Orthopedics

Feature Article 

The Safety of Continuing Antiplatelet Medication Among Elderly Patients Undergoing Urgent Hip Fracture Surgery

Sung-Yen Lin, MD; Hsuan-Ti Huang, MD; Shih-Hsiang Chou, MD; Cheng-Jung Ho, MD; Zi-Miao Liu, PhD; Chung-Hwan Chen, PhD; Cheng-Chang Lu, MD

Abstract

Elderly patients with hip fractures who are receiving antiplatelet therapy are commonly encountered in clinical practice. This study sought to elucidate the safety of urgent hip surgery without termination of antiplatelet medication among patients taking a combination of aspirin and dipyridamole, aspirin alone, or dipyridamole alone. This retrospective cohort study included 176 patients 55 years or older who had uncomplicated hip fractures and underwent surgery within 48 hours after admission. On the basis of the preoperative medication regimen, the patients were divided into the following 4 groups: those receiving aspirin and dipyridamole combined (n=29); those receiving aspirin alone (n=63); those receiving dipyridamole alone (n=28); and those not receiving antiplatelet medication (n=56). Main outcomes, including total blood loss, transfusion rate, and 1-year mortality, were analyzed. There was no significant difference in total blood loss, transfusion rate, or 1-year mortality among the 4 groups. The group receiving aspirin and dipyridamole combined preoperatively had increased intraoperative blood loss (mean, 309.14±189.15 mL) compared with the group not receiving antiplatelet medication (mean, 214.64±119.21 mL; P=.005). There was no significant difference in the hazard ratio (P>.05) for 1-year mortality among the 4 groups after adjusting for confounding covariates, including age, sex, Charlson Comorbidity Index, and duration of hospital stay. Patients receiving antiplatelet medication, including aspirin, dipyridamole, or both, who have uncomplicated hip fractures may undergo urgent surgery without a significant difference in total blood loss, transfusion rate, or 1-year mortality compared with patients not receiving anti-platelet medication. [Orthopedics. 2019; 42(5):268–274.]

Abstract

Elderly patients with hip fractures who are receiving antiplatelet therapy are commonly encountered in clinical practice. This study sought to elucidate the safety of urgent hip surgery without termination of antiplatelet medication among patients taking a combination of aspirin and dipyridamole, aspirin alone, or dipyridamole alone. This retrospective cohort study included 176 patients 55 years or older who had uncomplicated hip fractures and underwent surgery within 48 hours after admission. On the basis of the preoperative medication regimen, the patients were divided into the following 4 groups: those receiving aspirin and dipyridamole combined (n=29); those receiving aspirin alone (n=63); those receiving dipyridamole alone (n=28); and those not receiving antiplatelet medication (n=56). Main outcomes, including total blood loss, transfusion rate, and 1-year mortality, were analyzed. There was no significant difference in total blood loss, transfusion rate, or 1-year mortality among the 4 groups. The group receiving aspirin and dipyridamole combined preoperatively had increased intraoperative blood loss (mean, 309.14±189.15 mL) compared with the group not receiving antiplatelet medication (mean, 214.64±119.21 mL; P=.005). There was no significant difference in the hazard ratio (P>.05) for 1-year mortality among the 4 groups after adjusting for confounding covariates, including age, sex, Charlson Comorbidity Index, and duration of hospital stay. Patients receiving antiplatelet medication, including aspirin, dipyridamole, or both, who have uncomplicated hip fractures may undergo urgent surgery without a significant difference in total blood loss, transfusion rate, or 1-year mortality compared with patients not receiving anti-platelet medication. [Orthopedics. 2019; 42(5):268–274.]

Hip fractures commonly occur among elderly individuals, leading to significant mortality and morbidity. The early surgical stabilization of a hip fracture within 48 hours after admission is typically recommended to decrease perioperative complications.1,2 However, geriatric patients present a significant clinical challenge because they frequently have numerous comorbidities, including stroke and ischemic heart disease.3,4 The polypharmacy approach for these patients often includes antiplatelet agents to treat or prevent medical comorbidities. Coagulation deactivation by antiplatelet medication may increase blood loss and thus transfusion requirements in hip fracture surgery, as well as possibly increase the prevalence of related complications.5 Therefore, clinical management with antiplatelet medication should strike a balance between bleeding risks and the urgency of surgery for a given patient.

Although the benefit of early hip surgery among patients taking antiplatelet medications has been reported, the safety of this approach for geriatric patients remains controversial.6,7 Currently, there is no universal guideline regarding the management of hip fractures in patients taking antiplatelet agents and whether these patients should continue or stop taking these medications during the perioperative period. Furthermore, in addition to anti-platelet therapy with a single agent, some fracture patients may receive dual-agent regimens, such as aspirin combined with dipyridamole. The optimal approach for the coordinated and multidisciplinary care of hip fractures in elderly patients who are receiving antiplatelet agents, especially regimens that include a combination of medications, must be identified.

Therefore, this study was designed to evaluate outcomes after urgent hip surgery in elderly patients receiving or not receiving ongoing antiplatelet agents. The purpose of this study was to clarify the safety of early surgery without drug discontinuation for patients taking different types of antiplatelet medications, including aspirin and dipyridamole combined.

Materials and Methods

This cohort study received institutional review board approval. The authors retrospectively reviewed the medical records of patients who underwent surgery for hip fractures between January 2008 and July 2013. Patients 55 years or older with either a femoral neck fracture treated with a hemiarthroplasty or a stable type intertrochanteric fracture (OTA/AO types A1 and A2.1) treated with open reduction and internal fixation with a dynamic hip screw and plate undergoing surgery within 48 hours after admission were included. Cases involving Garden type I or type II femoral neck fractures planned for internal fixation with 3 cannulated screws, unstable intertrochanteric fractures, pathologic fractures, concomitant fractures, uncompensated liver cirrhosis, a history of deep venous thrombosis, end stage renal disease, and preoperative thrombocytopenia (platelet count <150,000/mL) were excluded.

After stabilization of all medical conditions, hemiarthroplasty or open reduction and internal fixation was performed according to fracture type within 48 hours after admission. All of these patients received laryngeal mask airway anesthesia. No drainage was used for any patient. All patients received mechanical devices to prevent deep venous thrombosis after surgery. The same standardized rehabilitation protocol, including muscle strengthening exercises, range of motion training, and gait training with tolerant weight bearing from the first day postoperatively, was used for all patients. Antiplatelet therapy was not discontinued during the perioperative period.

The primary outcome was a composite of blood loss, which included intraoperative blood loss, hidden blood loss, total blood loss, amount of transfusion, and transfusion rate. Hidden blood loss was defined as total blood loss minus intraoperative blood loss. The total blood loss was calculated by the hemoglobin balance method using the changes of hemoglobin and blood volume to estimate the true blood loss. Blood volume was estimated using the formula of Nadler et al,8 taking into account the patient's height, weight, and sex. Then, the total blood loss was calculated according to the equation in Figure 1.9

Equation for calculating total blood loss (TBL). Abbreviations: BV, blood volume; Hb, hemoglobin.

Figure 1:

Equation for calculating total blood loss (TBL). Abbreviations: BV, blood volume; Hb, hemoglobin.

According to measurements by the blood center of the authors' hospital, a unit of packed cell transfusion contains 35 g of hemoglobin. The transfusion decision was based on the guidelines for postoperative surgical patients suggested by the American Association of Blood Banks.10 These guidelines recommend that transfusions be decided by clinical assessment that is aided by laboratory data. Blood transfusions were considered for patients whose hemoglobin levels were less than 8.0 g/dL, or for patients with hemoglobin levels less than 9.0 g/dL combined with anemia symptoms that included tachycardia, light-headedness, shortness of breath, and so forth. The secondary outcome of this study was 1-year mortality postoperatively.

Statistical Analysis

One-way analysis of variance was used to determine significant differences in continuous variables (demographics and clinical measurements data) between the control and antiplatelet groups. Scheffe's test was used for post hoc pairwise comparisons when one-way analysis of variance approached a significant difference. Hazard ratios (HRs) with 95% confidence intervals (CIs) and their associated P values for 1-year mortality were calculated using Cox proportional hazards regression modeling, both with and without adjusting for covariates that included age, sex, Charlson Comorbidity Index, and duration of hospital stay. All statistical analyses were conducted using SPSS statistical software (IBM, Armonk, New York). Differences were considered statistically significant at P<.05.

Results

Preoperative, perioperative, and postoperative data are listed in Table 1. One hundred seventy-six patients (55 men), with a mean age of 77.7 years, were included in the study. These patients were divided into 4 groups according to medication received preoperatively: aspirin and dipyridamole combined (n=29), aspirin alone (n=63), dipyridamole alone (n=28), and no antiplatelet medication preoperatively or postoperatively (n=56). There was a significant difference in preoperative Charlson Comorbidity Index among the groups (P<.0001). Scheffe's test showed a significantly higher Charlson Comorbidity Index in the group of patients receiving combined antiplatelet therapy compared with the other groups. Regarding fracture type, there were 80 femoral neck fractures (45%) and 96 intertrochanteric fractures (55%). The mean time from admission to surgery was 18.3 hours. There was no significant difference regarding the mean time to surgery after admission among the patient groups (P=.1183). Similarly, there was no statistically significant difference in the mean operative time among the study groups (P=.2468).

Preoperative, Perioperative, and Postoperative Data by Patient Group

Table 1:

Preoperative, Perioperative, and Postoperative Data by Patient Group

No significant differences in hidden blood loss or total blood loss were found among the 4 groups (Figure 2). However, a trend approaching significance was noted for intraoperative blood loss among the 4 groups (P=.0514). The results of a post hoc subgroup analysis of intraoperative blood loss are shown in Table 2. The authors did not find a significant difference in intraoperative blood loss between patients receiving aspirin or dipyridamole alone and those not receiving antiplatelet treatment. However, intraoperative blood loss was significantly greater for patients receiving aspirin and dipyridamole combined compared with those not receiving antiplatelet treatment (mean, 309.14±189.15 mL vs 214.64±119.21 mL; P=.005) (Figure 2, Table 2). On postoperative outcome analysis, there was no significant difference in postoperative hemoglobin and hematocrit levels, mean transfusion amount and rate, duration of stay, or 1-year mortality among the study groups (Table 1).

The amount of perioperative blood loss for hip fracture patients who underwent urgent surgery while being prescribed aspirin and dipyridamole, aspirin alone, dipyridamole alone, or no antiplatelet agent (control). Significantly higher intraoperative blood loss was found in the aspirin and dipyridamole combined group (mean, 309.14±189.15 mL) compared with the control group (mean, 214.64±119.21 mL; P=.005).

Figure 2:

The amount of perioperative blood loss for hip fracture patients who underwent urgent surgery while being prescribed aspirin and dipyridamole, aspirin alone, dipyridamole alone, or no antiplatelet agent (control). Significantly higher intraoperative blood loss was found in the aspirin and dipyridamole combined group (mean, 309.14±189.15 mL) compared with the control group (mean, 214.64±119.21 mL; P=.005).

Results of Post Hoc Subgroup Analysis of Intraoperative Blood Loss Using Scheffe's Test

Table 2:

Results of Post Hoc Subgroup Analysis of Intraoperative Blood Loss Using Scheffe's Test

Cox proportional hazards modeling was used to determine the effect of antiplatelet therapy on 1-year mortality postoperatively while controlling for other confounding factors (Table 3). The HRs for the association of 1-year mortality with aspirin and dipyridamole combined, aspirin alone, or dipyridamole alone were not significant (1.29, 0.89, and 0.67, respectively; P>.05). Furthermore, there was no significant difference in these HRs among the 4 groups after adjusting for confounding covariates (age, sex, Charlson Comorbidity Index, and length of stay).

Results of a Cox Proportional Hazards Model for the Effect of Antiplatelet Exposure on 1-Year Mortality Postoperativelya

Table 3:

Results of a Cox Proportional Hazards Model for the Effect of Antiplatelet Exposure on 1-Year Mortality Postoperatively

Discussion

As a result of a genetic link between hip fracture and thromboembolic disease,3,4 it is not uncommon to encounter elderly patients receiving antiplatelet therapy who have hip fractures.6 Surgeons should strike a balance between the risk of bleeding and the benefit of urgent surgery for patients receiving antiplatelet agents. This study evaluated the outcomes of urgent surgery for uncomplicated hip fractures without the discontinuation of different kinds of antiplatelet drugs, including aspirin alone, dipyridamole alone, and aspirin and dipyridamole combined. The authors found that, compared with patients not receiving antiplatelet therapy, there was no significant difference in total blood loss, transfusion rate, or 1-year mortality for patients receiving antiplatelet therapy, despite significantly higher intraoperative blood loss for those receiving aspirin and dipyridamole combined.

There are different types of antiplatelet drugs used in clinical applications, with the most common being aspirin, dipyridamole, and clopidogrel. Although there are multiple studies regarding the outcomes of patients receiving long-term antiplatelet medications who underwent early hip surgery, the majority of these have focused on aspirin and clopidogrel either separately or combined.6,7,11,12 Dipyridamole inhibits the phosphodiesterase enzymes that break down cyclic adenosine monophosphate and cyclic guanosine monophosphate, which results in the prevention of thrombus formation. Nwachuku et al13 reported that early hip surgery for patients receiving clopidogrel or dipyridamole led to significantly greater blood loss and more postoperative complications when compared with delayed surgery of 48 hours or more; however, only 3 patients receiving dipyridamole were included in the study. To compare the safety of the combined therapy group, the current authors enrolled a group of 28 patients receiving dipyridamole alone who underwent urgent hip surgery without drug discontinuation. The results of this study revealed that patients receiving dipyridamole alone had intraoperative blood loss and other postoperative outcomes similar to those of patients not receiving antiplatelet therapy. This finding implies that dipyridamole, a less potent antiplatelet agent, does not increase operative blood loss or the 1-year postoperative mortality in patients who undergo urgent surgery for uncomplicated hip fractures.

The combined use of aspirin and dipyridamole has been strongly recommended over aspirin alone for preventing thromboembolic disease and decreasing the risk of overall mortality, non-fatal recurrent stroke, and myocardial infarction.14–17 However, the combination of aspirin and dipyridamole may carry a higher risk of hemorrhage from hip fracture surgery than therapy using a single antiplatelet agent. Chechik et al11 investigated the effect of clopidogrel and aspirin combined on blood loss for patients undergoing hip fracture surgery. The mean hidden blood loss for patients receiving this combination was 1312 mL, which was greater than that of those who received either clopidogrel alone (1091 mL) or aspirin alone (900 mL). Hicks et al18 found that greater blood loss was associated with the preoperative use of aspirin and dipyridamole, compared with dipyridamole alone, for patients undergoing coronary artery bypass surgery. The current authors found that patients receiving the combination of aspirin and dipyridamole had significantly greater intraoperative blood loss than those not receiving antiplatelet agents. In addition, when comparing patients who received antiplatelet monotherapy (aspirin or dipyridamole alone) with those administered a combination therapy, the latter had more intraoperative blood loss; however, this trend did not achieve statistical significance. Patients administered aspirin and dipyridamole combined had a significantly higher Charlson Comorbidity Index compared with other therapeutic groups. Therefore, the authors believe that the higher operative blood loss in the combined group is not only caused by the synergic antiplatelet effect of combined therapy but is also a result of the higher prevalence of comorbidity, which can cause unstable hemodynamic changes during anesthesia for surgery. However, the higher intraoperative blood loss among patients receiving aspirin and dipyridamole combined did not contribute to a significantly higher total blood loss, transfusion rate, transfusion amount, or 1-year mortality.

Blood loss and transfusion requirements following hip fracture surgery are associated with multiple factors, including type of fracture, type of fracture fixation, preoperative hemoglobin level, and age.5,19,20 Patients with more complicated fractures, with prolonged operative times, and receiving intramedullary femoral nails are reported to have greater blood loss during surgery.5,11,19,20 In the current study, the authors focused on patients with uncomplicated hip fractures who were treated with hemiarthroplasty or a dynamic hip screw to eliminate the influence of both complexity of trauma and type of surgery. Previous evidence suggests that patients with hip fractures have an increased risk of all-cause mortality.21,22 However, the impact of antiplatelet treatment on the 1-year all-cause mortality of patients with hip fractures who undergo urgent surgery remains unclear. A study by Kragh et al7 indicated that the preoperative administration of aspirin was associated with an increase in the number of required transfusions and the 1-year all-cause mortality after urgent hip fracture surgery. On the contrary, most studies did not find a relationship between the use of antiplatelet agents and the 1-year mortality after hip fracture surgery.12,23 In the current study, the authors performed a Cox proportional hazards regression analysis to examine whether the use of antiplatelet therapy was associated with mortality. Similarly, they did not find an association between the use of antiplatelet agents and the 1-year mortality after hip fracture surgery, even after adjusting for confounding covariates that included age, sex, body mass index, Charlson Comorbidity Index, and duration of hospital stay.

Antiplatelet cessation or continuation in the perioperative period remains controversial.11,23 In deciding between cessation and continuation of antiplatelet therapy for patients with hip fractures, the possible complications of delayed surgery due to drug cessation must be weighed against the risks associated with higher perioperative blood loss and other related complications resulting from antiplatelet drug continuation during surgery. It has previously been suggested that the administration of aspirin cease 7 to 10 days preoperatively, thereby allowing the number of newly generated platelets to recover sufficiently for adequate clotting.24,25 Current evidence indicates that platelet aggregation recovers in approximately 72 to 96 hours after antiplatelet agent discontinuation.23,24 Hence, for patients receiving preoperative antiplatelet agents who undergo urgent hip surgery within 48 hours, there is insufficient time for platelet function recovery, which increases bleeding risk. Moreover, early hip surgery will decrease the risk of lethal complications related to any rebound effects, such as acute coronary syndrome or thromboembolic complications.26 According to the results of the current study, the authors suggest that patients receiving antiplatelet agents can safely undergo urgent hip fracture surgery without drug cessation, regardless of greater intraoperative blood loss for patients receiving dipyridamole and aspirin combined.

Another concern is the possibility of vertebral canal hematoma associated with spinal anesthesia in patients receiving anticoagulants who undergo urgent hip surgery. The incidence of neurological dysfunction caused by the spinal hemorrhage during neuraxial blocks is reported to be less than 1 in 150,000 for epidural and 1 in 220,000 for spinal anesthesia.27 The risk of spinal hemorrhage when undergoing spinal or epidural anesthesia increases for patients receiving anticoagulation therapy.27 According to the guidelines of the American Society of Regional Anesthesia and Pain Medicine, taking aspirin does not increase the risk of vertebral canal hematoma and is not a contraindication to spinal block.28 The guidelines of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine indicate that there is no need to discontinue dipyridamole before spinal block when it is used alone.29 However, there is a lack of evidence regarding the safety of regional anesthesia for patients receiving aspirin and dipyridamole combined. Regarding vertebral canal hematoma after spinal block, all of the patients in the current study were administered laryngeal mask airway general anesthesia. Therefore, the relationship between the anticoagulants and spinal hemorrhage remains unclear. The safety of spinal anesthesia for patients receiving antiplatelet therapy who undergo urgent hip fracture surgery needs to be clarified.

The limitations of this study included that it was a retrospective review of medical data and had a relatively limited number of cases. A study with a larger sample is needed to confirm these results. Moreover, to decrease the influence of type of fracture and surgical procedures on patient blood loss, strict inclusion criteria were used for this study. Therefore, the results were limited to patients with uncomplicated hip fractures who received urgent hip fracture surgery. The effect of antiplatelet agents on patients with unstable hip fractures needs to be determined.

Conclusion

This study showed that aspirin and dipyridamole combined may increase intraoperative blood loss, but not total blood loss, transfusion rate, or 1-year mortality. The authors believe that patients receiving antiplatelet therapy, including aspirin, dipyridamole, or both, who have uncomplicated hip fractures may undergo urgent surgical stabilization without drug cessation. However, intraoperative blood loss should be closely monitored for patients receiving antiplatelet therapy who undergo urgent hip surgery.

References

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Preoperative, Perioperative, and Postoperative Data by Patient Group

ParameterAspirin+DipyridamoleAspirin AloneDipyridamole AloneControlPa
Patients, No.29632856
Age, mean±SD, y76.69±9.4578.48±7.8177.18±8.9977.61±4.34.7132
Male, No. (%)11 (37.93)12 (19.05)10 (35.71)22 (39.29).0748
Intracapsular fracture, No. (%)11 (37.93)30 (47.62)12 (42.86)27 (48.21).7942
Charlson Comorbidity Index, mean±SD3.83±1.912.51±1.662.00±1.021.59±1.58<.0001b
Time to surgery, mean±SD, h18.72±14.6219.70±13.9821.57±15.4514.95±10.47.1183
Operative time, mean±SD, min95.00±40.0794.68±29.3793.39±25.6484.73±24.98.2468
Preoperative hemoglobin, mean±SD, g/dL12.07±1.6411.94±1.7511.14±1.7611.85±1.72.1520
Preoperative hematocrit, mean±SD, %35.24±4.9734.79±6.1532.85±5.3135.83±4.99.1338
Postoperative hemoglobin, mean±SD, g/dL10.28±1.439.94±1.749.44±1.709.96±1.39.2448
Postoperative hematocrit, mean±SD, %30.53±4.2329.88±5.3128.02±4.9529.93±3.97.1956
Units transfused, mean±SD1.14±1.461.38±1.761.14±1.670.73±1.29.1625
Transfusion rate, No. (%)14 (48.28)31 (49.21)11 (39.29)17 (30.36).1710
Length of stay, mean±SD, d8.69±3.328.49±3.089.25±3.808.00±2.90.3903
1-year mortality, No. (%)4 (13.79)6 (9.52)2 (7.14)6 (10.71).8637

Results of Post Hoc Subgroup Analysis of Intraoperative Blood Loss Using Scheffe's Test

Variable1234Pa

Aspirin+DipyridamoleAspirin AloneDipyridamole AloneControl
Operative blood loss, mean, mL309.14244.37250.89214.64.0523
   Pb
    1
    2.0516
    3.1317.8445
    4.0052c.2733.2890

Results of a Cox Proportional Hazards Model for the Effect of Antiplatelet Exposure on 1-Year Mortality Postoperativelya

ParameterAspirin+DipyridamoleAspirin AloneDipyridamole AloneControl
Patients, Total no.29632856
1-year mortality, No. (%)4 (13.79)6 (9.52)2 (7.14)6 (10.71)
Crude hazard ratio (95% confidence interval)1.29 (0.36–4.56)0.89 (0.29–2.76)0.67 (0.13–3.30)1.00
   P.6956.8383.6195
Adjusted hazard ratio (95% confidence interval)1.23 (0.29–5.15)1.16 (0.34–3.95)0.73 (0.15–3.65)1.00
   P.7799.8136.7029
Authors

The authors are from the Department of Orthopaedics (SYL, SHC, CJH, ZML, CCL), Kaohsiung Medical University Hospital, the Department of Orthopaedics (SYL, HTH, CHC, CCL), School of Medicine, College of Medicine, the Orthopaedic Research Centre (SYL, CHC, CCL), and the Department of Orthopaedics (HTH, CHC), Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

The authors have no relevant financial relationships to disclose.

This study was supported in part by the Kaohsiung Municipal Ta-Tung Hospital (grant KMTTH100-004); the Ministry of Science and Technology, Taiwan (grant 106-2314-B-037-070); and the Ministry of Health and Welfare of Taiwan (grant MOHW107-TDU-B-212-123006).

The authors thank Miss Shu-Hua Ko for help collecting the data and Editage ( www.editage.com) for manuscript editing.

Correspondence should be addressed to: Cheng-Chang Lu, MD, Department of Orthopaedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100, Tzyou 1st Rd, San-Ming District, Kaohsiung 807, Taiwan ( cclu0880330@gmail.com).

Received: March 28, 2019
Accepted: July 02, 2019
Posted Online: July 29, 2019

10.3928/01477447-20190723-02

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