Review of perioperative outcomes and management of hip fracture patients on direct oral anticoagulants

in EFORT Open Reviews
Authors:
Pelle V Wall University of California San Diego School of Medicine, Gilman Drive, La Jolla, California, United States of America

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Brendon C Mitchell Department of Orthopaedic Surgery, University of California San Diego, West Arbor Drive, California, United States of America

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Canhnghi N Ta Department of Orthopaedic Surgery, University of California San Diego, West Arbor Drive, California, United States of America

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https://orcid.org/0000-0003-3737-2003
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William T Kent Department of Orthopaedic Surgery, University of California San Diego, West Arbor Drive, California, United States of America

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Correspondence should be addressed to W T Kent; Email: wkent@health.ucsd.edu
DOI:
https://doi.org/10.1530/EOR-22-0060
Volume/Issue:
Volume 8: Issue 7
Page Range:
561–571
Article Type:
Review Article
Online Publication Date:
03 Jul 2023
Copyright:
© the author(s) 2023
Category:
Hip
Open access

  • Anticoagulation use is common in elderly patients presenting with hip fractures and has been shown to delay time to surgery (TTS). Delays in operative treatment have been associated with worse outcomes in hip fracture patients. Direct oral anticoagulants (DOACs) comprise a steadily increasing proportion of all oral anticoagulation. Currently, no clear guidelines exist for perioperative management of hip fracture patients taking DOACs.

  • DOAC use is associated with increased TTS, with delays frequently greater than 48 h from hospital presentation. Increased mortality has not been widely demonstrated in DOAC patients, despite increased TTS. Timing of surgery was not found to be associated with increased risk of transfusion or bleeding.

  • Early surgery appears to be safe in patients taking DOACs presenting with a hip fracture, but is not currently widely accepted due to factors such as site-specific anesthesiologic protocols that periodically delay surgery. Direct oral anticoagulant use should not routinely delay surgical treatment in hip fracture patients.

  • Surgical strategies to limit blood loss should be considered and include efficient surgical fixation, topical application of hemostatic agents, and the use of intra-operative cell salvage.

  • Anesthesiologic strategies have utility in minimizing risk and a collaborative effort to minimize blood loss should be undertaken by the surgeon and anesthesiologist. Anesthesia team interventions include considerations regarding positioning, regional anesthesia, permissive hypotension, avoidance of hypothermia, judicious administration of blood products, and the use of systemic hemostatic agents.

Abstract

  • Anticoagulation use is common in elderly patients presenting with hip fractures and has been shown to delay time to surgery (TTS). Delays in operative treatment have been associated with worse outcomes in hip fracture patients. Direct oral anticoagulants (DOACs) comprise a steadily increasing proportion of all oral anticoagulation. Currently, no clear guidelines exist for perioperative management of hip fracture patients taking DOACs.

  • DOAC use is associated with increased TTS, with delays frequently greater than 48 h from hospital presentation. Increased mortality has not been widely demonstrated in DOAC patients, despite increased TTS. Timing of surgery was not found to be associated with increased risk of transfusion or bleeding.

  • Early surgery appears to be safe in patients taking DOACs presenting with a hip fracture, but is not currently widely accepted due to factors such as site-specific anesthesiologic protocols that periodically delay surgery. Direct oral anticoagulant use should not routinely delay surgical treatment in hip fracture patients.

  • Surgical strategies to limit blood loss should be considered and include efficient surgical fixation, topical application of hemostatic agents, and the use of intra-operative cell salvage.

  • Anesthesiologic strategies have utility in minimizing risk and a collaborative effort to minimize blood loss should be undertaken by the surgeon and anesthesiologist. Anesthesia team interventions include considerations regarding positioning, regional anesthesia, permissive hypotension, avoidance of hypothermia, judicious administration of blood products, and the use of systemic hemostatic agents.

Keywords: hip fracture; direct oral anticoagulant (DOAC); anticoagulation; trauma; geriatric; surgical timing; bleeding

Introduction

Hip fractures are common and morbid injuries affecting the elderly population, largely due to high rates of osteoporosis and other factors that contribute to decreased bone mineral density (1). The incidence of hip fractures has been shown to range widely based on country, with an annual incidence in the United States of 957/100 000 for women and 414/100 000 for men (2, 3). While age-standardized rates were declining from 1995 to 2005, rates appear to have leveled off in the last decade (3, 4). With an aging population, the rate of hip fractures in patients over age 50 in the United States is expected to increase from 300 000 in 1990 to 512 000 annually by 2040 (5). Worldwide, by 2050, 6.26 million hip fractures are expected each year (6).

Hip fractures are associated with significant morbidity, mortality, and cost. These critical injuries are associated with increased short- and long-term all-cause mortality, reducing life expectancy by 1.8 years or 25% compared with age and sex-matched controls (7, 8). Approximately one-third of patients will expire within 12 months of injury (3, 9). Additionally, the financial burden of hip fractures is significant, with a lifetime attributable cost of $81 300, 44% of which is incurred from expenses related to nursing care (8). The total annual cost of hip fractures in the United States is expected to increase from $7.3 billion in 1983 to $16 billion by the year 2040 (5).

Importance of timing in surgical treatment

Surgical intervention of hip fractures is often indicated, except in certain cases such as non-ambulatory or high-risk patients with multiple severe comorbidities. Non-operative management is associated with four-fold higher mortality at 1 year and three-fold higher mortality at 2 years compared to surgical treatment (10). Prompt operative intervention (within 48 h of injury) is associated with significantly improved outcomes (11, 12, 13). Further decreased time to surgery (within 24 h of hospital arrival) is associated with decreased pain and length of hospital stay (14). Meanwhile, delaying surgery for >48 h has been found to significantly increase the risk of short- and long-term mortality, minor and major medical complications, and the development of pressure sores (11, 12, 13, 14, 15).

Anticoagulation in hip fracture patients

Chronic anticoagulant use is frequently seen in elderly hip fracture patients due to underlying cardiovascular disease (16). This poses a significant challenge to timely operative intervention, with anticoagulated patients experiencing delays to surgical repair and longer hospital stays compared with non-anticoagulated patients (17). A survey study showed that 73.6% of surgeons felt that adequate clinical guidelines for patients with hip fractures receiving anticoagulation did not exist (18). Approximately 3–4% of all trauma patients are using oral anticoagulation prior to hospital arrival and in 2006, 12.8% of trauma patients aged 65 or older were utilizing Warfarin. As such, the proportion of hip fracture patients on anticoagulation is likely significant (19, 20).

Direct oral anticoagulants

Direct oral anticoagulants (DOACs) have emerged as a popular alternative to vitamin K antagonists (VKAs) for stroke prophylaxis in non-valvular atrial fibrillation, venous thromboembolism (VTE), and secondary prevention of adverse outcomes following acute coronary syndromes. DOACs include direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban, and betrixaban) and direct thrombin (factor IIa) inhibitors (dabigatran is the only current oral formulation), all of which affect the coagulation cascade (Fig. 1). The half-lives of DOACs range from 5 h to 27 h, largely relying on renal clearance, which may dramatically increase effective half-lives in the elderly (Table 1) (20, 21, 22, 23).

Figure 1
Figure 1

Coagulation cascade with direct oral anticoagulant sites of action.

Citation: EFORT Open Reviews 8, 7; 10.1530/EOR-22-0060

Table 1

Pharmacokinetics and pharmacodynamics of direct oral anticoagulants (22, 54, 55, 56).
Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban
Target Thrombin (IIa) Factor Xa Factor Xa Factor Xa Factor Xa
T1/2 (h) 12–17 Young, healthy: 5–9; Elderly: 11–13 8-15 10–14 19–27
Tmax (h) 2 2–4 1–3 1–2 3–4
Bioavailability (%) 7 66 50 62 34
Renal excretion (%) 80 66 25 35 17.8
Fecal excretion (%) 82–88 26.4 46.7–56 62.2 85
CYP450 metabolism No Yes Yes No No
Specific reversal agents Idarucizumab Andexanet alfa Andexanet alfa – –
Time alloted prior to spinal anesthesia (h) 24 24 24 24 72

h, hours; T1/2, drug half-life;Tmax , time to reach peak concentration in plasma after oral dose.

With a favorable safety profile, decreased risk of major bleeding, and no need for routine drug monitoring or dietary regulation, DOAC use has increased dramatically at the expense of VKAs since their introduction to clinical practice in 2010 (24, 25). DOACs have also shown comparable outcomes to low-molecular-weight heparin (LMWH) in the setting of hip fractures (26). In 2015, DOACs accounted for 56.5% of all oral anticoagulant prescriptions and are now the anticoagulant of choice for many patients with atrial fibrillation or a history of stroke/transient ischemic attack (TIA) (27).

DOAC use in hip fracture patients

Recent literature shows that DOAC use in hip fracture patients ranges from less than 1% to nearly 20% (Table 2). It should be noted that the proportion of anticoagulated patients on DOACs is rising, and a recent study showed that overall DOAC use percentages may not fully capture the most current rates (28). These trends in DOAC use have led to a need for further investigation of how DOACs affect hip fracture management (Fig. 2). The present paper summarizes existing literature and sheds light on optimal perioperative management of hip fracture patients on this form of anticoagulation.

Table 2

Epidemiology of DOAC, VKA use in hip fracture patients.
Study Study type Inclusion criteria n Hip fracture patients
DOAC VKA
Tran et al. (16) CCS* Operative, isolated hip fracture 2258 1.2% 10.3%
Lott et al. (43) RCS Isolated hip fracture, ≥60 years 479 0.8% 7.7%
Sabo et al. (31) PCS Low-energy, operative hip fracture 55 9.1% 14.5%
Taranu et al. (17) PCS Hip fracture, >60 years 1965 4.5% 7.1%
Bruckbauer et al. (35) RCS Isolated hip fracture, ≥65 years 320 16.9% 18.4%
Cafaro et al. (42) RCS Acute operative hip fracture, ≥18 years 472 6.6% 5.9%
Daugaard et al. (36) RCS First time hip fracture, ≥65 years 74791 1.4% 5.6%
Hourston et al. (32) RCS Surgically treated femoral neck fracture 844 3.8% 9.8%
Schermann et al. (40) RCS Operative (CRIF or HA only) intertrochanteric and femoral neck fracture, ≥65 years 1714 5.2% 9.3%
Schuetze et al. (47) RCS Operative, isolated per- or subtrochanteric fracture 327 15.9% 7.6%
Viktil et al. (23) PCS Operative acute hip fracture, ≥65 years 167 6.6% 8.4%
Creeper et al. (56) RCS Acute hip fracture 1240 6.6% 5.4%
Hoerlyck et al. (61) RCS Hip fracture, ≥50 years 2307 1.4% 8.7%
Meinig et al. (51) RCS Isolated operative fragility hip fracture, ≥65 years 459 19.8% 39.0%
Saliba et al. (39) RCS Operative hip fracture, ≥65 years 3418 7.2% 4.8%
Tarrant et al. (28) RCS Hip fracture, ≥65 years 3264 3.4%†

*Overall percentage, however, rates increased annually and were 9% in 2018; †Percentages for DOAC and VKA patients calculated from a cohort of all hip fracture patients.

CCS, case–-control study; CRIF, closed reduction internal fixation; DOAC, direct oral anticoagulation; HA, hemiarthroplasty; PCS, prospective cohort study; RCS, retrospective cohort study.

Figure 2
Figure 2

Proposed workup of otherwise medically cleared patients on DOAC prior to surgical repair of hip fracture.

Citation: EFORT Open Reviews 8, 7; 10.1530/EOR-22-0060

Time to surgery

A significantly increased time to surgery (TTS) in hip fracture patients on DOACs compared with non-anticoagulated patients has been described in several studies (Table 3). A recent systematic review and meta-analysis of 39 446 patients found DOAC patients faced an average surgical delay of 15.46 h (95% CI: 9.20–21.72 h) compared with non-anticoagulated controls (29). The amount of surgical delay DOAC patients faced compared with non-anticoagulated patients varies significantly between studies, ranging from no significant difference to 41 h longer (30, 31). However, these studies were limited by low sample size, as well as a retrospective design in the study by Leer-Salvesen et al., thereby making it difficult to draw definitive conclusions. The proportion of patients on DOACs who underwent surgery after 48 h was also greater than in non-anticoagulated patients in most studies (Table 3), but significant variation has been reported with proportions ranging from 9% to 49% (32, 33). You et al. found that anticoagulated patients had three-fold higher odds of receiving surgery >48 h from admission compared with non-anticoagulated controls, although they did not distinguish between DOAC and VKA users for this analysis (29). The shortest mean or median TTS for DOAC patients was 27.6 h and the longest was 66.9 h (Table 3) (16, 32).

Table 3

Time to surgery in hip fracture patients on DOAC vs VKA and no oral anticoagulation. Data are presented as mean±S.D., median or as median (IQR).
Study Study Design n No OAC TTS DOAC TTS VKA TTS Major Findings LOE
Tran et al. (16) CCS 520 26.2h (17.3-40.6) 66.9h (38.1-78.9) 39.4h (26.6-46.4) TTS: DOAC > VKA > No OAC III
Franklin et al. (41) CCS 93 21.4h ± 12.4 28.9h ± 11.8 TTS: DOAC > No OAC III
Frenkel Rutenberg et al. (33) CCS 796 28.7h ± 25.7; 92% <48h 55.3h ± 38.8; 51% <48h 59.2h ± 45; 59% <48h TTS >48h: DOAC > No OAC III
Sabo et al. (31) PCS 55 25h ± 19h 66h ± 16h 38h ± 21h TTS: DOAC > VKA > No OAC II
Taranu et al. (17) PCS 1965 22.57h Rivaroxaban: 35.04 h; Dabigatran: 48.28 h; Apixaban: 36.7h 28.34h (median) TTS: Anticoagulated > No OAC. II
Bruckbauer et al. (35) RCS 320 12h 85% <24h; 4.3% >48h 29.5h; 37% <24h; 13% >48h 50.8% <24h; 8.4% >48h TTS: DOAC > No OAC. Greater proportion DOAC operated on >48h after hospitalization III
Cafaro et al. (42) RCS 472 44h (28-63) 61 h (42-77) 64h (50-84) TTS: DOAC and VKA > No OAC, DOAC = VKA III
Daugaard et al. (36) RCS 74 791 44.1% <24h; 17.5% 24-36h; 38.4% >36h 37.7% <24 h; 21.3% 24–36 h; 40.7% >36 h TTS > 36 h in twice as many DOAC, VKA patients vs No OAC III
Hourston et al. (32) RCS 844 22 h 85% <36 h; 94% <48 h 29h; 59% <36 h; 91% <48 h 27h; 77% <36 h; 95% <48 h DOAC use independently associated with increased TTS >36 h but not >48 h. TTS VKA = No OAC III
Schermann et al. (40) RCS 1714 CRIF: 31.2h ± 22.2; 82% <48 h n.s.;

HA: 36.6 h ± 25.8 n.s.;

77.5% <48 h n.s.		 CRIF: 40.2± 26.9; 74% <48h n.s.;

HA: 42.3 h ± 27.3 h n.s.;

74% <48 h n.s.		 TTS: DOAC > No OAC in CRIF only. DOAC = No OAC in HA III
Viktil et al. (23) PCS 167 44 h 25 h TTS: DOAC > VKA III
Brown et al. (34) CCS 144 19.8 h± 10.5 h 27.6 h ± 16.3; 50% <24h; 92% <48 h TTS: DOAC > No OAC. No statistical comparison done for proportion of DOAC vs. *No-OAC receiving surgery <24 h, <4 8h III
Gosch et al. (62) CCS 102 30 h ± 18.7 42.7 h ± 14.2 40.5 h ± 15.1 TTS: OAC (DOAC + VKA) > No OAC III
King et al. (37) RCS 84 25.98 h ±11.4 32.21 h ± 7.83 TTS: DOAC > No OAC III
Leer-Salvesen et al. (30) RCS 314 26.1 h ± 19.0 h 28.9 h ± 12.9 n.s. TTS: DOAC = No OAC III
Saliba et al. (39) RCS 3418 24.6 h (17.3–30.7); 90.0% <48 h 31.8 h (24.9–52.8); 71.7% <48 h 31.4 h (22.5–55.3); 67.2% <48 h TTS: DOAC, VKA > No OAC. Lower proportion of DOAC, VKA patients operated on <48h after hospitalization III
Tarrant et al. (28) RCS 112 1.2d† ± 0.7 1.8d† ± 1.3 TTS: DOAC > No OAC III
Rostagno et al. (38) RCS 280 2.15 days ± 1.07 3.6 days ± 2.7 TTS: DOAC > No OAC III
You et al. (29) SRMA 39 446 Mean difference for DOAC TTS vs no-OAC: +15.46 h (95% CI: 9.20–21.72 h). TTS: DOAC = VKA III

†TTS was calculated from time of last DOAC dose, not from time of hospital arrival; *No statistical comparison specifically for patients on DOAC vs No OAC.

95% CI, 95% confidence interval; CCS, case-control study; CRIF, closed reduction internal fixation; d, days; DOAC, direct oral anticoagulant; h, hours; HA, hemiarthroplasty; IQR, interquartile range; LOE, level of evidence; n.s., not significantly different from comparison group(s); No OAC, no oral anticoagulation; PCS, prospective cohort study; SD, standard deviation; SRMA, systematic review/meta-analyses; TTS, time to surgery; RCS, retrospective cohort study; VKA, vitamin K antagonists.

While surgical delay in DOAC users compared with non-anticoagulated patients was near universal, no clear methodological reasons between studies explain the significant variation in the amount of surgical delay and absolute TTS that DOAC patients experienced. More likely, increasing familiarity with DOAC medications and variable access to DOAC reversal agents over time account for the TTS differences seen between studies. Tran et al., collecting data from 2010 to 2014, suspected the significant surgical delay they found in DOAC users was due to uncertainty surrounding perioperative management of DOACs (mean DOAC TTS of 66.9 h vs 26.2 h for non-anticoagulated patients) (16). A 2018 case–control study of 796 hip fractures found waiting for a decrease in DOAC drug activity was responsible for surgical delay in 70% of DOAC users (no DOAC patients were reversed), while only 32% of patients on VKA (who were routinely reversed with vitamin K) experienced a surgical delay due to INR levels (33). Bruckbauer et al. cite a lack of specific tests for rapid quantification of Xa and thrombin inhibitors, and no specific reversal agents for FXa inhibitors at the time, for the increased TTS and higher proportion of patients receiving surgery after 48 h observed in DOAC users compared with non-anticoagulated patients (35). Additionally, hospital and region-specific procedural differences, due to a lack of established guidelines, are likely to have played a role in the TTS variability seen between studies (30). These findings highlight the delay in definitive surgical treatment that frequently occurs in patients on DOACs and underscore the need for a better understanding of the anticoagulants, and comprehensive clinical guidelines for their management, in hip fractures.

Mortality consequences of delayed time to surgery in patients taking direct oral anticoagulants

Interestingly, the increased surgical delay seen in hip fracture patients on DOACs was not widely associated with increased mortality (Table 4). A retrospective cohort of 320 hip fracture patients ≥65 years old found no significant difference in mortality rates between DOAC, VKA, and non-anticoagulated patients (35). This was observed despite three times as many DOAC patients were operated on after 48 h as non-anticoagulated patients (13% DOAC vs 4.3% non-anticoagulated; mean TTS: 29.5 h for DOAC vs 12 h for non-anticoagulated) (35). Another study, which showed the largest discrepancy between the proportion of DOAC patients operated on after 48 hcompared with non-anticoagulated patients (48.9% DOAC vs 8% nonanticoagulated), also showed no difference in in-hospital or 1-ear mortality between groups (33). Multiple other studies, including a systematic review of 39 446 patients, have shown similar findings of no increased mortality risk associated with delayed surgery in DOAC users (28, 29, 32, 34, 36, 37, 38).

Table 4

Bleeding and transfusion rates, mortality and other complications associated with DOAC use in hip fracture.
Study Study type n Major findings LOE
Franklin et al. (41) RCCS 93 (19 DOAC, 74 No OAC control) Patients on DOAC operated on within 48 h showed no differences in transfusions, changes in Hgb levels, wound complications, or survival at any time point. DOAC patients had longer TTS and were more likely to undergo readmission within 30 d than controls (no readmissions for complications of the surgical site, bleeding, or VTE). III
Frenkel Rutenberg et al. (33) RCS 796 No increased morbidity, in-hospital, or 1-y mortality in DOAC users vs controls, despite significantly larger proportion of patients on DOACs experiencing delayed TTS (>48 h). DOAC users did not have adverse outcomes compared with VKA users. III
Mullins et al. (44) RCCS 125 (63 DOAC, 62 control) No relationship found between TTS and perioperative change in Hgb or probability of transfusion in patients on DOACs. III
Bruckbauer et al. (35) RCS 320 Patients on DOACs and VKAs were transfused at significantly higher rates than non-anticoagulated patients (53.7% of DOAC, 54.2% of VKA, vs 38% No OAC). DOAC use was associated with longer TTS. No difference in in-hospital mortality was observed between groups. III
Daugaard et al. (36) RCS 74 791 DOAC users had slightly increased risk of transfusion compared with non-DOAC users when operated on <24 h. DOAC users delayed >36 h had lower 30-d mortality risk than non-users. TTS of >36 h was twice as common for DOAC users vs non-DOAC users. III
Hourston et al. (32) RCS 844 DOAC use had no effect on 30 dy, 6 m, or 1 yr survival, whereas VKA use was associated with decreased 30-d survival. DOAC use, but not VKA use, was independently associated with increased TTS >36 h but not >48 h. Anticoagulation did not increase hospital LOS. III
Lott et al. (43) RCS 78 Patients receiving antiplatelet or DOAC therapy who underwent surgery <48 h from admission were at no higher risk for transfusion, increased surgical blood loss, longer operative time, or inpatient mortality. III
Schermann et al. (40) RCS 1714 Patients on DOACs who underwent CRIF had increased TTS and risk of 1-y mortality than non-AC patients. For both CRIF- and HA-treated patients, DOAC users had similar perioperative Hgb change, transfusion rates, and perioperative mortality compared to non-AC controls. III
Schuetze et al. (47) RCR 327 DOAC patients presented with lower Hgb concentrations and had 3.4-fold increased risk for intraoperative blood transfusions compared with controls. Anticoagulation showed no significant effect on complication rates and mortality in patients operated within 24 h. III
Aziz et al. (45) Mixed R/PCS 120 DOAC use associated with increased blood loss, transfusion rates, and TTS; however, DOAC patients presented to hospital with lower Hgb and subsequent blood loss was minimal. III
Brown et al. (34) RCCS 144 (36 DOAC, 108 No OAC controls Patients on DOACs had no difference in EBL, change in Hgb, or rates of transfusion, reoperation, readmission, DVT, or 30-day mortality compared with non-AC controls. DOAC users had longer TTS, but 92% were operated on within 48 h. III
Gosch et al. (62) RCCS 102 (6 DOAC, 15 VKA, 61 control) DOAC and VKA users had longer TTS and LOS than non-AC controls. DOAC and VKA use was associated with increased minor but not major bleeding; Hgb decrease was similar in all groups. Combined endpoint (in-hospital mortality, mortality, 3+ pRBCs, revision surgery, major bleeding, Hgb loss ≥ 6 g/dL, MI, stroke, thromboembolic events) was significantly higher for DOAC users than non-AC patients. No difference in mortality between groups. III
King et al. (37) RCS 84 No significant difference in perioperative Hgb levels, transfusion rates, or hematoma between DOAC users operated on <48 h, >48 h, and non-DOAC user controls operated on <48 h. DOAC users operated on >48 h had significantly more deaths than DOAC users operated on <48 h. DOAC users who received surgery <48 h still had significantly increased TTS compared to non-DOAC controls. III
Leer-Salvesen et al. (30) RCR 314 Perioperative blood loss, transfusion rates, and risk of bleeding complications and mortality were similar between DOAC users and non-AC patients. Five times more wound oozing in DOAC patients than non-OAC patients. No difference in TTS or hospital LOS was seen between groups. III
Saliba et al. (39) RCS 3418 DOAC use associated with reduced risk of 30-d and 90-d mortality among elderly patients with hip fracture. Only patients on VKA required significantly higher number of blood transfusions. DOAC and VKA use was associated with >TTS and >LOS than non-AC patients. III
Tarrant et al. (28) RCS 3264 Timing of surgery in DOAC users did not affect 30-d mortality, serious AEs, transfusions rates, or postoperative day 1 Hgb levels. DOAC patients had significantly longer TTS than age and sex-matched non-AC controls. III
Xu et al. (46) SRMA 21,417 Neither perioperative RBC transfusion nor EBL were significantly different between DOAC and non-AC patients. III
Rostagno et al. (38) RCS 280 Neither anticipation nor delay in surgery did result in increased mortality, length of stay or complication rates with the exception of larger perioperative blood loss (Hb levels < 8 g/dL) in DOAC patients.
You et al. (29) SRMA 39,446 DOAC users had longer TTS than no-OAC controls, but no difference in in-hospital or 30-d mortality, or hospital LOS. III

AC, anticoagulated; AEs, adverse events; CCS, case–control study; CRIF, closed reduction internal fixation; d, days; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; EBL, estimated blood loss; h, hours; Hgb, hemoglobin; HA, hemiarthroplasty; LOE, level of evidence; LOS, length of stay; MI, myocardial infarction; OAC, oral anticoagulant; pRBC, packed red blood cells; PCS, prospective cohort study; RCCS, retrospective CCS; RCS, retrospective cohort study; RCR, retrospective chart review; SRMA, systematic review/meta-analyses; TTS, time to surgery; VKA, vitamin K antagonist; VTE, venous thromboembolism; y, years.

One recent retrospective cohort of 3418 patients ≥65 years old who underwent operative repair for hip fracture found DOAC users to have a decreased risk of 30-day and 90-day mortality compared with non-anticoagulated patients, despite experiencing longer TTS and hospital length of stay (39). The authors attributed this to the antithrombotic and protective effects during the perioperative period despite the discontinuation of DOACs, early postoperative therapeutic dose anticoagulant administration, and healthy user effect-related biases. Additionally, they reported that the time delay was insignificant and likely utilized for anticoagulant reversal rather than acute medical optimization. The relative surgical delay for DOAC patients compared with non-anticoagulated patients in this study was small, however, with median TTS of 31.8 h in DOAC patients and 24.6 h in non-anticoagulated patients. Longer-term mortality was not assessed. To our knowledge, only one other study has replicated a decreased mortality rate in DOAC users despite increased surgical delay (36). This study showed a decreased 30-day mortality in DOAC users but only in the cohort undergoing surgery >36 h after admission. Interpretation of these data is complicated by the fact that DOAC users were compared with non-DOAC users (including patients on antiplatelet medication, VKAs, and no anticoagulation) rather than only non-anticoagulated patients, therefore adding methodological bias to this study.

Contrary to the majority of other studies, two publications found increased mortality among DOAC users (37, 40). The first study reported on a retrospective cohort of 1714 proximal hip fractures in patients ≥65 years old, looking only at patients surgically managed with closed reduction internal fixation (CRIF) or hemiarthroplasty (HA) (40). The authors found 1-year mortality was significantly higher in DOAC patients who underwent CRIF (but not HA), for which delayed TTS was an independent risk factor; however, other contributing risk factors for increased 1-year mortality existed in this subgroup including older age and higher comorbidity burden. TTS, 1-month mortality and 1-year mortality rates were not significantly different in DOAC and non-anticoagulated patients who underwent HA. The second, a case–control study of 84 hip fracture patients undergoing surgery <48 h vs>48 h from admission, found DOAC patients with >48 h surgical delay had a significantly higher 90-day mortality compared to those receiving early surgery (37). However, this DOAC patient group had a higher American Society of Anesthesiologists (ASA) physical status classification, increased preoperative medical complications, and lower preadmission mobility which may have acted as confounders for both TTS and 90-day mortality (13, 14).

The generally observed lack of increased mortality rates despite an increased TTS (often beyond the recommended 48 h) in DOAC users may be explained by the age and comorbidities of these patients. A systematic review and meta-analysis of 257 367 hip fracture patients found that older patients and those at higher baseline risk experience a lesser 1-year mortality benefit from early surgery than younger, lower risk patients (14). The majority of studies presently reviewed included only geriatric hip fractures; studies often excluded patients <65 years old, and average patients’ age was consistently in the 80s. Additionally, while most studies reported increased TTS in DOAC patients, the absolute delay relative to non-anticoagulated patients was often minimal and thus may not have been of clinical significance. For example, five studies (30, 32, 34, 40, 41) showed an absolute increase in mean or median DOAC TTS of less than 10 h relative to non-anticoagulated patients and eight studies (17, 30, 31, 34, 35, 40, 41, 42) showed an absolute increase in DOAC TTS of less than 24 h compared with non-anticoagulated patients.

Safety of early surgery

Early surgical treatment of hip fractures appears safe in DOAC users. A recent study compared hip fracture patients on DOACs who were surgically repaired <48 h vs>48 h after hospital admission, including a control group of non-anticoagulated patients who underwent surgery <48 h after admission (40). The authors found no significant difference in perioperative hemoglobin change, transfusion rates, or hematoma formation between early (<48 h) and late (>48 h) operated DOAC patients or between early operated DOAC and non-anticoagulated patients. These results are also consistent with another recent study that found no increased risk of transfusion, surgical blood loss, operative time, or inpatient mortality in DOAC patients who were operated on <48 h compared to those operated on >48 h from admission (43).

DOAC users also do not appear to fare worse than non-anticoagulated controls when operated on <48 h from admission. A case–control study compared 19 patients on DOACs aged 60–89 to 74 non-anticoagulated controls, all of whom underwent surgery within 48 h of admission (41). Non-anticoagulated controls were matched based on sex, construct (hemiarthroplasty, cephalomedullary nail [CMN], or sliding hip screw), and age as closely as possible. The authors found no significant differences between groups in estimated blood loss (EBL), transfusion rates, or the volume of blood transfused in patients who required transfusion. These findings persisted after adjusting for known differences in EBL between short and long CMN and on construct-based subgroup analysis. There were also no significant differences in surgical time, length of stay, or rates of perioperative complications, including hematoma formation, persistent serous drainage, or need for reoperation between groups. Furthermore, 30-day, 90-day, and 1-year survival were not significantly different between DOAC and non-anticoagulated patients in this cohort of patients undergoing surgery <48 h from admission.

Surgical timing, blood loss, and transfusion rates

Delaying surgery does not appear to reduce perioperative blood loss or transfusion rates in DOAC users. In a cohort of 63 first-time proximal femur fracture patients on DOACs, one study found no relationship between TTS from admission and probability of transfusion or perioperative hemoglobin change (44). Similarly, another study found no relationship between TTS from the last DOAC dose and transfusion rates or postoperative day 1 hemoglobin in a cohort of 112 patients age 65 and older admitted for proximal femur fracture (28). A third one found prolonged waiting for surgery in DOAC patients had no effect on blood loss (45).

Indeed, many studies have shown no increased risk of blood loss or transfusion rate in DOAC patients undergoing hip fracture surgery at all (Table 4). A systematic review and meta-analysis of hemostatic complications in 21 417 hip fracture patients found that neither perioperative red blood cell transfusion rates nor EBL wassignificantly different in DOAC and non-anticoagulated patients (transfusion OR 0.93–2.00; EBL +2.8 mL in DOAC, P = 0.83) (46). Similar rates of transfusion and blood loss between DOAC users and non-anticoagulated patients were seen even with similar TTS (<8-h difference) between groups (30, 34, 39, 41).

However, one study showed a 53.7% transfusion rate in DOAC vs 38% transfusion rate in non-anticoagulated patients, despite non-significantly different admission hemoglobin levels (34). Another retrospective cohort study also showed a slightly increased transfusion rate in DOAC patients (RR 1.14 [1.02–1.27]) compared with non-users but only in those patients operated on <24 h after admission (35). Hemoglobin on admission and hemoglobin drop were not reported. These latter data might suggest an increased risk of transfusion in DOAC patients operated on within 24 h of admission; however, interpretation of these findings is complicated by the fact that, unlike many similar studies, DOAC users were compared with non-users rather than non-anticoagulated patients. That is to say, the comparison group included all patients on VKA, antiplatelet therapy, and non-anticoagulated patients combined, thereby precluding the ability to draw strong conclusions when comparing the two cohorts in this study.

Other studies have also reported an increased rate of transfusion or hemoglobin loss in DOAC users, although these findings were associated with decreased hemoglobin levels on arrival. One study found that between 23% and 40% of DOAC users required transfusion, compared with 0% of non-anticoagulated controls (45). This difference was primarily due to DOAC users having a significantly lower arrival hemoglobin than non-anticoagulated patients (mean DOAC arrival Hgb: 86.7–89.3 g/L vs 122.1 g/L for controls). Similarly, another paper found that when DOAC users were operated on within 24 h, they were at 3.4 times increased risk of intraoperative transfusion compared with non-anticoagulated patients; again, this was predominantly driven by a significantly lower hemoglobin at admission compared with controls (47). These findings support the idea that most blood loss in DOAC patients occurs prior to hospital arrival rather than from intraoperative bleeding. If further substantiated, this would argue the futility of delaying surgery for purposes of mitigating surgery-associated blood loss.

Preoperative DOAC reversal

While increased perioperative blood loss in DOAC patients has not been consistently shown, DOAC reversal is an appealing option to mitigate concern for surgical bleeding. The FDA has approved two specific reversal agents for DOACs. Idarucizumab can be used to reverse dabigatran and andexanet alfa can be used to reverse apixaban and rivaroxaban (Table 1). However, cost, availability, preparation, and risk of thrombosis may complicate their use. Further, these reversal agents are not approved for all DOACs (48). Prothrombin complex concentrate (PCC) and activated prothrombin complex concentrate (APCC) have also been used off-label for DOAC reversal, although there is little clinical evidence to support their use (49). Activated charcoal may be administered to decrease DOAC blood levels but only if DOAC ingestion occurred within the last 2 h (49). Tranexamic acid (TXA) constitutes another potential option for treating DOAC-related bleeding. TXA is an antifibrinolytic that works by inhibiting plasminogen so that the fibrin matrix cannot be stabilized (50). While no clinical studies have yet been conducted examining the effect of TXA on DOAC-associated bleeding, consensus recommendations suggest TXA can be considered as an adjuvant in the acute setting as there are likely few negative effects (49).

To our knowledge, only two studies have directly compared the effects of anticoagulation reversal vs non-reversal in hip fractures (51, 52). Both studies found that reversing anticoagulation was not associated with decreased bleeding, transfusion rates, or mortality and reversed patients had increased TTS and hospital length of stay. Unfortunately, the application of these findings to DOACs specifically is limited. The first study contained only 51 patients on DOAC in a cohort of 459 anticoagulated patients (51). Reversal for DOAC patients was achieved via non-specific reversal agents or a ‘watch and wait’ strategy allowing for DOAC serum levels to decrease by 94–97%. No DOAC patients received idarucizumab, and andexanet alfa was not yet approved during study enrollment. The second study included 41 patients on DOACs of 1984 total anticoagulated patients with hip fractures of which only four were reversed (52). Further, the reversed patients in this latter study were significantly different from non-reversed patients, being significantly more likely to be white and male, having more comorbid conditions, and having a higher INR at admission. Neither study analyzed DOAC patients separately from VKA patients.

Other studies have incidentally compared reversal in DOAC and VKA patients with hip fractures. One found similar transfusion rates among DOAC and VKA patients (54% vs 53.8%, respectively), despite significantly reduced rates of reversal among the DOAC cohort (35). Another case–control study also showed no difference in outcomes between DOAC and VKA patients, despite no DOAC and all VKA patients receiving reversal (33). These findings suggest DOAC reversal may not be necessary, but the interpretation is greatly limited by the observational nature of the studies and the fact that no comparison was made between patients on DOACs who were reversed vs not reversed prior to surgery. Thus, additional research is urgently needed to determine the costs and benefits of using targeted reversal strategies for hip fracture patients on DOACs.

Preoperative DOAC clearance and serum level measurement

Early guidelines for patients on DOACs suggested a benefit to delaying emergency surgery 12–24 h from the last DOAC dose to allow for drug clearance (53). However, newer studies have suggested DOAC drug clearance is unpredictable and recommend anti-factor Xa levels to enable safe early surgery (55, 56). One study found approximately 40% of hip fracture patients had serum DOAC levels >80 ng/mL at 24 h, with 1 out of 36 patients having a level >80 ng/mL at 48 h, while another study found 52% of patients had drug levels <50 ng/mL within 12 h of presentation (55, 56). One caveat to consider with serum level testing is that no clear DOAC serum cutoff level has been established for safe surgery, with suggested levels ranging from 30–80 ng/mL (53, 55). Additionally, one study found that monitoring DOAC levels in hip fracture patients and waiting to operate until levels reached <50 ng/mL was actually associated with increased rates of transfusion and longer TTS than simply waiting 24 or 48 hh after the last DOAC dose (45). Of note, this particular cut-off level was per hospital protocol and not applicable to all DOACs due to various half-lives and therapeutic ranges. This finding occurred despite no differences in arrival hemoglobin between groups. The authors suggest the increased transfusion rate seen in later-operated DOAC patients (surgery once serum concentration reached <50 ng/mL) was secondary to additional complete blood counts and uncertainty that took place during the extra time before the operation.

While the majority of patients are likely to have acceptable serum DOAC levels at the time of surgery without additional delay for drug clearance or reversal, there may be a minority who have therapeutic concentrations that cause excessive bleeding. Renal impairment is one condition that is well known to predispose patients to higher circulating doses of DOACs, for longer periods of time. Indeed, one study showed a significant trend toward greater transfusion rates in DOAC patients with increasing chronic kidney disease (CKD) stages on admission for hip fracture (44).

Preoperative strategies to facilitate early and safe surgery

Current guidelines recommend early surgery for hip fractures within 48 h of injury, but more recent studies have suggested that early surgery within 24 h may further improve outcomes, highlighting the importance of optimizing preoperative management (57, 58). A recent study by Shah et al. proposed a systematic, evidence-based guideline for the perioperative management of hip fracture patients taking DOACs (59). The authors provided an algorithm accounting for renal impairment, liver profile, blood count, and coagulation screens, as well as DOAC-specific Anti-Xa assay to ensure a level of less than 50 ng/L, that could be used to better guide preoperative management and allow for earlier surgery. They also recommended a multidisciplinary approach to care that involves the patient, hematology, anesthesia, and orthopedic surgery teams (59).

Collaboration between the surgical and anesthesia teams to optimize the patient for surgery in the setting of DOAC use is tantamount to achieving a more safe and more efficient surgical setting. Anesthetic strategies described in another study by Shah et al. to minimize blood loss included tranexamic acid, permissive hypotension, central neuraxial anesthesia, correct patient positioning, and avoidance of hypothermia (60). The authors also reported promising hemostatic strategies that included the use of pharmacological agents such as desmopressin, prothrombic complex concentrate, fibrinogen concentrate, and the use of viscoelastic hemostatic assays. However, the optimal use for these agents is unclear at this time and represents important areas of ongoing research. Incorporating these strategies in the perioperative period with patients taking DOACs may facilitate and improve care.

Conclusions

Given the current evidence, we propose reserving DOAC levels and DOAC reversal for patients deemed at higher risk of bleeding complications, in particular, patients with decreased renal and/or hepatic function, and those on longer-acting DOAC medications such as betrixaban. For the majority of remaining DOAC patients, surgery should proceed as soon as the patient is medically cleared. Furthermore, close collaboration between surgery and anesthesia teams, as well as utilizing anesthetic strategies and pharmacologic agents to mitigate blood loss, is fundamental in optimizing patient care and outcomes. A comprehensive guideline to properly address and manage hip fracture patients taking DOACs is needed.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

References

  • 1.↑

    Dennison E, Mohamed MA & & Cooper C Epidemiology of osteoporosis. Rheumatic Disease Clinics 2006 32 617–629. (https:doi.org/10.1016/j.rdc.2006.08.003)

  • 2.↑

    Kanis JA, ,Odén A, McCloskey EV, Johansson H, Wahl DA, & Cooper C. A systematic review of hip fracture incidence and probability of fracture worldwide. Osteoporosis International 2012 2 3 2239–2256. (https://doi.org/10.1007/s00198-012-1964-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.↑

    Brauer CA. Incidence and mortality of hip fractures in the United States. JAMA 2009 3 02 1573. (https://doi.org/10.1001/jama.2009.1462)

  • 4.↑

    Michael Lewiecki EM, Wright NC, Curtis JR, Siris E, Gagel RF, Saag KG, Singer AJ, Steven PM, & Adler RA. Hip fracture trends in the United States, 2002 to 2015. Osteoporosis International 2018 29 717–722. (https://doi.org/10.1007/s00198-017-4345-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.↑

    Brainsky A, Glick H, Lydick E, Epstein R, Fox KM, Hawkes W, Kashner TM, Zimmerman SI, & Magaziner J. The economic Cost of hip fractures in community-dwelling older adults: a prospective study. Journal of the American Geriatrics Society 1997 45 281–287. (https://doi.org/10.1111/j.1532-5415.1997.tb00941.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.↑

    Cooper C, Cole ZA, Holroyd CR, Earl SC, Harvey NC, Dennison EM, Melton LJ, Cummings SR & & Kanis JA Secular trends in the incidence of hip and other osteoporotic fractures. Osteoporosis International 2011 22 1277–1288. (https://doi.org/10.1007/s00198-011-1601-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.↑

    Katsoulis M, Benetou V, Karapetyan T, Feskanich D, Grodstein F, & Pettersson-Kymmer U. Excess mortality after hip fracture in elderly persons from Europe and the USA: the CHANCES project. Journal of Internal Medicine 2017 281 300–310. (https://doi.org/10.1111/joim.12586)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.↑

    Braithwaite RS, Col NF, & Wong JB. Estimating hip fracture morbidity, mortality and costs. Journal of the American Geriatrics Society 2003 51 364–370. (https://doi.org/10.1046/j.1532-5415.2003.51110.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.↑

    Guzon-Illescas O, Perez Fernandez E, Crespí Villarias N, Quirós Donate FJ, Peña M, Alonso-Blas C, García-Vadillo A, & Mazzucchelli R. Mortality after osteoporotic hip fracture: incidence, trends, and associated factors. Journal of Orthopaedic Surgery 2019 14 329. (https://doi.org/10.1186/s13018-019-1226-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.↑

    Tay E. Hip fractures in the elderly: operative versus nonoperative management. Singapore Medical Journal 2016 57 178–181. (https://doi.org/10.11622/smedj.2016071)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.↑

    Moja L, Piatti A, Pecoraro V, Ricci C, Virgili G, Salanti G, Germagnoli L, Liberati A, & Banfi G. Timing matters in hip fracture surgery: patients operated within 48 hours have better outcomes: a meta-analysis and meta-regression of over 190,000 patients. PLoS One 2012 7 e46175. (https://doi.org/10.1371/journal.pone.0046175)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.↑

    Lefaivre KA, Macadam SA, Davidson DJ, Gandhi R, Chan H, & Broekhuyse HM. Length of stay, mortality, morbidity and delay to surgery in hip fractures. Journal of Bone and Joint Surgery. (British Volume) 2009 9 1-B 922–927. (https://doi.org/10.1302/0301-620X.91B7.22446)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.↑

    Simunovic N, Devereaux PJ, Sprague S, Guyatt GH, Schemitsch E, DeBeer J, & Bandari M. Effect of early surgery after hip fracture on mortality and complications: systematic review and meta-analysis. Canadian Medical Association Journal 2010 182 1609–1616. (https://doi.org/10.1503/cmaj.092220)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.↑

    Orosz GM, Magaziner J, Hannan EL, Morrison RS, Koval K, Gilbert M, McLaughlin M, Halm EA, Wang JJ & Litke A et al.Association of timing of surgery for hip fracture and patient outcomes. JAMA 2004 291 1738–1743. (https://doi.org/10.1001/jama.291.14.1738)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.↑

    Shiga T, Wajima Z, & Ohe Y. Is operative delay associated with increased mortality of hip fracture patients? Systematic review, meta-analysis, and meta-regression. Canadian Journal of Anesthesia 2008 55 146–154. (https://doi.org/10.1007/BF03016088)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.↑

    Tran T, Delluc A, de Wit C, Petrcich W, Le Gal G, & Carrier M. The impact of oral anticoagulation on time to surgery in patients hospitalized with hip fracture. Thrombosis Research 2015 136 962–965. (https://doi.org/10.1016/j.thromres.2015.09.017)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.↑

    Taranu R, Redclift C, Williams P, Diament M, Tate A, Maddox J, Wilson F, & Eardley W. Use of anticoagulants remains a significant threat to timely hip fracture surgery. Geriatric Orthopaedic Surgery & Rehabilitation 2018 9 215145931876415. (https://doi.org/10.1177/2151459318764150)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.↑

    White NJ, Reitzel SL, Doyle-Baker D, Sabo MT, Mattiello B, & Samuel TL. Management of patients with hip fracture receiving anticoagulation: what are we doing in Canada? Canadian Journal of Surgery 2021 64 E510–E515. (https://doi.org/10.1503/cjs.018520)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.↑

    Wood B, Nascimento B, Rizoli S, Sholzberg M, McFarlan A, Phillips A, & Ackery AD. The Anticoagulated trauma patient in the age of the direct oral anticoagulants: a Canadian perspective. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine 2017 25 1. (https://doi.org/10.1186/s13049-017-0420-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.↑

    Dossett LA, Riesel JN, Griffin MR, & Cotton BA. Prevalence and implications of preinjury warfarin use: an analysis of the National Trauma Databank. Archives of Surgery 2011 146 565–570. (https://doi.org/10.1001/archsurg.2010.313)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.↑

    Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clinical Pharmacokinetics 2013 52 69–82. (https://doi.org/10.1007/s40262-012-0030-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.↑

    Huisman MV, & Klok FA. Pharmacological properties of Betrixaban. European Heart Journal Supplements 2018 20(Supplement E) E12–E15. (https://doi.org/10.1093/eurheartj/suy016)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.↑

    Viktil KK, Lehre I, Ranhoff AH, & Molden E. Serum concentrations and elimination rates of direct-acting oral anticoagulants (DOACs) in older hip fracture patients hospitalized for surgery: a pilot study. Drugs and Aging 2019 36 65–71. (https://doi.org/10.1007/s40266-018-0609-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.↑

    Barnes GD, Lucas E, Alexander GC, & Goldberger ZD. National trends in ambulatory oral anticoagulant use. American Journal of Medicine 2015 128 1300-5.e2. (https://doi.org/10.1016/j.amjmed.2015.05.044)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.↑

    Ibáñez L, Sabaté M, Vidal X, Ballarin E, Rottenkolber M, Schmiedl S, Heeke A, Huerta C, Martin Merino E, Montero D, et al.Incidence of direct oral anticoagulant use in patients with nonvalvular atrial fibrillation and characteristics of users in 6 European countries (2008–2015): a cross ‐national drug utilization study. British Journal of Clinical Pharmacology 2019 85 2524–2539. (https://doi.org/10.1111/bcp.14071)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.↑

    Abatzis-Papadopoulos M, Tigkiropoulos K, Nikas S, Papoutsis I, Kostopoulou O, Stavridis K, Karamanos D, Lazaridis I, & Saratzis N. The effectiveness and safety of direct oral anticoagulants compared to conventional pharmacologic thromboprophylaxis in hip fracture patients: a systematic review and meta-analysis of randomized controlled trials. Orthopaedics and Traumatology, Surgery and Research 2023 109 103364. (https://doi.org/10.1016/j.otsr.2022.103364)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.↑

    Loo SY, Dell’Aniello S, Huiart L, & Renoux C. Trends in the prescription of novel oral anticoagulants in UK primary care: novel oral anticoagulant prescription trends. British Journal of Clinical Pharmacology. 2017 83 2096–2106. (https://doi.org/10.1111/bcp.13299)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.↑

    Tarrant SM, Catanach MJ, Sarrami M, Clapham M, Attia J, & Balogh ZJ. Direct oral anticoagulants and timing of hip fracture surgery. Journal of Clinical Medicine 2020 9 2200. (https://doi.org/10.3390/jcm9072200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.↑

    You D, Xu Y, Ponich B, Ronksley P, Skeith L, Korley R, Carrier M, & Schneider PS. Effect of oral anticoagulant use on surgical delay and mortality in hip fracture. Bone and Joint Journal 2021 103 222–233. (https://doi.org/10.1302/0301-620x.103b2.bjj-2020-0583.r2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.↑

    Leer-Salvesen S, Dybvik E, Ranhoff AH, Husebø BL, Dahl OE, Engesæter LB, & Gjertsen JE. Do direct oral anticoagulants (DOACs) cause delayed surgery, longer length of hospital stay, and poorer outcome for hip fracture patients? European Geriatric Medicine 2020 11 563–569. (https://doi.org/10.1007/s41999-020-00319-w)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.↑

    Sabo MT, Mahdi F, & Clark M. Emerging barrier to timely care of hip fracture patients: a prospective study of direct oral anticoagulation and time to surgery. Canadian Journal of General Internal Medicine 2018 13 e6–e9. (https://doi.org/https://doi.org/10.22374/cjgim.v13i4.272)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.↑

    Hourston GJ, Barrett MP, Khan WS, Vindlacheruvu M, & McDonnell SM. New drug, new problem: do hip fracture patients taking NOACs experience delayed surgery, longer hospital stay, or poorer outcomes? Hip International 2020 3 0 799–804. (https://doi.org/10.1177/1120700019841351)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.↑

    Frenkel Rutenberg T, Velkes S, Vitenberg M, Leader A, Halavy Y, Raanani P, Yassin M, & Spectre G. Morbidity and mortality after fragility hip fracture surgery in patients receiving vitamin K antagonists and direct oral anticoagulants. Thrombosis Research 2018 166 106–112. (https://doi.org/10.1016/j.thromres.2018.04.022)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.↑

    Brown A, Zmich Z, Roberts A, Lipof J & & Judd KT Expedited surgery in geriatric hip fracture patients taking direct oral anticoagulants is not associated with increased short-term complications or mortality rates. OTA International: The Open Access Journal of Orthopaedic Trauma 2020 3 e089. (https://doi.org/10.1097/OI9.0000000000000089)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.↑

    Bruckbauer M, Prexl O, Voelckel W, Ziegler B, Grottke O, Maegele M, & Schöchl M. Impact of direct oral anticoagulants in patients with hip fractures. Journal of Orthopaedic Trauma 2019 33 e8–e13. (https://doi.org/10.1097/BOT.0000000000001329)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.↑

    Daugaard C, Pedersen AB, Kristensen NR, & Johnsen SP. Preoperative antithrombotic therapy and risk of blood transfusion and mortality following hip fracture surgery: a Danish nationwide cohort study. Osteoporosis International 2019 30 583–591. (https://doi.org/10.1007/s00198-018-4786-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.↑

    King K, Polischuk M, Lynch G, Gergis A, Rajesh A, Shelfoon C, Kattar N, Sriselvakumar S, & Cooke C. Early surgical fixation for hip fractures in patients taking direct oral anticoagulation: a retrospective cohort study. Geriatric Orthopaedic Surgery and Rehabilitation 2020 11 2151459320944854. (https://doi.org/10.1177/2151459320944854)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.↑

    Rostagno C, Cartei A, Polidori G, Civinini R, Ceccofiglio A, Rubbieri G, Curcio M, Boccaccini A, Peris A, & Prisco D. Management of ongoing direct anticoagulant treatment in patients with hip fracture. Scientific Reports 2021 11 9467. (https://doi.org/10.1038/s41598-021-89077-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.↑

    Saliba W, Arbel A, Abu-Full Z, Cohen S, Rennert G, & Preis M. Preoperative direct oral anticoagulants treatment and all-cause mortality in elderly patients with hip fracture: a retrospective cohort study. Thrombosis Research 2020 189 48–54. (https://doi.org/10.1016/j.thromres.2020.03.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.↑

    Schermann H, Gurel R, Gold A, Maman E, Dolkart O, Steinberg EL, & Chechik E. Safety of urgent hip fracture surgery protocol under influence of direct oral anticoagulation medications. Injury 2019 50 398–402. (https://doi.org/10.1016/j.injury.2018.10.033)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.↑

    Franklin NA, Ali AH, Hurley RK, Mir HR, & Beltran MJ. Outcomes of early surgical intervention in geriatric proximal femur fractures among patients receiving direct oral anticoagulation. Journal of Orthopaedic Trauma 2018 32 269–273. (https://doi.org/10.1097/BOT.0000000000001146)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.↑

    Cafaro T, Simard C, Tagalakis V, & Koolian M. Delayed time to emergency hip surgery in patients taking oral anticoagulants. Thrombosis Research 2019 184 110–114. (https://doi.org/10.1016/j.thromres.2019.11.005)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.↑

    Lott A, Haglin J, Belayneh R, Konda SR, Leucht P, & Egol KA. Surgical delay is not warranted for patients with hip fractures receiving non-warfarin anticoagulants. Orthopedics 2019 42 e331–e335. (https://doi.org/10.3928/01477447-20190321-02)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.↑

    Mullins B, Akehurst H, Slattery D, & Chesser T. Should surgery be delayed in patients taking direct oral anticoagulants who suffer a hip fracture? A retrospective, case-controlled observational study at a UK major trauma centre. BMJ Open 2018 8 e020625. (https://doi.org/10.1136/bmjopen-2017-020625)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.↑

    Aziz S, Almeida K, & Taylor G. How should we manage hip fracture patients on direct oral anticoagulants? BMJ. Evidence-Based Medicine 2020 26 22–23. (https://doi.org/10.1136/bmjebm-2019-111317)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.↑

    Xu Y, You D, Krzyzaniak H, Ponich B, Ronksley P, Skeith L, Salo P, Korley R, Schneider P, & Carrier M. Effect of oral anticoagulants on hemostatic and thromboembolic complications in hip fracture: a systematic review and meta‐analysis. Journal of Thrombosis and Haemostasis 2020 18 2566–2581. (https://doi.org/10.1111/jth.14977)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.↑

    Schuetze K, Eickhoff A, Dehner C, Gebhard F, & Richter PH. Impact of oral anticoagulation on proximal femur fractures treated within 24 h – A retrospective chart review. Injury 2019 50 2040–2044. (https://doi.org/10.1016/j.injury.2019.09.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.↑

    Cuker A, Burnett A, Triller D, Crowther M, Ansell J, Cott EMV, Wirth D, & Kaatz S. Reversal of direct oral anticoagulants: guidance from the Anticoagulation Forum. American Journal of Hematology 2019 94 697–709. (https://doi.org/10.1002/ajh.25475)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.↑

    Eliasberg CD, Levack AE, Gausden EB, Garvin S, Russell LA, & Kelly AM. Perioperative use of novel oral anticoagulants in orthopaedic surgery: a critical analysis review. JBJS Reviews 2019 7 e4. (https://doi.org/10.2106/JBJS.RVW.18.00148)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.↑

    Chauncey JM, & Wieters JS. Tranexamic acid. StatPearls [Internet]. Treasure Island , FL: StatPearls Publishing 2020. Available at: http://www.ncbi.nlm.nih.gov/books/NBK532909

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.↑

    Meinig R, Jarvis S, Orlando A, Nwafo N, Banerjee R, McNair P, Woods B, Harrison P, Nentwig M & Kelly M et al.Is anticoagulation reversal necessary prior to surgical treatment of geriatric hip fractures? Journal of Clinical Orthopaedics 2020 11 S93–S99. (https://doi.org/10.1016/j.jcot.2019.10.004)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.↑

    Yoo MS, Zhu S, Jiang S, Hammer HL, McBride WJ, McCarthy CM, Green CE, & Ananias MP. Association of reversal of anticoagulation preoperatively on 30-day mortality and outcomes for hip fracture surgery. American Journal of Medicine 2020 133 969–975.e2. (https://doi.org/10.1016/j.amjmed.2020.01.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.↑

    Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, & Kirchhof P. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015 17 1467–1507. (https://doi.org/10.1093/europace/euv309)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.↑

    Hampton M, Salih S, & Gordon A. Measurement of anti-factor xa levels in patients presenting with a hip fracture taking Rivaroxaban or apixiban. can we predict drug clearance and prevent delay to surgery? Orthopaedic Proceedings of the British Editorial Society of Bone & Joint. Surgery 2019 101-B 8. (https://doi.org/https://doi.org/10.1302/1358-992X.2019.6.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55.↑

    Tripodi A, Marongiu F, Moia M, Palareti G, Pengo V, Poli D, Prisco D, Testa S, & Zanazzi M. The vexed question of 457 whether or not to measure levels of direct oral anticoagulants before surgery or invasive 458 procedures. Internal and Emergency Medicine 2018 13 1029–1036. (https://doi.org/10.1007/s11739-018-1854-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.↑

    Creeper K, Stafford A, Reynolds S, Samida S, P’Ng S, Glennon D, Seymour H, & Grove C. Outcomes and anticoagulation use for elderly patients that present with an Acute Hip Fracture: multi centre, retrospective analysis. Internal Medicine Journal 2022 52 418– 425. (https://doi.org/10.1111/imj.15007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57.↑

    Pincus D, Ravi B, Wasserstein D, Huang A, Paterson JM, Nathens AB, Kreder HJ, Jenkinson RJ, & Wodchis WP. Association between wait time and 30-day mortality in adults undergoing hip fracture surgery. JAMA 2017 318 1994–2003. (https://doi.org/10.1001/jama.2017.17606)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.↑

    Australian Commission on Safety & Quality in Health Care. Hip Fracture Care: Clinical Care Standard. Australian Commission on Safety and Quality in Health Care 2016. Available at: https://www.safetyandquality.gov.au/standards/clinical-care-standards/hip-fracture-care-clinical-care-standard

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.↑

    Shah R, Sheikh N, Mangwani J, Morgan N, & Khairandish H. Direct oral anticoagulants (DOACs) and neck of femur fractures: standardising the perioperative management and time to surgery. Journal of Clinical Orthopaedics and Trauma 2021 12 138–147. (https://doi.org/10.1016/j.jcot.2020.08.005)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.↑

    Shah A, Palmer AJR, & Klein AA. Strategies to minimize intraoperative blood loss during major surgery. British Journal of Surgery 2020 107 e26–e38. (https://doi.org/10.1002/bjs.11393)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61.↑

    Hoerlyck C, Ong T, Gregersen M, Damsgaard EM, Borris L, Chia JK, Yap YYW, Weerasuriya N, & Sahota O. Do anticoagulants affect outcomes of hip fracture surgery? A cross-sectional analysis. Archives of Orthopaedic and Trauma Surgery 2020 140 171-176. (https://doi.org/10.1007/s00402-019-03240-5)

    • PubMed
    • Export Citation
  • 62.↑

    Gosch M, Jacobs M, Bail H, Grueninger S & & Wicklein S. Outcome of older hip fracture patients on anticoagulation: a comparison of vitamin K-antagonists and Factor Xa inhibitors. Archives of Orthopaedic and Trauma Surgery 2021 141 637-643. (https://doi.org/10.1007/s00402-020-03547-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

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Online ISSN:
2058-5241
Copyright:
© the author(s) 2023
Article Type:
Review Article
Page Range:
561–571
Published Online:
03 Jul 2023
Keywords:
hip fracture; direct oral anticoagulant (DOAC); anticoagulation; trauma; geriatric; surgical timing; bleeding
  • Figure 1
    View in gallery
    Figure 1

    Coagulation cascade with direct oral anticoagulant sites of action.

  • Figure 2
    View in gallery
    Figure 2

    Proposed workup of otherwise medically cleared patients on DOAC prior to surgical repair of hip fracture.

Figure 1

Coagulation cascade with direct oral anticoagulant sites of action.
Figure 2

Proposed workup of otherwise medically cleared patients on DOAC prior to surgical repair of hip fracture.
  • 1.

    Dennison E, Mohamed MA & & Cooper C Epidemiology of osteoporosis. Rheumatic Disease Clinics 2006 32 617–629. (https:doi.org/10.1016/j.rdc.2006.08.003)

  • 2.

    Kanis JA, ,Odén A, McCloskey EV, Johansson H, Wahl DA, & Cooper C. A systematic review of hip fracture incidence and probability of fracture worldwide. Osteoporosis International 2012 2 3 2239–2256. (https://doi.org/10.1007/s00198-012-1964-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Brauer CA. Incidence and mortality of hip fractures in the United States. JAMA 2009 3 02 1573. (https://doi.org/10.1001/jama.2009.1462)

  • 4.

    Michael Lewiecki EM, Wright NC, Curtis JR, Siris E, Gagel RF, Saag KG, Singer AJ, Steven PM, & Adler RA. Hip fracture trends in the United States, 2002 to 2015. Osteoporosis International 2018 29 717–722. (https://doi.org/10.1007/s00198-017-4345-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Brainsky A, Glick H, Lydick E, Epstein R, Fox KM, Hawkes W, Kashner TM, Zimmerman SI, & Magaziner J. The economic Cost of hip fractures in community-dwelling older adults: a prospective study. Journal of the American Geriatrics Society 1997 45 281–287. (https://doi.org/10.1111/j.1532-5415.1997.tb00941.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Cooper C, Cole ZA, Holroyd CR, Earl SC, Harvey NC, Dennison EM, Melton LJ, Cummings SR & & Kanis JA Secular trends in the incidence of hip and other osteoporotic fractures. Osteoporosis International 2011 22 1277–1288. (https://doi.org/10.1007/s00198-011-1601-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Katsoulis M, Benetou V, Karapetyan T, Feskanich D, Grodstein F, & Pettersson-Kymmer U. Excess mortality after hip fracture in elderly persons from Europe and the USA: the CHANCES project. Journal of Internal Medicine 2017 281 300–310. (https://doi.org/10.1111/joim.12586)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Braithwaite RS, Col NF, & Wong JB. Estimating hip fracture morbidity, mortality and costs. Journal of the American Geriatrics Society 2003 51 364–370. (https://doi.org/10.1046/j.1532-5415.2003.51110.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Guzon-Illescas O, Perez Fernandez E, Crespí Villarias N, Quirós Donate FJ, Peña M, Alonso-Blas C, García-Vadillo A, & Mazzucchelli R. Mortality after osteoporotic hip fracture: incidence, trends, and associated factors. Journal of Orthopaedic Surgery 2019 14 329. (https://doi.org/10.1186/s13018-019-1226-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Tay E. Hip fractures in the elderly: operative versus nonoperative management. Singapore Medical Journal 2016 57 178–181. (https://doi.org/10.11622/smedj.2016071)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Moja L, Piatti A, Pecoraro V, Ricci C, Virgili G, Salanti G, Germagnoli L, Liberati A, & Banfi G. Timing matters in hip fracture surgery: patients operated within 48 hours have better outcomes: a meta-analysis and meta-regression of over 190,000 patients. PLoS One 2012 7 e46175. (https://doi.org/10.1371/journal.pone.0046175)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Lefaivre KA, Macadam SA, Davidson DJ, Gandhi R, Chan H, & Broekhuyse HM. Length of stay, mortality, morbidity and delay to surgery in hip fractures. Journal of Bone and Joint Surgery. (British Volume) 2009 9 1-B 922–927. (https://doi.org/10.1302/0301-620X.91B7.22446)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Simunovic N, Devereaux PJ, Sprague S, Guyatt GH, Schemitsch E, DeBeer J, & Bandari M. Effect of early surgery after hip fracture on mortality and complications: systematic review and meta-analysis. Canadian Medical Association Journal 2010 182 1609–1616. (https://doi.org/10.1503/cmaj.092220)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Orosz GM, Magaziner J, Hannan EL, Morrison RS, Koval K, Gilbert M, McLaughlin M, Halm EA, Wang JJ & Litke A et al.Association of timing of surgery for hip fracture and patient outcomes. JAMA 2004 291 1738–1743. (https://doi.org/10.1001/jama.291.14.1738)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Shiga T, Wajima Z, & Ohe Y. Is operative delay associated with increased mortality of hip fracture patients? Systematic review, meta-analysis, and meta-regression. Canadian Journal of Anesthesia 2008 55 146–154. (https://doi.org/10.1007/BF03016088)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Tran T, Delluc A, de Wit C, Petrcich W, Le Gal G, & Carrier M. The impact of oral anticoagulation on time to surgery in patients hospitalized with hip fracture. Thrombosis Research 2015 136 962–965. (https://doi.org/10.1016/j.thromres.2015.09.017)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Taranu R, Redclift C, Williams P, Diament M, Tate A, Maddox J, Wilson F, & Eardley W. Use of anticoagulants remains a significant threat to timely hip fracture surgery. Geriatric Orthopaedic Surgery & Rehabilitation 2018 9 215145931876415. (https://doi.org/10.1177/2151459318764150)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    White NJ, Reitzel SL, Doyle-Baker D, Sabo MT, Mattiello B, & Samuel TL. Management of patients with hip fracture receiving anticoagulation: what are we doing in Canada? Canadian Journal of Surgery 2021 64 E510–E515. (https://doi.org/10.1503/cjs.018520)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Wood B, Nascimento B, Rizoli S, Sholzberg M, McFarlan A, Phillips A, & Ackery AD. The Anticoagulated trauma patient in the age of the direct oral anticoagulants: a Canadian perspective. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine 2017 25 1. (https://doi.org/10.1186/s13049-017-0420-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Dossett LA, Riesel JN, Griffin MR, & Cotton BA. Prevalence and implications of preinjury warfarin use: an analysis of the National Trauma Databank. Archives of Surgery 2011 146 565–570. (https://doi.org/10.1001/archsurg.2010.313)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clinical Pharmacokinetics 2013 52 69–82. (https://doi.org/10.1007/s40262-012-0030-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Huisman MV, & Klok FA. Pharmacological properties of Betrixaban. European Heart Journal Supplements 2018 20(Supplement E) E12–E15. (https://doi.org/10.1093/eurheartj/suy016)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Viktil KK, Lehre I, Ranhoff AH, & Molden E. Serum concentrations and elimination rates of direct-acting oral anticoagulants (DOACs) in older hip fracture patients hospitalized for surgery: a pilot study. Drugs and Aging 2019 36 65–71. (https://doi.org/10.1007/s40266-018-0609-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Barnes GD, Lucas E, Alexander GC, & Goldberger ZD. National trends in ambulatory oral anticoagulant use. American Journal of Medicine 2015 128 1300-5.e2. (https://doi.org/10.1016/j.amjmed.2015.05.044)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Ibáñez L, Sabaté M, Vidal X, Ballarin E, Rottenkolber M, Schmiedl S, Heeke A, Huerta C, Martin Merino E, Montero D, et al.Incidence of direct oral anticoagulant use in patients with nonvalvular atrial fibrillation and characteristics of users in 6 European countries (2008–2015): a cross ‐national drug utilization study. British Journal of Clinical Pharmacology 2019 85 2524–2539. (https://doi.org/10.1111/bcp.14071)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Abatzis-Papadopoulos M, Tigkiropoulos K, Nikas S, Papoutsis I, Kostopoulou O, Stavridis K, Karamanos D, Lazaridis I, & Saratzis N. The effectiveness and safety of direct oral anticoagulants compared to conventional pharmacologic thromboprophylaxis in hip fracture patients: a systematic review and meta-analysis of randomized controlled trials. Orthopaedics and Traumatology, Surgery and Research 2023 109 103364. (https://doi.org/10.1016/j.otsr.2022.103364)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Loo SY, Dell’Aniello S, Huiart L, & Renoux C. Trends in the prescription of novel oral anticoagulants in UK primary care: novel oral anticoagulant prescription trends. British Journal of Clinical Pharmacology. 2017 83 2096–2106. (https://doi.org/10.1111/bcp.13299)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Tarrant SM, Catanach MJ, Sarrami M, Clapham M, Attia J, & Balogh ZJ. Direct oral anticoagulants and timing of hip fracture surgery. Journal of Clinical Medicine 2020 9 2200. (https://doi.org/10.3390/jcm9072200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    You D, Xu Y, Ponich B, Ronksley P, Skeith L, Korley R, Carrier M, & Schneider PS. Effect of oral anticoagulant use on surgical delay and mortality in hip fracture. Bone and Joint Journal 2021 103 222–233. (https://doi.org/10.1302/0301-620x.103b2.bjj-2020-0583.r2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Leer-Salvesen S, Dybvik E, Ranhoff AH, Husebø BL, Dahl OE, Engesæter LB, & Gjertsen JE. Do direct oral anticoagulants (DOACs) cause delayed surgery, longer length of hospital stay, and poorer outcome for hip fracture patients? European Geriatric Medicine 2020 11 563–569. (https://doi.org/10.1007/s41999-020-00319-w)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Sabo MT, Mahdi F, & Clark M. Emerging barrier to timely care of hip fracture patients: a prospective study of direct oral anticoagulation and time to surgery. Canadian Journal of General Internal Medicine 2018 13 e6–e9. (https://doi.org/https://doi.org/10.22374/cjgim.v13i4.272)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Hourston GJ, Barrett MP, Khan WS, Vindlacheruvu M, & McDonnell SM. New drug, new problem: do hip fracture patients taking NOACs experience delayed surgery, longer hospital stay, or poorer outcomes? Hip International 2020 3 0 799–804. (https://doi.org/10.1177/1120700019841351)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Frenkel Rutenberg T, Velkes S, Vitenberg M, Leader A, Halavy Y, Raanani P, Yassin M, & Spectre G. Morbidity and mortality after fragility hip fracture surgery in patients receiving vitamin K antagonists and direct oral anticoagulants. Thrombosis Research 2018 166 106–112. (https://doi.org/10.1016/j.thromres.2018.04.022)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Brown A, Zmich Z, Roberts A, Lipof J & & Judd KT Expedited surgery in geriatric hip fracture patients taking direct oral anticoagulants is not associated with increased short-term complications or mortality rates. OTA International: The Open Access Journal of Orthopaedic Trauma 2020 3 e089. (https://doi.org/10.1097/OI9.0000000000000089)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Bruckbauer M, Prexl O, Voelckel W, Ziegler B, Grottke O, Maegele M, & Schöchl M. Impact of direct oral anticoagulants in patients with hip fractures. Journal of Orthopaedic Trauma 2019 33 e8–e13. (https://doi.org/10.1097/BOT.0000000000001329)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Daugaard C, Pedersen AB, Kristensen NR, & Johnsen SP. Preoperative antithrombotic therapy and risk of blood transfusion and mortality following hip fracture surgery: a Danish nationwide cohort study. Osteoporosis International 2019 30 583–591. (https://doi.org/10.1007/s00198-018-4786-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    King K, Polischuk M, Lynch G, Gergis A, Rajesh A, Shelfoon C, Kattar N, Sriselvakumar S, & Cooke C. Early surgical fixation for hip fractures in patients taking direct oral anticoagulation: a retrospective cohort study. Geriatric Orthopaedic Surgery and Rehabilitation 2020 11 2151459320944854. (https://doi.org/10.1177/2151459320944854)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Rostagno C, Cartei A, Polidori G, Civinini R, Ceccofiglio A, Rubbieri G, Curcio M, Boccaccini A, Peris A, & Prisco D. Management of ongoing direct anticoagulant treatment in patients with hip fracture. Scientific Reports 2021 11 9467. (https://doi.org/10.1038/s41598-021-89077-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Saliba W, Arbel A, Abu-Full Z, Cohen S, Rennert G, & Preis M. Preoperative direct oral anticoagulants treatment and all-cause mortality in elderly patients with hip fracture: a retrospective cohort study. Thrombosis Research 2020 189 48–54. (https://doi.org/10.1016/j.thromres.2020.03.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Schermann H, Gurel R, Gold A, Maman E, Dolkart O, Steinberg EL, & Chechik E. Safety of urgent hip fracture surgery protocol under influence of direct oral anticoagulation medications. Injury 2019 50 398–402. (https://doi.org/10.1016/j.injury.2018.10.033)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Franklin NA, Ali AH, Hurley RK, Mir HR, & Beltran MJ. Outcomes of early surgical intervention in geriatric proximal femur fractures among patients receiving direct oral anticoagulation. Journal of Orthopaedic Trauma 2018 32 269–273. (https://doi.org/10.1097/BOT.0000000000001146)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Cafaro T, Simard C, Tagalakis V, & Koolian M. Delayed time to emergency hip surgery in patients taking oral anticoagulants. Thrombosis Research 2019 184 110–114. (https://doi.org/10.1016/j.thromres.2019.11.005)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Lott A, Haglin J, Belayneh R, Konda SR, Leucht P, & Egol KA. Surgical delay is not warranted for patients with hip fractures receiving non-warfarin anticoagulants. Orthopedics 2019 42 e331–e335. (https://doi.org/10.3928/01477447-20190321-02)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Mullins B, Akehurst H, Slattery D, & Chesser T. Should surgery be delayed in patients taking direct oral anticoagulants who suffer a hip fracture? A retrospective, case-controlled observational study at a UK major trauma centre. BMJ Open 2018 8 e020625. (https://doi.org/10.1136/bmjopen-2017-020625)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Aziz S, Almeida K, & Taylor G. How should we manage hip fracture patients on direct oral anticoagulants? BMJ. Evidence-Based Medicine 2020 26 22–23. (https://doi.org/10.1136/bmjebm-2019-111317)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Xu Y, You D, Krzyzaniak H, Ponich B, Ronksley P, Skeith L, Salo P, Korley R, Schneider P, & Carrier M. Effect of oral anticoagulants on hemostatic and thromboembolic complications in hip fracture: a systematic review and meta‐analysis. Journal of Thrombosis and Haemostasis 2020 18 2566–2581. (https://doi.org/10.1111/jth.14977)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Schuetze K, Eickhoff A, Dehner C, Gebhard F, & Richter PH. Impact of oral anticoagulation on proximal femur fractures treated within 24 h – A retrospective chart review. Injury 2019 50 2040–2044. (https://doi.org/10.1016/j.injury.2019.09.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Cuker A, Burnett A, Triller D, Crowther M, Ansell J, Cott EMV, Wirth D, & Kaatz S. Reversal of direct oral anticoagulants: guidance from the Anticoagulation Forum. American Journal of Hematology 2019 94 697–709. (https://doi.org/10.1002/ajh.25475)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Eliasberg CD, Levack AE, Gausden EB, Garvin S, Russell LA, & Kelly AM. Perioperative use of novel oral anticoagulants in orthopaedic surgery: a critical analysis review. JBJS Reviews 2019 7 e4. (https://doi.org/10.2106/JBJS.RVW.18.00148)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Chauncey JM, & Wieters JS. Tranexamic acid. StatPearls [Internet]. Treasure Island , FL: StatPearls Publishing 2020. Available at: http://www.ncbi.nlm.nih.gov/books/NBK532909

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Meinig R, Jarvis S, Orlando A, Nwafo N, Banerjee R, McNair P, Woods B, Harrison P, Nentwig M & Kelly M et al.Is anticoagulation reversal necessary prior to surgical treatment of geriatric hip fractures? Journal of Clinical Orthopaedics 2020 11 S93–S99. (https://doi.org/10.1016/j.jcot.2019.10.004)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Yoo MS, Zhu S, Jiang S, Hammer HL, McBride WJ, McCarthy CM, Green CE, & Ananias MP. Association of reversal of anticoagulation preoperatively on 30-day mortality and outcomes for hip fracture surgery. American Journal of Medicine 2020 133 969–975.e2. (https://doi.org/10.1016/j.amjmed.2020.01.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, & Kirchhof P. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015 17 1467–1507. (https://doi.org/10.1093/europace/euv309)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Hampton M, Salih S, & Gordon A. Measurement of anti-factor xa levels in patients presenting with a hip fracture taking Rivaroxaban or apixiban. can we predict drug clearance and prevent delay to surgery? Orthopaedic Proceedings of the British Editorial Society of Bone & Joint. Surgery 2019 101-B 8. (https://doi.org/https://doi.org/10.1302/1358-992X.2019.6.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55.

    Tripodi A, Marongiu F, Moia M, Palareti G, Pengo V, Poli D, Prisco D, Testa S, & Zanazzi M. The vexed question of 457 whether or not to measure levels of direct oral anticoagulants before surgery or invasive 458 procedures. Internal and Emergency Medicine 2018 13 1029–1036. (https://doi.org/10.1007/s11739-018-1854-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Creeper K, Stafford A, Reynolds S, Samida S, P’Ng S, Glennon D, Seymour H, & Grove C. Outcomes and anticoagulation use for elderly patients that present with an Acute Hip Fracture: multi centre, retrospective analysis. Internal Medicine Journal 2022 52 418– 425. (https://doi.org/10.1111/imj.15007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57.

    Pincus D, Ravi B, Wasserstein D, Huang A, Paterson JM, Nathens AB, Kreder HJ, Jenkinson RJ, & Wodchis WP. Association between wait time and 30-day mortality in adults undergoing hip fracture surgery. JAMA 2017 318 1994–2003. (https://doi.org/10.1001/jama.2017.17606)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.

    Australian Commission on Safety & Quality in Health Care. Hip Fracture Care: Clinical Care Standard. Australian Commission on Safety and Quality in Health Care 2016. Available at: https://www.safetyandquality.gov.au/standards/clinical-care-standards/hip-fracture-care-clinical-care-standard

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.

    Shah R, Sheikh N, Mangwani J, Morgan N, & Khairandish H. Direct oral anticoagulants (DOACs) and neck of femur fractures: standardising the perioperative management and time to surgery. Journal of Clinical Orthopaedics and Trauma 2021 12 138–147. (https://doi.org/10.1016/j.jcot.2020.08.005)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Shah A, Palmer AJR, & Klein AA. Strategies to minimize intraoperative blood loss during major surgery. British Journal of Surgery 2020 107 e26–e38. (https://doi.org/10.1002/bjs.11393)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61.

    Hoerlyck C, Ong T, Gregersen M, Damsgaard EM, Borris L, Chia JK, Yap YYW, Weerasuriya N, & Sahota O. Do anticoagulants affect outcomes of hip fracture surgery? A cross-sectional analysis. Archives of Orthopaedic and Trauma Surgery 2020 140 171-176. (https://doi.org/10.1007/s00402-019-03240-5)

    • PubMed
    • Export Citation
  • 62.

    Gosch M, Jacobs M, Bail H, Grueninger S & & Wicklein S. Outcome of older hip fracture patients on anticoagulation: a comparison of vitamin K-antagonists and Factor Xa inhibitors. Archives of Orthopaedic and Trauma Surgery 2021 141 637-643. (https://doi.org/10.1007/s00402-020-03547-8)

    • PubMed
    • Search Google Scholar
    • Export Citation