Among 9,217 patients with nonvalvular atrial fibrillation contributing 33,497 person-years on warfarin, we identified 397 eligible thromboembolic events (including 364 ischemic strokes and 33 systemic emboli) and 164 eligible ICHs (including 83 intracerebral hemorrhages, 55 subdural hemorrhages, and 26 “other” intracranial bleeding events) with an index INR level available. We identified 4 matched controls for 559 of the 561 total events (395 TE and 164 ICH), and 1 control for 1 TE case. We excluded the 1 remaining TE event because there were no matched controls.
Matching created a group of controls very similar to the cases in their matched characteristics for both the TE and ICH events (). The mean age for TE cases was 77.4 years, and the mean age for TE controls was 77.2 years. The mean age for ICH cases was 77.7 years versus 77.6 years for ICH controls. Likewise, the percent of cases and controls with the matched features of sex, diagnosis of prior stroke, diabetes, hypertension, heart failure, and consequent CHADS2 scores were the same. The median INR for TE cases was 1.7 (interquartile range 1.3-2.2) and the median INR for TE controls was 2.2 (interquartile range 1.8-2.7). Sixty-three percent of the TE cases occurred when INR values were below the standard range of 2.0-3.0 while only 33% of the TE controls’ INRs were below 2.0. Median INR for ICH cases was 2.6 (interquartile range 2.0-3.4) and median INR for ICH controls was 2.3 (interquartile range 1.9-2.8). Twenty-two percent of ICH cases and 5% of ICH controls had an INR ≥3.6. While most TE events on warfarin occurred at clearly sub-therapeutic levels, most ICH events did not occur during periods of excessive anticoagulation intensity.
Case and Control Characteristics by Event Type
In we plot the odds ratio, relative to INR 2.0-2.5, of TE and of ICH versus eight ordered INR categories for the entire set of cases and controls. For TE the point estimate of the odds ratio remains close to 1.0 for all INR values of ≥1.8, although we note the confidence interval for INR 1.8-1.9 is broad and skewed to values above 1.0 (OR=1.25, 95%CI: 0.80-1.96). The odds ratio increases strikingly at INR 1.4-1.7 (OR=3.72, 95%CI: 2.67-5.19) and increases further at INR ≤1.3 (OR=7.52, 95%CI: 5.20-10.86). For ICH the odds ratios increase strikingly at INR values above 3.5. For INR 3.6-4.5 the OR is 3.56 (95%CI: 1.70-7.46, and for INR >4.5 the OR rises remarkably to 12.27 (95%CI: 5.45-27.61). There was a small, non-significant increase in the odds of ICH at INR 2.6-3.0 (OR=1.60, 95%CI: 0.97-2.62) but the odds actually decreased in the next higher INR interval. Of note, there was no decrease in the odds of ICH relative to INR 2.0-2.5 at INR values below 2.0. The “U-shaped” curve resulting from the overlap of the TE and ICH curves in shows a pattern of markedly higher TE risk at INR<1.8 and markedly higher ICH risk at INR values greater than 3.5. The relative odds for both types of outcome are lowest in the INR range of 1.8-3.5.
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 (more ...)
To preserve power in the analysis of subgroup effects we reduced the number of INR categories from eight to six, using two broader categories under INR 2.0 (i.e., 1.5-1.9 and <1.5) and only one category for INR values above 3.5 (i.e., INR ≥3.6). plots the odds ratios of TE and of ICH relative to INR 2.0-2.5 as a function of this set of six INR categories for the entire set of cases and controls. As is evident, the main features of the INR/outcomes relationships are preserved.
For patients with and without a history of prior ischemic stroke, we again observed a significant increase in odds of TE at INR levels below 2.0 (). Compared with INR 2.0-2.5, the odds of TE were more than doubled in the INR 1.5-1.9 range for those with (OR=2.34, 95%CI: 1.17-4.66) and without prior stroke (OR=2.31, 95%CI: 1.62-3.31). This effect was even more pronounced at INR levels <1.5 (OR=6.87, 95%CI: 3.37-14.00, for those with a history of prior stroke; OR=7.40, 95%CI: 4.98-10.99, for those without a history of prior stroke). Odds ratios for ICH at INR ≥3.6 were 3.83 (95%CI: 1.26-11.66) and 7.45 (95%CI: 3.82-14.53), for those with and without stroke, respectively. For those with and without a prior stroke, the odds of TE did not decrease significantly at INR levels above 3.0. Similarly, for those with and without a prior stroke, the odds of ICH did not decrease significantly at INR levels below 2.0. As reflected in our overall analyses, there was a small increase in odds of ICH at INR 2.6-3.0 among those without a prior stroke that was of borderline significance (OR=1.76, p=0.050). This effect was not preserved in the INR 3.1-3.5 range. The odds of ICH were not increased at INR 2.6-3.0 for those with a prior stroke.
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 (more ...)
Analyses with age dichotomized as <75 and ≥75 () show that risk of TE was significantly elevated in both age groups at INR<2.0. At INR levels above 2.5, risk of TE was low in both age groups and not significantly different from the risk at INR 2.0-2.5. For both age groups the odds of ICH rose strikingly at INR levels ≥3.6 (OR=5.26, 95%CI: 2.17-12.76, for those age <75 years; OR=6.83, 95%CI: 3.23-14.47, for those age ≥75 years). Among those age 75 or older, the relative odds of ICH was modestly elevated at INR levels of 2.6-3.0 (OR=2.06, p=0.016) but was not significantly elevated at INR 3.1-3.5 (OR=1.74, p=0.14).
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 (more ...)
displays the ORs for TE and ICH according to CHADS2 stroke risk score dichotomized as CHADS2 0-2 (lower stroke risk), and CHADS2 3-6 (higher stroke risk). Consistent with our previous analyses, for both CHADS2 categories there was a significant increase in the odds of TE at INR levels <2.0. Odds of TE for both CHADS2 groups remained essentially flat above INR 2.5 relative to INR 2.0-2.5. The relative odds for ICH increased significantly in both groups at INR ≥3.6 but this increase was more striking in the lower risk CHADS2 category (OR=11.01, 95%CI: 5.07-23.88 versus OR=2.90, 95%CI: 1.20-7.03). For INR below 2.0, the odds of ICH were largely the same as those for the referent category of INR 2.0-2.5. Once again, we observed a modest increase in relative odds for ICH at INR 2.6-3.0 in a subgroup, here CHADS2 0-2 (OR=1.90, 95%CI: 0.98-3.68) but the relative odds decreased to 1.0 (95%CI: 0.38-2.61) at INR 3.1-3.5.
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 (more ...)
Concomitant use of aspirin was noted in 4.5% of TE cases and 6.7% of ICH cases and was not related to INR level at the time of the event (p=0.39 for cases of TE; p=0.83 for cases of ICH, both by Fisher’s exact test).
In separate logistic models of TE and ICH, we explored interactions between INR categories and the subgroup variables of prior stroke, age (dichotomized at age 75 years), and CHADS2 categories (categorized as 0-2 versus 3-6). Of the 30 interaction terms tested in the six separate models, the only statistically significant interaction detected was between CHADS2 categories and INR ≥3.6 (p=0.026) in the logistic model of ICH.