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Keywords:

  • diagnosis;
  • hip surgery;
  • knee surgery;
  • low-molecular-weight heparin;
  • venography

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

Summary. Background: Venography is commonly used to compare the efficacy of different thromboprophylaxis strategies for preventing deep vein thrombosis (DVT) in patients undergoing total hip replacement (THR) or total knee replacement (TKR). Methods: We explored the relation between asymptomatic DVT and symptomatic venous thromboembolism (VTE) in patients undergoing THR or TKR treated with standard doses of enoxaparin (30 mg b.i.d. or 40 mg o.d.) by comparing the incidence of asymptomatic DVT in venographic studies with the incidence of symptomatic VTE in studies where venography was not performed. Results: In 10 venographic studies involving 5796 patients, the incidence of asymptomatic DVT after THR was 13.2% [95% CI, 12.2–14.2%] and after TKR was 38.1% (95% CI, 35.5–40.8%). In two studies involving 3500 patients who did not undergo venography, the 90-day incidence of symptomatic VTE after THR was 2.7% (95% CI, 2.1–3.4%) and after TKR was 1.8% (95% CI, 0.9–2.7%). For every symptomatic VTE in THR studies where venography was not performed there were five asymptomatic DVTs in the venographic studies; for TKR, the ratio was 1:21. The incidence of asymptomatic DVT and the symptomatic VTE/asymptomatic DVT ratio was influenced by the venogram reading committee (Gothenburg vs. Hamilton: total DVT after THR, 19.5% vs. 8.7%, < 0.0001; for TKR, 42.7% vs. 27.2%, < 0.0001). Conclusions: Comparisons across trials show a consistent relation between asymptomatic venographic DVT in patients undergoing elective THR or TKR surgery and symptomatic VTE in patients not undergoing venography. Differences exist in the strength of the relation depending on the type of surgery and the venogram reading committee.


Background

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

Asymptomatic deep vein thrombosis (DVT) detected by screening contrast venography is accepted as a valid surrogate for symptomatic venous thromboembolism (VTE) [1] and is widely used to compare the efficacy of different thromboprophylaxis strategies [2]. However, the true relation between asymptomatic DVT and symptomatic DVT is uncertain [3]. In trials where screening venography is routinely performed, knowledge of the results of venography can affect subsequent clinical decisions to perform diagnostic tests for VTE (diagnostic suspicion bias), which can falsely inflate the reported incidence of symptomatic thrombosis. Treatment of asymptomatic thrombi that are detected by screening venography will reduce the risk of developing symptomatic thrombi in treated patients and can falsely lower the reported incidence of symptomatic thrombosis. Thus, conclusions concerning the relation between asymptomatic DVT and symptomatic thrombi that are based solely on trials in which routine screening venography is performed may not be valid.

The most reliable approach to determining the relation between asymptomatic thrombi detected by screening venography and symptomatic thrombosis is to blind patients and health care providers to the results of venography. Blinding will ensure that asymptomatic thrombi remain untreated and that clinical assessment for symptomatic DVT and pulmonary embolism (PE) is not affected by knowledge of the results of screening venography. However, most clinicians believe that it is not ethical to conceal the results of screening venography because they are concerned that the risk of fatal PE will be increased if asymptomatic DVT remains untreated.

An alternative approach to obtain more reliable estimates of the relation between asymptomatic venographic thrombi and symptomatic VTE is to compare the incidence of asymptomatic DVT in venographic studies with the incidence of symptomatic thrombi in studies that did not perform screening venography. Comparison across studies is also subject to potential biases, resulting from differences between the studies in patient characteristics, surgical approaches and thromboprophylaxis strategies. Each of the aforementioned biases can affect the reported incidence of asymptomatic thrombi as well as the reported incidence of symptomatic VTE, thereby distorting the relation between them. A further potential source of bias when comparing across studies is differences between the studies in the methods of performing and interpreting the results of screening venography. For example, two of the most experienced adjudication centers, located in Gothenburg, Sweden [4–10] and in Hamilton, Canada [11–19], use markedly different approaches to the interpretation of venograms. Despite these limitations, consistent evidence of a relation between asymptomatic venographic DVT and symptomatic VTE from comparisons across trials, which are subject to a different set of biases to comparisons within trials, would strengthen the evidence that asymptomatic DVT detected by screening venography is a valid surrogate measure for symptomatic thrombosis.

The objective of this study was to obtain estimates of the incidence of asymptomatic DVT detected by routine venography in patients undergoing elective total hip replacement (THR) or total knee replacement (TKR) surgery and to compare these data with estimates of the incidence of symptomatic VTE in studies in which screening venography was not performed. We attempted to minimize the impact of between-trial differences in the following ways.

  • 1
    We included only those studies in which patients received a standard dose and duration of treatment with the low-molecular weight heparin (LMWH), enoxaparin.
  • 2
    We restricted the inclusion of venographic studies to those studies in which the results of venography were adjudicated by the Gothenburg and Hamilton centers, and we analyzed the data from the two adjudication centers separately.
  • 3
    We analyzed data from elective THR and TKR studies separately.

Methods

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

A protocol was prospectively developed, detailing the specific objectives, criteria for study selection, primary and secondary outcomes, and statistical methodology.

Search strategy

We searched electronic databases (MEDLINE and EMBASE) and Cochrane Controlled Trial Registry for randomized clinical trials and prospective cohort studies. The search was limited to English language papers that were published between January 1980 and August 2006. The keywords used for the search were thrombosis, VTE, PE, DVT, randomized controlled trial, controlled clinical trial, prospective study, cohort study, LMWH, enoxaparin, venography, venogram, arthroplasty, knee replacement and hip replacement. We hand-searched bibliographies of journal articles and abstracts from major international meetings to locate additional studies. Relevance was assessed using a hierarchical approach based on title, abstract, and published or unpublished manuscripts.

Study selection

Two investigators (DJQ, JWE) independently evaluated studies for possible inclusion and any disagreements were resolved by discussion. We considered for inclusion all relevant published and unpublished unconfounded, prospective studies involving at least 200 patients who received the LMWH, enoxaparin, at a dose of either 40 mg once daily or 30 mg b.i.d. for a mean duration of seven to nine days for the prevention of VTE after major orthopedic surgery (TKR, THR). We only included studies that performed routine screening venography if bilateral venography was performed at the end of treatment and if the venograms were adjudicated by the Gothenburg or Hamilton centers. We only included studies that did not perform screening venography if the incidence of objectively confirmed, symptomatic VTE was reported.

Data extraction

Two investigators (DJQ, JWE) independently extracted data on study design and the following outcomes from the venographic studies: (i) asymptomatic distal DVT; (ii) asymptomatic proximal DVT; (iii) total asymptomatic DVT. From the studies in which screening venography was not performed we only extracted outcome data on symptomatic VTE. We accepted the authors’ definitions of the outcomes. The data abstracted for each trial were confirmed by reviewer consensus.

Statistical analysis

Analyses were performed separately in patients undergoing THR or TKR, and were performed overall and separately in studies in which venograms were adjudicated in Gothenburg or Hamilton. We calculated the frequency of thrombosis by dividing the number of events by the number of evaluable patients. We determined the pooled frequencies and 95% CIs from all the studies using a fixed effects model. Frequencies from the individual studies were weighted by the inverse of the variance [20]. In situations where there were no events reported, 0.25 was added to each cell to enable the variance to be estimated. For studies in which screening venography was performed, we calculated the pooled frequency of asymptomatic total DVT (proximal and distal) using data from patients who had evaluable venograms. For studies in which the incidence of symptomatic thrombosis was reported, we calculated the pooled frequency of thrombosis using the outcome frequencies that were reported at the end of follow-up.

A chi-squared test was used to determine the statistical significance of any differences between the groups in the frequency of thrombosis. A P-value of < 0.05 was considered statistically significant. A chi-squared test was used to test for heterogeneity and a P-value < 0.10 was considered to denote statistically significant heterogeneity [21,22]. In situations where there was statistically significant heterogeneity, we compared the results of pooled analyses obtained by a fixed effects model with results obtained using a random effects model, as described by DerSimonian and Laird [23] and Laird and Mosteller [24]. The latter approach provides a pooled estimate of the frequency of thrombosis after weighting data from the individual studies by the reciprocal of the variance from each study as well as the between-study variance.

Results

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

Study selection and quality

Our search identified 502 potentially eligible citations. After scanning titles and abstracts, 482 citations were excluded and 20 were retained for further evaluation. For the venographic studies, two performed unilateral venography [13,17], one included less than 200 patients [9], and another study, published only as an abstract, did not report a breakdown of asymptomatic and symptomatic events [8]. For the symptomatic outcome studies, four studies did not report outcomes separately for patients treated with enoxaparin [25–28], while another study did not report outcomes separately for THR and TKR [29]. After excluding the aforementioned studies, 12 studies remained to be included in our review.

Studies in which screening venography was performed

Table 1 summarizes the baseline characteristics of the patients enrolled in studies in which screening venography was performed.

Table 1.   Baseline data of enoxaparin studies estimating patients with asymptomatic deep vein thrombosis (DVT) at day 14
ReferenceStudy name Country/regionSurgeryNo. patients receiving enoxaparinMean age (range) in yearsEnoxaparin regimenStartMedian (range) in daysConcomitant prophylaxis methodsReading committee Non-evaluable venograms§
  1. *Median treatment duration not reported. Range not reported, recommended treatment range described. Mean. §As reported by the venogram adjudication committee; does not include patients who did not undergo venography or underwent venography outside specified interval. ¶Based on total study population. ASA, aspirin; GCS, graduated compression stockings; NK, not known; THR, total hip replacement; TKR, total knee replacement.

Eriksson et al. [30]r-HirudinSwedenTHR102867 (18–87)40 mg o.d.Pre-op. (8–12)*NKGothenburg9.8%
Bauer et al. [12]PENTAMAKSNorth AmericaTKR5236730 mg b.d.Post-op.7 (2–10)GCS recommendedMcMaster14.5%
Turpie et al. [11]PENTATHLONNorth AmericaTHR26066 (26–86)30 mg b.d.Post-op.6 (5–10)NKMcMaster16.9%
Turpie et al. [16]PENTATHLON 2000North AmericaTHR112967 (19–91)30 mg b.d.Post-op.7 (5–11)GCS recommendedMcMaster13.7%
Lassen et al. [15]EPHESUSEuropeTHR113367 (24–97)40 mg o.d.Pre-op.8 (1–10)GCS recommendedMcMaster6.2%
Eriksson et al. [4]METHRO IIIEuropeTHR/TKR138966 (26–93)40 mg o.d.Pre-op. (8–11)*ASA, GCS allowedGothenburg12.5%¶
Eriksson et al. [5]EXPRESSEuropeTHR/TKR138767 (20–89)40 mg o.d.Pre-op. (8–11)*ASA allowedGothenburg8.9%¶
Eriksson et al. [6]BISTRO IIEuropeTHR/TKR39265 (20–86)40 mg o.d.Pre-op.7 (7–11)ASA, GCS allowedGothenburg11.1%
Turpie et al. [7]ODIXa-KNEENorth AmericaTKR10466 (47–83)30 mg b.d.Post-op.7GCS allowedGothenburg16.2%
Eriksson et al. [10]ODIXa-HIPEuropeTHR13265 (27–82)40 mg o.d.Pre-op.8GCS allowedGothenburg11.0%

The pooled frequency of DVT detected by venography is presented in Table 2. In 10 studies involving 5796 patients in which bilateral venography was performed, the incidence of post-operative asymptomatic DVT was 13.2% (95% CI, 12.2–14.2%) following THR and 38.1% (95% CI, 35.5–40.8%) after TKR.

Table 2.   Comparison of asymptomatic deep vein thrombosis (DVT) rates according to venogram reading committees
Reading committeeTotal hip replacementTotal knee replacement
Total DVT % (95% CI)Proximal DVT % (95% CI)Distal DVT % (95% CI)Total DVT % (95% CI)Proximal DVT % (95% CI)Distal DVT % (95% CI)
  1. *P for heterogeneity 0.0004; between the two reading committees; P for heterogeneity < 0.0001; §P for heterogeneity 0.0012. CI, confidence interval.

All13.2 (12.2–14.2)3.0 (2.5–3.5)10.0 (9.2–10.9)38.1 (35.5–40.8)5.7 (4.4–7.0)32.2 (29.7–34.8)
McMaster8.7 (7.4–10.0)1.7 (1.1–2.3)7.1 (5.9–8.2)27.2 (22.6–31.7)5.4 (3.1–7.7)21.3 (17.1–25.5)
Gothenburg19.5 (18.0–21.0)*5.8 (5.0–6.7)13.9 (12.6–15.2)42.7 (39.4–46.0)5.6 (4.0–7.1)37.9 (34.7–41.1)
Absolute difference (%)10.9 4.1 6.815.60.216.6
Relative difference (%)125239§9757378

Exploring heterogeneity  There was significant heterogeneity for venographic DVT outcomes overall and when considered separately for THR and TKR (P < 0.0001). When trials adjudicated at McMaster were considered separately from trials adjudicated at Gothenburg (discussed in more detail below), there was no statistical heterogeneity for the McMaster studies but heterogeneity remained evident for the Gothenberg THR studies. The 1997 THR study by Eriksson et al. [30], which was adjudicated by Gothenburg, had a substantially higher event rate than other studies included in the pooled Gothenburg THR analysis (26% vs. 18% for the remaining studies), and when this study was eliminated from the Gothenburg analysis there was no longer any significant heterogeneity.

Effect of venogram reading committee  The reported frequency of asymptomatic DVT was significantly influenced by the center in which the venograms were adjudicated. A higher frequency of asymptomatic DVT was reported by Gothenburg compared with McMaster for both THR (19.5% vs. 8.7%; < 0.0001, relative difference = 125%) and TKR (42.7% vs. 27.2%; < 0.0001, relative difference = 57%) (Table 2). The difference in DVT frequency was most evident for proximal DVT in patients undergoing THR, where the pooled frequency was 5.8% at Gothenburg compared with 1.7% at McMaster (P = 0.0012), a relative difference of 239%.

Studies in which screening venography was not performed

Table 3 summarizes the baseline characteristics of the patients enrolled in studies in which screening venography was not performed and in which clinical VTE outcomes were reported.

Table 3.   Baseline data of enoxaparin studies estimating patients with symptomatic venous thromboembolism day 14–90
Study Country/regionSurgeryNo. patients receiving enoxaparinMean ageEnoxaparin regimenStartProphylaxis duration – mean (range)Follow-up duration (d)Concomitant prophylaxis methods
  1. THR, total hip replacement; TKR, total knee replacement; GCS, graduated compression stocking.

Leclerc et al. [32]North AmericaTHR/TKR19846830 mg b.d.Post-op.9 (8–12) days84Not known
Colwell et al. [33]North AmericaTHR15166430 mg b.d.Post-op.7.5 (5–9) days90GCS recommended

The pooled frequency of symptomatic VTE after THR was 2.7% (95% CI, 2.1–3.4%) and after TKR was 1.8% (95% CI, 0.9–2.7%).

Ratio of asymptomatic DVT to symptomatic VTE

The ratio of symptomatic VTE, estimated using the observed ratio of asymptomatic DVT: symptomatic VTE in THR patients was 5; for TKR, the ratio was 21. The venogram adjudication center substantially impacted the ratio for THR. For McMaster adjudication, the ratio was 3, compared with 7 for Gothenburg (= 0.0005). There was a similar pattern for TKR (McMaster ratio = 15; Gothenburg ratio = 24, = 0.0023) (Table 4).

Table 4.   Ratio to asymptomatic deep-vein thrombosis to symptomatic venous thromboembolism according to adjudication center
 Total hip replacement % (95% CI)Total knee replacement % (95% CI)
Overall4.8 (3.8–6.1)21.4 (14.1–42.8)
McMaster3.2 (2.4–4.2)15.3 (9.7–30.8)
Gothenburg7.2 (5.7–9.3)24.0 (15.8–48.0)

Fixed vs. random effects model

Similar estimates of incidence of asymptomatic DVT were obtained when using a random effects model compared with a fixed effects model for all estimates.

Discussion

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

Our analyses provide estimates of the frequency of asymptomatic DVT detected by venography and the frequency of symptomatic VTE in patients undergoing elective hip or knee replacement who received short duration (7–9 days) thromboprophylaxis with the most commonly used LMWH, enoxaparin.

There are three major findings. First, our estimates of the incidence of asymptomatic DVT (13.2% for THR and 38.1% for TKR) and of the incidence of symptomatic VTE (2.7% for THR and 1.8% for TKR) are similar to those reported previously [3,31] and confirm that THR patients are more likely to experience a symptomatic event than TKR patients, despite having a lower frequency of asymptomatic DVT detected by venography.

Secondly, the ratio of asymptomatic DVT at hospital discharge to symptomatic VTE within the next three months was about 5:1 for THR and 21:1 for TKR.

Thirdly, there was remarkable consistency in the frequency of venographic DVT for THR and for TKR that was reported within each adjudication center, but the reported frequencies were consistently higher in studies adjudicated by Gothenburg compared with McMaster. For example, the incidence of asymptomatic DVT was 15–26% in THR studies adjudicated by Gothenburg [4–7,10], compared with 8–9% in THR studies adjudicated by McMaster [11,15,16]. Consequently, the ratios of asymptomatic DVT to symptomatic VTE were substantially higher for Gothenburg than for McMaster, both for proximal and distal DVT. The higher ratios for distal DVT may reflect reduced reporting of muscular calf vein thrombosis by McMaster [17] (Table 5) but the higher ratios for proximal DVT are unexplained and merit further study.

Table 5.   Venography technique and criteria for evaluation
CharacteristicGothenburgMcMaster
Use of tourniquetNoNot specified
Degree of table tilt60o45o
Volume of contrast100 mL75–100 mL
Number of images required> 9> 9
Lateral calf viewsYesNo
Anterior tibial and muscular vein fillingRequiredNot required
Visualization of deep femoral and Internal iliac veinsNot requiredNot required
Definition of proximal deep-vein thrombosisIn or above popliteal veinIn or above popliteal vein

The strengths of our study are that we performed a thorough literature search to identify relevant studies, carefully selected the studies to minimize differences among the patient populations that could lead to bias, and analyzed the data separately according to type of surgery and adjudication center to further minimize the potential for bias. Our analyses involved a combined total of nearly 9500 patients, which yielded good power to detect meaningful differences in event rates.

Our study also has limitations. Firstly, as discussed earlier, comparisons across trials are subject to potential biases caused by differences in patient characteristics, interventions and outcome definitions between the studies. Nevertheless, we believe our estimates of the rates of asymptomatic DVT from the two adjudication centers are likely to be valid because they are derived from contemporary studies of similar design, the patients had similar baseline characteristics, the studies all used standard enoxaparin doses, and the same definitions of a positive venogram were used within each adjudication committee. Secondly, the small numbers of patients in clinically important subgroups of the venographic studies (e.g. patients treated with enoxaparin 40 mg once daily vs. 30 mg b.i.d.) precluded reliable comparisons between them. Thirdly, there were only two studies meeting our inclusion criteria that reported the incidence of symptomatic VTE. Fourthly, our analyses were confined to patients treated with the LMWH, enoxaparin, and may not be generalizable to other settings.

Conclusion

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

After short-duration prophylaxis with enoxaparin, our results indicate that for every five patients undergoing THR found to have an asymptomatic DVT on a screening venogram, one patient will experience symptomatic VTE within three months of the operation. For every 21 patients undergoing TKR who are found to have DVT on a screening venogram, one patient will experience symptomatic VTE within three months of the operation. The consistency of our results with the results of previous reports that compared the rates of venographically detected asymptomatic DVT with symptomatic VTE within individual trials strengthens the evidence that venographic DVT is a valid surrogate for symptomatic VTE. There are differences in the relation between asymptomatic DVT and symptomatic VTE depending on the type of the surgery and on the venogram reading committee.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

J.W. Eikelboom is the recipient of a Tier II Chair in Cardiovascular Medicine from the Canadian Institutes for Health Research. We thank Q. Yi for providing statistical assistance.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

The authors state that they have no conflict of interest.

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  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
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