Pulmonary Embolism Prophylaxis in More Than 30,000 Total Knee Arthroplasty Patients: Is There a Best Choice?

Pulmonary Embolism Prophylaxis in More Than 30,000 Total Knee Arthroplasty Patients: Is There a Best Choice?

The Journal of Arthroplasty Vol. 27 No. 2 2012 Pulmonary Embolism Prophylaxis in More Than 30,000 Total Knee Arthroplasty Patients: Is There a Best C...

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The Journal of Arthroplasty Vol. 27 No. 2 2012

Pulmonary Embolism Prophylaxis in More Than 30,000 Total Knee Arthroplasty Patients: Is There a Best Choice? Monti Khatod, MD,* Maria C.S. Inacio, MS,y Stefano A. Bini, MD,z and Elizabeth W. Paxton, MAy

Abstract: Prophylaxis for pulmonary embolism (PE) prevention in total knee arthroplasty remains controversial. A joint registry evaluated venous thromboembolism prophylaxis and anesthesia impact on the incidence of PE, fatal PE, and death. Patients received mechanical prophylaxis alone or chemical with or without mechanical prophylaxis. The overall PE incidence was 0.45%; fatal PE, 0.01%; and death, 0.31%. The only significant difference in any outcome was the incidence of PE between Coumadin and mechanical prophylaxis alone. Variables associated with a higher incidence of PE were age, an American Society of Anesthesiologists score of 3 or higher, and the use of general anesthesia. Based on the findings, general anesthesia can be discouraged, and only Coumadin fared better than mechanical prophylaxis alone, whereas other forms of chemical prophylaxis revealed no significant differences. Keywords: knee arthroplasty, pulmonary embolism, prophylaxis, registry. © 2012 Elsevier Inc. All rights reserved.

Total knee arthroplasty (TKA) is a proven and effective treatment for arthritic knee pain [1,2]. The knee arthroplasty surgeon has the obligation to provide predictable pain relief while attempting to minimize complications. One known and potentially fatal complication is pulmonary embolism (PE). Thus, a primary goal of the arthroplasty surgeon is to avoid and possibly prevent PE and fatal PE. Significant debate exists regarding the optimal prophylaxis against PE, and conflicting national guidelines exist. These guidelines differ over whether they aim to prevent PE or deep venous thrombosis (DVT), a surrogate end measure for PE. Randomized controlled studies that measure PE rates after various interventions are prohibitive in size and cost due to the low incidence of symptomatic embolism. From the *Department of Orthopaedic Surgery, Southern California Permanente Medical Group, Baldwin Park, California; yDepartment of Surgical Outcomes and Analysis, Southern California Permanente Medical Group, San Diego, California; and zDepartment of Orthopaedic Surgery, The Permanente Medical Group, Oakland, California. Submitted January 19, 2011; accepted April 2, 2011. Source of funding: There was no external funding source. The Conflict of Interest statement associated with this article can be found at doi:10.1016/j.arth.2011.04.006. Reprint requests: Monti Khatod, MD, Department of Orthopaedic Surgery, Kaiser Permanente Baldwin Park, 1011 Baldwin Park Blvd. Baldwin Park, CA 91706. © 2012 Elsevier Inc. All rights reserved. 0883-5403/2702-0002$36.00/0 doi:10.1016/j.arth.2011.04.006

The American College of Chest Physician (ACCP) guidelines are based on the results of venographic studies [3,4], and Eikelboom and colleagues recently published a strong defense of these guidelines [5]. However, the American Academy of Orthopaedic Surgery has noted that reducing DVT rates has not been shown to reduce the rate of symptomatic or fatal PE after TKA [6]. In support of the latter position, The National Institutes of Health total knee arthroplasty consensus conference concluded that DVT prophylaxis does not alter the occurrence of symptomatic DVT or PE and further recommended a randomized, placebocontrolled trial [7]. Despite the lack of consensus on what constitutes effective prophylaxis against PE after TKA, public reporting of “appropriate” venous thromboembolism (VTE) prophylaxis as defined in the ACCP guidelines is occurring through the Surgical Care Improvement Program [8]. The Surgical Care Improvement Program is a collaborative effort between the Centers for Medicare and Medicaid Services (CMS) and The Joint Commission. In this study, we aim to shed some light on this controversy by reviewing the prospectively collected outcomes of prophylaxis after primary TKA in a large community-based total joint arthroplasty registry and report the rates of PE, fatal PE, and death for any reason within 90 days in relation to the prophylactic protocol and anesthetic selection. We also perform a multivariate


168 The Journal of Arthroplasty Vol. 27 No. 2 February 2012 analysis to evaluate if, after controlling for known confounders, differences in outcome still exist. Our aims are to determine if a best prophylactic agent exists for the prevention of postoperative PE, fatal PE or death, and the effect of other variables on PE rates.

Methods This study is a retrospective analysis of a prospectively collected cohort data using a large health maintenance organization Total Joint Replacement Registry (TJRR). The TJRR is reflective of the practice of 350 surgeons in 28 medical centers in California. The TJRR comprises clinical data entered by the clinician at the point of care in conjunction with data abstracted from administrative databases and electronic health records in an integrated health care delivery system [9]. The TJRR data collection forms include a preoperative, intraoperative, and status (postoperative). Surgeons and providers evaluating the patient complete these forms. The data collection methods of the TJRR have been previously described in the literature [9]. After a TKA is entered into its database, the TJRR then screens all electronic data sources available at our institution to determine if adverse events occurred postoperative; a chart review is then performed by a trained research assistant to determine whether any complications identified fit the Agency for Healthcare Research and Quality guidelines [10]. The large health maintenance organization where this study was conducted is an integrated health care organization, and patients receive their care almost entirely within our hospital system. When, rarely, care at an outside hospital is delivered, the patient is usually repatriated, and treatment and diagnostic codes are captured. Study Population Using the TJRR, we identified all primary, unilateral TKA procedures in patients with no history of DVT or PE performed between April 1, 2001, and March 31, 2008, within the organization's Southern California and Northern California regions (n = 30 020). The occurrence of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code V12.51 (disease of the circulatory system: venous thrombosis and embolism, PE) in the patient's electronic medical record or in the discharge diagnoses from the organization's hospital administrative database was used to identify history of disease of the circulatory systems, an exclusion criteria for this study. Prophylactic Groups The operating surgeon entered the intended type of PE prophylaxis and type of anesthesia used during surgery. The dosage and duration of prophylaxis are not captured in the TJRR. Prophylaxis information was obtained from the TJRR operative form. Surgeons can

choose from the major options of modern prophylaxis such as Coumadin, aspirin, anti-inflammatory, lowmolecular-weight heparin (LMWH), thromboembolism deterrent (TED) hose, foot pump, and sequential compression device, as well as a free-text option. Using these available categories, the prophylaxis-type groups were created: mechanical only, Coumadin, LMWH, aspirin, anti-inflammatory, combination chemical prophylaxis, and other. Within the chemoprophylactic groups, there were patients who also received adjuvant mechanical prophylaxis. For the purpose of this analysis, these patients were included in the chemoprophylactic category. Mechanical-only prophylaxis was defined by the use of a sequential compression device, TED hose, or foot pump as prophylaxis. For some analyses, the mechanical-only group was subdivided into those using TED hose only vs those using some other configuration of mechanical-only prophylaxis. General anesthesia was also studied to identify whether there was a different proportion of patients having PE, fatal PE, and death. Outcome of Interest: Adverse Events Adverse events were defined as PE (all), fatal PE, and death occurring within 90 days of surgery. The codes of ICD-9-CM used to define adverse events are part of an algorithm developed by the Agency for Healthcare Research and Quality to screen thromboembolic complications and is reported to have high sensitivity in capturing these events [10–12]. The ICD-9-CM codes used to identify PEs are as follows: 415.1, 415.11, and 415.19. This algorithm was used to search the whole organization's integrated electronic health record system, which includes inpatient hospital stays, outpatient, urgent care, emergency room, and ambulatory care visits. All diagnoses during a visit within 90 days postoperative were searched using the algorithm. Once a patient was noted as having a PE, his/her chart was then reviewed by a study coordinator to assure that the case was not a coding error and therefore properly confirm the adverse event. Either a positive computer tomography scan of the chest or a ventilation perfusion scan with moderate or high probability was required for the confirmation of a PE. This combined electronic screening for PEs and chart review assured that falsepositive cases, a possible limitation of this algorithm, was minimized. The principle investigator, blinded as to prophylaxis type, reviewed and approved all adverse events to ensure accuracy by reviewing each patient's charts a second time. Deaths were ascertained using the organization's membership information, which is periodically updated with patients' medical record information, county death records, and Social Security Administration Death Master Files. Deaths in which no information regarding cause of death could be obtained were labeled as unknown cause of death.

Pulmonary Embolism in TKA patients  Khatod et al

Because patients with unknown cause of death could have had a fatal PE, a separate worst-case scenario analysis was performed. Statistical Analyses Comparisons of rates of adverse events across VTE prophylaxis group and anesthesia type were analyzed using Pearson χ2 statistic, or, where necessary for lowfrequency categorical variables, Fisher exact test. A Kruskal-Wallis test was used to assess differences in age across prophylaxis groups. A binary logistic regression model was used to assess whether prophylaxis type was associated with PE while controlling for age (continuous), sex (female vs male), American Society of Anesthesiologists (ASA) category (1 and 2 vs 3 or more), and anesthesia type (other vs general anesthesia). Odds ratios and 95% confidence intervals (CIs) are provided for this analysis. Missing values were excluded from the regression models created. Using the same model, we performed a worst-case scenario analysis in which all deaths of unknown cause were considered deaths due to PE while being censored in the standard analysis. All reported P values were 2-sided and were considered to indicate statistical significance if the P value was less than .05. All analyses were performed using the SPSS program (SPSS for Windows Release 14.0.0; SPSS Inc, Chicago, Ill) or SAS statistical software (SAS version 9.1.3 SP4; SAS Institute, Cary, NC).

Results Study Population Patient demographics are presented in Table 1. Sixtyfour percent of cases were female, and b1% of unknown sex. Although 58% of cases were listed as ASA score of 1 Table 1. Frequencies and Proportions of Study Population Regional Area, Sex, ASA Category Mean, and Minimum and Maximum Study Population Age by Prophylaxis Type Region Sex

ASA category *

Northern California Southern California Female Male Unknown 1 or 2 ≥3 Unknown



14 019 16 001 19 101 10 637 282 17 451 10 926 1643

46.7 53.3 63.6 35.4 0.9 58.1 36.4 5.5




Overall Total Coumadin Total LMWH Total aspirin TED hose only Mechanical only, other

68.0 68.3 68.0 67.2 67.0 67.8

18-101 26-97 25-97 19-96 31-87 18-100

* ASA is a category physical status classification system for assessing a patient before surgery.


or 2, 5.5% of cases were missing an ASA rating. Mean age for the registry was 68 years, with a range from 18 to 101 years. Age varied significantly (P b .0001) across prophylaxis group; the aspirin group had the lowest mean age (67.2 years), and the Coumadin group had the highest (68.3 years). Anesthesia-type distribution was significantly different across the prophylaxis categories, with aspirin having the lowest percentage of general anesthesia (24.1%) and Coumadin having the highest (34.7%; P b .001). Prophylactic Groups The following numbers of patients were identified for each PE prophylaxis group: 3059, mechanical only; 9634, Coumadin (7708 with and 1926 without adjuvant mechanical prophylaxis); 10 662, LMWH (9128 with and 1534 without adjuvant mechanical prophylaxis); 3,777, aspirin (3479 with and 298 without adjuvant mechanical prophylaxis); 91, anti-inflammatory; 909, combination chemical prophylaxis; and 1,888, other (unknown). Adverse Events A total of 135 PEs (0.45%; 95% CI, 0.37%-0.53%) were identified, and 102 deaths (0.3%; 95% CI, 0.25%0.63%) occurred within 90 days of the index procedures. The median time for a PE to be diagnosed was 5 days (interquartile range, 2-15 days). Only 3 confirmed fatal PEs occurred in the entire cohort, with one occurrence in each prophylaxis group except for the aspirin group, which had none. In the worst-case scenario analysis, if all deaths due to an unknown cause were attributed to PE, then the overall PE rate rises to 0.57% (95% CI, 0.48%-0.65%), with 24 (0.86%; 95% CI, 0.52%-1.21%) occurrences in the mechanicalonly group, 41 (0.43%; 95% CI, 0.30%-0.56%) in the Coumadin group, 68 (0.64%; 95% CI, 0.49%-0.79%) in the LMWH group, and 21 (0.56%; 95% CI, 0.32%0.79%) in the aspirin group (P = .107). If all deaths due to unknown cases are attributed to PE, then the rate of fatal PE increases to 0.13% (95% CI, 0.09%-0.17%), and this is not statistically significantly different among the prophylactic choices either, P = .954. Stratified by prophylaxis group, all adverse events occurring within 90 days after primary TKA are presented in Table 2. Outcomes stratified by general anesthesia status are shown in Table 3. Looking specifically at overall raw PE incidence (Table 2), there is a 0.38% difference between the lowest group, Coumadin, at 0.32%, and the highest, mechanical only, at 0.72%. Our hypothesis that no difference exists between these groups was false, P = .039. There is, however, no significant difference in incidence of events across prophylaxis categories for the other outcomes of fatal PE and death. Also, in Table 2, we can see the proportion of PEs when the mechanical-only category is subdivided

170 The Journal of Arthroplasty Vol. 27 No. 2 February 2012 Table 2. Frequencies, Proportions, and 95% CIs of 90-day Postoperative Outcomes PE, Fatal PE, and Mortality by Prophylaxis Group Total Type of Prophylaxis Total No. of patients TED hose only Mechanical only * Aspirin total Aspirin with mechanical Aspirin without mechanical Coumadin total Coumadin with mechanical Coumadin without mechanical LMWH total LMWH with mechanical LMWH without mechanical Other † Unknown


Fatal PE






95% CI



95% CI



95% CI

30 020 280 2779 3777 3479 298 9634 7708 1926 10 662 9128 1534 1000 1888

100.00 0.93 9.26 12.58 11.59 0.99 32.09 25.68 6.42 35.52 30.41 5.11 3.33 6.29

135 1 20 16 15 1 31 23 8 55 47 8 4 8

0.45 0.36 0.72 0.42 0.43 0.34 0.32 0.30 0.42 0.52 0.51 0.52 1.43 0.42

(0.37-0.53) (0.00-1.06) (0.41-1.03) (0.22-0.63) (0.21-0.65) (0.00-0.99) (0.21-0.43) (0.18-0.42) (0.13-0.70) (0.38-0.65) (0.37-0.66) (0.16-0.88) (0.69-2.16) (0.13-0.72)

4 0 1 0 0 0 1 1 0 1 1 0 1 0

0.01 0.00 0.04 0.00 0.00 0.00 0.01 0.01 0.00 0.01 0.01 0.00 0.11 0.00

(0.00-0.03) (0.00-0.00) (0.00-0.11) (0.00-0.00) (0.00-0.00) (0.00-0.00) (0.00-0.03) (0.00-0.04) (0.00-0.00) (0.00-0.03) (0.00-0.03) (0.00-0.00) (0.00-0.32) (0.00-0.00)

94 0 9 8 7 1 28 23 5 36 27 9 6 7

0.31 0.00 0.32 0.21 0.20 0.34 0.29 0.30 0.26 0.34 0.30 0.59 1.65 0.37

(0.25-0.63) (0.00-0.00) (0.11-0.65) (0.07-0.42) (0.05-0.40) (0.00-0.67) (0.18-0.58) (0.18-0.58) (0.18-0.60) (0.03-0.52) (0.18-0.59) (0.20-1.17) (0.86-3.30) (0.10-0.74)

* Excludes TED Hose. † Other = combination of mechanical and chemical as well as chemical only.

into TED hose only, and all other prophylaxis groups' rates can be evaluated with or without mechanical prophylaxis. With respect to anesthesia type, the incidence of PE differed significantly (P = .005) between general anesthesia (0.60%; 95% CI, 0.44%-0.76%) and non– general anesthesia (0.40%; 95% CI, 0.31%-0.49%), as shown in Table 3. Incidence of death or fatal PE did not differ by type of anesthesia. The results of the logistic regression analysis are shown in Table 4. Age is a significant risk factor for PE, with the odds of PE increasing 2% for each additional year of age (95% CI, 0%-4%), but sex showed no association with increase odds of an event. American Society of Anesthesiologists category of 3 or more vs 1 or 2 was a significant risk factor, raising the odds of PE by 67% (95% CI, 15%– 143%). General anesthesia was also found to be a significant risk factor compared to non–general anesthesia, increasing the odds of an event by 67% (95% CI, 14%-144%; P = .009). When controlling for age, ASA score, and anesthesia type, Coumadin was the only group significantly protective against PE when compared with mechanical prophylaxis only (excluding TED hose alone), reducing the odds of PE by 54% (95% CI, 17%-74%; P = .010).

Discussion The results from this study provide clinically relevant outcomes for the practice of PE prevention in unilateral TKA surgery. Data are abstracted from a large contemporary community-based total joint registry, which is reflective of practice in the United States [13]. The data integrity is high because each complication is manually reviewed for accuracy, thus decreasing the potential for coding errors. Furthermore, our patient population is very stable, with no patients lost to follow-up in this study. Statistically, unadjusted PE rates differ significantly across prophylaxis categories, with Coumadin having the lowest rate (0.30%) and mechanical only the highest (0.70%; P = .039). Separating out patients who used TED hoses alone changes the P value of the analysis to a trend (P = .058). According to the ACCP review, patients who underwent TKA develop a 1.5% to 10% prevalence of total PE and a 0.1% to 1.7% prevalence of fatal PE [4]. Our data reveal a PE rate of only 0.45% and a fatal PE rate of only 0.01%. In our cohort, there appears to be a high overall success of all prophylactic methods, as we observed an extremely low rate of PE and no difference in death rate among the groups. Furthermore, our report of very low rates of PE underscores the fact that the higher rates of PE used in the ACCP guidelines to

Table 3. Frequencies, Proportions, and 95% CIs of 90-day Postoperative Outcomes, PE, and Mortality by Anesthesia Status PE *

Total Other type of anesthesia General anesthesia Total

Mortality (NS)





95% CI



95% CI

20 492 9528 30 020

68.26 31.74 100.00

77 58 135

0.40 0.60 0.40

(0.09-0.31) (0.44-0.76) (0.33-0.47)

69 33 102

0.30 0.30 0.30

(0.23-0.37) (0.19-0.41) (0.24-0.36)

NS indicates not statistically significant. * P = .005.

Pulmonary Embolism in TKA patients  Khatod et al Table 4. Binary Logistic Regression Model for the Association of PE and Prophylaxis Type and General Anesthesia While Adjusting for Age, Sex, and ASA Category (Odds Ratios, 95% CIs, P Values) * Odds Ratio Age (per 1-y increase) Sex: female vs male ASA category: ≥3 vs 1 or 2 Prophylaxis: Coumadin vs mechanical only Prophylaxis: LMHW vs mechanical only Prophylaxis: aspirin vs mechanical only Prophylaxis: TED hose only vs mechanical only General anesthesia (yes vs no)

95% CI


1.02 1.06 1.67 0.46

(1.00-1.04) (0.72-1.57) (1.15-2.43) (0.26-0.83)

.049 .753 .007 .010













* Model n = 25 388, excludes those with missing value for age, sex, or ASA category (n = 4632).

justify their recommendations are of historical interest and may no longer be relevant in the context of modern rehabilitation protocols. A contemporary study using large populations with clinically relevant outcomes of proximal DVT and PE should be undertaken before public reporting of treatment protocols is implemented. The rarity of PE in any treatment arm underscores the importance of the multivariate regression analysis, which adjusts for the different distributions of age, sex, ASA category, and anesthesia type within each of the treatment arms. Both ASA score of 3 or more and general anesthesia revealed marked increased odds of PE by 67%. Increasing age was also found to significantly increase the odds of PE by 2% per year. A direct comparison between the Coumadin and mechanicalonly (excluding TED hose) groups demonstrated a significant odds ratio of 0.46 in favor of Coumadin. Our approach takes into account the complex interplay of variables that can contribute to PE, and the variety of strategies that can be used, either alone or in combination, to prevent it. To our knowledge, no other modern, English language study has directly compared Coumadin with mechanical prophylaxis. The most recent study by Hodge [14] in 1991 found no difference between the 2 prophylactic choices in 129 patients enrolled in a venographic study. Mechanical prophylaxis alone and in combination with aspirin has been supported in the literature as a viable option for DVT and PE prophylaxis in TKA and reported to be superior to aspirin alone in one study [15,16]. Of note, we believe that we are the first to document that non–general anesthesia significantly reduces the PE rate in TKA patients. This is consistent with studies that show that neuraxial anesthesia improves venous blood flow and reduces pulmonary complications [17–19]. We believe that this is an important new finding, as prior


studies looking at VTE rates frequently did not account for anesthesia type and may have a higher percentage of general anesthesia usage. This further supports our opinion that these older studies may no longer reflect common practice in the community and should be used with caution in the creation of clinical guidelines. Moreover, the use of modern rehabilitative techniques such as rapid mobilization, anti-inflammatory medications, peripheral nerve blocks, and indwelling peripheral catheters needs to be taken into account when comparing current studies with past research or meta-analyses that include older data. Early mobilization, especially walking, has been shown to activate the venous plexus on the sole of the foot and reduce thrombus formation [20]. Limitations of this study include the use of administrative database for outcomes detection. Administrative databases may include coding errors leading to overdiagnosis or underdiagnosis of a particular outcome [21]. To limit coding errors, we limited the outcomes of interest to diagnoses that would lead to admission. We further validated our outcome data by manual chart review to minimize the potential for inaccuracy. Ours is a level II prospective observational cohort study that is not randomized, and therefore, clinical usage bias may have occurred. We attempted to minimize this potential bias by excluding bilateral TKA, revision TKA, and patients with a history of DVT or PE. Furthermore, a logistic regression analysis adjusts for confounding variables among the prophylactic options. Not all patients' cause of death could be determined. This could result in the underrepresentation of fatal PE in our outcomes analysis. We therefore ran a best- and worst-case scenario, which revealed no difference in PE or fatal PE outcome relative to prophylactic choice. The methodology in determining the outcome of fatal PE was the same for all prophylactic choices and did not bias the possibility of missing a fatal PE from one choice over another. Proximal DVT, wound drainage, hemarthrosis, reoperation for bleeding complications, and other systemic bleeding complications are all clinically relevant outcomes associated with VTE prophylaxis but are not reported here. In one study, an institution chose to abandon the use of ACCP grade 1A recommendations, use of LMWH, due to an unacceptably high rate of postoperative bleeding complications [22]. Other clinically important variables that were beyond the scope of this study were duration of surgery, dosage of the agents used, timing of initial administration, and length of duration of prophylaxis. Strengths of this study are the complete follow-up of an extremely large cohort of TKA patients treated using modern rehabilitative protocols in a community setting. It therefore reflects real-world experience on the effectiveness of these agents in clinical practice. Furthermore, the outcomes data from the registry are highly

172 The Journal of Arthroplasty Vol. 27 No. 2 February 2012 specific and validated. The use of PE rather than venographic DVT as the end point of the study avoids the use of surrogate variables and is therefore more clinically relevant. Several important new findings from this research are that age, ASA category, and anesthesia type are significant and independent risk factors for PE after primary TKA. The data suggest that risk stratification of patients may further reduce the overall incidence of both VTE and complication from VTE prophylaxis. In conclusion, arthroplasty surgeons using modern rehabilitation techniques involving early mobilization are performing a highly successful operation with a low incidence of PE and death. No matter what prophylactic regimen is chosen, aspirin included, the reported adverse outcome rates are far lower than historically reported [4]. Coumadin was found to have a significantly lower rate of PE than mechanical prophylaxis alone, and non–general anesthesia was found to be significantly protective of PE vs general anesthesia. It should be noted, however, that the relative differences in PE rates were never greater than 0.5% between treatment groups. In more than 30 000 TKAs, only 3 confirmed fatal PEs were identified.

Acknowledgments The authors would like to thank all Kaiser Permanente orthopedic surgeons and the staff of the Department of Surgical Outcomes and Analysis who have contributed to the success of the National Total Joint Replacement Registry.

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