Significant blood loss, bleeding-related complications, and a need for transfusions are major complications after a total knee arthroplasty (TKA).1–5 The attending surgeon must decide whether to continue or discontinue aspirin therapy during the perioperative period in patients with a history of cerebrovascular or cardiovascular disease. The risks of bleeding and perioperative thromboembolic events (cerebrovascular and cardiovascular events, deep vein thrombosis [DVT], and pulmonary embolisms) should be considered. The American Academy of Orthopedics Surgeons (AAOS) moderately recommends in its September 2011 guideline4 that antiplatelet agents be discontinued before hip or knee arthroplasty. The American College of Chest Physicians (ACCP) also recommends in its February 2012 guideline6 stopping aspirin for 7–10 days before surgery in low-risk patients. However, continued aspirin therapy in patients undergoing non-cardiac surgeries reduces the risks of major thromboembolic events, but discontinued or no aspirin therapy is associated with higher risks of adverse cardiac events.7–10 Therefore, perioperative management of aspirin therapy in patients undergoing TKA is controversial.
There are few studies on whether to continue aspirin therapy during a TKA. A comparative study (Schwab et al.,11) reported that the risks of bleeding and the need for a transfusion were not significantly different between patients undergoing unicompartmental or TKA who were or were not on continued aspirin mono-therapy. However, venous thromboembolic events were not analyzed as an end point. Meier et al.12 said that blood loss and local bleeding complications were not significantly higher in patients on continued aspirin therapy undergoing TKA or total hip arthroplasty (THA). There tended to be a lower risk of cardiac complications in patients who continued aspirin. However, only 17 of 337 patients who had undergone a TKA were on continued aspirin therapy.
We hypothesized that continued aspirin mono-therapy in patients undergoing TKA would lead to a higher risk of bleeding but to a similar rate of thromboembolic events as in patients who had never been on aspirin therapy.
Between December 2010 and December 2012, we enrolled a series of 1655 patients who underwent unilateral (n = 1295) or simultaneous bilateral (n = 360) primary, minimally invasive TKA, done by the same surgeon, for osteoarthritis, spontaneous osteonecrosis of the knee, or rheumatoid arthritis. Exclusion criteria were a previous TKA, or primary septic arthritis that required staged surgery or reconstruction after resection of benign, or malignant bone tumors around the knee joint. This study has been approved by the institution review board (IRB number 2018-04-003AC). One group of 272 patients (unilateral TKA in 217, bilateral in 55) had undergone surgery with continued aspirin mono-therapy. A second group of 1383 patients (unilateral TKA in 1078, bilateral in 305) had not previously been on aspirin therapy, and were not during the surgery. Patients who were on antiplatelet medications other than aspirin (e.g. clopidogrel, cilostazol, dipyridamole) or anticoagulation (e.g. warfarin) in both groups were also excluded. Patients who had undergone unilateral TKA on continued aspirin mono-therapy were older (74.2 ± 7.3 vs. 71.6 ± 8.4 years), weighed more (68.1 ± 11.3 vs. 66.0 ± 11.9 kg), and had higher body mass indices (BMIs) (28.7 ± 4.7 vs. 27.6 ± 4.4), higher percentages of histories of hypertension (91.2% vs. 60.5%), coronary artery disease (14.3% vs. 4.6%), and cerebrovascular disease (5.5% vs. 1.2%) than did those not on continued aspirin therapy (Table 1). Patients who had undergone bilateral TKAs on continued aspirin mono-therapy were older (74.9 ± 6.2 vs. 71.0 ± 7.2 years), taller (156.0 ± 8.1 vs. 153.3 ± 7.6 cm), and had higher percentages of histories of hypertension (80.0% vs. 62.6%), diabetes mellitus (34.5% vs. 22.0%), and coronary artery disease (27.3% vs. 3.9%) than did those not on aspirin therapy.
Patients were given a spinal block (spinal anesthesia) whenever possible. A tourniquet was inflated before the knee incision and released after all TKA components had been implanted. We deflated the tourniquet and did hemostasis before wound closure. Cuff pressure was set at 100–120 mmHg higher than the systolic blood pressure immediately before the tourniquet was inflated. A minimally invasive medial midvastus approach was used in all patients. Nexgen® (Zimmer, Warsaw, IN, USA) and Scorpio NRG® (Stryker, Mahwah, NJ, USA) were the implants of choice in this study. An evacuator (Hemovac®; Zimmer, Warsaw, IN, USA) was inserted in every patient. No patients were injected with local hemostatic agents, e.g., intra-articular tranexamic acid, or periarticular injection for pain control during this period.
After surgery, all patients were immediately allowed to walk without weight-bearing restrictions, and with walking aids if necessary. On postoperative Day 1, we started active and passive range-of-motion exercises with ice-packs, and we checked patients’ hemoglobin levels. Blood transfusions were considered for patients whose hemoglobin level was ≤9 g/dL or between 9 and 10 g/dL with symptoms of anemia. These criteria were used for all patients throughout this period. The Hemovac was removed on postoperative Day 2, regardless of the drainage amount. Indications for thrombosis prophylaxis were: body mass index ≥30, severe varicose veins over the lower legs, and a history of thromboembolic events: DVT and pulmonary embolisms. The other patients did not receive chemical or mechanical prophylaxis. Early ambulation and ankle pump exercise were started immediately after surgery as tolerable. The thrombosis prophylaxis protocol consisted of an injection of low molecular weight heparin (enoxaparin, Clexane®, 2000 IU, 0.2 cc) immediately after surgery and daily until postoperative Day 3, and low-dose aspirin (Bokey®) (100 mg) for 2 weeks from postoperative Day 4. A higher proportion (28.6% vs. 18.9%) of patients who underwent unilateral TKA with continued aspirin mono-therapy were treated with this protocol than were patients without continued aspirin therapy. In patients who had undergone bilateral TKA, the proportion was not significantly different (18.2% vs. 23.6%). Lower extremity ultrasonography was not routinely used to screen for DVT, except for patients suspected of having DVT. With confirmed DVT or with significant clinical symptoms but without ultrasonographic evidence, prolonged low-dose aspirin was prescribed until the symptoms subsided. If there were no unexpected adverse events, patients were usually discharged on postoperative Days 4–6. Time points for outpatient department follow-up included postoperative 2 weeks, 6 weeks, 3 months, 1 year, and then annually. Follow-up rates were 100% at 2 weeks, 98.7% at 6 weeks, 97.2% at 3 months, and 95.2% at 1 year.
Primary outcome parameters consisted of postoperative drainage amount (Days 1 and 2), postoperative hemoglobin level, change in hemoglobin, calculated blood loss,3 incidence and the amount of blood transfused, proportions of thromboembolic events: symptomatic DVT and pulmonary embolisms.
Secondary outcome parameters consisted of tourniquet time, cuff pressure, length of hospital stay, and surgical and medical complications.
For statistical analysis, Kolmogorov–Smirnov tests were first used to assess whether the data were normally distributed. For continuous variables, independent t tests and Mann–Whitney U tests were used to analyze normally and abnormally distributed data, respectively. For categorical variables, χ2 and Fisher’s exact tests were used. SPSS 17 for Windows (SPSS Inc, Chicago, IL, USA) was used for all statistical analyses. Significance was set at p < 0.05. We used G*Power software (Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany) to perform post hoc power analysis in each comparison of primary outcome parameters with an alpha probability of 0.05. A power more than 0.8 was considered sufficient.
3.1. Primary outcomes
In patients who had undergone unilateral TKA, preoperative and postoperative hemoglobin levels and changes in hemoglobin levels were not significantly different. The drainage amounts on postoperative Day 1 (698.1 ± 256.8 vs. 651.8 ± 256.2 ml) and Day 2 (214.0 ± 95.9 vs. 198.2 ± 83.0 ml) were significantly higher in patients not on aspirin therapy. In contrast, calculated blood loss (969.1 ± 324.9 vs. 904.0 ± 315.5 ml), transfusion incidence (53.0% vs. 40.2%), and the amount of blood transfused (1.3 ± 1.5 vs. 1.0 ± 1.3 IU) were all significantly higher in patients with continued aspirin mono-therapy (Table 2).
In patients who had undergone bilateral TKA, baseline and postoperative hemoglobin levels were all significantly higher in patients who were not on aspirin therapy, but changes in hemoglobin levels were not significantly different. The primary outcomes of both groups (drainage amount of calculated blood loss, postoperative Days 1 and 2, transfusion incidence, and the amount of blood transfused) were not significantly different (Table 2).
3.2. Secondary outcomes
Cuff pressure, tourniquet time, and length of hospital stay were not significantly different between groups in patients who underwent unilateral and bilateral TKA. There was no in-hospital mortality (Table 2).
The overall complication rates in patients who had undergone unilateral TKA with and without aspirin therapy were not significantly different (9.2% vs. 7.1%), nor were the proportions of patients with positive clinical and ultrasonographic findings or with only positive clinical symptoms of DVT but negative findings on ultrasonography (4.6% vs. 5.4%). No patients developed a pulmonary embolism. Minor wound complications (1.8% vs. 1.6%) consisted of excessive bullae formation, delayed wound healing, or superficial wound infections. Other complications included postoperative ileus in 2 patients (0.2%), exacerbated heart failure in 2 (0.2%), and periprosthetic fractures in 2 others. Time points for the two periprosthetic fractures were 7 and 11 months after surgery (Table 3).
The overall complication rate in patients who had undergone bilateral TKA with and without aspirin therapy were not significantly different (3.6% vs. 6.6%), nor were the proportions with positive clinical or ultrasonographic findings of symptomatic DVT (3.6% vs. 4.6%). Notably, in patients not on aspirin therapy, 1 (0.3%) developed a pulmonary embolism and 2 others (0.6%) had cerebrovascular events. Other complications included Cushing syndrome in 1 patient (0.3%) and a flare-up of herpes zoster in 2 others (0.6%) (Table 3).
The most important finding of this study was that continued aspirin mono-therapy might be a safe and reasonable management during the perioperative period of TKA. Patients who underwent unilateral TKA and were on continued aspirin mono-therapy had slightly (but significantly) more transfusions, transfusion amounts, and calculated blood losses. Outcome parameters were not significantly different for patients who had undergone simultaneous bilateral TKA. Notably, patients on aspirin mono-therapy had no perioperative cerebrovascular or cardiovascular events, and their proportions of symptomatic DVT were low. Pulmonary embolism occurred in only one patient who was not on aspirin therapy.
Continued aspirin therapy to prevent major thromboembolic events in high-risk patients undergoing non-cardiac surgeries has been supported in some studies.7–10,13 Eisenberg et al.7 suggested that, in patients who had a cardiac stent for coronary artery disease, elective total joint arthroplasty be delayed until clopidogrel can be stopped and that aspirin therapy be continued. Stopping both antiplatelet agents might lead to increased perioperative thrombotic events. Biondi-Zoccai et al.8 concluded that discontinuing aspirin therapy in patients with coronary artery disease leads to a higher risk of major adverse cardiac events, and to an even higher risk in patients with intracoronary stents. In a randomized, double blinded, placebo-controlled trial9 in high-risk patients undergoing non-cardiac surgeries, low-dose aspirin reduced the risk of major adverse cardiac events. Mantz et al.13 found no difference in major thrombotic or bleeding events in a multicenter randomized, blinded, placebo-controlled trial of 291 intermediate-to high-risk patients undergoing mixed elective surgeries. Gerstein et al.10 hypothesized that, except in intracranial, middle ear, posterior eye, intramedullary spine, and transurethral prostatectomy surgeries, the perioperative bleeding risks might not outweigh concomitant thromboembolic risks. Those studies9,10,13 involved a variety of non-cardiac surgeries and concluded that clinicians should weigh the risks and benefits of continued aspirin therapy with a patient-specific strategy.
The AAOS 2011 guideline moderately recommends that aspirin therapy be discontinued before total joint arthroplasty,14 and the ACCP 2012 guideline recommends discontinuing aspirin therapy for 7–10 days before surgery in low-risk patients.6 One case-control study of patients with femoral neck fractures reported that continued aspirin therapy was associated with a higher incidence of postoperative transfusions, but that differences in blood loss and changes in hematocrit were not significant.15 In patients who had surgery for proximal femoral fractures, those on continued aspirin therapy had higher transfusion amounts than those who were not on aspirin therapy, but drainage amounts, hemoglobin levels, and wound complications were not significantly different.16 In spine fusion surgeries, patients who were or had been on low-dose aspirin therapy had higher postoperative blood drainage and transfusion amounts.17 However, Nuttall et al.18 said that, in a multiple regression analysis, aspirin was not related to increased bleeding in their 38 patients. A comparative study11 of 601 patients who underwent unicompartmental knee arthroplasty or TKA showed no significant changes in hemoglobin level, calculated blood loss, number of transfusions, or transfusion amount, regardless of whether they were on aspirin therapy. Aspirin therapy was continued in both high- and low-risk patients without a risk of increased bleeding, and the need for risk stratification was eliminated. However, venous thromboembolic events were not analyzed as an end point. In our series of 1655 patients, patients who underwent unilateral but not bilateral TKA had more transfusions, a higher transfusion amount, and a higher calculated blood loss. Notably, the proportions of symptomatic DVT were comparable. There were no pulmonary embolisms or cardiovascular or cerebrovascular events in patients on continued aspirin mono-therapy. The overall incidence of symptomatic DVT in our study was 5.1%, which was relatively low compared with those reported in the literature, which ranged from 0.75% to 26.6%.19–23 This widely reported incidence might be the product of different study designs, indications for ultrasonography examinations, different populations, or the pharmacological prophylaxis of thromboembolisms. The incidence of pulmonary embolisms was 0.06% (range: 0.01%–0.4%), which is comparable with what is reported in the literature.22–24
This study has some limitations. First, the study should have focused on whether to continue aspirin mono-therapy in low-risk patients, in which case, a double-blinded, placebo-based control group design with randomly discontinued perioperative aspirin would have been ideal. However, we hypothesized that there would be only a nonsignificant increase in the risk of bleeding that would not outweigh the risk of a thromboembolism. Therefore, we continued aspirin in all patients without risk stratification. Second, there was a potential bias affecting the bleeding risk. There was an older mean age, lower preoperative hemoglobin level, higher proportion of medical comorbidities and higher proportion of patients receiving thromboembolism prophylaxis in patients who were on aspirin mono-therapy than in those who were not. Ahmed et al.1 found, in a multivariate regression analysis, that old age and lower preoperative hemoglobin levels were factors that increased the risk of needing a postoperative blood transfusion. Despite the presence of those positive confounding factors that might lead to increased bleeding risk, we found that patients who underwent unilateral but not bilateral TKA had higher calculated blood losses and needed more transfusions. Third, transfusion rate for unilateral total knee arthroplasty in both groups were 40.2% and 53.0% We did not use systemic or intraarticular hemostatic agents during this study period. We started the use of intraarticular tranexamic acid injection since year 2013. We did not include those patients to avoid confounding. In addition, our transfusion criteria were less strict than the American Association of Blood Banks clinical practice guideline on transfusion.25 Therefore, this transfusion rate was relatively high compared with those reported, ranged from 21% to 70%.26 Fourth, it was underpowered to conclude for the risk difference of thromboembolic events including deep vein thrombosis, pulmonary embolism, cardiovascular or cerebrovascular events between groups. Therefore, we can only conclude that risk of thromboembolic events in patients who were on continued aspirin mono-therapy was low rather than a risk difference.
The strengths of this study are that this was a large series of surgeries done by the same surgeon within a relatively short study period, and that the postoperative follow-up rate was high (95.2% at postoperative 1 year) to record surgical and medical complications, especially thromboembolic events. Indications for thromboembolic prophylaxis, blood transfusion, postoperative care, rehabilitation, and follow-up protocols were consistent throughout this study.
In conclusion, continued aspirin mono-therapy during unilateral and simultaneous bilateral TKA might be a safe strategy with a low risk of perioperative cerebrovascular, cardiovascular, and venous thromboembolic events. A slightly higher bleeding risk might not outweigh the potential risk of thromboembolic events in TKA.
We thank Bill Franke for the proof-reading of this manuscript.
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