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Antithrombotic therapy in patients with atrial fibrillation : the Tasmanian experience

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Bista, D (2016) Antithrombotic therapy in patients with atrial fibrillation : the Tasmanian experience. PhD thesis, University of Tasmania.

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Abstract

Atrial fibrillation (AF) is the most common sustained cardiac rhythm disorder and is increasing in incidence and prevalence in ageing populations. It is estimated that 1.5-2% of the developed world suffers from AF. The risk of stroke and thromboembolism (TE) is increased 4-5 fold by non-valvular atrial fibrillation (NVAF) and nearly 15% of all strokes are caused by AF. Judicious use of antithrombotic therapy significantly reduces the risk of stroke for most patients who have AF. Conversely, underuse of antithrombotic therapy is associated with an increase in the rates of death and ischaemic events (stroke, transient ischaemic attack [TIA], or myocardial infarction [MI]). Despite the proven benefits of anticoagulant therapy among high-risk patients with AF, there have been frequent reports of discordance between guideline recommendations and anticoagulant prescribing patterns leading to problem of underutilisation in patients with AF in real-world practices.
During the time period of this study there were limited data available on the characteristics, clinical management and outcomes of patients with AF from an Australian perspective. The available literature suggested that there was underutilisation of anticoagulant therapy, although this data came from relatively small observational trials in selected patient groups. The Commonwealth Review of Anticoagulation Therapies in AF in Australia identified that stroke prevention in individuals with AF required improvement, and highlighted a range of issues to be addressed related to the assessment of patients for stroke and bleeding risk, appropriate choice of antithrombotic agent(s) in patients with multiple comorbidities, and the monitoring of patients. The review stressed the need for local data on which to base recommendations regarding the treatment of AF. Meanwhile, little was known about the clinical outcomes and safety of direct oral anticoagulants (DOACs) outside the trial setting. In 2011, dabigatran’s sponsor launched a patient familiarisation program in which over 28,000 Australians were enrolled. Thus, we established that there was a critical need for local data regarding the safety of antithrombotic medications, including the DOACs, in the treatment of AF. We designed this study, the Tasmanian AF (TAF) Study, as a starting point to providing comprehensive data describing the outcomes of stroke prevention strategies in Tasmanian patients with AF. The TAF study is an ongoing retrospective study that enrols patients from 3 different hospitals in Tasmania, Australia; the Royal Hobart Hospital (RHH), Launceston General Hospital (LGH) and North West Regional Hospital (NWRH). The rationale behind this project was to derive local data on usage pattern of antithrombotic therapy, clinical outcomes and their safety profile in Australian sub-population - initially prior to the Pharmaceutical Benefits Scheme (PBS) listing of DOACs, and then to use the established database to monitor the impact of the introduction of the DOACs into clinical practice.
Our main objectives in the work reported here were to retrospectively i) review the patient characteristics and antithrombotic treatment patterns among patients with AF in Tasmanian hospitals, ii) compare the anticoagulant utilisation to earlier data in the same population and identify predictors of anticoagulant prescribing among patients with NVAF, iii) evaluate the rates of, and factors associated with, hospital readmissions due to bleeding or TE complications among patients newly diagnosed with AF, and iv) compare the patient characteristics, antithrombotic prescribing patterns, and rates of bleeding or TE outcomes between older and younger patients diagnosed with AF.
To study the patient characteristics and antithrombotic prescribing patterns we reviewed and followed patients with AF admitted to Tasmania’s 3 major hospitals between January 2011 and June 2012. In identifying the predictors of anticoagulant prescribing among patients with NVAF and to compare the anticoagulant utilisation pattern to earlier data in the same population, we reviewed patients only with NVAF from the above population. To examine the rates of, and factors associated, with hospital readmission due to bleeding and TE, we recruited patients newly diagnosed with AF and admitted to the RHH between 1st January 2011 and 30th June 2012 and followed them for the first 3 months, and then at least 18 months, from the time of hospital discharge after their index admission. During short-term follow-up, patients were followed for 3 months from time of hospital discharge after their index admission with newly diagnosed AF or until the occurrence of a primary outcome or death, whichever came first. Similarly, for longer-term follow-up, patients were followed for at least 18 months from time of hospital discharge after their index admission with newly diagnosed AF, or until the occurrence of a primary outcome, death or December 31, 2013, whichever occurred first. Finally, to compare the patient characteristics, antithrombotic prescribing patterns, and rates of bleeding or TE outcomes between older and younger patients diagnosed with AF, we divided patients into two age groups - a younger group aged <75 and an older group aged 75 or above. Included patients were then followed from their index admission for at least 18 months from time of hospital discharge after their index admission or until the occurrence of a primary outcome, death or December 31, 2013, whichever occurred first. Our primary outcomes were readmissions due to: 1) major bleeding, including haemorrhagic stroke requiring hospitalisation, and 2) TE (ischaemic stroke and systemic embolism, MI and TIA).
Our patient population demonstrated high rates of comorbid conditions, especially cardiovascular disease. Nevertheless, their characteristics proved to be largely similar to some of the populations studied in international registries. Our study also compares well to the patient cohorts studied in clinical trials comparing DOACs to warfarin, in terms of mean age and stroke risk. As seen in other real-world studies we also observed discordance between AF guideline recommendations and anticoagulant prescribing patterns despite the high risk of stroke observed. We also observed the relatively high rate of prescribing of combination anticoagulant/antiplatelet therapy in patients newly initiated on therapy and among those with existing AF from admission to discharge. In another study designed to compare the anticoagulant utilisation pattern to 15 year earlier data in the same population, and identify the predictors of anticoagulant prescribing among patients with NVAF, we observed that while there has been improvement over the past 15 years, suboptimal use of anticoagulant therapy among high risk patients with NVAF remains common. Younger age (odds ratio \([OR] 0.99\), \(95\)% \(CI 0.97-1.0; P=0.04), CHADS_2=1\), relative to \(0 (OR 1.68\), \(95\)% \(CI 1.07-2.63\); \(P=0.02)\), \(CHF (OR 1.56\), \(95\)% \(CI 1.12-2.15\); \(P=0.008)\) and embolic disease history (\(OR 1.77\), \(95\)% \(CI 1.09-2.86\); \(P=0.02\)) were significant predictors of anticoagulant prescribing. Despite guideline recommendations, we did not observe `CHADS_2 ≥2` as a significant predictor of anticoagulant prescribing in our population.
In our study to evaluate the rates of, and factors associated with, hospital readmissions due to bleeding or TE complications among patients newly diagnosed with AF, the rates per 100 person-years (PY) of bleeding and TE-related readmissions within 3 months were 4.8 (95% CI 2.2-7.5) and 8.1 (95% CI 4.8-11.4), respectively. The rates per 100 PY of bleeding and TE-related readmissions during a mean of 2.1 years’ follow-up were 1.5 (95% CI 0.02-3.0) and 3.7 (95% CI 1.4-6.0), respectively. Patients with peripheral vascular disease (PVD) (OR 8.1, 95% CI 1.3-52.1) and renal impairment (OR 15.1, 95% CI 2.3-101.2) were more likely to be readmitted for bleeding, while those with a history of MI (OR 6.3, 95% CI 2.2-18.1) were more likely to be readmitted for TE during longer-term follow-up. We thus observed higher rates of bleeding or TE-related readmissions in the initial 3 months following AF diagnosis and initiation of treatment.
Finally in our study to compare the patient characteristics, antithrombotic prescribing patterns, and rates of bleeding or TE outcomes between older and younger patients diagnosed with AF, we observed that among high-risk patients aged ≥75 years, only 51.8% received anticoagulant treatment (vs. 64.6% in the younger group; P=0.02). After a mean follow-up of 2.2 years, elderly patients were observed to be at higher risk of major bleeding (hazard ratio (HR) 3.2, 95% CI) 1.4-7.5, P=0.004) but the incidence of TE did not differ significantly (HR 1.5, 95% CI 0.9-2.7, P=0.15) between the groups. Elderly patients prescribed anticoagulant therapy were at significantly higher risk of major bleeding (HR 3.0, 95% CI 1.1-8.3, P=0.02) but at similar risk of TE (HR 0.9, 95% CI 0.4-1.8, P=0.69) compared to those on no anticoagulant therapy. In this study, anticoagulant therapy was underused among high-risk elderly patients with AF compared to their younger counterparts. Elderly patients had higher incidence of major bleeding but similar risk of TE compared to younger patients in this cohort.
Our study provides some important findings from the Australian perspective. Despite improvements in the use of anticoagulant therapy among high-risk patients with AF over a period of time, our findings highlight a gap between the evidence-based risk stratification and antithrombotic management pattern among patients with AF in Tasmania. In the absence of contemporary local guidelines, there appears to be a need to better support prescribers to assist in the identification and quantification of patient risk according to accepted international guidelines to optimise thromboprophylaxis and reduce the risk of thromboembolic and bleeding complications in this vulnerable patient group. Given the fact that suboptimal oral anticoagulant use in patients with AF and poor compliance with guidelines still persist despite a transition to a new era of anticoagulation featuring DOACs, these findings remain pertinent. It is also acknowledged that monitoring of the patients newly initiated on treatment could play a significant role in minimising fatal bleeding and TE-related events in these patients. Our findings regarding the predictors of bleeding or TE outcomes suggest several risk factors that should be considered as ‘red flags’ when managing patients with AF. Patients with these conditions need special attention when managing concomitant AF. In fact, these patient groups are a potential target for intervention in future AF studies so as to minimise the incidence of bleeding or TE-related hospitalisations. Finally, underuse of anticoagulant therapy among high-risk elderly patients could have been influenced by the higher bleeding risk in this cohort compared to the younger group. Our finding that the elderly cohort were at higher risk of major bleeding due to anticoagulant therapy compared to the younger group requires further investigations so as to identify associated reasons for such outcome.

Item Type: Thesis (PhD)
Keywords: atrial fibrillation, anticoagulants, bleeding, thromboembolism
Copyright Information:

Copyright 2016 The author

Additional Information:

Chapter 3 appears to be the equivalent of a post-print version of an article published as: Bista, D., Chalmers, L., Peterson, G. M., Bereznicki, L. R. E., 2016, Anticoagulant use in patients with nonvalvular atrial fibrillation: has prescribing improved? Clinical and applied thrombosis/hemostasis, published online April 12, 2016

Date Deposited: 04 Apr 2017 03:47
Last Modified: 10 Apr 2017 04:14
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