Multimodal Stratified Approach for Prevention of Thromboembolism in Patients Undergoing Total Hip Arthroplasty

Objective: To demonstrate the efficacy and safety of a multimodal stratified approach for prevention of thromboembolism in patients undergoing primary total hip arthroplasty. Method: A longitudinal retrospective clinical study of a cohort of 341 individuals undergoing total hip arthroplasty between March 2008 and July 2016. Of these, 242 patients met the criteria for inclusion in the study. Individuals with a history of deep vein thrombosis or pulmonary thromboembolism, thrombophilia, hypercoagulation conditions, and chronic users of anticoagulants before surgery received enoxaparin at a dose of 40 mg/day for 21 days. For the other group, acetylsalicylic acid was prescribed at a dose of 200 mg/day for 30 days. All patients had surgical risk assessed by the American Anesthesiology Association classified as I or II, and underwent regional anesthesia, effective hydration, the same protocol of early postoperative rehabilitation, and the use of compression stockings. Drug cost analysis was performed based on the Brasíndice. To date, there are no publications in PubMed and Scielo on this subject regarding the Brazilian population. Results: The need for blood transfusion in the enoxaparin group was higher and the overall complication and hemorrhagic rates were also significantly higher (p < 0.010) in this group. Aspirin prescription costs 39 times less than enoxaparin. Conclusion: In patients without predisposing factors to thromboembolism and undergoing primary total hip arthroplasty, the multimodal approach with acetylsalicylic acid seems to be effective, with low cost and a low rate of complications.


Introduction
Total hip arthroplasty (THA) is one of the surgical procedures with a high success rate in orthopedic surgery, eliminating pain and restoring hip function in osteoarthrosis cases [1].It is a surgical procedure with a major impact on the natural history of degenerative hip arthritis, providing the patient with a marked and rapid improvement in function and quality of life, assessed by specific scores such as the Harris Hip Score and the SF-36 [2] [3].
However, a number of local and systemic complications may occur.Thromboembolic phenomena are one of the main systemic complications.The incidence of deep vein thrombosis (DVT) may reach 15% in these patients, even with preventive measures and pulmonary thromboembolism (PE) occurs in 1% to 3% of cases, with up to 50% mortality [4].Various alternatives have been proposed in search of the best method capable of reducing the incidence of DVT/PE, recognized as preventable events.The use of several anticoagulant agents such as warfarin, heparin and enoxaparin and an aggressive chemical prophylaxis were the standard of care for all patients during two decades associated to the use of elastic compression stockings and early mobilization.More recently, oral drugs dabigatran and rivaroxaban were also introduced with the same purposes.Preventing symptomatic and/or fatal pulmonary thromboembolism is the main objective of prophylaxis [5].
The guidelines of the American College of Chest Physicians (ACCP) which emphasized prophylaxis with potent anticoagulant agents, did not modify the rate of symptomatic or fatal pulmonary thromboembolism over more than a decade.In addition, they increased morbidity in the major orthopedic surgery setting, mainly related to hemorrhagic complications, thus motivating the search and the proposal for alternative protocols [6].
Several authors relate the use of anticoagulants to a higher rate of complications from excessive bleeding and infections, as well as the need for blood transfusion [7] [8].The constant search for the best method and/or most effective drug with less undesirable effects is the subject of intense debate over new alternatives which have been changing the traditionally accepted guidelines [9].Prophylaxis based on a set of mechanical measures and on the use of aspirin in patients who do not present risk factors for developing DVT and PE, has been gaining increasing credibility, anchored in large studies with high scientific impact, although there is still no consensus about the best chemical agent for thromboprophylaxis after THA [10].
In 2006, the American Academy of Orthopaedic Surgeons (AAOS) created a task force to define strategies for the prevention of thromboembolic phenomena in patients undergoing major orthopedic surgery.Since then, the understanding on the subject has been changing substantially [11].Salvati et al. [12] emphasized the efficacy and safety of a multimodal approach using acetylsalicylic acid in patients with no predisposing factors to DVT/PE and who can be mobilized early.Intraoperative tactics are also recommended for the Johanson et al. [14] corroborate this paradigm shift as it provides the orthopedic surgeon with a wider range of options and allows for the selection of less aggressive protocols.Thus, an equivalent level of efficacy and safety in the prevention of thromboembolic events, combined with the reduction of the undesirable effects of intensive anticoagulation is maintained [12].
The objective of the present study was to evaluate the efficacy and safety of the stratified multimodal approach using acetylsalicylic acid as chemoprophylaxis for DVT and PE in patients submitted to primary THA and to measure the incidence of thromboembolism and complications in the sample studied.

Material and Methods
The study was submitted to the institution's Research Ethics Committee under CAAE No. 13710914.6.0000.5133/opinion779.089 and all the individuals selected explicitly agreed to participate by means of a free and informed consent form.
In a longitudinal retrospective clinical study, a cohort of 341 patients was analyzed.They had undergone primary or revision THA, for any diagnosis, between March 2008 and July 2016, were operated on by the same senior surgeon, using the lateral approach [15], in 3 general hospitals, one a teaching hospital.
The mean hospital stay after surgery was 72 hours.Of these, 242 patients fulfilled the criteria for inclusion in the study, that is, patients who had undergone total primary hip arthroplasty, with an ASA (American Society of Anesthesiologists) I or II surgical risk [16] and monitored for a period of 6 months.
Among those excluded from the analysis were 48 patients who had undergone revision THA surgery, 17 patients with incomplete documentation, 25 individuals for whom a postoperative suction drain was used, and 9 patients with a body mass index (BMI) of 30 or higher.
Blood transfusion of two units of packed red blood cells was indicated in cases with a hemoglobin level below 9 g/dl, collected 24 hours after the procedure.
Individuals were divided into two groups: one group composed of patients with a personal history of DVT or PE, thrombophilia, hypercoagulability, and chronic anticoagulant users prior to surgery, who received enoxaparin at a dose of 40 mg day for 21 days, commencing 12 hours after the surgical procedure (Group I-56 individuals).For the rest, acetylsalicylic acid was administered at a dose of 200 mg/day for a period of 30 days, commencing 12 hours after the surgical procedure (Group II-186 individuals).All were submitted to regional anesthesia, to effective hydration, to the same early postoperative rehabilitation protocol with mobilization in bed beginning in the sixth postoperative hour, to the use of elastic compression stockings, and intraoperative precautions to reduce the time of femoral instrumentation and extreme limb positions.
The cost study of the drugs used, acetylsalicylic acid 200 mg for 30 days and enoxaparin 40 mg for 21 days, was performed based on the mean consumer price published in the Brasíndice, December 2016 edition [17].
The data analysis was developed using the Statistical Package for the Social Sciences (SPSS), version 15.0 (Chicago, IL, USA).Incidence measurements were obtained for events after 180 days of follow-up.The quantitative variables were described in terms of means and standard deviations.
In the bivariate analysis, the chi-square test was used for nominal variables, with Fischer's correction when necessary, and crude odds ratios were obtained.
Quantitative variables were analyzed via t-test for meeting the normal data distribution criterion.
The logistic regression analysis sought to control the effect of confounding variables and estimated the adjusted odds ratios, with model goodness-of-fit assessed by the Hosmer and Lemeshow method.The significance level was 5%.
The term "hemorrhagic complication" was used, encompassing hematomas and/or serohematic drainage from the wound for more than 5 days.

Results
Fifty-six individuals (23.10%) comprised group I with administration of enoxaparin.
One hundred and eighty-six individuals (76.09%) were included in group II and used acetylsalicylic acid (Table 1).Of the patients in group I, 35.70% were male and 64.30% female.In group II, 57.50% were male and 42.50% were female, with a p-value = 0.030 (Figure 1).
The description of the sample according to demographic, diagnosis, and intervention characteristics is shown in Table 1.
The mean age of patients in group I was 68.79 years (SD 10.12) and in group II was 57.87 years (SD 11.94), p-value = 0.110.The distribution is depicted in Figure 2.
The mean age of the group that received injectable anticoagulant was higher than the group that was given acetylsalicylic acid (68.79 years and 57.87 years, respectively), although not statistically significant (p-value of 0.110).The female gender predominated in the enoxaparin group (p-value of 0.030) (Figure 2).
Figure 3 shows the etiological diagnosis of the sample studied, and the distribution by etiological diagnosis according to the drug used is shown in Table 1, with no significant difference between the groups.
Regarding the type of implant used, 62.5% of the cases that used enoxaparin and 61.80% of those who used acetylsalicylic acid received a hybrid implant (cemented femoral stem).The non-cemented THA was used in 32.10% of the cases in group I and 29.60% in group II.Cemented prostheses were used in 5.40% of the individuals in group I and 8.60% in group II (Table 1).
The incidence of complications was higher for the enoxaparin group, with statistical significance (p-value < 0.001).The variables analyzed and the most frequent types of complications are listed in Table 2, covering a period of 180 days of postoperative follow-up.Blood transfusion was performed in 25.00% of the individuals in group I and 5.40% in group II, with a p-value < 0.010 (Table 1).It was inferred that the use of enoxaparin represented an increased risk for blood transfusion and hematoma/seroma formation and/or suspected infection.The incidence of DVT was 1.8% and PE was 1.8% in group I.No cases were registered in group II (Table 2).
Suspected DVT not confirmed by venous Doppler was noted in 3.6% of the individuals in the enoxaparin group and 0.5% of the cases in the group that used acetylsalicylic acid.Post-thrombotic syndrome was identified in the 180-day follow-up in 0.5% of those who received acetylsalicylic acid.
The patients diagnosed with hip dysplasia had a higher need for blood transfusion (38%) compared to the general rate (p < 0.0001).Such diagnosis therefore defined a possible risk factor for bleeding in the pre-operative period, a variable independent of the use of any of the drugs considered.
The mean cost of acetylsalicylic acid 200 mg, used for the 30

Discussion
The use of potent anticoagulants in the pre and post-operative periods of orthopedic surgery has come under intense debate and is still a controversial issue.
The increase in the risk of bleeding, blood transfusions, and clinical intercurrences are reported.On the other hand, the incidence of PE deaths has not changed over decades, even with the use of anticoagulants.The ACCP guidelines recommending potent anticoagulation tend to underestimate the risks of bleeding and its consequences and, until recently, contraindicated the use of acetylsalicylic acid as a single-agent drug in thromboprophylaxis [18] [19] [20] [21] [22].
The high incidence of complications in patients submitted to the ACCP protocol for the prevention of DVT/PE motivated the AAOS to propose new guidelines more appropriate to the orthopedic surgery scenario and its specifics, with the objective of preventing symptomatic PE and reducing the prevalence of DVT and, at the same time, minimizing the undesirable complications associated with more aggressive anticoagulation [12].
Burnett et al. [23], in a series of 290 prospectively evaluated patients and following the guidelines of the ACCP in the use of enoxaparin, found 9% of serious complications, DVT in 3.8%, and nonfatal PE in 1.3%, associated with a high rate of readmissions and interventions, prolonged drainage from the surgical wound, and 3.4% of infections.They noted that a body mass index of 35 or higher is predictive of prolonged drainage from the wound, and that drainage of more than 7 days is predictive of readmission and reoperation.
Various publications in the last ten years advocate careful selection of patients and less aggressive conduct in the prevention of DVT/PE, with the use of simple protocols, with low cost and with lower risks, yet effective in preventing such events [24].
Ogonda et al. [25] analyzed 11,459 individuals submitted to hip and knee arthroplasties, for whom acetylsalicylic acid was the primary agent for thromboprophylaxis, and they support the individualized risk approach as part of a multimodal strategy.They concluded that acetylsalicylic acidis safe as a thromboprophylactic agent in arthroplasties and was not associated with an increased incidence of DVT, PE, or death.The main causes of death were ischemic heart disease and respiratory disorders, with PE accounting for only 18% of the deaths, whose incidence in 90 postoperative days was 0.39%.The incidence of PE after THA was 0.6%, and 0.3% for DVT in their study.
The use of the multimodal protocol for the prevention of DVT/PE with elastic compression stockings, early mobilization and ambulation, plus the administration of acetylsalicylic acid in the postoperative period, has proven to be effective and with a lower risk of bleeding, according to various authors [26].To date there are no published studies on the topic, involving the Brazilian population, in the PubMed and Scielo databases.Open Journal of Orthopedics Acetylsalicylic acid would even have effects in reducing the risk of arterial complications and on heterotopic ossification, being easy to administer and well tolerated by most patients.Its use is beneficial in the three elements of Virchow's Triad (venous stasis, endothelial lesion, and hypercoagulation), with rates of 2.5% for DVT, 0.6% for non-fatal PE and an absence of major bleeding events, as reported by González Della Valle et al. [27].Salvati et al. [12] justify the multimodal approach owing to its lower rates of mortality, non-fatal PE and bleeding, forming an effective strategy with fewer complications when using an acetylsalicylic acid dose of 650 mg/day [18].
Other authors [28] recommend doses below 300 mg/day and, therefore, there is still no consensus regarding the most appropriate dose of acetylsalicylic acid.
The choice of an acetylsalicylic acid dose of 200 mg/day in the present sample was due to the practicality of administration with the most commonly offered medication available in the Brazilian market, being defined by the average between the dosages proposed by different authors.
In the present analysis, a homogeneity was observed between the two groups in most of the variables considered, and there were no significant differences in the demographic variables, in the diagnosis, and in the type of implant used, except for the mean age of the acetylsalicylic acid group being lower than that of the group who received enoxaparin, and the predominance of the male gender in the acetylsalicylic acid group.
The protocol was applied with no distinctions for the public network and private clinic patients.
The present study's data analysis demonstrated a greater need for blood transfusion in patients undergoing anticoagulation with enoxaparin (p < 0.010) and a higher risk of bleeding associated with the presence of hematoma/seroma in the same group (OR 6.44; CI 2.70 -15.36; p-value < 0.010), data in agreement with the literature researched.Some authors report that the greater volume of drainage from the surgical wound in the postoperative period was related to an increased risk of infection of 42% in patients submitted to THA and 29% in patients submitted to total knee arthroplasty (TKA) [29] [30].In this series, statistical significance was not attained in relation to the prevalence of infection.However, the group receiving enoxaparin had a higher rate of reintervention (p-value = 0.007) and postoperative drainage with OR 4.06 (0.56 -29.41).
In a study with 473 low-risk patients for the development of DVT/PE who underwent total knee arthroplasty and were treated with a multimodal protocol and acetylsalicylic acid, Callaghan et al. reported the non-occurrence of death and a very low cost to carry out the prevention of thromboembolic phenomena [31].
The only recorded death in the sample under analysis was due to a coronary event in the first 12 hours postoperatively.
Adherence to treatment also seems to be associated with the cost of the drug.
It is observed that this is one of the main reasons for not adhering to the pre-Open Journal of Orthopedics scribed medication use in the correct way and for the time required, especially among the most needy population attended by the Brazilian Unified Health System (SUS).The extremely high financial cost of enoxaparin (R$1073.05)compared to acetylsalicylic acid (R$26.04),for the period of 21 and 30 days respectively [17], clearly favors the option for using the latter [32].
Johanson et al. [14], in the guidelines recommended by the AAOS in 2009, affirm it is advisable to evaluate the risk not only of thromboembolic events, but also of postoperative bleeding, and that mechanical prophylactic measures with early mobilization are recommended to all individuals who undergo hip or knee arthroplasties, without distinctions.They also highlight the recommendations on drug selection for different groups of patients.For individuals with a normal risk for thromboembolism and/or a high risk for bleeding, the choice of aspirin is supported.For individuals with a high risk of thromboembolism and a normal level of risk for bleeding, low molecular weight heparin, or other more potent agents, also have an established role.
It was also observed in this series that patients with a diagnosis of hip dysplasia presented a higher risk of complications related to bleeding.
It should be noted that the use of aspirin does not require periodic control of the International Normalized Ratio (INR), further reducing the secondary additional costs and facilitating the follow-up of cases.Likewise, the increasing number of younger-age-group individuals favors the use of less aggressive protocols for anticoagulation, combined even with the fact that most thromboembolic events occur on the first three postoperative days [22].
Recent changes in the guidelines of both the AAOS and the ACCP converge in favor of aspirin use in the context of a multimodal approach in correctly selected patients.Bayley et al. [33], in a prospective study involving 7983 THAs, suggest aspirin as an appropriate thromboprophylactic agent as part of a multimodal regimen, noting that pulmonary embolism is rare in this context and that potent anticoagulants have a higher rate of complications.

Conclusions
Data analysis showed a higher overall rate of complications such as bleeding and hematoma/seroma formation, as well as in the indication of blood transfusion in patients submitted to prevention of thromboembolic events with enoxaparin compared to those who received aspirin, with statistical significance.The financial cost of the multimodal approach with aspirin proved exponentially lower than the use of enoxaparin.

Figure 1 .
Figure 1.Distribution of the gender of the patients analyzed by type of drug used.

Figure 2 .
Figure 2. Mean age of the patients analyzed by type of drug used.

Figure 3 .
Figure 3. Distribution of the patients analyzed by etiological diagnosis.
While noting the limitations of the present study in relation to the sample size, the low incidence of complications combined with the low cost of the aspirin administered for most cases (76.09%) may represent a relevant indication for the prophylaxis strategy of DVT/PE in the postoperative period of THA in the Brazilian population, especially in the low-income group attended by the Unified Health System (SUS).

Table 1 .
Demographic, diagnosis, and intervention variables, by drug used.

Table 2 .
Complications according to the drug used (180 days).

Table 3 .
Multivariate analysis* for the occurrence of selected complications and the use of enoxaparin.
Notes: *Controlled for gender, mean age, and type of prosthesis; † Deep vein thrombosis and pulmonary thromboembolism; ‡ Hematoma, serous drainage, and need for transfusion.Legend: OR-Odds Ratio; CI-Confidence Interval.