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

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.Oral anticoagulant therapy is essential for the treatment and prevention of many thromboembolic disorders. Since anticoagulants can cause serious adverse events,^1–3 physicians monitor the international normalized ratios of patients taking these drugs to ensure that their ratios fall within a target range.An international normalized ratio of 2–3 is the most common target range. Results of previous studies revealed an increased risk of bleeding among patients whose ratios exceeded 4, an increased risk of stroke among patients whose ratios were 1.5–2 and a decreased risk of stroke at a ratio of 2.4.^4,5 However, the evidence supporting the range of 2–3 has some deficiencies. We sought to determine whether the risk of hemorrhagic and thromboembolic events is minimized at an international normalized ratio of 2–3 among patients taking anticoagulants. In addition, it has been observed that patients spend more time with a ratio below 2 than above 3.^6,7 The impact of such systematic underanticoagulation on patient outcomes is unknown. We sought to determine the effect of under-or overanticoagulation on the risk of thromboemboli and hemorrhage.