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Duration of Anticoagulation Following Venous Thromboembolism A Meta-analysis

David Ost, MD; Josh Tepper, MD; Hanako Mihara, MD, MPH; Owen Lander, MD; Raphael Heinzer, MD; Alan Fein, MD
JAMA. 2005;294(6):706-715. doi:10.1001/jama.294.6.706.
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Published online

Context Patients with venous thromboembolism (VTE) are susceptible to recurrent events, but whether prolonging anticoagulation is warranted in patients with VTE remains controversial.

Objective To review the available evidence and quantify the risks and benefits of extending the duration of anticoagulation in patients with VTE.

Data Sources PubMed, EMBase Pharmacology, the Cochrane database, clinical trial Web sites, and a hand search of reference lists.

Study Selection Included studies were randomized controlled trials with results published from 1969 through 2004 and evaluating the duration of anticoagulation in patients with VTE that measured recurrent VTE. Excluded studies were those enrolling only pure populations of high-risk patients. Two independent reviewers assessed each article for inclusion and exclusion criteria, with adjudication by a third reviewer in cases of disagreement. Fifteen of 67 studies were included in the analysis.

Data Extraction Two independent reviewers performed data extraction using a standardized form, with adjudication by the remainder of the investigators in cases of disagreement. Data regarding recurrent VTE, major bleeding, person-time at risk, and study quality were extracted.

Data Synthesis If patients in the long-term therapy group remained receiving anticoagulation, the risk of recurrent VTE with long- vs short-term therapy was reduced (weighted incidence rate, 0.020 vs 0.126 events/person-year; rate difference, −0.106 [95% confidence interval {CI}, −0.145 to −0.067]; P<.001; pooled incidence rate ratio [IRR], 0.21 [95% CI, 0.14 to 0.31]; P<.001). If anticoagulation in the long-term therapy group was discontinued, the risk reduction was less pronounced (weighted incidence rate, 0.052 vs 0.072 events/person-year; rate difference, –0.020 [95% CI, −0.039 to −0.001]; P = .04; pooled IRR, 0.69 [95% CI, 0.53 to 0.91]; P = .009). The risk of major bleeding with long- vs short-term therapy was similar (weighted incidence rate, 0.011 vs 0.006 events/person-year; rate difference, 0.005 [95% CI, −0.002 to 0.011]; P = .14; pooled IRR, 1.80 [95% CI, 0.72 to 4.51]; P = .21).

Conclusions Patients who receive extended anticoagulation are protected from recurrent VTE while receiving long-term therapy. The clinical benefit is maintained after anticoagulation is discontinued, but the magnitude of the benefit is less pronounced.

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Figures

Figure 1. Hypothetical Model for Defining Time Points for Assessing Risk of Recurrent Venous Thromboembolism (VTE) in Randomized Controlled Trials of Anticoagulation Therapy
Graphic Jump Location

Patients are diagnosed with VTE (time A) and receive short-term anticoagulation (12 weeks in this hypothetical example). At time B, patients are randomly assigned to either stop anticoagulation (ie, short-term anticoagulation) or to receive long-term anticoagulation (24 weeks in this example, for a total of 36 weeks). At time C, long-term anticoagulation is stopped, but follow-up continues in both groups. At time D, the study is concluded and there is no additional follow-up. Note that for both short- and long-term anticoagulation there is a period immediately after anticoagulation is stopped when the slope of the line is steepest, indicating an increased risk for recurrent VTE. After this period the risk decreases to a lower level, but not as low as when patients were receiving full anticoagulation. The horizontal bars below the graph indicate the periods during which VTE and bleeding events are counted for calculation of incidence rates. DVT indicates deep vein thrombosis; PE, pulmonary embolism.

Figure 2. Flow Diagram of Study Selection
Graphic Jump Location

RCT indicates randomized controlled trial; VTE, venous thromboembolism.

Figure 3. Relative Risk and Risk Difference During Study and Follow-up, From Random-Effects Model
Graphic Jump Location

The period for defining incidence rates for measurement purposes begins when short-term anticoagulation is stopped but long-term therapy continues. The period ends at study completion, which was at least 3 months after long-term therapy had been stopped. Relative risk <1 and rate difference <0 favor long-term therapy. Sizes of data markers are proportional to the weight of each study in the meta-analysis. Error bars indicate 95% confidence intervals.

Figure 4. Relative Risk and Risk Difference During Study and Follow-up, Limited to Studies Reporting Person-Time at Risk, From Random-Effects Model
Graphic Jump Location

The period for defining incidence rates for measurement purposes begins when short-term anticoagulation is stopped but long-term therapy continues. The period ends at study completion, which was at least 3 months after long-term therapy had been stopped. Studies are ranked according to the duration of therapy in the group receiving short-term therapy, with the studies having the shortest duration at the top. As the duration of therapy increases, the magnitude of the benefit of long-term therapy decreases in terms of both relative risk and risk difference (P = .04 and P = .005, respectively). Sizes of data markers are proportional to the weight of each study in the meta-analysis. Error bars indicate 95% confidence intervals.

Figure 5. Relative Risk and Risk Difference During Lifelong vs Fixed-Duration Therapy, From Random-Effects Model
Graphic Jump Location

The period for defining incidence rates for measurement purposes begins when short-term anticoagulation is stopped but long-term therapy continues. The period ends when long-term therapy stops. Relative risk <1 and rate difference <0 favor long-term therapy. Sizes of data markers are proportional to the weight of each study in the meta-analysis. Error bars indicate 95% confidence intervals.

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