Incidence and Fate of “Symptomatic” Venous Thromboembolism After Knee Arthroplasty Without Pharmacologic Prophylaxis in an Asian Population

Accepted Manuscript Incidence and fate of ‘symptomatic’ venous thromboembolism after knee arthroplasty without pharmacologic prophylaxis in an Asian population Yong-Geun Park, M.D., Chul-Won Ha, M.D., Sung Sahn Lee, M.D., Aseem Arif Shaikh, M.S., Yong-Beom Park, M.D. PII:

S0883-5403(15)01052-9

DOI:

10.1016/j.arth.2015.11.028

Reference:

YARTH 54824

To appear in:

The Journal of Arthroplasty

Received Date: 20 January 2015 Revised Date:

27 October 2015

Accepted Date: 20 November 2015

Please cite this article as: Park Y-G, Ha C-W, Lee SS, Shaikh AA, Park Y-B, Incidence and fate of ‘symptomatic’ venous thromboembolism after knee arthroplasty without pharmacologic prophylaxis in an Asian population, The Journal of Arthroplasty (2016), doi: 10.1016/j.arth.2015.11.028. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Incidence and fate of ‘symptomatic’ venous thromboembolism after knee arthroplasty without

RI PT

pharmacologic prophylaxis in an Asian population

(Short title: 'symptomatic` VTE after TKA without pharmacologic prophylaxis)

SC

Yong-Geun Park,2 M.D., Chul-Won Ha,*1 M.D., Sung Sahn Lee1, M.D., Aseem Arif Shaikh1,

M AN U

M.S., and Yong-Beom Park1, M.D.

1. Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

TE D

2. Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University

EP

School of Medicine, Jeju, South Korea

AC C

* Please address all correspondence to: Chul-Won Ha, M.D. Department of Orthopedic Surgery, Samsung Medical Center, SungKyunKwan University School of Medicine, Irwon-dong 50,

Gangnam-gu, Seoul 135-710, South Korea

E-mail: [email protected], [email protected] Phone: +82-2-3410-0275 FAX: +82-2-3410-0061

This study was approved by institutional review board of Samsung Medical Center (IRB file No.2012-03-072-001). We attached the IRB approval as a separated file.

ACCEPTED MANUSCRIPT

Incidence and fate of ‘symptomatic’ venous

RI PT

thromboembolism after knee arthroplasty without pharmacologic prophylaxis in an Asian population

AC C

EP

TE D

M AN U

SC

(Short title: 'symptomatic` VTE after TKA without pharmacologic prophylaxis)

ACCEPTED MANUSCRIPT

ABSTRACT

2

Background: As the possibility of developing complications after an ‘asymptomatic’ VTE

3

after TKA has been reported very low, ‘symptomatic’ VTEs seem to be the real concern

4

among orthopedic surgeons. Therefore, the purpose of this study was to determine the

5

incidence of ‘symptomatic’ VTEs and the fate of ‘symptomatic’ VTEs after anticoagulation

6

therapy, and assess whether routine pharmacological prophylaxis is necessary in TKA

7

patients.

8

Methods: We retrospectively reviewed 2891 consecutive TKAs in 1933 patients. Graduated

9

compression stockings and intermittent pneumatic calf compression devices were employed

10

for VTE prophylaxis. The incidence of symptomatic VTE was investigated until 6 months

11

postoperatively. Patients with VTE underwent anticoagulation therapy and followed up to

12

evaluate ROM, KSS, WOMAC scores and presence of any complications (mean follow-up

13

period: 3.6 years).

14

Results: Fifty-three (1.83%) out of the 2891 TKAs had suggestive symptoms/sign of VTE.

15

Of these 53 cases, 26 (0.90%) were diagnosed as symptomatic VTE, which comprised of 10

16

(0.35%) symptomatic DVTs, 11 (0.38%) symptomatic PEs, 5 (0.17%) symptomatic DVTs

17

combined with PEs, and no fatal PE. There was no significant difference in ROM, KSS and

18

WOMAC scores between the groups with or without symptomatic VTE. When treated

19

properly after the diagnosis of symptomatic VTE, no specific complications were identified.

20

Conclusion: Symptomatic VTEs are rare in patients who undergo TKAs with mechanical

21

prophylaxis only. Patients with symptomatic VTEs after TKA can be treated without

22

significant sequelae once they are properly treated with anticoagulation after the diagnosis.

AC C

EP

TE D

M AN U

SC

RI PT

1

23 1

ACCEPTED MANUSCRIPT 24

Keywords: VTE prophylaxis, total knee arthroplasty, symptomatic VTE, symptomatic DVT,

25

symptomatic PE

AC C

EP

TE D

M AN U

SC

RI PT

26

2

ACCEPTED MANUSCRIPT 27

INTRODUCTION The necessity of routine pharmacologic prophylaxis of venous thromboembolism (VTE)

29

after total knee arthroplasty (TKA) is still controversial, probably because the incidence and

30

fate of the ‘symptomatic’ VTEs after TKA are not well known yet. The current approved

31

options for VTE prophylaxis along with the pros and cons of each has been established by the

32

American College of Chest Physicians (ACCP) guidelines for the prevention of any deep

33

venous thrombosis (DVT) or the American Academy of Orthopaedic Surgeons (AAOS)

34

clinical guidelines for prevention of VTE in patients undergoing TKA1,2. The previous

35

guidelines of the ACCP and National Institute for Health and Clinical Excellence (NICE)

36

seemed to overemphasize the prophylaxis with pharmacologic agents and underrate the risks

37

of bleeding and other subsequent adverse outcomes related to these agents1,3,4. The AAOS

38

and ACCP guideline recently acknowledged the usage of intermittent pneumatic compression

39

(IPC) device only without pharmacological prophylaxis as a viable option for VTE

40

prophylaxis in patients undergoing TKA2,5. The AAOS guideline recommends the use of

41

pharmacologic agents and/or mechanical compressive devices for the prevention of venous

42

thromboembolism in patients undergoing elective knee arthroplasty, and who are not at

43

elevated risk beyond that of the surgery itself for venous thromboembolism or bleeding 2. It is

44

also stated that “Current evidence is unclear about which prophylactic strategy (or strategies)

45

is/are optimal or suboptimal. Therefore, we are unable to recommend for or against specific

46

prophylactics in these patients.”2. Yet, it is hard to find reports on the outcome of VTE

47

prophylaxis without pharmaceutical agents on TKA patients.

AC C

EP

TE D

M AN U

SC

RI PT

28

48

The risk of developing complications such as pulmonary embolism (PE) or post-

49

thrombotic syndrome secondary to VTE following TKA is low6-8. Therefore the real concern 3

ACCEPTED MANUSCRIPT is ‘symptomatic’ VTE's. However, most previous reports on VTE after TKA have focused on

51

VTE as a whole and have not distinguished between the ‘asymptomatic’ and ‘symptomatic’

52

VTE. The incidence of overall VTE (asymptomatic and symptomatic) after TKA was 40.4%,

53

and the incidences varied from 0% to 76% depending on the study9. Consequently, the

54

literature is lacking on ‘symptomatic’ VTEs which are clinically more significant9-12.

55

Moreover, there is a paucity in the literature on the fate of the ‘symptomatic’ VTEs after

56

TKA once treated properly after the diagnosis of the VTE.

SC

RI PT

50

Therefore, the purpose of this study was to determine the incidence and fate of the

58

symptomatic VTE following TKA using only mechanical prophylaxis without any routine

59

pharmacologic prophylaxis, and thereby to assess whether employing the mechanical

60

prophylaxis only is consistent with protecting the patients undergoing TKAs.

M AN U

57

61 62

MATERIALS and METHODS

TE D

63

We retrospectively reviewed the medical records of 2963 TKA operations in 1994

65

patients who underwent primary or revision TKAs performed by the senior author from

66

January 2002 to December 2011 at our institution. Thirty patients who had a history of a

67

thromboembolic

68

anticoagulation peri-operatively, were excluded from the study. Thirty one patients (1.6%)

69

were lost to follow-up within 12 months post operatively and were excluded from the study

70

but were contacted via telephone to identify and question for any VTE related complications.

71

Therefore, the cohort of this study consisted of 2891 consecutive operations in 1933 patients

72

(Fig 1). The study cohort consists of 2694 women and 197 men. The procedures included

EP

64

or

cardiovascular

surgery

and

were

on

pharmacological

AC C

event

4

ACCEPTED MANUSCRIPT 2790 primary TKAs and 101 revision TKAs. Among them, 952 patients had multiple

74

operations: 940 patients had two operations (907 patients; staged bilateral TKAs, 33 patients;

75

primary TKA + one revision TKA), eleven patients had three (staged bilateral TKAs + one

76

revision TKA), and one patient had four (staged bilateral TKAs + two revision TKAs).

77

Bilateral TKAs were performed as a staged operation, thus, no patients had two arthroplasty

78

procedures under the same anesthesia. The mean age of the patients was 66.0 years (range, 27

79

to 94 years). The mean body mass index was 28.2 (range, 15.1 to 41.0). The mean follow-up

80

period was 4.6 years (range, 2 to 12years). The design and protocol of this study were

81

approved by the institutional review board at our institution.

M AN U

SC

RI PT

73

The senior author performed all the operations. Regional anesthesia was employed for

83

TKAs if it was feasible. A pneumatic tourniquet was utilized along with a closed suction

84

drain in all cases. After the surgery, all patients received a graduated compression stocking

85

(GCS) and an IPC device for VTE prophylaxis. Pharmacologic prophylaxis was not

86

employed for VTE prophylaxis in any of the patients in this study cohort. Peripheral

87

saturation monitoring was used on every patient and was maintained until the second

88

postoperative day. Pain control was achieved using patient controlled analgesia (PCA) and

89

oral opioids. On the second postoperative day, closed suction drainage was removed and the

90

patients were encouraged to carry out a range of motion (ROM) exercise with a continuous

91

passive motion (CPM) machine and the quadriceps muscle strengthening exercise. All

92

pateints were examined by the orthopedics residents. Weight-bearing ambulation using

93

assistive devices was encouraged and the IPC was applied whole day until discharge (average

94

hospital stay: 11.0 days (range, 7-34 days)). The GCS were applied until postoperative 3

95

months. Patients were followed up routinely at 6 weeks, 3 months, 6 months postoperatively

AC C

EP

TE D

82

5

ACCEPTED MANUSCRIPT 96

and yearly thereafter. Each patients were evaluated on ROM, knee society score (KSS),

97

Western Ontario and McMaster Universities index (WOMAC) score and any complications. Our protocol for detection of ‘symptomatic’ VTE (DVT and/or PE) included diagnostic

99

studies only on those patients with signs and symptoms suggestive of VTE13-15. Suggestive

100

symptoms/signs of DVT delineated were 1) localized tenderness along the distribution of the

101

deep venous system, 2) entire leg swollen, 3) calf swelling > 3 cm when compared with

102

asymptomatic leg, 4) pitting edema, or 5) positive Homans` sign. Suggestive symptoms/signs

103

of PE delineated were 1) tachycardia (HR > 100/min) of unknown origin, 2) clinical sign of

104

DVT, 3) dyspnea or tachypnea, 4) sudden chest pain of unknown origins, or 5) desaturation

105

on oxygen saturation monitoring. All patients with suggestive symptoms/signs were

106

examined with Doppler ultrasonography, Computerized Tomography (CT) venography, or

107

ventilation/perfusion CT16 for a definitive diagnosis of VTE depending on recommendation

108

by vascular and pulmonology specialist. Patients diagnosed ‘symptomatic’ VTE (DVT and/or

109

PE) were treated with anticoagulation therapy which was comprised of heparinization

110

followed by oral warfarin. ‘Symptomatic’ VTE (DVT and/or PE) was treated with an INR

111

target of 2.5 and anticoagulation treatment period was determined by consultation with the

112

internists.

EP

TE D

M AN U

SC

RI PT

98

Key study measures consisted of the followings: the incidence and timing of VTE,

114

assessment on possible risk factors by comparison of epidemiologic and perioperative factors

115

between VTE (+) and VTE (-) group (Fig 1), comparison of clinical results in the two groups,

116

and any complication of the symptomatic VTE or adverse events after VTE treatment. The

117

incidence and timing of symptomatic VTE was assessed within the first 6 months following

118

surgery. The incidence of symptomatic DVT and symptomatic PE according to the type of

AC C

113

6

ACCEPTED MANUSCRIPT surgery (primary or revision TKA) were also assessed. To evaluate the possible risk factors,

120

univariate comparisons between the VTE (+) group and the VTE (-) group were made based

121

on the demographic data and perioperative parameters, including age, gender, BMI, type of

122

surgery, type of anesthesia, operation time, volume of blood transfusion, type of prophylaxis

123

modalities, and type of medical comorbidities. The fate of VTE after TKA was evaluated by

124

comparing the clinical outcome of VTE (+) vs. VTE (-) group. The clinical outcome

125

measures consisted of ROM, KSS, and WOMAC score preoperatively, and at the latest

126

follow up. Any adverse events associated with VTE treatments were also investigated. For

127

those with insufficient data from the medical records of follow up visits, telephone interviews

128

were performed to reveal any complications.

M AN U

SC

RI PT

119

Sample size analysis was performed with the data from similar population whose

130

incidence of symptomatic VTE was 2.3%17. On the basis of an 80% power of analysis,

131

significance level of 5%, and an estimated rate of VTE of 0.7% in our patient population11,

132

the inclusion of 1762 cases was estimated as minimal sample size. Sample size of this study

133

was 2891 cases and was ascertained to be sufficient to assess the incidence of symptomatic

134

VTE with statistical significance. The statistical analysis was performed with the SPSS 18.0

135

software package (SPSS Inc, Chicago, IL). The Pearson chi-square test or Fisher`s exact test

136

was performed to analyze the incidence of VTEs among variables such as gender, the type of

137

anesthesia (general or regional), the type of surgery (primary or revision), the type of

138

prophylaxis modalities, and associated medical comorbidities. The Student t-test or Mann-

139

Whitney test was used to analyze the occurrence of VTEs on the basis of age, body mass

140

index, operation time, volume of blood transfusion and clinical parameters (ROM, KSS and

141

WOMAC score).

AC C

EP

TE D

129

7

ACCEPTED MANUSCRIPT 142 143

RESULTS Among the 2891 operations in this study cohort, 26 were diagnosed with symptomatic

145

VTEs, resulting in an incidence of 0.90% (95% CI: 0.55%-1.25%), which comprised of 10

146

(0.35%) symptomatic DVTs, 11 (0.38%) symptomatic PEs, 5 (0.17%) symptomatic DVTs

147

combined with PEs. No patient had a fatal PE. Before the confirmed diagnosis, suggestive

148

symptoms or signs of VTE occurred in 53 (1.83% (95% CI: 1.34%-2.32%)) of the 2891

149

operations. Suggestive symptoms or signs of DVTs were identified in 23 cases, suggestive

150

symptoms or signs of PEs were identified in 25 cases, and suggestive symptoms of both

151

DVTs and PEs were identified in 5 cases. None of the 10 patients with confirmed

152

symptomatic DVT developed a symptomatic PE. Among the 11 patients diagnosed with

153

symptomatic PEs, 5 patients were detected with thrombus in above knee level, and the

154

remaining 6 patients did not show any evidence of thrombus in the leg. Other tests were not

155

performed to detect the rare origin of the clots. Finally, the incidence of symptomatic VTEs

156

was 0.86% (95% CI: 0.52%-1.20%) in primary TKA, and 1.98% (95% CI: 1.71%-1.25%) in

157

revision TKAs (Table 1).

EP

TE D

M AN U

SC

RI PT

144

Analysis of the risk factors for VTE revealed that there was no significant difference

159

between patients with or without symptomatic VTEs in terms of gender, body mass index,

160

volume of blood transfusion, type of prophylaxis modalities, or medical comorbidities. Only

161

the surgical time showed significant difference, with average 10 minutes longer in VTE (+)

162

group than VTE (-) group (p < 0.01) (Table 2).

AC C

158

163

Among the 26 patients with symptomatic VTE, 25 patients were treated with

164

anticoagulation therapy. One patient with a symptomatic DVT refused the treatment. The 8

ACCEPTED MANUSCRIPT mean treatment period after the diagnosis of VTEs was mean 15.3 weeks in symptomatic

166

DVT patients and mean 18.6 weeks in symptomatic PE patients. There was no significant

167

difference in clinical results between patients with and without symptomatic VTEs (Table 3).

168

Seven (26.9%) of the 26 patients who had anticoagulation therapy for the symptomatic VTEs

169

had knee hemarthrosis or hematomas, requiring a joint aspiration or a delay in rehabilitation.

170

None of the seven patients required a reoperation or resulted in a reduced ROM. There were

171

another seven patients (26.9 %) with wound problems. Four patients with minor wound

172

dehiscence or superficial infection were additionally prescribed with oral antibiotics for 2 to 3

173

weeks, and 1 patient with oozing from the incision site was withheld the anticoagulation

174

therapy for 8 days till the oozing stopped. Hematuria temporarily manifested in two patients

175

whose PT/INR level was more than 3 or uncontrolled. The hematuria subsided by controlling

176

PT/INR level back to 2 to 3. Other adverse events such as arrhythmia, anemia, drug-induced

177

hepatitis, heart failure, or pneumonia appeared, related or non-related to the anticoagulation

178

therapy, were managed without any sequelae.

179

thrombotic syndrome developed in one patient who refused anticoagulation therapy after the

180

diagnosis of DVT (Table 4).

183

SC

M AN U

TE D

EP

182

A chronic calf DVT and subsequent post

AC C

181

RI PT

165

DISCUSSION

184

Since the risk of developing complications after an ‘asymptomatic’ VTE after TKA has

185

been reported very low, the real concern following TKA are the ‘symptomatic’ VTE's. The

186

necessity of routine pharmacologic prophylaxis after TKA is still controversial, probably

187

because the incidence and fate of the ‘symptomatic’ VTEs without pharmacologic 9

ACCEPTED MANUSCRIPT prophylaxis are not well known yet. Therefore, the purpose of this study was to reveal the

189

incidence and the fate of ‘symptomatic’ VTEs without pharmacological prophylaxis, and

190

thereby to assess whether employing the mechanical prophylaxis only is consistent with

191

protecting the patients undergoing TKAs. According to ACCP guideline published in 2012,

192

use of initial aspirin for DVT prophylaxis was recommendable5. We think that use of aspirin

193

as a simple adjunct to mechanical prophylaxis can be an attractive alternative.

RI PT

188

Limitations of this study need to be addressed. First, there is an inherent limitation of

195

the retrospective study with regard to the completeness of the data. However, suggestive

196

symptoms or signs of VTEs are serious medical occasions which always need immediate

197

attention by medical staffs. Therefore, we are sure that there should have been very little

198

chance that a symptomatic VTE was not documented in the medical records. Also, as we

199

reviewed the medical records thoroughly up to 6 months postoperatively regarding any VTE

200

related incidents in every patient in the study cohort, such a limitation seems to have very

201

little effect on the results of this study. In addition, all of the 31 patients (1.6%) who were lost

202

to follow-up within 12 months were contacted via telephone to identify and question for any

203

VTE related complications. Therefore, we believe that any patient with a serious

204

complication like mortality (from symptomatic or asymptomatic VTE) was very unlikely to

205

be missed. Second, the incidence of VTE is known to be lower in the Asian population11.

206

However, some studies on the overall VTE incidence reported significant incidence even in

207

Asian patients after major orthopedic surgery9,17. In recent studies involving Asian patients

208

undergoing TKA, the incidence of VTE following TKA was noted to be higher than expected,

209

being similar to that noted for Western populations18. The reports of VTE incidence after

210

TKA in Asian patients varies from 4.3 to 35%7,9,19-21. Although the result of this study may

AC C

EP

TE D

M AN U

SC

194

10

ACCEPTED MANUSCRIPT not be directly applied to the Western population, we believe that the results are valuable in

212

considering the role of mechanical prophylaxis or in considering the necessity of routine

213

pharmacological prophylaxis. Third, patients in this study have heavy preponderance of

214

female patients. This study involved all of the patients who underwent TKAs in the period of

215

time of this study. In our patient population, female predominance in ostoearthritis patients is

216

typical10. As there are no differences in VTE prevalence between genders after TKAs9,19,21,22,

217

we do not think this female predomince in our study may skew the interpretation of the

218

results.

SC

RI PT

211

The results of this study show that the incidence of ‘symptomatic’ VTE after TKA

220

without routine pharmacologic prophylaxis in this study cohort was very low. In contrast,

221

there are other studies indicating relatively high figures in Asian patients7,9,17-21. We realized

222

that they did not differentiate the ‘asymptomatic’ and ‘symptomatic’ VTEs for the incidence.

223

There was also a recent report of meta-analysis which showed a very low incidence of

224

‘symptomatic’ VTE after TKA without prophylaxis in Asian patients, which is in line with

225

the results of this study11. To our knowledge, the current study is the largest single cohort

226

study in Asian patients evaluating the incidence of the ‘symptomatic’ VTEs as well as the

227

fate of the patients with the symptomatic VTE treated with anticoagulation therapy.

EP

TE D

M AN U

219

In this study, significant complications were not detected associated with the

229

symptomatic VTEs once it was properly treated with anticoagulation after the initial

230

diagnosis. It is known that the anticoagulation therapy itself may lead to complications such

231

as bleeding, compromised joint function, or mortality23,24. Our study also had 7 patients with

232

operative site hemorrhage and 2 patients with non-operative site hemorrhage, which were

233

resolved without any sequelae by controlling warfarin dosage. Considering the very low

AC C

228

11

ACCEPTED MANUSCRIPT incidence of symptomatic VTEs, we believe that the risk of employing the routine

235

pharmacologic prophylaxis of VTE for TKA patients should be greater than employing the

236

anti-coagulation therapy only for those patients who developed symptomatic VTEs. The fact

237

that one patient with symptomatic VTE who refused the anticoagulation therapy eventually

238

developed post-thrombotic syndrome shows that proper treatment is essential to avoid any

239

sequelae.

RI PT

234

Regarding the diagnosis and management of ‘asymptomatic’ VTE, the gold standard is

241

not yet clear, but the guideline has been changed to recommend against routine evaluation

242

and treatment for asymptomatic VTE1-3. Kim et al7 suggested that thrombi in the calf are

243

unlikely to produce symptomatic emboli and these patients do not require anticoagulation

244

therapy. Regarding mortality from asymptomatic PE after TKA, we were not able to find a

245

report in the literature. There are reported mortalities from asymptomatic PE in a few studies

246

regarding cancer patients, however, these patients were either terminal or were being treated

247

for cancer25. We think that it is difficult to relate this finding to usual TKA patients. It has

248

also been shown that asymptomatic DVTs have no increase in mortality risks in previous

249

reports after TKA7,8,26-28. Besides, there is no proven evidence that pharmacologic

250

prophylaxis reduce mortality from asymptomatic VTE. On the other hand, there are reported

251

studies that pharmacologic prophylaxis caused mortality from fatal bleeding, and other

252

studies reported favorable outcomes among patients with asymptomatic PE receiving no

253

treatment for VTE29,30. Recently, the guidelines recommend against routine post-operative

254

ultrasonography screening of patients who undergo elective TKA1,2, which seem to imply

255

that the asymptomatic VTE is not a major concern. We agree with that perspectives as there

256

have been no clinical problems from asymptomatic VTE in the whole cohort of this study.

AC C

EP

TE D

M AN U

SC

240

12

ACCEPTED MANUSCRIPT In this study, we could not find a difference between the VTE (+) and VTE (-) groups

258

in terms of underlying medical comorbidities which are known to be possible risk factors for

259

the development of VTE17. Because most underlying diseases were treated or carefully

260

managed perioperatively, physiologic changes resulting from the underlying diseases should

261

have been limited. Evidence regarding risk factors for VTE after TKA are still scarce. It may

262

be because of the difficulty in obtaining appropriate sample size for the statistical

263

significance due to the low incidence of VTE.

SC

RI PT

257

264

CONCLUSION

M AN U

265

Symptomatic VTEs are rare in patients who undergo TKAs only with mechanical

267

prophylaxis. Patients with symptomatic VTEs after TKA can be treated without significant

268

sequelae once they are properly treated with anticoagulation after the diagnosis.

AC C

EP

TE D

266

13

ACCEPTED MANUSCRIPT

REFERENCES

269 270 271

1.

Callaghan JJ, Dorr LD, Engh GA, et al. Prophylaxis for thromboembolic disease: recommendations from the American College of Chest Physicians--are they appropriate

273

for orthopaedic surgery? J Arthroplasty 2005;20:273.

274

2.

RI PT

272

Mont MA, Jacobs JJ, Boggio LN, et al. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg

276

2011;19:768.

277

3.

SC

275

Hill J, Treasure T, Guideline Development G. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients

279

admitted to hospital: summary of the NICE guideline. Heart 2010;96:879. 4.

281 282

Patel VP, Walsh M, Sehgal B, et al. Factors associated with prolonged wound drainage after primary total hip and knee arthroplasty. J Bone Joint Surg Am 2007;89:33.

5.

Guyatt GH, Akl EA, Crowther M, et al. Executive summary: Antithrombotic Therapy

TE D

280

M AN U

278

283

and Prevention of Thrombosis, 9th ed: American College of Chest Physicians

284

Evidence-Based Clinical Practice Guidelines. Chest 2012;141:7S. 6.

Ciuti G, Grifoni E, Pavellini A, et al. Incidence and characteristics of asymptomatic

EP

285

distal deep vein thrombosis unexpectedly found at admission in an Internal Medicine

287

setting. Thromb Res 2012;471:1523.

288

7.

289 290 291

AC C

286

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.

8.

Reidy M, Macinnes A, Pillai A. Are we missing post-thrombotic syndrome syndrome? An orthopaedic perspective in lower limb arthroplasty. Thrombosis 2012;2012:324320. 14

ACCEPTED MANUSCRIPT 292

9.

Won MH, Lee GW, Lee TJ, et al. Prevalence and risk factors of thromboembolism after

293

joint arthroplasty without chemical thromboprophylaxis in an Asian population. J

294

Arthroplasty 2011;26:1106. 10.

296 297

Cho HJ, Chang CB, Kim KW, et al. Gender and prevalence of knee osteoarthritis types in elderly Koreans. J Arthroplasty 2011;26:994.

11.

RI PT

295

Lee WS, Kim KI, Lee HJ, et al. The Incidence of Pulmonary Embolism and Deep Vein Thrombosis After Knee Arthroplasty in Asians Remains Low: A Meta-analysis. Clin

299

Orthop Relat Res 2012;471:1523. 12.

Piovella F, Wang CJ, Lu H, et al. Deep-vein thrombosis rates after major orthopedic

M AN U

300

SC

298

301

surgery in Asia. An epidemiological study based on postoperative screening with

302

centrally adjudicated bilateral venography. J Thromb Haemost 2005;3:2664. 13.

304

14.

306 307

15.

16.

314

Kim YJ, Hur CI, Song EK, et al. Availability of D-dimer test for the diagnosis of deep vein thrombosis after total knee arthroplasty. J Korean Orthop Assoc 2007;42:523.

17.

312 313

Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003;349:1227.

310 311

Unay K, Akan K, Sener N, et al. Evaluating the effectiveness of a deep-vein thrombosis prophylaxis protocol in orthopaedics and traumatology. J Eval Clin Pract 2009;15:668.

308 309

TE D

thrombosis. J Thromb Thrombolysis 2006;21:41.

EP

305

Kahn SR. The post-thrombotic syndrome: the forgotten morbidity of deep venous

AC C

303

Leizorovicz A. Epidemiology of post-operative venous thromboembolism in Asian patients. Results of the SMART venography study. Haematologica 2007;92:1194.

18.

Chung LH, Chen WM, Chen CF, et al. Deep vein thrombosis after total knee arthroplasty in asian patients without prophylactic anticoagulation. Orthopedics 15

ACCEPTED MANUSCRIPT 315

19.

317 318

total knee arthroplasty. J Arthroplasty 2011;26:1112. 20.

319 320

Kim KI, Cho KY, Jin W, et al. Recent Korean perspective of deep vein thrombosis after

Kim YH. The incidence of deep vein thrombosis after cementless and cemented knee replacement. J Bone Joint Surg Br 1990;72:779.

21.

RI PT

316

2011;34:15.

Park KH, Cheon SH, Lee JH, et al. Incidence of venous thromboembolism using 64 channel multidetector row computed tomography-indirect venography and anti-

322

coagulation therapy after total knee arthroplasty in Korea. Knee Surg Relat Res

323

2012;24:19. 22.

M AN U

324

SC

321

Ryu YJ, Chun EM, Shim SS, et al. Risk factors for pulmonary complications, including

325

pulmonary embolism, after total knee arthroplasty (TKA) in elderly Koreans. Arch

326

Gerontol Geriatr 2010;51:299.

327

23.

Dorr LD, Gendelman V, Maheshwari AV, et al. Multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment. J Bone Joint Surg Am

329

2007;89:2648.

331 332

enoxaparin treatment after arthroplasty. Clin Orthop Relat Res 2010;468:115. 25.

333

Tiseo M, Bersanelli M, Pesenti Barili M, et al. Asymptomatic pulmonary embolism in lung cancer: prevalence and analysis of clinical and radiological characteristics in 141

334 335

Neviaser AS, Chang C, Lyman S, et al. High incidence of complications from

EP

24.

AC C

330

TE D

328

outpatients. Tumori 2012;98:594.

26.

Persson LM, Lapidus LJ, Larfars G, et al. Asymptomatic deep venous thrombosis is

336

associated with a low risk of post-thrombotic syndrome. Eur J Vasc Endovasc Surg

337

2009;38:229. 16

ACCEPTED MANUSCRIPT 338

27.

339 340

Rosfors S, Persson LM, Larfars G, et al. A follow-up study of the fate of small asymptomatic deep venous thromboses. Thromb J 2010;8:4.

28.

Sun Y, Chen D, Xu Z, et al. Incidence of symptomatic and asymptomatic venous thromboembolism after elective knee arthroscopic surgery: a retrospective study with

342

routinely applied venography. Arthroscopy 2014;30:818.

343

29.

RI PT

341

Barrellier MT, Samama CM. [Benefit/risk ratio analysis from a possible anticoagulation of asymptomatic deep venous thrombosis in major orthopedic surgery].

345

J Mal Vasc 2013;38:178.

M AN U

Engelke C, Rummeny EJ, Marten K. Pulmonary embolism at multi-detector row CT of

TE D

chest: one-year survival of treated and untreated patients. Radiology 2006;239:563.

EP

347

30.

AC C

346

SC

344

17

ACCEPTED MANUSCRIPT

Table 1. Incidence and time of VTE Symptomatic DVT†

Suggestive Sx of PE

Symptomatic PE†

Time

Incidence

Time

Incidence

Time

Incidence

% (95% CI, %)

POD* (mean±SD) (range)

% (95% CI, %)

POD (mean±SD) (range)

% (95% CI, %)

POD (mean±SD) (range)

% (95% CI, %)

0.86

14.7±23.4

1.08

3.5±3.3

0.47

(0.52-1.20)

(1-90)

(0.69-1.47)

(1-15)

(0.22-0.72)

3.96

6.0±2.7

0

1.98

(357-4.35)

(2-8)

(0.00)

(1.71-2.25)

Total

0.97

13.5±21.8

1.03

3.5±3.3

(n=2891)

(0.61-1.33)

(1-90)

(0.66-1.40)

(1-15)

Fatal PE

Symptomatic VTE

Incidence

Time

Incidence

Incidence

Time

POD (mean±SD) (range)

% (95% CI, %)

POD (mean±SD) (range)

% (95% CI, %)

% (95% CI, %)

POD (mean±SD) (range)

6.0±3.7

0.57

4.0±2.9

0.18

3.4±2.4

0

0.86

5.2±3.5

(1-13)

(0.29-0.85)

(1-10)

(0.03-0.32)

(1-6)

(0.00)

(0.52-1.20)

(1-13)

4.5±3.5

0

0

0

1.98

4.5±3.5

(2-7)

(0.00)

(0.00)

(0.00)

(1.71-2.25)

(1-13)

0.52

5.8±3.6

0.55

4.0±2.9

0.17

3.0±2.0

0

0.90

5.1±3.4

(0.26-0.78)

(1-13)

(0.28-0.82)

(1-10)

(0.02-0.32)

(1-15)

(0.00)

(0.55-1.25)

(1-13)

TKA (n=2790) Revision

AC C

EP

TE D

TKA (n=101)

M AN U

Primary

Time

SC

Incidence

Symptomatic DVT + PE

RI PT

Suggestive Sx of DVT

CI; confidence inverval, POD; postoperative days, SD; standard deviation, †: include patients who has symptomatic DVT combined PE

1

ACCEPTED MANUSCRIPT Table 2. Comparison of epidemiologic and perioperative factors in patients with or without symptomatic VTE

Age (ys) (mean±SD)

Symptomatic VTE (-)

Symptomatic VTE (+)

p-value

67.5±7.2

68.7±5.8

0.592†

Gender (n, (%))

0.166‡‡

197 (100.0)

0 (0.0)

Female

2694 (99.0)

26 (1.0)

27.2±8.9

27.7±4.6

Regional

2715 (99.2)

22 (0.8)

General

150 (97.4)

SC

Male

BMI (kg/m2) (mean±SD)

M AN U

Anesthesia (n, (%))

Operation time (minutes) (mean±SD) Transfusion vol. (mL) (mean±SD) Prophylaxis modalities (n, (%))

78.3±25.4

<0.01†

702.7±636.5

964.3±599.0

0.330†

20 (0.9)

718 (99.2)

Medical comorbidities (n, (%))

0.136

68.6±26.2

2147 (99.1)

GCS + IPC

0.585††

4 (2.6)

TE D

GCS

RI PT

Factors

0.969‡‡

6 (0.8)

213 (99.2)

3 (0.8)

0.307‡‡

119 (99.2)

1 (0.8)

0.706‡‡

Hepatic and biliary pathologies

86 (97.7)

2 (2.3)

0.187‡

Renal pathologies

50 (100.0)

0 (0.0)

0.634‡

625 (98.9)

7 (1.1)

0.339‡‡

Malignancy

116 (98.3)

2 (1.7)

0.287‡‡

HTN

1557 (98.9)

16 (1.1)

0.092‡‡

DM

512 (99.2)

4 (0.8)

0.493‡‡

Cardiac pathologies

AC C

EP

Respiratory pathologies

Endocrine

and

Metabolic

pathologies

1

ACCEPTED MANUSCRIPT SD; standard deviation, GCS; graduated compression stocking, IPC; intermittent pneumatic compression devices †: Mann-Whitney test ††: Student t-test

RI PT

‡: Fisher`s exact test

AC C

EP

TE D

M AN U

SC

‡‡: Pearson chi-square test

2

ACCEPTED MANUSCRIPT Compariaon of clinical results Symptomatic VTE (-)

ROM (°) (mean±SD)

Symptomatic VTE (+)

Preop

123.7±24.1

12.80±23.9

0.263

Latest F/U

139.4±16.2.2

141.8±15.5

0.292

Preop

46.5±12.7

47.6±11.2

Latest F/U

86.2±29.9

84.9±6.5

Preop

42.9±7.6

43.2±7.8

Latest F/U

19.3±11.3

(range, 1 - 11yrs)

KSS (mean±SD)

M AN U

(range, 1 - 11yrs)

SC

(range, 1 - 11yrs)

WOMAC (mean±SD)

p-value

RI PT

Table 3.

19.6±8.1

0.669

0.350

0.944 0.604

AC C

EP

TE D

ROM; range of motion, SD; standard deviation, KSS; WOMAC; Western Ontario and McMaster Universities (WOMAC) Arthritis Index

1

ACCEPTED MANUSCRIPT Table 4. Adverse events in patients with symptomatic VTE Complication

Cases

*

Hemarthrosis

5

Hematoma

2

3

Wound dehiscence

2

Superficial wound infection

2

Op site woozing

1 2

Arrhythmia

2

anemia

1

Chronic DVT

1

M AN U

Hematuria

SC

Bulae

RI PT

Wound problem

Drug-induced hepatitis

1

Heart failure

1

Pneumonia

1

AC C

EP

TE D

* patients with hemarthrosis that needed interventions such as aspiration or operation

1

ACCEPTED MANUSCRIPT FIGURE LEGEND

Fig. 1 Study flow diagram a) TKA: Total Knee Arthroplasty

RI PT

b) DVT: Deep Vein Thrombosis

AC C

EP

TE D

M AN U

SC

c) VTE: Venous Thromboembolism

1

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT