Anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis

Abstract

Background: Patients taking oral anticoagulant therapy balance the risks of hemorrhage and thromboembolism. We sought to determine the association between anticoagulation intensity and the risk of hemorrhagic and thromboembolic events. We also sought to determine how under-or overanticoagulation would influence patient outcomes.

Methods: We reviewed the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and CINAHL databases to identify studies involving patients taking anticoagulants that reported person-years of observation and the number of hemorrhages or thromboemboli in 3 or more discrete ranges of international normalized ratios. We estimated the overall relative and absolute risks of events specific to anticoagulation intensity.

Results: We included 19 studies. The risk of hemorrhage increased significantly at high international normalized ratios. Compared with the therapeutic ratio of 2-3, the relative risk (RR) of hemorrhage (and 95% confidence intervals [CIs]) were 2.7 (1.8-3.9; p < 0.01) at a ratio of 3-5 and 21.8 (12.1-39.4; p < 0.01) at a ratio greater than 5. The risk of thromboemboli increased significantly at ratios less than 2, with a relative risk of 3.5 (95% CI 2.8-4.4; p < 0.01). The risk of hemorrhagic or thromboembolic events was lower at ratios of 3-5 (RR 1.8, 95% CI 1.2-2.6) than at ratios of less than 2 (RR 2.4, 95% CI 1.9-3.1; p = 0.10). We found that a ratio of 2-3 had the lowest absolute risk (AR) of events (AR 4.3%/yr, 95% CI 3.0%-6.3%).

Conclusions: The risks of hemorrhage and thromboemboli are minimized at international normalized ratios of 2-3. Ratios that are moderately higher than this therapeutic range appear safe and more effective than subtherapeutic ratios.

Figures

Figure 1: Retrieval and selection of studies involving patients taking oral anticoagulants that captured hemorrhagic or thromboembolic events and person-years of observation.

Figure 2: Anticoagulation intensity and risk of hemorrhagic events. An international normalized ratio of 2–3 was the reference range. Studies that did not report events at a ratio greater than 5 reported a maximum range of ratio greater than 3. We grouped these data into the range of 3–5. CI = confidence interval, EAFT = European Atrial Fibrillation Trial Study Group, ESPRIT = European and Australian Stroke Prevention in Reversible Ischaemia Trial, RR = relative risk. Confidence intervals are in Appendix 5, available online at www.cmaj.ca/cgi/content/full/179/3/235/DC2.

Figure 3: Anticoagulation intensity and risk of thromboembolic events. An international normalized ratio of 2–3 was the reference range. Studies that did not report events at a ratio greater than 5 reported a maximum range of ratio greater than 3. We grouped these data into the range of 3–5. CI = confidence interval, EAFT = European Atrial Fibrillation Trial Study Group, ESPRIT = European and Australian Stroke Prevention in Reversible Ischaemia Trial, RR = relative risk. Confidence intervals are in Appendix 5, available online at www.cmaj.ca/cgi/content/full/179/3/235/DC2.

Figure 4: Anticoagulation intensity and risk of hemorrhagic or thromboembolic events combined. An international normalized ratio of 2–3 was the reference range. Studies that did not report events at a ratio greater than 5 reported a maximum range of ratio greater than 3. We grouped these data into the range of 3–5. CI = confidence interval, EAFT = European Atrial Fibrillation Trial Study Group, ESPRIT = European and Australian Stroke Prevention in Reversible Ischaemia Trial, RR = relative risk. Confidence intervals are in Appendix 5, available online at www.cmaj.ca/cgi/content/full/179/3/235/DC2.