- Email: [email protected]
Operative Risk of Staged Bilateral Knee Arthroplasty is Underestimated in Retrospective Studies
The Journal of Arthroplasty Vol. 26 No. 8 2011
Operative Risk of Staged Bilateral Knee Arthroplasty is Underestimated in Retrospective Studies Sunny Kim, PhD,* John P. Meehan, MD,* and Richard White, MD, FACPy
Abstract: To find a safer surgical option, a number of studies have compared postoperative complications after bilateral total knee arthroplasty vs staged total knee arthroplasty (STKA) by contrasting postoperative complications collected retrospectively. However, we believe that a comparison based on retrospective studies could be biased. The purpose of this study was to demonstrate the misclassification bias associated with a retrospective study in comparing operative outcomes. Our analysis indicates that any conclusions based simply on retrospective analysis of subjects who successfully completed STKA is biased because it includes only cases that recovered after the first operation, rather than all of the patients who had planned STKA. In the absence of a prospective study to date, published studies should be interpreted with caution. Keywords: arthroplasty, TKA, operative risk, safety, complications. Published by Elsevier Inc.
Approximately 16.4% of the population 45 years and older in the United States has symptomatic osteoarthritis of the knee [1]. When nonsurgical treatment modalities have proved unsuccessful, total knee arthroplasty (TKA) is considered [2]. Joint arthroplasty effectively provide improved physical function as well as pain relief [3,4], and these surgical treatments have received widespread acceptance. Nearly one half million primary knee arthroplasties were performed during 2006 in the United States [5], and the number of surgeries is increasing at a steep rate [6-8]. Total knee arthroplasty is one of the most successful surgeries, but there are still risks of venous thrombosis, pulmonary embolism (PE), infection, bleeding, stroke, myocardial infarction, or even death. The most common complication after TKA is venous thrombosis. Deep vein thrombosis (DVT) often causes delayed hospital discharge. It also exposes patients to prolonged anticoagulation and the potential risk of postthrombotic syndrome. Postthrombotic syndrome, involving pain, swelling, and skin changes in the affected extremity,
From the *Department of Orthopaedic Surgery, University of California, Davis; and yDepartment of Internal Medicine, University of California, Davis. Submitted May 25, 2010; accepted January 2, 2011. The Conflict of Interest statement associated with this article can be found at doi:10.1016/j.arth.2011.01.004. Reprint requests: Sunny Kim, PhD, Department of Orthopaedic Surgery, 4860 Y Street, Suite 3800, Sacramento, CA 95817. Published by Elsevier Inc. 0883-5403/2608-0014$36.00/0 doi:10.1016/j.arth.2011.01.004
occurs in approximately 20% to 50% of patients within 1 to 2 years of an episode of DVT [9]. The greatest risk of DVT is its potential for life-threatening PE. In the absence of prophylaxis, TKA carries a risk of DVT in 56% to 66% of patients [10,11] and symptomatic PE in 1.9% [11]. Of the patients who received anticoagulant prophylaxis, the incidence of symptomatic nonfatal venous thrombosis is 1.4% to 3.0% and that of fatal PE is 0 to 0.12% [12,13]. Overall, mortality within 1 year after primary TKA is approximately 0.4%, and the median time to death is 9 days following primary TKA [13]. Among the Medicare population, the mortality during the 3 months after primary TKA is 0.7% [14]. Bilateral knee osteoarthritis is more prevalent than unilateral knee osteoarthritis [15]. Surgical options for patients with symptomatic bilateral knee osteoarthritis are (1) simultaneous bilateral TKA (BTKA) under 1 anesthesia and (2) staged TKA (STKA) with 2 distinct operations separated by a few days to years. Although there is no consensus regarding the time interval between 2 operations, most surgeons reported that they perform STKA within 1 year [16]. Among Medicare enrollees in the United States, approximately 72% of patient who underwent STKA had 2 surgeries within a year, and the remaining 28% had 2 surgeries between 1 and 2 years apart [17]. Although it is possible that patients can have 2 operations during the same hospitalization [18,19], in most cases, the first knee surgery (referred to as STKA-1 hereafter) is done during one hospitalization and the contralateral knee surgery
1198
Postoperative Risk of Bilateral Knee Arthroplasty Kim et al
(referred to as STKA-2 hereafter) is done during a subsequent hospitalization. The STKA is performed more frequently than BTKA. Staged TKA was 2.1 times more frequent than BTKA in the United States [17] and 2.4 times more frequent in Ontario [16]. Compared with STKA, BTKA is a convenient option for patients because it requires only 1 hospitalization and 1 recovery process. In addition, from a Medicare's perspective, BTKA is less costly compared with STKA [20]. The patient “out-of -pocket” cost is also less for BTKA compared with STKA [21]. From the health care system's perspective, given the steeply increasing demand of knee arthroplasty, BTKA can reduce some strain on hospitals and surgeons as well. Due to some benefits listed above, BTKA surgeries are increasing steeply in the United States [22]. However, the safety of BTKA has been questioned because BTKA requires longer operating time compared with STKA-1 or STKA-2. To find a safer surgical option for patients with bilateral knee osteoarthritis, a number of studies have compared postoperative complications of BTKA vs STKA based on retrospective analyses of medical records. Although some studies have demonstrated no significant increase in complications after BTKA compared with STKA [23-25], or even compared with unilateral TKA (UTKA) [26-28], other studies including meta-analyses reported that the postoperative complication is higher for BTKA compared with STKA [29,30]. In either case, we believed that these study results based on retrospective analyses of medical record may be
Plan at time of the first surgery (unknown)
Change after the first surgery
Observed one year after the first surgery (known)
P(A)
Unilateral
biased. Retrospective analysis of medical record fails to account for the patients who had planned STKA but who never completed the second stage due to death or a serious postoperative complication after the first operation, leading to cancellation of the second STKA (consequently, misclassified as UTKA). The purpose of this study was to demonstrate the misclassification bias in comparing postoperative complications. The issue of operative complications of knee arthroplasty is crucial in surgical treatment decision making. We demonstrated that STKA always appears to be safer than BTKA, even if the true proportion of postoperative complications were in fact the same.
Research Methods To demonstrate the bias, a mathematical derivation and graphical presentation were developed. Patients who changed the initial surgery plan independent of postoperative complication may not introduce systematic errors in comparing STKA and BTKA. However, if patients changed to receiving (or declining) STKA-2 based on the presence (or absence) of postoperative complications after STKA-1, this systematic error in the STKA group threatens the validity of the study. There are 2 major mechanisms of misclassifying patients into the STKA group in retrospective studies (Fig. 1). First, patients who had serious complications after STKA-1 tend to decline STKA-2 (dropout). For instance, a proportion of patients (denoted by P[B] in Fig. 1) who experienced major cardiac complications or stroke
Staged bilateral
Unilateral
1199
Simultaneous bilateral
P(B)
Staged bilateral
Simultaneous bilateral
P(A): Proportion of unilateral patients who proceed to have the second surgery after the satisfactory surgery experience P(B): Among patients who initially planned SKA, the proportion of patients with complications who did not pursue the second operation
Fig. 1. Direction of bias in comparing adverse outcomes after TKA in retrospective studies.
1200 The Journal of Arthroplasty Vol. 26 No. 8 December 2011 Table 1. Proportion of True and Observed Postoperative Complications in the Population Surgery Unilateral Staged Simultaneous
Adverse Outcome P11(P11 *) P21(P21 *) P31
No Adverse Outcome P12(P12 *) P22(P22 *) P32
Total P1.(P1. *) P2.(P2. *) P3. 1.00
* Corresponding observed proportions if observed and true proportions are different.
decline STKA-2. In an extreme case, a patient who dies from complications of STKA-1 does not have a chance to undergo STKA-2 and thus would be misclassified into the UTKA group despite the initial intention to undergo STKA. Second, among patients with bilateral osteoarthritis, we sometimes see a patient who initially plans UTKA but returns for contralateral TKA after having a successful first operation (denoted by P[A] in Fig. 1). It seems that some patients focus on the other knee only after the significantly more painful one has been repaired. Despite the initial intention to have UTKA, this patient would be misclassified as STKA in retrospective studies. Table 1 shows the true proportion and its corresponding observed proportion in parentheses. True proportion is the portion of patients who experienced postoperative
complications among who had planned (or intended) UTKA, STKA, or BTKA. Observed proportion is the portion of patients who experienced postoperative complications among who actually completed UTKA, STKA, or BTKA. Consider the proportion of patients Pxy in Table 1. Let its row number be x (x = 1 if unilateral, x = 2 if staged, and x = 3 is simultaneous bilateral) and its column number be y (y = 1 if patients experienced postoperative complication, and y = 2 if patients did not experience postoperative complication). The true probability P21 (row 2 column 1) is proportion of patients who experienced complications among those who intended STKA even if patients could not be recovered after the STKA-1. This true probability of an adverse event is unknown to researchers conducting retrospective studies because of a lack of information on intent-to-treat (ITT). Initial treatment plan is typically unknown when researchers do not have access to original charts. The probability of P21 is an observed proportion of patients who experienced complications after STKA-1 or STKA-2 among those who completed both STKA-1 and STKA-2. Because we have no basis to believe otherwise, the true probabilities of adverse events after STKA-1 and STKA-2 were assumed to be the same, for simplicity. To address 2 objectives of the study, a mathematical derivation and graphical presentation were used.
Results Bias in Estimating in Postoperative Risk After STKA To calculate the bias in the observed proportion of complications among patients who underwent STKA, the proportions of true and observed complications were compared. For the observed proportion of complications for STKA (P21*), the denominator and numerator can be defined as follows. Denominator for P21* (total number of observed patients with STKA). Let N denote the total number of knee arthroplasty procedures performed. As shown in Fig. 1, let P(A) be the proportion of UTKA patients who changed plans and had contralateral TKA after satisfactory UTKA. Let P(B) be the proportion of patients with complications who did not complete the initially planned STKA-2. The total number of observed patients who finished STKA is as follows. ½N × P2: + ½NP1: P12 P ð AÞ − ½NP2: × 0:5P21 × P ðBÞ The first term is the total number of patients who planned STKA. The second term is the number of patients who changed plans after satisfactory UTKA and instead also underwent STKA-2. The third term is the number of patients who declined STKA-2 due to complications from STKA-1. Numerator for P21* (total number of patient with complication among observed STKA groups). ½NP2: × 0:5P21 −½NP2: × 0:5P21 × PðBÞ + denominator × 0:5P21 The first term is the total number of patients who experienced complications after STKA-1 among those who initially planned STKA. The second term is the number of patients who declined STKA-2 due to complications from STKA-1; therefore, these patients were not classified into the STKA group in retrospective studies. The third term is the number of patients who experienced complications after STKA-2. P21* (observed proportion of patients with complications among those who finished STKA).
Postoperative Risk of Bilateral Knee Arthroplasty Kim et al
1201
For the observed proportion of complications from STKA, the denominator and numerator can be defined as follows. P21 4 =
½NP2: × 0:5P21 + ½NP2: −ðNP2: × 0:5P21 × P ðBÞÞ + ðNP1: P12 P ð AÞÞ × 0:5P21 − ½NP2: × 0:5P21 × P ðBÞ NP2: − ½NP2: × 0:5P21 × P ðBÞ + ½NP1: P12 P ð AÞ
We canceled out the total number of knee arthroplasties performed (denoted as N) in both the numerator and denominator of the equation. P21 4 =
½P2: × 0:5P21 − ½P2: × 0:5P21 × P ðBÞ + ½P2: − ½P2: × 0:5P21 × P ðBÞ + ½P1: P12 Pð AÞ × 0:5P21 ½P2: − ½P2: × 0:5P21 × PðBÞ + ½P1: P12 Pð AÞ
Mathematically, we were able to show that the function of bias, f(x) = P21*–P21 is always negative within the valid range of P21, which is between 0 and 1. If f(x) = 0, then no bias exist. Because the bias is always negative for all possible ranges of P21, this supports that P21* always underestimates P21. Therefore, the observed proportion of complications after STKA is always smaller than the true proportion of complications after STKA (that is, P21* b P21). Details of mathematical solution will be available from the corresponding author upon request. II. Simulation of Bias in Prevalence of Complication After STKA Bias in Comparing Postoperative Complications Between BTKA and STKA We calculated the observed proportion of complications (P21*) for the probable range of other parameters. In this simulation, the true postoperative complications value was set to be the same for BTKA and STKA. Because postoperative complications for BTKA and STKA were the same, the true odds ratio should be 1. True Odds Ratio =
P21 P22:
Odds of complication for STKA = =1 P31 Odds of complication for BTKA P32
However, if P21* is underestimated (= less than P21), then the observed odds ratio should be less than 1. Observed Odds Ratio
=
P21 4 P22:
Odds of complication for STKA = b1 P31 4 Odds of complication for BTKA P32
To demonstrate the bias for various ranges of P(A) and P(B) in Fig. 1, we calculated the odds ratio using the true complication rate of 1%, which is approximately the incidence of infection when antibiotic prophylaxis was used [31]. Among US Medicare enrollees who had an index TKA, approximately 78% were UTKA, 15% were STKA, and 7% were BTKA [17]. Therefore, we used P1. = 0.78, P2. = 0.15, and P3. = 0.07 in our simulation. Fig. 2 demonstrates the bias in odds ratio in comparing complications between STKA and BTKA. The complication rate used was 1%, which is approximately the infection incidence rate. In this simulation, the percentage of UTKA patients who had surgery on the other knee after satisfactory UTKA ranged from 1% to 25%. The percentage of patients with complications who declined STKA-2 ranged from 10% to 50%. The probability of P(A) played a significant role in distorting the true odds ratio. Although the true odds ratio was set as 1 in this simulation, the observed odds ratio ranged from 0.90 to 0.56 for 0.01 b P(A) b 0.25 and 0.1 b P(B) b 0.5 (Fig. 2). As shown in Table 2, if 10% of UTKA patients changed plans and had contralateral surgery after satisfactory UTKA (P(A) = 0.1) and a half of patients who experienced infection did not complete the initially planned STKA-2 (P(B) = 0.5), the odds of infection for STKA compared with BTKA appeared to be 0.61 when the true odds ratio was set as 1. Therefore, STKA appeared to be safer than BTKA when the actual infection risk was the same in our simulated data. We repeated the same simulation with a complication rate of 2.5%, which is approximately the symptomatic nonfatal DVT incidence after TKA. Because the postoperative risk is higher, the bias was slightly larger. Regardless, the conclusion was almost the same; the observed odds ratio ranged from 0.89 to 0.54 for 0.01 b P(A) b 0.25 and 0.1 b P(B) b 0.5 (Table 2). In an extreme case if a patient died from complications of STKA-1, then P(B) plays a significant role in distorting the true odds ratio in comparing mortality (Table 2). Patients died after STKA-1 cannot not have a chance to undergo STKA-2; therefore, P(B) is always equal to 1.0. As shown in Table 2, the odds of death for STKA appeared to be half compared with BTKA even if the actual mortality was the same in our simulated data.
1202 The Journal of Arthroplasty Vol. 26 No. 8 December 2011
Fig. 2. Observed odds ratio for postoperative complications between STKA and BTKA when the true odds ratio was set to 1.
Comments We illustrated the source of misclassification bias in comparing postoperative complications between BTKA and STKA. We also demonstrated that in retrospective analyses of medical records, the operative risk of STKA appeared to be lower than it truly is. A number of published studies have reported that BTKA has a higher risk of serious cardiac complications, pulmonary complications, and mortality [29,30]. However, our research suggests that study results based on retrospective analysis without considering the initial treatment plan are biased because STKA patients who had adverse outcomes are less likely to be identified in the STKA group; therefore, STKA appears to be a safer procedure than it truly is (conversely, the risk of BTKA is overstated). This type of bias is well recognized in prospective clinical trials; therefore, an ITT analysis is used to avoid a misleading conclusion [32]. Intent-totreat analysis in prospective clinical trials is based on the initial treatment intent rather the treatment eventually administered. In most retrospective studies, however, ITT is unknown, and this lack of information could lead to misclassifying patients into the wrong treatment group. Therefore, if a patient was dropped from the initial treatment plan, this is a more serious validity issue in retrospective studies because the patient can be
classified into another treatment group that was never intended. Many studies compared the operative risk between BTKA and STKA [17,19,23-26,29,30,33,34]. However, to our knowledge, no published study has adjusted for this misclassification bias. The study results based on biased data may not offer adequate guidelines for patient care. In the absence of a prospective study, published studies should be interpreted with caution. Without P(A) and P(B) estimates, we are unable to estimate the amount of bias in published studies. However, our simulation results help us to understand the previous study on the risk of mortality, which is seemingly counterintuitive; a study reported that the proportion of mortality within 30 days after UTKA is twice compared with that of STKA-2 (0.29% after UTKA and 0.14%-0.15% after STKA-2) [30]. We posit that this phenomenon is due to the fact that STKA-2 group includes only patients who were able to be recovered after the first operation. The safety of BTKAs remains controversial. A meta-analysis reported that the odds ratios for mortality following BTKA is 2.24, and it is significantly higher than STKA [29]. However, as shown in our simulation, the odds of death for BTKA in retrospective studies appeared to be 2 times larger compared with STKA, even if the actual mortality was the same in our simulated data. The elevated risk of
Postoperative Risk of Bilateral Knee Arthroplasty Kim et al Table 2. Observed Odds Ratios for Selected Postoperative Complications Between Staged Knee Arthroplasties and Simultaneous Knee Arthroplasties When the True Odds Ratio Was Set to 1 Types of Complication Infection P(B) P(A)
0.01 0.05 0.10 0.15 0.20 0.25
0.10
0.20
0.30
0.40
0.50
1.00
0.90 0.78 0.70 0.66 0.63 0.61
0.85 0.75 0.68 0.64 0.62 0.60
0.81 0.72 0.66 0.62 0.60 0.58
0.76 0.68 0.63 0.60 0.58 0.57
0.72 0.65 0.61 0.58 0.57 0.56
0.49 0.49 0.49 0.49 0.49 0.49
Symptomatic Nonfatal DVT P(B) P(A)
0.01 0.05 0.10 0.15 0.20 0.25
0.10
0.20
0.30
0.40
0.50
1.00
0.89 0.77 0.69 0.65 0.62 0.60
0.84 0.80 0.74 0.70 0.67 0.64 0.63 0.61 0.60 0.59 0.58 0.57 Death
0.75 0.67 0.62 0.59 0.57 0.56
0.71 0.64 0.60 0.57 0.55 0.54
0.47 0.47 0.47 0.47 0.47 0.47
P(B) P(A)
0.01 0.05 0.10 0.15 0.20 0.25
0.10
0.20
0.30
0.40
0.50
1.00
* * * * * *
* * * * * *
* * * * * *
* * * * * *
* * * * * *
0.49 0.49 0.49 0.49 0.49 0.49
* Not applicable. Odds ratios are underestimated due to a lack of ITT information. P(A): proportion of unilateral patients who proceed to have the contralateral surgery after the satisfactory surgery experience. P(B): the proportion of patients with complications who did not pursue the contralateral operation among who initially planned staged knee arthroplasties.
mortality associated with BTKA in previous studies could be, in part, due to the misclassification bias. To our knowledge, there are no published prospective studies that considered an initial surgery plan. In an effort to overcome difficulty in identifying the STKA group, some studies compared the relative risk between BTKA and STKA by assuming that the risk of STKA is twice that of UTKA [30,34]. However this approach is based on the improbable assumption that STKA and UTKA patients are comparable. Obesity is more strongly associated with bilateral osteoarthritis of the knee than with unilateral osteoarthritis [15]. Knee injury is a stronger predictor for unilateral OA. Therefore, patients with bilateral OA are likely to have an elevated risk of cardiovascular complications compared with patients with unilateral OA. Our study should be interpreted within the limitations of a simulated study. Because the percentage of patients
1203
failing to return for the STKA-2 after experiencing adverse events after STKA-1 is unknown, we performed simulations with a wide range of probabilities. Although we demonstrated that the postoperative risk after BTKA was overstated, the exact amount of bias remains elusive. In our simulation, we did not consider patient characteristics. In general, older patients or high-risk patients are more likely to undergo STKA than BTKA because studies support the hypothesis that patients 80 years or older who undergo BTKA are at increased risk [35,36]. Appropriate patient selection may be the key for a favorable surgical outcome, but this is beyond the scope of our study. The bias in retrospective analysis of medical records exists, regardless of whether the patients are at high or low risk. As a future research, identification of subgroups with favorable prognosis for BTKA or STKA would be a good guideline in clinical practice. We believe that the relative risk between frequency and time length of operation depends on a patient's characteristics and comorbid condition. Some patients may experience more severe postoperative complications after BTKA than other patients, depending on their age, sex, or comorbid condition [24,33,36]. Due to the absence of any prospective study, heterogeneity of treatment is not well understood either [37]. Further prospective studies would help identify the patient characteristics associated with favorable outcomes after BTKA or STKA.
Conclusion Although the safety of BTKA remains controversial, in general, BTKA has been believed to be riskier than STKA. However, our study demonstrated that the relative risk of the BTKA is overstated. Our study suggested that conclusions based on retrospective studies could be biased because the surgical plan at the time of the first surgery and the surgery eventually performed are not always the same in knee osteoarthritis patients. Intent-to-treat is unknown in most retrospective studies. The information gap on the relative postoperative complications between BTKA and STKA is largely due to the absence of a prospective study. This study calls for a prospective follow-up study for comparative effectiveness research, which is important for clinicians and patients to decide the best treatment.
Acknowledgment The authors wish to thank Drs Betty Guo and Jeffrey Elias at the UC Davis Clinical and Translational Science Center for editorial advice.
References 1. Jordan JM, Helmick CG, Renner JB, et al. Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the
1204 The Journal of Arthroplasty Vol. 26 No. 8 December 2011
2. 3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Johnston County Osteoarthritis Project. J Rheumatol 2007;34:172. Kippel J. Primer on the rheumatic disease. Atlanta, GA: Arthritis Foundation; 2001. Vastag B. Knee replacement underused, says panel: useful option when nonsurgical therapies fail. JAMA 2004;291: 413. Diduch DR, Insall JN, Scott WN, et al. Total knee replacement in young, active patients. Long-term followup and functional outcome. J Bone Joint Surg Am 1997; 79:575. Kim S. Morbid obesity and excessive hospital resource consumption for primary total hip and knee arthroplasty. The Journal of Arthroplasty In press; Kim S. Changes in surgical loads and economic burden of hip and knee replacements in the US: 1997-2004. Arthritis Rheum 2008;59:481. Kurtz S, Mowat F, Ong K, et al. Prevalence of primary and revision total hip and knee arthroplasty in the United States from 1990 through 2002. J Bone Joint Surg Am 2005;87:1487. Jain NB, Higgins LD, Ozumba D, et al. Trends in epidemiology of knee arthroplasty in the United States, 1990-2000. Arthritis Rheum 2005;52:3928. Kahn SR, Ginsberg JS. Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch Intern Med 2004;164:17. Clarke MT, Green JS, Harper WM, et al. Screening for deep-venous thrombosis after hip and knee replacement without prophylaxis. J Bone Joint Surg Br 1997;79:787. Stringer MD, Steadman CA, Hedges AR, et al. Deep vein thrombosis after elective knee surgery. An incidence study in 312 patients. J Bone Joint Surg Br 1989;71:492. Douketis JD, Eikelboom JW, Quinlan DJ, et al. Shortduration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of prospective studies investigating symptomatic outcomes. Arch Intern Med 2002;162:1465. Mantilla CB, Horlocker TT, Schroeder DR, et al. Frequency of myocardial infarction, pulmonary embolism, deep venous thrombosis, and death following primary hip or knee arthroplasty. Anesthesiology 2002;96:1140. Mahomed NN, Barrett J, Katz JN, et al. Epidemiology of total knee replacement in the United States Medicare population. J Bone Joint Surg Am 2005;87:1222. Davis MA, Ettinger WH, Neuhaus JM, et al. The association of knee injury and obesity with unilateral and bilateral osteoarthritis of the knee. Am J Epidemiol 1989;130:278. Leitch KK, Dalgorf D, Borkhoff CM, et al. Bilateral total knee arthroplasty–staged or simultaneous? Ontario's orthopedic surgeons reply. Can J Surg 2005;48:273. Barrett J, Baron JA, Losina E, et al. Bilateral total knee replacement: staging and pulmonary embolism. J Bone Joint Surg Am 2006;88:2146. Sliva CD, Callaghan JJ, Goetz DD, et al. Staggered bilateral total knee arthroplasty performed four to seven days apart during a single hospitalization. J Bone Joint Surg Am 2005;87:508. Memtsoudis SG, Ma Y, Gonzalez Della Valle A, et al. Perioperative outcomes after unilateral and bilateral total knee arthroplasty. Anesthesiology 2009;111:1206.
20. Kim S, Meenan PJ, Jamali AA. Changes in Medicare diagnosis related group (DRG) system for primary and revision hip and knee replacements and their implications on hospital reimbursement. Curr Orthopaedic Pract 2010 In Press. 21. March LM, Cross M, Tribe KL, et al. Two knees or not two knees? Patient costs and outcomes following bilateral and unilateral total knee joint replacement surgery for OA. Osteoarthritis Cartilage 2004;12:400. 22. Memtsoudis SG, Besculides MC, Reid S, et al. Trends in bilateral total knee arthroplasties: 153,259 discharges between 1990 and 2004. Clin Orthop Relat Res 2009; 467:1568. 23. Ritter MA, Harty LD, Davis KE, et al. Simultaneous bilateral, staged bilateral, and unilateral total knee arthroplasty. A survival analysis. J Bone Joint Surg Am 2003;85-A:1532. 24. Yoon HS, Han CD, Yang IH. Comparison of simultaneous bilateral and staged bilateral total knee arthroplasty in terms of perioperative complications. J Arthroplasty 2009. 25. Hutchinson JR, Parish EN, Cross MJ. A comparison of bilateral uncemented total knee arthroplasty: simultaneous or staged? J Bone Joint Surg Br 2006;88:40. 26. Bullock DP, Sporer SM, Shirreffs Jr TG. Comparison of simultaneous bilateral with unilateral total knee arthroplasty in terms of perioperative complications. J Bone Joint Surg Am 2003;85-A:1981. 27. Zeni Jr JA, Snyder-Mackler L. Clinical outcomes after simultaneous bilateral total knee arthroplasty comparison to unilateral total knee arthroplasty and healthy controls. J Arthroplasty 2009. 28. Kim YH, Choi YW, Kim JS. Simultaneous bilateral sequential total knee replacement is as safe as unilateral total knee replacement. J Bone Joint Surg Br 2009;91:64. 29. Restrepo C, Parvizi J, Dietrich T, et al. Safety of simultaneous bilateral total knee arthroplasty. A metaanalysis. J Bone Joint Surg Am 2007;89:1220. 30. Stefansdottir A, Lidgren L, Robertsson O. Higher early mortality with simultaneous rather than staged bilateral TKAs: results from the Swedish Knee Arthroplasty Register. Clin Orthop Relat Res 2008;466:3066. 31. Blom AW, Brown J, Taylor AH, et al. Infection after total knee arthroplasty. J Bone Joint Surg Br 2004;86:688. 32. Lachin JM. Statistical considerations in the intent-to-treat principle. Control Clin Trials 2000;21:167. 33. Oakes DA, Hanssen AD. Bilateral total knee replacement using the same anesthetic is not justified by assessment of the risks. Clin Orthop Relat Res 2004;87. 34. Memtsoudis SG, Gonzalez Della Valle A, Besculides MC, et al. In-hospital complications and mortality of unilateral, bilateral, and revision TKA: based on an estimate of 4,159,661 discharges. Clin Orthop Relat Res 2008;466:2617. 35. Lombardi AV, Mallory TH, Fada RA, et al. Simultaneous bilateral total knee arthroplasties: who decides? Clin Orthop Relat Res 2001;319. 36. Lynch NM, Trousdale RT, Ilstrup DM. Complications after concomitant bilateral total knee arthroplasty in elderly patients. Mayo Clin Proc 1997;72:799. 37. Kent DM, Alsheikh-Ali A, Hayward RA. Competing risk and heterogeneity of treatment effect in clinical trials. Trials 2008;9:30.
Operative Risk of Staged Bilateral Knee Arthroplasty is Underestimated in Retrospective Studies Sunny Kim, PhD,* John P. Meehan, MD,* and Richard White, MD, FACPy
Abstract: To find a safer surgical option, a number of studies have compared postoperative complications after bilateral total knee arthroplasty vs staged total knee arthroplasty (STKA) by contrasting postoperative complications collected retrospectively. However, we believe that a comparison based on retrospective studies could be biased. The purpose of this study was to demonstrate the misclassification bias associated with a retrospective study in comparing operative outcomes. Our analysis indicates that any conclusions based simply on retrospective analysis of subjects who successfully completed STKA is biased because it includes only cases that recovered after the first operation, rather than all of the patients who had planned STKA. In the absence of a prospective study to date, published studies should be interpreted with caution. Keywords: arthroplasty, TKA, operative risk, safety, complications. Published by Elsevier Inc.
Approximately 16.4% of the population 45 years and older in the United States has symptomatic osteoarthritis of the knee [1]. When nonsurgical treatment modalities have proved unsuccessful, total knee arthroplasty (TKA) is considered [2]. Joint arthroplasty effectively provide improved physical function as well as pain relief [3,4], and these surgical treatments have received widespread acceptance. Nearly one half million primary knee arthroplasties were performed during 2006 in the United States [5], and the number of surgeries is increasing at a steep rate [6-8]. Total knee arthroplasty is one of the most successful surgeries, but there are still risks of venous thrombosis, pulmonary embolism (PE), infection, bleeding, stroke, myocardial infarction, or even death. The most common complication after TKA is venous thrombosis. Deep vein thrombosis (DVT) often causes delayed hospital discharge. It also exposes patients to prolonged anticoagulation and the potential risk of postthrombotic syndrome. Postthrombotic syndrome, involving pain, swelling, and skin changes in the affected extremity,
From the *Department of Orthopaedic Surgery, University of California, Davis; and yDepartment of Internal Medicine, University of California, Davis. Submitted May 25, 2010; accepted January 2, 2011. The Conflict of Interest statement associated with this article can be found at doi:10.1016/j.arth.2011.01.004. Reprint requests: Sunny Kim, PhD, Department of Orthopaedic Surgery, 4860 Y Street, Suite 3800, Sacramento, CA 95817. Published by Elsevier Inc. 0883-5403/2608-0014$36.00/0 doi:10.1016/j.arth.2011.01.004
occurs in approximately 20% to 50% of patients within 1 to 2 years of an episode of DVT [9]. The greatest risk of DVT is its potential for life-threatening PE. In the absence of prophylaxis, TKA carries a risk of DVT in 56% to 66% of patients [10,11] and symptomatic PE in 1.9% [11]. Of the patients who received anticoagulant prophylaxis, the incidence of symptomatic nonfatal venous thrombosis is 1.4% to 3.0% and that of fatal PE is 0 to 0.12% [12,13]. Overall, mortality within 1 year after primary TKA is approximately 0.4%, and the median time to death is 9 days following primary TKA [13]. Among the Medicare population, the mortality during the 3 months after primary TKA is 0.7% [14]. Bilateral knee osteoarthritis is more prevalent than unilateral knee osteoarthritis [15]. Surgical options for patients with symptomatic bilateral knee osteoarthritis are (1) simultaneous bilateral TKA (BTKA) under 1 anesthesia and (2) staged TKA (STKA) with 2 distinct operations separated by a few days to years. Although there is no consensus regarding the time interval between 2 operations, most surgeons reported that they perform STKA within 1 year [16]. Among Medicare enrollees in the United States, approximately 72% of patient who underwent STKA had 2 surgeries within a year, and the remaining 28% had 2 surgeries between 1 and 2 years apart [17]. Although it is possible that patients can have 2 operations during the same hospitalization [18,19], in most cases, the first knee surgery (referred to as STKA-1 hereafter) is done during one hospitalization and the contralateral knee surgery
1198
Postoperative Risk of Bilateral Knee Arthroplasty Kim et al
(referred to as STKA-2 hereafter) is done during a subsequent hospitalization. The STKA is performed more frequently than BTKA. Staged TKA was 2.1 times more frequent than BTKA in the United States [17] and 2.4 times more frequent in Ontario [16]. Compared with STKA, BTKA is a convenient option for patients because it requires only 1 hospitalization and 1 recovery process. In addition, from a Medicare's perspective, BTKA is less costly compared with STKA [20]. The patient “out-of -pocket” cost is also less for BTKA compared with STKA [21]. From the health care system's perspective, given the steeply increasing demand of knee arthroplasty, BTKA can reduce some strain on hospitals and surgeons as well. Due to some benefits listed above, BTKA surgeries are increasing steeply in the United States [22]. However, the safety of BTKA has been questioned because BTKA requires longer operating time compared with STKA-1 or STKA-2. To find a safer surgical option for patients with bilateral knee osteoarthritis, a number of studies have compared postoperative complications of BTKA vs STKA based on retrospective analyses of medical records. Although some studies have demonstrated no significant increase in complications after BTKA compared with STKA [23-25], or even compared with unilateral TKA (UTKA) [26-28], other studies including meta-analyses reported that the postoperative complication is higher for BTKA compared with STKA [29,30]. In either case, we believed that these study results based on retrospective analyses of medical record may be
Plan at time of the first surgery (unknown)
Change after the first surgery
Observed one year after the first surgery (known)
P(A)
Unilateral
biased. Retrospective analysis of medical record fails to account for the patients who had planned STKA but who never completed the second stage due to death or a serious postoperative complication after the first operation, leading to cancellation of the second STKA (consequently, misclassified as UTKA). The purpose of this study was to demonstrate the misclassification bias in comparing postoperative complications. The issue of operative complications of knee arthroplasty is crucial in surgical treatment decision making. We demonstrated that STKA always appears to be safer than BTKA, even if the true proportion of postoperative complications were in fact the same.
Research Methods To demonstrate the bias, a mathematical derivation and graphical presentation were developed. Patients who changed the initial surgery plan independent of postoperative complication may not introduce systematic errors in comparing STKA and BTKA. However, if patients changed to receiving (or declining) STKA-2 based on the presence (or absence) of postoperative complications after STKA-1, this systematic error in the STKA group threatens the validity of the study. There are 2 major mechanisms of misclassifying patients into the STKA group in retrospective studies (Fig. 1). First, patients who had serious complications after STKA-1 tend to decline STKA-2 (dropout). For instance, a proportion of patients (denoted by P[B] in Fig. 1) who experienced major cardiac complications or stroke
Staged bilateral
Unilateral
1199
Simultaneous bilateral
P(B)
Staged bilateral
Simultaneous bilateral
P(A): Proportion of unilateral patients who proceed to have the second surgery after the satisfactory surgery experience P(B): Among patients who initially planned SKA, the proportion of patients with complications who did not pursue the second operation
Fig. 1. Direction of bias in comparing adverse outcomes after TKA in retrospective studies.
1200 The Journal of Arthroplasty Vol. 26 No. 8 December 2011 Table 1. Proportion of True and Observed Postoperative Complications in the Population Surgery Unilateral Staged Simultaneous
Adverse Outcome P11(P11 *) P21(P21 *) P31
No Adverse Outcome P12(P12 *) P22(P22 *) P32
Total P1.(P1. *) P2.(P2. *) P3. 1.00
* Corresponding observed proportions if observed and true proportions are different.
decline STKA-2. In an extreme case, a patient who dies from complications of STKA-1 does not have a chance to undergo STKA-2 and thus would be misclassified into the UTKA group despite the initial intention to undergo STKA. Second, among patients with bilateral osteoarthritis, we sometimes see a patient who initially plans UTKA but returns for contralateral TKA after having a successful first operation (denoted by P[A] in Fig. 1). It seems that some patients focus on the other knee only after the significantly more painful one has been repaired. Despite the initial intention to have UTKA, this patient would be misclassified as STKA in retrospective studies. Table 1 shows the true proportion and its corresponding observed proportion in parentheses. True proportion is the portion of patients who experienced postoperative
complications among who had planned (or intended) UTKA, STKA, or BTKA. Observed proportion is the portion of patients who experienced postoperative complications among who actually completed UTKA, STKA, or BTKA. Consider the proportion of patients Pxy in Table 1. Let its row number be x (x = 1 if unilateral, x = 2 if staged, and x = 3 is simultaneous bilateral) and its column number be y (y = 1 if patients experienced postoperative complication, and y = 2 if patients did not experience postoperative complication). The true probability P21 (row 2 column 1) is proportion of patients who experienced complications among those who intended STKA even if patients could not be recovered after the STKA-1. This true probability of an adverse event is unknown to researchers conducting retrospective studies because of a lack of information on intent-to-treat (ITT). Initial treatment plan is typically unknown when researchers do not have access to original charts. The probability of P21 is an observed proportion of patients who experienced complications after STKA-1 or STKA-2 among those who completed both STKA-1 and STKA-2. Because we have no basis to believe otherwise, the true probabilities of adverse events after STKA-1 and STKA-2 were assumed to be the same, for simplicity. To address 2 objectives of the study, a mathematical derivation and graphical presentation were used.
Results Bias in Estimating in Postoperative Risk After STKA To calculate the bias in the observed proportion of complications among patients who underwent STKA, the proportions of true and observed complications were compared. For the observed proportion of complications for STKA (P21*), the denominator and numerator can be defined as follows. Denominator for P21* (total number of observed patients with STKA). Let N denote the total number of knee arthroplasty procedures performed. As shown in Fig. 1, let P(A) be the proportion of UTKA patients who changed plans and had contralateral TKA after satisfactory UTKA. Let P(B) be the proportion of patients with complications who did not complete the initially planned STKA-2. The total number of observed patients who finished STKA is as follows. ½N × P2: + ½NP1: P12 P ð AÞ − ½NP2: × 0:5P21 × P ðBÞ The first term is the total number of patients who planned STKA. The second term is the number of patients who changed plans after satisfactory UTKA and instead also underwent STKA-2. The third term is the number of patients who declined STKA-2 due to complications from STKA-1. Numerator for P21* (total number of patient with complication among observed STKA groups). ½NP2: × 0:5P21 −½NP2: × 0:5P21 × PðBÞ + denominator × 0:5P21 The first term is the total number of patients who experienced complications after STKA-1 among those who initially planned STKA. The second term is the number of patients who declined STKA-2 due to complications from STKA-1; therefore, these patients were not classified into the STKA group in retrospective studies. The third term is the number of patients who experienced complications after STKA-2. P21* (observed proportion of patients with complications among those who finished STKA).
Postoperative Risk of Bilateral Knee Arthroplasty Kim et al
1201
For the observed proportion of complications from STKA, the denominator and numerator can be defined as follows. P21 4 =
½NP2: × 0:5P21 + ½NP2: −ðNP2: × 0:5P21 × P ðBÞÞ + ðNP1: P12 P ð AÞÞ × 0:5P21 − ½NP2: × 0:5P21 × P ðBÞ NP2: − ½NP2: × 0:5P21 × P ðBÞ + ½NP1: P12 P ð AÞ
We canceled out the total number of knee arthroplasties performed (denoted as N) in both the numerator and denominator of the equation. P21 4 =
½P2: × 0:5P21 − ½P2: × 0:5P21 × P ðBÞ + ½P2: − ½P2: × 0:5P21 × P ðBÞ + ½P1: P12 Pð AÞ × 0:5P21 ½P2: − ½P2: × 0:5P21 × PðBÞ + ½P1: P12 Pð AÞ
Mathematically, we were able to show that the function of bias, f(x) = P21*–P21 is always negative within the valid range of P21, which is between 0 and 1. If f(x) = 0, then no bias exist. Because the bias is always negative for all possible ranges of P21, this supports that P21* always underestimates P21. Therefore, the observed proportion of complications after STKA is always smaller than the true proportion of complications after STKA (that is, P21* b P21). Details of mathematical solution will be available from the corresponding author upon request. II. Simulation of Bias in Prevalence of Complication After STKA Bias in Comparing Postoperative Complications Between BTKA and STKA We calculated the observed proportion of complications (P21*) for the probable range of other parameters. In this simulation, the true postoperative complications value was set to be the same for BTKA and STKA. Because postoperative complications for BTKA and STKA were the same, the true odds ratio should be 1. True Odds Ratio =
P21 P22:
Odds of complication for STKA = =1 P31 Odds of complication for BTKA P32
However, if P21* is underestimated (= less than P21), then the observed odds ratio should be less than 1. Observed Odds Ratio
=
P21 4 P22:
Odds of complication for STKA = b1 P31 4 Odds of complication for BTKA P32
To demonstrate the bias for various ranges of P(A) and P(B) in Fig. 1, we calculated the odds ratio using the true complication rate of 1%, which is approximately the incidence of infection when antibiotic prophylaxis was used [31]. Among US Medicare enrollees who had an index TKA, approximately 78% were UTKA, 15% were STKA, and 7% were BTKA [17]. Therefore, we used P1. = 0.78, P2. = 0.15, and P3. = 0.07 in our simulation. Fig. 2 demonstrates the bias in odds ratio in comparing complications between STKA and BTKA. The complication rate used was 1%, which is approximately the infection incidence rate. In this simulation, the percentage of UTKA patients who had surgery on the other knee after satisfactory UTKA ranged from 1% to 25%. The percentage of patients with complications who declined STKA-2 ranged from 10% to 50%. The probability of P(A) played a significant role in distorting the true odds ratio. Although the true odds ratio was set as 1 in this simulation, the observed odds ratio ranged from 0.90 to 0.56 for 0.01 b P(A) b 0.25 and 0.1 b P(B) b 0.5 (Fig. 2). As shown in Table 2, if 10% of UTKA patients changed plans and had contralateral surgery after satisfactory UTKA (P(A) = 0.1) and a half of patients who experienced infection did not complete the initially planned STKA-2 (P(B) = 0.5), the odds of infection for STKA compared with BTKA appeared to be 0.61 when the true odds ratio was set as 1. Therefore, STKA appeared to be safer than BTKA when the actual infection risk was the same in our simulated data. We repeated the same simulation with a complication rate of 2.5%, which is approximately the symptomatic nonfatal DVT incidence after TKA. Because the postoperative risk is higher, the bias was slightly larger. Regardless, the conclusion was almost the same; the observed odds ratio ranged from 0.89 to 0.54 for 0.01 b P(A) b 0.25 and 0.1 b P(B) b 0.5 (Table 2). In an extreme case if a patient died from complications of STKA-1, then P(B) plays a significant role in distorting the true odds ratio in comparing mortality (Table 2). Patients died after STKA-1 cannot not have a chance to undergo STKA-2; therefore, P(B) is always equal to 1.0. As shown in Table 2, the odds of death for STKA appeared to be half compared with BTKA even if the actual mortality was the same in our simulated data.
1202 The Journal of Arthroplasty Vol. 26 No. 8 December 2011
Fig. 2. Observed odds ratio for postoperative complications between STKA and BTKA when the true odds ratio was set to 1.
Comments We illustrated the source of misclassification bias in comparing postoperative complications between BTKA and STKA. We also demonstrated that in retrospective analyses of medical records, the operative risk of STKA appeared to be lower than it truly is. A number of published studies have reported that BTKA has a higher risk of serious cardiac complications, pulmonary complications, and mortality [29,30]. However, our research suggests that study results based on retrospective analysis without considering the initial treatment plan are biased because STKA patients who had adverse outcomes are less likely to be identified in the STKA group; therefore, STKA appears to be a safer procedure than it truly is (conversely, the risk of BTKA is overstated). This type of bias is well recognized in prospective clinical trials; therefore, an ITT analysis is used to avoid a misleading conclusion [32]. Intent-totreat analysis in prospective clinical trials is based on the initial treatment intent rather the treatment eventually administered. In most retrospective studies, however, ITT is unknown, and this lack of information could lead to misclassifying patients into the wrong treatment group. Therefore, if a patient was dropped from the initial treatment plan, this is a more serious validity issue in retrospective studies because the patient can be
classified into another treatment group that was never intended. Many studies compared the operative risk between BTKA and STKA [17,19,23-26,29,30,33,34]. However, to our knowledge, no published study has adjusted for this misclassification bias. The study results based on biased data may not offer adequate guidelines for patient care. In the absence of a prospective study, published studies should be interpreted with caution. Without P(A) and P(B) estimates, we are unable to estimate the amount of bias in published studies. However, our simulation results help us to understand the previous study on the risk of mortality, which is seemingly counterintuitive; a study reported that the proportion of mortality within 30 days after UTKA is twice compared with that of STKA-2 (0.29% after UTKA and 0.14%-0.15% after STKA-2) [30]. We posit that this phenomenon is due to the fact that STKA-2 group includes only patients who were able to be recovered after the first operation. The safety of BTKAs remains controversial. A meta-analysis reported that the odds ratios for mortality following BTKA is 2.24, and it is significantly higher than STKA [29]. However, as shown in our simulation, the odds of death for BTKA in retrospective studies appeared to be 2 times larger compared with STKA, even if the actual mortality was the same in our simulated data. The elevated risk of
Postoperative Risk of Bilateral Knee Arthroplasty Kim et al Table 2. Observed Odds Ratios for Selected Postoperative Complications Between Staged Knee Arthroplasties and Simultaneous Knee Arthroplasties When the True Odds Ratio Was Set to 1 Types of Complication Infection P(B) P(A)
0.01 0.05 0.10 0.15 0.20 0.25
0.10
0.20
0.30
0.40
0.50
1.00
0.90 0.78 0.70 0.66 0.63 0.61
0.85 0.75 0.68 0.64 0.62 0.60
0.81 0.72 0.66 0.62 0.60 0.58
0.76 0.68 0.63 0.60 0.58 0.57
0.72 0.65 0.61 0.58 0.57 0.56
0.49 0.49 0.49 0.49 0.49 0.49
Symptomatic Nonfatal DVT P(B) P(A)
0.01 0.05 0.10 0.15 0.20 0.25
0.10
0.20
0.30
0.40
0.50
1.00
0.89 0.77 0.69 0.65 0.62 0.60
0.84 0.80 0.74 0.70 0.67 0.64 0.63 0.61 0.60 0.59 0.58 0.57 Death
0.75 0.67 0.62 0.59 0.57 0.56
0.71 0.64 0.60 0.57 0.55 0.54
0.47 0.47 0.47 0.47 0.47 0.47
P(B) P(A)
0.01 0.05 0.10 0.15 0.20 0.25
0.10
0.20
0.30
0.40
0.50
1.00
* * * * * *
* * * * * *
* * * * * *
* * * * * *
* * * * * *
0.49 0.49 0.49 0.49 0.49 0.49
* Not applicable. Odds ratios are underestimated due to a lack of ITT information. P(A): proportion of unilateral patients who proceed to have the contralateral surgery after the satisfactory surgery experience. P(B): the proportion of patients with complications who did not pursue the contralateral operation among who initially planned staged knee arthroplasties.
mortality associated with BTKA in previous studies could be, in part, due to the misclassification bias. To our knowledge, there are no published prospective studies that considered an initial surgery plan. In an effort to overcome difficulty in identifying the STKA group, some studies compared the relative risk between BTKA and STKA by assuming that the risk of STKA is twice that of UTKA [30,34]. However this approach is based on the improbable assumption that STKA and UTKA patients are comparable. Obesity is more strongly associated with bilateral osteoarthritis of the knee than with unilateral osteoarthritis [15]. Knee injury is a stronger predictor for unilateral OA. Therefore, patients with bilateral OA are likely to have an elevated risk of cardiovascular complications compared with patients with unilateral OA. Our study should be interpreted within the limitations of a simulated study. Because the percentage of patients
1203
failing to return for the STKA-2 after experiencing adverse events after STKA-1 is unknown, we performed simulations with a wide range of probabilities. Although we demonstrated that the postoperative risk after BTKA was overstated, the exact amount of bias remains elusive. In our simulation, we did not consider patient characteristics. In general, older patients or high-risk patients are more likely to undergo STKA than BTKA because studies support the hypothesis that patients 80 years or older who undergo BTKA are at increased risk [35,36]. Appropriate patient selection may be the key for a favorable surgical outcome, but this is beyond the scope of our study. The bias in retrospective analysis of medical records exists, regardless of whether the patients are at high or low risk. As a future research, identification of subgroups with favorable prognosis for BTKA or STKA would be a good guideline in clinical practice. We believe that the relative risk between frequency and time length of operation depends on a patient's characteristics and comorbid condition. Some patients may experience more severe postoperative complications after BTKA than other patients, depending on their age, sex, or comorbid condition [24,33,36]. Due to the absence of any prospective study, heterogeneity of treatment is not well understood either [37]. Further prospective studies would help identify the patient characteristics associated with favorable outcomes after BTKA or STKA.
Conclusion Although the safety of BTKA remains controversial, in general, BTKA has been believed to be riskier than STKA. However, our study demonstrated that the relative risk of the BTKA is overstated. Our study suggested that conclusions based on retrospective studies could be biased because the surgical plan at the time of the first surgery and the surgery eventually performed are not always the same in knee osteoarthritis patients. Intent-to-treat is unknown in most retrospective studies. The information gap on the relative postoperative complications between BTKA and STKA is largely due to the absence of a prospective study. This study calls for a prospective follow-up study for comparative effectiveness research, which is important for clinicians and patients to decide the best treatment.
Acknowledgment The authors wish to thank Drs Betty Guo and Jeffrey Elias at the UC Davis Clinical and Translational Science Center for editorial advice.
References 1. Jordan JM, Helmick CG, Renner JB, et al. Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the
1204 The Journal of Arthroplasty Vol. 26 No. 8 December 2011
2. 3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Johnston County Osteoarthritis Project. J Rheumatol 2007;34:172. Kippel J. Primer on the rheumatic disease. Atlanta, GA: Arthritis Foundation; 2001. Vastag B. Knee replacement underused, says panel: useful option when nonsurgical therapies fail. JAMA 2004;291: 413. Diduch DR, Insall JN, Scott WN, et al. Total knee replacement in young, active patients. Long-term followup and functional outcome. J Bone Joint Surg Am 1997; 79:575. Kim S. Morbid obesity and excessive hospital resource consumption for primary total hip and knee arthroplasty. The Journal of Arthroplasty In press; Kim S. Changes in surgical loads and economic burden of hip and knee replacements in the US: 1997-2004. Arthritis Rheum 2008;59:481. Kurtz S, Mowat F, Ong K, et al. Prevalence of primary and revision total hip and knee arthroplasty in the United States from 1990 through 2002. J Bone Joint Surg Am 2005;87:1487. Jain NB, Higgins LD, Ozumba D, et al. Trends in epidemiology of knee arthroplasty in the United States, 1990-2000. Arthritis Rheum 2005;52:3928. Kahn SR, Ginsberg JS. Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch Intern Med 2004;164:17. Clarke MT, Green JS, Harper WM, et al. Screening for deep-venous thrombosis after hip and knee replacement without prophylaxis. J Bone Joint Surg Br 1997;79:787. Stringer MD, Steadman CA, Hedges AR, et al. Deep vein thrombosis after elective knee surgery. An incidence study in 312 patients. J Bone Joint Surg Br 1989;71:492. Douketis JD, Eikelboom JW, Quinlan DJ, et al. Shortduration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of prospective studies investigating symptomatic outcomes. Arch Intern Med 2002;162:1465. Mantilla CB, Horlocker TT, Schroeder DR, et al. Frequency of myocardial infarction, pulmonary embolism, deep venous thrombosis, and death following primary hip or knee arthroplasty. Anesthesiology 2002;96:1140. Mahomed NN, Barrett J, Katz JN, et al. Epidemiology of total knee replacement in the United States Medicare population. J Bone Joint Surg Am 2005;87:1222. Davis MA, Ettinger WH, Neuhaus JM, et al. The association of knee injury and obesity with unilateral and bilateral osteoarthritis of the knee. Am J Epidemiol 1989;130:278. Leitch KK, Dalgorf D, Borkhoff CM, et al. Bilateral total knee arthroplasty–staged or simultaneous? Ontario's orthopedic surgeons reply. Can J Surg 2005;48:273. Barrett J, Baron JA, Losina E, et al. Bilateral total knee replacement: staging and pulmonary embolism. J Bone Joint Surg Am 2006;88:2146. Sliva CD, Callaghan JJ, Goetz DD, et al. Staggered bilateral total knee arthroplasty performed four to seven days apart during a single hospitalization. J Bone Joint Surg Am 2005;87:508. Memtsoudis SG, Ma Y, Gonzalez Della Valle A, et al. Perioperative outcomes after unilateral and bilateral total knee arthroplasty. Anesthesiology 2009;111:1206.
20. Kim S, Meenan PJ, Jamali AA. Changes in Medicare diagnosis related group (DRG) system for primary and revision hip and knee replacements and their implications on hospital reimbursement. Curr Orthopaedic Pract 2010 In Press. 21. March LM, Cross M, Tribe KL, et al. Two knees or not two knees? Patient costs and outcomes following bilateral and unilateral total knee joint replacement surgery for OA. Osteoarthritis Cartilage 2004;12:400. 22. Memtsoudis SG, Besculides MC, Reid S, et al. Trends in bilateral total knee arthroplasties: 153,259 discharges between 1990 and 2004. Clin Orthop Relat Res 2009; 467:1568. 23. Ritter MA, Harty LD, Davis KE, et al. Simultaneous bilateral, staged bilateral, and unilateral total knee arthroplasty. A survival analysis. J Bone Joint Surg Am 2003;85-A:1532. 24. Yoon HS, Han CD, Yang IH. Comparison of simultaneous bilateral and staged bilateral total knee arthroplasty in terms of perioperative complications. J Arthroplasty 2009. 25. Hutchinson JR, Parish EN, Cross MJ. A comparison of bilateral uncemented total knee arthroplasty: simultaneous or staged? J Bone Joint Surg Br 2006;88:40. 26. Bullock DP, Sporer SM, Shirreffs Jr TG. Comparison of simultaneous bilateral with unilateral total knee arthroplasty in terms of perioperative complications. J Bone Joint Surg Am 2003;85-A:1981. 27. Zeni Jr JA, Snyder-Mackler L. Clinical outcomes after simultaneous bilateral total knee arthroplasty comparison to unilateral total knee arthroplasty and healthy controls. J Arthroplasty 2009. 28. Kim YH, Choi YW, Kim JS. Simultaneous bilateral sequential total knee replacement is as safe as unilateral total knee replacement. J Bone Joint Surg Br 2009;91:64. 29. Restrepo C, Parvizi J, Dietrich T, et al. Safety of simultaneous bilateral total knee arthroplasty. A metaanalysis. J Bone Joint Surg Am 2007;89:1220. 30. Stefansdottir A, Lidgren L, Robertsson O. Higher early mortality with simultaneous rather than staged bilateral TKAs: results from the Swedish Knee Arthroplasty Register. Clin Orthop Relat Res 2008;466:3066. 31. Blom AW, Brown J, Taylor AH, et al. Infection after total knee arthroplasty. J Bone Joint Surg Br 2004;86:688. 32. Lachin JM. Statistical considerations in the intent-to-treat principle. Control Clin Trials 2000;21:167. 33. Oakes DA, Hanssen AD. Bilateral total knee replacement using the same anesthetic is not justified by assessment of the risks. Clin Orthop Relat Res 2004;87. 34. Memtsoudis SG, Gonzalez Della Valle A, Besculides MC, et al. In-hospital complications and mortality of unilateral, bilateral, and revision TKA: based on an estimate of 4,159,661 discharges. Clin Orthop Relat Res 2008;466:2617. 35. Lombardi AV, Mallory TH, Fada RA, et al. Simultaneous bilateral total knee arthroplasties: who decides? Clin Orthop Relat Res 2001;319. 36. Lynch NM, Trousdale RT, Ilstrup DM. Complications after concomitant bilateral total knee arthroplasty in elderly patients. Mayo Clin Proc 1997;72:799. 37. Kent DM, Alsheikh-Ali A, Hayward RA. Competing risk and heterogeneity of treatment effect in clinical trials. Trials 2008;9:30.