Variability of INR and its relationship with mortality, stroke, bleeding and hospitalisations in patients with atrial fibrillation

Abstract

Background – rationale for study

Atrial fibrillation is associated with an increased risk of stroke and mortality which is reduced by treatment with Warfarin. The most commonly used tool to assess the effectiveness of warfarin therapy is the time in therapeutic Range (TTR) of International Normalised Ratio (INR) 2.0-3.0. Our aim was to study whether INR variability, as assessed by the standard deviation of transformed INR (SDT_INR) is more prognostically important than the TTR.

Methods and Results

We studied 19,180 patients with atrial fibrillation on warfarin therapy to evaluate the association of TTR and that of SDT_INR with all-cause mortality, stroke, bleeding and hospitalisation.

The SDT_INR was more prognostically important than the TTR. One standard deviation (SD) higher of SDT_INR had a hazard ratio (HR) of 1.59 (95% CI 1.52-1.66) of mortality compared with 1.18 (95% CI 1.13-1.24) for one SD lower of TTR. For the other 3 events the HR was also higher for the SDT_INR than for the TTR (stroke 1.30 (95% CI 1.22-1.39) vs. 1.06 (95% CI 1.00-1.13), bleeding 1.27 (95% CI 1.20-1.35) vs. 1.07 (95% CI 1.01-1.14) , hospitalisation 1.47 (95% CI 1.45-1.49) vs. 1.13 (95% CI 1.10-1.15). When both metrics were included in the same analysis only the SDT_INR was of significant predictive value.

Conclusions

The SDT_INR is a better predictor of mortality, stroke, bleeding and hospitalisation than the TTR in patients with atrial fibrillation receiving warfarin therapy.

Introduction

Atrial fibrillation affects a large proportion of the population, is a common cause of stroke and increases mortality [1]. Anticoagulant therapy with warfarin is widely used in patients with atrial fibrillation to prevent these complications, but appropriate dose adjustment is critical to balance the benefit of thromboembolism prevention and the risk of bleeding [2].

In order to maximize the benefits and minimize the risk of warfarin therapy, its dose is typically adjusted by monitoring the prothrombin time, expressed as the international normalised ratio (INR). Currently, the accepted goal of the INR-directed warfarin therapy is 2.0-3.0 for most patients with atrial fibrillation [1]. Maintaining the INR within this target range is one of the major pillars of atrial fibrillation management. In fact, the time in the therapeutic range of INR (TTR) has been accepted as a surrogate outcome of clinical effectiveness and safety, and used extensively as an endpoint in clinical trials, [3], [4].

However, whether the TTR is the metric that is most predictive of clinical outcomes (such as death, stroke and bleeding) remains unknown, as it has not been directly compared with other measures of INR variability. Because it does not capture the full amplitude of INR fluctuations (either outside or within the therapeutic window), the TTR is a relatively crude measure of INR lability. Our aim was to study whether INR variability, as measured by the standard deviation of transformed INR values (SDT_INR) is more prognostically important than the current standard.