The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 93, Issue 14

Scientific Articles | July 20, 2011

Venous Thromboembolism in Patients Having Knee Replacement and Receiving Thromboprophylaxis: A Danish Population-Based Follow-up Study

Alma B. Pedersen, MD, PhD¹; Frank Mehnert, MSc¹; Soren P. Johnsen, MD, PhD¹; Steen Husted, MD, DMSc²; Henrik T. Sorensen, MD, DMSc¹

¹ Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Alle 43-45, 8200 Aarhus N, Denmark. E-mail address for A.B. Pedersen: abp@dce.au.dk. E-mail address for F. Mehnert: fm@dce.au.dk. E-mail address for S.P. Johnsen: spj@dce.au.dk. E-mail address for H.T. Sorensen: hts@dce.au.dk
² Department of Cardiology, Aarhus University Hospital, Tage Hansensgade 2, 8000 Aarhus C, Denmark. E-mail address: steehust@rm.dk

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Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. None of the authors, or their institution(s), have had any financial relationship, in the thirty-six months prior to submission of this work, with any entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, no author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by the authors of this work are available with the online version of this article at jbjs.org.

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Investigation performed at the Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark

A commentary by Seth S. Leopold, MD, is linked to the online version of this article at jbjs.org.

J Bone Joint Surg Am, 2011 Jul 20;93(14):1281-1287. doi: 10.2106/JBJS.J.00676

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Abstract

Background:

We examined the rate of venous thromboembolism, as well as changes over time, in a population-based cohort of patients who underwent knee arthroplasty.

Methods:

Using medical databases, we identified all patients who underwent primary knee arthroplasties with pharmacological thromboprophylaxis performed in Denmark from 1997 to 2007. The outcome was hospitalization with symptomatic venous thromboembolism within ninety days of surgery. We examined several potential patient and surgery-related predictors for venous thromboembolism using Cox regression analyses.

Results:

The overall rate of hospitalization for venous thromboembolism among 37,223 patients within ninety days after primary knee arthroplasty was 1.2% (441 patients) at a median of fifteen days. The rate of hospitalization was 0.9% (323 patients) for deep venous thrombosis and 0.3% (127 patients) for pulmonary embolism, with nine patients who had both. The rate of venous thromboembolism increased during the ten-year study period. Patients with a high score on the Charlson comorbidity index had an increased relative risk for venous thromboembolism compared with patients with a low score (adjusted relative risk = 1.73; 95% confidence interval, 1.24 to 2.41). Patients with a history of cardiovascular disease or a previous venous thromboembolism had an increased risk for postoperative venous thromboembolism compared with patients without these conditions. Surgery-related factors were not predictors for venous thromboembolism.

Conclusions:

Despite pharmacological thromboprophylaxis, patients undergoing knee arthroplasty remain susceptible for venous thromboembolism events after surgery. Future efforts should focus on the improvement of prophylaxis following hospital discharge, particularly among elderly patients and those with a history of cardiovascular diseases or previous venous thromboembolism.

Level of Evidence:

Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.

Figures in this Article

Introduction

The rate of knee arthroplasty has increased substantially worldwide¹, and continued increases are anticipated in the future². Venous thromboembolism, including deep venous thrombosis and pulmonary embolism, are serious complications in patients undergoing knee arthroplasty. Prophylactic measures are implemented to reduce their occurrence³. Although the efficacy of these measures is high, their effectiveness in routine clinical practice is more uncertain. Reported rates of deep venous thrombosis (symptomatic and asymptomatic) three months after knee arthroplasty are approximately 40% to 50%^4,5 in patients without thromboprophylaxis and 16% to 27% in patients receiving thromboprophylaxis^6,7. In the latter group, the rate of symptomatic venous thromboembolism (or death) has been reported as 1.3% to 2.3%^6-8; symptomatic deep venous thrombosis, as 1.4%⁹; and pulmonary embolism, as <0.8%^9,10. Asymptomatic deep venous thrombosis is common^5,11, and most thrombi resolve spontaneously⁵. Data describing the change in the occurrence of venous thromboembolism over the last ten to fifteen years^12,13 have been inconsistent. A recent review of randomized controlled trials showed a decline in the rate of deep venous thrombosis over time among patients undergoing knee replacement and receiving thromboprophylaxis¹⁴. Several predictors for venous thromboembolism have been reported. A history of a thromboembolism has been associated with increased risk of symptomatic venous thromboembolism following knee replacement in some⁸, but not all^15-17, studies. Two investigations^8,18 found female sex as a risk factor for venous thromboembolism, but this was not confirmed by others^16,17. The presence of a malignant lesion is a risk factor for venous thromboembolism in general¹⁹, but not among patients undergoing total hip and knee arthroplasty, or hip fracture surgery¹⁷.

We conducted a nationwide follow-up study in Denmark to provide accurate estimates of the rate and changes over time of symptomatic venous thromboembolism events among patients undergoing knee arthroplasty and receiving pharmacological thromboprophylaxis, and to identify factors associated with increased risk of venous thromboembolism in these patients.

Materials and Methods

Study Design

The Danish National Health Service provides tax-supported health care for all Danish citizens, guaranteeing free medical care for both emergency and general admissions to hospitals and outpatient clinics. Denmark has a total population of approximately 5.5 million inhabitants. The population-based follow-up design of this study utilized data from prospective, nationwide Danish medical registries^20-22. The Danish Knee Arthroplasty Registry contains data on primary knee arthroplasties and revisions performed in Denmark since 1997. This registry is a nationwide population-based clinical database approved by the Danish National Board of Health. The Danish Knee Arthroplasty Registry cooperates closely with the Danish Hip and Shoulder Arthroplasty Registries, as well as the Danish Cruciate Ligament Registry, as a part of the Danish Orthopedic Common Database. The primary aim of the Danish Knee Arthroplasty Registry is to evaluate quality improvement of knee arthroplasty in Denmark. This is achieved through the continuous audit of measured quality indicators for surgery performance and feedback to participating departments, which enable comparison of results across departments and hospitals, as well as comparison with the national average. All forty-five orthopaedic departments in Denmark, including twelve private hospitals, provide data to this registry. Preoperative and perioperative data are provided by the operating surgeon. The Danish National Registry of Patients holds data on all admissions to public and private nonpsychiatric hospitals in Denmark since 1977²¹. Its records include dates of all admissions and discharges and up to twenty diagnoses for each admission. Diagnoses are classified according to the International Classification of Diseases (ICD), ICD-8 before 1993 and ICD-10 thereafter. All diagnoses are coded by the physician discharging the patient. We scanned the Danish National Registry of Patients both to identify the study outcome and to compile each patient's entire hospitalization history prior to surgery. The Danish Civil Registration System holds data on vital status, date of death, residence, and migration for the entire Danish population since 1968. All Danish citizens are assigned a unique ten-digit personal identification number at birth or on immigration, permitting unambiguous linkage among all Danish administrative registries, as well as tracking of patients who died, emigrated, or were admitted to different hospitals²².

Patients

We identified all patients who underwent primary knee arthroplasty and also received pharmacological thromboprophylaxis from January 1, 1997, to December 31, 2007, from the Danish Knee Arthroplasty Registry. During the same time period, only 0.5% of patients having a knee replacement in Denmark did not receive pharmacological thromboprophylaxis and these patients are excluded from our study. We excluded bilateral primary knee replacements performed during a one-stage procedure (1196 procedures in 598 patients) because of the associated increase in venous thromboembolism risk^23,24. Data on 37,223 primary knee arthroplasties, including 25,871 patients with one knee procedure and 5676 patients with procedures on both knees (11,352 procedures in so-called two-stage procedures), were available for analysis. The patient would typically first come to an outpatient clinic for clinical evaluation, laboratory tests, and radiographs and would be assigned a surgery date. The patient would then be admitted on the day before surgery and remain hospitalized for an average of seven days before discharge home. The postoperative rehabilitation of these patients is done at home.

Study Outcome

The study outcome was the time to hospitalization with symptomatic nonfatal venous thromboembolism within ninety days following primary knee replacement, as well as venous thromboembolism occurring during the primary hospitalization for knee replacement. Both primary and secondary discharge diagnoses of deep venous thrombosis or pulmonary embolism (ICD-10 codes I26, I80.1 to I80.9, and I82.1 to I82.9) from the Danish National Registry of Patients were included. We excluded seventy-seven patients who were seen only in the emergency room because of a low validity of the venous thromboembolism diagnosis²⁵. Studies on the validity of venous thromboembolism diagnosis in the Danish National Registry of Patients showed that the venous thromboembolism diagnosis is based on symptomatic events, confirmed by ultrasonography, venography, high-probability lung scanning, or computed tomographic angiography, according to current diagnostic guidelines and their application^26,27.

Predictors for Venous Thromboembolism

Available potential predictors for venous thromboembolism are presented in a table (see Appendix). The indication (diagnosis) for primary knee replacement termed secondary osteoarthritis included sequelae of tibial, femoral, and patellar fractures. The category of anesthesia termed other included an epidural in combination with spinal anesthesia, regional changed to general anesthesia, and lumbosacral or regional blockade. Information on all predictors except for comorbidity was collected from the Danish Knee Arthroplasty Registry. As a measure of comorbidity, we calculated a Charlson comorbidity index²⁸, described in detail elsewhere²⁹, at the time of surgery. We defined three comorbidity levels according to the Charlson comorbidity index: a score of 0 (low), given to patients with no previously recorded disease categories included in the index; a score of 1 to 2 points (medium); and a score of ≥3 points (high)³⁰. We also examined whether specific comorbidities prior to the knee surgery (see Appendix) were associated with venous thromboembolism risk following knee replacement. Information on these predictors was obtained from the Danish National Registry of Patients with use of ICD-8 and ICD-10 discharge diagnoses for fifteen years prior to surgery for each patient. Length of hospital stay (less than six days, seven to ten days, and more than eleven days) was studied in relation to the risk of venous thromboembolism.

Statistical Methods

The follow-up period began on the day of primary knee arthroplasty and ended on the day of rehospitalization with the first venous thromboembolism; the day of discharge from the primary hospitalization for knee arthroplasty if the venous thromboembolism occurred during the primary hospitalization; or on the date of death, emigration, or ninety days after surgery. We calculated the cumulative rate of venous thromboembolism and the median time to hospitalization with venous thromboembolism. A marginal Cox model with a common baseline hazard function (Wei-Lin-Weissfeld model) was used to examine the association between potential predictors and time to hospitalization with venous thromboembolism within ninety days of surgery, accounting for clustering within hospitals. We estimated a hazard ratio as a measure of relative risk (RR), with a 95% confidence interval (CI) for each factor, mutually adjusted for all possible predictors. The assumption of the Cox hazard model was assessed graphically with use of log-log plots and found suitable. The study was approved by the Danish Data Protection Agency.

Source of Funding

There was no external funding source.

Results

From the Danish Knee Arthroplasty Registry, we identified 37,223 primary knee arthroplasties performed from January 1, 1997, to December 31, 2007, in patients who had pharmacological thromboprophylaxis. The majority of patients received treatment with low-molecular-weight heparin (33% received dalteparin [Fragmin], 33% received enoxaparin [Klexane], 15% received tinzaparin [Innohep], 2% received fondaparinux [Arixtra]), and the rest of the patients received a mixed group of other drugs in the short preoperative and postoperative period. Characteristics of the study population are presented in a table (see Appendix).

Rate of Venous Thromboembolism

A total of 441 (1.2%) of 37,223 patients who had primary knee arthroplasty and received pharmacological thromboprophylaxis were hospitalized with venous thromboembolism within ninety days after surgery, at a median of fifteen days (25th to 75th percentile: eight to thirty-two days). Within ninety days, the rate of deep venous thrombosis was 0.9% (323 of 37,223) and that of pulmonary embolism was 0.3% (127 of 37,223), with nine patients hospitalized with both deep venous thrombosis and pulmonary embolism. Of the 441 patients hospitalized with venous thromboembolism, seventy-seven (17.5%) were, after initial hospitalization, treated as outpatients for the remainder of the venous thromboembolism course. Sixty-eight (21%) of the 323 patients initially hospitalized with deep venous thrombosis were later treated as outpatients, whereas ten (7.9%) of the 127 patients initially hospitalized with a pulmonary embolism were later treated as outpatients. Among patients hospitalized with venous thromboembolism, 145 (32.9%) were admitted to orthopaedic departments and 296 (67.1%) were admitted to other departments, mainly general internal medicine. The rate of venous thromboembolism (441 patients who had nonfatal symptomatic venous thromboembolism and 161 deaths due to all causes) within ninety days of surgery was 1.6%.

Strikingly, the overall rate of hospitalization with venous thromboembolism increased over the study period. Compared with patients undergoing a knee replacement procedure during 1997 to1999, patients who underwent that procedure in 2000 to 2003 had an adjusted RR of 1.35 (95% CI, 0.90 to 2.02) and those undergoing surgery in 2004 to 2007 had an adjusted RR of 1.28 (95% CI, 1.05 to 1.57) (Table I). The length of hospital stay did not influence the overall risk for venous thromboembolism (Table I), but the risk for deep venous thrombosis was elevated for patients who were hospitalized for more than eleven days (adjusted RR = 1.64; 95% CI, 1.16 to 2.33) compared with those hospitalized less than six days.

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TABLE I Risk of Hospitalization with Venous Thromboembolism within Ninety Days Following Primary Knee Arthroplasty

Predictors	Venous Thromboembolism (no. of patients)	Crude Relative Risk* (95% CI)	Adjusted Relative Risk† (95% CI)
Sex
Female	273 (1.15%)	1.0 (reference)	1.0 (reference)
Male	168 (1.25%)	1.09 (0.88-1.35)	1.08 (0.86-1.35)
Age (yr)
10-49	15 (0.86%)	1.0 (reference)	1.0 (reference)
50-59	66 (1.09%)	1.26 (0.78-2.05)	1.26 (0.76-2.11)
60-69	139 (1.15%)	1.33 (0.88-2.01)	1.29 (0.83-2.01)
70-79	153 (1.23%)	1.44 (0.93-2.22)	1.40 (0.85-2.33)
≥80	68 (1.41%)	1.65 (1.11-2.43)	1.58 (1.01-2.47)
Primary knee diagnosis
Primary osteoarthritis	361 (1.20%)	1.0 (reference)	1.0 (reference)
Secondary osteoarthritis	52 (1.31%)	1.09 (0.82-1.45)	1.16 (0.85-1.57)
Rheumatoid arthritis	12 (0.74%)	0.61 (0.39-0.97)	0.61 (0.38-0.98)
Other diagnoses	16 (1.00%)	0.83 (0.43-1.59)	0.86 (0.42-1.67)
Charlson comorbidity index
Low score (0)	279 (1.10%)	1.0 (reference)	1.0 (reference)
Medium score (1-2)	126 (1.25%)	1.13 (0.92-1.38)	1.14 (0.93-1.41)
High score (≥3)	36 (1.95%)	1.78 (1.30-2.45)	1.73 (1.24-2.41)
Specific comorbidities‡
Previous deep venous thrombosis and pulmonary embolism	56 (6.00%)	5.78 (4.37-7.65)	5.30 (3.99-7.05)
Cardiovascular diseases	66 (1.59%)	1.41 (1.10-1.81)	1.33 (1.01-1.74)
Liver and kidney diseases	13 (1.72%)	1.48 (0.92-2.37)	1.49 (0.92-2.42)
Cancer within one year before surgery	2 (0.9%)	0.76 (0.22-2.64)	0.57 (0.16 -2.02)
Cancer more than a year before surgery	37 (1.2%)	0.99 (0.72-1.36)	0.69 (0.48-1.00)
Diabetes	22 (1.33%)	1.13 (0.70-1.82)	1.07 (0.66-1.73)
Surgery type
Total knee	419 (1.22%)	1.0 (reference)	1.0 (reference)
Partial knee (medial or lateral)	18 (0.73%)	0.60 (0.35-1.04)	0.57 (0.32-1.02)
Other surgery	4 (1.31%)	1.08 (0.47-2.45)	1.04 (0.43-2.54)
Laterality
One knee replaced	322 (1.24%)	1.0 (reference)	1.0 (reference)
Both knees replaced	119 (1.05%)	0.84 (0.69-1.03)	0.85 (0.69-1.06)
Type of anesthesia
Regional	314 (1.11%)	1.0 (reference)	1.0 (reference)
General	106 (1.38%)	1.24 (0.86 -1.77)	1.28 (0.89 -1.82)
Combination general and regional	14 (1.45%)	1.31 (0.76 -2.25)	1.34 (0.78 -2.30)
Other	6 (2.27%)	1.83 (0.52 -6.50)	1.79 (0.50 -6.38)
Duration of surgery (min)
≤60	120 (1.16%)	1.0 (reference)	1.0 (reference)
61-120	307 (1.21%)	1.04 (0.83 -1.30)	1.07 (0.86 -1.34)
≥121	13 (1.0%)	0.84 (0.54 -1.31)	0.89 (0.57 -1.34)
Year of surgery
1997-1999	40 (0.82%)	1.0 (reference)	1.0 (reference)
2000-2003	131 (1.10%)	1.34 (0.89-2.00)	1.35 (0.90-2.02)
2004-2007	270 (1.32%)	1.27 (1.05-1.55)	1.28 (1.05-1.57)
Length of hospital stay§
0-6 days	138 (1.28%)	1.0 (reference)	1.0 (reference)
7-10 days	136 (1.0%)	0.80 (0.64-1.01)	0.83 (0.63-1.09)
≥11 days	154 (1.34%)	1.07 (0.84-1.37)	1.26 (0.89-1.80)

*Crude relative risk with 95% confidence interval (CI).
†Relative risk with 95% confidence interval mutually adjusted for all other risk factors.
‡Reference group is patients without previous hospitalization with the specific comorbidity.
§The number of venous thromboembolism events does not sum to 441 because of 1364 missing observations on length of hospital stay.

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TABLE I Risk of Hospitalization with Venous Thromboembolism within Ninety Days Following Primary Knee Arthroplasty

Predictors	Venous Thromboembolism (no. of patients)	Crude Relative Risk* (95% CI)	Adjusted Relative Risk† (95% CI)
Sex
Female	273 (1.15%)	1.0 (reference)	1.0 (reference)
Male	168 (1.25%)	1.09 (0.88-1.35)	1.08 (0.86-1.35)
Age (yr)
10-49	15 (0.86%)	1.0 (reference)	1.0 (reference)
50-59	66 (1.09%)	1.26 (0.78-2.05)	1.26 (0.76-2.11)
60-69	139 (1.15%)	1.33 (0.88-2.01)	1.29 (0.83-2.01)
70-79	153 (1.23%)	1.44 (0.93-2.22)	1.40 (0.85-2.33)
≥80	68 (1.41%)	1.65 (1.11-2.43)	1.58 (1.01-2.47)
Primary knee diagnosis
Primary osteoarthritis	361 (1.20%)	1.0 (reference)	1.0 (reference)
Secondary osteoarthritis	52 (1.31%)	1.09 (0.82-1.45)	1.16 (0.85-1.57)
Rheumatoid arthritis	12 (0.74%)	0.61 (0.39-0.97)	0.61 (0.38-0.98)
Other diagnoses	16 (1.00%)	0.83 (0.43-1.59)	0.86 (0.42-1.67)
Charlson comorbidity index
Low score (0)	279 (1.10%)	1.0 (reference)	1.0 (reference)
Medium score (1-2)	126 (1.25%)	1.13 (0.92-1.38)	1.14 (0.93-1.41)
High score (≥3)	36 (1.95%)	1.78 (1.30-2.45)	1.73 (1.24-2.41)
Specific comorbidities‡
Previous deep venous thrombosis and pulmonary embolism	56 (6.00%)	5.78 (4.37-7.65)	5.30 (3.99-7.05)
Cardiovascular diseases	66 (1.59%)	1.41 (1.10-1.81)	1.33 (1.01-1.74)
Liver and kidney diseases	13 (1.72%)	1.48 (0.92-2.37)	1.49 (0.92-2.42)
Cancer within one year before surgery	2 (0.9%)	0.76 (0.22-2.64)	0.57 (0.16 -2.02)
Cancer more than a year before surgery	37 (1.2%)	0.99 (0.72-1.36)	0.69 (0.48-1.00)
Diabetes	22 (1.33%)	1.13 (0.70-1.82)	1.07 (0.66-1.73)
Surgery type
Total knee	419 (1.22%)	1.0 (reference)	1.0 (reference)
Partial knee (medial or lateral)	18 (0.73%)	0.60 (0.35-1.04)	0.57 (0.32-1.02)
Other surgery	4 (1.31%)	1.08 (0.47-2.45)	1.04 (0.43-2.54)
Laterality
One knee replaced	322 (1.24%)	1.0 (reference)	1.0 (reference)
Both knees replaced	119 (1.05%)	0.84 (0.69-1.03)	0.85 (0.69-1.06)
Type of anesthesia
Regional	314 (1.11%)	1.0 (reference)	1.0 (reference)
General	106 (1.38%)	1.24 (0.86 -1.77)	1.28 (0.89 -1.82)
Combination general and regional	14 (1.45%)	1.31 (0.76 -2.25)	1.34 (0.78 -2.30)
Other	6 (2.27%)	1.83 (0.52 -6.50)	1.79 (0.50 -6.38)
Duration of surgery (min)
≤60	120 (1.16%)	1.0 (reference)	1.0 (reference)
61-120	307 (1.21%)	1.04 (0.83 -1.30)	1.07 (0.86 -1.34)
≥121	13 (1.0%)	0.84 (0.54 -1.31)	0.89 (0.57 -1.34)
Year of surgery
1997-1999	40 (0.82%)	1.0 (reference)	1.0 (reference)
2000-2003	131 (1.10%)	1.34 (0.89-2.00)	1.35 (0.90-2.02)
2004-2007	270 (1.32%)	1.27 (1.05-1.55)	1.28 (1.05-1.57)
Length of hospital stay§
0-6 days	138 (1.28%)	1.0 (reference)	1.0 (reference)
7-10 days	136 (1.0%)	0.80 (0.64-1.01)	0.83 (0.63-1.09)
≥11 days	154 (1.34%)	1.07 (0.84-1.37)	1.26 (0.89-1.80)

Patient-Related Predictors

Patients who had a primary knee arthroplasty for rheumatoid arthritis had a low overall rate for venous thromboembolism (0.74%) and an adjusted RR for hospitalization with venous thromboembolism of 0.61 (95% CI, 0.38 to 0.98) compared with patients with primary osteoarthritis (Table I). The risk of hospitalization with venous thromboembolism increased with increasing age, being highest for patients over eighty years old at the time of surgery (adjusted RR = 1.58; 95% CI, 1.01 to 2.47) compared with patients less than fifty years.

Patients with a high Charlson comorbidity index had an elevated overall rate for venous thromboembolism (1.95%) and an increased RR for venous thromboembolism (adjusted RR = 1.73; 95% CI, 1.24 to 2.41) compared with patients with a low Charlson comorbidity index score. The overall rate of hospitalization with venous thromboembolism among patients managed with knee arthroplasty who had been previously hospitalized with cardiovascular diseases was 1.59%. Their RR of venous thromboembolism was elevated (adjusted RR = 1.33; 95% CI, 1.01 to 1.74) compared with patients who had not been hospitalized with these diseases. Patients previously hospitalized with venous thromboembolism had an overall rate of hospitalization with a new venous thromboembolism of 6% and an adjusted RR of 5.30 (95% CI, 3.99 to 7.05) compared with patients with no previous venous thromboembolism-related hospitalization (Table I). Previous hospitalization with any type of cancer did not influence the risk of hospitalization with venous thromboembolism (Table I).

Procedure-Related Predictors

Type of anesthesia, operative time, and laterality (only one knee compared with both knees replaced) were not associated with a risk of venous thromboembolism in our population (Table I). Patients undergoing partial knee arthroplasty (medial or lateral) had a low overall rate for venous thromboembolisms (0.73%) and an adjusted RR for hospitalization with venous thromboembolism of 0.57 (95% CI, 0.32 to 1.02) compared with patients undergoing total knee arthroplasty.

Discussion

In a meta-analyses of seventeen studies published from 1993 to 2001, Douketis et al.⁶ reported a 1.4% incidence of symptomatic nonfatal venous thromboembolism three months following knee arthroplasty. On the basis of 5100 cases in Scotland, Clayton et al.³¹ reported a 1.6% incidence of symptomatic venous thromboembolism three months following total knee arthroplasty, while White et al.⁹ found a 2.1% incidence of venous thromboembolism in their sample of >24,000 knee arthroplasties. Two additional studies found an incidence of symptomatic venous thromboembolism, both fatal and nonfatal, of 1.8% and 2.3% at three months^8,13. The slightly discrepant findings may result from the characteristics of the study population, study design, type of data sources, definition of outcomes, methods of outcome ascertainment, and type and regimen of pharmacological thromboprophylaxis. The overall rate of symptomatic venous thromboembolism of 1.2% in our population could be considered high, given previous research showing that venous thromboembolism is associated with mortality and a new venous thromboembolism event³². Contrary to the latest systematic review of randomized trials¹⁴, our study identified an apparent increase in the rate of postoperative venous thromboembolism since 1997. This is in agreement with findings from Memtsoudis et al.¹⁸, while no change in the incidence of venous thromboembolism since 1992 was observed by Howie et al.¹³. Given the decline in the length of hospitalization for knee arthroplasty³³, lack of compliance with guidelines for postdischarge thromboprophylaxis³⁴, improvement in the diagnostic management of patients with suspected venous thromboembolism because of the introduction of new diagnostic methods, and high sensitivity of available diagnostic tests³⁵, our findings are not surprising. Considering the lack of individual data on the duration and type of thromboprophylaxis, and the data on possible variation in venous thromboembolism prevention strategies over the study period, our results should be interpreted with caution. We found that the risk period for venous thromboembolism extends beyond the current average length of hospitalization³³, and the risk tends to increase with longer hospitalization, emphasizing the need for clinical practice to comply with updated guidelines on the use of thromboprophylaxis³⁶. Prophylaxis has traditionally been given in Denmark during the short hospitalization period for knee surgery. Nevertheless, residual confounding by comorbidity and prolonged immobilization could affect the observed association.

The increasing rate of venous thromboembolism with age in our study confirms traditional knowledge of age as a risk factor for venous thromboembolism^19,37, but is contrary to the findings of two studies on patients managed with hip and knee arthroplasty^8,16. Although studies in other settings have suggested that age alone is a less important risk factor for venous thromboembolism than underlying comorbidity, this does not appear to apply to orthopaedic patients³⁸. In our study, a high Charlson comorbidity index at the time of surgery, particularly a history of cardiovascular disease or a previous venous thromboembolism, was associated with an increased risk of venous thromboembolism. The latter have been identified as risk factors for venous thromboembolism following hip and knee arthroplasty in some^8,18,39, but not all, earlier studies^16,17. An association between severity of illness prior to surgery measured by American Society of Anesthesiologists physical status and cardiac complications has been suggested^16,40. A lower risk of venous thromboembolism after knee arthroplasty in patients with rheumatoid arthritis was confirmed among Danish patients after hip arthroplasty²⁹. The risk for venous thromboembolism was similar for patients with rheumatoid arthritis and those with osteoarthritis in two studies of <300 orthopaedic patients^41,42. Patients with rheumatoid arthritis, compared with patients with osteoarthritis, are more likely to receive medications such as methotrexate, sulfasalazine, and steroids, but their impact on the risk of venous thromboembolism is unclear. Although cancer is a well-recognized risk factor for venous thromboembolism⁴³ in general, we found no difference in venous thromboembolism risk in patients with and without cancer. Schiff et al.¹⁷ reported no association between cancer and venous thromboembolism risk among 310 orthopaedic patients (30% underwent knee replacement), whereas Lyman et al.³⁷ reported an association among patients who had shoulder arthroplasty. As orthopaedic surgery is an important independent risk factor for thromboembolism, cancer as a contraindication for surgery may introduce a selection problem in our study and lessen our possibility to find any association between cancer and venous thromboembolism.

In the context of surgery-related risk factors, the type of anesthesia was not associated with venous thromboembolism risk in our study. Our findings agree with the report by Mantilla et al.¹⁶, but not with previous reports^44,45 among orthopaedic patients in general. Nevertheless, in the latest meta-analyses of twenty-one randomized studies, Hu et al. also found that regional anesthesia substantially reduced the venous thromboembolism risk⁴⁶. However, their subgroup analyses of four studies, including only patients who received thromboprophylaxis, revealed no significant difference in venous thromboembolism risk between regional and general anesthesia.

Universal availability of care through Denmark's tax-supported National Health Service eliminated referral bias. The positive predictive value of comorbid diagnoses included in the Charlson comorbidity index ranged between 94% and 100%⁴⁷. The predictive value of a discharge diagnosis of venous thromboembolism in the Danish National Registry of Patients was found to be between 75% and 95%^25,47,48, depending on the study design. The exact date of diagnosis for events occurring during the primary hospitalization was unavailable in the Danish National Registry of Patients. Since the autopsy rate in Denmark is <20%⁴⁹, it is difficult to determine the exact rate of fatal pulmonary embolism that was not preceded by a hospitalization. Any venous thromboembolism cases missing from the Danish National Registry of Patients and the lack of data from autopsies would lead to an underestimation of the overall venous thromboembolism risk. However, since missing venous thromboembolism registrations and the lack of autopsy results are most likely independent of predictors investigated, our RR estimates should not be biased. Compared with the Danish National Registry of Patients (the gold standard), registration of arthroplasties in the Danish Knee Arthroplasty Registry has been 80% to 90% complete during the last ten years, and the registration of predictive factors is virtually 100% complete²⁰. Given the prospective registration of data in the Danish Knee Arthroplasty Registry and the follow-up design of our study, it is highly unlikely that any missing registration of procedures or misclassification of predictors is systematically linked to later venous thromboembolism status.

In conclusion, in this study of 37,223 patients who underwent knee arthroplasty with pharmacological thromboprophylaxis, 1.2% experienced symptomatic venous thromboembolism within ninety days of surgery. The risk extended well beyond the standard length of hospitalization in Denmark. Our findings are important as they emphasize that future effort should focus on the improvement of prophylaxis following hospital discharge, particularly among elderly patients and those with a history of cardiovascular disease or a previous venous thromboembolism.

Appendix

A table showing the characteristics of the 37,223 patients who underwent primary knee arthroplasty in Denmark from 1997 to 2007 is available with the online version of this article at jbjs.org.

Acknowledgements

Note: The authors thank the orthopaedic surgeons at all hospitals in Denmark for cooperation regarding the Danish Knee Arthroplasty Registry.

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Topics

knee replacement arthroplasty ; thromboprophylaxis ; venous thromboembolism

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Alma B. Pedersen, Frank Mehnert, Soren P. Johnsen, Steen Husted, Henrik T. Sorensen; Venous Thromboembolism in Patients Having Knee Replacement and Receiving ThromboprophylaxisA Danish Population-Based Follow-up Study. The Journal of Bone & Joint Surgery. 2011 Jul;93(14):1281-1287.

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