This review found that, compared with short-term anticoagulation therapy, long-term anticoagulation therapy can protect against recurrent venous thromboembolism. This was a well-conducted review and the conclusions are reliable based on the evidence presented. However, it is possible that some relevant studies might not have been identified.

To quantify the risks and benefits of extending the duration of anticoagulation in patients with venous thromboembolism (VTE).

PubMed, EMBASE: Pharmacology and the Cochrane CENTRAL Register were searched from 1969 to 2004 for articles in the English language; the search terms were reported. Clinical trial websites and citations of relevant review articles were also manually searched. Studies available only as an abstract were excluded from the review.

Randomised controlled trials (RCTs) with a minimum of 3 months' follow-up were eligible for inclusion.

Studies of anticoagulation therapy that was administered for different durations (long- or short-term) between study groups and involved one or more anticoagulants, with similar initial therapy administered to both groups, were eligible for inclusion. The median duration of short-term therapy was 1.5 months and the median duration of long-term therapy was 6 months.

Studies of adults that primarily involved a first episode of VTE were eligible for inclusion. Studies were excluded if they comprised a high-risk population only, such as those with protein S or C deficiency.

Studies that reported the recurrence of VTE were eligible for inclusion. The review also evaluated death from VTE and the occurrence of major bleeding.

Two reviewers independently assessed each article for inclusion. Any disagreements were resolved by adjudication by a third reviewer.

Each study was assessed and assigned two quality scores using the Jadad instrument and a scale specific to VTE. The Jadad scale assesses randomisation, blinding and withdrawals, with a score ranging from 1 to 5 points. The VTE scale assesses quality based on 7 similar characteristics, such as objective criteria for diagnosis and recurrence, and description of risk factors, with a score ranging from 0 to 1. Two reviewers independently assessed and scored each study for validity. Any disagreements were resolved by adjudication by a third reviewer.

Two reviewers independently extracted the data using a standardised form. Any disagreements were resolved by adjudication by a third reviewer. Data on VTE, major bleeding and person-time risk were extracted and used to calculate the incidence rates in events per person-year at risk for the outcomes of recurrent VTE, death from VTE and major bleeding. Person-time data were estimated when not directly reported in the papers or indirectly through Kaplan-Meier curves. Where necessary, the authors were contacted for further information and to verify data. Data on the risk factors of the study populations were extracted using a standard definition.

A pooled incidence rate ratio (IRR) and rate difference with 95% confidence intervals (CIs) were calculated for the primary and secondary analyses of interest for each time interval. This was done using a random-effects model, weighted by the inverse of the variance (DerSimonian and Laird method). Publication bias was assessed using the Begg rank correlation method and the Egger weighted regression method.

Statistical heterogeneity was formally assessed by calculating the Q statistic for each pooled estimate. A meta-regression was also conducted to assess the effect of low-quality studies on the overall pooled estimates and the possibility of publication bias. Studies were also omitted one-by-one from the pooled estimates, in order to determine the individual influence for each study on the pooled result. A cumulative meta-analysis, according to the year of publication, was also performed.

Eleven RCTs (n=3,556) met the predefined inclusion criteria. A further 4 RCTs (n=2,026) were identified that did not have a period of follow-up after cessation of treatment. These were not eligible for the primary analysis, although they were included in the secondary analysis comparing the risk recurrence with lifelong and fixed duration therapy.

Both quality scales rated the quality of the included studies as generally good.

Recurrent VTE.

The primary analysis of interest in the review (11 studies) found that longer durations of anticoagulation therapy were associated with a decrease in the risk of recurrent VTE events in comparison with short-term therapy; the IRR was 0.69 (95% CI: 0.53, 0.91, P=0.009) and the rate difference -0.20 (95% CI: -0.039, -0.001, P=0.04). No evidence of significant statistical heterogeneity was identified (P=0.33 and P=0.13, respectively).

The secondary analysis (12 studies) found that lifelong therapy was associated with a decrease in the risk of recurrent VTE in comparison with fixed duration therapy; the IRR was 0.21 (95% CI: 0.14, 0.31, P<0.001) and the rate difference -0.106 (95% CI: -0.145, -0.067, P<0.001). There was evidence of significant statistical heterogeneity in the pooled rate difference (P<0.001), but not in the pooled IRR (P=0.13).

The meta-regression found no relationship between outcome and level of anticoagulation, percentage of patients with risk factors or percentage of those with idiopathic VTE, or study quality. There was no evidence of publication bias using the Begg rank correlation method or meta-regression. However, the Egger weighted regression method showed evidence of some publication bias.

Death from recurrence of pulmonary embolism (10 studies).

There was a slight reduction in the risk of death from recurrence of pulmonary embolism in those receiving long-term therapy compared with short-term therapy, but this was not statistically significant (IRR 0.92, 95% CI: 0.43, 1.94, P=0.82). No evidence of significant statistical heterogeneity was identified.

Major bleeding while receiving treatment (7 studies). There was an increased risk of major bleeding in those receiving long-term therapy compared with short-term therapy, but this was not statistically significant (IRR 1.8, 95% CI: 0.72, 4.51, P=0.21). No evidence of significant statistical heterogeneity was identified.

Compared with short-term therapy, long-term anticoagulation therapy can protect against recurrent VTE. This protective effect is maintained after the discontinuation of therapy, but its magnitude is less pronounced.

The review question was focused and the inclusion criteria for the intervention, participants, study design and outcome of interest were appropriate. Several relevant sources were searched for eligible studies, but studies were only eligible if they were published in English and in peer-reviewed journals, thus publication and language bias was possible. Furthermore, some evidence of publication bias was found in a formal assessment of this bias. The study selection, data extraction and quality assessment processes were carried out in duplicate, which minimises reviewer bias and errors.

The analyses were defined a priori, and adequate details of the individual studies were presented. The quality of the individual studies was assessed and used in the analysis. Appropriate measures of effect were calculated according to the duration of therapy. The authors assessed statistical and clinical heterogeneity and, if identified, investigated further using appropriate methods. Overall, this was a well-conducted review and the conclusions follow from the evidence identified, although the search strategy employed might not have identified all relevant studies.

Practice: The authors stated that risk stratification should be used and populations at a high risk of VTE recurrence may need lifelong anticoagulation. For low-risk populations, a shorter course of anticoagulation therapy may be preferred.

Research: The authors did not state any implications for future research.

These additional published commentaries may also be of interest. Witt DM. Review: long-term anticoagulation reduces recurrent venous thromboembolism. ACP J Club 2006;144:33. Witt DM. Review: long-term anticoagulation reduces recurrent venous thromboembolism. Evid Based Med 2006;11:45.

This record is a structured abstract written by CRD reviewers. The original has met a set of quality criteria. Since September 1996 abstracts have been sent to authors for comment. Additional factual information is incorporated into the record. Noted as [A:....].