Original Research Articles

Adequacy of anticoagulation according to CHADS2 criteria in patients with atrial fibrillation in general practice – a retrospective cohort study

Background: Atrial fibrillation (AF) is a common arrhythmia associated with an increased risk of stroke.  Strategies to reduce stroke incidence involve identification of at-risk patients using scoring systems such as the CHADS2  score (Congestive Heart Failure, Hypertension, Age ≥75 years, Diabetes or Stroke) to guide pharmacological prophylaxis. Aim: The aim of this research project was to determine the prevalence and management of AF patients within the general practice (GP) setting and to assess the adequacy of anticoagulation or antiplatelet prophylaxis according to the CHADS2  score. Methods: This study was a retrospective cohort study of 100 AF patients ≥50 years conducted at a South Coast NSW Medical Centre over a 3-year period.   Data was obtained from existing medical records. CHADS2   scores were determined at baseline, 12 months and 3 years and were compared with medications to assess whether patients were undertreated, adequately treated or over-treated according to their CHADS2 score. Results: Prevalence of AF in patients >50 years was 5.8%. At baseline, 65% of patients (n=100) were at high risk of stroke (CHADS2  score ≥2).   This increased to 75.3% of patients at 12 months (n=89) and 78.4% of patients at 3 years (n=60).  Adequate treatment occurred in 79.0% of patients at baseline and 83.1% and 76.7% at 12 months and 3-years, respectively.  There were three instances of stroke or trans-ischemic attack during the study period. Conclusion: GPs play a critical role in prevention of stroke in patients with AF.   Adequate pharmacological interventions occurred in the majority of cases, however, identification and treatment of at-risk patients could be further improved.



Atrial fibrillation (AF) is the most common cardiac arrhythmia in Australia, affecting 8% of the population over the age of 80 years. [1,2]  The morbidity and mortality associated with AF is primarily due to an increased risk of thromboembolic events such as stroke, with studies reporting up to a five-fold increase in the annual risk of stroke among patients with AF who have not received prophylaxis with either anticoagulant or antiplatelet therapies. [3,4]

It has been demonstrated that the incidence of stroke in patients with AF can be significantly reduced with the use of pharmacological agents, such as anticoagulant and antiplatelet medications including warfarin and aspirin, respectively. [5] More recently, the development of new oral anticoagulant (NOAC) medications such as dabigatran and rivaroxaban have also been approved for use in patients with AF. [6] However, several studies indicate that the use of anticoagulants and antiplatelets for the prevention of thromboembolic events is often underutilised. [7,8]  It is estimated that up to 51% of patients eligible for anticoagulant therapy do not receive it. [9]   Furthermore, an estimated 86% of patients who suffer from AF and have a subsequent stroke were not receiving adequate anticoagulation therapy following their AF diagnosis. [10]

In contrast, pharmacological treatments for stroke prophylaxis have been associated with an increased risk of intracerebral haemorrhage, particularly amongst the elderly. [11]  A study of 170 patients with AF over the age of 85 years demonstrated that the rate of haemorrhagic stroke was 2.5 times higher in those receiving anticoagulant therapy compared to controls (OR=2.5, 95% CI: 1.3-2.7). [12]  Therefore, the need to optimise the management of patients with AF in the general practice (GP) setting is of high importance for stroke prevention and requires an individualised pharmacological approach in order to achieve a balance between stroke reduction and bleeding side effects.

Consequently, the development of validated risk stratification tools such as the CHADS2 score (Congestive Heart Failure, Hypertension, Age ≥75 years, Diabetes, Previous Stroke or Trans-ischemic Attack (TIA)) has enabled more accurate identification of AF patients who are at an increased risk of stroke by assessing co-morbidities and additional risk factors to determine the appropriateness of anticoagulation or antiplatelet prophylaxis to reduce the risk of thromboembolic events. [13]

The aim of this research project was to determine the prevalence of AF among patients within a GP cohort and to assess the adequacy of pharmacological stroke prophylaxis according to the CHADS2  criteria. The results of this study will enable GPs to determine whether the current management of patients with AF is adequate and whether closer follow-up of these patients needs to occur in order to minimise associated bleeding and stroke complications.


Study design and ethics

This study was a retrospective cohort study of the prevalence, patient characteristics and adequacy of anticoagulation according to the CHADS2  score in GP patients with AF over a 3-year period.  The study was approved by the University of Wollongong Human Research Ethics Committee (Appendix 1, HREC 13/031).


Participants were identified using a search of the practice database (Best Practice, Version, Pyefinch Software Pty Ltd), at a South Coast NSW Medical Centre using the database search tool.  Search criteria included any patient (recorded as alive or deceased) who attended the practice with a recorded diagnosis of AF over a 3-year period (between November 2010 – November 2013) and were ≥50 years of age. This included both patients with long-term AF diagnosed before the study period in addition to those newly diagnosed with AF during the study period.   The total number of all patients aged ≥50 years who attended the practice at least once during the same period was recorded to determine the prevalence of AF at the practice.

Exclusion Criteria

Exclusion   criteria   included   patients   <50   years   of   age,   patients with incomplete medical records or those diagnosed with AF who subsequently moved from the practice during the study period.


CHADS2  score

The CHADS2   score was chosen for the purpose of this study as it is a validated risk-stratification tool for patients with AF. [13-15]  The scoring system assigns one point each for the presence of Congestive Heart Failure, Hypertension, Age ≥75 years or Diabetes and assigns two points if a patient has a history of previous Stroke or TIA.  AF patients with a CHADS2 score of 0 are considered to be at low risk of a thromboembolic event (0.5 – 1.7% per year stroke rate); a score of 1 indicates intermediate risk (2.0% per year stroke rate) and a score ≥2 indicates high risk (4.0% per year stroke rate). [16]

Data Search and Extraction

Patient data was manually extracted from individual patient records, coded  and  recorded  into  a  spreadsheet  (Microsoft  Excel,  2007). Basic data including date of birth and sex were recorded.  Date of AF diagnosis (assessed as the first documented episode of AF within the patient record) and co-morbidities including hypertension, congestive heart failure, diabetes, stroke or TIA were included if documented within the patient medical record.   Correspondence from specialists and hospital discharge summaries were also analysed for any diagnosis made outside of the medical centre and not subsequently recorded in the medical record.

Lifestyle factors were recorded from the practice database including
alcohol use (light/moderate/heavy or none) and smoking status (nonsmoker, ex-smoker or current smoker). Complications arising from
pharmacological prophylaxis (including any documented bleeding or
side-effects) or discontinuation of treatments were included. Individual
patient visits were analysed for any documented non-compliance with
medications. Where possible, cause of death was also recorded.

Adequacy of Anticoagulation

Individual CHADS2 scores were determined for each patient at baseline,
12 months and 3 years. At each of these time points, CHADS2 scores
were compared to each patient’s medication regime (i.e. no medication
use, an anticoagulant agent or an antiplatelet agent). The use of other
medications for the treatment of AF (for example, agents for rate or
rhythm control) was not assessed. Patients were then classified as
being undertreated, adequately treated or over-treated according to
the CHADS2 score obtained at baseline, 12 months and 3 years as per
the current therapeutic guidelines (Figure 1). [17]


Adequate treatment was considered to be patients receiving treatments
in accordance with the therapeutic guidelines. [17] Undertreated
patients included those who received no treatment when an oral
anticoagulant was indicated (CHADS2 score ≥2). Over-treated patients
included those treated with an oral anticoagulant where it was not
indicated according to the current guidelines (CHADS2 score = 0).

Statistical Analysis

Results are presented as mean ± standard deviation.   A p-value of <0.05 was considered to be statistically significant.  One-way ANOVA was  used  to  assess  between-group  differences  in  CHADS2    scores at each time point (Baseline, 12 months and 3 years).   Descriptive data is presented where relevant.   Prevalence of AF at the practice was calculated using the formula; (patients with AF ≥50 years / total number of patients ≥50 years at the practice, X 100).




A total of 346 patients with AF aged ≥50 years were identified. Of these, 246 participants were excluded – (n=213 due to insufficient data within their medical record, and n=33 patients had left the practice during the study period) leaving a total of 100 patients for inclusion in the analysis (Figure 2).  Due to the nature of the search strategy (which identified any patient with AF during the period of November 2010-November 2013), both newly-diagnosed patients and patients with long-term AF were included in the analysis. Therefore, long-term data was available for n=89 participants at 12 months, and n=60 participants at 3 years. There were no statistically significant differences in age (p=0.91) or sex (p=0.86) between the included and excluded participants.


Including all patients initially identified with AF (n=346), the overall prevalence of AF among patients at the practice was 5.8%. Participant characteristics are presented in Table 1.  The mean age of participants at diagnosis was 74.9 ± 10.0 years, with more males suffering from AF (60%) compared to females (40%).  Over half of patients had a history of smoking (57%), and hypertension was the most common co- morbidity (74%).  13% of participants were listed within the practice database as being deceased.



At baseline, 65.0% of patients were classified as high risk of stroke (CHADS score ≥2).  This increased to 75.3% of patients and 78.4% of patients at 12 months and 3 years, respectively (Graph 1). There were no patients with a CHADS2 score of 6 at any of the study time points. Analysis of participants who had 3-year follow-up data available (n=60) demonstrated  a  statistically significant increase  in  average  CHADS2 scores among patients between baseline vs. 12 months (p<0.05) and baseline vs. 3 years (p<0.01).   There was no statistically significant difference in CHADS2 scores between 12 months vs. 3 years (p=0.54).


Graph 2 demonstrates changes in treatment adequacy over time based on patients’ initial treatment group allocation at baseline. For patients who were initially identified as being undertreated at baseline, there was a trend toward adequate treatment by 3-years.  For patients initially identified as over-treated at baseline, the trend towards adequate treatment occurred more rapidly (p=non-significant) (on average by 12 months).


Patient pharmacological  treatments and adequacy of treatment at baseline, 12 months and 3 years are shown in Table 2.



There were several reported side-effects and documented instances of medication cessation from anticoagulation and antiplatelet therapy. A total of eight patients were non-compliant and ceased warfarin during the study period and eight patients had their warfarin ceased by their treating doctor (reason for cessation unknown).  A further eight patients ceased warfarin therapy due to side-effects (Intracranial haemorrhage   (n=1),   Gastrointestinal  bleeding   (n=3),   Haematuria (n=1), Unknown bleeding (n=3)).   One patient ceased aspirin due to oesophageal irritation.   No other pharmacological therapies were ceased due to side-effects. Warfarin was ceased in one case due to an elective surgical procedure.

A total of two patients suffered an embolic or haemorrhagic stroke and a further two patients suffered a TIA during the study period.  Prior to their thromboembolic event, one patient was undertreated with aspirin (CHADS2 score = 2), one was adequately treated with clopidogrel (CHADS2    score  =  1)  and  a  further  one  patient  was  undertreated on aspirin (CHADS2 score = 3).  Cause of death was unknown in six patients. No patients had stroke or TIA listed as their cause of death in their medical record.


It  has  been  suggested  that  Australian  patients  with  AF  may  not be receiving optimal prophylactic anticoagulant and antiplatelet medications for the prevention of thromboembolic events. [7,8]  The aims of this retrospective cohort study were to assess stroke risk and the adequacy of anticoagulation in 100 AF patients ≥50 years over a 3 year period in a GP setting.

Results from the current study indicate that overall, the use of anticoagulant and antiplatelet strategies for stroke prophylaxis was appropriate in the majority of cases and consistent with published therapeutic guidelines. [17]  The prevalence of AF at the practice of 5.8% was similar with other studies, which report a prevalence of AF in the GP setting of between 4-8%. [18, 19]  In the current study, there were more males with AF than females, however this trend has also been found in several other studies which have reported a higher prevalence of AF amongst males. [15,18]

CHADS2  scores increased between baseline and 12 months and baseline and 3 years.   This increase was to be expected as patients are likely to gain additional risk factors as they age.  The majority of patients at all time points were at high risk of stroke (CHADS2 score ≥2), with warfarin or similar anticoagulation therapy being indicated.

Overall, treatment adequacy increased between baseline and 12 months (79% versus 83.1%), then decreased by 3 years (83.1% versus 76.7%).  This trend is likely to represent aggressive management of AF at the initial diagnosis then a decline in optimal stroke prophylaxis as patients age, develop additional side-effects or become at increased risk of falls.  Additionally, older patient groups (those >70 years) were more likely to be undertreated.  This may be due to several factors, including patient non-compliance with warfarin therapy, doctor reluctance to prescribe warfarin to patients at risk of falls, and the incidence of side-effects such as bleeding.   Similar causes of under- treatment of elderly patients with AF have been outlined in other studies. [20,21]  In younger patients, there was a trend towards over- treatment at the time of diagnosis.

In the current study, one patient suffered an embolic stroke during the study period and two patients had a TIA. Appropriately, all three of these patients were subsequently changed to warfarin.  One patient who was adequately treated on warfarin with a CHADS2   score of 1 was changed to aspirin following an intracranial haemorrhage (and consequently remained classified as adequately treated).  Although these were isolated cases within the study, it should be noted that the life-long morbidity of stroke for these individuals is significant.

Strengths of the current study include the large number of patients and the comprehensive assessment of medical records for the main study outcomes of CHADS2  scores and anticoagulation or antiplatelet therapies.  By assessing individual medical records, a comprehensive assessment of patient data was available for inclusion in the study analysis.

There are some limitations in the current study. As data was extracted from  an  existing  database  of  patient  medical  records  (which  was not kept for the purpose of conducting research) there were some instances of missing or incomplete data.  However, the majority of missing data was, in general, relating to the patient’s social history (such as smoking rates and alcohol use), which were not central to the main research aims and would not have influenced the results.

A thorough assessment of medication regimes was able to be carried out for the purpose of this study.   As all medication changes are automatically recorded by the Best Practice program at each visit, the author is confident that this aspect of the data is accurate. However, it should be noted that it is possible that some patients may have been taking over the counter aspirin, which may not have been recorded on their medication list and consequently some patients may have been assessed as ‘undertreated’.  An additional consideration relates to the use of warfarin and whether patients’ prescribed warfarin were within the therapeutic range, however, the assessment of multiple INR readings for each patient over a 3-year period was thought to be beyond the scope of this study. Only two patients at the practice had been prescribed NOACs (Dabigatran) for anticoagulation, therefore analysis of this medication was limited.

The  calculation  of  CHADS2   scores was  able  to  be  assessed for all patients.  Although most co-morbidities were well documented, theremay have been some limitations with regards to the identification of some co-morbidities such as hypertension, diabetes and the presence of congestive heart failure among some patients.   For example, in some instances some patients did not have a recorded diagnosis of hypertension, but a review of blood pressure readings demonstrated several high systolic blood pressure readings which could have been diagnostic for hypertension.  Where this occurred, patients were not considered to have hypertension or congestive heart failure and were not assigned an additional CHADS2 point.

The CHADS2   score was chosen for the purpose of this study due to its simplicity and validation for the identification of patients at risk of stroke [13-15].  More recently, refinements to the CHADS2  score has led to the development of the CHA2DS2-VASC score, which assigns additional points to higher age groups, female patients and patients with vascular disease. [22]  The CHA2DS2-VASC score provides a more comprehensive overview of stroke risk factors in an individual and has  also  been  validated  for  the  purpose  of  determining  the  need for pharmacological stroke prophylaxis.  More recently, studies have shown that application of the CHA2DS2-VASC score is most useful for clarifying the stratification of patients within the low-intermediate stroke risk categories (i.e. determining those with CHADS2  scores of 0-1 who are truly at low risk and do not require aspirin). [23]  Because the aims of the current study were to identify patients at high risk of stroke and determine the appropriateness of their treatment, the CHA2DS2-VASC score was not utilised in this study.  However, it should be noted that the CHA2DS2-VASC may provide additional clarification in the assessment of patients with low-intermediate CHADS2 scores.

An additional consideration in this study relates to the nature of the AF suffered by patients.  Although patients were included if they had a known diagnosis of AF, it is almost impossible to determine how long patients had already been suffering from AF prior to and after their diagnosis.  In addition, it was not possible to determine whether patients had paroxysmal or sustained/chronic AF.   However, it has been demonstrated that there may be little difference in outcomes for patients with paroxysmal versus persistent AF, [24,25] with a large cohort study comparing stroke rates in patients with paroxysmal versus sustained  AF  reporting no  significant  difference  in  rates  of  stroke (3.2% versus 3.3%, respectively). [24] Therefore, it is unlikely that determination of paroxysmal and sustained AF patterns would have influenced results of the current study.


The results obtained from this study will allow GPs to optimise the management of patients with AF in the community setting.  Although this study found that the management of patients with AF at the practice is consistent with the current guidelines in the majority of cases, further improvements can be made to minimise the risk of stroke among patients with AF, especially with regards to targeting undertreated patients.   Additionally, the current study may raise greater awareness of the incidence of AF within the practice and the need to assess stroke risk and treat patients accordingly, especially as  CHADS2 scores  were  rarely recorded  formally  at  the  time  of diagnosis.  GPs are well placed to optimise the treatment of AF and prevent strokes though treatment of co-morbidities and implementing lifestyle interventions, such as encouraging smoking cessation and the minimisation of alcohol use, and may further reduce the incidence of stroke and TIA in patients with AF.


The author would like to acknowledge Dr Darryl McAndrew, Dr Brett Thomson, Prof Peter McLennan, Dr Judy Mullan and Dr Sal Sanzone for their contribution to this research project.

Conflict of interest

None declared.


S Macleod:


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[2] Wong, C, Brooks, A, Leong, D, Roberts, K, Sanders, P. The increasing burden of atrial fibrillation compared with heart failure and myocardial infarction: A 15-year study of all hospitalizations in Australia. Arch Int Med. 2012; 172 (9): 739-741.

[3] Lip, G, Boos, C. Antithrombotic treatment in atrial fibrillation. Heart. 2006; 92 (2): 155-161.

[4] Medi, C, Hankey, G, Freedman, S. Stroke risk and antithrombotic strategies in atrial fibrillation. Stroke. 2010; 41: 2705-2713.

[5] Gould, P, Power, J, Broughton, A, Kaye, D. Review of the current management of atrial fibrillaiton. Exp Opin Pharmacother. 2003; 4 (11): 1889-1899.

[6] Brieger, D, Curnow, J, Anticoagulation: A GP primer on the new anticoagulants. Aust Fam Physician 2014, 43 (5): 254-259.

[7] Gladstone, D, Bui, E, Fang, J, Laupacis, A, Lindsay, P, Tu, J, et. al. Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke. 2009; 40: 235-240.

[8] Olgilvie, I, Newton, N, Welner, S, Cowell, W, Lip, G. Underuse of oral anticoagulants in atrial fibrillation: A systematic review. Am J Med. 2010; 123 (7): 638-645.

[9] Pisters, R, Van Oostenbrugger, R, Knottnerus, I. The likelihood of decreasing strokes in atrial fibrillation patients by strict application of guidelines. Europace. 2010; 12: 779-784. [10] Leyden, J, Kleinig, T, Newbury, J, Castles, S, Cranefield, J, Anderson, C, et. al. Adelaide Stroke Incidence Study: Declining stroke rates but many preventable cardioembolic strokes. Stroke. 2013; 44: 1226-1231.

[11] Vitry, A, Roughead, E, Ramsay, E, Preiss, A, Ryan, P, Pilbert, A, et. al. Major bleeding risk associated with warfarin and co-medications in the elderly population. Pharmacoepidem Drug Safe. 2011; 20 (10): 1057-1063.

[12] Fang, M, Change, Y, Hylek, E, Rosand, J, Greenberg, S, Go, A, et. al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Int Med. 2004; 141: 745-752.

[13] Gage B, Waterman, A, Shannon, W. Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation. JAMA. 2001; 285: 2864-2870.

[14] Khoo, C, Lip, G. Initiation and persistance on warfarin or aspirin as thromboprophylaxis in chronic atrial fibrillation in general practice. Thromb Haemost. 2008; 6: 1622-1624.

[15] Rietbrock, S, Heeley, E, Plumb, J, Van Staa, T. Chronic atrial fibrillation: Incidence, prevalence, and prediction of stroke using the congestive heart failure, hypertension, age >75, diabetes mellitus, and prior stroke or transient ischemic attack (CHADS2) risk stratification scheme. Am Heart J. 2008; 156: 57-64.

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[17] e-Therapeutic Guidelines. Prophylaxis of stroke in patients with atrial fibrillation.[Internet]. 2012 [Cited 2014 Mar 9]. Available from:

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[19] Lowres, N, Freedman, S, Redfern, J, McLachlan, A, Krass, I, Bennet, A, et. al. Screening education and recognition in community pharmacies of atrial fibrillation to prevent stroke in and ambulant population aged ≥65 years (SEARCH-AF Stroke Prevention Study): A cross-sectional study protocol. BMJ. 2012; 2 (Online).


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[21] Hickey, K. Anticoagulation management in clinical practice: Preventing stroke in patients with atrial fibrillation. Heart Lung. 2012; 41: 146-156.

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Review Articles

Stroke prevention in non-valvular atrial fibrillation: advances in medical therapy

Introduction: The aim of this article is to review the literature and evaluate the evidence of the different medical treatments for stroke prevention in non-valvular atrial fibrillation. Methods: A literature search using MEDLINE plus OvidSP, PubMed, CINAHL and the New England Journal of Medicine databases was performed with the search terms stroke prevention, atrial fibrillation, anticoagulation, novel anticoagulants, direct thrombin inhibitors and factor Xa inhibitors. Results: Eight studies were identified which assessed the efficacy and adverse effects of the different treatments in stroke prevention in those with non-valvular atrial fibrillation.  Conclusion:  Evidence  suggests  that  target  specific oral  anticoagulants  have  similar  or  superior  efficacy compared to warfarin for stroke prevention in patients with non-valvular atrial fibrillation, however more long term follow-up studies are required.



Atrial fibrillation (AF) is defined as an arrhythmia caused by rapid and irregular depolarisation and contraction of the atrium and is the most common sustained cardiac arrhythmia. [1] It is classified into three subgroups: paroxysmal, persistent and permanent. [2] Paroxysmal AF is recurrent AF where the rhythm disturbance terminates spontaneously within seven days, persistent AF is where the rhythm disturbance is sustained for greater than seven days, and permanent AF is where the rhythm disturbance has lasted for longer than one year and not been terminated by medical intervention. [2] AF affects 1–2% of the general Australian population and importantly this incidence increases with age, with 9% of people over the age of 80 being affected. [3] Although often considered a benign arrhythmia, AF is a major cause of morbidity and mortality. [3] The most feared complication is systemic embolism leading to stroke. [3] AF accounts for 1 in 5 strokes, [4] with morbidity and mortality determined by the vessel that is occluded and the extent of ischaemia. This is reflected in the stroke prognostic scores (PLAN) which take into account preadmission comorbidities, level of consciousness, age and neurologic deficit, and predict patients who will have a poorer outcome after  hospitalisation for acute ischaemic stroke. [5] Treatment of AF consists of rate and rhythm control as well as antithrombotic therapy to prevent stroke.

There are multiple mechanisms responsible for the increased risk of thromboembolic stroke in individuals with AF. Firstly, altered atrial contraction results in blood stasis in the atria. Secondly, the left atrial appendage acts like a pocket to promote platelet aggregation and thrombus formation. Changes in systemic circulation also increase the risk of clot formation.

Evidence-based guidelines support the use of warfarin and aspirin as  the two  leading  medical  therapies  for  stroke  prevention in  AF. [6] Warfarin has been used as the mainstay treatment for the last 60 years, but this has not been without problems. There has been a recent emergence of new therapies, with 20 new novel anticoagulants currently under investigation, many showing promising results in phase III trials. [7] These drugs have been collectively referred to as new oral anticoagulants (NOACs), and more recently, target specific oral anticoagulants (TSOACs). Recently in Australia the Therapeutic Goods Administration (TGA) has approved a direct thrombin inhibitor, dabigatran, and two factor Xa inhibitors, rivaroxaban and apixaban, for stroke prevention in AF patients. [8,9] The recent attention on emerging treatment options makes us question what the evidence is behind their use in the context of stroke prevention in AF patients as compared to traditional therapies.


The objective of this review was to compare the efficacy and safety profile of TSOACs, in particular the TGA-approved TSOACs, dabigatran, rivaroxaban and apixaban, to standard medical therapy for stroke prevention in AF.


Search criteria

A literature search of MEDLINE plus OvidSP, NCBI PubMed and CINAHL via EBSCOhost and the New England Journal of Medicine databases was conducted. Limits were set to include articles published between the  years  1999  to  current  to  reflect modern  practice. The  search terms used were “stroke prevention” AND “atrial fibrillation” AND “anticoagulation” AND “novel anticoagulants” OR “direct thrombin inhibitors” OR “factor Xa inhibitors”. The reference lists of included studies were also manually reviewed to identify additional relevant literature.

Eligibility criteria

Studies were included if they assessed the efficacy and safety profile of TSOACs as well as standard medical therapy for stroke prevention in  those  with  non-valvular  AF.  Only  studies  conducted  in  humans and published in English were included. There was no restriction on publication type and no limit on study size.

Results and discussion

Search results

Database and reference searches yielded 1149 articles of which 89 full text papers were selected and reviewed. 81 articles were excluded, mainly due to lack of focus on the standard medical therapies and TGA- approved TSOACs (dabigatran, rivaroxaban and apixaban) in those with non-valvular AF. Based on the inclusion and exclusion criteria, eight studies were eligible for inclusion in the review. These studies varied in their characteristics with participant groups. Of these studies there were two meta-analyses (level I evidence), one prospective open-label randomised trial, one randomised double-blind controlled trial (level II evidence) and four randomised controlled trials (level II evidence).

Current guidelines

Treatment for stroke prevention in patients with AF is guided by risk stratification by the CHADS2  or the CHA2DS2-VASc scores. [10] In the CHADS2  score, patients are given one point each for age greater than 75, hypertension, diabetes mellitus and heart failure, and two points if they have a history of previous stroke or transient ischaemic attack (TIA). A CHADS2  score of zero confers low risk, one confers moderate risk and a score of equal or greater than two means the patient is at high risk of stroke. [10] In those with a CHADS2 score of 0, there is a risk of 0.6 events per 100 person-years and this increases to 13.0 events per 100 person-years in those with a CHADS2  score of 6. Compared to the CHADS2 score, the CHA2DS2-VASc score for non-valvular AF has a larger score range (0 to 9) and incorporates a greater number of risk factors (female sex, 65 to 74 years of age, and vascular disease). The CHA2DS2- VASc score has been shown in several studies to better discriminate stroke risk among patients with a baseline CHADS2  score of 0 to 1, as well as in older women. Furthermore there are a range of scores to identify patients at increased bleeding risk. These include the HAS- BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalising ratio (INR), Elderly, Drugs/alcohol concomitantly) and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) scores to name a few. Although helpful clinically, they are not used in the current treatment guidelines. [11]

In Australia, current therapeutic guidelines recommend that those with a CHADS2 score of 0 should be treated with aspirin or no therapy, with a preference for no therapy. Those with a score of 1 should be treated with oral anticoagulation with warfarin, dabigatran or aspirin with a preference for oral anticoagulation. Those with a score of 2 or more would benefit from oral anticoagulation with warfarin or dabigatran. Warfarin should be maintained at therapeutic levels with INR between 2.0 and 3.0 with a target INR of 2.5. [10] Although not in the guidelines, the TGA has approved the use of rivaroxaban 20mg once daily and apixaban 5mg twice daily for stroke prevention. [8,9]

The European Society of Cardiology recommends that the CHA2DS2- VASc score should be used to assess stroke risk. Warfarin is the drug of choice in those with mechanical heart valves.  In those with a prior stroke, TIA, or CHA2DS2-VASc score greater than 2, oral anticoagulation is recommended with warfarin, dabigatran, rivaroxaban, or apixaban. If therapeutic INR is unable to be maintained then a direct thrombin inhibitor or factor Xa inhibitor is recommended. In those with non- valvular AF and CHA2DS2-VASc score of 0, the guidelines state that it is reasonable to omit antithrombotic therapy. In those with a CHA2DS2- VASc score of 1, no antithrombotic therapy or treatment with an oral anticoagulant or aspirin may be considered. [12]

The American College of Cardiology / American Heart Association recommend that antithrombotic therapy should be based on the presence of risk factors for stroke and thromboembolism. They recommend that the CHADS2  stroke risk stratification should be used to assess stroke risk. In patients with a CHADS2  score of greater than 2, long term oral anticoagulation therapy, for example with warfarin, is recommended. In patients with a CHADS2  score of 0 to 1, they recommend CHA2DS2-VASc be used to further stratify their risk. They further go on to state that in those with a CHA2DS2-VASc score of 1, aspirin may be considered rather than oral anticoagulation therapy. [11] The importance of shared decision-making, the patient’s preferences as well as discussion of risks of stroke and bleeding is recommended in all guidelines. [11,12]

Traditional medical therapy

Vitamin K antagonist – warfarin

Historically  warfarin  has  been  the  cornerstone of  pharmacological therapy in stroke prevention in those with AF. [13] Since approval in 1954 warfarin has been the leading oral anticoagulant choice especially in those at high risk. [14]

Warfarin interferes with the cyclic interconversion of vitamin K and its 2,3-epoxide. Vitamin K is a cofactor in the pathway of synthesis of  vitamin  K-dependent  coagulation factors  (factors  II,  VII,  IX,  and X). Warfarin may have a procoagulant effect during initiation of treatment due to earlier clearance of the protein C (half-life 8 h) which is an antithrombotic, compared to prothrombin (50–72 h) which is a prothrombotic. [15] The dose is titrated with the level of the INR and hence INR needs to be monitored regularly. [16] Treatment with vitamin K will reverse the anticoagulant effect of warfarin. Plasma products such as fresh frozen plasma and prothrombin complex concentrate may also be used when urgent reversal is required. This is seen as one of the main advantages in choosing this treatment. [14]

The efficacy of warfarin has been extensively proven. In six trials of warfarin versus placebo warfarin showed a 62% reduction in stroke. Number to treat analysis revealed that one would need to treat 32 patients for one year to prevent one stroke. [2,17]

Although warfarin has been widely proven to be efficacious in stroke prevention, it still remains under-prescribed. The Canadian Stroke Network study found that in high-risk patients with pre-existing AF with no contraindications to anticoagulation, only 40% received warfarin and the majority were not in the therapeutic range. [18]

Treatment with warfarin is not without limitations. At supra- therapeutic  levels  warfarin  predisposes  patients  to  fatal  bleeding. A meta-analysis by Haft et al. found that, compared with placebo, adjusted-dose warfarin was associated with a 130% increase in the relative risk for major extracranial haemorrhage. [19] The therapeutic range is relatively narrow, resulting in the need for frequent monitoring. [19,20] As one can imagine patient compliance becomes a big factor in the success of treatment.

In addition to this, keeping the INR in therapeutic range is challenging and the dose of warfarin is subject to change as there are many drug– drug, drug–disease and drug–food interactions. Certain medications such as rifampicin, metronidazole and amiodarone can affect INR. Foods that have high vitamin K content such as leafy green vegetables can potentially reverse the anticoagulant effects of warfarin. Medical conditions like diarrhoea, fever, heart failure, liver disease and hyperthyroidism can potentiate warfarin’s anticoagulant effects whereas hypothyroidism can reduce its effects. [16]

Furthermore what cannot be underestimated is the deep-seated fear in clinical practice of the adverse effect of fatal bleeding leading to reluctance in prescribing. Practitioners tend to overestimate warfarin’s bleeding risk while at the same time underestimate the benefits in stroke prevention. [18]

Acetylsalicylic acid – aspirin

Acetylsalicylic   acid   directly   and   irreversibly   inhibits   the   activity of cyclooxygenase  (COX-1  and  COX-2)  to  reduce  the  formation of thromboxane  A2  and  inhibit  platelet  aggregation.  [21]  A pooled analysis of the AFASAK I and Stroke Prevention in Atrial Fibrillation (SPAF) I studies on aspirin for stroke prevention found that aspirin reduced the risk of stroke by 36%. [17]

Like warfarin, the concern with aspirin, especially in the elderly, is the risk of fatal bleeding. The BAFTA trial found that elderly AF patients randomised to warfarin treatment experienced a 52% lower risk of fatal or disabling stroke or intracranial haemorrhage compared to aspirin. This was further confirmed by the WASPO trial which reported higher rates of adverse events and intolerance to aspirin in 80–90–year-old patients. Interestingly the effect of aspirin on stroke attenuates with age and randomised controlled trials found no evidence that aspirin reduces the risk of cardioembolic stroke in those greater than 80 years old. [2]

Warfarin vs. aspirin

There  is  significant evidence  to  suggest  superiority  of  warfarin to aspirin in primary stroke prevention. Five randomised controlled trials showed that adjusted-dose warfarin resulted in a relative risk reduction of 36% when compared with aspirin. Meta-analysis of 13 trials found that warfarin was superior to both aspirin and placebo in reducing the risk of stroke or embolism. [13] For combination therapy, results from the SPAF III trial found a relative risk reduction of 74% with standard intensity warfarin (INR 2.0–3.0) compared to aspirin plus low intensity warfarin (INR 1.2–1.5). [17]


Dual antiplatelet therapy (aspirin plus clopidogrel)

Dual antiplatelet therapy has also been studied in two large randomised control trials: ACTIVE-W and ACTIVE-A. [2,22] ACTIVE-W compared aspirin plus clopidogrel with warfarin. The trial was stopped early due to the clear superiority of warfarin with the risk of stroke lower in those treated with warfarin as compared to dual antiplatelet therapy (3.9% vs. 5.6% per year). The risk of major haemorrhage was similar between the two groups but minor bleeding was significantly higher in the dual antiplatelet group. [22]

New advances in therapy: target-specific oral anticoagulants

Direct thrombin inhibitors – dabigatran 

Dabigatran  is  a  direct  competitive  inhibitor  of  thrombin, blocking directly at factor IIa, the final step in blood coagulation. The onset of action is two hours and the half-life is 12–17 hours. [7] Dabigatran is eliminated by renal excretion, making its use difficult in patients with renal insufficiency. [13]

The  Randomised  Evaluation of  Long Term Anticoagulation Therapy (RE-LY) study was a multicentre, prospective open label randomised controlled trial which included patients with non-valvular AF at moderate to high risk of stroke or systemic embolism as determined by the CHADS2  score. 18113 patients were randomised to receive dabigatran  110  mg  twice  daily,  150  mg  twice  daily  or  warfarin. The  mean  duration  of  follow  up  was  two  years.  The  trial  found that dabigatran 110 mg twice daily was non-inferior to warfarin in preventing stroke or systemic embolism (1.53% vs. 1.69% per year, p<0.001) and superior to warfarin in regards to major bleeding (2.71% vs. 3.36% per year, p=0.003). The higher dose of 150 mg twice daily was found to be superior to warfarin in preventing stroke and systemic embolism (1.11% vs. 1.69% per year, p<0.001) and non-inferior to warfarin in terms of major bleeding. Although both doses resulted in fewer intracranial haemorrhages compared to warfarin, there was a higher incidence of gastrointestinal bleeding in the higher dose group. [7,23] Importantly discontinuation rate was also higher in the dabigatran group with the most common reason being gastrointestinal symptoms. [6,7,14,20,23–25]

Furthermore the study by Salazar et al. found that direct thrombin inhibitors were as efficacious as vitamin K antagonists for the outcomes of  vascular  death  and  ischaemic  events.  Importantly  they  found that only the dose of dabigatran 150 mg twice daily was found to be superior to warfarin. Direct thrombin inhibitors were also associated with fewer major haemorrhagic events. Interestingly, adverse events occurred more frequently with direct thrombin inhibitors and led to the discontinuation of treatment. [26]

Factor Xa inhibitors

These drugs bind directly to the active site of factor Xa, which is located on the  convergence  of  the  intrinsic  and  extrinsic  pathways.  This inhibits thrombin formation from both pathways and inhibits thrombin formation upstream. [7]


Rivaroxaban is a potent selective reversible factor Xa inhibitor which inhibits free factor Xa. The time to peak concentration is three hours with a half-life of 9–13 hours. [7] Rivaroxaban is partially metabolised by the cytochrome P450 (CYP450) system making it subject to drug interactions, and two-thirds is eliminated by the kidneys. [6,7,14]

The Rivaroxaban once daily Oral direct factor Xa inhibition Compared with vitamin K antagonist for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) was a randomised double-blind study enrolling 14264 patients allocated either rivaroxaban 20 mg once daily (or 15 mg once daily if creatinine clearance was 30–49 ml/min), and dose-adjusted  warfarin  with  target  INR  2.0–3.0.  [7,27]  ROCKET-AF was different from other trials due to the medical comorbidities of the study population: 55% of the participants had a history of stroke, 62% had heart failure and 87% had a CHADS2 score of 3 or greater, indicative of a high risk population. [7] ROCKET-AF found rivaroxaban to be non-inferior to warfarin for stroke and systemic embolism (1.7% vs. 2.2% per year, p<0.001) and the rates of major bleeding were similar between the two groups (14.9% vs. 14.5% per year, p=0.44). Importantly, the rivaroxaban group had significant reductions in intracranial haemorrhage (.5% vs. 0.7%, p=0.02) and fatal bleeding (0.2% vs. 0.5%, p=0.003), suggesting that rivaroxaban may be safer than warfarin. [7,27]

Furthermore in a study by Bruins Slot et al. it was shown that in patients with AF, factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin. [28] Factor Xa inhibitors also appeared to reduce the number of major bleeds and intracranial haemorrhages compared with warfarin. [28] Further head-to-head studies of the different factor Xa inhibitors are required and are currently underway to conclusively determine the most effective and safest factor Xa inhibitor for patients with AF.


Apixaban is an oral factor Xa inhibitor with a half-life of 8–15 hours. [7] It is eliminated in various pathways, and among the TSOACs has the lowest renal elimination of 25%. [25] It does not inhibit or induce CYP450 therefore has a low potential for drug interactions. [7]

There have been two major studies assessing its use in stroke prevention: the  Apixaban  Verses  acetylsalicyclic  acid  to  prevent stroke in AF patients who have failed or are unsuitable for vitamin K antagonist treatment (AVERROES) trial and Apixiban for prevention of stroke in subjects with atrial fibrillation (ARISTOTLE) trial. [29,30]

The AVERROES trial was stopped early due to clear benefits of apixaban compared with aspirin. It included 5599 patients in whom vitamin K antagonist therapy was unsuitable. Patients were randomised to receive apixaban 5 mg twice daily or aspirin 81–325 mg once daily. Patients with apixaban had significantly lower rates of stroke and systemic embolic events (1.6% vs. 3.7%, p<0.001) with no increase in bleeding (1.4% vs. 1.2%, p=0.57). Patients receiving apixaban also had fewer cardiovascular hospitalisations. [29]

The ARISTOTLE study compared apixaban to warfarin in 18201 AF patients who had at least one other cardiovascular risk factor. This study found that the annual rate of stroke and systemic embolism was 1.27% in the apixaban group compared to 1.60% in the warfarin group (p=0.01). Apixaban was also associated with fewer major haemorrhages (2.13% vs. 3.09% per year, p<0.001) and overall adverse events were similar with a lower discontinuation rate in the apixaban group. Importantly the apixaban group had a lower mortality rate compared to the warfarin group and is the first oral anticoagulant to show a significant mortality benefit over warfarin. [30]

It is unclear which of these TSOACs is most effective and safe in patients with AF. These trials provide the strongest evidence for apixaban, however there have been no head-to-head trials comparing different TSOACs. The described  studies  had differing patient demographics and baseline characteristics making it difficult to make comparisons between trials. [7] Further investigation is needed before one can be said to be superior to another.

Advantages and disadvantages of target specific oral anticoagulants The TSOACs offer many advantages over traditional therapy. They have predictable anticoagulation effects, which allow fixed dosing. [6,14] They also have a wider therapeutic index therefore avoiding the need for routine monitoring. [6] In general they have lower potential for interactions; dabigatran and apixaban in particular have fewer drug and food interactions as they are not metabolised by CYP450 isoenzymes. [7] Rivaroxaban however is metabolised to some degree by CYP450 and so there is potential for medication interactions. [7,14,19,24]

Nevertheless they too have their own limitations. Like warfarin, bleeding is the main adverse effect in all the TSOACs. A recent meta- analysis by Chai-Adisaksopha et al. found that, when compared with vitamin K antagonists, TSOACs are associated with less major bleeding, fatal bleeding, intracranial bleeding, clinically relevant non-major bleeding, and total bleeding. Additionally, TSOACs do not increase the risk of gastrointestinal bleeding. [31]

The main limitation of TSOACs is the lack of specific antidotes to reverse their anticoagulant effects. Although the short half-lives are reassuring in the sense that drug concentrations should decline rapidly when it is discontinued, in situations where reversibility is an emergency, such as trauma, life-threatening bleeding, emergency surgery or in renal insufficiency, it may well be a deadly disadvantage. [15] Additionally in the absence of monitoring it may be difficult to assess patient compliance. [10]

While many of the novel agents do not utilise the CYP450 pathway they are still subject to interactions to some degree as all three are p-glycoprotein (P-GP) substrates. P-GP is an intracellular drug transport system that has a role in drug absorption and distribution. Food and drugs can affect its activity. For example rifampicin, a P-GP inducer, results in decreased serum concentration of dabigatran and should be avoided. Likewise antifungals and HIV proteases are contraindicated as they can result in increased serum concentration and may therefore increase the risk of haemorrhage. [7]

Use of these new agents can only be confidently endorsed once long term follow-up studies are conducted, as anticoagulation therapy is a lifelong treatment. Many of the aforementioned studies had a follow- up period of 2–3 years, however are expected to report long term follow-up results in the coming years. [7] The long term safety profile of these drugs will need to be considered before widespread transition to TSOACs can be recommended. [19]

The United States Food and Drug Administration (FDA) has issued boxed  warnings  on  dabigatran,  rivaroxaban  and  apixaban  in  their use for non-valvular AF. It has been shown in clinical trials that discontinuation of these agents without appropriate cover by another anticoagulant places patients at an increased risk of thrombotic events. Therefore it is recommended to strongly consider replacement with another anticoagulant if these agents are to be discontinued for any reason other than pathological bleeding. [32-34] Additionally the FDA has reported that epidural and spinal hematomas have occurred in

patients treated with dabigatran who receive neuraxial anesthesia or spinal puncture. These may result in long-term or permanent paralysis. [32]

Exciting new research is underway to identify an antidote for the TSOACs. Phase I trials demonstrate that idarucizumab produces an immediate, complete and sustained reversal of the anticoagulant effect of dabigatran in healthy participants. [35] Patient enrolment has also started into a randomised, double-blind, placebo-controlled phase III trial. [35,36] This trial will assess the efficacy of andexanetalfa, a factor Xa inhibitor reversal agent, in rapidly reversing rivaroxaban induced anticoagulation. The safety profile will also be evaluated with a follow up period of 43 days. [36] The synthetic molecule PER977 is also being studied in its ability to reverse the anticoagulant effect of edoxaban. In this study, haemostasis was restored within 10–30 minutes of administration of 100–300 mg of PER977 and was sustained for 24 hours. Additional phase II clinical studies are ongoing. [37] These ‘FDA- designated breakthrough therapies’ are under an accelerated approval pathway with the hope of bringing the agent into market as soon as possible and potentially overcoming the biggest drawback in the use of TSOACs. [36]


This review suggests that TSOACs have similar or superior efficacy than  warfarin  for  stroke  prevention  in  patients  with  non-valvular AF. Importantly, trials consistently demonstrate a favourable side- effect profile for these drugs. Research is currently underway into development of an antidote, overcoming the main argument against their use. [35]  This advancing research will likely see TSOACs replace warfarin as the treatment of choice for stroke prevention in non- valvular AF.



Conflict of interest

None declared.


K Zobair:


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