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Prevention of venous thromboembolism after arthroscopic knee surgery in a low-risk population with the use of aspirin: a randomized trial.

Historically, venous thromboembolism (VTE) in the setting of elective knee arthroscopy has been considered rare. This assessment has been largely based on retrospective series, which were only identifying symptomatic deep vein thromboses (DVT) and pulmonary emboli (PE). (1-3) However, several prospective studies have identified overall rates of deep vein thrombosis (DVT) ranging from 3.1% to 17.9% (symptomatic DVT 0% to 1%), (4-9) with a recent meta-analysis determining an overall weighted rate of DVT of 9.9%. (10) With increasing recognition of potential for the development of thromboembolic events, several randomized trials have evaluated the efficacy of chemoprophylaxis in reducing the risk of VTE.

Those studies examining the benefits of thromboprophylaxis in the setting of knee arthroscopy have all used low molecular weight heparin (LMWH) as the primary intervention with reductions in the risk of DVT ranging from 65% to 93%. (7,9,11,12) Even though data suggests that chemoprophylaxis reduces the incidence of VTE, several national and international organizations, including the American College of Chest Physicians, do not recommend pharmacologic prophylaxis after arthroscopic knee surgery unless the patient has a history of DVT. (13) Similarly, the American Academy of Orthopaedic Surgeons, while recommending pharmacologic prophylaxis after hip and knee arthroplasty, do not recommend for or against the use of prophylaxis after arthroscopic knee surgery.

Part of the hesitancy to recommend chemoprophylaxis after arthroscopy revolves around the purported side effects of such intervention, including bleeding, for a complication with an historically low incidence. Aspirin has been used successfully for VTE prophylaxis following orthopaedic surgery with the benefit of efficacious prophylaxis, ease of administration, decreased cost, and decreased risk of bleeding when compared to low molecular weight heparins. (14,15) The American Academy of Orthopaedic Surgeons and the American College of Chest Physicians both include aspirin as an acceptable form of chemoprophylaxis against VTE following hip and knee arthroplasty. No studies to date have evaluated the efficacy of aspirin in reducing the risk of VTE following elective knee arthroscopy.

The aim of the current study is to prospectively determine the incidence of DVT and PE in an elective, outpatient setting for patients undergoing knee arthroscopy and to evaluate the efficacy of a 14 day regimen of 325 mg of aspirin daily in the prevention of VTE. Our hypothesis is that aspirin is a safe and effective means of preventing venous thromboembolism following elective knee arthroscopy.

Methods

A prospective, randomized, single-blind controlled study, including 381 consecutive patients undergoing arthroscopic knee surgery at our hospital between June 2011 and June 2013, was performed. Patients ranging in age from 18 to 70 years who were scheduled for arthroscopic knee surgery were identified and included for randomization to receive aspirin as VTE prophylaxis following arthroscopic knee surgery or no form of chemoprophylaxis. All patients received a venous duplex ultrasound 10 to 14 days after surgery. Patients were excluded from the study if they were pregnant; had been diagnosed with thrombocytopenia, anemia, coagulopathy; were undergoing active treatment for deep venous thrombosis; if they had a history of bleeding, of deep venous thrombosis, or of pulmonary embolism; had active infections or undergoing active treatment for cancer; had hypersensitivity or allergy to aspirin; were smokers; or were using oral contraceptive or hormonal medications. One hundred seventy patients met inclusion criteria and were evaluated (Fig. 1). The study was approved by the In stitutional Review Board at our hospital, and all the patients were informed and gave written consent.

Operative Procedure

Nine experienced sports medicine fellowship-trained orthopaedic sports surgeons performed arthroscopic knee surgeries using a standard two portal technique for most of the procedures except in cases such as ACL reconstruction where an additional portal may have been utilized. After knee examination under anesthesia, at the discretion of the operating surgeon, a pneumatic tourniquet was placed on the operative leg. All but one of the surgeons uses a leg holder, and for these cases, the operative leg was placed in a well-padded leg holder with the contralateral leg allowed to hang freely from the table, supported by a padded bump. The calf of the operative leg was kept in a hanging position, allowing free knee flexion to approximately 90[degrees]. When a tourniquet was used, the leg was exsanguinated with an Esmarch bandage, and the tourniquet was inflated to 250 to 300 mmHg.

Data regarding the surgical procedure, type of anesthesia, tourniquet time, complications, and demographic information were collected. Patients were discharged the same day of the procedure and instructed to bear weight as tolerated immediately after the procedure.

Randomization and Interventions

All patients were advised to stop taking any antiplatelet agents 7 days before the procedure. Patients were randomly allocated to the aspirin or no aspirin group by using sealed envelopes; the operating surgeon sequentially opened the envelope after each surgical procedure.

Patients allocated to the aspirin group were instructed to take a 325 mg aspirin tablet daily for 14 days starting on the first postoperative day. Patients allocated in the non-pharmacological group (control group) were instructed not to take any non-steroidal anti-inflammatory drugs for the first 14 days postoperatively.

Outcome Measurement

The primary outcome measure was the development of postoperative DVT or PE. All patients participating in the study had bilateral, whole leg, compression venous duplex ultrasonography 10 to 14 days postoperatively. A single radiologist, who was unaware of the allocation group of the patients, performed the ultrasound evaluations. A research assistant instructed all patients to conceal their allocation from the operator on the day of the ultrasound.

A secondary outcome measure was the development of any complications. Patients were evaluated at two postoperative visits, at 1 week and 4 weeks postoperatively, by the operating surgeons who evaluated and recorded any postoperative complications.

Safety Monitoring

The safety of aspirin was monitored by clinical exam. All patients participating in the study were seen at approximately 7 to 10 days postoperatively and examined by their respective orthopaedic surgeon to determine if there were any excessive drainage from the wound or any adverse bleeding elsewhere in the body. Patients in the thromboprophylaxis group were asked if they experienced any side effects from the use of aspirin, and if intolerable, the aspirin regimen would have been discontinued. No patients were unable to tolerate aspirin use.

Statistical Analysis

To detect a 15% difference between the control group and the thromboprophylaxis group with 80% power and p-value of less than 0.05, 133 patients per group were required. As no DVTs were found in either study cohort, no statistical analysis was needed. For the association of clinical characteristics and the development of postoperative complications, logistic regression analysis was used. A univariate analysis was used to determine significant factors to be included in a second multivariate analysis.

Results

During the 24 month period of study, 170 patients underwent an arthroscopic knee procedure, were evaluated with a venous duplex ultrasound, and were available for follow-up, 66 (39%) who received aspirin as VTE prophylaxis and 104 (61%) who did not (Table 1). There were 104 men (61%) and 66 women (39%) with a mean age ([+ or -] SD) of 44.4 [+ or -] 14.4. The average patient BMI ([+ or -] SD) was 26.9 [+ or -] 4.3 kg/[m.sup.2]. One hundred nine of the cases (64%) were meniscectomies, 23 cases (14%) were ACL reconstructions, and 38 cases (22%) were categorized as others. Those 38 cases included chondroplasty, lysis of adhesions or manipulation, cyst removal, meniscal allograft transplantation, meniscus repair, lateral release, synovectomy, subchondroplasty, biopsy, and removal of loose body. One hundred forty-five cases (85%) were performed under general anesthesia, 13 cases (8%) received regional blocks, and 12 cases (7%) received both general anesthesia and a block. Ninety-seven cases (57%) were performed with the use of a tourniquet with an average tourniquet time ([+ or -] SD) of 44.1 [+ or -] 32.9 minutes.

While no DVTs or PEs were identified in either group, 29 patients (17%) experienced a complication. While no significant complications were found, minor complications existed. Those were categorized as pain and swelling (15 cases, 9%), residual joint line tenderness (5 cases, 3%), and others (9 cases, 5%), which consisted of incidental finding of a Baker's cyst (6 cases), arthrofibrosis (1 case), instability after a fall (1 case), and a limp (1 case). Only three patients developed knee swelling. Two of them were randomized to the aspirin group, and one of those patients required a knee aspiration.

A logistic regression analysis was used to check for the association between complications and clinical characteristics. In the univariate analysis (Table 2), the use of a tourniquet (p = 0.03, OR 0.39 [CI 0.17 - 0.89]), BMI greater than 35 (p = 0.05 OR 5.31 [CI 1.01 - 27.76], and the use of combined anesthesia, general, and a block, (p = 0.09 OR 0.37 [CI 0.12 - 1.17] were identified as significant and included in the multivariate analysis. In the multivariate analysis (Table 3), only the use of a tourniquet remained statistically significant (p = 0.01) for a decreased risk of complication following arthroscopic knee surgery (OR 0.32 CI 0.13 = 0.80). In the univariate analyses, the use of aspirin was associated with an odds ratio of 1.14 for the development of complications, which was not statistically significant (p = 0.76).

Discussion

A prospective, randomized, single blind controlled study evaluating the effects of aspirin as a chemoprophylactic agent against the development of VTE after arthroscopic knee surgery was performed. Although three other studies performed a prospective analysis of chemoprophylaxis for the prevention of DVT after arthroscopic knee surgery, those studies used low molecular weight heparins. Aspirin has been used for thromboprophylaxis successfully in total hip and knee replacement surgery, and several recent studies have reported noninferior results of aspirin compared to other traditional antithrombotics for the prevention of VTE. Moreover, aspirin has a better safety profile in terms of drainage than other forms of chemoprophylaxis such as low molecular weight heparins. (16-19)

The three prior prospective randomized controlled trials evaluating the efficacy of chemoprophylaxis in preventing DVT after knee arthroscopy have found increased rates of DVT compared to the current study, and all found reduced rates among those who received prophylaxis. Camporese and colleagues (11) evaluated 1,761 patients undergoing knee arthroscopy and randomized the cohorts to either compression stockings or LMWH for 7 days postoperatively. The cumulative incidence of asymptomatic proximal DVT, symptomatic VTE, and all-cause mortality was 3.2% in the stocking group versus 0.9% in the LMWH group (p = 0.005). Clinically significant bleeding occurred in 0.3% of those with compression stockings compared to 0.9% of those taking LMWH. The investigators recommend a short course of LMWH to all patients undergoing knee arthroscopy.

Michot and associates (7) randomized 130 patients to receive LMWH or no form of prophylaxis for the prevention of VTE following knee arthroscopy. One patient (1.5%) taking LMWH postoperatively developed a DVT compared to 10 patients (15.6%) without prophylaxis (p = 0.004). However, all DVTs were distal DVTs; the significance of which is unknown. Four patients taking LMWH developed soft tissue hemorrhage (hemarthrosis), two of whom required drainage, compared to three patients without prophylaxis, none of whom required an intervention.

Lastly, Wirth and coworkers (9) randomized 262 patients undergoing elective knee arthroscopy to receive either no treatment or reviparin once daily subcutaneously for 7 to 10 days. Using postoperative venous duplex, DVTs were found in 4.1% of the control group compared to 0.85% in the intervention group. In the reviparin group, there was no major bleeding, and four patients developed minor bleeds. The investigators concluded that patients undergoing knee arthroscopy have a moderate risk of VTE, and effective prophylaxis can be achieved with LMWH (reviparin).

While all three studies found reduced rates of DVT after arthroscopic knee surgery for those who were received chemoprophylaxis, a Cochrane review (20) found insufficient evidence to recommend for or against the use of DVT prophylaxis after arthroscopic knee surgery. The reluctance to recommend prophylaxis was largely based on the unknown clinical significance of distal and asymptomatic DVTs, the majority of those identified in these studies, coupled with the relatively few and small prospective studies in the literature.

DVT prevention primarily aims to prevent the more devastating secondary complication of a pulmonary embolus. However, DVTs themselves may be symptomatic causing pain, swelling, cramping, and tenderness. Moreover, DVTs may lead to postthrombotic syndrome, ranging from barely visible skin changes to skin ulceration requiring amputation. But no cases of postthrombotic syndrome have ever been reported following a knee arthroscopy. Similarly, the incidence of post-arthroscopy pulmonary embolism is exceedingly rare. Hestroni and associates (2) reviewed 418,323 arthroscopies by reviewing the New York Department of Health records and found a 90 day pulmonary embolism rate of 0.03%.

Proximal DVT, thrombosis above or at the level of the popliteal fossa, has been clearly shown to increase the risk of pulmonary embolism (50% of people with symptomatic proximal DVT will have PE in lung scans). However, the clinical relevance of distal DVT is controversial in the literature, and the consensus is that isolated calf DVT is rarely symptomatic. (21) Moreover, the incidence of PE in distal and asymptomatic DVT varies between 1.6% and 21% and is probably more related to the patient risk factors. (21)

Given the uncertainty regarding the clinical significance of asymptomatic DVT and distal DVTs, the low incidence of proximal DVTs and PE after knee arthroscopy and the potential complications of anti-thrombotic medication, perhaps a more tailored approach to prophylaxis is warranted. Delis and colleagues (4) identified several risk factors for the development of DVT in knee arthroscopy, and noted that if any two or more were present, the risk for development of thrombosis after knee arthroscopy was increased. Those risk factors included age greater than 65 years, BMI greater than 30 kg/[m.sup.2], smoking, use of oral contraceptive or hormone replacement therapy, and chronic venous insufficiency. Also, a history of malignancy or a previous history of VTE were independent risk factors for the development of DVT after knee arthroscopy.

While no DVTs were identified in the current study, 29 complications were found. Although BMI greater than 35 increased the risk of development of a complication fivefold in the univariate analysis, in the multivariate analysis, BMI was not found to be a statistically significant risk factor. The only statistically significant factor was the use of a tourniquet, which actually showed a protective benefit for the development of a complication. No study has previously identified tourniquet use to be protective; most have found no significance with or without tourniquet use. Conversely, some studies have identified prolonged tourniquet time as a risk for complications in knee arthroscopy. Demers and coworkers (5) found that tourniquet time greater than 60 minutes increased the risk for DVT. Similarly, Hestroni and associates (2) found that increased tourniquet time increased the risk for DVT but qualified their findings with the possibility that increased case time may reflect an increased case complexity, which may itself predispose to VTE.

Limitations

Although prior rates of DVT after arthroscopic knee surgery have been reported to range from 3% to 18%, we did not identify any cases of DVT among 170 patients undergoing arthroscopic surgery. Although the study was underpowered to detect a statistically significant difference regarding the effects of aspirin in this setting, the lack of identified DVTs was unexpected. A meta-analysis of methods for the detection of DVT showed that in low risk populations, such as those undergoing arthroscopic knee surgery, a venous duplex is an appropriate screening tool. (22) Rather than undiagnosed DVTs, it is more likely that the characteristics of this study population, which excluded patients at risk for development of DVT, in concert with a regimen of early mobilization, may have accounted for the lack of development of DVTs.

Conclusion

Ultimately, this study did not identify a single case of a DVT or PE, perhaps reflecting its uncommon occurrence in a low-risk, mobilized population. Even those studies that have identified increased rates of DVT have identified primarily distal and asymptomatic occurances; the significance of which is unknown. The rates of symptomatic and proximal DVT after arthroscopic knee surgery is 0% to 1%. (23) The risk of having a distal thrombosis with its unpredictable and quite low incidence or a proximal DVT with its even lower incidence but more grave consequences must be weighed against the minor complications caused by anti-thrombotic medication. Targeting those at high risk for thrombosis and appropriately treating those patients may protect those who are at high risk while preventing untoward complications in those patients unlikely to develop thromboses anyway. Further study may be directed at identifying and treating this population while potentially sparing those at low risk the unneeded complications of chemoprophylaxis. Based on the lack of identified DVT in either arm of the study, the use of aspirin in a low risk population as chemoprophylaxis against DVT may not be warranted.

References

(1.) Bohensky MA, de Steiger R, Kondogiannis C, et al. Adverse outcomes associated with elective knee arthroscopy: a population-based cohort study. Arthroscopy. 2013 Apr; 29(4): 716-25.

(2.) Hetsroni I, Lyman S, Do H, et al. Symptomatic pulmonary embolism after outpatient arthroscopic procedures of the knee: the incidence and risk factors in 418,323 arthroscopies. J Bone Joint Surg Br. 2011 Jan; 93(1):47-51.

(3.) Maletis GB, Inacio MD, Reynolds S, Funahashi TT. Incidence of symptomatic venous thromboembolism after elective knee arthroscopy. J Bone J Surg Am. 2012 Apr 18; 94(8):714-20.

(4.) Delis KT, Hunt N, Strachan RK, Nicolaides AN. Incidence, natural history, and risk factors of deep vein thrombosis in elective knee arthroscopy. Thromb Haemost. 2001 Sep; 86(3):817-21.

(5.) Demers C, Marcoux S, Ginsberg JS, et al. Incidence of venographically proved deep vein thrombosis after knee arthroscopy. Arch Intern Med. 1998 Jan 12; 158(1):47-50.

(6.) Durica S, Raskob G, Johnson C, et al. Incidence of deep vein thrombosis after arthroscopic knee surgery. Thromb Haemost. 1997; 79:183.

(7.) Michot M, Conen D, Holtz D, et al. Prevention of deep-vein thrombosis in ambulatory arthroscopic knee surgery a randomized trial of prophylaxis with low-molecular weight heparin. Arthroscopy. 2002 Mar; 18(3):257-63.

(8.) Williams JS, Hulstyn MJ, Fadale PD, et al. Incidence of deep vein thrombosis after arthroscopic knee surgery; a prospective study. Arthroscopy. 1995 Dec; 11(6):701-5.

(9.) Wirth T, Schneider B, Misselwitz F, et al. Prevention of venous thromboembolism after knee arthroscopy with low-molecular weight heparin (reviparin): results of a randomly controlled trial. Arthroscopy. 2001 Apr; 17(4):393-9.

(10.) Ilahi OA, Reddy J, Ahmad I. Deep vein thrombosis after knee arthroscopy; a meta-analysis. Arthroscopy. 2005 Jun; 21(6):727-30.

(11.) Camporese G, Bernardi E, Prandoni P, et al. Low molecular weight heparin versus compression stockings for thromboprophylaxis after knee arthroscopy: a randomized trial. Ann Intern Med. 2008 Jul 15; 149(2):73-82.

(12.) Marlovits S, Striessnig G, Schuster R, et al. Extended-duration thromboprophylaxis with enoxaparin after arthroscopic surgery of the anterior cruciate ligament: a prospective, randomized, placebo-controlled study. Arthroscopy. 2007 Jul; 23(7):696-702.

(13.) Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb; 141(2 Suppl):e278S-325S.

(14.) Antiplatelet Trialists' Collaboration. Collaborative overview of randomized trials of antiplatelet therapy-III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ. 1994 Jan 22; 308(6923):235-46.

(15.) Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: pulmonary embolism prevention trial. Lancet. 2000 Apr 15; 355(9212):1295-302.

(16.) Bozic KJ, Vail TP, Pekow PS, et al. Does aspirin have a role in venous thromboembolism prophylaxis in total knee arthroplasty patients? J Arthroplasty. 2010 Oct; 25(7):1053-60.

(17.) Brown GA. Venous thromboembolism prophylaxis after major orthopaedic surgery: a pooled analysis of randomized controlled trials. J Arthroplasty. 2009 Sep; 24(6 Suppl):77-83.

(18.) 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. 2007 Dec; 89(12):2648-57.

(19.) Powers PJ, Gent M, Jay RM, et al. A randomized trial of less intense postoperative warfarin or aspirin therapy in the prevention of venous thromboembolism after surgery for fractured hip. Arch Intern Med. 1989 Apr; 149(4):771-4.

(20.) Ramos J, Perrotta C, Badariotti G, Berenstein G. Interventions for preventing venous thromboembolism in adults undergoing knee arthroscopy. Cochrane Database Syst Rev. 2008 Oct 8; (4):CD005259.

(21.) Kearon C. Natural history of venous thromboembolism. Circulation. 2003 Jun 17; 107(23 Suppl 1):I22-30.

(22.) Goodacre S, Sampson F, Thomas S, et al. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for DVT. BMC Med Imaging. 2005 Oct 3; 5:6.

(23.) Graham WC, Flanigan DC. Venous thromboembolism following arthroscopic knee surgery: a current concepts review of incidence, prophylaxis, and preoperative risk assessment. Sports Med. 2014 Mar; 44(3):331-43.

I. David Kaye, M.D., Deepan N. Patel, M.D., Eric J. Strauss, M.D., Michael J. Alaia, M.D., Garret Garofolo, B.Sc., Amaury Martinez, B.A., and Laith M. Jazrawi, M.D.

I. David Kaye, M.D., Deepan N. Patel, M.D., Eric J. Strauss, M.D., Michael J. Alaia, M.D., Garret Garofolo, B.Sc., Amaury Martinez, B.A., and Laith M. Jazrawi, M.D., Hospital for Joint Diseases, NYU Langone Medical Center, New York, New York.

Correspondence: I. David Kaye, M.D., New York University, Hospital for Joint Diseases, 301 East 17th Street, New York, New York 10003; Ian.Kaye@nyumc.org.

Caption: Figure 1 Patient inclusion criteria.

Table 1 Patient Demographics

            Aspirin (66)   No aspirin (104)         Overall

Age (avg)       46.0             43.4         44.4 ([+ or -] 14.4)
Sex
Male          38 (58%)         66 (63%)            104 (61%)
Female        28 (42%)         38 (37%)             66 (39%)
BMI (avg)       27.2             26.8         26.9 ([+ or -] 4.3)

Table 2 Univariate Logistic Regression Analysis of Association
between Patient Characteristics and Complications

Patient characteristics              P-value   Odds Ratio [95% CI]

Aspirin                               0.76     1.14 [0.50 - 2.56]
Surgery (Meniscectomy)                0.86     1.14 [0.50 - 2.56]
Surgery (ACL)                         0.26     1.14 [0.50 - 2.56]
Use of Tourniquet                    0.03 *    1.14 [0.50 - 2.56]
Tourniquet Time (10 min)              0.12     1.14 [0.50 - 2.56]
Anesthesia (General and regional)    0.09 *    1.14 [0.50 - 2.56]
Age > 55                              0.50     1.14 [0.50 - 2.56]
BMI > 35                             0.05 *    1.14 [0.50 - 2.56]
BMI > 30                              0.48     1.14 [0.50 - 2.56]
BMI (continuous)                      0.29     1.14 [0.50 - 2.56]
Sex (Female)                          0.76     1.14 [0.50 - 2.56]

* Chosen as significant based on predefined significance of p < 0.1
to use for variables in multivariate analysis.

Table 3 Multivariate Logistic Regression Analysis for
Association between Patient Characteristics and Complications

Patient characteristics                P-value/OR [95% CI]

Use of Tourniquet                   0.01/ 0.32 [0.13 - 0.80]
BMI > 35                            0.25/ 2.89 [0.45 - 17.28]
Anesthesia (General and regional)   0.11/ 0.37 [0.11 - 1.26]


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Author:Kaye, I. David; Patel, Deepan N.; Strauss, Eric J.; Alaia, Michael J.; Garofolo, Garret; Martinez, A
Publication:Bulletin of the NYU Hospital for Joint Diseases
Article Type:Report
Date:Oct 1, 2015
Words:3883
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