Chest
Volume 126, Issue 6, December 2004, Pages 1938-1945
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Warfarin Anticoagulation and Outcomes in Patients With Atrial Fibrillation: A Systematic Review and Metaanalysis

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Objective:

To examine the relationship between international normalized ratio (INR) and outcomes (major bleeding events and strokes) in patients with atrial fibrillation (AF) receiving anticoagulation with warfarin.

Methods:

A systematic review and metaanalysis of studies published in the English language between January 1, 1985, and October 30, 2002, was performed. MEDLINE (PubMed), Current Contents, and relevant reference lists were searched. Studies enrolling patients with nonvalvular AF receiving warfarin anticoagulation were eligible for inclusion if they reported stroke and/or major bleeding events in relation to INR, or time spent in therapeutic range. The risk of bleeds in overanticoagulated patients (INR > 3) and the risk of strokes in underanticoagulated patients (INR < 2) were assessed.

Results:

Twenty-one studies (6,248 patients) met all inclusion criteria. Of the 21 studies, a target conventional INR of 2 to 3 was used in 9 studies. An INR < 2, compared with an INR ≥ 2, was associated with an odds ratio (OR) for ischemic events of 5.07 (95% confidence interval [CI], 2.92 to 8.80). An INR > 3, compared with an INR ≤ 3, was associated with an OR for bleeding events of 3.21 (95% CI, 1.24 to 8.28). On average, in the four studies with a target INR range of 2 to 3, patients with AF receiving warfarin spent 61% of time within, 13% of time above, and 26% below the therapeutic range.

Conclusion:

Available evidence indicates that in patients with nonvalvular AF, the risk of ischemic stroke with insufficient warfarin anticoagulation (INR < 2), and the risk of bleeding events with overanticoagulation (INR > 3) are significantly higher relative to patients with AF maintained within the recommended INR of 2 to 3. However, the published data are sparse, heterogeneous, and primarily reported from clinical trials. More studies evaluating clinical outcomes in relation to INR are needed, especially in a real-world setting.

Section snippets

Materials and Methods

In general, procedures for this review followed established best methods for the evolving science of systematic review research.1112 A protocol was written prospectively, which stated the objectives, search criteria, study selection criteria, data elements of interest, and plans for analysis.

Studies

Seven hundred forty-one abstracts were screened, and 211 full articles were retrieved. Of these, 21 primary (and 9 linked) studies5678914151617181920212223242526272829303132333435363738 met our inclusion criteria and were accepted for this review. Most of the remaining articles were rejected either because INR was not reported, or the study included a mixed population, in which outcomes for patients with AF were not separable.

Table 1presents a summary of study characteristics for the accepted

Discussion

The results are in line with the current clinical belief39 that low INR is associated with an increased risk of stroke and high INR is associated with increased risk of bleeding. The available evidence indicates a higher incidence of ischemic stroke in patients with nonvalvular AF with insufficient anticoagulation (INR < 2), and a higher incidence of bleeding events in overanticoagulated patients with nonvalvular AF (INR > 3). Further, the results of well-controlled, published clinical trials723

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    Sponsored by AstraZeneca LP, Wilmington, DE.

    Dr. Reynolds is an employee of MetaWorks whose company was contracted by AstraZeneca to conduct the systematic review and metaanalysis presented in this article. Other coauthors of this article have not received anything of value either directly or indirectly from a commercial or other party related directly or indirectly to the subject of this article submission.

    For instructions on attaining CME credit, see page A-56 or visit www.chestnet.org

    Learning Objectives: 1. To recognize that the INR below 2.0 was associated with a 5-fold increase in the risk of stroke in patients with nonvalvular atrial fibrillation. 2. To understand that an INR over 3 increased the risk of major bleeding 3-fold.

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