Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?: the ATRIA study

Abstract

Background: Randomized trials and observational studies support using an international normalized ratio (INR) target of 2.0 to 3.0 for preventing ischemic stroke in atrial fibrillation. We assessed whether the INR target should be adjusted based on selected patient characteristics.

Methods and results: We conducted a case-control study nested within the ATRIA cohort's 9217 atrial fibrillation patients taking warfarin to define the relationship between INR level and the odds of thromboembolism (TE; mainly stroke) and of intracranial hemorrhage (ICH) relative to INR 2.0 to 2.5. We identified 396 TE cases and 164 ICH cases during follow-up. Each case was compared with 4 randomly selected controls matched on calendar date and stroke risk factors using matched univariable analyses and conditional logistic regression. We explored modification of the INR-outcome relationships by the following stroke risk factors: prior stroke, age, and CHADS(2) risk score. Overall, the odds of TE were low and stable above INR 1.8. Compared with INR 2.0 to 2.5, the relative odds of TE increased strikingly at INR <1.8 (eg, odds ratio, 3.72; 95% CI, 2.67 to 5.19, at INR 1.4 to 1.7). The odds of ICH increased markedly at INR values >3.5 (eg, odds ratio, 3.56; 95% CI: 1.70 to 7.46, at INR 3.6 to 4.5). The relative odds of ICH were consistently low at INR <3.6. There was no evidence of lower ICH risk at INR levels <2.0. These patterns of risk did not differ substantially by history of stroke, age, or CHADS(2) risk score.

Conclusions: Our results confirm that the current standard of INR 2.0 to 3.0 for atrial fibrillation falls in the optimal INR range. Our findings do not support adjustment of INR targets according to previously defined stroke risk factors.

Figure 1

a. Odds ratios for thromboembolic events (396 cases, 1581 controls) and intracranial hemorrhages (164 cases, 656 controls) by INR level in adults with nonvalvular atrial fibrillation, with 8 INR categories using INR 2.0-2.5 as the referent. Vertical bars indicate 95% confidence intervals. The numbers of cases and controls for each INR category are given below the figure. b. Odds ratios for thromboembolic events (396 cases, 1581 controls) and intracranial hemorrhages (164 cases, 656 controls) by INR level in adults with nonvalvular atrial fibrillation, with 6 INR categories using INR 2.0-2.5 as the referent. Vertical bars indicate 95% confidence intervals. The numbers of cases and controls for each INR category are given below the figure.

Figure 1

a. Odds ratios for thromboembolic events (396 cases, 1581 controls) and intracranial hemorrhages (164 cases, 656 controls) by INR level in adults with nonvalvular atrial fibrillation, with 8 INR categories using INR 2.0-2.5 as the referent. Vertical bars indicate 95% confidence intervals. The numbers of cases and controls for each INR category are given below the figure. b. Odds ratios for thromboembolic events (396 cases, 1581 controls) and intracranial hemorrhages (164 cases, 656 controls) by INR level in adults with nonvalvular atrial fibrillation, with 6 INR categories using INR 2.0-2.5 as the referent. Vertical bars indicate 95% confidence intervals. The numbers of cases and controls for each INR category are given below the figure.

Figure 2

Odds ratios for thromboembolic events and intracranial hemorrhages by INR level in adults with nonvalvular atrial fibrillation, stratified by history of ischemic stroke using INR 2.0-2.5 as the referent. For 95% confidence intervals for the odds ratios see Appendix A.

Figure 3

Odds ratios for thromboembolic events and intracranial hemorrhages by INR level in adults with nonvalvular atrial fibrillation, stratified by age group (<75 versus ≥75 years), using INR 2.0-2.5 as the referent. For 95% confidence intervals for the odds ratios see Appendix A.

Figure 4

Odds ratios for thromboembolic events and intracranial hemorrhages by INR level in adults with nonvalvular atrial fibrillation, stratified by CHADS₂ score (CHADS₂=0-2 versus CHADS₂=3-6), using INR 2.0-2.5 as the referent. For 95% confidence intervals for the odds ratios see Appendix A.