.The rates of VTE in the DOAC and LMWH groups were 0%and 3.4%, respectively, which are comparable to the litera-ture.21,22In a randomized controlled trial (RCT) by Tang andcolleagues, the rate of VTE was significantly lower withDOAC use at 5.2%compared to LMWH use at 14.7%.19The lower rates of VTE reported in both the DOAC and LMWHgroups in the present study can be attributed to difference instudy design. Patients enrolled in RCTs undergo routine inves-tigation for VTE leading to detection of asymptomatic PE andDVT, although there remains considerable debate regarding theclinical significance of these.23In contrast, patients in our studyonly underwent further testing in the presence of clinical fea-tures, so only symptomatic VTE were identified.Both the DOAC and LMWH cohorts in this study are verysimilar in terms of age, gender, fracture pattern, and classifi-cation. However, a larger proportion of patients in the DOACgroup had an ASA classification grade of 3 or more, which maysuggest a poorer prognosis for these patients. Furthermore,total hip replacements were performed more frequently in theLMWH group. This may be indicative of a higher baselinelevel of function and mobility in the LMWH group comparedto the DOAC group. It must be noted that the DOAC group hada lower incidence of stage 4 and stage 5 chronic kidney disease,which may have influenced the decision to prescribe a DOACover LMWH. The timing of DOAC administration remainsunclear and varies with the DOAC type. The current consensusis that the DOAC should be resumed postoperatively oncehemostasis has been achieved and after at least 24 hours (typi-cally 2-3 days) following major surgery.24,25There are several limitations that must be considered in thepresent study. The retrospective design of the study results ininherent biases and confounding factors that could potentiallyinfluence our findings. To minimize the effects of these, multi-variate analysis was used. The decision to prescribe a DOACwas made at the discretion of a senior clinician based on thepresence of clinical risk factors for thromboembolic eventssuch as atrial fibrillation or previous cerebrovascular accident,which was balanced against the risk of hemorrhage. Thus, theDOAC cohort is likely to represent a carefully selected popu-lation of patients who are most likely to benefit from therapy.The sample size of our study was restricted to 321 patients, andthere was no a priori estimate of sample size. It is likely that alarger sample size would be required to detect a clinicallysignificant difference between the 2 groups. This is reflectiveof prescribing practice in the United Kingdom where LMWHremains the first-line treatment for VTE prophylaxis, so only asmall proportion of patients receive DOACs In the present study of a carefully selected cohort of patients,the effect of DOACs in reducing the risk of VTE followingsurgery for hip fracture in older adults was comparable toLMWH. However, a trend toward an increased risk of hemor-rhage was noted, which necessitates further investigation. Theelderly hip fracture population present an important clinicalconundrum given that they are at increased risk of developingVTE as well as life-threatening hemorrhage. These risks can bemitigated through careful selection of patients. Future studieswith larger patient populations will be required to identifypatients who stand to benefit the most from treatment.

En Lin Goh