Optimising stroke prevention in patients with atrial fibrillation in primary care

Yassir Javaid

Cite this article as: BJMP 2016;9(1):a904
Download PDF


Abstract

In clinical practice, atrial fibrillation (AF) is the most common cardiac arrhythmia seen, and with an ageing population its prevalence is expected to rise. Guidelines recommend anticoagulant therapy for AF-related stroke prevention, based on an individual’s predicted risk of stroke; options include vitamin K antagonists (VKAs) and the non-VKA oral anticoagulants (NOACs), including apixaban, dabigatran, edoxaban, and rivaroxaban. The NOACs fulfil most criteria associated with an ideal anticoagulant and have demonstrated improved benefit–risk profiles compared with warfarin in patients with non-valvular AF. Although patients with AF commonly have other chronic conditions that may complicate treatment, a recent meta-analysis showed a similar treatment effect of NOACs in almost all challenging-to-treat subgroups encountered in clinical practice compared with the general patient population. Encouragingly, data on the real-world efficacy and safety of NOACs are growing and lend support to the increased use of NOACs in this indication.

Keywords: Anticoagulation, atrial fibrillation, real-world, stroke prevention

Summary points

  • The non-vitamin K antagonist oral anticoagulants have demonstrated favourable benefit–risk profiles in large phase III trials, and these findings have been supported by real-world studies involving unselected patients representative of those encountered in routine clinical practice and including those deemed ‘challenging-to-treat’
  • Accurate detection of atrial fibrillation and assessment of stroke and bleeding risk is crucial in identifying patients who should receive anticoagulation
  • Elderly populations represent a significant proportion of patients seen in general practice, and advanced age should not be regarded as a contraindication to treatment; acetylsalicylic acid is not considered an effective treatment option to reduce the risk of stroke in patients with non-valvular atrial fibrillation (except for those declining oral anticoagulation), particularly in fragile elderly patients, for whom this drug was historically prescribed
  • The frequency of follow-up visits, in particular to check compliance, should be tailored according to patients’ clinical characteristics and needs, but there is no requirement for routine coagulation monitoring, unlike vitamin K antagonists

Atrial fibrillation: a clinical and economic burden to society

Atrial fibrillation (AF) is the most frequently encountered sustained cardiac arrhythmia, with a prevalence of about 1.5–2% in the general population1,2. Its incidence is predicted to rise sharply over the coming years as a consequence of the ageing population and increased life expectancy in those with ischaemic and other structural heart disease2. In addition to being associated with significantly increased rates of mortality3, AF is also associated with significantly increased rates of heart failure, which is both a common cause and consequence of AF and greatly worsens the prognosis4. However, it is stroke that is the most devastating consequence of AF, with an average fivefold increased risk5.

AF-related strokes are often more severe than other strokes6,7because the clots that embolise from the left atrium or left atrial appendage are often much larger8than from other sources of emboli. These clots usually lodge in large cerebral vessels, commonly the middle cerebral artery, resulting in huge neurological and functional deficits and increased mortality compared with other stroke types. Moreover, the strokes suffered by patients with AF are more likely to lead to extended hospital care than strokes in patients without AF, thus impacting on patients’ quality of life7.

Current evidence suggests that, in the UK, AF has a causative role in almost 20% of all strokes9. This is likely to represent a significant underestimate given that long term electrocardiogram (ECG) monitoring in patients who would previously have been diagnosed as having cryptogenic stroke has demonstrated a significant AF burden in these patients10.

With improved AF detection and stroke prevention, it is estimated that approximately 8000 strokes could be avoided and 2100 lives saved every year in the UK, resulting in substantial healthcare savings of £96 million11,12.

A key objective of this short review is to provide primary care clinicians with the confidence to manage patients with AF in need of anticoagulation, including the safe and appropriate use of the non-vitamin K antagonist oral anticoagulants (NOACs) apixaban, dabigatran, rivaroxaban (approved in the EU, US and several other countries worldwide) and edoxaban (approved in the EU, US and Japan).13-20The focus will be on how to accurately identify, risk-stratify and counsel patients on the risks and benefits associated with the different treatment options.

Who to treat. Accurate detection and assessment of stroke and bleeding risk

Many patients with AF are asymptomatic, particularly the elderly, less active patients who may not notice the reduction in cardiac performance associated with AF. Unfortunately, it remains the case that AF is undetected in up to 45% of patients21, and stroke is very often the first presentation of AF.

Both the National Institute for Health and Care Excellence (NICE) and the European Society of Cardiology (ESC) guidelines recommend opportunistic screening in patients aged ≥65 years by manual pulse palpation followed by ECG in patients found to have an irregular pulse1,22. Opportunistic screening (manual pulse palpation) was shown to be as effective as systematic screening (ECG) in detecting new cases23, and this simple strategy should be used to screen at-risk patient groups as often as possible. Hypertension and increasing age are the two leading risk factors for developing AF, but other high-risk groups include patients with obstructive sleep apnoea, morbid obesity or a history of ischaemic heart disease24-26. In the context of proactive AF detection, many initiatives have been launched worldwide to encourage primary care clinicians to integrate manual pulse checks into their routine practice. The Know Your Pulse campaign was launched by the AF Association and Arrhythmia Alliance during Heart Rhythm Week in 2009 and was quickly endorsed by the Department of Health in the UK and by many other countries. This initiative has assisted in diminishing some of the gaps in AF detection21.

The most frequently used tools to evaluate stroke risk in patients with non-valvular AF (AF that is not associated with rheumatic valvular disease or prosthetic heart valves) are the CHADS227 and CHA2DS2-VASc28scores, with recent guidelines favouring the use of the latter and emphasising the need to effectively identify ‘truly low-risk’ patients1. The CHA2DS2-VASc score is superior to CHADS2 in identifying these truly low-risk patients, who should not be routinely offered anticoagulation1. Patients with any form of AF (i.e. paroxysmal, persistent or permanent), and regardless of whether they are symptomatic, should be risk stratified in this way. The risk of stroke should also be assessed using CHA2DS2-VASc in patients with atrial flutter and probably for the majority of patients who have been successfully cardioverted in the past22. Unless the initial underlying cause has been removed (e.g. corrected hyperthyroidism) and there is no significant underlying structural heart disease, the risk of patients suffering from a recurrence of AF following ‘successful’ cardioversion remains high29. The ESC guidelines recommend that anticoagulation should be offered to patients with a CHA2DS2-VASc score ≥1 based on assessment of risk of bleeding complications and the patient’s clinical features and preferences1.

The new Quality and Outcomes Framework (QOF) for 2015–2016 now recommends the use of CHA2DS2-VASc for risk stratification and no longer recommends antiplatelet agents as a therapeutic option for stroke prevention in patients with non-valvular AF30; this should result in significantly more patients receiving anticoagulation for this indication. The changes to QOF 2015–2016 compared with 2014–2015 are summarised in Table 130.

Table 1. Summary of changes to UK the Quality and Outcomes Framework (QOF) 2015–201630

NICE indicator ID Changes 2014–2015 points 2015–2016 points
NM45: Patients with AF and CHADS2=1 currently treated with anticoagulant therapy or antiplatelet therapy Retired 6
NM46: Patients with AF and a latest record of a CHADS2 ≥1 currently treated with anticoagulant therapy Replaced by NM82 6
NM82: Patients with AF and CHA2DS2-VASc ≥2 currently treated with anticoagulant therapy Replacement 12
NM81: Patients with AF in whom stroke risk has been assessed using the CHA2DS2-VASc risk-stratification scoring system in the preceding 12 months (excluding those with a previous CHADS2 or CHA2DS2-VASc ≥2) New indicator 12

Key: AF = atrial fibrillation; CHADS2 = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes, Stroke (doubled); CHA2DS2-VASc = Congestive heart failure or left ventricular dysfunction Hypertension, Age ≥75 years (doubled), Diabetes, Stroke (doubled)-Vascular disease, Age 65–74 years, Sex category (female); NICE = National Institute for Health and Care Excellence

The Guidance on Risk Assessment and Stroke Prevention in Atrial Fibrillation (GRASP-AF) clinical audit software detection tool is now very widely used in primary care to improve clinical outcomes in the AF population by identifying patients likely to benefit from anticoagulation. GRASP-AF systematically scans general practice software systems and calculates CHADS2 and CHA2DS2-VASc scores in patients who are coded as having AF, thus enabling physicians to identify high-risk patients who are not adequately treated for stroke prevention31. Identification of AF patients who are poorly controlled on warfarin (defined as having a time in therapeutic range <65% or a labile international normalised ratio [INR], e.g. one INR value >8 or two INR values <1.5 or >5 within the past 6 months)22 is crucial because these patients are more likely to experience major bleeding or stroke. These patients should be reviewed and, if possible, the cause for the poor warfarin control should be identified. The Warfarin Patient Safety Audit tool is another software tool that has been developed to help identify patients with poor warfarin control32.

Primary care clinicians are being urged to objectively assess the bleeding risk of AF patients who are receiving, or about to receive, anticoagulation1,22,32. HAS-BLED is the bleeding assessment scheme advocated by both NICE and the ESC1,22, this has been validated in several independent cohorts and was shown to correlate well with the risk of major bleeding, in particular intracranial bleeding1. The key aspect of HAS-BLED is that, unlike CHADS2 and CHA2DS2-VASc, it consists of risk factors that are modifiable. It should, therefore, not be a tool to influence the decision of whether to anticoagulate, but instead to identify ways to reduce the risk of bleeding in patients receiving an anticoagulant; for example, optimising blood pressure control, stopping unnecessary antiplatelet or anti-inflammatory agents and reducing alcohol consumption can all significantly reduce HAS-BLED scores and bleeding risk1. In addition, it needs to be emphasised that the absolute number of patients with AF experiencing a serious bleeding event while receiving anticoagulant therapy is low (~2–3%/year in the XANTUS, PMSS and Dresden NOAC Registry real-world studies) , with prospective real-world studies indicating that most bleeding events can be managed conservatively33-35. Whilst concerns have been raised about not having a reversal agent to counter the anticoagulant action of NOACs in patients who experience serious bleeding, the low incidence of major bleeding in real-world and phase III studies and its conservative management in most cases demonstrate that such agents would not be required routinely. Despite these low rates of major bleeding, reversal agents have been developed and successfully completed phase III studies and undergone approval in some markets, including idarucizumab in the UK36,37. Notably, high-risk patients with AF were shown to be more willing to endure bleeding events in order to avoid a stroke and its consequences38, thus reinforcing the message that “we can replace blood but we cannot replace brain tissue”.

Adequate anticoagulation therapy should follow appropriate patient identification

Identifying the right treatment option for patients with AF is likely to improve clinical outcomes. Involving patients in the decision-making process and rationale, and ensuring they understand the net benefit–risk of treatment options, is likely to lead to better compliance and improved clinical outcomes. The ESC guidelines consider patients with valvular AF (patients with AF in the presence of either rheumatic mitral stenosis [very rare now in the UK] or prosthetic heart valves) to be at high risk, and these patients should be anticoagulated with a VKA regardless of the presence of any other risk factors1. Warfarin is very effective at reducing the risk of stroke compared with acetylsalicylic acid (ASA)39,40, but an unpredictable dose–response relationship and multiple drug and food interactions can be problematic for some patients, and many patients remain sub-optimally treated41. ASA is also not considered an effective treatment option to reduce the risk of stroke in patients with non-valvular AF especially in frail, elderly patients in whom ASA was historically prescribed. The GARFIELD-AF registry (10,614 patients enrolled in the first cohort) revealed that real-world anticoagulant prescribing in AF populations deviates substantially from guideline recommendations: 40.7% of patients with a CHA2DS2-VASc score ≥2 did not receive anticoagulant therapy, and a further 38.7% with a score of 0 received anticoagulant therapy. At diagnosis, 55.8% of patients overall were given a VKA, just over one quarter (25.3%) received an antiplatelet drug alone, and ~4.5% received a NOAC24. Inappropriate prescribing was further confirmed by data from UK general practices (n=1857, representing a practice population of 13.1 million registered patients) using the GRASP-AF tool. Only 55% of patients with high-risk AF (CHADS2 ≥2) were receiving oral anticoagulation (OAC) therapy, whereas a further 34% of patients with no known contraindication did not receive OAC therapy42.

The NOACs have altered the landscape in terms of stroke prevention management by increasing the available options for patients. These agents exhibit some important practical advantages over traditional therapy (e.g. no requirement for routine anticoagulation monitoring, simple fixed dosing oral regimens, fast onset of action, fewer drug reactions and no food interactions), leading to their increased uptake in primary care.

Key patient groups who are likely to benefit from the NOACs include patients poorly controlled on VKAs, those predicted to require medications that interact with VKAs (e.g. patients who require frequent antibiotics), those without severe renal impairment or those with a prior ischaemic stroke while receiving a VKA with an adequate INR. These agents could also be a good choice for patients living a considerable distance from their local hospital or surgery and commuters. The NICE guidelines state that primary care clinicians should consider clinical features and patient preference before deciding on the most appropriate option for patients22. In addition, cost may be important in some settings. All of the NOACs have demonstrated cost-effectiveness versus warfarin, and although cost models vary by country, there is little doubt that these agents provide cost-effectiveness largely through the number of adverse events avoided and their associated costs43.

Choice of anticoagulant: which to choose?

The demonstration of a favourable benefit–risk profile (stroke prevention vs bleeding events) in large phase III studies involving over 70,000 patients has resulted in the regulatory approval of apixaban, dabigatran, edoxaban and rivaroxaban44-47for the prevention of stroke and systemic embolism in patients with non-valvular AF and one or more risk factors.

Overall, NOACs have demonstrated an improved benefit compared with warfarin, with lower rates of intracranial haemorrhage (for all NOACs) and similar or superior efficacy for stroke prevention44-48. Statistically significant relative risk reductions (RRRs) in the incidence of fatal bleeding events were seen with low-dose dabigatran (110 mg twice daily [bd]; RRR=42%), both tested doses of edoxaban (30 mg once daily [od] and 60 mg od; RRR=65% and 45%, respectively) and rivaroxaban (20 mg od; RRR=50%)46,47,49; rates of fatal bleeding were also lower in patients treated with apixaban compared with warfarin (34 patients vs 55 patients, respectively)44. These data are promising, especially considering the current lack of a specific antidote for any of the NOACs, and it is likely that the very short half-life of these drugs play an important role in mitigating the bleeding risk.

Owing to a lack of head-to-head comparisons between the NOACs in phase III clinical trials, patient characteristics, drug compliance, tolerability issues and cost may be important considerations1. In addition, subanalyses of phase III trial data for rivaroxaban, apixaban and dabigatran indicate that the challenging-to-treat patient groups often encountered by primary care clinicians can be treated effectively and safely with the NOACs (Table 2). A recent meta-analysis showed a similar treatment effect for almost all subgroups encountered in clinical practice; NOACs appeared to be at least as effective as VKAs in reducing the risk of stroke and systemic embolism and no more hazardous in relation to the risk of major bleeding events, irrespective of patient co-morbidities50.

Table 2.Novel oral anticoagulants studied in key patient subgroups*

Subgroup analysis Rivaroxaban Dabigatran Apixaban
Factors related to disease ROCKET AF RE-LY ARISTOTLE
Heart failure ü59 ü60 ü61
Renal impairment ü62 ü63 ü64
Prior stroke ü65 ü66 ü67
VKA-naïve ü68 ü69 ü70
Prior MI or CAD ü(prior MI)71 ü(CAD or prior MI)72 üCAD73
PAD ü74
PK/PD ü75 ü76
East Asian patients ü77 ü78 79
Elderly ü80 ü49 ü81
Major bleeding predictors ü82
Obesity
Diabetes ü83 ü84 ü85
Valvular heart disease ü86 ü87
Paroxysmal versus persistent AF ü88 ü89 ü90

*No subgroup analyses have been presented for edoxaban Key: AF = atrial fibrillation; ARISTOTLE = Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation; CAD = coronary artery disease; CHADS2= Congestive heart failure, Hypertension, Age ≥75 years, Diabetes, Stroke (doubled); MI = myocardial infarction; PAD = peripheral artery disease; PK/PD = pharmacodynamics/pharmacokinetics; RE-LY = Randomized Evaluation of Long-term anticoagulation therapy; ROCKET AF = Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation; VKA = vitamin K antagonist

Because patient selection in clinical trials is based on strict inclusion/exclusion criteria, patient populations in such studies are not always representative of patients routinely seen in real-world practice. In addition, bleeding events may be managed differently in clinical trials versus routine clinical practice. Real-world data are, therefore, needed to help validate drug safety and effectiveness in unselected patient populations. Following phase III clinical trials and the widespread approval of the NOACs in stroke prevention in patients with non-valvular AF, real-world experience has been steadily accumulating. The current real-world data for rivaroxaban, apixaban and dabigatran have been very reassuring and bridge the evidence gap between clinical studies and real-world experience33-35,51-57.

The lack of routine coagulation monitoring with NOACs does not remove the necessity for regular follow-up. Instead, the frequency of visits can be tailored according to patients’ clinical characteristics and needs. NOACs are all partially eliminated by the kidneys; therefore, regular monitoring of renal function is important either to use a lower recommended dose of these drugs or to avoid them. For example, renal function should be monitored every 6 months in patients who have stage III chronic kidney disease (creatinine clearance [CrCl] 30–60 ml/min)58. Apixaban, rivaroxaban and edoxaban are not recommended in patients with CrCl <15 ml/min, and dabigatran is contraindicated in patients with CrCl <30 ml/min13,15,17,19. Reduced-dose regimens of NOACs are recommended for patients at higher risk of bleeding events, including those with reduced renal function. For example, a reduced apixaban dose of 2.5 mg bd is indicated in patients with at least two of the following characteristics: age ≥80 years, body weight ≤60 kg or serum creatinine ≥1.5 mg/dl (133 μmol/l); a reduced rivaroxaban dose of 15 mg od is indicated in patients with CrCl 15‒49 ml/min58; edoxaban is recommended at a reduced dose of 30 mg od in patients with CrCl 15‒50 ml/min and contraindicated in patients with CrCl >95 ml/min58; and a reduced dose of 110 mg bd dabigatran should be considered in patients with CrCl 30‒50 ml/min who are at a high risk of bleeding58. Follow-up visits should also systematically document patient compliance, thromboembolic and bleeding events, side-effects, co-medications and blood test results58.

Conclusions

The NOACs have demonstrated favourable benefit–risk profiles in large phase III trials, and these findings have been supported by real-world studies involving unselected patients, including those deemed challenging to treat. The NOACs also address many of the limitations associated with VKA use, thus assisting with their integration into clinical practice for stroke prevention in patients with non-valvular AF. In addition, the results from subgroup analyses should provide primary care clinicians with the confidence to manage stroke-prevention strategies in a wide variety of patients with AF.

Acknowledgements
The author would like to acknowledge Sofia Konisti, who provided editorial support with funding from Bayer HealthCare Pharmaceuticals.
Competing Interests
Dr Javaid has received honoraria and/or travel grants from a number of pharmaceutical companies, including Bayer, Boehringer Ingelheim, Pfizer/BMS and Astra Zeneca.
Author Details
YASSIR JAVAID, Primary Care Cardiovascular Lead, East Midlands Strategic Clinical Network, Danes Camp Surgery, Northampton, NN4 0NY, United Kingdom.
CORRESPONDENCE: Yassir Javaid, Danes Camp Surgery, Northampton, NN4 0NY, United Kingdom.
Email: submission4044@hotmail.co.uk

References

  1. Camm AJ, Lip GYH, De Caterina R, et al. 2012 focussed update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33:2719-2747.
  2. Camm AJ, Kirchhof P, Lip GYH, et al. Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369-2429.
  3. Miyasaka Y, Barnes ME, Bailey KR, et al. Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study. J Am Coll Cardiol. 2007;49:986-992.
  4. Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003;107:2920-2925.
  5. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-988.
  6. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke. 1996;27:1760-1764.
  7. Jørgensen HS, Nakayama H, Reith J, et al. Acute stroke with atrial fibrillation. The Copenhagen Stroke Study. Stroke. 1996;27:1765-1769.
  8. Atrial Fibrillation Association, AntiCoagulation Europe (UK). The AF Report. Atrial fibrillation: Preventing a stroke crisis. 2011. Available from: http://www.preventaf-strokecrisis.org/files/files/The%20AF%20Report%2014%20April%202012.pdf [accessed 8 February 2016].
  9. Royal College of Physicians. Sentinel Stroke National Audit Programme (SSNAP). Clinical audit July-September 2014 public report. 2015. Available from: https://www.strokeaudit.org/Documents/Results/National/JulSep2014/JulSep2014-PublicReport.aspx [accessed 8 February 2016].
  10. Camm AJ, Corbucci G, Padeletti L. Usefulness of continuous electrocardiographic monitoring for atrial fibrillation. Am J Cardiol. 2012;112:270-276.
  11. Department of Health. Cardiovascular disease outcomes strategy: improving outcomes for people with or at risk of cardiovascular disease. 2013. Available from: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/217118/9387-2900853-CVD-Outcomes_web1.pdf [accessed 18 May 2015].
  12. National Health Service. The best of clinical pathway redesign - practical examples delivering benefits to patients. 2011. Available from: http://www.nhsiq.nhs.uk/resource-search/publications/nhs-imp-best-of-clinical-pathway-redesign.aspx [accessed 8 February 2016].
  13. Bayer Pharma AG. Xarelto® (rivaroxaban) Summary of Product Characteristics. 2015. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf [accessed 4 February 2016].
  14. Janssen Pharmaceuticals Inc. Xarelto® (rivaroxaban) Prescribing Information. 2015. Available from: http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf [accessed 4 February 2016].
  15. Boehringer Ingelheim International GmbH. Pradaxa® (dabigatran etexilate) Summary of Product Characteristics. 2015. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf [accessed 4 February 2016].
  16. Boehringer Ingelheim Pharmaceuticals Inc. Pradaxa® (dabigatran etexilate) Prescribing Information. 2015. Available from: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf [accessed 4 February 2016].
  17. Bristol-Myers Squibb, Pfizer. Eliquis® (apixaban) Summary of Product Characteristics. 2015. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf [accessed 4 February 2016].
  18. Bristol-Myers Squibb Company, Pfizer Inc. Eliquis® (apixaban) Prescribing Information. 2015. Available from: http://packageinserts.bms.com/pi/pi_eliquis.pdf [accessed 4 February 2016].
  19. Daiichi Sankyo Inc. Savaysa® (edoxaban) Prescribing Information. 2015. Available from: http://dsi.com/prescribing-information-portlet/getPIContent?productName=Savaysa&inline=true [accessed 4 February 2016].
  20. Daiichi Sankyo Europe GmbH. Lixiana® (edoxaban) Summary of Product Characteristics. 2015. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002629/WC500189045.pdf [accessed 4 February 2016].
  21. Atrial Fibrillation Association. European atlas on the prevention of AF-related stroke. 2014. Available from: http://www.atrialfibrillation.org.uk/publications/european-atlas-on-the-prevention-of-af-related-stroke.html [accessed 8 February 2016].
  22. National Institute for Health and Care Excellence. Atrial fibrillation: management. NICE Clinical guideline 180. 2014. Available from: https://www.nice.org.uk/guidance/cg180 [accessed 8 February 2016].
  23. Hobbs FDR, Fitzmaurice DA, Mant J, et al. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study. Health Technol Assess. 2005;9:1-74.
  24. Kakkar AK, Mueller I, Bassand JP, et al. Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD Registry. PLoS One. 2013;8:e63479.
  25. Marinigh R, Lip GYH, Fiotti N, et al. Age as a risk factor for stroke in atrial fibrillation patients implications for thromboprophylaxis: Implications for thromboprophylaxis. J Am Coll Cardiol. 2010;56:827-837.
  26. Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation. 2004;110:364-367.
  27. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864-2870.
  28. Lip GYH, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor based approach: The Euro Heart Survey on Atrial Fibrillation. Chest. 2010;137:263-272.
  29. Anter E, Callans DJ, Wyse DG. Pharmacological and electrical conversion of atrial fibrillation to sinus rhythm is worth the effort. Circulation. 2009;120:1436-1443.
  30. National Health Service. Summary of changes to QOF 2015/16 - England. 2014. Available from: http://www.nhsemployers.org/~/media/Employers/Documents/Primary%20care%20contracts/QOF/QOF%20Home%20Page/2015-16%20Summary%20of%20changes%20to%20QOF.pdf [accessed 8 February 2016].
  31. Atrial Fibrillation Association. Grasp the initiative. 2012. Available from: http://www.atrialfibrillation.org.uk/files/file/GRASP%20the%20Initiative%20Report.pdf [accessed 8 February 2016].
  32. University of Nottingham. Warfarin patient safety audit instructional guide. 2015. Available from: http://www.nottingham.ac.uk/primis/documents/audit-docs/wps-instruction-guide.pdf [accessed 8 February 2016].
  33. Beyer-Westendorf J, Förster K, Pannach S, et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC Registry. Blood. 2014;124:955-962.
  34. Camm AJ, Amarenco P, Haas S, et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J. 2015:doi:10.1093/eurheartj/ehv466.
  35. Tamayo S, Frank PW, Patel M, et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol. 2015;38:63-68.
  36. Pollack CV, Jr., Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511-520.
  37. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373:2413-2424.
  38. Devereaux PJ, Anderson DR, Gardner MJ, et al. Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study. Br Med J. 2001;323:1218-1222.
  39. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867.
  40. Lip GYH, Edwards SJ. Stroke prevention with aspirin, warfarin and ximelagatran in patients with non-valvular atrial fibrillation: A systematic review and meta-analysis. Thromb Res. 2006;118:321-333.
  41. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:e44S-e88S.
  42. Cowan C, Healicon R, Robson I, et al. The use of anticoagulants in the management of atrial fibrillation among general practices in England. Heart. 2013;99:1166-1172.
  43. Limone BL, Baker WL, Kluger J, et al. Novel anticoagulants for stroke prevention in atrial fibrillation: a systematic review of cost-effectiveness models. PLoS One. 2013;8:e62183.
  44. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.
  45. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
  46. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in non-valvular atrial fibrillation. N Engl J Med. 2011;365:883-891.
  47. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-2104.
  48. Connolly SJ, Wallentin L, Yusuf S. Additional events in the RE-LY trial. N Engl J Med. 2014;371:1464-1465.
  49. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011;123:2363-2372.
  50. Lega JC, Bertoletti L, Gremillet C, et al. Consistency of safety and efficacy of new oral anticoagulants across subgroups of patients with atrial fibrillation. PLoS One. 2014;9:e91398.
  51. Peacock WF, Patel M, Tamayo S, et al. Major bleeding in a post-marketing assessment of 39,052 non-valvular atrial fibrillation patients on rivaroxaban. Eur Heart J. 2015;36:687. Abstract P4066.
  52. Laliberté F, Cloutier M, Nelson WW, et al. Real-world comparative effectiveness and safety of rivaroxaban and warfarin in nonvalvular atrial fibrillation patients. Curr Med Res Opin. 2014;30:1317-1325.
  53. Nelson WW, Song X, Coleman CI, et al. Medication persistence and discontinuation of rivaroxaban versus warfarin among patients with non-valvular atrial fibrillation. Curr Med Res Opin. 2014;30:2461-2469.
  54. Beyer-Westendorf J, Förster K, Ebertz F, et al. Drug persistence with rivaroxaban therapy in atrial fibrillation patients-results from the Dresden non-interventional oral anticoagulation registry. Europace. 2015;17:530-538.
  55. Beyer-Westendorf J, Ebertz F, Förster K, et al. Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost. 2015;113:1247-1257.
  56. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for non-valvular atrial fibrillation. Circulation. 2015;131:157-164.
  57. Beyer-Westendorf J, Werth S, Tittl L, et al. Real life efficacy and safety of apixaban for stroke prevention in atrial fibrillation - results of the prospective NOAC registry (NCT01588119). J Thromb Haemost. 2015;13 Abstract AS098.
  58. Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15:625-651.
  59. van Diepen S, Hellkamp AS, Patel MR, et al. Efficacy and safety of rivaroxaban in patients with heart failure and nonvalvular atrial fibrillation: insights from ROCKET AF. Circ Heart Fail. 2013;6:740-747.
  60. Ferreira J, Ezekowitz MD, Connolly SJ, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and symptomatic heart failure: a subgroup analysis of the RE-LY trial. Eur J Heart Fail. 2013;15:1053-1061.
  61. McMurray JJ, Ezekowitz JA, Lewis BS, et al. Left ventricular systolic dysfunction, heart failure, and the risk of stroke and systemic embolism in patients with atrial fibrillation: insights from the ARISTOTLE trial. Circ Heart Fail. 2013;6:451-460.
  62. Fox KAA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32:2387-2394.
  63. Hijazi Z, Hohnloser SH, Oldgren J, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation. 2014;129:961-970.
  64. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2012;33:2821-2830.
  65. Hankey GJ, Patel MR, Stevens SR, et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012;11:315-322.
  66. Diener HC, Connolly SJ, Ezekowitz MD, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol. 2010;9:1157-1163.
  67. Easton JD, Lopes RD, Bahit MC, et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol. 2012;11:503-511.
  68. Mahaffey KW, Wojdyla D, Hankey GJ, et al. Clinical outcomes with rivaroxaban in patients transitioned from vitamin K antagonist therapy: a subgroup analysis of a randomized trial. Ann Intern Med. 2013;158:861-868.
  69. Ezekowitz MD, Wallentin L, Connolly SJ, et al. Dabigatran and warfarin in vitamin K antagonist-naive and -experienced cohorts with atrial fibrillation. Circulation. 2010;122:2246-2253.
  70. Garcia DA, Wallentin L, Lopes RD, et al. Apixaban versus warfarin in patients with atrial fibrillation according to prior warfarin use: results from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial. Am Heart J. 2013;166:549-558.
  71. Mahaffey KW, Stevens SR, White HD, et al. Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or Factor Xa inhibition: results from the ROCKET AF trial. Eur Heart J. 2014;35:233-241.
  72. Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation. 2012;125:669-676.
  73. Bahit MC, Lopes RD, Wojdyla DM, et al. Apixaban in patients with atrial fibrillation and prior coronary artery disease: insights from the ARISTOTLE trial. Int J Cardiol. 2013;170:215-220.
  74. Jones WS, Hellkamp AS, Halperin J, et al. Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF. Eur Heart J. 2014;35:242-249.
  75. Girgis IG, Patel MR, Peters GR, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: Results from ROCKET AF. J Clin Pharmacol. 2014;54:917-927.
  76. Liesenfeld KH, Lehr T, Dansirikul C, et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost. 2011;9:2168-2175.
  77. Wong KS, Hu DY, Oomman A, et al. Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial. Stroke. 2014;45:1739-1747.
  78. Hori M, Connolly SJ, Zhu J, et al. Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation. Stroke. 2013;44:1891-1896.
  79. Goto S, Zhu J, Liu L, et al. Efficacy and safety of apixaban compared with warfarin for stroke prevention in patients with atrial fibrillation from East Asia: a subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Am Heart J. 2014;168:303-309.
  80. Halperin JL, Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with non-valvular atrial fibrillation in the Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation. 2014;130:138-146.
  81. Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J. 2014;35:1864-1872.
  82. Goodman SG, Wojdyla DM, Piccini JP, et al. Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol. 2014;63:891-900.
  83. Halperin JL, Bloomgarden Z, Hellkamp A, et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and diabetes: a subgroup analysis of the ROCKET AF trial. American Heart Association Scientific Sessions 2012. Los Angeles, United States, 3–7 November 2012; Abstract A15544.
  84. Darius H, Clemens A, Healey JS, et al. Comparison of dabigatran versus warfarin in diabetic patients with atrial fibrillation: results from the RE-LY trial. Circulation. 2012;126 Abstract A15937.
  85. Ezekowitz JA, Lewis B, Lopes R, et al. Apixaban compared with warfarin in patients with diabetes and nonvalvular atrial fibrillation in the ARISTOTLE trial. J Am Coll Cardiol. 2014;63:A372.
  86. Breithardt G, Berkowitz SD, Baumgartner H, et al. Outcomes of patients with atrial fibrillation and significant valvular lesions: comparison of the effects of rivaroxaban and warfarin in the ROCKET AF trial. American College of Cardiology 2013 62nd Annual Scientific Session. San Francisco, USA, 9–11 May 2013; Poster 1191M-47. Available from: http://content.onlinejacc.org/article.aspx?articleid=1664486
  87. Avezum A, Lopes RD, Schulte PJ, et al. Apixaban compared with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the ARISTOTLE trial. Circulation. 2015;132:624-632.
  88. Steinberg BA, Hellkamp AS, Lokhnygina Y, et al. Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. Eur Heart J. 2015;36:288-296.
  89. Flaker G, Ezekowitz M, Yusuf S, et al. Efficacy and safety of dabigatran compared to warfarin in patients with paroxysmal, persistent, and permanent atrial fibrillation: results from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study. J Am Coll Cardiol. 2012;59:854-855.
  90. Al Khatib SM, Thomas L, Wallentin L, et al. Outcomes of apixaban vs. warfarin by type and duration of atrial fibrillation: results from the ARISTOTLE trial. Eur Heart J. 2013;34:2464-2471.


Creative Commons Licence
The above article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.


share