Time in Therapeutic Range and Percentage of International Normalized Ratio in the Therapeutic Range as a Measure of Quality of Anticoagulation Control in Patients With Atrial Fibrillation

Accepted Manuscript Time in Therapeutic Range and Percentage of INRs in Therapeutic Range as measure of quality of anticoagulation control in atrial fibrillation patients Pak-Hei Chan, MBBS, Wen Hua Li, MBBS, Jo-Jo Hai, MBBS, Esther W. Chan, PhD, Ian CK. Wong, PhD, Hung-Fat Tse, MD, PhD, Gregory YH. Lip, MD, Chung-Wah Siu, MD PII:

S0828-282X(15)01572-X

DOI:

10.1016/j.cjca.2015.10.029

Reference:

CJCA 1920

To appear in:

Canadian Journal of Cardiology

Received Date: 6 July 2015 Revised Date:

26 September 2015

Accepted Date: 11 October 2015

Please cite this article as: Chan P-H, Hua Li W, Hai J-J, Chan EW, Wong IC, Tse H-F, Lip GY, Siu CW, Time in Therapeutic Range and Percentage of INRs in Therapeutic Range as measure of quality of anticoagulation control in atrial fibrillation patients, Canadian Journal of Cardiology (2015), doi: 10.1016/ j.cjca.2015.10.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Time in Therapeutic Range and Percentage of INRs in Therapeutic Range as measure of quality of anticoagulation control in atrial fibrillation patients 1

Pak-Hei CHAN, MBBS; 1Wen Hua LI, MBBS; 1Jo-Jo HAI, MBBS; 2Esther W #3, 4

Gregory YH

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CHAN, PhD; 2Ian CK WONG, PhD; #1Hung-Fat TSE, MD, PhD; LIP, MD; #1Chung-Wah SIU, MD 1

Division of Cardiology, Department of Medicine, the University of Hong Kong,

Hong Kong SAR, China; 2Department of Pharmacology and Pharmacy, the 3

University of Birmingham Centre for

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University of Hong Kong; and

Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom, and 4

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Aalborg Thrombosis Research Unit, Department of Clinical Medicine,

Aalborg University, Aalborg, Denmark. #

Joint senior authors

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Cover title: TTR vs PINRR - quality of anticoagulation control Number of Tables: 1; Number of Figures: 3 [1, 2A&B, 3]

section.

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Conflict of interest: None related to current study. Detailed in Disclosure

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Key words: Time in therapeutic range; Percentage of INRs in therapeutic range; atrial fibrillation; Warfarin; ischemic stroke; and intracranial hemorrhage Correspondence:

Chung-Wah SIU, MD Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China. Tel: (852) 2255-4694, Fax: (852) 2818-6304, E-mail: [email protected]

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ACCEPTED MANUSCRIPT Brief summary for the electronic table of contents Time in Therapeutic Range (TTR), a measurement of anticoagulation control quality for warfarin, is underutilized due to its tedious calculation. In this study,

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we have shown that Percentage of INR measurements in Range (PINRR) provides a more user-friendly alternative and correlates with clinical adverse

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events of ischemic stroke and intracranial hemorrhage, similar to TTR.

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ACCEPTED MANUSCRIPT ABSTRACT BACKGROUND: Time in therapeutic range (TTR), albeit being the standard measure of quality of anticoagulation control for warfarin, is underutilized in everyday clinical practice due to its tedious calculation. In contrast, the

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Percentage of INR measurements in Range (PINRR) is a convenient alternative. Our objective is to investigate the correlation between PINRR and TTR, and whether PINRR has clinical utility for prediction of ischemic stroke

METHODS AND RESULTS:

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and intracranial hemorrhage in a ‘real world’ atrial fibrillation (AF) cohort.

Amongst 1,428 Chinese AF patients taking

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warfarin (76.2±8.7 years, mean CHA2DS2-VASc: 4.2±1.6, and HAS-BLED: 2.3±0.9), mean and median TTR values were 38.2±24.4% and 38.8% (interquartile range: 17.9% and 56.2%), respectively. Patients with TTR≥65% (14.8%) had a lower annual risk of ischemic stroke (3.04%/year) than those

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with TTR<65% (5.35%/year). Mean and median PINRR were 34.3±17.1% and 34.2% (interquartile range: 22.7% and 46.0%), respectively. TTR significantly correlated with PINRR in a linear fashion (r= 0.81, p<0.0001).

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A cut-off of PINRR ≤56.1% was a good discriminator of TTR<65%, with a high

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sensitivity (98.3%) and positive predictive value (91.9%). The annual ischemic stroke risk in patients with PINRR>56.1% was 2.56%/year, lower than those with TTR≥65% (3.04%/year). Patients with PINRR>56.1% had an annual incidence of ICH comparable to those with TTR ≥65% (0.49%/year vs. 0.68%/year). CONCLUSIONS: Amongst AF patients on warfarin, the PINRR is a userfriendly alternative to TTR, having a high sensitivity and positive predictive

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As with TTRs, PINRR is associated with clinical

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adverse events, i.e. ischemic stroke and intracranial hemorrhage.

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ACCEPTED MANUSCRIPT INTRODUCTION Stroke prevention is central to the modern management of atrial fibrillation (AF), and Vitamin K Antagonist (VKA, e.g. warfarin) therapy with target international normalized ratio (INR) between 2 and 3 has long been established as the

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standard therapy for patients with AF who have ≥1 additional stroke risk factor(s).1-4

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Amongst AF patients treated with warfarin, however, good quality of anticoagulation control as determined by the average individual time in

and safety of such therapy11.

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therapeutic range (TTR),5-10 is of paramount importance for the best efficacy Indeed, patients with suboptimal TTR (for

example, <65%), not only have a higher incidence of ischemic stroke, but also intracranial hemorrhage.5 Therefore, guidelines recommend switching from

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warfarin to non-vitamin K oral anticoagulants (NOACs) for those on warfarin with suboptimal TTRs despite efforts to maintain a therapeutic INR.1-4

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Notwithstanding the guideline recommendations, the calculation of TTR remains a tedious process for everyday clinical practice. With one of the

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commonly used methods, the Rosendaal method,12 the INR is assumed to change in a linear manner between measurements, and INR values on the days without measurement were interpolated and the percentage of time during which a patient had an INR within 2.0-3.0 is thus considered as the TTR. As a result, TTR is seldom calculated in routine clinical practice.

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ACCEPTED MANUSCRIPT As an alternative, the percentage of INR measurements in range (PINRR) can be more easily calculated. However, there are limited published data using PINRR as a marker for quality of anticoagulation control, and most publications reported PINRR at center-level,9,

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or region-level,14,

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instead of at the

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individual patient-level, thus rendering the validity for individual patient application.

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In this analysis, we aimed to correlate PINRR with TTR, the well-established marker for quality of anticoagulation control in a cohort of Chinese AF patients

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taking warfarin therapy. Second, we relate both these parameters to ischemic

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stroke and intracranial hemorrhage in this cohort.

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METHODS Study Design

This was an observational study based on a hospital based AF registry approved by local Institutional Review Board. Details of the registry have been previously

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described.16-19 Briefly, patients diagnosed to have AF in Queen Mary Hospital, Hong Kong, from July 1997 to December 2011, were identified via a computerized database of our hospital clinical management system. Patients

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were excluded if they had significant valvular heart disease or previous valvular replacement. In addition, patients were also excluded if they were not on warfarin,

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or with less than 10 retrievable INR measurements. According to the center’s protocol, INR was measured every 8 weeks and more frequently when INR was not within the therapeutic range. INR measurements within the first 6 weeks of warfarin therapy were excluded from analysis due to the more frequent INR and

adjustment.20, 21

large fluctuation

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during

initial

warfarin

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testings

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Demographic data, cardiovascular risk factors, and medications were recorded at baseline. The index date was defined as the date of the first occurrence of AF.

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Ischemic stroke risk was estimated at baseline using the CHA2DS2-VASc score (C: congestive heart failure [1 point]; H: hypertension [1 point]; A2: age 65-74 years [1 point] and age ≥75 years [2 points]; D: diabetes mellitus [1 point]; S: prior stroke or transient ischemic attack [2 points]; VA: vascular disease [1 point]; and Sc: sex category [female] [1 point] scores as described in recent guidelines.1, 2, 22

The HAS-BLED score was likewise calculated at baseline as a measure of

potential bleeding risk.23

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TTR was calculated for each patient using Rosendaal method,12 in which INR was assumed to change in a linear manner between measurements, and INR values on the days without measurement were interpolated. The percentage of time during which a patient had an INR within 2.0-3.0 was taken as the patient’s

      ℎ ℎ         

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 (%) = 100 (%) ×

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PINRR was calculated by the following equation:

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TTR.

Outcomes, Variables and Data Sources

The primary outcome was hospital admission for ischemic stroke, whereas the secondary outcome was admission for intracranial hemorrhage. Stroke was

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defined as a neurological deficit of sudden onset, persisting for >24 hours, corresponding to a vascular territory and not explained by other causes (e.g. trauma,

infection).24

Neuroimaging

evidence,

either

from

computerized

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tomography or magnetic resonance imaging, was required to confirm the

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diagnosis of stroke and intracranial hemorrhage. Data were retrieved from the medical records and discharge summaries from the territory-wide information network of all public hospitals in Hong Kong.

Statistical Analysis Continuous and discrete variables are expressed as mean ± standard derivation and percentages, respectively. Statistical comparison of the baseline clinical characteristics was performed using Student’s t test or one-way ANOVA as appropriate. Kaplan-Meier survival analyses with the log-rank test were carried out 8

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and Cox proportional hazards regression model was used to calculate hazard ratios (HRs) of some predictive factors and their 95% confidence interval (CIs) for the incidence of stroke. Calculations were performed using SPSS software (version 21.0). All tests were two-sided, and p-values were considered significant if

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<0.05.

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RESULTS

A total of 1,428 patients (76.2±8.7 years, 47.5% male) with non-valvular AF on warfarin were included in the final analysis. Table 1 summarizes the clinical characteristics of the study population: 64.6% patients had hypertension, 34.7%

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had previous stroke/transient ischemic attack, and 2.6% had previous intracranial hemorrhage. The mean CHA2DS2-VASc and HAS-BLED scores were 4.2±1.6 and

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2.3±0.9, respectively.

Of the whole cohort, the mean and median TTR were 38.2±24.4% and 38.8%

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(interquartile range: 17.9%-56.2%), respectively. Only 212 out of 1,417 patients (14.8%) had TTR ≥65%. Patients with TTR≥65% were younger (73.7±8.6 years vs. 76.5±8.6 years, p<0.01), less diabetes mellitus (17.9% vs. 28.7%, p<0.01) and dialysis (0%, vs. 2.4%, p=0.02), but more likely to have previous stroke/transient

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ischemic attack (44.3% vs. 33.1%, p=0.01) and intracranial hemorrhage (6.1% vs. 2.0%, p<0.01), when compared with those with TTR<65%. There were no statistically significant differences in CHA2DS2-VASc score (4.0±1.5, vs. 4.3±1.6,

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groups.

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p=0.09) and HAS-BLED score (2.3±0.9, vs. 2.3±0.9, p=0.80) between the two

After a mean follow-up of 4.7±0.9 years, the annual incidence of ischemic stroke of the entire cohort was 4.96%/year. As expected, patients with TTR≥65% had a lower annual risk of ischemic stroke 3.04%/year than those with TTR<65% (5.35%/year). Kaplan-Meier analyses demonstrates that patients with TTR≥65% had a significant lower incidence of ischemic stroke compared with those with TTR<65% (HR: 0.56, 95% CI: 0.47-0.83) (Figure 1).

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The annual risks of intracranial hemorrhage amongst patients with TTR≥65% were 0.68%/year, in comparison with 0.95%/year in patients with TTR<65%.

Percentage of INR measurements in Range (PINRR)

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In the whole cohort, the mean and median PINRR were 34.3±17.1% and 34.2% (interquartile range: 22.7% and 46.0%), respectively. Figure 2A depicts a scatterplot of PINRR vs TTR, where PINRR was positively correlated with TTR in

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a linear fashion. The Pearson’s correlation coefficient (r) between PINRR and TTR

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was 0.81 (p<0.0001).

In order to decide a cut-off of PINRR for good TTR, patients were categorized into 10 deciles of PINRR. Figure 2B depicts the mean TTR across the 10 deciles. Of note, the mean TTR of patients at the top decile, i.e., PINRR>56.1%, was The cut-off value of PINRR ≤56.1% appears to be a good

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73.9±13.3%.

discriminator of TTR<65%, with a high sensitivity of 98.3% and positive predictive value 91.9%; its specificity was 50.0% and the negative predictive value was

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83.5%.

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Patients with PINRR>56.1% had a lower annual risk of ischemic stroke 2.56%/year compared to those with PINRR ≤56.1% (5.24%/year). Kaplan-Meier analyses shows that patients with PINRR>56.1% had a significantly lower risk of ischemic stroke compared with those with PINRR≤56.1% (HR: 0.48, 95% CI: 0.410.83) (Figure 3). Also, the annual risks of intracranial hemorrhage amongst patients with PINRR>56.1%, were 0.49%/year in comparison with 0.83%/year in patients with PINRR≤56.1%.

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DISCUSSION

In this study, our principal finding is the overall poor TTR in our cohort of Chinese AF patients (only 14.8% had TTR≥65%) and those with high TTR had lower ischemic stroke and intracranial hemorrhage rates, despite similar baseline

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CHA2DS2-VASc and HAS-BLED scores irrespective of low or high TTR categories. Second, TTR correlates well with ischemic stroke and intracranial hemorrhage, but this parameter is difficult to calculate; in contrast, we show the

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PINRR (which has a good correlation to TTR) with a cut-off value of PINRR ≤56.1%, appears to be a good discriminator of TTR<65%, with a high sensitivity

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and positive predictive value to identify patients with poor TTR, where switching to a NOAC may be a better option.

PINRR is much easier to obtain and simpler to calculate, and where a TTR is not easily obtainable, the PINRR could be used in everyday clinical practice, when

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assessing patients with AF who are taking warfarin.

The TTR has been recommended by the main international guidelines as a

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measure of the quality of anticoagulation control.1, 2, 20 A striking feature of the

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present Chinese cohort is the low TTR overall, consistent with previous studies in Asian populations25.

Even in contemporary randomized control trials, Asian

patients had generally had poorer TTRs compared to non-Asians.25-27 This may partly account for the higher stroke and hemorrhage rates in Asian patients taking warfarin when compared to non-Asian patients in these studies25. In real world clinical practice, quality of anticoagulation in Asian population is even worse, as seen in the present cohort, where the median TTR was as low as 38.8%. Indeed, the Japanese guideline recommends an INR of 1.6–2.6 for 12

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patients with AF older than 70 years on the basis of the findings from a small retrospective cohort studies. However, there are no prospective clinical data to support such recommendations. Although the reasons remain unclear, it is likely that both physician and patient factors contribute to a poor INR control amongst

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Asian patients, which included the use of herbal medications,28 high vegetable consumption, lower body mass index and need for different dosing regimes, pharmacogenetics,28 and being reluctant to keep higher INR and or tendency to

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keep INR in the lower range <2.0 by many physicians.26

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One of the main differences between PINRR and TTR is that time taken between INR measurements has not been taken into account when calculating the PINRR. In contrast to PINRR, Rosendaal’s method for TTR calculation allocates an INR to each day, including days between INR measurements, therefore

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minimizing the disproportionate effect of temporary frequent INR testing and would be expected to provide a better correlation with adverse clinical events. Indeed, the TTR has been consistently shown to correlated with ischemic stroke,

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hemorrhage, and mortality.7-9 Albeit with these strengths, use of the TTR has not gained much popularity in real world clinical practice due to its tedious

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calculation. In addition to TTR<65%, the NICE guidelines recommends use of 2 other practical, although not validated, criteria to identify patients treated with warfarin with poor anticoagulation control: (1) two INR values >5 or 1 INR value >8 within the past 6 months; and (2) two INR values <2.0 within the past 6 months. In such cases, a NOAC may be the better option.

In a stark contrast, PINRR is a parameter which is much easier to calculate, and can be readily obtained even in a busy outpatient clinic setting without any 13

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computer programming. Theoretically, PINRR would be a good reflection of TTR, provided there are relatively evenly distributed time intervals between INR measurements. In a systemic review9 analysing 7 cohorts of AF patients on warfarin from 2 publications14, 15 reporting both center-PINRR and center-TTR,

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there was an excellent correlation between center-PINRR and center-TTR with r=0.99 (p<0.001). Counter-intuitively, while center-TTR negatively correlated with thrombotic events and major hemorrhage, there was no significant relationship

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between center-PINRR and clinical adverse outcomes.9

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Nonetheless, the relationships between PINRR and TTR, and between PINRR and clinical adverse outcomes have not been previously explored at individual level. In concordance to this, our data has demonstrated in a AF population with poor TTR, that there is a very good correlation between PINRR and TTR with

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r=0.81 (p<0.0001), despite a numerical discrepancy between them. Specifically, PINRR was numerically less than that of TTR, perhaps consistent with previous reports studying center-TTR and center-PINRR.14 One underlying reason would

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be that more frequent INR measurements are required to increase TTR. Despite a good correlation between the 2 parameters, PINRR with a cut-off value

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set at the top decile, i.e., PINRR <56.1% was very sensitive (98.3%) and had a high positive predictive value in identifying patients with TTR<65%. Thereby, PINRR would represent a good screening test to identify patients with poor TTR, whereby the standard TTR calculation (e.g. using the Rosendaal method) would otherwise be needed to confirm the poor quality of anticoagulation control.

In

the present study, individual PINRR per se was also predictive of adverse clinical outcomes in contrast to prior studies using center-PINRR.9 Using the same cutoff, patients with PINRR>56.1% had 52% lower ischemic stroke risk compared 14

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with those with PINRR≤56.1% (2.56%/year vs. 5.24%/year); likewise, the annual incidence of intracranial hemorrhage was also lower amongst those with PINRR>56.1% (0.49%/year vs. 0.83%/year) in patients with PINRR ≤56.1%. Patients on warfarin identified to have poor quality anticoagulation control now

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have an option to switch to one of the NOACs. Furthermore, amongst patients planned for long-term oral anticoagulation, a simple clinical score, the SAMeTT2R2 score (S: Sex [female] [1 point]; A: age <60 years [1 point]; Me: Medical

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History [>2 of the following comorbidities: hypertension, diabetes, coronary artery disease/myocardial infarction, peripheral arterial disease, congestive heart

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failure, previous stroke, pulmonary disease, hepatic or renal disease] [1 [point]; T: Treatment [interacting drugs e.g. Amiodarone for rhythm control] [1 point]; T: Tobacco use (within 2 years) [2 points]; and R: Race [non-white] [2 points]) has been proposed to predict the likelihood to have good TTR– whereby a score of 0-

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2 suggests that the patient is likely to stay well on warfarin therapy following its introduction, whilst a score >2 suggests that on probability a high TTR is less likely, and the patient may be better off on a NOAC.29-31 Alternatively, educational

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and more intense review efforts may improve TTRs.32

Study Limitations

This study is based on a single centre, and uses a hospital-based cohort of AF patients. Whether our data are generalizable to ‘stable’ community-based AF patients is uncertain, but high rates of hospitalisation are evident in AF patients.33 Due to the observational nature of this study which spans a period of 14 years from 1997 to 2011, previous less awareness among physicians and patients of the importance of maintaining therapeutic INRs might partly account for the low 15

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mean and median TTR. Despite a protocol-recommended practice in the institution, INR measurements in some patients were checked more frequently or less frequently than 8 weeks due to multifactorial reasons including patient’s noncompliance and absence of nurse-led anticoagulation clinic in the institution

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causing frequent INR testing cumbersome in some of these patients. For those patients who required temporary cessation of warfarin e.g. for surgery, resulting in sub-therapeutic INR values, the INR measurements for calculation of TTR and

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PINRR were not excluded which might affect such calculations to different extents. Finally, data from the multi-national randomized clinical trials on NOAC

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enrolling both Asian and non-Asian patients showed that Asian patients tend to have a higher ischemic stroke risk than non-Asian patients with the same CHA2DS2-VASc score.34-39 CONCLUSION

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PINRR (which has a good correlation to TTR) with a cut-off value of PINRR ≤56.1% was shown to be a good discriminator of TTR<65%, with a high sensitivity and positive predictive value to identify patients with poor TTR, where

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switching to a NOAC may be a better option.

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The PINRR is much easier to obtain and simpler to calculate, and where a TTR is not easily obtainable, the PINRR could be used in everyday clinical practice, when assessing patients with AF who are taking warfarin.

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ACKNOWLEDGEMENTS

AUTHOR CONTRIBURTIONS

C.W.S had full access to all of the data in the study and takes responsibility

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for the integrity of the data and the accuracy of the data analysis. C.W.S, P.H.C, G.Y.L. H.F.T contributed to the study design, data analysis and interpretation, and preparation, review, and approval of the manuscript; all authors contributed

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to the design and conduct of the study, data collection, management, analysis,

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and interpretation, and preparation, review, and approval of the manuscript. DISCLOSURES

Prof. Lip has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi, BMS/Pfizer, Daiichi-Sankyo, Medtronic, Biotronik, Portola and Boehringer

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Ingelheim and has been on the speaker bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, Medtronic, Daiichi-Sankyo and Sanofi Aventis.

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None related to the current study.

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25. 26.

27.

28.

19

34.

35.

36.

37.

38.

AC C

39.

RI PT

33.

SC

32.

M AN U

31.

TE D

30.

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Gallego P, Roldan V, Marin F, et al. SAMe-TT2R2 score, time in therapeutic range, and outcomes in anticoagulated patients with atrial fibrillation. The American journal of medicine. 2014;127:1083-1088. Apostolakis S, Sullivan RM, Olshansky B, Lip GY. Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe-TT(2)R(2) score. Chest. 2013;144:1555-1563. Poli D, Antonucci E, Testa S, Lip GY. A prospective validation of the SAME-TT2R 2 score: how to identify atrial fibrillation patients who will have good anticoagulation control on warfarin. Internal and emergency medicine. 2014;9:443-447. Clarkesmith DE, Pattison HM, Lip GY, Lane DA. Educational intervention improves anticoagulation control in atrial fibrillation patients: the TREAT randomised trial. PloS one. 2013;8:e74037. Friberg L, Rosenqvist M. Cardiovascular hospitalization as a surrogate endpoint for mortality in studies of atrial fibrillation: report from the Stockholm Cohort Study of Atrial Fibrillation. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2011;13:626-633. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. The New England journal of medicine. 2011;365:883-891. Wong KSL, Hu DY, Oomman A, et al. Rivaroxaban for Stroke Prevention in East Asian Patients From the ROCKET AF Trial. Stroke. 2014;45:17391747. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 2009;361:1139-1151. Hori M, Connolly SJ, Zhu J, et al. Dabigatran Versus Warfarin: Effects on Ischemic and Hemorrhagic Strokes and Bleeding in Asians and NonAsians With Atrial Fibrillation. Stroke. 2013;44:1891-1896. Goto S, Zhu J, Liu L, et al. Efficacy and Safety of Apixaban Compared with Warfarin for Stroke Prevention in Patients with Atrial Fibrillation from East Asia: A Subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. American heart journal.168:303-309. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 2011;365:981-992.

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Legends:

Figure 1. Kaplan-Meier estimates of ischemic stroke-free survival AF patients

RI PT

with time in therapeutic range (TTR) ≥65% and TTR<65%.

Figure 2. Relation between time in therapeutic range (TTR) and percentage of INR in therapeutic range (PINRR): (A) Scatterplot of TTR and PINRR; and (B)

SC

TTR across the 10 deciles of PINRR.

with

percentage

of

INR

therapeutic

AC C

EP

TE D

PINRR≤56.1%.

in

M AN U

Figure 3. Kaplan-Meier estimates of ischemic stroke-free survival AF patients

21

range

(PINRR)

>56.1%

and

ACCEPTED MANUSCRIPT Table 1. Baseline characteristics All (n = 1,428)

TTR

AC C

EP

TE D

M AN U

SC

RI PT

p-value ≥65% <65% (n=212) (n=1,216) Mean age, (yrs) 76.2±8.7 73.7±8.6 76.5±8.6 <0.01* Female, n (%) 750 (52.5) 107 (50.5) 643 (52.9) 0.52 HT, n (%) 922 (64.6) 141 (66.5) 781 (64.2) 0.52 DM, n (%) 387 (27.1) 38 (17.9) 349 (28.7) <0.01* Hyperthyroidism, n (%) 97 (6.8) 13 (6.1) 84 (6.9) 0.68 Dialysis, n (%) 29 (2.0) 0 (0) 29 (2.4) 0.02* Heart failure, n (%) 367 (25.7) 43 (20.3) 324 (26.6) 0.05 CAD, n (%) 407 (28.5) 59 (27.8) 348 (28.6) 0.82 Stroke/TIA, n (%) 496 (34.7) 96 (44.3) 402 (33.1) <0.01* Previous ICH, n (%) 37 (2.6) 13 (6.1) 24 (2.0) <0.01* 4.2±1.6 4.0±1.5 4.3±1.6 0.09 Mean CHA2DS2-VASc Mean HAS-BLED 2.3±0.9 2.3±0.9 2.3±0.9 0.80 1 p-value for comparison between patients with TTR ≥65% and TTR<65% HT = Hypertension; DM = Diabetes mellitus; CAD = Coronary artery disease; PAD = Peripheral artery disease; TIA = Transient ischemic attack; ICH = Intracranial haemorrhage; TTR = Time in therapeutic range

1

RI PT

100

SC

90

TTR≥65%

M AN U

80

TTR<65%

TE D

70

EP

60

Log-rank: 10.68, p=0.001* HR: 0.56, 95% CI: 0.47-0.83

50 0

AC C

Percentage of patients with ischemic stroke free survival (%)

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12

24 36 Months

48

60

Figure 1

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RI PT

90 80

SC

70

M AN U

60 50 40

TE D

30

EP

20 10 0 0

10

AC C

Time in therapeutic range (%)

100

20

30

40

50

N=1,428 TTR = 1.0971PINRR + 3.2188 R = 0.81

60

70

80

90

100

Percentage of INR measurements in therapeutic range Figure 2A

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RI PT

90 80

50 40 30

27.9

20 8.3

0 1st <11.6%

55.6 49.9 42.6

37.4

EP

19.5

60.0

TE D

34.9

M AN U

60

10

73.9

SC

70

2nd

AC C

Time in therapeutic range (%)

100

3rd

4th

5th

6th

7th

8th

9th

>11.6-19.1% >19.1-25.5% >25.5-29.8% >29.8-34.2% >34.2-38.3% >38.3-43.2% >43.2-50.0% >50.0-56.1%

10th >56.1%

Deciles of percentage of INR measurements in therapeutic range Figure 2B

RI PT

100

PINRR > 56.1

M AN U

SC

90 80

PINRR ≤ 56.1

TE D

70

EP

60

Log-rank: 8.84, p=0.003* HR: 0.48, 95% CI: 0.41- 0.83

50 0

AC C

Percentage of patients with ischemic stroke free survival (%)

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12

24 36 Months

48

60

Figure 3