Time in therapeutic range, quality of life and treatment satisfaction of patients on long-term warfarin for non-valvular atrial fibrillation: a cross-sectional study

Atrial fibrillation (AF) is the commonest arrhythmia and represents substantial health care burden globally [1]. In 2010, the estimated prevalence of AF was 592 per 100,000 in men and 360 per 100,000 in woman [2]. The risk of developing AF doubles with each progressive decade and exceeds 20% by 80 years old [3]. AF is associated with a five-fold increase in thromboembolic events, particularly stroke [4]. Studies have shown that one in six embolic strokes are attributed to underlying AF [5]. Without anticoagulant, the risk of embolic stroke in patients with AF ranges between 1.9 and 18.2% [6]. The common causes of AF include hypertension, diabetes mellitus, obesity, congestive heart failure, coronary heart disease, rheumatic heart disease and valvular heart disease [7]. Non-valvular AF (NVAF) is defined as AF not due to mitral disease or metallic valves [8].

Warfarin is a vitamin K antagonist broadly used to prevent embolic stroke in patients with AF. The therapeutic efficacy of warfarin is measured in international normalised ratio (INR). The target range of INR varies depending on the indications for anticoagulation [9]. The INR range recommended by American College of Chest Physician for patients with NVAF is 2.0–3.0 [9]. The time in therapeutic range (TTR) is defined as the percentage of time the patients INR was within the target range. Patients with higher TTR value have been reported to have better outcome such as lesser stroke, major haemorrhagic events and death [10].

The use of warfarin in patients with NVAF can be challenging. First, warfarin has narrow therapeutic index, therefore patients may need to attend healthcare facilities regularly for INR monitoring and dose adjustment. Second, the daily maintenance dose of warfarin can vary among patients and in the same patients. Third, the metabolism of warfarin can be affected by certain foods, drugs and alcohol [11]. Fourth, genetic variation has been shown to influence the metabolism of warfarin [12]. In spite of these challenges, warfarin is still a popular oral anticoagulant in NVAF, mainly due to its affordability and availability.

Health-related quality of life (HRQoL) is defined as individuals’ satisfaction or happiness with an aspect of life determined by their physical, mental, emotional or social functioning [13]. It is an emerging focus among patients receiving warfarin for NVAF due to the longer life expectancy brought about by the advancement in healthcare. Treatment satisfaction is defined as individuals’ rating of important attributes of the process and outcomes of their treatment experience, which involve the interaction of expectation, preference and satisfaction [14, 15]. The HRQoL of patients on warfarin is frequently impaired due to change in their lifestyle, risk of bleeding, as well as lack of objective symptomatic relief from the medications. At the same time, their HRQoL may also be affected by their treatment satisfaction. Improving and enhancing satisfaction with the treatment regime is an important aspect in management of patients with chronic illness, such as AF [16]. Studies have shown a higher satisfaction, higher adherence, better knowledge and lower apprehension to warfarin therapy is associated with significantly better INR control [17‐19].

To date, studies that assess the TTR, HRQoL and treatment satisfaction of patients taking warfarin for NVAF concurrently are still limited. Therefore, this study aims to evaluate the TTR, HRQoL and treatment satisfaction of patients taking warfarin for NVAF in a tertiary cardiology referral center located in Sarawak, a state in Malaysia. The HRQoL and treatment satisfaction of patients were also compared based on their TTR.

In the present study, only a quarter of patients had good TTR. Higher education level is the independent predictor of better TTR. The HRQoL of these patients was moderate, but their treatment satisfaction was good. The HRQoL and treatment satisfaction was similar irrespective of patients’ TTR. The only exception was patients with good TTR tends to have a better social functioning. Nearly one-fifth of patients had been hospitalised for bleeding tendency. Hospitalisations and bleeding tendency were independent of patients’ TTR.

Existing studies concluded patients from western countries had better TTR than their Asian counterpart. The International Study of Anticoagulant Management (INSAM) was a retrospective analysis of the real-world patients receiving warfarin for NVAF in five western countries, namely the United State, Canada, France, Italy and Spain [28]. The reported mean TTR was 57.0–68.9%, while the proportion of patients with good TTR (≥ 60%) was 47.7–75.1%. The Global Anticoagulant Registry in the Field (GARFIELD) AF reported an overall mean TTR of 55.4% and overall good TTR (≥ 65%) of 41.1% among their patients [21]. The subgroup analysis however demonstrated only 16.7% of Asian cohort had good TTR compare to 49.4% of European cohort. In another study by Chan et al., Hong Kong patients on warfarin for NVAF were reported to have a mean TTR of 38.8% and good TTR (≥ 65%) of 14.8% [29]. Oh et al. reported only 27% of Korean on warfarin for NVAF had good TTR (≥ 60%) [30]. Therefore, the lower mean TTR and the fewer good TTR among patients in this study were similar to other Asia studies. The possible explanations for this variation include Asian may have different diet and genetic, such as polymorphisms of VKOR1 and CYP2C9 genes [11, 12, 31]. The INSAM study and a meta-analysis by van Walraven et al. reported the clinical setting of warfarin given was the strongest predictor of patients TTR, being highest in randomised control trials, followed by anticoagulant clinic and community practise [28, 32]. The present study further added low education level was associated with a poorer TTR.

Regardless of the TTR, patients receiving warfarin for NVAF in the present study have markedly lower score in each domain of SF-12v2 (good TTR: 47.9–56.9; poor TTR: 46.5–56.1) when compare to Malaysia general population (SF-36, 66.7–86.0) [33], therefore significates a poorer HRQoL. To date, there is no published data that compares the HRQoL of adult patients on warfarin for NVAF based on their TTR. Most of the existing studies either compare the HRQoL of these patients versus those on DOAC, or in a longitudinal manner. Ng et al. [34], Benzimra et al. [35], Contreras et al. [36] and Alegret et al. [37] have reported no significant difference in the HRQoL of patients with NVAF receiving long-term warfarin versus DOAC in real-world scenario. On the other hand, Balci et al. reported significant improvement in every domain of SF-12v2 (all p < 0.001) [38], while de Caterina et al. reported significant improvement in severe mobility problem (p = 0.003), pain/discomfort (p = 0.035), and anxiety/depression (p < 0.001) of EuroQoL Instrument 5 levels (EQ-5D-5L) among NVAF patients after switching from warfarin to DOAC [39]. The patients in the current study had slightly higher value in each domain of the SF-12v2 except SF, but much lower mean TTR (47.0% vs. 54.9%) and proportion with good TTR (24.3% vs. 45.0%) when compared to similar subgroup of patients reported in Ng et al. [34]. Both studies were conducted in the anticoagulant clinic of a tertiary hospital, but the latter located in the Peninsular of Malaysia. The better social functioning among patients with good TTR in the current study could be due to their higher education level.

In this study, the finding of treatment satisfaction was independent of patients’ TTR was consistent with that reported in previous study. In the Outcome Registry for Better Informed Treatment of AF (ORBIT-AF) study, the treatment satisfaction of patients on warfarin for AF evaluated by using Anti-Clot Treatment scale (ACTS) was not affected by the TTR [40]. Similar finding was also observed in the Korean patients who received warfarin for NVAF when assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM) [30]. A post-hoc study (ALADIN and ESPARTA) however reported significantly higher ACTS burden scale (better satisfaction) in NVAF patients with good TTR (≥ 50%) (p = 0.024) [19]. The cut-off point of good TTR in this study was lower than that commonly used (60–65%), therefore unable to make direct comparison with the current study.

The current study concludes that majority of the NVAF patients attending SHC had poor anticoagulant control, which may be attributed to lower education level. We recommend patients with poor TTR should be reassured that achieving a good TTR confers a better clinical outcome but does not compromise their HRQoL or satisfaction. These patients may benefit from frequent education on anticoagulant by clinicians and pharmacists during their follow-up appointments. Furthermore, the implementation of warfarin medication therapy adherence clinic (WMTAC) protocol may also help to improve patients’ INR control [41]. Switching from warfarin to DOAC should be consider in NVAF patients with poor TTR in view of the better efficacy, HRQoL and treatment satisfaction, as well as lesser side-effects. In area where the poor INR control among NVAF patients is common, DOAC should be consider as the first-line anticoagulant.

To our knowledge, this is the first study that compares the HRQoL of NVAF patients on long-term warfarin based on their TTR. Analysis of each domain of the SF12v2 and each item of the DASS were performed in order to provide a more detailed comparison. The analyses of HRQoL and treatment satisfaction were adjusted for treatment duration and education level as cofounders to minimise the result bias. This study had several limitations. Firstly, it was performed in a single centre, thus limiting the generalisability of the results. Secondly, the cross-sectional design might not be able to completely reflect the HRQoL, as HRQoL may vary over time. Thirdly, the patients HAS-BLED score and severity of bleeding was not assessed. Most of the patients were unable to remember their non-clinical significant minor bleed episode. Fourthly, patients with vascular disease taking anti-platelet were excluded. Fifthly, the TTR was calculated by using Rosendaal technique only, without comparison to the traditional method. The former assumes the changes between consecutive INR measurements are linear over time, while the latter only consider the INR value at a point of time. Finally, the treatment complications were subject to the recall bias of patients, but this was minimised by double checking available medical records.

Majority of the patients on long-term warfarin for NVAF in the current study have poor TTR. Their HRQoL and treatment satisfaction are independent of their TTR. Achieving a good TTR do not compromise the HRQOL and treatment satisfaction. Therefore, appropriate measures should be taken to optimise INR control, failing which DOAC therapy should be considered. Self-management of warfarin can improve patients’ HRQoL, while adequate anticoagulant education that promote better understanding of different dosage forms, drug regime and potential side-effects can improve their treatment satisfaction.