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Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation
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Heart, Lung and Circulation (2019) -, -–1443-9506/19/$36.00 https://doi.org/10.1016/j.hlc.2019.11.006
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ORIGINAL ARTICLE
Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation Mau T. Nguyen, MBBS, BMedSci, Celine Gallagher, RN, PhD, Bradley M. Pitman, BSc, Mehrdad Emami, MBBS, Kadhim Kadhim, MBChB, Jeroen M. Hendriks, RN, PhD, Melissa E. Middeldorp, PhD, Kurt C. Roberts-Thomson, MBBS, PhD, Rajiv Mahajan, MD, PhD, Dennis H. Lau, MBBS, PhD, Prashanthan Sanders, MBBS, PhD, Christopher X. Wong, MBBS, MSc, MPH, PhD* Centre for Heart Rhythm (CHRD), South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide and the Royal Adelaide Hospital, Adelaide, SA, Australia Received 23 September 2019; received in revised form 20 October 2019; accepted 10 November 2019; online published-ahead-of-print xxx
Background
Studies have shown that suboptimal anticoagulation quality, as measured by time in therapeutic range (TTR), affects a significant percentage of patients with atrial fibrillation (AF). However, TTR has not been previously characterised in Indigenous Australians who experience a greater burden of AF and stroke.
Method
Indigenous and non-Indigenous Australians with AF on warfarin anticoagulation therapy were identified from a large tertiary referral centre between 1999 and 2012. Time in therapeutic range was calculated as a proportion of daily international normalised ratio (INR) values between 2 and 3 for non-valvular AF and 2.5 to 3.5 for valvular AF. INR values between tests were imputed using the Rosendaal technique. Linear regression models were employed to characterise predictors of TTR.
Results
Five hundred twelve (512) patients with AF on warfarin were included (88 Indigenous and 424 nonIndigenous). Despite younger age (51613 vs 71612 years, p,0.001), Indigenous Australians had greater valvular heart disease, diabetes, and alcohol excess compared to non-Indigenous Australians (p,0.05 for all). Time in therapeutic range was significantly lower in Indigenous compared to non-Indigenous Australians (40629 vs 50631%, p=0.006). Univariate predictors of poorer TTR included Indigenous ethnicity, younger age, diuretic use, and comorbidities, such as valvular heart disease, heart failure and chronic obstructive pulmonary disease (p,0.05 for all). Valvular heart disease remained a significant predictor of poorer TTR in multivariate analyses (p=0.004).
Conclusion
Indigenous Australians experience particularly poor warfarin anticoagulation quality. Our data also suggest that many non-Indigenous Australians spend suboptimal time in therapeutic range. These findings reinforce the importance of monitoring warfarin anticoagulation quality to minimise stroke risk.
Keywords
Atrial fibrillation Anticoagulation Warfarin Stroke Indigenous
*Corresponding author at: Department of Cardiology, Royal Adelaide Hospital Adelaide, SA 5000, Australia., Email: [email protected] Ó 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Nguyen MT, et al. Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.006
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Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia and a leading cause of preventable stroke [1–6]. It affects over 33 million people worldwide and increases the risk of ischaemic stroke by three- to five-fold [4,7–10]. Fortunately, appropriate anticoagulation therapy in patients with AF can reduce the risk of ischaemic stroke by almost 70% [11]. Thus, it is critical that patients with AF who are eligible for anticoagulation therapy be treated according to recommended guidelines [12]. Warfarin, a vitamin K antagonist, is the most widely used anticoagulant in the world and is used routinely for stroke prevention in AF [13,14]. Despite the introduction of newer, non-vitamin K oral anticoagulants that overcome several limitations associated with warfarin, the use of warfarin remains common in many settings [14,15]. Briefly, limitations of warfarin include extensive drug-drug interactions and a narrow therapeutic index that requires close monitoring [13]. Monitoring of warfarin therapy is achieved using a standardised laboratory measure—the International Normalised Ratio (INR). Multiple studies have reported that patients with AF on warfarin spend as much as 50% of the time outside pre-determined therapeutic ranges [16–18]. This is of concern as sub-therapeutic administration of warfarin increases the risk of thrombotic events while supra-therapeutic dosing increases the risks of haemorrhage [13]. In keeping with other countries that report racial differences in the prevalence of AF, data from us and other investigators have reported a disproportionate burden of AF in Indigenous Australians compared to their non-Indigenous counterparts [19,20]. We have also shown that Indigenous Australians were more likely to receive non-guideline recommendation antithrombotic therapy for AF [21]. These studies suggest that AF and suboptimal anticoagulation may be a contributing factor to the disproportionate burden of stroke experienced by disadvantaged populations, of which Indigenous Australians are a well reported subgroup in Australia. However, there is little data on the quality of warfarin anticoagulation therapy in Australian patients with AF and whether this differs in Indigenous populations. Therefore, the aim of the present study was to characterise the quality of warfarin anticoagulation therapy and predictors of time in therapeutic range (TTR) in Indigenous and nonIndigenous Australians.
Methods Study Population Consecutive Indigenous and non-Indigenous Australians with AF were identified from clinical and administrative databases at the Royal Adelaide Hospital, a metropolitan-based tertiary referral centre and teaching hospital of the universities of Adelaide and South Australia, between 1999 and 2012. Indigenous status was based on self-identified ethnicity. Patients with AF on warfarin anticoagulation therapy were
M.T. Nguyen et al.
identified from these databases. Eligible Indigenous Australians with AF on warfarin were subsequently randomly matched only on ethnicity to non-Indigenous Australians with AF on warfarin on a 1:4 basis. Administrative, clinical, prescriptive and laboratory data for included patients were linked. Comorbidities were derived from clinical databases as recorded by treating physicians, with the exception of valvular heart disease which we defined as at valvular dysfunction of at least moderate severity or in the presence of a prosthetic valve. Medication use was derived from prescription databases.
Calculation of Time in Therapeutic Range (TTR) Patient INR results were derived from formal laboratory testing and accessed from a centralised electronic database. Individual patient TTR was then calculated as a proportion of daily INR values within a range of INR 2.0–3.0. This was varied where clinical records stated a different target (e.g. INR 2.5–3.5 for mechanical valves). As is standard and previously described, daily INR values between consecutive measurements were assumed to be linear and the data were interpolated using the Rosendaal technique [22]. Based on manual adjudication of clinical records, the INR values from the first 7 days after warfarin treatment was started or restarted, time after permanent discontinuation of anticoagulation, and time greater than 5 days from temporary discontinuation was not included in the calculation of TTR.
Statistical Analysis Continuous variables were reported as mean 6 standard deviation (SD) as appropriate to distribution. Study sample characteristics were compared using independent sample t-test or chi-squared tests as appropriate. The difference in TTR between Indigenous and non-Indigenous Australians was assessed using an independent sample t-test. Univariate linear regression analyses were employed to determine associations between baseline variables and TTR as a continuous variable. Age, gender, Indigenous ethnicity, and other baseline variables with an alpha of 0.1 in univariate analyses were included in subsequent multivariate linear regression analyses. All statistical analyses were performed using Stata 13.0 (Stata Statistical Software, StataCorp LP, Release 13, College Station, TX, USA) with p,0.05 considered statistically significant.
Results Baseline Characteristics This study included a total of 512 patients with AF on warfarin anticoagulation therapy (Table 1). Of these, 17.2% were Indigenous Australians (n=88) and 82.8% were nonIndigenous Australians (n=424). Despite their younger age (51613 vs 71612 years, p,0.001) Indigenous Australians had significantly greater rates of valvular heart disease
Please cite this article in press as: Nguyen MT, et al. Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.006
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Table 1 Baseline Characteristics. Indigenous Australians with AF (n=88)
Non-Indigenous Patients with AF (n=424) 71 (12)
P-value ,0.001
Age, year (SD)
51 (13)
Female, n (%)
41 (46.6)
235 (55.4)
0.13
Valvular heart disease, n (%)
26 (29.6)
34 (8.0)
,0.001
Hypertension, n (%)
46 (52.3)
241 (56.8)
0.43
Ischaemic heart disease, n (%)
45 (51.1)
189 (44.6)
0.26
Prior myocardial infarction, n (%) Peripheral vascular disease, n (%)
39 (44.3) 5 (5.7)
161 (38.0) 40 (9.4)
0.27 0.26
Pre-existing heart failure, n (%)
46 (52.3)
188 (44.3)
0.17
5 (5.7)
70 (16.5)
0.009
Diabetes mellitus, n (%)
49 (55.7)
184 (43.4)
0.035
Chronic obstructive pulmonary
14 (15.9)
76 (17.9)
0.65
22 (25)
Prior stroke or TIA, n (%)
disease, n (%) Chronic kidney disease, n (%)
70 (16.5)
0.06
9 (10.2)
13 (3.1)
0.003
ACEI, n (%)
59 (67.1)
219 (51.7)
0.008
ARB, n (%)
11 (12.5)
66 (15.6)
0.46
Calcium channel blockers, n (%)
17 (19.3)
123 (29.0)
0.06
Beta blockers, n (%)
43 (48.9)
207 (48.8)
0.99
Diuretics, n (%)
56 (63.6)
223 (52.6)
0.06
Amiodarone, n (%)
18 (20.5)
77 (18.2)
0.61
Statin, n (%)
32 (36.4)
85 (20.1)
0.001
Alcoholism Medications:
Abbreviations: SD, standard deviation; n, number; TIA, transient ischaemic attack; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker.
(29.6% vs 8.0%, p,0.001), diabetes mellitus (55.7% vs 43.4%, p,0.05), and alcohol excess (10.2% vs 3.1%, p,0.01). Furthermore, Indigenous Australians had greater prescription of angiotensin converting enzyme inhibitors (67.1% vs 51.7%, p,0.01) and statins (36.4% vs 20.1%, p,0.01)
80
60
40
20
0 Indigenous Australians
compared to their non-Indigenous counterparts. In contrast, a prior history of stroke was more common in the nonIndigenous population (16.5% vs 5.7%, p,0.01).
Indigenous Status and Time in Therapeutic Range Overall, Indigenous Australians had a significantly lower TTR compared to non-Indigenous Australians (40629 vs 50631%, p=0.006; Figure 1). Univariate predictors significantly associated with poorer TTR included Indigenous status (p=0.006), younger age (p,0.05), diuretic use (p,0.001), and the presence of comorbidities such as heart failure (p,0.05), valvular heart disease (p,0.001) and chronic obstructive pulmonary disease (p,0.05; Table 2). In multivariate analyses, the association between Indigenous Australian status and poorer TTR was attenuated, with only the presence of valvular heart disease (p=0.004) remaining a significant predictor of poorer TTR (Table 3).
p<0.001
100
TTR (Mean %)
249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313
Non-Indigenous Australians
Figure 1 Quality of warfarin anticoagulation determined by TTR between Indigenous and non-Indigenous Australians. Abbreviation: TTR, time in therapeutic range.
Discussion Major Findings In this study we sought to quantify the degree and variability of warfarin therapy in Indigenous and non-Indigenous
Please cite this article in press as: Nguyen MT, et al. Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.006
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Table 2 Univariable predictors of time in therapeutic range (TTR). Coefficient 95% Confidence P-value Interval Indigenous status
-9.97
-17.0 to -2.9
0.006
Age
0.22
0.03 to 0.41
0.023
Female
2.09
-3.3 to 7.5
Valvular heart disease Hypertension
-17.88
-26.1 to -9.7
0.444 ,0.001
2.46
-2.9 to 7.9
0.37
-2.05
-7.4 to 3.3
0.45
-1.38
-6.9 to 4.1
0.62
Peripheral vascular
-8.81
-18.2 to 0.6
0.067
disease Pre-existing heart
-5.80
-11.2 to -0.5
0.033
Ischaemic heart disease Prior myocardial infarction
failure Prior stroke or TIA
2.03
-5.5 to 9.6
0.60
Diabetes mellitus
-3.65
-9.0 to 1.7
0.18
Chronic obstructive
-8.08
-15.1 to -1.1
0.023
Chronic kidney
-3.11
-10.1 to 3.9
0.38
disease Alcoholism
-1.38
-14.6 to 11.8
0.84
pulmonary disease
Medications: ACE
-4.39
-9.8 to 1.0
0.11
ARB
2.60
-4.9 to 10.1
0.50
-0.63
-6.6 to 5.4
0.84
Beta blockers
1.25
4.1 to 6.6
Diuretics Amiodarone
-9.65 -6.58
Calcium channel blockers
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Statin
0.18
-15.0 to -4.4 -13.4 to 0.3 -6.2 to 6.
0.65 ,0.001 0.060 0.96
Abbreviations: TIA, transient ischaemic attack; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker.
Australians. Our data demonstrate that the quality of warfarin anticoagulation therapy, as measured by TTR, is significantly worse in Indigenous Australians compared to non-Indigenous Australians. Multivariable analyses suggested this association may be at least in-part related to younger age, the presence of comorbidities, and medication use. Prior studies have consistently reported that poor quality of warfarin anticoagulation, as reflected by suboptimal TTR, is significantly predictive of worse outcomes [23]. Our current findings thus suggest that efforts to improve anticoagulation quality in both Indigenous and non-Indigenous Australians are likely to be of significant clinical and population benefit.
Anticoagulation for AF With a reported ischaemic stroke risk reduction of 70%, warfarin is an effective anticoagulant for many patients with
AF [8]. Recently, several non-vitamin K oral anticoagulants (NOACs) have become available for use as an alternative to warfarin. NOACs act through the direct inhibition of thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban and edoxaban). Meta-analyses have demonstrated that NOACs are at least non-inferior to warfarin in terms of thromboembolism prevention and superior from a bleeding point of view [24,25]. One possible conclusion from our data is that some Indigenous Australians with particularly poor TTR may benefit from transition to NOACs. However, many individuals are likely to be continued on warfarin anticoagulation [14,26]. Furthermore, NOACs are not suitable in certain patient subgroups. The major randomised controlled trials evaluating NOACs excluded patients with valvular heart disease [27]. Moreover, the use of NOACs is contraindicated in patients with significant renal impairment [27,28]. These contraindications are of particular concern to Indigenous Australians who have significantly higher rates of valvular heart disease and chronic kidney disease compared to non-Indigenous Australians [21,29].
Previous Studies Several previous studies conducted outside Australia have shown commonly suboptimal TTR while on warfarin, with reported values around 50% [16–18,30]. This is concerning as previous studies have shown that patients who have optimal TTR (i.e. greater than 70%) have significantly lower rates of stroke and systemic embolism (1.1% vs 2.1%), major bleeding (1.6% vs 3.9%) and mortality (1.7% vs 4.2%) compared to those who have poor control (TTR below 60%) [31]. However, to the best of our knowledge, there is a paucity of data conducted in Australian settings characterising the quality of warfarin therapy in patients with AF and even less in Indigenous individuals. One small study has described the quality of warfarin therapy in 167 patients living in remote communities of Northern Australia [14]. They report that patients were within therapeutic range 55% of the time using the Rosendaal technique. This is comparable to the TTR from the non-Indigenous arm of our study. However, there are several study differences worth discussing. Firstly, whether these results are applicable to urban patients remains unclear. Secondly, the prior study had a relatively small sample and was conducted in a remote setting where access to pathology services and specialised staff is a significant issue [32]. Lastly, while there is a high representation of Indigenous Australians in remote Australia, their data regarding TTR was not presented according to ethnicity, thus limiting direct comparison to our data in which Indigenous Australians had significantly lower (approximately 40%) compared to their non-Indigenous counterparts (approximately 50%).
Possible Factors Associated With Poor TTR We sought to determine factors that were predictive of TTR in Indigenous and non-Indigenous Australians. A knowledge of factors associated with TTR in clinical practice may
Please cite this article in press as: Nguyen MT, et al. Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.006
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Table 3 Multivariable-adjusted associations with time in therapeutic range (TTR). Coefficient Indigenous status
95% Confidence Interval
P-value
-4.91
-13.3 to 3.5
0.25
Age
0.09
-0.1 to 0.3
0.43
Gender
1.39
-4.0 to 6.8
0.61
-12.73
-21.5 to 4.0
0.004
-0.89
-6.6 to 4.8
0.76
-5.32
-12.5 to 1.9
0.15
-8.13
-17.5 to 1.3
0.09
-4.88 -4.12
-10.8 to 1.0 -11.0 to 2.7
0.10 0.24
Valvular heart disease Pre-existing heart failure Chronic obstructive pulmonary disease Peripheral vascular disease Diuretic use Amiodarone
Abbreviation: TTR, time in therapeutic range.
provide opportunities to improve outcomes in patients with AF through preventative measures, intensifying follow-up and/or the consideration of other treatment options, such as NOACs. In the present study, we found that Indigenous ethnicity and younger age were significantly associated with poorer TTR. However, the association between Indigenous ethnicity and TTR was attenuated and non-significant in multivariable analyses, suggesting part of this relationship is mediated by differences in other comorbid factors. While our data suggested that gender was not significantly associated with TTR, other studies have reported female gender to be a predictor of poor TTR [33]. Furthermore, the presence of preexisting comorbidities, such as valvular heart disease, heart failure, peripheral vascular disease and chronic obstructive pulmonary disease, and diuretic use were significantly associated with lower TTR. This is in keeping with other studies that report similar associations between poor TTR and other comorbidities commonly seen with AF, such as diabetes and hypertension [34]. Our data showed a trend towards a negative univariate association between amiodarone use and TTR, consistent with prior data [33]. The underlying mechanism between amiodarone and TTR is most likely related to the up-regulation of CYP2C9 which is the main P450 liver enzyme that metabolises warfarin and terminates its pharmacological activity [35]. In addition to the burden of medical comorbidities, prior research has shown that patient non-adherence to warfarin therapy is common and remains an ongoing issue for care providers; even in the setting of dedicated anticoagulation clinics [36,37]. Given that the determinants of medication adherence are complex and may involve different factors for different populations, concerted efforts to identify and address these factors will likely improve adherence and thus TTR. In regard to Indigenous Australians, poor health
literacy, increased patient mobility due to sociocultural obligations and difficulties in accessing medicines have been reported as barriers to adherence [38,39]. Taken together, these data suggest that Australians who are of Indigenous ethnicity, younger age and who have significant comorbidities and medication burden may require more attention, active monitoring and personalisation of patientdoctor interaction to improve TTR in those treated with warfarin.
Implications Our findings provide evidence of a previously underrecognised factor that is likely to be contributing to the health disparities existing between Indigenous and nonIndigenous Australians. We demonstrated that, although the quality of warfarin therapy was suboptimal regardless of ethnicity, Indigenous Australians had significantly worse TTR. Given the suboptimal TTR observed in both groups, any improvement is likely to have a significant impact on the incidence of complications associated with subtherapeutic and supratherapeutic warfarin therapy such as stroke and bleeding respectively. For example, prior data suggest that ischaemic stroke rates are inversely related to TTR, with a 0.74% increase in ischaemic stroke incidence per year for every 10% decrease in TTR [40]. Apart from efforts to improve TTR, one potential conclusion from our data is that patients with poor TTR should be considered for NOACs. Indeed, prior data suggest that a larger clinical benefit from NOAC compared to warfarin is present in those with poor TTR, supporting this as a potential strategy in eligible Indigenous patients with particularly poor TTR [40]. However, given the significant proportion of valvular AF and chronic kidney disease in Indigenous Australians, warfarin is likely to remain the main option for anticoagulation in these patients. Therefore, in patients with contraindications to NOAC efforts should be aimed at addressing patient factors that may affect optimal warfarin therapy, such as improving access to point of care testing and education initiatives. Furthermore, other data propose that a target threshold TTR of at least 58% exists, below which there may be little additional benefit from warfarin anticoagulation therapy [41]. Our current findings thus have significant implications given that both Indigenous and non-Indigenous populations had mean TTR below this threshold. These findings highlight the importance of vigilant monitoring and the need to improve current routine clinical practice in order to maximise the therapeutic benefit for all patients on warfarin anticoagulation therapy.
Study Limitations A number of study limitations are worthy of consideration. The retrospective nature precluded prespecified and prospective collection of data and clinical encounters. For example, there is likely to be ethnic differences in access to health care that may result in under-diagnoses of comorbidities in Indigenous Australians. There was also no regular,
Please cite this article in press as: Nguyen MT, et al. Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.006
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prospective collection of INR measurements. However, every effort was made to correlate INR trends with administrative records to identify periods of treatment alteration and, in some cases, cessation of warfarin treatment which could introduce inaccuracies to TTR calculation. Furthermore, medication adherence and persistence could not be assessed in this study. This is relevant to both Indigenous and nonIndigenous individuals and is also likely to influence TTR. Our cohort size was relatively small which limits statistical power in regression models. This may potentially explain discrepancies between some variables not found to significantly associated with TTR in the present report in contrast to other studies with larger cohort sizes. Finally, the single centre and metropolitan nature of our study also limits the generalisability of our results. Given access of care may vary in different settings, future studies should confirm our findings in other populations.
Conclusion Our study showed that the quality of warfarin anticoagulation therapy, as determined by TTR, is suboptimal in Indigenous Australians compared to their non-Indigenous counterparts. This discrepancy may be in-part due to differences in age, comorbidities and medication use. However, warfarin anticoagulation quality was also suboptimal in nonIndigenous Australians, suggesting that efforts to improve monitoring and implementation of corrective measures may be warranted in general.
Acknowledgements Q3
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Sources of Funding Dr Gallagher and Dr Middeldorp are supported by Postdoctoral Fellowships from the University of Adelaide. Dr Hendriks is supported by a Future Leader Fellowship from the National Heart Foundation of Australia. Dr. Lau and Dr Wong are supported by Mid-Career Fellowships from The Hospital Research Foundation. Dr. Wong is also supported by a Postdoctoral Fellowship from the National Heart Foundation of Australia. Dr. Sanders is supported by a Practitioner Fellowship from NHMRC and by the National Heart Foundation of Australia.
Potential Conflict of Interest Q4
Dr. Lau reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Abbott Medical, Bayer, Boehringer Ingelheim, Biotronik, Medtronic and Pfizer. Dr Sanders reports having served on the advisory board of Biosense-Webster, Medtronic, St Jude Medical, Boston Scientific and CathRx. Dr Sanders reports that the University of Adelaide has received on his behalf lecture
M.T. Nguyen et al.
and/or consulting fees from Biosense-Webster, Medtronic, St Jude Medical, and Boston Scientific. Dr Sanders reports that the University of Adelaide has received on his behalf research funding from Medtronic, St Jude Medical, Boston Scientific, Biotronik and LivaNova. Dr. Wong reports that the University of Adelaide has received on his behalf lecture, travel and/or research funding from Novartis, Servier, Boehringer Ingelheim and Medtronic.
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[19] Wong CX, Brooks AG, Cheng YH, Lau DH, Rangnekar G, RobertsThomson KC, et al. Atrial fibrillation in Indigenous and non-Indigenous Australians: a cross-sectional study. BMJ open 2014;4(10):e006242. [20] Katzenellenbogen JM, Teng TH, Lopez D, Hung J, Knuiman MW, Sanfilippo FM, et al. Initial hospitalisation for atrial fibrillation in Aboriginal and non-Aboriginal populations in Western Australia. Heart 2015;101(9):712–9. [21] Wong CX, Lee SW, Gan SW, Mahajan R, Rangnekar G, Pathak RK, et al. Underuse and overuse of anticoagulation for atrial fibrillation: A study in Indigenous and non-Indigenous Australians. Int J Cardiol 2015;191:20–4. [22] Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemos 1993;69(3):236–9. [23] Currie CJ, McEwan P, Emmas C, Morgan CL, Peters JR. Anticoagulation in patients with non-valvular atrial fibrillation: an evaluation of stability and early factors that predict longer-term stability on warfarin in a large UK population. Curr Med Res Opin 2005;21(12):1905–13. [24] Hicks T, Stewart F, Eisinga A. NOACs versus warfarin for stroke prevention in patients with AF: a systematic review and meta-analysis. Open heart 2016;3(1):e000279. [25] Capodanno D, Capranzano P, Giacchi G, Calvi V, Tamburino C. Novel oral anticoagulants versus warfarin in non-valvular atrial fibrillation: a meta-analysis of 50,578 patients. Int J Cardiol 2013;167(4):1237–41. [26] Di Biase L. Use of direct oral anticoagulants in patients with atrial fibrillation and valvular heart lesions. J Am Heart Assoc 2016;5(2). [27] Manning W, Singer D, GYH L. Atrial fibrillation: anticoagulant therapy to prevent embolization. Waltham, MA: UpToDate; 2017. [28] Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag 2015;11:967–77. [29] Preston-Thomas A, Cass A, O’Rourke P. Time to systematically replace warfarin with a new oral anticoagulant for higher-risk patients with nonvalvular atrial fibrillation? Aust N Z J Public Health 2007;31(5):419–21. [30] Leong-Sit P, Healey JS. Is It Time to Systematically Replace Warfarin With a New Oral Anticoagulant for Higher-Risk Patients With Nonvalvular Atrial Fibrillation? Can J Cardiol 2016;32(10):1203.e9–1203.e11. [31] White HD, Gruber M, Feyzi J, Kaatz S, Tse HF, Husted S, et al. Comparison of outcomes among patients randomized to warfarin therapy
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according to anticoagulant control: results from SPORTIF III and V. Arch Intern Med 2007;167(3):239–45. Jackson SL, Bereznicki LR, Peterson GM, Marsden KA, Jupe DM, Vial JH, et al. Accuracy and clinical usefulness of the near-patient testing CoaguChek S international normalised ratio monitor in rural medical practice. Aust J Rural Health 2004;12(4):137–42. Lobos-Bejarano JM, Barrios V, Polo-Garcia J, Escobar C, Vargas-Ortega D, Marin-Montanes N, et al. Evaluation of SAMe-TT2R2 score and other clinical factors influencing the quality of anticoagulation therapy in non-valvular atrial fibrillation: a nationwide study in Spain. Current medical research and opinion 2016;32(7):1201–7. Nelson WW, Choi JC, Vanderpoel J, Damaraju CV, Wildgoose P, Fields LE, et al. Impact of co-morbidities and patient characteristics on international normalized ratio control over time in patients with nonvalvular atrial fibrillation. Am J Cardiol 2013;112(4):509–12. McDonald MG, Au NT, Wittkowsky AK, Rettie AE. Warfarin-amiodarone drug-drug interactions: determination of [I](u)/K(I,u) for amiodarone and its plasma metabolites. Clin Pharmacol Ther 2012;91(4):709–17. Cruess DG, Localio AR, Platt AB, Brensinger CM, Christie JD, Gross R, et al. Patient attitudinal and behavioral factors associated with warfarin non-adherence at outpatient anticoagulation clinics. Int J Behav Med 2010;17(1):33–42. Platt AB, Localio AR, Brensinger CM, Cruess DG, Christie JD, Gross R, et al. Risk factors for nonadherence to warfarin: results from the IN-RANGE study. Pharmacoepidemiol Drug Saf 2008;17(9):853–60. de Dassel JL, Ralph AP, Cass A. A systematic review of adherence in Indigenous Australians: an opportunity to improve chronic condition management. BMC Health Serv Res 2017;17(1):845. Davidson PM, Abbott P, Davison J, Digiacomo M. Improving medication uptake in aboriginal and Torres Strait islander peoples. Heart Lung Cir 2010;19(5-6):372–7. Chan PH, Huang D, Lau CP, Chan EW, Wong IC, Lip GY, et al. Net clinical benefit of dabigatran over warfarin in patients with atrial fibrillation stratified by CHA2DS2-VASc and time in therapeutic range. Can J Cardiol 2016;32(10):1247.e15–21. Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi MG, et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008;118(20): 2029–37.
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ORIGINAL ARTICLE
Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation Mau T. Nguyen, MBBS, BMedSci, Celine Gallagher, RN, PhD, Bradley M. Pitman, BSc, Mehrdad Emami, MBBS, Kadhim Kadhim, MBChB, Jeroen M. Hendriks, RN, PhD, Melissa E. Middeldorp, PhD, Kurt C. Roberts-Thomson, MBBS, PhD, Rajiv Mahajan, MD, PhD, Dennis H. Lau, MBBS, PhD, Prashanthan Sanders, MBBS, PhD, Christopher X. Wong, MBBS, MSc, MPH, PhD* Centre for Heart Rhythm (CHRD), South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide and the Royal Adelaide Hospital, Adelaide, SA, Australia Received 23 September 2019; received in revised form 20 October 2019; accepted 10 November 2019; online published-ahead-of-print xxx
Background
Studies have shown that suboptimal anticoagulation quality, as measured by time in therapeutic range (TTR), affects a significant percentage of patients with atrial fibrillation (AF). However, TTR has not been previously characterised in Indigenous Australians who experience a greater burden of AF and stroke.
Method
Indigenous and non-Indigenous Australians with AF on warfarin anticoagulation therapy were identified from a large tertiary referral centre between 1999 and 2012. Time in therapeutic range was calculated as a proportion of daily international normalised ratio (INR) values between 2 and 3 for non-valvular AF and 2.5 to 3.5 for valvular AF. INR values between tests were imputed using the Rosendaal technique. Linear regression models were employed to characterise predictors of TTR.
Results
Five hundred twelve (512) patients with AF on warfarin were included (88 Indigenous and 424 nonIndigenous). Despite younger age (51613 vs 71612 years, p,0.001), Indigenous Australians had greater valvular heart disease, diabetes, and alcohol excess compared to non-Indigenous Australians (p,0.05 for all). Time in therapeutic range was significantly lower in Indigenous compared to non-Indigenous Australians (40629 vs 50631%, p=0.006). Univariate predictors of poorer TTR included Indigenous ethnicity, younger age, diuretic use, and comorbidities, such as valvular heart disease, heart failure and chronic obstructive pulmonary disease (p,0.05 for all). Valvular heart disease remained a significant predictor of poorer TTR in multivariate analyses (p=0.004).
Conclusion
Indigenous Australians experience particularly poor warfarin anticoagulation quality. Our data also suggest that many non-Indigenous Australians spend suboptimal time in therapeutic range. These findings reinforce the importance of monitoring warfarin anticoagulation quality to minimise stroke risk.
Keywords
Atrial fibrillation Anticoagulation Warfarin Stroke Indigenous
*Corresponding author at: Department of Cardiology, Royal Adelaide Hospital Adelaide, SA 5000, Australia., Email: [email protected] Ó 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Nguyen MT, et al. Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.006
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Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia and a leading cause of preventable stroke [1–6]. It affects over 33 million people worldwide and increases the risk of ischaemic stroke by three- to five-fold [4,7–10]. Fortunately, appropriate anticoagulation therapy in patients with AF can reduce the risk of ischaemic stroke by almost 70% [11]. Thus, it is critical that patients with AF who are eligible for anticoagulation therapy be treated according to recommended guidelines [12]. Warfarin, a vitamin K antagonist, is the most widely used anticoagulant in the world and is used routinely for stroke prevention in AF [13,14]. Despite the introduction of newer, non-vitamin K oral anticoagulants that overcome several limitations associated with warfarin, the use of warfarin remains common in many settings [14,15]. Briefly, limitations of warfarin include extensive drug-drug interactions and a narrow therapeutic index that requires close monitoring [13]. Monitoring of warfarin therapy is achieved using a standardised laboratory measure—the International Normalised Ratio (INR). Multiple studies have reported that patients with AF on warfarin spend as much as 50% of the time outside pre-determined therapeutic ranges [16–18]. This is of concern as sub-therapeutic administration of warfarin increases the risk of thrombotic events while supra-therapeutic dosing increases the risks of haemorrhage [13]. In keeping with other countries that report racial differences in the prevalence of AF, data from us and other investigators have reported a disproportionate burden of AF in Indigenous Australians compared to their non-Indigenous counterparts [19,20]. We have also shown that Indigenous Australians were more likely to receive non-guideline recommendation antithrombotic therapy for AF [21]. These studies suggest that AF and suboptimal anticoagulation may be a contributing factor to the disproportionate burden of stroke experienced by disadvantaged populations, of which Indigenous Australians are a well reported subgroup in Australia. However, there is little data on the quality of warfarin anticoagulation therapy in Australian patients with AF and whether this differs in Indigenous populations. Therefore, the aim of the present study was to characterise the quality of warfarin anticoagulation therapy and predictors of time in therapeutic range (TTR) in Indigenous and nonIndigenous Australians.
Methods Study Population Consecutive Indigenous and non-Indigenous Australians with AF were identified from clinical and administrative databases at the Royal Adelaide Hospital, a metropolitan-based tertiary referral centre and teaching hospital of the universities of Adelaide and South Australia, between 1999 and 2012. Indigenous status was based on self-identified ethnicity. Patients with AF on warfarin anticoagulation therapy were
M.T. Nguyen et al.
identified from these databases. Eligible Indigenous Australians with AF on warfarin were subsequently randomly matched only on ethnicity to non-Indigenous Australians with AF on warfarin on a 1:4 basis. Administrative, clinical, prescriptive and laboratory data for included patients were linked. Comorbidities were derived from clinical databases as recorded by treating physicians, with the exception of valvular heart disease which we defined as at valvular dysfunction of at least moderate severity or in the presence of a prosthetic valve. Medication use was derived from prescription databases.
Calculation of Time in Therapeutic Range (TTR) Patient INR results were derived from formal laboratory testing and accessed from a centralised electronic database. Individual patient TTR was then calculated as a proportion of daily INR values within a range of INR 2.0–3.0. This was varied where clinical records stated a different target (e.g. INR 2.5–3.5 for mechanical valves). As is standard and previously described, daily INR values between consecutive measurements were assumed to be linear and the data were interpolated using the Rosendaal technique [22]. Based on manual adjudication of clinical records, the INR values from the first 7 days after warfarin treatment was started or restarted, time after permanent discontinuation of anticoagulation, and time greater than 5 days from temporary discontinuation was not included in the calculation of TTR.
Statistical Analysis Continuous variables were reported as mean 6 standard deviation (SD) as appropriate to distribution. Study sample characteristics were compared using independent sample t-test or chi-squared tests as appropriate. The difference in TTR between Indigenous and non-Indigenous Australians was assessed using an independent sample t-test. Univariate linear regression analyses were employed to determine associations between baseline variables and TTR as a continuous variable. Age, gender, Indigenous ethnicity, and other baseline variables with an alpha of 0.1 in univariate analyses were included in subsequent multivariate linear regression analyses. All statistical analyses were performed using Stata 13.0 (Stata Statistical Software, StataCorp LP, Release 13, College Station, TX, USA) with p,0.05 considered statistically significant.
Results Baseline Characteristics This study included a total of 512 patients with AF on warfarin anticoagulation therapy (Table 1). Of these, 17.2% were Indigenous Australians (n=88) and 82.8% were nonIndigenous Australians (n=424). Despite their younger age (51613 vs 71612 years, p,0.001) Indigenous Australians had significantly greater rates of valvular heart disease
Please cite this article in press as: Nguyen MT, et al. Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.006
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Table 1 Baseline Characteristics. Indigenous Australians with AF (n=88)
Non-Indigenous Patients with AF (n=424) 71 (12)
P-value ,0.001
Age, year (SD)
51 (13)
Female, n (%)
41 (46.6)
235 (55.4)
0.13
Valvular heart disease, n (%)
26 (29.6)
34 (8.0)
,0.001
Hypertension, n (%)
46 (52.3)
241 (56.8)
0.43
Ischaemic heart disease, n (%)
45 (51.1)
189 (44.6)
0.26
Prior myocardial infarction, n (%) Peripheral vascular disease, n (%)
39 (44.3) 5 (5.7)
161 (38.0) 40 (9.4)
0.27 0.26
Pre-existing heart failure, n (%)
46 (52.3)
188 (44.3)
0.17
5 (5.7)
70 (16.5)
0.009
Diabetes mellitus, n (%)
49 (55.7)
184 (43.4)
0.035
Chronic obstructive pulmonary
14 (15.9)
76 (17.9)
0.65
22 (25)
Prior stroke or TIA, n (%)
disease, n (%) Chronic kidney disease, n (%)
70 (16.5)
0.06
9 (10.2)
13 (3.1)
0.003
ACEI, n (%)
59 (67.1)
219 (51.7)
0.008
ARB, n (%)
11 (12.5)
66 (15.6)
0.46
Calcium channel blockers, n (%)
17 (19.3)
123 (29.0)
0.06
Beta blockers, n (%)
43 (48.9)
207 (48.8)
0.99
Diuretics, n (%)
56 (63.6)
223 (52.6)
0.06
Amiodarone, n (%)
18 (20.5)
77 (18.2)
0.61
Statin, n (%)
32 (36.4)
85 (20.1)
0.001
Alcoholism Medications:
Abbreviations: SD, standard deviation; n, number; TIA, transient ischaemic attack; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker.
(29.6% vs 8.0%, p,0.001), diabetes mellitus (55.7% vs 43.4%, p,0.05), and alcohol excess (10.2% vs 3.1%, p,0.01). Furthermore, Indigenous Australians had greater prescription of angiotensin converting enzyme inhibitors (67.1% vs 51.7%, p,0.01) and statins (36.4% vs 20.1%, p,0.01)
80
60
40
20
0 Indigenous Australians
compared to their non-Indigenous counterparts. In contrast, a prior history of stroke was more common in the nonIndigenous population (16.5% vs 5.7%, p,0.01).
Indigenous Status and Time in Therapeutic Range Overall, Indigenous Australians had a significantly lower TTR compared to non-Indigenous Australians (40629 vs 50631%, p=0.006; Figure 1). Univariate predictors significantly associated with poorer TTR included Indigenous status (p=0.006), younger age (p,0.05), diuretic use (p,0.001), and the presence of comorbidities such as heart failure (p,0.05), valvular heart disease (p,0.001) and chronic obstructive pulmonary disease (p,0.05; Table 2). In multivariate analyses, the association between Indigenous Australian status and poorer TTR was attenuated, with only the presence of valvular heart disease (p=0.004) remaining a significant predictor of poorer TTR (Table 3).
p<0.001
100
TTR (Mean %)
249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313
Non-Indigenous Australians
Figure 1 Quality of warfarin anticoagulation determined by TTR between Indigenous and non-Indigenous Australians. Abbreviation: TTR, time in therapeutic range.
Discussion Major Findings In this study we sought to quantify the degree and variability of warfarin therapy in Indigenous and non-Indigenous
Please cite this article in press as: Nguyen MT, et al. Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.006
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Table 2 Univariable predictors of time in therapeutic range (TTR). Coefficient 95% Confidence P-value Interval Indigenous status
-9.97
-17.0 to -2.9
0.006
Age
0.22
0.03 to 0.41
0.023
Female
2.09
-3.3 to 7.5
Valvular heart disease Hypertension
-17.88
-26.1 to -9.7
0.444 ,0.001
2.46
-2.9 to 7.9
0.37
-2.05
-7.4 to 3.3
0.45
-1.38
-6.9 to 4.1
0.62
Peripheral vascular
-8.81
-18.2 to 0.6
0.067
disease Pre-existing heart
-5.80
-11.2 to -0.5
0.033
Ischaemic heart disease Prior myocardial infarction
failure Prior stroke or TIA
2.03
-5.5 to 9.6
0.60
Diabetes mellitus
-3.65
-9.0 to 1.7
0.18
Chronic obstructive
-8.08
-15.1 to -1.1
0.023
Chronic kidney
-3.11
-10.1 to 3.9
0.38
disease Alcoholism
-1.38
-14.6 to 11.8
0.84
pulmonary disease
Medications: ACE
-4.39
-9.8 to 1.0
0.11
ARB
2.60
-4.9 to 10.1
0.50
-0.63
-6.6 to 5.4
0.84
Beta blockers
1.25
4.1 to 6.6
Diuretics Amiodarone
-9.65 -6.58
Calcium channel blockers
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Statin
0.18
-15.0 to -4.4 -13.4 to 0.3 -6.2 to 6.
0.65 ,0.001 0.060 0.96
Abbreviations: TIA, transient ischaemic attack; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker.
Australians. Our data demonstrate that the quality of warfarin anticoagulation therapy, as measured by TTR, is significantly worse in Indigenous Australians compared to non-Indigenous Australians. Multivariable analyses suggested this association may be at least in-part related to younger age, the presence of comorbidities, and medication use. Prior studies have consistently reported that poor quality of warfarin anticoagulation, as reflected by suboptimal TTR, is significantly predictive of worse outcomes [23]. Our current findings thus suggest that efforts to improve anticoagulation quality in both Indigenous and non-Indigenous Australians are likely to be of significant clinical and population benefit.
Anticoagulation for AF With a reported ischaemic stroke risk reduction of 70%, warfarin is an effective anticoagulant for many patients with
AF [8]. Recently, several non-vitamin K oral anticoagulants (NOACs) have become available for use as an alternative to warfarin. NOACs act through the direct inhibition of thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban and edoxaban). Meta-analyses have demonstrated that NOACs are at least non-inferior to warfarin in terms of thromboembolism prevention and superior from a bleeding point of view [24,25]. One possible conclusion from our data is that some Indigenous Australians with particularly poor TTR may benefit from transition to NOACs. However, many individuals are likely to be continued on warfarin anticoagulation [14,26]. Furthermore, NOACs are not suitable in certain patient subgroups. The major randomised controlled trials evaluating NOACs excluded patients with valvular heart disease [27]. Moreover, the use of NOACs is contraindicated in patients with significant renal impairment [27,28]. These contraindications are of particular concern to Indigenous Australians who have significantly higher rates of valvular heart disease and chronic kidney disease compared to non-Indigenous Australians [21,29].
Previous Studies Several previous studies conducted outside Australia have shown commonly suboptimal TTR while on warfarin, with reported values around 50% [16–18,30]. This is concerning as previous studies have shown that patients who have optimal TTR (i.e. greater than 70%) have significantly lower rates of stroke and systemic embolism (1.1% vs 2.1%), major bleeding (1.6% vs 3.9%) and mortality (1.7% vs 4.2%) compared to those who have poor control (TTR below 60%) [31]. However, to the best of our knowledge, there is a paucity of data conducted in Australian settings characterising the quality of warfarin therapy in patients with AF and even less in Indigenous individuals. One small study has described the quality of warfarin therapy in 167 patients living in remote communities of Northern Australia [14]. They report that patients were within therapeutic range 55% of the time using the Rosendaal technique. This is comparable to the TTR from the non-Indigenous arm of our study. However, there are several study differences worth discussing. Firstly, whether these results are applicable to urban patients remains unclear. Secondly, the prior study had a relatively small sample and was conducted in a remote setting where access to pathology services and specialised staff is a significant issue [32]. Lastly, while there is a high representation of Indigenous Australians in remote Australia, their data regarding TTR was not presented according to ethnicity, thus limiting direct comparison to our data in which Indigenous Australians had significantly lower (approximately 40%) compared to their non-Indigenous counterparts (approximately 50%).
Possible Factors Associated With Poor TTR We sought to determine factors that were predictive of TTR in Indigenous and non-Indigenous Australians. A knowledge of factors associated with TTR in clinical practice may
Please cite this article in press as: Nguyen MT, et al. Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.006
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Table 3 Multivariable-adjusted associations with time in therapeutic range (TTR). Coefficient Indigenous status
95% Confidence Interval
P-value
-4.91
-13.3 to 3.5
0.25
Age
0.09
-0.1 to 0.3
0.43
Gender
1.39
-4.0 to 6.8
0.61
-12.73
-21.5 to 4.0
0.004
-0.89
-6.6 to 4.8
0.76
-5.32
-12.5 to 1.9
0.15
-8.13
-17.5 to 1.3
0.09
-4.88 -4.12
-10.8 to 1.0 -11.0 to 2.7
0.10 0.24
Valvular heart disease Pre-existing heart failure Chronic obstructive pulmonary disease Peripheral vascular disease Diuretic use Amiodarone
Abbreviation: TTR, time in therapeutic range.
provide opportunities to improve outcomes in patients with AF through preventative measures, intensifying follow-up and/or the consideration of other treatment options, such as NOACs. In the present study, we found that Indigenous ethnicity and younger age were significantly associated with poorer TTR. However, the association between Indigenous ethnicity and TTR was attenuated and non-significant in multivariable analyses, suggesting part of this relationship is mediated by differences in other comorbid factors. While our data suggested that gender was not significantly associated with TTR, other studies have reported female gender to be a predictor of poor TTR [33]. Furthermore, the presence of preexisting comorbidities, such as valvular heart disease, heart failure, peripheral vascular disease and chronic obstructive pulmonary disease, and diuretic use were significantly associated with lower TTR. This is in keeping with other studies that report similar associations between poor TTR and other comorbidities commonly seen with AF, such as diabetes and hypertension [34]. Our data showed a trend towards a negative univariate association between amiodarone use and TTR, consistent with prior data [33]. The underlying mechanism between amiodarone and TTR is most likely related to the up-regulation of CYP2C9 which is the main P450 liver enzyme that metabolises warfarin and terminates its pharmacological activity [35]. In addition to the burden of medical comorbidities, prior research has shown that patient non-adherence to warfarin therapy is common and remains an ongoing issue for care providers; even in the setting of dedicated anticoagulation clinics [36,37]. Given that the determinants of medication adherence are complex and may involve different factors for different populations, concerted efforts to identify and address these factors will likely improve adherence and thus TTR. In regard to Indigenous Australians, poor health
literacy, increased patient mobility due to sociocultural obligations and difficulties in accessing medicines have been reported as barriers to adherence [38,39]. Taken together, these data suggest that Australians who are of Indigenous ethnicity, younger age and who have significant comorbidities and medication burden may require more attention, active monitoring and personalisation of patientdoctor interaction to improve TTR in those treated with warfarin.
Implications Our findings provide evidence of a previously underrecognised factor that is likely to be contributing to the health disparities existing between Indigenous and nonIndigenous Australians. We demonstrated that, although the quality of warfarin therapy was suboptimal regardless of ethnicity, Indigenous Australians had significantly worse TTR. Given the suboptimal TTR observed in both groups, any improvement is likely to have a significant impact on the incidence of complications associated with subtherapeutic and supratherapeutic warfarin therapy such as stroke and bleeding respectively. For example, prior data suggest that ischaemic stroke rates are inversely related to TTR, with a 0.74% increase in ischaemic stroke incidence per year for every 10% decrease in TTR [40]. Apart from efforts to improve TTR, one potential conclusion from our data is that patients with poor TTR should be considered for NOACs. Indeed, prior data suggest that a larger clinical benefit from NOAC compared to warfarin is present in those with poor TTR, supporting this as a potential strategy in eligible Indigenous patients with particularly poor TTR [40]. However, given the significant proportion of valvular AF and chronic kidney disease in Indigenous Australians, warfarin is likely to remain the main option for anticoagulation in these patients. Therefore, in patients with contraindications to NOAC efforts should be aimed at addressing patient factors that may affect optimal warfarin therapy, such as improving access to point of care testing and education initiatives. Furthermore, other data propose that a target threshold TTR of at least 58% exists, below which there may be little additional benefit from warfarin anticoagulation therapy [41]. Our current findings thus have significant implications given that both Indigenous and non-Indigenous populations had mean TTR below this threshold. These findings highlight the importance of vigilant monitoring and the need to improve current routine clinical practice in order to maximise the therapeutic benefit for all patients on warfarin anticoagulation therapy.
Study Limitations A number of study limitations are worthy of consideration. The retrospective nature precluded prespecified and prospective collection of data and clinical encounters. For example, there is likely to be ethnic differences in access to health care that may result in under-diagnoses of comorbidities in Indigenous Australians. There was also no regular,
Please cite this article in press as: Nguyen MT, et al. Quality of Warfarin Anticoagulation in Indigenous and Non-Indigenous Australians With Atrial Fibrillation. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.006
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prospective collection of INR measurements. However, every effort was made to correlate INR trends with administrative records to identify periods of treatment alteration and, in some cases, cessation of warfarin treatment which could introduce inaccuracies to TTR calculation. Furthermore, medication adherence and persistence could not be assessed in this study. This is relevant to both Indigenous and nonIndigenous individuals and is also likely to influence TTR. Our cohort size was relatively small which limits statistical power in regression models. This may potentially explain discrepancies between some variables not found to significantly associated with TTR in the present report in contrast to other studies with larger cohort sizes. Finally, the single centre and metropolitan nature of our study also limits the generalisability of our results. Given access of care may vary in different settings, future studies should confirm our findings in other populations.
Conclusion Our study showed that the quality of warfarin anticoagulation therapy, as determined by TTR, is suboptimal in Indigenous Australians compared to their non-Indigenous counterparts. This discrepancy may be in-part due to differences in age, comorbidities and medication use. However, warfarin anticoagulation quality was also suboptimal in nonIndigenous Australians, suggesting that efforts to improve monitoring and implementation of corrective measures may be warranted in general.
Acknowledgements Q3
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Sources of Funding Dr Gallagher and Dr Middeldorp are supported by Postdoctoral Fellowships from the University of Adelaide. Dr Hendriks is supported by a Future Leader Fellowship from the National Heart Foundation of Australia. Dr. Lau and Dr Wong are supported by Mid-Career Fellowships from The Hospital Research Foundation. Dr. Wong is also supported by a Postdoctoral Fellowship from the National Heart Foundation of Australia. Dr. Sanders is supported by a Practitioner Fellowship from NHMRC and by the National Heart Foundation of Australia.
Potential Conflict of Interest Q4
Dr. Lau reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Abbott Medical, Bayer, Boehringer Ingelheim, Biotronik, Medtronic and Pfizer. Dr Sanders reports having served on the advisory board of Biosense-Webster, Medtronic, St Jude Medical, Boston Scientific and CathRx. Dr Sanders reports that the University of Adelaide has received on his behalf lecture
M.T. Nguyen et al.
and/or consulting fees from Biosense-Webster, Medtronic, St Jude Medical, and Boston Scientific. Dr Sanders reports that the University of Adelaide has received on his behalf research funding from Medtronic, St Jude Medical, Boston Scientific, Biotronik and LivaNova. Dr. Wong reports that the University of Adelaide has received on his behalf lecture, travel and/or research funding from Novartis, Servier, Boehringer Ingelheim and Medtronic.
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