Design: Record linkage study of routine activity records and INR measurements.

Setting: Cardiff and the Vale of Glamorgan, South Wales, UK.

Participants: 2223 patients with NVAF, no history of heart valve replacement, and with at least five INR measurements.

Main outcome measures: Mortality, ischaemic stroke, all thromboembolic events, bleeding events, hospitalisation, and patterns of INR monitoring.

Results: Patients treated with warfarin were outside the INR target range 32.1% of the time, with 15.4% INR values > 3.0 and 16.7% INR values < 2.0. However, the quartile with worst control spent 71.6% of their time out of target range compared with only 16.3% out of range in the best controlled quartile. The median period between INR tests was 16 days. Time spent outside the target range decreased as the duration of INR monitoring increased, from 52% in the first three months of monitoring to 30% after two years. A multivariate logistic regression model showed that a 10% increase in time out of range was associated with an increased risk of mortality (odds ratio (OR) 1.29, p < 0.001) and of an ischaemic stroke (OR 1.10, p = 0.006) and other thromboembolic events (OR 1.12, p < 0.001). The rate of hospitalisation was higher when INR was outside the target range.

Long term anticoagulation treatment of patients with non-valvar atrial fibrillation (NVAF) can reduce the annual risk of stroke by two thirds.^4,5 Such treatment compares favourably with the alternative, aspirin treatment.⁶ However, the pharmacokinetic profile of warfarin is complex,⁷ and monitoring is required to avoid both thromboembolic events associated with low intensity anticoagulation and haemorrhagic complications associated with higher intensity. Target levels of oral anticoagulation are disease specific and measured with the international normalised ratio (INR). In the case of NVAF, the range is 2.0–3.0. To attain INR values within this range, patients are routinely monitored and their doses are adjusted when necessary. In practice, it is recognised that long term stability is difficult to achieve because of unexpected fluctuations of the INR values in patients, which can be attributed to numerous factors including change in diet, poor compliance with medication, alcohol consumption, seasonal variation, and drug to drug interactions.^7–9

The objective of the study was to evaluate how well patients with NVAF were maintained within the recommended INR target of 2.0–3.0 and to explore the relation between achieved INR control and clinical outcome.

There was a clear pattern of consecutive clinic visits occurring either weekly (13.3%), bi-weekly (12.7%), or monthly (8.8%) (fig 1​1).). The mean (SD) time between consecutive visits was 15.7 (18.1 days), with a median of 12 days and an interquartile range of 4–22 days. Of the 137 507 INR measurements, 46.6% were outside the target range.

In a plot of interpolated INR values, the distribution of INR intensity is asymmetrical and positively skewed (fig 2​2).). Under these conditions, the mean (SD) INR value was 2.5 (0.69), with a median of 2.4 and an interquartile range of 2.4–2.8. In a plot of interpolated data, patients were outside the target range 32.1% of the time, with 15.4% of INR values > 3.0 and 16.7% of INR values < 2.0. However, division of the patients into quartiles based on proportion of time spent in target range highlighted that these average figures disguised a wide variation in the time spent out of target range. On average, patients in the quartile with worst control were out of target range for 71.6% of the time, as compared with 16.3% in the best controlled quartile.

Figure 3​3 shows the relation between the proportion of results within, above, and below the desired INR range of 2.0–3.0 by duration of treatment. The proportion of INR results outside the desired target range decreased as the duration of warfarin treatment increased, ranging from 52% outside the target range in the first month and decreasing to 30% after two years of monitoring.

There were 5350 hospital admissions for patients from the study group after the initial admission with a diagnosis of NVAF. The rate of hospitalisation increased the further the INR value deviated from the target range (fig 4​4).). The rates of admission were lowest when the INR value for the day before admission was towards the midpoint of the target range.

Within the group of patients who were routinely monitored with INR readings—assumed to result from warfarin treatment—almost a third of the treatment time and close to half of the raw INR readings were outside the target range. Even so, this result was rather low compared with those found in other published data,^17,18 possibly reflecting that the centre where this study took place is a university teaching hospital. Patients treated in other, non-academic settings may not achieve this level of control. The quality of care may also relate to the frequency of testing. The patients in our population had INR tests 23 times a year on average, whereas monitoring rates as high as 13 times within three months and as low as six times over a year have been reported.^19,20 The frequency of testing appears to depend on the local model of anticoagulation and, in addition to the quality of control provided, has direct consequences on the cost of AF management.²¹

The overall figure for the study group also conceals wide variation in the actual time spent in range by any individual patient. The quartile of patients with the poorest control spent, on average, almost three times as long out of range as the group with the best control. Patients were least likely to die or be admitted to hospital when their INR values were near to the midpoint of the target range. Although, in view of the influence of illness and changes in medication, it would be overly simplistic to assume a direct relation between a point INR result and overall outcomes, this may tend to confirm the target range as the optimal level of anticoagulation in NVAF.

Because of the inherent difficulty in maintaining control at the individual level, characterising what we mean by poor control in these patients was in itself difficult from a mathematical perspective. We investigated measurement of poor control through a number of alternative parameters in multivariate analysis, standardising for age, sex, and baseline morbidity. All of the selected measurements were associated with poor outcome.

Even in this group of patients, who at a population level appear to have good control, instability of INR values has significant implications for mortality and other clinical outcomes. We have shown an association between INR values outside the target range and increased rate of hospitalisation. In addition we have shown that a 10% increase in the amount of time out of range is associated with an increase in the likelihood of death of 29.3% and increased the probability of a thromboembolic event by 12.4%, confirming previous findings.^1,2 Since INR control was worst during the first three months after the initiation of warfarin and poor control was linked to an increased risk of events, it was likely that patients were at higher risk of events during their first months of treatment while an appropriate dose of warfarin was being established. However, some patients were anticoagulated after an index stroke event, which in itself predicts future stroke events.¹³ The improvements in time spent in range that occur over time may in part be caused by the withdrawal from treatment of patients who have the greatest difficulty with warfarin treatment, either in control or adverse events.

There were limitations to this study. No data were available describing medication including warfarin or warfarin dosage. Because of this we assumed that only patients who had some degree of continuous monitoring (> 4 INR observations) were treated with warfarin. We were unable to control for confounding factors including other medications and co-morbidities where that information was primarily held in primary care records. The lack of primary care health records also prevented us stratifying patients by their underlying risk of stroke, although it has been calculated that as few as 6% of patients with AF are at low risk of stroke.²² Furthermore, only patients who had an inpatient diagnosis of NVAF were included. Patients with AF diagnosed in primary care could not be identified; therefore, the patients included in the study may have greater morbidity than a sample selected from both the hospital and community. There are also methodological issues when attempting to estimate the proportion of time a patient is within or outside the target INR range.¹ The assumption that INR values change in a linear fashion is unlikely to be the case. Values may change sharply soon after a reading has been taken as a result of treatment management or before a reading that has been initiated by a clinical event. As a result extreme values of INR may lead to a bias, as the time spent at either extreme is overestimated. However, the proportion of measurements at these extreme values would be small¹³ and linear interpolation has been shown to be the simplest and most valid technique compared with other methods.²³ Given these limitations, these data describe the care and monitoring of a large cohort of patients, with a very large number of INR values over a lengthy study period.