Incidence of Clinically Significant Venous Thromboembolic Events in Asian Patients Undergoing Total Knee Arthroplasty Without Anticoagulation

The Journal of Arthroplasty Vol. 27 No. 6 2012

Incidence of Clinically Significant Venous Thromboembolic Events in Asian Patients Undergoing Total Knee Arthroplasty Without Anticoagulation Hamid Rahmatullah Bin Abd Razak, MBBS, Ang Teng Soon, MBBS, Ian Dominic Dhanaraj, MBBS, and Andrew Hwee Chye Tan, MBBS, FRCS (Orth)

Abstract: This study aimed to evaluate the incidence of clinically significant venous thromboembolic events (VTE) in Asian patients undergoing total knee arthroplasty (TKA) without anticoagulation. All patients who underwent TKA by a single surgeon from 2006 to 2010 in Singapore General Hospital were reviewed. Only symptomatic patients were referred for ultrasonography. Of the 531 patients reviewed, 3 patients developed symptoms of deep vein thrombosis with subsequent ultrasonographic confirmation, whereas 1 patient developed fatal pulmonary embolism without any clinical or radiologic evidence of deep vein thrombosis. Hence, the incidence of clinically significant VTE was 0.75%. Given the low incidence of clinically significant VTE, there is a need to review the current practice of routine chemoprophylaxis in Asian patients undergoing TKA. Keywords: venous thromboembolism, total knee arthroplasty, anticoagulation. © 2012 Elsevier Inc. All rights reserved.

Historically, in Western populations, the incidence of post–total knee arthroplasty (TKA) deep vein thrombosis (DVT) and pulmonary embolism (PE) has been quoted to be as high as 46% to 86% [1,2]. It has been established by several studies that this incidence ranges from 14% to 30% [3,4] in the Asian population. However, recent studies have reported incidences as high as 63% [5-7]. The current Western guidelines recommend routine chemoprophylaxis for all patients who undergo TKA to reduce the incidence of VTE, although they are divided on the type of drug to be given [8]. Many studies have reported that a large thrombus proximal to the knee poses a higher risk of PE [9-11]. The importance of DVT in the calf, however, is poorly understood, and the treatment is controversial. Some studies have reported that the risks of treatment may be greater than those of the thrombosis itself [12-14]. Furthermore, early mobilization [15] and passive mobilization with the use of devices such as continuous From the Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore. Submitted May 25, 2011; accepted September 23, 2011. The Conflict of Interest statement associated with this article can be found at doi:10.1016/j.arth.2011.09.024. Reprint requests: Hamid Rahmatullah, MBBS, Department of Orthopaedic Surgery, Singapore General Hospital, Outram Road, Singapore 169608. © 2012 Elsevier Inc. All rights reserved. 0883-5403/2706-0050$36.00/0 doi:10.1016/j.arth.2011.09.024

passive mobilizers [16] and intermittent pneumatic compression [17] have been shown to be beneficial in reducing incidence of VTE. We conducted this study to evaluate whether routine chemical prophylaxis is necessary, given the low incidence of clinically significant VTE in the Asian population.

Materials and Methods From January 2006 to May 2009, 531 patients who underwent elective TKA were retrospectively studied. Patients from a single surgeon, the senior author of the study, were selected for consistency of surgical technique and postoperative care. Our institutional review board approved the study. Exclusion criteria were the use of anticoagulants or aspirin, a history of PE or DVT in the previous year, preoperative prolonged immobilization or being wheelchair bound, surgery in the previous 6 months, history of varicose veins or chronic venous insufficiency, and prothrombotic dyscrasias. A total of 39 patients were excluded from this study based on the above exclusion criteria. All patients underwent unilateral TKA by a single surgeon. All patients had tourniquet applied to the operated limb throughout the course of the surgery. Total knee arthroplasty was performed in a standard fashion for all patients. The medial parapatellar approach was used for patients with varus knees and the lateral parapatellar approach for those with valgus

1128

Clinically Significant VTEs in Patients Undergoing TKA  Bin Abd Razak et al Table 1. Demographic Data and Clinical Details for Patients in the Study

asked for clinical symptoms of DVT such as calf swelling, erythema, tenderness, and fever. The surgeon also examined each patient for clinical signs of DVT, paying particular attention to calf girth. Parameters assessed include age, race, sex, body mass index, type of anesthesia, tourniquet time, and number of comorbidities. Hypertension, diabetes mellitus, and asthma were the most common comorbidities in these patients. The incidence of VTE in the patients was then calculated using a standard formula. The Student t test was used to compare means where applicable. All statistical analyses were done using the Statistical Package for the Social Sciences version 17 (SPSS, Chicago, Ill).

Distribution (n = 531) Age (y), mean (range) Sex * Male Female Race * Chinese Malay Indian Body mass index (kg/m2), mean (±SD) No. of comorbidities, mean (±SD) Type of anesthesia * General Regional Tourniquet time (min), mean (±SD) Hospital stay (d), mean (±SD)

1129

66.22 (50-84) 113 (21.3) 418 (78.7) 469 (88.3) 34 (6.4) 28 (5.3) 27.8 (±1.6) 1.7 (±0.8) 194 (36.5) 337 (63.5) 72 (±15.9) 5.2 (±2.4)

Results

* The data are given as the number of patients with the percentage in parenthesis.

Our patient demographics closely resemble that of the general Singapore population (Table 1) except for sex, where there were a higher proportion of women. A total of 418 patients (78.7%) in our study group were women, whereas 113 (21.3%) were men. The mean (±SD) age was 66 (±7.7) years. The mean ((±SD) body mass index was 27.8 (±1.6) kg/m 2. One hundred ninety-four (36.5%) of our patients underwent general anesthesia, whereas 337 (63.5%) underwent regional anesthesia. The mean (±SD) tourniquet time was 72 (15.9) minutes. Only 4 patients (Table 2) were found to have clinically significant VTE. The incidence of clinically significant VTE in our study population was, thus, 0.75%. Of this patient group, 3 patients developed clinical symptoms of DVT and were referred for ultrasonographic assessment, which confirmed the clinical findings. All 3 patients were referred to hematologists for assessment, and only 1 patient was started on anticoagulation. The results of

knees. No patellar resurfacing was performed. Postsurgical drains were inserted for all patients and removed on either postoperative day 2 or when the drainage was less than 100 mL, whichever occurred earlier. All patients received standardized postoperative care, which included appropriate analgesia, pneumatic calf pumps, continuous passive motion from first postoperative day, and daily physiotherapy assessment. All patients began ambulation on the second postoperative day. None of the patients received any form of chemoprophylaxis against VTE. The surgeon and his team reviewed the patients daily, and any clinical signs of VTE were recorded in the case sheets. Only symptomatic patients with clinical signs of VTE were referred for radiologic and/or biochemical evaluation. Postoperatively, patients were followed up at 2 weeks; 1, 3, and 6 months; and 1 year. Up till 6 months postoperatively, patients were

Table 2. Demographics and Clinical Details of Patients With VTE Age (y) Sex Race BMI (kg/m2) Type of anesthesia Tourniquet time (min) No. of comorbidities Diagnosis

Day of onset of symptoms Days of scan Treatment

Patient 1

Patient 2

Patient 3

63 Female Chinese 36.1 RA * 75 0 Partial thrombosis of the right posterior tibial and peroneal veins 5 6 None

68 Female Chinese 28.9 GA † 80 4 Thrombosis of the right posterior tibial and peroneal veins 2 2 Subcutaneous enoxaparin while inpatient; discharged with oral warfarin for 6 mo

77 Female Chinese 26.4 RA 60 2 Thrombosis of the right soleal vein

63 Female Chinese 26.8 GA 160 0 Large PE

6 7 None

2 2 Intravenous heparin

BMI indicates body mass index. * Regional anesthesia. † General anesthesia.

Patient 4

1130 The Journal of Arthroplasty Vol. 27 No. 6 June 2012 the standard investigations consisting of the full blood count, prothrombin time, and partial thromboplastin time were normal in all 3 patients. The results of the thrombophilia screening consisting of protein C, protein S, antithrombin, and lupus anticoagulant assays were negative in all 3 patients. All 3 patients recovered uneventfully without any long-term sequelae. The forth patient developed fatal PE without any clinical or radiologic evidence of DVT. A review of the case notes of all patients revealed that none of them developed clinical signs and symptoms of VTE up to 6 months after surgery. One patient had to be readmitted for prosthetic infection and underwent revision surgery. However, radiologic investigation excluded the presence of any VTE.

Discussion Several studies have reiterated the lower incidence of VTE in Asian patients who undergo TKA [3,4] as compared with their Western counterparts. Our study has revealed that the incidence of VTE in patients who underwent TKA without anticoagulation is low at 0.75%. In this study, imaging was only used in patients with symptomatic VTE because it is the symptomatic DVT and PE that impair postsurgical rehabilitation in patients undergoing TKA. For this reason, our incidence is much lower compared with previous studies. Furthermore, stringent patient selection by the surgeon as well as the exclusion criteria in our study could have led to our study group being a low-risk one to begin with. Kim et al [18] evaluated a total of 473 knees to determine the incidence of DVT and PE in those who were not given thromboprophylaxis after TKA. They used roentgenographic venography for all their patients. Their study reported an incidence of 22% of positive venograms, of which only 37% had clinical signs of VTE. They also cited early mobilization, low prevalence of venous disease, low frequency of obesity, and low prevalence of hyperlipidemia as factors that lead to a low incidence of DVT and PE. They also suggested that both genetic factors and dietary patterns (mainly vegetarianism) might play a role in leading to low incidence of DVT and PE. These factors are the same as those reported for Chinese people living in their native countries and Asians living in the Western portion of the United States. Because risk factors for VTE are similar in Asians and Westerners, the lower incidence of VTE in Asians must be attributable to factors unrelated to the procedure. There are some data that support genetic differences as a partial cause of a lower risk of VTE in Asians. Of the known genetic traits, the most prevalent is activated protein C, a mutation known as factor V Leiden [19,20] that increases VTE risk about 7 times in heterozygotes and about 80 times in homozygotes. It is found in approximately 5% of Westerners but is less common

in Africans and rare in Asians [21,22]. We could not confirm the prevalence of the factor V Leiden in our study population but believe that protective genetic mechanisms may be an important reason for the low incidence of VTE. Detailed evaluation of possible risk factors for VTE was not possible in this study because of the nature of the study as well as the low incidence. However, we believe that relatively shorter operating time, tourniquet application, and use of mechanical thromboprophylaxis could have been factors that led to the low incidence of VTE [23]. In our study, all 3 patients with symptomatic DVT had thrombosis in the distal calf veins. Researchers [9,11] have suggested that thrombi in the calf, regardless of size, are unlikely to produce symptomatic emboli and that, therefore, these patients do not require anticoagulation. It has been proposed that thrombi in the calf are attached relatively securely and resolve rapidly and spontaneously [24]. In a study conducted by Parisi et al [25], it is found that only 2.9% of distal calf DVT showed proximal progression. There is still a considerable debate on the ideal mode of therapy for distal calf DVT. This ranges from nontreatment with close radiologic monitoring to full treatment with anticoagulants with regimens in-between. Schellong [26] states that 80% to 90% of patients with distal DVT do not require anticoagulation, and for the remaining 10% to 20% of patients, he recommends 2 approaches. One approach is not to actively look for distal DVT but to opt for serial monitoring of symptoms and radiologic evaluation, whereas the other is to look for distal DVT and subsequently to risk stratify patients for treatment. Wang et al [27] reported that DVTs in the calf after TKA disappear spontaneously with time. In their study, no patient developed a recurrent DVT, proximal propagation, or embolization. He recommended that treatment of DVT in the calf after TKA should be based on the severity of the symptoms during the immediate postoperative period. In our study, only 1 of the 3 patients who had symptomatic thrombosis of the right posterior tibial and peroneal veins was treated with anticoagulants. Ansari et al [28] conducted a study on 1201 patients to evaluate the incidence of fatal PE after TKA without routine anticoagulation. He reported a maximum incidence of 0.4%. He concluded that the risk of fatal PE after unilateral TKA and unicompartment knee arthroplasty is low. Comparatively, the incidence of fatal PE in our study was 0.2%. The patient who had fatal PE did not show any clinical signs of lower-limb DVT, and ultrasound examination confirmed the absence of any thrombi. This suggests that routine ultrasound examination after TKA may not be useful in preventing PE [29]. However, it is important to note that the tourniquet time for this patient was

Clinically Significant VTEs in Patients Undergoing TKA  Bin Abd Razak et al

160 minutes, significantly longer than the mean of the study population (72 minutes). In a recent study by Chung et al [30], the incidence of DVT appeared to be increased in patients with a longer tourniquet time, although not statistically significant. However, imaging had showed that there was no DVT in our patient, although the unlikely phenomenon of immediate propagation of a thrombus cannot be altogether ruled out. An increased tourniquet time also implies that the patient had been under general anesthesia for a prolonged duration. Ragucci et al [31] reported that epidural anesthesia in combination with other nonpharmacologic modalities seems to be a more effective approach to prevent VTE. In addition, Hu et al [32] comprehensively stated in their meta-analysis that regional anesthesia seems to improve outcome in patients undergoing arthroplasty compared with general anesthesia. Hence, it is possible that prolonged exposure to general anesthesia could have predisposed the patient in discussion to a higher risk of de novo PE. Routine anticoagulation is not without its risks. Chin et al [23] reported a 11% incidence of bleeding complications with use of enoxaparin, whereas Sutherland and Schurman [33] reported an incidence of 4% for systemic complications and 12% for wound complications with use of warfarin. These complications have a detrimental effect on postsurgical rehabilitation, and prolonged hospitalization from these complications may put a strain on hospital resources. The low incidence of VTE in our study necessitates a deeper riskbenefit evaluation of routine chemoprophylaxis in patients undergoing TKA. Our study shows that although there is sufficient evidence in the Western literature to advocate routine chemoprophylaxis in patients undergoing TKA, incidence of VTE in the Asian population remains low. Routine postoperative radiologic evaluation was not carried out for the patients in this study because we wanted to delineate clinically significant DVT, which has an imperative effect on postoperative rehabilitation. Shorter duration of tourniquet application, early postoperative mobilization, and use of mechanical prophylaxis were not evaluated in our study but may be protective against VTE. The limitations of our study were related to its retrospective nature. Confounding and bias are inherent in a retrospective study despite efforts made to reduce their impact on error. Furthermore, comparative statistics were not possible because of the very low incidence of VTE. Hence, it is not appropriate that we make any recommendations about chemoprophylaxis against VTE in patients undergoing TKA. However, we concur with Gillespie et al [34] and advocate that orthopedic surgeons should use prophylaxis only for high-risk patients in whom the potential benefits clearly appear to outweigh the risks. However, a close clinical

1131

monitoring with a high level of suspicion for VTE must be exercised at all times. In conclusion, our study shows that without routine anticoagulation, incidence of VTE in low-risk Asian patients undergoing TKA remains low. Given the risks of bleeding complications, the practice of routine chemoprophylaxis should be reevaluated. All patients undergoing TKA should be risk stratified, and chemoprophylaxis should be considered only if the benefits clearly outweigh the risks involved.

References 1. Stulberg BN, Insall JN, Williams GW, et al. Deep-vein thrombosis following total knee replacement. An analysis of six hundred and thirty-eight arthroplasties. J Bone Joint Surg Am 1984;66:194. 2. Lieberman JR, Geerts WH. Prevention of venous thromboembolism after total hip and knee arthroplasty. J Bone Joint Surg Am 1994;76:1239. 3. Ruban P, Yeo SJ, Seow KH, et al. Deep vein thrombosis after total knee replacement. Ann Acad Med Singapore 2000;29:428. 4. Ko PS, Chan WF, Siu TH, et al. Deep venous thrombosis after total hip or knee arthroplasty in a “low-risk” Chinese population. J Arthroplasty 2003;18:174. 5. Wang CJ, Wang JW, Chen LM, et al. Deep vein thrombosis after total knee arthroplasty. J Formos Med Assoc 2000;99:848. 6. Chau KU, Yuen ST, Ng TH, et al. An autopsy study of pulmonary thromboembolism in Hong Kong Chinese. Pathology 1991;23:181. 7. Chau KY, Yuen ST, Wong MP. Clinicopathological pattern of pulmonary thromboembolism in Chinese autopsy patients: comparison with Caucasian series. Pathology 1997;29:263. 8. Eikelboom JW, Karthikeyan G, Fagel N, et al. American Association of Orthopaedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients? Chest 2009;135:513. 9. Lotke PA, Steinberg ME, Ecker ML. Significance of deep venous thrombosis in the lower extremity after total joint arthroplasty. Clin Orthop 1994;299:25. 10. Lotke PA, Wong RY, Ecker ML. Asymptomatic pulmonary embolism after total knee replacement. Orthop Trans 1986;10:490. 11. Moser KM, LeMoine JR. Is embolic risk conditioned by location of deep venous thrombosis? Ann Intern Med 1981;94:439. 12. Giachino A. Relationship between deep-vein thrombosis in the calf and fatal pulmonary embolism. Can J Surg 1988;31:129. 13. Lotke PA, Ecker ML, Alavi A, et al. Indications for the treatment of deep venous thrombosis following total knee replacement. J Bone Joint Surg [Am] 1984; 66-A:202. 14. Francis CW, Ricotta JJ, Evarts CM, et al. Long-term clinical observations and venous functional abnormalities after

1132 The Journal of Arthroplasty Vol. 27 No. 6 June 2012

15.

16.

17.

18.

19. 20.

21.

22. 23.

24.

asymptomatic venous thrombosis following total hip or knee arthroplasty. Clin Orthop 1988;232:271. Sivashankar C, Siva KA, Jason T, et al. Early mobilization after total knee replacement reduces the incidence of deep venous thrombosis. ANZ J Surg 2009;79:526. Lynch JA, Baker PL, Polly RE. Mechanical measures in the prophylaxis of postoperative thromboembolism in total knee arthroplasty. Clin Orthop 1990;220:24. Westrich GH, Haas SB, Mosca P, et al. Meta-analysis of thromboembolic prophylaxis after total knee arthroplasty. J Bone Joint Surg Br 2000;82-B:795. Kim YH, Yoo JH, Kim JS. Factors leading to decreased rates of deep vein thrombosis and pulmonary embolism after total knee arthroplasty. J Arthroplasty 2007; 22:974. Thomas DP, Roberts HR. Hypercoagulability in venous and arterial thrombosis. Ann Intern Med 1997;126:638. Price DT, Ridker PM. Factor V Leiden mutation and the risk for thromboembolic disease: a clinical perspective. Ann Intern Med 1997;127:895. Ridker PM, Miletich JP, Hennekens CH, et al. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA 1997;277:1305. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995;346:1133. Chin PL, Amin MS, Yang KY, et al. Thromboembolic prophylaxis for total knee arthroplasty in Asian patients: a randomized controlled trial. J Orthop Surg (Hong Kong) 2009;17:1. Kakkar VV, Howe CT, Flanc C, et al. Natural history of postoperative deep-vein thrombosis. Lancet 1969;2:230.

25. Parisi R, Visona A, Camporese G, et al. Isolated distal deep vein thrombosis: efficacy and safety of a protocol of treatment. Treatment of isolated calf thrombosis (TICT) study. Int Angiol 2009;28:68. 26. Schellong SM. Distal DVT: worth diagnosing? Yes. J Thromb Haemost 2007;5(Suppl 1):51. 27. Wang CJ, Wang JW, Weng LH, et al. Outcome of calf deepvein thrombosis after total knee arthroplasty. J Bone Joint Surg Br 2003;85-B:841. 28. Ansari S, Warwick D, Ackroyd CE, et al. Incidence of fatal pulmonary embolism after 1390 knee arthroplasties without routine prophylactic anticoagulation, except in high-risk cases. J Arthroplasty 1997;12:599. 29. Iorio R, Dhupar S, Healy WL, et al. Routine duplex ultrasound screening after TKA is not necessary. Clin Orthop 2006;452:171. 30. Chung LH, Chen WM, Chen CF, et al. Deep vein thrombosis after total knee arthroplasty in Asian patients without prophylactic anticoagulation. Orthopaedics 2011; 34:15. 31. Ragucci MV, Leali A, Moroz A, et al. Comprehensive deep venous thrombosis prevention strategy after total knee arthroplasty. Am J Phys Med Rehabil 2003;82:164. 32. Hu S, Zhang ZY, Hua YQ, et al. A comparison of regional and general anaesthesia for total replacement of the hip or knee: a meta-analysis. J Bone Joint Surg Br 2009;91:935. 33. Sutherland CJ, Schurman JR. Complications associated with warfarin prophylaxis in total knee arthroplasty. Clin Orthop 1987;219:158. 34. Gillespie W, Murray D, Gregg PJ, et al. Risks and benefits of prophylaxis against venous thromboembolism in orthopaedic surgery. J Bone Joint Surg Br 2000;82:475.