# The Tasmanian atrial fibrillation study : transition to direct oral anticoagulants

Alamneh, EA ORCID: 0000-0002-4924-719X 2018 , 'The Tasmanian atrial fibrillation study : transition to direct oral anticoagulants', PhD thesis, University of Tasmania.

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## Abstract

Atrial fibrillation (AF) is the most common cardiac dysrhythmia in the world, mainly affecting elderly individuals. The incidence and prevalence of AF are increasing globally owing to an increase in the aging population and associated risk factors. Epidemiological data show the overall prevalence of AF to be 1.5-2%, increasing from 0.7% in people aged 55-60 years to 17.8% in those aged ≥ 85 years. AF adversely affects cardiac haemodynamics leading to thromboembolism, manifesting as ischaemic stroke/transient ischaemic attack (TIA), deep venous thrombosis, pulmonary embolism, and myocardial infarction. Patients with AF have a 5-fold increase in the risk of stroke compared to patients without AF, and about 15-20% of all strokes are due to AF. AF-related strokes are often more severe, resulting in greater disability, and higher fatality and recurrence rates than non-AF-related strokes.
Oral anticoagulant (OAC) therapy is essential for thromboprophylaxis in AF. Evidence-based AF guidelines recommend OACs for patients with additional stroke risk factors. Optimal use of OAC therapy in AF reduces the risk of stroke by about 60-70% compared to placebo. For many decades, vitamin K antagonists (VKAs) such as warfarin have been the only OACs available for long-term anticoagulation in AF. However, VKAs are limited by their narrow therapeutic window requiring frequent monitoring and dose adjustment, drug-drug interactions, and adverse drug reactions, primarily fatal and non-fatal bleeding events. These limitations have resulted in guideline discordance, poor adherence, and suboptimal patient outcomes. According to contemporary AF guidelines, the majority of patients with AF are categorised as being at high risk of stroke according to the CHA$$_2$$DS$$_2$$-VASc score (i.e. CHA$$_2$$DS$$_2$$-VASc ≥ 2) and thus eligible for OAC therapy. However, observational studies confirm widespread under-prescribing of OACs in at-risk AF patients. Despite changes in clinical guidelines, antiplatelet (APT) agents remain commonly used for stroke prevention in AF.
The challenge of optimal anticoagulation in AF has prompted the search for “ideal OACs” that are safe, effective, and convenient to use in AF. Since 2008, four direct-acting OACs (DOACs), namely dabigatran, rivaroxaban, apixaban, and edoxaban, have been approved as alternative anticoagulants to VKAs for stroke prevention in patients with non-valvular AF (NVAF). Analysis of data from large randomised controlled trials (RCTs) has shown that DOACs have comparable efficacy, with a lower rate of major bleeding than warfarin. Moreover, DOACs are convenient for dosing, have predictable pharmacokinetics and routine monitoring is not required. With the introduction of DOACs, a new era has started resulting in a paradigm shift in the management of AF patients requiring anticoagulation. AF guidelines in most countries now recommend DOACs as first-line agents for stroke prevention in NVAF.
DOACs were launched in Australia with market approval of dabigatran in 2011. However, these agents only became widely available after being listed on the Pharmaceutical Benefits Scheme (PBS) for subsidy by the government in August 2013. At the commencement of this study, limited data was available from the Australian perspective regarding the clinical integration of DOACs, their impact on anticoagulation practices, and clinical outcomes of antithrombotic therapy in AF. The Tasmanian Atrial Fibrillation study (TAFs) was established in 2011 to generate current data pertaining to the evolving antithrombotic therapy patterns and outcomes of antithrombotic treatment in AF. The TAFs was initiated at three Tasmanian Hospitals - the Royal Hobart Hospital (RHH), Launceston General Hospital, and North West Regional Hospital. The current study was part of the TAFs, specifically focussed on patients with AF as primary or secondary diagnosis who were admitted to the RHH between 2011 and 2015, for whom long-term follow-up data were readily available. It is intended that the findings from this study could be used by practitioners to inform decision making in the management of AF, and by policymakers to analyse the impacts of the new therapies on AF care and the overall health care system.
The main objectives of the studies contained in this thesis were to: i) describe antithrombotic prescribing patterns in AF with a particular focus on the clinical integration of DOACs in the five years after they were introduced into Australian clinical practice, ii) investigate anticoagulation practices in relation to current AF guidelines before and after DOACs became widely available in Australia, iii) assess rates of, and risk factors for thrombosis and all-cause mortality in the pre- and post-DOAC eras, and iv) investigate bleeding-related hospitalisations in patients with AF who received antithrombotic therapy.
To describe antithrombotic prescribing patterns and assess the clinical integration of DOACs, we assessed patients with AF admitted to the RHH between 2011 and 2015. Digital medical records were used as the data source. Study participants were grouped into three cohorts based on the antithrombotic therapy prescribed at discharge of index admission (first admission during the study period): 1) warfarin - patients discharged with lone warfarin or warfarin-APT therapy, 2) DOAC - patients discharged with lone DOAC or DOAC-APT therapy, and 3) APT - patients prescribed lone or dual-APT therapy. Index admission dates were organised into quarterly (Q) periods, and the proportion of antithrombotic prescribing in each cohort was determined by dividing the number of patients prescribed each agent by total patients receiving antithrombotic therapy within the respective period.
In total, 3265 patient records were reviewed, of which 2390 were included in the assessment of antithrombotic prescribing patterns. Overall, participants of this study were relatively more comorbid and had higher stroke and bleeding risk scores versus those observed in the RCTs that compared warfarin and DOACs. However, patient demographics and comorbidities in our study were broadly similar to large AF-registry data reported elsewhere. Antithrombotic agents were prescribed for the majority of our study population. DOACs accounted for 18.4% of patients receiving antithrombotic therapy in 2011-2015; the proportion of patients receiving a DOAC steadily increased from 3.9% among OAC users in Q3, 2011, to 67.6% in Q2, 2015 (p < 0.001). Accordingly, DOACs became the most commonly prescribed antithrombotic medications in AF soon after they became government subsidised and listed on the BPS for public use. Warfarin and APT prescribing, on the other hand, declined significantly, although a substantial proportion of patients continued to be prescribed APT therapy.
In a subsequent study to investigate OAC prescribing in relation to AF guidelines and assess the impact of the availability of DOACs on anticoagulation practices, we reviewed patients with NVAF admitted to RHH between 2011 and 2015. Based on index admission periods, patients were grouped into two cohorts: pre-DOAC era - admission before the listing of DOACs on the PBS (January 2011 to July 2013), and post-DOAC era - admissions between August 2013 and July 2015. Patients’ stroke risk scores were estimated using the CHA$$_2$$DS$$_2$$-VASc method. The proportion of OAC prescribing overall, and by stroke risk stratification was compared between the two eras. Logistic regression was used to identify factors associated with OAC prescribing in the pre-DOAC, post-DOAC, and overall study periods.
In this analysis, we identified 2118 patients with NVAF (1089 vs 1029 from the pre- and post-DOAC eras, respectively). Overall, anticoagulation increased from 52.5% in the pre-DOAC to 60.7% in the post-DOAC era (p < 0.001). Furthermore, anticoagulation of high-risk patients (CHA$$_2$$DS$$_2$$-VASc ≥ 2) improved significantly (55.2% vs 63.1%, p = 0.001). In multivariate analysis, DOAC era (OR 1.40, 95% CI 1.17-1.68) and CHA$$_2$$DS$$_2$$-VASc ≥ 2 (OR 1.95, 95% CI 1.36 - 2.80) were independent predictors of OAC prescribing in both eras and the whole study period. Conversely, increasing age and prior bleeding were inversely associated with OAC prescribing. In summary, a significant increase in OAC prescribing was observed particularly among high-risk patients in the post-DOAC era. This was likely driven by the widespread availability of DOACs, as well as updates in the AF guidelines associated with the introduction of the new agents. However, OAC underuse in high-risk and overuse in low-risk patients was apparent throughout the study period highlighting the need for further improvement.
The third study aimed to investigate the impact of DOAC availability on thromboembolic events (TEs) and all-cause mortality in patients with AF. We compared incidence rates of TEs and all-cause mortality in the pre-DOAC and post-DOAC time periods (as above). Primary outcome measures included TEs (ischaemic stroke/TIA, systemic embolic events, myocardial infarction), and all-cause mortality. Event rates were estimated by following patients with AF newly initiating antithrombotic therapy to the first TE event, treatment switch/discontinuation, death or end of study period, whichever occurred first. Cox regression analysis was used to identify risk factors associated with incident TE and all-cause mortality. Among 1125 patients newly initiated on antithrombotic agents (542 and 583 patients from the pre- and post-DOAC eras, respectively), we observed a significant decrease in the incidence rates of overall TE (rate per 100 PY, 2.2 vs 3.3, p < 0.001) and ischaemic stroke/TIA (1.8 vs 2.2, p = 0.023) in the post-DOAC era compared to the pre-DOAC era. Furthermore, the rate of all-cause mortality was significantly lower in the post-DOAC era than the pre-DOAC era (2.5 vs 3.1, p = 0.002). Increasing age, prior stroke, and admission in the pre-DOAC era represented risk factors for incident TE, ischaemic stroke/TIA, and mortality in this study population.
In the final analysis, to evaluate hospital admission due to bleeding, we included all AF patients who received antithrombotic treatment during the study period. Bleeding rates were estimated by following patients newly initiating thromboprophylaxis to the first bleeding event, treatment switch/discontinuation, death or end of the study period. Multivariate logistic regression was used to identify predictors of bleeding-related hospitalisation. In total, 2202 AF patients who received antithrombotic agents were included; 113 presented to the hospital with a major or minor bleeding event during a mean follow-up period of 1.8 years. The combined incidence of major and minor bleeding was significantly higher in warfarin- vs DOAC- and APT-treated patients (4.1 vs 3.0 vs 1.2 per 100 PY, respectively; p = 0.002). Similarly, the rate of major bleeding was higher in the warfarin group as compared to the DOAC and APT cohorts (2.4 vs 0.4 vs 0.6 per 100 PY, respectively; p = 0.001). Increasing age, a history of prior bleeding, and discharge antithrombotic choice of warfarin or multiple antithrombotic therapies were independently associated with bleeding events.
In summary, in this real-world cohort of the TAFs, antithrombotic prescribing in patients with AF has changed profoundly over the study period, characterised by a major shift towards the prescribing of DOACs. The availability of DOACs has been associated with a significant increase in the rates of anticoagulation. However, a large proportion of high-risk patients still receive APT therapy or remain untreated. Conversely, a substantial proportion of low-risk patients with AF receive OACs highlighting the need for further improvement. This data also suggested that TEs and all-cause mortality rates tended to decline during the post-DOAC study period when compared to the pre-DOAC era, possibly driven by the increasing anticoagulation rates and the use of DOACs in preference to warfarin. Furthermore, the rate of major bleeding and ICH, in particular, was lower in DOAC- than warfarin-treated patients. We also identified several factors associated with thromboembolic and bleeding events that could be targeted for future intervention, notably increasing age, comorbidities (prior stroke and bleeding), and warfarin, and multiple antithrombotic prescribing. Further studies are warranted to investigate barriers to OAC prescribing, primarily among the elderly patients, including those with a history of prior bleeding; comparative effectiveness of individual DOACs; and the appropriateness and clinical outcomes of multiple antithrombotic treatments in AF.
The body of work presented in this thesis provides a number of real benefits to the various stakeholders involved in the management of AF. Policy makers will be able to better analyse impacts of the changing landscape of anticoagulation on the overall health service expenditure. Practitioners will have additional information for a more tailored approach in selecting the right treatment to the best benefit of individual patients. Our data could also be used as an input in the revision/development of local and national AF guidelines. Lastly, the findings reported in this research can be used in promoting the understanding of the various OAC options including associated risks and benefits. While the quality of stroke prevention and the outcomes of AF patients have improved in recent years, stroke prevention in AF is not yet optimal. The data presented in this thesis highlight these improvements and deficiencies in the Australian setting and can potentially be used to fully realise the benefits of OACs in the prevention of stroke associated with AF.

Item Type: Thesis - PhD Alamneh, EA Atrial fibrillation, stroke, warfarin, direct oral anticoagulant, antiplatelets, bleeding Copyright 2018 the author Chapter 2 appears to be the equivalent of a post-peer-review, pre-copyedit version of an article published in American journal of cardiovascular drugs. The final authenticated version is available online at: http://dx.doi.org/10.1007/s40256-016-0161-8Chapter 3 appears to be the equivalent of the peer reviewed version of the following article: Alamneh, E. A., Chalmers, L., Bereznicki, L. R., 2017. The Tasmanian atrial fibrillation study: transition to direct oral anticoagulants 2011-2015, Cardiovascular therapeutics, 35(3), 1-9, which has been published in final form at [https://doi.org/10.1111/1755-5922.12254. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Chapter 4 appears to be the equivalent of a post-print version of an article published as: Alamneh, E. A., Chalmers, L., Bereznicki, L. R., 2017. Changes in oralanticoagulant prescribing for stroke prevention in patients with atrial fibrillation, American journal of cardiology, 120(7), 1133-1138Chapter 5 appears to be the equivalent of a post-print version of an article published as: Alamneh, E. A., Chalmers, L., Bereznicki, L. R., 2018. Thromboembolism and mortality in the Tasmanian atrial fibrillation study, Journal of cardiovascular pharmacology and therapeutics, 23(4), 329-336Chapter 6 appears to be the equivalent of a post-print version of an article published as: Alamneh, E. A., Chalmers, L., Bereznicki, L. R., 2018. Bleeding-related admissions in patients with atrial fibrillation receiving antithrombotic therapy: results from the Tasmanian atrial fibrillation (TAF) study, European journal of clinical pharmacology, 73(12), 1681–1689 View statistics for this item

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