Elsevier

The Lancet

Volume 358, Issue 9275, 7 July 2001, Pages 9-15
The Lancet

Articles
Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials

https://doi.org/10.1016/S0140-6736(00)05249-1Get rights and content

Summary

Background

The optimum duration of prophylaxis against venous-thromboembolism after total hip or knee replacement is uncertain. Our primary objective was to establish the efficacy of extended-duration prophylaxis on symptomatic venous thromboembolic events.

Methods

We identified randomised trials comparing extended-duration prophylaxis using heparin or warfarin with placebo or untreated control in patients undergoing elective total hip or knee replacement by searching electronic databases (MEDLINE, EMBASE), references from retrieved articles, and abstracts from conference proceedings, and by contact with pharmaceutical companies and investigators. Two reviewers independently extracted data on study design, symptomatic and symptomless venographic venous thromboembolism, death, and bleeding outcomes. Results from individual trials were combined with the Mantel-Haenszel method.

Findings

Nine studies met our inclusion criteria (3999 patients), eight with low molecular weight heparin, and one with unfractionated heparin. Extended-duration prophylaxis for 30–42 days significantly reduced the frequency of symptomatic venous thromboembolism (1·3% vs 3·3%, OR 0·38; 95% CI 0·24–0·61, numbers needed to treat [NNT]=50), with no statistical evidence of heterogeneity (χ2 test, p=0·69). There was a greater risk reduction in patients undergoing hip replacement (1·4% vs 4·3%, 0·33; 0·19–0·56, 34) compared with knee replacement (1·0% vs 1·4%, 0·74; 0·26–2·15, 250). A significant reduction in symptomless venographic deep vein thrombosis was also observed (9·6% vs 19·6%, 0·48; 0·36–0·63, 10). There was no increase in major bleeding but extended-duration prophylaxis was associated with excess minor bleeding (3·7% vs 2·5%, 1·56; 1·08–2·26, numbers needed to harm [NNH]=83).

Interpretation

Among patients undergoing total hip or knee replacement, extended-duration prophylaxis significantly reduces the frequency of symptomatic venous thromboembolism. The reduction in risk is equivalent to about 20 symptomatic events per 1000 patients treated.

Introduction

The optimum duration of prophylaxis against venous thromboembolism after total hip or knee replacement surgery remains uncertain.1 It is common practice to administer prophylaxis until discharge from hospital, usually 7 to 14 days after surgery. However, in patients receiving in-hospital prophylaxis, the frequency of venographic deep vein thrombosis is still 15–30% at the time of hospital discharge, and an additional 10–25% of patients develop symptomless new deep vein thrombosis during the next 3 to 4 weeks.2, 3, 4, 5 Randomised trials have shown that extending prophylaxis beyond the time of hospital discharge substantially reduces the risk of developing new symptomless thrombi at 30 to 45 days,3, 4, 5 which has led these investigators to recommend that longer duration prophylaxis should be used in all patients undergoing hip replacement.

More recently, however, two prospective studies conducted in patients without known proximal deep vein thrombosis at the time of discharge from hospital demonstrated that the frequency of new out-of-hospital symptomatic deep vein thrombosis or pulmonary embolism without extended-duration prophylaxis was only about 2% after 3 months of follow-up.6, 7 These data suggest that most symptomless thrombi remain clinically silent irrespective of whether extended-duration prophylaxis is given. Meanwhile, the effect of extended-duration prophylaxis on symptomatic venous thromboembolism remains to be clarified. In the only study, to our knowledge, specifically designed to examine the effect of extended-duration prophylaxis on clinical outcomes,8 a significant reduction in symptomatic venous thromboembolism could not be shown. This led these investigators to conclude that prophylaxis confined to the in-hospital phase is adequate in most patients. Existing international guidelines for prevention of venous thromboembolism also recommend only 7–10 days of therapy with warfarin or low molecular weight heparin after total hip or knee replacement.1, 9

To further clarify the role of extended-duration prophylaxis, we conducted a meta-analysis of all randomised trials assessing the efficacy and safety of extended-duration prophylaxis in patients undergoing elective hip or knee replacement surgery. The primary outcome was symptomatic venous thromboembolism, including deep vein thrombosis and pulmonary embolism. Secondary outcomes were symptomless proximal and distal deep vein thrombosis detected by venography, all-cause mortality, and adverse events including major and minor bleeding.

Section snippets

Methods

We prospectively developed a protocol detailing the specific objectives, criteria for study selection, the approach to assessing study quality, primary and secondary outcomes, and statistical methods.

Study identification

We attempted to identify all relevant published and unpublished unconfounded randomised trials that compared extended-duration anticoagulant thromboprophylaxis with placebo or untreated control in patients undergoing hip or knee arthroplasty. We searched the MEDLINE and EMBASE electronic databases from January, 1980, to July, 2000, using the terms thrombosis, thromboembolism, pulmonary embolism, randomised controlled trial, controlled clinical trial, random, placebo, hip arthroplasty, and knee

Study selection

Two investigators (JWE, DJQ) independently assessed studies for possible inclusion and any disagreements were resolved by discussion. To be included, studies had to be properly randomised; include patients undergoing elective total hip or total knee replacement; compare extended-duration prophylaxis with low molecular weight heparin, unfractionated heparin, or warfarin with placebo or untreated control; and use objective methods to confirm the diagnosis of symptomatic venous thromboembolism. We

Assessment of study quality and data extraction

We adopted the study-quality criteria developed by Schultz and colleagues10 to assess the studies included in our meta-analysis. These criteria include proper generation of the treatment allocation sequence; proper concealment of the allocation sequence; masking of patient and the investigator assessing clinical outcomes to treatment allocation; and completeness of follow-up.

Two investigators (JWE, DJQ) independently extracted data on study design, study quality, and the following efficacy and

Statistical analysis

We assessed agreement for study selection with a weighted kappa statistic and by calculating the observed percentage agreement. We used a fixed-effects model based on the Mantel-Haenszel method for combining results from the individual trials.11 This model is also known as an assumption-free model since it does not assume that included studies are a random sample of the universe of studies, and provides a pooled estimate of treatment effect that is conditional on the trial data that are

Subgroup analyses

We prespecified the following subgroup analyses for the primary outcome: hip replacement versus knee replacement; agent (low molecular weight heparin, unfractionated heparin, warfarin); duration of in-hospital prophylaxis (up to 10 days, 10–14 days, 15 days or more); and in trials with mandatory discharge venography versus trials in which mandatory discharge venography was not performed.

Sensitivity analyses

We did sensitivity analyses to further explore the robustness of our results. To identify any study that may have exerted a disproportionate influence on the summary treatment effect, we deleted studies one at a time. We examined the effect of excluding lower quality (open-label studies and studies with incomplete follow-up) from the analysis. An inverted funnel plot of treatment effect versus study precision was created for the primary outcome to look for possible publication bias,12 a

Results

Figure 1 shows the process of study selection. Our search identified 304 potentially eligible citations. After scanning their titles and abstracts, 289 citations were excluded and 15 were retained for further assessment. Two studies originally reported only in abstract form were subsequently published as full reports5, 8 and we obtained the completed manuscript13 for a third abstract14 from the investigators. These three studies were included. Of the 12 remaining citations, one was excluded

Discussion

We have shown that extended-duration prophylaxis with low molecular weight heparin or unfractionated heparin in patients undergoing major hip or knee replacement surgery significantly reduces the risk of symptomatic venous thromboembolism. This benefit is achieved with no excess major bleeding but with increased minor bleeding. About 50 patients need to be treated to prevent one episode of symptomatic venous thromboembolism, whereas a minor bleed occurs in every 80 patients treated. A

References (35)

  • JR Leclerc et al.

    The incidence of venographic venous thromboembolism during and after prophylaxis with enoxaparin: a multi-institutional cohort study in patients who underwent hip or knee arthroplasty

    Arch Intern Med

    (1998)
  • JA Heit et al.

    Ardeparin sodium for extended out-of-hospital prophylaxis against venous thromboembolism after total hip or knee replacement. A randomized, double-blind, placebo-controlled trial

    Ann Intern Med

    (2000)
  • AN Nicolaides

    Prevention of venous thromboembolism: International Consensus Statement—guidelines compiled in accordance with the scientific evidence

    Int Angiol

    (2001)
  • KF Schulz et al.

    Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials

    JAMA

    (1995)
  • N Mantel et al.

    Statistical aspects of the analysis of data from retrospective studies of disease

    J Natl Cancer Inst

    (1959)
  • M Egger et al.

    Bias in metaanalysis detected by a simple, graphical test

    BMJ

    (1997)
  • PC Comp et al.

    Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement

    J Bone Joint Surg Am

    (2001)
  • Cited by (0)

    View full text