Departments of Clinical Epidemiology and Biostatistics and of Medicine

Application for inclusion of novel oral anticoagulants for the treatment of non valvular atrial fibrillation in the WHO Model List of Essential Medicines 2015 Submitted by Ignacio Neumann, MD, PhD Holger J. Schünemann, MD, PhD Departments of Clinical Epidemiology and Biostatistics and of Medicine Co Director, WHO Collaborating Center for Evidence Informed Policy, McMaster University Potential conflicts of interest Dr. Neumann and Dr. Schünemann declare that they have no COI. Date: Dec 7, 2014 1

Application to add Novel Oral Anticoagulants (NOAC) to the Essential List of Medicines As a medicine for treatment of non valvular atrial fibrillation 1. Summary statement of the proposal for inclusion In patients with atrial fibrillation and increased risk of stroke, moderate quality evidence suggests that the use of Novel Oral Anticoagulants (NOAC) is as effective and safe than the current standard: Vitamin K Antagonists (VKA). Further, VKAs require frequent laboratory monitoring and dose adjustment to maintain their therapeutic effect. Additionally, the effect of VKAs is modified by several drugs and by the amount of vitamin K on the diet. Appropriate levels of anticoagulation (International Normalized Ratio from 2 to 3), even on ideal circumstances, are achieved only 60% of the time with VKAs. 1 3 Since NOACs do not require monitoring or changes in diet or lifestyle, they offer convenient alternative for patients. Also, there is a broad consensus in the literature that novel oral anticoagulants are cost effective versus Vitamin K Antagonists in a variety of settings and perspectives. 2. Name of the focal point in WHO submitting or supporting the application 3. Name of the organization(s) consulted and/or supporting the application Dr. Ignacio Neumann and Dr. Holger Schünemann, Department of Clinical Epidemiology and Biostatistics and WHO collaborating center for evidence informed policy making McMaster University, Hamilton, Ontario, Canada Ignacio.neumann@gmail.com; holger.schunemann@mcmaster.ca 4. International Nonproprietary Name (INN, generic name) of the medicine Dabigatran Rivaroxaban Apixaban 5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) Dabigatran: Oral tablets of 150 mg. Rivaroxaban: Oral tablets of 20 mg. Apixaban: Oral tablets of 5 mg. There is no formulation for children or pregnant women. 2

6. International availability sources, of possible manufacturers and trade names Dabigatran Manufacturer: Boehringer Ingelheim Trade name: Pradaxa Rivaroxaban Manufacturer: Bayer Trade name: Xarelto Apixaban Manufacturer: Bristol Myers Squibb Trade name: Eliquis 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group As a therapeutic group consisting of the three listed anticoagulants. 8. Information supporting the public health relevance Non valvular atrial fibrillation is the most common sustained cardiac arrhythmia. In developed countries its prevalence has been estimated as 6.6 per 1000 in men and 3.9 per 1000 in women; while in developing countries, in 5.7 per 1000 in men and 3.7 in women. 4 Without antithrombotic treatment, the risk of stroke in patients with atrial fibrillation is around 5% per year, but it can be higher than 10% if other risk factors are present. 5 The global burden of the disease has been increasing during the past 20 years. In 1990, the estimated age adjusted DALYs resulting from atrial fibrillation were 54.3 for men and 38.6 for women (per 100.000 individuals). This number increased to 64.5 in men and 45.9 in women in 2010, representing a difference of almost 20%. 4 The use of oral anticoagulation can reduce the relative risk of stroke by 66% in individuals with atrial fibrillation. 5 However, the drugs typically used to this purpose Vitamin K Antagonists require frequent laboratory monitoring and dose adjustment to maintain appropriated levels of anticoagulation. Additionally, the effect of Vitamin K Antagonists is modified by several drugs and by the amount of vitamin K on the diet. In recent years, a new generation of anticoagulants has been introduced, which do no require monitoring of or changes in diet or life style. Access to monitoring can be an impediment to anticoagulation because monitoring is not available in all settings. While self monitoring presents a viable alternative only about 25% of patients requiring oral anticoagulation are able to do so. 6 9. Treatment details and guidelines In individuals with non valvular atrial fibrillation, the net effect of anticoagulation treatment varies largely with the base line risks of stroke and bleeding. Several stroke risk stratification schemes have been published. Unfortunately all available schemes 3

have only a modest predictive validity for the main outcome. 7 The CHADS 2 score is the most extensively validated risk scheme: it has been tested and validated in more than 10 separate cohorts after it original introduction. 5 The score gives a single point to each of the following: heart failure, hypertension, age over 75 years and diabetes mellitus; and two points to prior stroke or transient ischemic attack (TIA). 8 The CHA 2DS 2VASc score is another prominent risk stratification system. It combines the original factors of the CHADS 2 score with 3 additional risk factors, which have shown a moderate association with stroke in some studies (age over 65 years, female gender and the presence of vascular disease). 9 Studies comparing the CHA 2DS 2VASc and CHADS 2 scores have found that both schemes have similar predictive accuracy. 7 There is no WHO guideline addressing the treatment of non valvular atrial fibrillation, but the UK National Institute for Health and Clinical Excellence (NICE) recommends anticoagulation (strong recommendation) in people at high risk of stroke (CHA 2DS 2VASc over 2 in this case) and suggest considering anticoagulation (conditional recommendation) in people at intermediate risk of stroke (CHA 2DS 2VASc 1). In both cases, NICE recommends to individualize the decision to patients values and preferences and use one of the following alternatives: apixaban, dabigatran etexilate, rivaroxaban or a vitamin K antagonist: 10 Offer anticoagulation to people with a CHA2DS2 VASc score of 2 or above, taking bleeding risk into account. Consider anticoagulation for men with a CHA2DS2 VASc score of 1. Take the bleeding risk into account. Anticoagulation may be with apixaban, dabigatran etexilate, rivaroxaban or a vitamin K antagonist. The 9th edition of the Antithrombotic Guidelines of the American College of Chest Physicians recommends anticoagulation over no treatment (strong recommendation) in patients at high risk of stroke (CHADS 2 score 2 or more) and suggests anticoagulation (conditional recommendation) in patients at intermediate risk of stroke (CHADS 2 score 1). On both cases, the panel suggested the use of NOACs over Vitamin K antagonists (conditional recommendation): 5 For patients with AF, including those with paroxysmal AF, who are at high risk of stroke (eg, CHADS 2 score over 2), we recommend oral anticoagulation rather than no therapy (Grade 1A), aspirin (75 mg to 325 mg once daily) (Grade 1B), or combination therapy with aspirin and clopidogrel (Grade 1B) For patients with AF, including those with paroxysmal AF, who are at intermediate risk of stroke (eg, CHADS 2 score 1), we recommend oral anticoagulation rather than no therapy (Grade 1B. We suggest oral anticoagulation rather than aspirin (75 mg to 325 mg once daily) (Grade 2B) or combination therapy with aspirin and clopidogrel (Grade 2B). 4

For patients with AF, including those with paroxysmal AF, for recommendations in favor of oral anticoagulation, we suggest dabigatran 150 mg twice daily rather than adjusteddose vitamin K antagonist (VKA) therapy (target INR range, 2.0 3.0) (Grade 2B). 10. Summary of comparative effectiveness: In the context of the development of a guideline regarding the antithrombotic treatment of non valvular atrial fibrillation, we conducted a systematic search of MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials (CENTRAL) up to January 2014. We identified the following trials: RE LY trial 1 : Non inferiority trial of 18,113 patients who had non valvular atrial fibrillation and increased risk of stroke randomly allocated to receive, in a blinded fashion, fixed doses of dabigatran 110 mg or 150 mg twice daily or, in an unblinded fashion, adjusted dose warfarin. ROCKET AF trial 2 : Double blind trial of 14,264 patients with non valvular atrial fibrillation and increased risk of stroke randomly allocated to receive either rivaroxaban (at a daily dose of 20 mg) or dose adjusted warfarin. ARISTOTLE trial 3 : Double blind trial of 18,201 patients with non valvular atrial fibrillation and at least one additional risk factor for stroke randomly allocated to apixaban (at a dose of 5 mg twice daily) or warfarin (target international normalized ratio, 2.0 to 3.0) J ROCKET AF 11 : Trial conducted on Japan, including 1,280 individuals with non valvular atrial fibrillation at increased risk for stroke, who were randomized to receive 15 mg once daily rivaroxaban or dose adjusted warfarin ARISTOTLE J trial 12 : Trial conducted on Japan, including 222 individuals with non valvular atrial fibrillation at increased risk for stroke, who were randomized to receive either apixaban 2.5 or 5mg b.i.d. or open label warfarin (target international normalized ratio 2.0 3.0; 2.0 2.6 if age 70 years) PETRO trial 13 : Trial of 502 individuals with atrial fibrillation at increased risk for stroke randomized to receive blinded doses of 50, 150, or 300 mg dabigatran twice daily alone or combined with 81 or 325 mg aspirin or open label warfarin administered to achieve an international normalized ratio of 2 to 3 We included in our analysis the following doses: dabigatran 150 mg twice a day, rivaroxaban 20 mg once a day, and apixaban 5 mg twice a day (thus we excluded the J ROCKET trial, which tested rivaroxaban 15 mg once a day, and the arms testing lower 5

doses on the ARISTOTLE J and PETRO trials). We conducted a standard meta analysis using the Mantel Haenszel method, random effect model and used the GRADE approach to assess the confidence in the estimates of effects, also known as quality of the evidence. 14 We found that the use of Novel Oral Anticoagulants instead of Vitamin K Antagonists can reduce the risk of death (5 fewer deaths per 1000 patients for a year; high quality evidence) and the risk of stroke (2 9 fewer strokes per 1000 patients for a year; high quality evidence). Additionally, the use of NOACs probably reduces the risk of major bleeding in comparison to Vitamin K Antagonists (2 fewer bleeds per 1000 patients for a year; moderate quality evidence) (Table 1). The quality of the evidence according to GRADE was moderate to high for the main outcomes. 14 It seems prudent to assume that in settings or situations where monitoring of anticoagulation or self monitoring is not available the benefits of Novel Oral Anticoagulants outweigh the harms and burden. 6

Table 1 Summary of Findings Should Novel Oral Anticoagulants (NOAC) rather Vitamin K Antagonists (VKA) be used in patients with non-valvular atrial fibrillation? Patient or population: Patients with non-valvular atrial fibrillation Settings: outpatients Intervention: Novel Oral Anticoagulants (NOAC) Comparison: Vitamin K Antagonists (VKA) Outcomes No of Participants (studies) All-Cause Mortality Follow-up: 3 to 30 months Relative effects (95% CI) RR 0.88 (0.82 to 0.95) Anticipated absolute effects With VKA With NOAC Difference (95% CI) 38 deaths per 1000 patients at 1 year 1 33 deaths 5 fewer deaths per 1000 patients (from 7 to 2 fewer at 1 year per 1000 patients) Quality of the evidence (GRADE) High What happens NOACs decrease mortality 44,827 (5 studies) Stroke Follow-up: 3 to 30 months RR 0.76 (0.66 to 0.88) 8 strokes per 1000 patients at 1 year 1 CHADS 2 score 1 6 strokes 2 fewer strokes per 1000 patients (from 3 to 1 fewer at 1 year per 1000 patients) High NOACs decrease risk of stroke CHADS 2 score 2 17 strokes 13 strokes 4 fewer strokes per 1000 patients per 1000 patients (from 6 to 2 fewer at 1 year 1 at 1 year per 1000 patients) 44,827 (5 studies) Systemic embolism Follow-up: 3 to 30 months 44,827 (5 studies) Major Bleeding Follow-up: 3 to 30 months RR 0.59 (0.27 to 1.29) RR 0.87 (0.71 to 1.08) 44,827 (5 studies) CI: Confidence interval; RR: risk ratio. CHADS 2 score 3-6 36 strokes 27 strokes 9 fewer strokes per 1000 patients per 1000 patients (from 12 to 4 fewer at 1 year 1 at 1 year per 1000 patients) 2 embolisms per 1000 patients at 1 year 1 13 bleeds per 1000 patients at 1 year 1 1 embolism per 1000 patients at 1 year 11 bleeds per 1000 patients at 1 year 1 fewer embolism (from 1 fewer to 1 more per 1000 patients) 2 fewer bleeds (from 4 fewer to 1 more per 1000 patients) Moderate 2,3 due to inconsistency Moderate 2,3 due to inconsistency NOACs probably do not change the risk of systemic embolism NOACs probably decrease the risk of major bleeding EXPLANATIONS 1 To estimate the absolute effects, we used the base-line risks reported by the 9th edition of the Antithrombotic Guidelines of the American College of Chest Physicians. 2 Although the 95% confidence interval around the relative effect is wide, the 95% confidence interval around the absolute effect is precise and we did not downgrade the quality of evidence for imprecision. The imprecision is also a result of the inconsistency. 3 We observed substantial unexplained inconsistency in the point estimates and high I 2 in the meta-analysis 11. Summary of comparative evidence on safety: There is no long term data available regarding the use of Novel Oral Anticoagulants rather than Vitamin K Antagonists in individuals with non valvular atrial fibrillation. The tables 2 and 3 describe the adverse events reported in large randomized trials for dabigatran and rivaroxaban. There is no detailed report available of the adverse events observed with apixaban in the ARISTOTLE trial. 7

In November 2011, the observation of an apparent excess of serious bleeding events in patients treated with dabigatran motivated an investigation by the US Food and Drug Administration (FDA). In February 2012, the FDA stated that The results of this Mini Sentinel assessment indicate that bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the large clinical trial used to approve Pradaxa (the RE LY trial) (available at: http://www.fda.gov/drugs/drugsafety/ucm326580.htm). In a recent post marketing study conducted in more than 134,000 Medicare patients, 65 years or older (available at: http://www.fda.gov/drugs/drugsafety/ucm396470.htm), dabigatran showed to decrease the risk stroke and mortality. However, an increase of the rate of gastrointestinal bleeding of 7.7 per 1,000 person years was observed (table 4). We found no relevant post marketing data for rivaroxaban or apixaban. It is important to note that NOACs have not been tested in pregnant women, children or in individuals with severe renal failure (creatinine clearance of less than 30 ml per minute), heart valve disorder, active liver disease or stroke within the previous 7 14 days. Therefore, their use in such populations is not advisable Table 2 Adverse events reported on RE LY trial Adverse events Dabigatran (n=6076) (%) Warfarin (n = 6022) (%) Dyspepsia 688 (11.3) 348 (5.8) Dizziness 506 (8.3) 568 (9.4) Dyspnea 580 (9.5) 586 (9.7) Peripheral edema 478 (7.9) 468 (7.8) Fatigue 401 (6.6) 372 (6.2) Cough 348 (5.7) 364 (6.0) Chest pain 377 (6.2) 357 (5.9) Back pain 314 (5.2) 337 (5.6) Arthralgia 335 (5.5) 346 (5.7) Nasopharyngitis 330 (5.4) 336 (5.6) Diarrhea 397 (6.5) 346 (5.7) Urinary tract infection 289 (4.8) 335 (5.6) Table 3 Adverse events reported on ROCKET AF trial Adverse events Rivaroxaban (n=7111) (%) Warfarin (n = 7125) (%) Epistaxis 721 (10.14) 609 (8.55) Peripheral edema 435 (6.12) 444 (6.23) Dizziness 433 (6.09) 449 (6.30) Nasopharyngitis 421 (5.92) 455 (6.39) Cardiac failure 397 (5.58) 420 (5.89) Bronchitis 396 (5.57) 417 (5.85) Dyspnea 380 (5.34) 394 (5.53) Diarrhea 379 (5.33) 397 (5.57) Cough 343 (4.82) 353 (4.95) Back pain 338 (4.75) 347 (4.87) Respiratory tract infection 336 (4.73) 325 (4.56) Headache 324 (4.56) 363 (5.09) Arthralgia 301 (4.23) 331 (4.65) Hematuria 296 (4.16) 242 (3.40) Urinary tract infection 293 (4.12) 321 (4.51) 8

Table 4 Results of a post marketing study conducted in more than 134,000 Medicare patients, 65 years or older (available at: http://www.fda.gov/drugs/drugsafety/ucm396470.htm) Incidence rate per 1,000 person-years Pradaxa (dabigatran) Warfarin Adjusted hazard ratio (95% CI) Ischemic stroke 11.3 13.9 0.80 (0.67-0.96) Intracranial hemorrhage 3.3 9.6 0.34 (0.26-0.46) Major GI bleeding 34.2 26.5 1.28 (1.14-1.44) Acute MI 15.7 16.9 0.92 (0.78-1.08) Mortality 32.6 37.8 0.86 (0.77-0.96) 12. Summary of available data on comparative cost and cost effectiveness within the pharmacological class or therapeutic group The direct cost of NOACs is 2 to 4 times higher than Vitamin K antagonists (Table 5). However, since NOACs do not require follow up and laboratory monitoring there is broad consensus that novel oral anticoagulants are cost effective versus warfarin. A recent systematic review 15 of 16 economic evaluations (13 evaluating dabigatran, 3 apixaban and 2 rivaroxaban) found that although there is substantial heterogeneity between the numerical findings of economic evaluations, all of them conclude that NOACs are cost effective in comparison to Vitamin K Antagonists. Table 6 summarizes the results. Table 5 Direct cost of Novel Oral Anticoagulants and Vitamin K Antagonists (VKA). Adapted from Kansal et al. 15 Drug US (USD) Canada (CAD) UK ( ) Price per day Sweden ( ) Denmark ( ) Switzerland (CHF) Spain ( ) Warfarin (VKA) 1.2 1.8 1.2 0.6 1.2 1.6 1.7 1.6 1.2 Dabigatran 6.8 8.8 3.2 2.5 2.8 2.6 4 3.0 Rivaroxaban 6.8 2.8 - - - - - Apixaban 6.8 7.0 - - - - - - 9

Table 6 Summary of economic evaluation addressing the comparison NOAC vs VKA. Adapted from Kansal et al. 15 Study Country/Perspective ICER (cost/qaly) Authors conclusions Freeman et al. (2011), Annals of Internal Medicine Shah and Gage (2011), Circulation Sorensen et al. (2011), Thrombosis and Haemostasis Pink et al. (2011), BMJ Davidson et al. (2013), European Heart Journal Kamel et al. (2012), Stroke Kansal et al. (2012), Heart Langkilde et al. (2012), Journal of Medical Economics González-Juanatey et al. (2012), Revista Espanola de Cargiologia Pletscher et al. (2013), Swiss Medical Weekly Wouters et al. (2013), Journal of Medical Economics You et al. (2012), PLoS One Kamel et al. (2012), Neurology Lee et al. (2012), PLoS One Lee et al. (2012), Circulation: Cardiovascular Quality and Outcomes US health care setting US health care setting Canadian health care setting UK National Health Service Sweden societal US health care setting UK National Health Service Danish health care setting Spain National Health System Swiss payer perspective Belgian health care setting US payer perspective US health care setting US Medicare perspective US payer/medicare perspective Dabigatran 150 mg vs. warfarin: $12,386 Dabigatran 150 mg vs. warfarin: $86,000 Dabigatran 150 mg vs. triallike warfarin: $9041 Dabigatran 150 mg vs. warfarin: 23,082 Dabigatran vs. warfarin 7742 Dabigatran vs. warfarin $25,000 Dabigatran vs. warfarin 4831 Dabigatran vs. warfarin: 7000 Dabigatran vs. real-world warfarin: 14,118 Dabigatran 150 mg vs. VKA: CHF 9702 Dabigatran vs. warfarin (real-world INR control): 970 Dabigatran vs. genotypeguided warfarin: $13,810 Apixaban vs. warfarin $11,400 Apixaban dominates warfarin. Rivaroxaban vs. warfarin $27,498 Dabigatran is a costeffective alternative to warfarin. Dabigatran 150 mg bid was cost-effective in AF populations at high risk of hemorrhage or stroke Dabigatran is highly costeffective High-dose dabigatran can be cost-effective for patients at high risk of stroke or with poorly controlled INR; Dabigatran is cost-effective compared to warfarin. Dabigatran is likely to be a cost-effective alternative to warfarin for stroke prevention in AF population with stroke history. Dabigatran as a first-line treatment is likely to be costeffective in eligible UK patients with AF. Dabigatran is a costeffective alternative to warfarin. Dabigatran is cost-effective compared to warfarin from NHS perspective and would be dominant from societal perspective. Dabigatran can be considered cost-effective in comparison with VKA. Dabigatran is cost-effective compared to warfarin. Dabigatran 150 mg is costeffective if TTR 64%. Apixaban is cost-effective relative to warfarin Apixaban may be a costeffective alternative to warfarin for AF patients with 1 additional risk factor for stroke Rivaroxaban may be a costeffective alternative to adjusted-dose warfarin. 10

13. Summary of regulatory status of the medicine (in various countries) Dabigatran, Rivaroxaban and Apixaban are approved and licensed as anticoagulant for patients with non valvular atrial fibrillation by: The US Food and Drug Administration (FDA), Health Canada, the European Medicines Agency (EMA) and the Australian Government. 14. Availability of pharmacopoeial standards Dabigatran International Pharmacopoeia: No British Pharmacopoeia: No European Pharmacopoeia: No United States Pharmacopoeia: No Rivaroxaban International Pharmacopoeia: No British Pharmacopoeia: No European Pharmacopoeia: No United States Pharmacopoeia: No Apixaban International Pharmacopoeia: No British Pharmacopoeia: No European Pharmacopoeia: No United States Pharmacopoeia: No 15. Proposed new text that could be included in a revised WHO Model Formulary DABIGATRAN Tablets: 150 mg Indications: Treatment of non valvular atrial fibrillation Contraindications: Severe renal failure (creatinine clearance of less than 15 ml per minute) Active bleeding Precautions: Dabigatran has not been tested in Children individuals with severe renal failure (creatinine clearance of less than 30 ml per minute), heart valve disorder, active liver disease or stroke within the previous 7 14 days. Premature discontinuation may increase the risk of stroke or thrombotic events. Dosage: 150 mg; 1 twice daily 11

Adverse effects: Bleeding, Dyspepsia. RIVAROXABAN Tablets: 20 mg Indications: Treatment of non valvular atrial fibrillation Contraindications: Severe renal failure (creatinine clearance of less than 15 ml per minute) Active bleeding Precautions: Rivaroxaban has not been tested in Children individuals with severe renal failure (creatinine clearance of less than 30 ml per minute), heart valve disorder, active liver disease or stroke within the previous 7 14 days. Premature discontinuation may increase the risk of stroke or thrombotic events. Dosage: 20 mg; 1 tablet daily Adverse effects: Bleeding APIXABAN Tablets: 5 mg Indications: Treatment of non valvular atrial fibrillation Contraindications: Severe renal failure (creatinine clearance of less than 15 ml per minute) Active bleeding Precautions: Apixaban has not been tested in Children individuals with severe renal failure (creatinine clearance of less than 30 ml per minute), heart valve disorder, active liver disease or stroke within the previous 7 14 days. Premature discontinuation may increase the risk of stroke or thrombotic events. Dosage: 5 mg; 1 Tablet twice daily Adverse effects: Bleeding 12

References 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine 2009;361:1139 1151. 2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine 2011;365:883 891. 3. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine 2011;365:981 992. 4. Chugh SS, Havmoeller R Fau Narayanan K, Narayanan K Fau Singh D, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837 47. 5. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence based clinical practice guidelines. Chest 2012;141:e531S e575s. 6. Brown A, Wells P, Jaffey J, McGahan L, Poon M C, Cimon K, Campbell K. Devices for pointof care monitoring of long term oral anticoagulation therapy: clinical and cost effectiveness [Technology overview number 24]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007.. 7. Odum LE, Cochran KA, Aistrope DS, et al. The CHADS2 versus the New CHA2DS2 VASc Scoring Systems for Guiding Antithrombotic Treatment of Patients with Atrial Fibrillation: Review of the Literature and Recommendations for Use. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 2012;32:285 296. 8. 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. 9. 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. 10. NICE. Atrial fibrillation: the management of atrial fibrillation. guidance.nice.org.uk/cg180 2014. 11. Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs. Warfarin in Japanese Patients With Atrial Fibrillation; The J ROCKET AF Study. Circulation Journal 2012;76:2104 2111. 12. Ogawa S, Shinohara Y, Kanmuri K. Safety and Efficacy of the Oral Direct Factor Xa Inhibitor Apixaban in Japanese Patients With Non Valvular Atrial Fibrillation; The ARISTOTLE J Study. Circulation Journal 2011;75:1852 1859. 13. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran With or Without Concomitant Aspirin Compared With Warfarin Alone in Patients With Nonvalvular Atrial Fibrillation (PETRO Study). The American Journal of Cardiology 2007;100:1419 1426. 14. Guyatt G, Oxman AD, Sultan S, et al. GRADE guidelines: 11. Making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. J Clin Epidemiol 2013;66:151 7. 15. Kansal AR, Zheng Y, Pokora T, et al. Cost effectiveness of new oral anticoagulants in the prevention of stroke in patients with atrial fibrillation. Best Practice & Research Clinical Haematology 2013;26:225 237. 13