John Z. Edwards, MD,* Pamela A. Pulido, BSN,y Kace A. Ezzet, MD,z Steven N. Copp, MD,z Richard H. Walker, MD,z and Clifford W.

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1 The Journal of Arthroplasty Vol. 23 No Portable Compression Device and Low-Molecular-Weight Heparin Compared With Low-Molecular-Weight Heparin for Thromboprophylaxis After Total Joint Arthroplasty John Z. Edwards, MD,* Pamela A. Pulido, BSN,y Kace A. Ezzet, MD,z Steven N. Copp, MD,z Richard H. Walker, MD,z and Clifford W. Colwell Jr, MDyz Abstract: This preliminary prospective study to determine the rate of deep venous thrombosis (DVT) examined 277 patients undergoing total knee or total hip arthroplasty (TKA or THA) who were randomized to use a portable, continuous enhanced circulation therapy (CECT) compression device and low-molecular-weight heparin (LMWH) or to receive LMWH alone. Patients were screened for DVT using duplex ultrasound at hospital discharge and followed clinically for 3 months. In TKA, 5 DVTs (6.6%) occurred in the CECT + LMWH group compared with one pulmonary embolism and 14 DVTs (19.5%) in the LMWH group (P =.018). In THA, 1 DVT (1.5%) occurred in the CECT + LMWH group and 2 DVTs (3.4%) occurred in the LMWH group. This preliminary study demonstrated significant reduction in rate of DVT after TKA when the CECT device was combined with LMWH. Key words: thrombosis, total hip arthroplasty, total knee arthroplasty, CECT device, lowmolecular-weight heparin Elsevier Inc. All rights reserved. Thromboembolic disease is a common complication of total joint arthroplasty that has been recognized since the National Institutes of Health consensus conference in 1986 [1]. Without prophylaxis, the rate of deep venous thrombosis (DVT) after total hip arthroplasty (THA) is as high as 50% [2]. After total knee arthroplasty (TKA), the rate of DVT has been From the *Gem City Bone and Joint, Laramie, Wyoming; yshiley Center for Orthopaedic Research and Education at Scripps Clinic, La Jolla, California; and zdivision of Orthopaedic Surgery, Scripps Clinic, La Jolla, California. Submitted April 18, 2007; accepted November 15, Benefits or funds were received in partial or total support of the research material described in this article. These benefits or funds were received from Medical Compression ActiveCare DVT, Medical Compression Systems, Or Akiva, Israel. Reprint requests: Clifford W. Colwell Jr, MD, Shiley Center for Orthopaedic Research and Education at Scripps Clinic, North Torrey Pines Road, Suite 140, La Jolla, CA Elsevier Inc. All rights reserved /08/ $34.00/0 doi: /j.arth observed to be as high as 88% [3]. Because 90% of symptomatic pulmonary emboli are estimated to originate from lower extremity DVT [4], prevention of DVT has become the standard of care after total joint arthroplasty. Excellent methods of chemoprophylaxis using warfarin, low-molecular-weight heparin (LMWH), or fondaparinux are available based on the evidence in the literature. Chemoprophylaxis, however, carries a bleeding risk. Mechanical methods of prophylaxis are often used in patients with higher bleeding risk or as an adjunct to anticoagulant-based prophylaxis. The use of a mechanical compression device as DVT prophylaxis continues to be an attractive option because few complications have been identified. Mechanical compression devices have been theorized to prevent clot formation by increasing venous blood flow from the legs [5], causing the release of endothelial-derived relaxing factor [6], and causing the release of urokinase [7,8]. Relaxing factor and 1122

2 Portable Compression Device and LMWH Compared With LMWH for Thromboprophylaxis Edwards et al 1123 urokinase are substances that prevent DVT development and help break down clots that start to form. Mechanical compression has been associated with rare reports of compartment syndrome and peroneal nerve palsy [9,10]. Bleeding with intermittent pneumatic compression devices is considered to be similar to placebo, reported at about 4% for THA [11] and 6% for TKA [12]. A potential problem with mechanical compression devices is a lack of patient compliance in using the devices [13]. Most mechanical compression devices are not portable and have to be disconnected whenever the patient is ambulating. To overcome the problem of poor patient compliance, a new type of mechanical compression device has been developed. This device is portable, can be battery powered, has form-fitting calf sleeves that are easy to apply, and can be worn while the patient is out of bed with minimal inconvenience. The purpose of this study was to perform a prospective, randomized, controlled trial examining the ability of this new type of mechanical compression device used in conjunction with LMWH compared with LMWH alone to decrease the rate of DVT and pulmonary embolism (PE) after lower extremity total joint arthroplasty. flow to reduce the risk of clot formation. The disposable limb sleeves fit over the patient s calves in a form-fitting fashion and are secured with hook and loop fasteners. The sleeves are then connected to the pump with plastic hoses. The 1.5-lb pump and battery pack, which can function for up to 6 hours on battery, will be recharged when plugged into an electrical outlet (Fig. 1). This device provides a maximum pressure during inflation of 50 mm Hg and uses 8 seconds of compression followed by 52 seconds of decompression. The THA patients had a CECT device placed on the nonoperative leg before being draped, and a sterile CECT device was placed on the operative leg just before skin incision. The patients in the CECT + LMWH group wore the device for the length of their hospitalization. For unilateral TKA patients, the CECT device was placed on the nonoperative leg in the operating room before the patients were draped. The CECT device was placed on the operative leg after the dressing was applied and Materials and Methods Three hundred twenty patients undergoing THA or TKA were consented for the study after approval by the institutional review board. Ten of the consented patients canceled their surgery. Thirtythree patients were excluded for protocol violations, such as missed ultrasound (9), surgery other than THA or TKA (1), previous history of thrombosis (12), prophylaxis other than LMWH (8), and other protocol deviations (3). Two hundred seventy-seven patients were available for per-protocol analysis. The study was done in parallel; 124 THA patients and 153 TKA patients were enrolled. Both groups received LMWH (enoxaparin 30 mg every 12 hours for 7 to 8 days after surgery; Sanofi- Aventis, Bridgewater, NJ) starting the morning after surgery. In addition to the LMWH, the continuous enhanced circulation therapy (CECT + LMWH) group received the CECT device (ActiveCare DVT; Medical Compression Systems, Or Akiva, Israel), which was placed on the calves of the patient in the operating room and continued during hospitalization. The LMWH group received only the LMWH. The CECT device applies intermittent, sequential pressure to the patient's leg in a systematic pattern, increasing the peak venous velocity of venous blood Fig. 1. Patient wearing the CECT device.

3 1124 The Journal of Arthroplasty Vol. 23 No. 8 December 2008 before the patient left the operating room. For bilateral TKA patients, the CECT device was placed on both legs after the dressing was applied and before the patient left the operating room. Patients in both groups were closely monitored throughout their hospitalization. Before discharge from the hospital, both the CECT + LMWH group and the LMWH group had duplex ultrasound of the lower extremity, which has excellent specificity and accuracy in both calf and thigh at our institution [14], performed to detect occult DVT. All patients were followed clinically for 3 months for signs or symptoms of DVT or PE. χ 2 tests and Fisher's exact tests were used to assess group differences in categorical variables. Independent t tests were used to compare continuous variables. All statistical analyses were performed using SPSS version 13.0 (Chicago, Ill); the P value was set at.05. A power analysis was performed before enrolling patients. Prior data from our institution revealed that the rate of DVT among joint arthroplasty patients receiving LMWH was 14.7%. If the use of the CECT device reduced the rate of DVT by half to 7.35%, we would need to enroll approximately 150 patients in each group to obtain a P value of less than.05. Results Of the 277 evaluable patients in this preliminary study, 153 patients had TKA (76 in the CECT + LMWH group, 77 in the LMWH group) and 124 patients had THA (65 in the CECT + LMWH group, 59 in the LMWH group). Demographics were similar in both groups (Table 1). The amount of blood lost during surgery and the number and type of transfusions were similar between the 2 groups in both TKA and THA patients except autologous blood transfused in THA patients (Table 2). All DVTs were distal on ultrasound examination, and no deaths occurred in either group. Five DVTs occurred in TKA patients (none bilateral) in the CECT + LMWH group. One of these 5 patients who was positive for a distal DVT at discharge developed a symptomatic PE 29 days after surgery. One of these 5 patients was negative at discharge, but developed a symptomatic DVT confirmed by ultrasound at another facility after discharge. In the LMWH group, 14 DVTs and 1 PE occurred in TKA patients (6 patients bilateral in the same setting). Four patients having bilateral knee arthroplasty had DVT in both legs. One of the 14 positive DVT patients was negative on ultrasound at discharge but returned 4 days after discharge with DVT symptoms that were positive on ultrasound. The PE occurred on day 2 in a unilateral TKA patient with a negative ultrasound. The difference in thromboembolism in TKA patients was significant, with 6.6% (5 of 76 patients) occurrence in the CECT + LMWH group and 19.5% (15 of 77 patients) occurrence in the LMWH group (P =.018) (Fig. 2A). In the THA patients, the occurrence of DVT was 1.5% (1 of 65 patients) in the CECT + LMWH group and 3.4% (2 in 59 patients) in the LMWH group. No statistically significant (P =.60) difference was found between the groups in THA patients (Fig. 2B). Because the compliance of the use of compression devices is a concern, we measured the time the patient used the device by an internal timer in the pump unit. The TKA patients negative for DVT in the CECT + LMWH group used the device an average of 20.0 hours per day (83% compliance rate), whereas the 5 patients positive for DVT used the device 18.6 hours per day (77% compliance rate). The THA patients in the CECT + LMWH group negative for DVT wore the device an average of 20.9 hours per day for an 87.1% compliance rate. Only one THA patient in the CECT + LMWH group was positive for DVT, and that patient wore the device 23 hours per day. Discussion We evaluated the effect of a new type of intermittent compression device, called CECT, combined with LMWH prophylaxis compared with Table 1. Demographics by Treatment Group among TKA and THA Patients Demographic TKA THA CECT + LMWH LMWH P CECT + LMWH LMWH P n = 76 n = 77 n = 65 n = 59 Mean age, y (range) 68.1 ( ) 68.7 ( ) ( ) 67.7 ( ).11 Mean weight, lb (range) ( ) ( ) ( ) (90-340).87 Female, % (n) 63.1 (48) 55.8 (43) (36) 59.3 (35).66 History of malignancy, % (n) 17.1 (13) 15.6 (12) (11) 18.6 (11).80 Mean length of stay, d

4 Portable Compression Device and LMWH Compared With LMWH for Thromboprophylaxis Edwards et al 1125 Table 2. Amount of Surgical Blood Loss and Number of Patients Transfused During Hospitalization n Preoperative Hemoglobin (g/dl) (mean ± SD) Mean Surgical Blood Loss, ml Any Blood Transfusion, Transfusion by Type of Blood Autologous Blood, Allogeneic Blood, ConstaVac Blood, Discharge Hemoglobin (g/dl) (mean ± SD) TKA CECT + LMWH ± (76) 22 (29) 10 (13) 43 (57) 10.1 ± 1.1 LMWH ± (77) 29 (38) 11 (14) 47 (61) 10.0 ± 1.0 P THA CECT + LMWH ± (57) 28 (43) 14 (21) ± 1.1 LMWH ± (76) 36 (61) 15 (25) 1 (1.7) 10.0 ± 1.0 P Patient may have received more than one type of blood transfusion. Surgical blood loss and blood transfusions by type of transfusion. LMWH prophylaxis alone on the rate of DVT and PE in TKA and THA patients. Overall, the rate of DVT was 6 (4%) in patients treated with CECT and LMWH compared with 17 (12%) in patients treated with LMWH alone. We found no difference in the incidence of symptomatic PE, 1 in each treatment group and both in TKA patients. For TKA patients, we found a rate of 6.6% (5 of 76 patients) positive for DVT in the CECT + LMWH group and a rate of 19.5% (15 of 77 patients) positive for DVT in the LMWH group (P =.018). In a study using the same CECT device with aspirin compared with enoxaparin 40 mg daily and venography to detect DVT, Gelfer et al found a rate of 14.3% (4 of 28 patients) of DVT in TKA patients in the CECT group compared with a rate of 20% (4 of 20 patients) of DVT in the LMWH group [15]. In our study, we found no difference between the CECT + LMWH group with 1.5% (1 of 65 patients) and the LMWH group with 3.4% (2 of 59 patients) incidence of DVT in patients undergoing THA. Gelfer et al did report a significant difference (P b.012) in DVT between the CECT group with no DVT compared with the LMWH group who had 13 DVTs [16]. Paiement et al found the rate of DVT similar in a cohort of hip arthroplasty patients who received either low-dose warfarin or a pneumatic compression device. They reported DVT in 17% (12 of 72 patients) in the warfarin group and in 17% (11 of 66 patients) in the pneumatic compression group [17]. By contrast, Bailey et al found a thigh-high pneumatic compression device with 6% (3 of 50 patients) positive for DVT to be statistically significantly better (P b.006) than low-dose warfarin with 27% (12 of 45 patients) positive for DVT in hip arthroplasty patients [18]. Warwick et al demonstrated equivalent DVT prevention between a cohort of hip arthroplasty patients treated with LMWH (enoxaparin) (13%, 18 of 138 patients) and a cohort treated with a foot pneumatic compression device (18%, 24 of 136 patients) [19]. Pitto et al found half the rate of DVT in a group of hip arthroplasty patients who had prophylaxis with an intermittent pneumatic compression device (3%, 3 of 100 patients) compared with a group that received LMWH (6%, 6 of 100 patients) (P b.05) [20]. Fig. 2. A, Comparison of DVT and PE in TKA by treatment group. B, Comparison of DVT and PE in THA by treatment group.

5 1126 The Journal of Arthroplasty Vol. 23 No. 8 December 2008 This study found a significant difference (P =.018) in TKA between the CECT + LMWH group with 6.6% (5 of 76 patients) DVT and the LMWH group with 19.5% (15 of 77 patients) DVT. No other study that we are aware of has reported a rate of DVT this low in TKA. A TKA study of similar size randomized patients to either enoxaparin and a calf compression device or aspirin and a calf compression device and reported 12.6% (17/135) DVT for the enoxaparin group and 14.0% (18/129) for the aspirin group by ultrasound examination at 3 to 5 days after surgery [21]. Using thigh-high pneumatic compression devices, Hass et al reported a statistically significantly better incidence of DVT (22%, 8 of 26 patients) compared with DVT incidence with aspirin prophylaxis (47%, 17 of 36 patients) in TKA patients [22]. In a meta-analysis, Westrich et al reviewed 23 studies of DVT prophylaxis in TKA and reported no statistically significant difference between pneumatic compression and LMWH in preventing DVT (17% vs 29%, respectively) [23]. Compliance in the use of pneumatic devices remains a concern. Our TKA and THA patients used the CECT device for 20.4 of 24 hours for an 85% compliance rate. A study of trauma patients comparing traditional leg pneumatic compression devices with the CECT device found that CECT patients wore their compression devices 78% of the time compared with 59% usage with the traditional leg compression devices (P =.004) [24]. Clearly, no device will increase blood flow or cause the release of intrinsic anticoagulants if the patient removes the device from his legs because of discomfort or activity. A direct correlation has been reported between the amount of time a pneumatic compression device is worn and its effectiveness. Westrich et al found that among TKA patients who used a pneumatic compression device as the primary form of DVT prophylaxis, the pneumatic compression device was worn for 56% (13.4 hours per day) of the time by patients who developed DVT and for 80% (19.2 hours per day) of the time by patients who did not develop a DVT (P b.001) [25]. Our data demonstrated no correlation between the time the CECT device was used and the presence of DVT. The 71 TKA patients without clots wore the CECT device for 83% (20.0 hours per day) of the time, and the 5 TKA patients who developed DVT wore the CECT device for 77% (18.6 hours per day) of the time. This result may be due to the low number of clots rather than the rate of compliance. Our results showed that the addition of the CECT device to LMWH prophylaxis provided an absolute risk reduction of DVT of 12.9% (P =.018) in TKA patients. This preliminary study of the new CECT device demonstrated a significant reduction in the rate of DVT with no difference in symptomatic PE after TKA when combined with an LMWH regimen. The addition of the CECT device to LMWH prophylaxis did not significantly change the number of DVTs in THA patients. Further research is under way comparing the CECT device alone with LMWH in THA patients. With the use of a light, portable, and easy-to-use device such as the CECT, patients can be mobile with apparent protection that is additive in TKA patients. Acknowledgment The authors would like to thank Mary E. Hardwick, MSN, RN, and Julie Sandwell, MPH(c), for their diligence with data analysis and manuscript preparation. References 1. Prevention of venous thrombosis and pulmonary embolism. NIH Consensus Development. JAMA 1986;256: Johnson R, Carmichael JH, Almond HG, et al. Deep venous thrombosis following Charnley arthroplasty. Clin Orthop Relat Res 1978: McKenna R, Bachmann F, Kaushal SP, et al. Thromboembolic disease in patients undergoing total knee replacement. J Bone Joint Surg Am 1976; 58: Westrich GH, Rana AJ. Prevention and treatment of thromboembolic disease: an overview. Tech Orthop 2001;16: Sculco TP, Bottner F. Current concepts of nonpharmacologic thromboembolic prophylaxis. Instr Course Lect 2002;51: Vanhoutte PM, Boulanger CM, Mombouli JV. Endothelium-derived relaxing factors and converting enzyme inhibition. Am J Cardiol 1995;76:3E. 7. DiGiovanni CW, Restrepo A, Gonzalez DV, et al. The safety and efficacy of intraoperative heparin in total hip arthroplasty. Clin Orthop Relat Res 2000: Allenby F, Boardman L, Pflug JJ, et al. Effects of external pneumatic intermittent compression on fibrinolysis in man. Lancet 1973;2: McGrory BJ, Burke DW. Peroneal nerve palsy following intermittent sequential pneumatic compression. Orthopedics 2000;23: Lachmann EA, Rook JL, Tunkel R, et al. Complications associated with intermittent pneumatic compression. Arch Phys Med Rehabil 1992;73: Colwell Jr CW, Spiro TE. Efficacy and safety of enoxaparin to prevent deep vein thrombosis after hip arthroplasty. Clin Orthop 1995:215.

6 Portable Compression Device and LMWH Compared With LMWH for Thromboprophylaxis Edwards et al Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of deep vein thrombosis after major knee surgery a randomized, double-blind trial comparing a low molecular weight heparin fragment (enoxaparin) to placebo. Thromb Haemost 1992;67: Westrich GH, Jhon PH, Sanchez PM. Compliance in using a pneumatic compression device after total knee arthroplasty. Am J Orthop 2003;32: Grady-Benson JC, Oishi CS, Hanson PB, et al. Routine postoperative duplex ultrasonography screening and monitoring for the detection of deep vein thrombosis. A survey of 110 total hip arthroplasties. Clin Orthop Relat Res 1994: Gelfer Y, Tavor H, Oron A, et al. Deep vein thrombosis prevention in joint arthroplasties: continuous enhanced circulation therapy vs low molecular weight heparin. J Arthroplasty 2006;21: Gelfer Y, Tavor H, Oron A, et al. Deep vein thrombosis prevention in joint arthroplasties: continuous enhanced circulation therapy vs low molecular weight heparin. J Arthroplasty 2006;21: Paiement G, Wessinger SJ, Waltman AC, et al. Lowdose warfarin versus external pneumatic compression for prophylaxis against venous thromboembolism following total hip replacement. J Arthroplasty 1987;2: Bailey JP, Kruger MP, Solano FX, et al. Prospective randomized trial of sequential compression devices vs low-dose warfarin for deep venous thrombosis prophylaxis in total hip arthroplasty. J Arthroplasty 1991;6(Suppl):S Warwick D, Harrison J, Glew D, et al. Comparison of the use of a foot pump with the use of low-molecularweight heparin for the prevention of deep-vein thrombosis after total hip replacement. A prospective, randomized trial. J Bone Joint Surg Am 1998;80: Pitto RP, Hamer H, Heiss-Dunlop W, et al. Mechanical prophylaxis of deep-vein thrombosis after total hip replacement: a randomised clinical trial. J Bone Joint Surg Br 2004;86: Westrich GH, Bottner F, Windsor RE, et al. VenaFlow plus Lovenox vs VenaFlow plus aspirin for thromboembolic disease prophylaxis in total knee arthroplasty. J Arthroplasty 2006;21: Haas SB, Insall JN, Scuderi GR, et al. Pneumatic sequential-compression boots compared with aspirin prophylaxis of deep-vein thrombosis after total knee arthroplasty. J Bone Joint Surg Am 1990;72: Westrich GH, Haas SB, Mosca P, et al. Meta-analysis of thromboembolic prophylaxis after total knee arthroplasty. J Bone Joint Surg Br 2000;82: Murakami M, McDill TL, Cindrick-Pounds L, et al. Deep venous thrombosis prophylaxis in trauma: improved compliance with a novel miniaturized pneumatic compression device. J Vasc Surg 2003;38: Westrich GH, Sculco TP. Prophylaxis against deep venous thrombosis after total knee arthroplasty. Pneumatic plantar compression and aspirin compared with aspirin alone. J Bone Joint Surg Am 1996;78: 826.