Introduction

Venous thromboembolism (VTE), which includes asymptomatic and symptomatic deep-vein thrombosis (DVT) and/or pulmonary thromboembolism (PE), has to be considered as a potentially serious complication after total hip arthroplasty (THA) and total knee arthroplasty (TKA). The vast majority of VTEs are asymptomatic, but can also be associated with long-term morbidity when compared with symptomatic events [1]. Patients with symptomatic VTE have a higher likelihood of prolonged hospital stay and a greater rate of re-hospitalization. Reduced quality of life and increased health care expenditures may also occur as a consequence [2].

Combined prevalence rates of 0.9–28 % for pulmonary embolism and 0.1–2 % for fatal pulmonary embolism following THA or TKA, respectively, have been reported [1]. Despite promotion and implementation of more potent and aggressive chemical prophylaxis, the rate of VTE-associated death has not been reduced over the last 30 years, especially after THA or TKA [1, 3]. Most guidelines [4–9] for prevention of VTE are presented in a general fashion including outcome of major orthopedic surgery with no detailed emphasis on TKA/THA surgery. Therefore, we targeted risk factors for patients undergoing after THA or TKA and more importantly wanted to assess the weighting of pre- and perioperative risk factors. Hence, we conducted a meta-analysis to assess the quality of available epidemiologic evidence, to evaluate the risk factors for VTE after THA or TKA in order to provide more information and improved guidance for surgeons and doctors managing this sub-group of patients and to allow for better risk stratification.

Methods

Search strategy and data source

A meta-analysis was conducted using PubMed database, the Cochrane Library, OVID MEDLINE and American Academy of Orthopaedic Surgeons (AAOS). The keywords were identified and MeSH descriptors or subject headings were arranged for the following search terms: “total hip arthroplasty”, “total hip replacement”, “THA”, “THR”, “total knee arthroplasty”, “total knee replacement”, “TKA”, “TKR”, “venous thrombus”, “venous thromboembolism”, “vein thrombosis”, “venous thrombosis”, “VTE”, “risk”, “risk assessment”. Articles which investigated the association between risk factors and VTE after THA or TKA were identified. An additional article was selected from references of relevant reviews and studies presented at major orthopedic journals such as the Journal of Bone and Joint Surgery (JBJS) and Japanese Orthopaedic Association (JOA). For further information, “Google Scholar” was also used. The evidence available from NICE [6], in particular the evidence tables [7] were also cross-checked and included for our analysis.

Study selection

According to the inclusion criteria presented in Table 1, all identified articles were reviewed independently on an initial screening of titles or abstracts to select potentially relevant articles. The results were cross-checked and then a second screening of all remaining full-text articles was reviewed by all of four authors separately to appraise the eligibility. The summarized results were cross-checked again. Any disagreements were resolved through discussion among all authors.

Table 1 Criteria for selection of studies in review
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Quality assessment

Articles were reviewed by all of authors independently on separate occasions. The Newcastle-Ottawa Scale (NOS) was used as the quality assessment tool to evaluate the methodological quality of the studies included in the current review. Disagreements were resolved through discussion among all authors.

Data extraction

A specifically developed data-collection form was used to collect basic information of participants in each original study. The information from each study was recorded in the Table 2.

Table 2 Characteristics of the studies on venous thromboembolism after total hip arthroplasty or total knee arthroplasty
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Odds ratios (OR) were regarded as the evaluation indicators of our meta-analysis. Extracted from original studies, the event and sample size were used to calculate the ORs value to devise forest plots. One author independently performed this procedure, resolving controversies by consensus with a second author.

Statistical analysis

Odds ratios (OR) and 95 % confidence interval (CI) were used as the common measures in our analysis. OR < 1 is negatively correlated with disease while it is positive when OR > 1. If OR equals 1, there is no statistical significance. Statistical significance was considered to be reached only if 95 % CI did not contain 1 or else no statistical significance existed. Calculated OR was used to make a list of weighting of risk factors.

The origins of heterogeneity consisted of differences in scores of quality, study design (prospective cohort or cases–control/retrospective), years of publication, characteristics of participants and prophylaxis across our studies. The presence of heterogeneity was assessed by Chi-squared test while the degree of heterogeneity was measured by I 2 statistic [10]. If P value calculated from Chi-squared test was less than 0.05, existence of statistical heterogeneity was affirmed. The statistical results with I 2 values provided an assessment level of heterogeneity. Less than 25 % was considered as little heterogeneity, 25–50 % as low level, 50–75 % as moderate level and exceeding 75 % as high level [11].

A fixed-effect model was employed for studies which showed homogeneity, while a random-effects model was used for those that did not. A sensitivity analysis was conducted to assess the stability of synthesis results and to identify sources of heterogeneity by removing every single study and analyzing the effect on overall results. Potential publication bias, which could affect the validity of the conclusion, was assessed by a funnel-plot. All analysis was performed by using Review Manager 5.2.9. P < 0.05 was considered statistically significant.

Results

Selection of studies

The initial search strategy yielded 1007 articles, 150 remained for screening based on the inclusion criteria after reviewing titles and abstracts. Of these 150 articles, 63 full-text articles were selected for further appraisal. After the assessment of full-text articles, 50 studies were excluded. Finally, 14 studies were included with one article retrieved from checking references lists. Table 2 provides a summary of characteristics of these studies, including author, year of publication, nation, study design, no. of patients, dropout rate, follow-up time, anesthesia, prophylaxis, operation side, diagnosis of VTE, and operation type (seen in Appendix Table 2). The entire selection process of articles according to PRISMA [12] Statement is presented in Fig. 1.

Fig. 1
figure 1

Flow chart of identifying and including studies

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Study characteristics and results

Two studies [13, 14] designed as prospective cohort studies were included in this meta-analysis for data collection while other 12 included studies [2, 15–24] were designed as retrospective case–control studies. Ten articles [2, 14–18, 20, 23–25] related to participants undergoing THA or TKA and two articles [13, 22] only included THA patients, while the remaining articles [19, 21] only studied TKA patients. Among the 14 papers included in our article for data extraction and analysis about VTE, only in one article Ref. [25] made to the method of diagnosis of DVT or PE (either by venous Doppler ultrasonography or venography), but in the remainder [2, 13–24] no information was given as to how the diagnosis of VTE was confirmed. Meta-analysis was conducted for ten factors: gender, age, race, obesity, history of VTE, DM, malignancy, hypertension, CHF, varicose veins (seen in Appendix Table 3). Insufficient data were available for other risk factors (see NICE evidence tables) and hence no ORs could be calculated. The pooled ORs and 95 % confidence intervals of these risk factors were summarized in Table 4: five (age ≥ 70, race, DM, history of VTE, varicose veins) possessed significant heterogeneity, while the others showed no, low or moderate level of heterogeneity. Therefore, a random-effects model was preferred to pool the ORs for these five studies. As judged by Egger’s test, there was no evidence of publication bias being present at 5 % significance level for any of the risk factors.

Table 3 Distribution of factors among selected articles
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Table 4 Pooled OR and 95 % CI in the fixed-effects model and random-effects model (data include asymptomatic and symptomatic DVT-PE)
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Gender

Nine studies amounting to a total of 979,693 patients [2, 14–16, 21–25] provided eligible data. With statistics extracted from those 9 papers, the pooled OR calculated by the fixed-effect model was 0.93 (95 % CI 0.89–0.97, P = 0.0004 I 2 = 50 %) which revealed that females are more likely to have VTE after THA or TKA. Hence, our analyses revealed that females had a greater propensity to develop postoperative VTE after THA or TKA than males (shown in Fig. 2).

Fig. 2
figure 2

Heterogeneity, pooled OR and forest plot for group of gender from 9 studies analyzed gender as a risk factor for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)

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Age

Age as a risk factor was reported in eight inclusive studies [2, 13, 15, 16, 21, 23–25] with a total of 1,031,683 patients. Due to different categorization of age-groups in these studies, only 2 studies (a total of 120,989 patients) [15, 21] were included in the comparison of the age ≥ 60 and the age < 60, the fixed-effect pooled OR was 0.92 (95 % CI 0.80–1.05, P = 0.23) with no heterogeneity (I 2 = 0 %). To combine the effect sizes of these 8 studies, we compared the age ≥ 70 with the age < 70. The result showed a high level of heterogeneity (I 2 = 90 %) and the random-effect pooled OR was 0.97 (95 % CI 0.84–1.13, P = 0.73). However, significant difference was found between the age ≥ 80 and age < 80 (a total of 437,660 patients) [15, 16, 21, 25] in the incidence of VTE after THA or TKA. The result of the meta-analysis showed no heterogeneity (I 2 = 0 %) and the fixed-effect pooled OR for age ≥ 80 compared to age < 80 was 0.91(95 % CI 0.85–0.98, P = 0.01). In a conclusion, age ≥ 80 was a risk factor after THA or TKA while age ≥ 60 and age ≥ 70 did not increase the incidence of VTE (shown in Figs. 3, 4, 5).

Fig. 3
figure 3

Heterogeneity, pooled OR and forest plot for group of age (≥60) from 2 studies analyzed age as a risk factor for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)

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Fig. 4
figure 4

Heterogeneity, pooled OR and forest plot for group of age (≥70) from 8 studies analyzed age as a risk factor for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)

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Fig. 5
figure 5

Heterogeneity, pooled OR and forest plot for group of age (≥80) from 3 studies analyzed age as a risk factor for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)

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Race

There were 3 studies (total of 922,051 patients) [14, 18, 23] providing extractable data and confirming that black race is a risk factor for VTE after THA or TKA. In assessment of this factor, the fixed-effect model was used and the pooled effect size (OR = 1.29, 95 % CI 1.19–1.39, P < 0.00001) demonstrated that VTE was related to the black race. As a result of a substantial heterogeneity (I 2 = 77 %), the random-effects model was used and pooled odd ratio for the black race was 1.32 (95 % CI 1.10–1.58, P = 0.002) in study effect size estimate (shown in Fig. 6).

Fig. 6
figure 6

Heterogeneity, pooled OR and forest plot for group of race from 3 studies analyzed race as a risk factor for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)

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Obesity

Two studies (total of 14,302 patients) [13, 17] with details of data referring to obesity were included. Significant difference in the incidence of VTE after THA or TKA was found between patients with BMI ≥ 30 and BMI < 30. It is found that BMI ≥ 30 was a risk factor to increase the morbidity of VTE. The result of the meta-analysis showed a low level of heterogeneity (I 2 = 27 %) and the fixed-effect pooled OR for BMI ≥ 30 compared to BMI < 30 was 0.78 (95 % CI 0.66–0.92, P = 0.003) (shown in Fig. 7).

Fig. 7
figure 7

Heterogeneity, pooled OR and forest plot for obesity of gender from 2 studies analyzed obesity as a risk factor for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)

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History of VTE

Three studies (total of 153,196 patients) [13, 16, 21] provided available data to analyze the history of VTE. The fixed-effect pooled OR for patients with history of VTE compared to those without history of VTE was 11.87 (95 % CI 9.93–14.18, P < 0.00001), showing that patients with history of VTE were at a significant risk of VTE after THA or TKA. However, because of the high heterogeneity (I 2 = 98 %), the random-effects model was employed to estimate the pooled OR with an outcome of 10.67 (95 % CI 2.40–47.48, P = 0.002) (shown in Fig. 8).

Fig. 8
figure 8

Heterogeneity, pooled OR and forest plot for group of history of VTE from 3 studies analyzed history of VTE as a risk factor for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)

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Diabetes mellitus (DM)

Five studies (total of 598,216 patients) [16, 19, 21, 24, 25] were included. We used the fixed-effect model to evaluate the pooled effect size (OR = 0.94, 95 % CI 0.87–1.01, P = 0.09) which revealed no correlation between DM and postoperative VTE. However, there was a high-level heterogeneity (I 2 = 86 %) in these studies and thus the random-effects model was employed to estimate the pooled OR with the outcome of 1.02 (95 % CI 0.80–1.31, P = 0.88) (shown in Fig. 9).

Fig. 9
figure 9

Heterogeneity, pooled OR and forest plot for group of DM from 5 studies analyzed DM as a risk factor for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)

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Malignancy

Statistics from 5 studies (total of 465,758 patients) [2, 13, 21, 23, 24] referred to malignancy and significant difference was found from the pooled data between malignancy and postoperative VTE. The result showed that the fixed-effect pooled OR for the patients with “active” cancer compared to those without “active” cancer was 1.28 (95 % CI 1.01–1.62, P = 0.04) with a moderate-level heterogeneity (I 2 = 54 %) (shown in Fig. 10).

Fig. 10
figure 10

Heterogeneity, pooled OR and forest plot for group of malignancy from 5 studies analyzed malignancy as a risk factor for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)

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Hypertension

There were four studies (total of 539,965 patients) [14, 16, 23, 24] providing the extractable statistics of hypertension. In the fixed-effect model, hypertension was associated with an increased incidence of VTE (OR = 1.20, 95 % CI 1.07–1.34, P = 0.001). There was low level of statistical heterogeneity (I 2 = 35 %) (shown in Fig. 11).

Fig. 11
figure 11

Heterogeneity, pooled OR and forest plot for group of hypertension from 4 studies analyzed hypertension as a risk factor for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)

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Congestive heart failure (CHF)

Four studies (total of 522,449 patients) [13, 16, 24, 25] provided specific statistics. The result of our meta-analysis (OR = 2.03, 95 % CI 1.77–2.34, P < 0.00001) revealed that CHF was also significantly associated with a higher risk for postoperative VTE with a low level of heterogeneity (I 2 = 32 %) (shown in Fig. 12).

Fig. 12
figure 12

Heterogeneity, pooled OR and forest plot for group of CHF from 4 studies analyzed CHF as a risk factor for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)

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Varicose veins

Two studies (a total of 223,249 patients) [16, 20] provided specific statistics. We used the fixed-effect model to evaluate the pooled effect size (OR = 2.60, 95 % CI 1.74–3.88, P < 0.00001) which revealed patients with varicose veins were at an elevated risk of VTE. However, there was a large amount of heterogeneity (I 2 = 82 %) in these studies and thus the random-effects model was employed to estimate the pooled OR with the outcome of 2.76 (95 % CI 1.08–7.06, P = 0.03) (shown in Fig. 13).

Fig. 13
figure 13

Heterogeneity, pooled OR and forest plot for group of varicose vein from 2 studies analyzed varicose vein as a risk factor for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)

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Main findings

The results from our meta-analyses of 14 studies showed that mainly history of VTE (RR > 10) and varicose veins and CHF (RR > 2) have to be considered as the most significant risk factors for postoperative VTE after THA and THA. Gender (female), age (≥80), obesity, race (black), active malignancy, and hypertension, and were only associated with a ‘marginally’ increased VTE risk (RR 1.08–1.32). Age (≥60), age (≥70) and DM did not correlate with postoperative VTE risk.

Discussion

The results of this meta-analysis showed an increased risk for VTE after THA and TKA for the following factors: history of VTE > varicose veins > CHF > black race > BMI ≥ 30 > malignancy > hypertension > age over 80 > female gender. According to the Scottish national guideline of prevention and management of venous thromboembolism [4] and the NICE guidance [6, 7], most of these factors have also been previously identified to increase the risk/incidence of VTE. Our results do not support the SIGN guideline’s [4] suggestion that male gender, age (≥60; ≥70) are relevant risk factors for VTE. Furthermore, our analysis also suggests that the black race seems to be a risk factor which cannot be found in the guideline [4]. As for race, genetic factors may contribute to the finding of black race as an independent predictive factor for increased complications following THA and TKA. Some studies [26, 27] also revealed that the black race has higher incidence of VTE given that higher factor V Leiden III levels [e.g., (150 IU/dl)] are reported to occur more frequently among the black race than in Caucasians [27]. As a ‘new’ finding and in contrast to previous publications [4, 26], our analysis suggests that female, rather than male gender has a higher morbidity of VTE after THA or TKA. A study Silverstein et al. [28] showed the incidence of deep-vein thrombosis remained constant over time in male, while it decreased for females <55 years and increased for females >60 years [28]. Similarly, another study has reported that the incidence of VTE among men over age 80 was lower compared to older women [29]. In our meta-analysis, most of the patients undergoing THA or TKA were over age 60 (number of patients over 60: under 60 = 21:1), which may be the reason why our analysis suggested female being a risk factor of VTE after THA or TKA. In any case, the evaluation of male or female gender as a risk factor seems more closely associated with age rather than a gender-specific risk factor.

Advanced age is generally regarded as a risk factor for VTE [4]. In our analysis, the result did not show a higher incidence of VTE among patients at age over 60 or even over 70. However, patients >80 were at a higher risk of VTE after THA or TKA. Anderson et al. and Montagnana et al. [26, 30] also showed that the incidence of VTE increases with age. In keeping with our findings, Onur et al. and Baser et al. [2, 23] also demonstrated the obvious rise in the incidence of VTE among patients over 80. Thus more attention should be paid to VTE prophylaxis in patients of advanced age especially for those over 80.

Obesity (BMI ≥ 30) has been confirmed as a risk factor in our analysis which is in accordance with statements in the guidelines [4, 6]. Other studies also show obesity to be correlated with VTE risk, but only two articles were included in our meta-analysis to extract available statistics because others lacked unified group division of weight and there is different categorization of weight-groups. Some studies suggested that obesity may contribute to the risk of VTE by decreasing antithrombin III levels and fibrinolytic activity and is associated with venous stasis and with higher levels of prothrombotic factors such as fibrinogen, plasminogen activator inhibitor I and factor VII. In addition, obese patients have metabolic disturbance, are less active and more prone to being hospitalized for medical conditions or surgery, with the concomitant immobilization that may lead to VTE [31–33]. As a result, further studies may be needed to give a more persuasive statistical result. Some studies [34, 35] came to the same conclusion as our study that diabetes (DM) could not be considered as a risk factor. However, other studies revealed that DM is often associated with increased levels of procoagulant factors and the inhibition of endogenous fibrinolysis [36, 37] to increase incidence of VTE while Walter Ageno [38] found that DM was a risk factor of VTE by statistical analysis.

As is commonly acknowledged, malignancy was confirmed as risk factor for VTE after THA or TKA in our study. It has been suggested that the absolute risk is associated with the tumor type, the stage or extent of the cancer, and treatment with antineoplastic agents [39]. One of the hypotheses explained that “active” cancer cells can produce a cancer procoagulant and tissue factor (TF), which can induce a dose-dependent platelet activation by a mechanism similar to thrombin generation, and also release more cytokines and chemokines, such as vascular endothelial growth factor, interleukin-1 and tumor necrosis factor-alpha (TNF-alpha), which act on endothelial cells and leucocytes to synthesize and express TF and other cell adhesion molecules that predispose to VTE [13].

In our study, CHF (RR > 2) and to a lesser extent hypertension were risk factors for postoperative VTE which might be ascribed to blood hypercoagulable state [40–45]. CHF probably reflect both reduced patient mobility and impaired venous flow/return, hence similar to varicose veins.

Varicose veins (VVs) has been identified to increase the risk by >2.5 in our analysis, VVs can increase the backpressure in the venous system, resulting in valvular incompetency, both in the superficial veins and at the junctions between the deep and superficial systems [46]. Valvular incompetency can result in venous stasis and vessel damage within the superficial venous system and this is transmitted to the deep veins via the perforators [20]. We found that all related studies had not differentiated between superficial and deep (asymptomatic vs symptomatic) thrombosis. Therefore, the role and importance of VVs remains somewhat uncertain and further and better data are required to conclusively answer this question.

For rheumatoid arthritis (RA) recent literature suggests a protective effect of RA in comparison to OA and only an increased risk for patients, who are on anti-TNF DMARD medication [47]. The use of nonsteroidal anti-inflammatory drugs (NSAID) was considered as the main reason to explain this phenomenon, but this assumption is more than questionable given the findings by Niki et al. [48], who found that the incidence of DVT was equivalent in the two groups when the patients were matched for age and NSAID use. Importantly, however, Kawakami et al. [47] found that perioperative interruption of TNF blockers decreased the rate of SSI (surgical site infection) and DVT development in RA patients following major orthopedic surgery. Further well-designed studies with larger sample sizes [5] will be needed to evaluate these controversial risk factors.

As mentioned in NICE [6], prolonged immobilization was also identified as a risk factor of DVT or PE for decreasing the venous return and resulting in venous stasis [22]. It may well be that the majority of identified factors, e.g., age > 80, CHF and obesity are important indicators for poorer pre- and also postoperative mobility. Further studies with emphasis on mobility, e.g., using computer-based devices/pedometers, would shed more light into this incompletely answered topic.

Although risk assessment of VTE and relevant prophylactic guidance have been well presented in SIGN and NICE guidelines [4, 6], these still lack complete weighting of all risk factors. We have re-assessed the NICE evidence tables and have been unable in conjunction with our own data to produce valid Forest plots for some other risk factors, e.g., contraception, HRT and others poor mobility. Although THA or TKA as surgical procedure have been considered as risk factors for VTE per se, there is insufficient evidence to show whether the interactions between risk factors are additive or greater as has been previously suggested [4]. However, despite the lack of quality data and hence the absence of related forest plots/RRs, we do not suggest that the other suggested risk factors by SIGN/NICE do not exist or can be ignored.

Limitations

We have to recognize and point out some study limitations:

  1. 1.

    Among 14 studies taken in, 9 provided follow-up time while the rest did not. Quality of included studies may be slightly affected by the incomplete data of follow-up time.

  2. 2.

    The following reasons may contribute to heterogeneity in this paper. Firstly, individual differences exist in the study population of our analysis, for example, authors from 6 countries did the researches whose data comprised our analysis and racial difference may contribute to heterogeneity. Secondly, we noticed that heterogeneity was also owed to the variety of operative methods and used VTE prophylaxis (as showed in Table 2) following THA or TKA;

  3. 3.

    It is acknowledged that the vast majority of VTEs are asymptomatic DVT and risk factors may have different, i.e., direct or indirect (or indeed a combination of both) influence on the incidence of symptomatic and asymptomatic DVT and PE. However, among the 14 crucial papers included in our article for data extraction and analysis about VTE, only one [17] can be used to differentiate between symptomatic and asymptomatic DVT and PE. Seven articles mentioned the difference between them but gave no data [13–16, 20–22] the remaining six [2, 18, 19, 23–25] did not even acknowledge this clinically relevant distinction. In order to improve the efficiency of prevention of VTE and avoiding death, more attention should be paid to symptomatic and asymptomatic DVT and PE after THA or TKA in future studies. More data will also be needed to differentiate between DVT and PE from total VTE patients (forest plots per risk factor see Fig. 14, RRs in Table 5) to enable better risk stratification and more selective chemical prophylaxis.

    Fig. 14
    figure 14

    Summary forest plots for all the risk factors

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    Table 5 Weighting of risk factors for VTE after THA or TKA (data include asymptomatic and symptomatic DVT-PE)
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Conclusions

Despite these methodological limitations, given the large number of patient numbers included, we believe that our article contributes to the current understanding by providing weighting of risk factors for VTE after THA or TKA.

Importantly, however, our meta-analysis analysis suggests that mainly a history of VTE (RR > 10)—irrespective of family or individual history, varicose veins (RR 2.76) and CHF (RR 2.03) have to be considered as the most important risk factors and hence indication for potent chemical prophylaxis. All other factors identified may be considered as more relative indications.

We accept that our data did not include VTE prophylaxis and hence no conclusive recommendations can be made. However, when considering the most up-to date ACCP guideline recommendations from 2012 [9], which include Aspirin and when considering the evidence from NICE (evidence tables), that more potent anticoagulation only marginally reduced the VTE incidence (when compared with Aspirin plus mechanical prophylaxis), but substantially increases the risk of bleeding, it seems reasonable to conclude that routine prescription of potent chemical prophylaxis in the absence of the high-risk factors identified does not seem to be justified. Individual patient risk assessment, rather than a “blanket policy”, is considered the best management strategy before deciding on the type of chemical prophylaxis in addition to mechanical means to try and balance potential benefits and risks (bleeding and infection) associated with more potent chemical agents.