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Application for inclusion of non-vitamin K antagonists oral anticoagulant (NOACs) for the treatment of non-valvular atrial fibrillation in the WHO Model List of Essential Medicines 2019

Biraj Karmacharya, Department of Community Programs, Dhulikhel Hospital Kathmandu University Hospital, Nepal

Abiodun Adeoye, Cardiovascular Unit, Department of Medicine, University College Hospital, Ibadan / College of Medicine, University of Ibadan, Ibadan, Nigeria; Director, Community Cardiovascular Research Unit, Elyon Heart Rehabilitation Centre Mariachiara Di Cesare, Department of Natural Science, School of Science and Technology, Middlesex University London, UK Ferdous Hakim, Research and Publication Unit, World Health Organization, Bangladesh Mark D. Huffman, Departments of Preventive Medicine and Medicine, Northwestern University's Feinberg School of Medicine and Food Policy Division, The George Institute for Global Health

Asim Katbeh, International PhD Programme in Cardiovascular Pathophysiology and Therapeutics, CardioPaTh Xinyi Leng, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR Lis Neubeck, School of Health and Social Care, Edinburgh Napier University; Honorary Professor, the University of Sydney Susan Wakil School for Nursing and Midwifery, Charles Perkins Centre, Sydney Stephanie Partridge, Westmead Applied Research Centre and Prevention Research Collaboration, Faculty of Medicine and Health, The University of Sydney Pablo Perel, Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine

Ezequiel Zaidel, Cardiology Department, Sanatorio Güemes University Hospital, Pharmacology Department, School of Medicine, University of Buenos Aires Coordinated and submitted by Mariachiara Di Cesare, Department of Natural Science, School of Science and Technology, Middlesex University London, UK Xinyi Leng, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR Ezequiel Zaidel, Cardiology Department, Sanatorio Güemes University Hospital, Pharmacology Department, School of Medicine, University of Buenos Aires

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List of acronyms. AF or NVAF Non-valvular Atrial Fibrillation CrCl Creatinine Clearance GI Gastrointestinal INR International Normalized Ratio NOACs non-vitamin K antagonists oral anticoagulants OAC Oral anticoagulant RWD Real-world data VKAs vitamin K antagonists

Classes of recommendations in guidelines – definitions. Class I Evidence and/or general agreement that a given treatment or procedure is

beneficial, useful, effective. Class II

Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure.

Class IIa Weight of evidence / opinion is in favour of usefulness/efficacy Class IIb Usefulness/efficacy is less well established by evidence/opinion. Class III Evidence or general agreement that the given treatment or procedure is not

useful/effective, and in some cases may be harmful. Levels of evidence in guidelines – definitions. Level of evidence A Data derived from multiple randomized clinical trials or meta-analyses. Level of evidence B Data derived from a single randomized clinical trial or large non-

randomized studies. Level of evidence C Consensus of opinion of the experts and/ or small studies, retrospective

studies, registries.

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GENERAL ITEMS 1. Summary statement of the proposal for inclusion, change or deletion.

We propose the inclusion of the non-vitamin K antagonists oral anticoagulant (NOACs) for the treatment of non-valvular atrial fibrillation (AF) in the WHO Model List of Essential Medicines based on high-quality evidence demonstrating their superiority to vitamin K antagonists (VKAs) in reducing stroke and systemic embolism, as well as the composite endpoint of stroke and systemic embolism, all-cause mortality, and major bleeding including intracranial haemorrhage.

AF is a major public health issue affecting almost 50 million people globally, with projected increases in the incidence and prevalence in the next three decades due to population growth, aging, and better survival among patients with AF, though major treatment gaps remain. Patients with AF have a high risk of hospital admission, stroke and premature death. Timely and effective diagnosis and management of atrial fibrillation is required to prevent the complications of AF.

Patients with AF who are treated with VKAs must be carefully monitored with frequent dose titration to achieve therapeutic dosing measured by International Normalized Ratio (INR) to minimize the risk of bleeding while also reducing the risk of thromboembolic events, including stroke. Vitamin K-rich foods, alcohol, medicines, and illness frequently interfere with patients’ ability to stay within their therapeutic range, which further compounds the challenges of constant monitoring. NOAC represents a paradigm shift in the treatment of AF for stroke prevention because they do not require routine INR testing and because they have far fewer interactions. NOACs show a favourable balance between efficacy and safety compared with VKAs, with significant reductions in stroke, intracranial haemorrhage, and mortality. As a result, major clinical practice guidelines around the world recommend NOAC over warfarin for initial treatment of AF for stroke prevention. As costs have substantially declined since the introduction of NOACs in 2009, these drugs represent an effective, cost-effective, and affordable alternative to VKA for patients with AF, especially for those with limited access to health care for whom routine INR monitoring is difficult.

This application supports access to NOACs for AF patients around the world.

2. Relevant WHO technical department and focal point (if applicable). None 3. Name of organization(s) consulted and/or supporting the application. Arrhythmia Alliance Hearts4Heart Nigeria Stroke Society Pan-African Society of Cardiology Stroke Investigative Research & Education Network World Heart Federation 4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine.

Dabigatran etexilate B01AE07 Rivaroxaban B01AF01 Apixaban B01AF02 Edoxaban B01AF03 5. Dose forms(s) and strength(s) proposed for inclusion; including adult and age-appropriate paediatric dose forms/strengths (if appropriate).

Dabigatran: Oral capsules of 110 mg and 150 mg twice daily Rivaroxaban: Oral tablets of 15 mg and 20 mg once daily Apixaban: Oral tablets of 2.5 mg and 5 mg twice daily Edoxaban: Oral tablets of 30 mg and 60 mg once daily

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Dabigatran - Full dose recommended: 150 mg twice daily The RE-LY trial tested a high and low dose (110 mg and 150 mg twice daily, respectively) for

anticoagulation of patients with non-valvular AF for prevention of thromboembolism; however, recommendations from regulatory agencies differ:

• European Medicines Agency: Dose reduction (110 mg twice daily) recommended for patients ≥80

years (sequential dosing strategy accepted in different countries) or concomitant verapamil use, and dose reduction considered for patients at high risk of bleeding (creatinine clearance 30 to 50 ml/min and additional factors for bleeding) [1].

• Food and Drug Administration: 150 mg twice daily for patients with creatinine clearance greater than 30 ml/min . For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of dabigatran is 150 mg twice daily. For patients with severe renal impairment (CrCl 15-30 mL/min), the recommended dose is 75 mg twice daily. Consider reducing the dose of dabigatran to 75 mg twice daily when dronedarone or systemic ketoconazole is co-administered with dabigatran in patients with moderate renal impairment (CrCl 30-50 mL/min). Avoid use of dabigatran and P-glicoprotein inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min). Dabigatran is contraindicated in severe renal failure or dialysis [2].

Rivaroxaban - Full dose recommended: 20 mg once daily

The ROCKET-AF trial used the adjusted dose (15 mg once daily) for patients with non-valvular AF with CrCl 30-50 ml/min. For Japan, accepted doses are 15 and 10 mg daily, respectively (J-ROCKET) [3, 4]. Rivaroxaban is contraindicated in severe renal failure or dialysis. Apixaban - Full dose recommended: 5 mg twice daily

The ARISTOTLE trial used adjusted dose (2.5 mg twice daily) if two out of three criteria in patients with non-valvular AF: over 80 years, creatinine over 1.5 g/dL (133 mmol/l), or weight less than 60 kg [5]. Apixaban is contraindicated if serum creatinine is > 2.5 mg/dl or if the patient is on dialysis.

Edoxaban - Full dose recommended: 60 mg once daily The ENGAGE AF-TIMI trial tested a high and low dose (60 and 30 mg daily) and used an adjusted dose

(30 or 15 mg daily, respectively) in patients with non-valvular AF if CrCl 30 to 50 ml/min or if P-glicoprotein inhibitors used (verapmil or quinidine), or body weight less than 60 kg [6].

The Cockroft Gault formula was used in trials.

The European Society of Cardiology/European Heart Rhythm Association (ESC/EHRA) guidelines also suggest the use of Factor Xa inhibitors in patients with CrCl 15 to 30 ml/min (with caution), and apixaban, dabigatran and edoxaban in patients with mild hepatic failure (Child-Pugh B) [7]. Contraindications:

• Apixaban o Active bleeding, malignant neoplasm, oesophageal varices, recent brain surgery, recent GI

ulcer, recent intracranial hemorrhage, recent ophthalmic surgery, recent spine surgery, significant risk of major bleeding, vascular aneurysm.

o Avoid in pregnancy, breast feeding, severe hepatic impairment, if CrCl less than 15 ml/min.

• Edoxaban o Active bleeding, arteriovenous malformations, GI ulceration, hepatic disease, oesophageal

varices, recent brain surgery, recent GI ulcer, recent intracranial hemorrhage, recent ophthalmic surgery, recent spine surgery, uncontrolled severe hypertension, vascular aneurysm.

o Avoid in pregnancy, breast feeding, severe hepatic impairment (use cautiously in mild to moderate impairment), in end stage renal disease or patient undergoing dialysis.

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• Rivaroxaban

o Active bleeding, in acute coronary syndrome –malignant neoplasm, oesophageal varices, recent brain surgery, recent GI ulcer, recent intracranial hemorrhage, recent ophthalmic surgery, recent spine surgery, significant risk of major bleeding, vascular aneurysm.

o Avoid in pregnancy, breast feeding, liver disease with coagulopathy, CrCl less than 15 ml/min.

• Dabigatran

o Active bleeding, do not use as anticoagulant for prosthetic heart valve, malignant neoplasm, oesophageal varices, recent brain surgery, recent GI ulcer, recent intracranial hemorrhage, recent ophthalmic surgery, recent spine surgery, significant risk of major bleeding, vascular aneurysm.

o Avoid in pregnancy, breast feeding, severe liver disease especially if prothrombin time really prolonged, CrCl less than 30 ml/min.

Table 1. Current market availability of NOACs.

Dabigatran Etexilate Rivaroxaban Apixaban Edoxaban Canada Capsules (110/150 mg) Tablets (10/15/20 mg) Tablets (2.5/5 mg) Tablets (15/30/60 mg) UK Capsules (75/110/150 mg) Tablets (2.5/10/15/20 mg) Tablets (2.5/5 mg) Tablets (15/30/60 mg) USA Capsules (75/150 mg) Tablets (10/15/20 mg) Tablets (2.5/5 mg) Tablets (15/30/60 mg) EU Capsules (75/110/150 mg) Tablets (2.5/10/15/20 mg) Tablets (2.5/5 mg) Tablets (15/30/60 mg) India Hard gelatine capsules

(75/110/150 mg) Tablets (15/20 mg) Tablets (2.5/5 mg)

Bangladesh Capsules (75/110 mg) Tablets (10/20 mg) Tablets (2.5/5 mg) Nepal Capsules (75/110/150 mg) Mexico Capsules (75/110/ mg) Tablets (10/15/20 mg) Tablets (2.5) Argentina Capsules (75/110/150 mg) Tablets (2.5/10/15/20 mg) Tablets (2.5/5 mg) Brazil Capsules (75/110/ mg) Tablets (10 mg) Tablets (2.5 mg) Tablets (30/60 mg)

Use of NOACs for venous thromboembolism (VTE) is not covered in this application but represents

another potential therapeutic target. 6. Whether listing is requested as an individual medicine or as representative of a pharmacological class.

The listing is as a representative of a pharmacological class: (□) Dabigatran Other NOACs include: Rivaroxaban Apixaban Edoxaban

The rationale for the choice of Dabigatran as square box: first NOACs licenced for marketing, more evidence available (10 years) in real world data, currently available in most countries compared to other NOACs, generic dabigatran already available in some countries (e.g. India). In addition treatments to reverse anticoagulation effects due to dabigatran exist (idarucizumab). TREATMENT DETAILS, PUBLIC HEALTH RELEVANCE AND EVIDENCE APPRAISAL AND SYNTHESIS 7. Treatment details (requirements for diagnosis, treatment and monitoring)

Atrial fibrillation (AF) is an atrial tachyarrhythmia characterised by predominantly uncoordinated atrial activation with consequent deterioration of atrial mechanical function. AF is classified as [8]:

• First diagnosed AF: AF that has not been diagnosed before, irrespective of the duration of the arrhythmia or the presence and severity of AF-related symptoms.

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• Paroxysmal AF: Self-terminating, in most cases within 48 hours. • Persistent AF: AF that lasts longer than 7 days, including episodes that are terminated by

cardioversion, after 7 days or more. • Long-standing persistent AF: Continuous AF lasting for ≥1 year when it is decided to adopt a rhythm

control strategy. • Permanent AF: AF that is accepted by the patient (and physician) to be permanent with no plan for

rhythm control.

Diagnosis and assessment of atrial fibrillation [9] - Manual pulse palpation to assess for the presence of an irregular pulse in people presenting any of the

following symptoms: breathlessness/dyspnoea, palpitations, syncope/dizziness, chest discomfort, stroke/transient ischaemic attack;

- Electrocardiogram (ECG) in all people, whether symptomatic or not, in whom atrial fibrillation is suspected because an irregular pulse has been detected;

- In people with suspected paroxysmal atrial fibrillation undetected by standard ECG recording: 24-hour ambulatory ECG monitor in those with suspected asymptomatic episodes or symptomatic episodes less than 24 hours apart, and an event recorder ECG in those with symptomatic episodes more than 24 hours apart;

- Transthoracic echocardiography (TTE) in people with atrial fibrillation: for whom a baseline echocardiogram is important for long-term management; for whom a rhythm-control strategy that includes cardioversion (electrical or pharmacological) is being considered; in whom there is a high risk or a suspicion of underlying structural/functional heart disease (such as heart failure or based on the presence of heart murmur) that influences their subsequent management (for example, choice of antiarrhythmic drug); in whom refinement of clinical risk stratification for antithrombotic therapy is needed.

AF increases the risk of stroke and systemic embolism. Since the risk of AF-associated stroke is not

uniform and depends on patients’ ages, sex and other comorbidities, clinical risk scores have been formulated to stratify for prevention of stroke and untoward bleeding with thromboprophylaxis use. 7.1. Stroke risk stratification

In 2010, the CHA2DS2-VASc score was developed, validated, and demonstrated to be superior to the CHADS2 score [10] in identifying low-risk patients in whom anticoagulation was unlikely to confer benefit [11].

• C = congestive heart failure or left ventricular dysfunction (1 point) • H = hypertension (1 point) • A2 = age > 75 years old (2 points) • D = diabetes mellitus (1 point) • S2 = stroke or transient ischemic attack or thromboembolism (2 points) • V = vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque) (1 point) • A = age 65-74 years old (1 point) • Sc = sex category (i.e. female gender) (1 point)

In the first publication of CHA2DS2-VASc score [11], the annual incidence rates of stroke or systemic

embolism were 0%, 0.6%, and 3% in scores 0, 1, and ≥2 , respectively. The CHA2DS2-VASc score has improved discrimination of patients with very low risk of stroke compared to CHADS2 score (annual incidence rates of stroke or systemic embolism were 1.4%, 2.4%, and 3.2%, for CHADS2 scores 0, 1, and ≥2, respectively). The CHA2DS2-VASc score’s C-statistic for predicting stroke or systemic embolism was 0.61 [95% CI, 0.51-0.69] compared with a C statistic of 0.56 [95% CI, 0.45-0.62] for the CHADS2 score. Further cohorts provided external validation of the CHA2DS2-VASc score and its improved performance, including nationwide cohorts from Denmark [12], Taiwan [13], the United Kingdom [14], and Sweden [15].

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The CHA2DS2-VASc score is now recommended for risk stratification by major clinical practice guidelines such as the European Society of Cardiology (ESC), American College of Cardiology/American Heart Association (ACC/AHA), and the National Institute for Health and Care Excellence (NICE). 7.2. Bleeding risk assessment

Assessment of bleeding risk before starting anticoagulation among patients with AF is important. As for stroke risk stratification, several bleeding risk scores have also been developed and validated for clinical practice. However, bleeding risk scores should be used only to identify patients at risk for bleeding with the aim to have more regular review and follow-up, and importantly, to address reversible bleeding-related risk factors such as uncontrolled hypertension, labile INRs (for a warfarin user) and concomitant use of aspirin, NSAIDs or alcohol excess. The HAS-BLED score has been proposed as a simple clinical score to predict clinically relevant bleeding in AF patients [16].

• H = hypertension (1 point) • A = abnormal renal and liver function (1 point each) • S = stroke (1 point) • B = bleeding (1 point) • L = labile INRs (1 point) • E = elderly (age > 65 years old) (1 points) • D = drugs or alcohol (1 point each)

A HAS-BLED score ≥3 indicates a high risk of bleeding (≥3.74 bleeds per 100 Patient-years compared to less than 2% in HAS-BLED ≤2), and previous studies have demonstrated that the HAS-BLED score performed better than other bleeding scores.

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7.3. Treatment guidelines For patients with AF, including those with paroxysmal AF, for recommendations in favour of oral

anticoagulation, treatment guidelines by stroke risk stratification are as follows:

Low stroke risk

(CHA2DS2-VASc = 0)

Moderate stroke risk (CHA2DS2-VASc = 1)

High stroke risk (CHA2DS2-VASc ≥ 2)

American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines

No anticoagulants

Oral anticoagulant or aspirin (IIb)

Warfarin (Ia), Apixaban, Rivaroxaban (Ib)

European Society of Cardiology/European Heart Rhythm Association guidelines

No antiplatelet or

anticoagulant treatment (IIIb)

Oral anticoagulant should be

considered (IIa-B)

NOACs (IA), Vitamin K antagonist (IA)

United Kingdom’s National Institute for Clinical Excellence guidelines

No antithrombotic

therapy

Consider oral anticoagulant (Warfarin or NOACs Apixaban,

Dabigatran, Rivaroxaban)

Offer oral anticoagulant (Warfarin or NOACs

Apixaban, Dabigatran, Rivaroxaban)

Asia Pacific Society of Cardiology guidelines

No anticoagulants Oral anticoagulant NOACs preferred to

warfarin

Canadian Cardiac Society guidelines

No antithrombotic

therapy

Oral anticoagulant or Aspirin NOACs

Cardiology Society of Australia and New Zealand guidelines

No anticoagulants

Oral anticoagulant (GRADE: Strong recommendation;

Quality of evidence: Moderate)

Warfarin, NOACs (apixaban, dabigatran or rivaroxaban) (GRADE:

Strong; Evidence: High)

A high bleeding risk score should generally not result in withholding OAC. Rather, bleeding risk factors

should be identified and treatable factors corrected [8]. 7.4. Management of bleeding complications

● Mild bleeding which stops spontaneously: no intervention is needed after ascertaining the dosage and timing of drug for patients taking NOACs.

● Moderate bleeding: oral anticoagulants should be withheld immediately and standard supportive measurements must be started.

● Life-threatening bleeding: treatments to reverse anticoagulation effects should be considered, such as idarucizumab in patients receiving dabigatran. When idarucizumab is not available, hemodialysis accelerates the clearance of dabigatran from the body.

● For patients on factor Xa inhibitors, prothrombin complex concentrate or activated prothrombin complex concentrate concentrates can be considered in severe or life-threatening bleeding.

● For patients on Apixaban and Rivaroxaban that require urgent reversion of anticoagulation, andexanet alfa is suggested (specific reversal agent approved by FDA 2018).

8. Information supporting the public health relevance. 8.1. Epidemiological information on diseases burden

Atrial fibrillation (AF) is a major public health issue affecting 37.6 million people globally in 2017[17], with a high risk of frequent hospital admissions, stroke, and premature death. In 2017, the age-standardised prevalence rate (per 100,000 population) for atrial fibrillation was 561.3 (95% Uncertainty Interval (UI) 486.2-635.5) for males and 415.7 (95% UI, 359.4-471.8) for females. In low-income countries, the 2017 prevalence was 418.0 (95% UI, 356.5-483.0) for males and 323.1 (95% UI, 276.0-372.7) for females, which may be an

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underestimate due to lower diagnosis rates in low-income countries compared with other settings. In 2017, the estimated age adjusted disability-adjusted life years resulting from AF were 84.0 for males and 72.7 for females (per 100 000 population) [17]. Current projections suggest an expected increase in the incidence and prevalence of AF in the next three decades [18-20].

Effective, evidence-based treatments to prevent AF-related strokes exist. A 2007 systematic review, including 29 trials and over 28,000 participants, demonstrated that effective treatment with Vitamin K Antagonist (VKAs) oral anticoagulants reduce the risk of risk of stroke or systemic thromboembolic in people with AF by two-thirds (95% confidence interval [CI], 49% to 74%) [21]. However, patients treated with VKAs must be carefully controlled within a therapeutic range as measured by the International Normalised Ratio (INR) 2.0-3.0 to effectively reduce the risk of embolic stroke while minimizing bleeding risks [21]. Furthermore, dietary intake, alcohol, medications, and illness can all affect INR levels. Thus, treatment with VKA requires regular monitoring to ensure optimal time in therapeutic range, which is challenging for many patients and health systems. For example, the US Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) including 5,210 patients with AF treated with VKA estimated that only 65% of time was spent in therapeutic range, with those at greatest risk of having a stroke being least likely to be within the therapeutic range [22]. Rates of time in therapeutic range are lower in LMICs [23]. A post-hoc analysis of the ORBIT-AF study showed the median time is spent in therapeutic range in middle-income countries varied between 46% to 65%, whereas in high-income countries it varied between 55% to 78% [24]. In addition, patient-specific characteristics were associated with lower likelihood of being therapeutic range, including factors such as lower income, frequent hospitalisation, and polypharmacy [25]. The laboratory monitoring and dose adjustment required by VKAs represent a major challenge in resource-limited settings. An analysis of management of AF in 46 countries using the RE-LY Atrial Fibrillation Registry has shown that the use of oral anticoagulation among patients with a CHADS2 score ≥2 was greatest in North America (66%) but was only 11% in China and that the mean time in the therapeutic range was 62% in Western Europe, 51% in North America, but only between 32% and 40% in India, China, Southeast Asia, and Africa [23].

Patient preferences for oral anticoagulants are important to ensure medication adherence and subsequent AF-related stroke and systemic embolism risk reduction. In a 2017 systematic review, 27 studies conducted in 12 different countries (n=7226) examined patient preferences towards OAC. Sixteen of the 27 studies compared OAC to no treatment [26]. The authors concluded that most studies show that patients are willing to accept bleeding risks if they can be assured of a certain threshold in stroke-risk reduction. However, within this systematic review, 11/27 publications (n=3737) examined preferences between warfarin and NOACs. Eight of 11 of the included studies, using either survey or discrete choice methodology, showed that patients prefer NOACs treatment based on convenience and reduced need for blood tests and fewer dietary restrictions when compared to warfarin. In the 3/11 studies where preference was for warfarin, all were conducted in high-income countries and among current anticoagulant users. The patients noted that they were anxious about the lack of laboratory testing and would prefer to be continued to be reviewed regularly by an oral anticoagulant clinic [26]. However, a 2016 Canadian survey suggests that the key influence in decision making about use of warfarin or NOACs is physician preference and bias for laboratory monitoring, which consequently influences the choices of the patients [27]. In Germany, experiment including 486 people with AF demonstrated that patients significantly preferred the attribute levels associated with NOAC use (in order of patients' importance) "once daily intake", "bridging necessary", "distance to practitioner of ≤1 km, "interactions with food/nutrition" and "need of INR controls/dose adjustment" [28].

In countries where access to regular monitoring of warfarin is limited by distance and accessibility the

consideration about regular monitoring is likely of lower importance compared to the ability to have an effective drug with fewer restrictions on lifestyle and easier convenience [29]. 8.2. Assessment of current use

NOACs are used as single therapy for stroke and systemic embolism prevention in patients with non-valvular AF. Data from the facility-based Global Anticoagulant Registry in the Field (GARFIELD-AF) from 35 countries, show a decrease in VKAs therapy (from 83% to 51%) and an increase in the NOACs use (from 4% to 37%) since 2010 (Figure 1) [30]. Similarly, in the National Cardiovascular Data registry Practice

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INNovation And CLinical Excellence (NCDR PINNACLE) from US, the use of oral anticoagulant therapy increased from 52% to 61% after the introduction of NOACs since 2009 (Figure 2) [31].

Figure 1. Evolution in baseline treatment for patients enrolled in sequential cohort of GARFIELD-AF (source: www.af.garfieldresgistry.org)

Figure 2. Anticoagulant use by year/quarter [31]. 8.3. Target population

The target population includes patients with non-valvular AF who are at high risk of stroke (CHA2DS2-VASc >2). Some guidelines suggest use of NOACs in people with low-moderate risk of stroke (CHA2DS2-VASc=1). The Canadian and Australian guidelines suggest not including female sex in classifications. Patients with mechanical heart valves and those with moderate-to-severe mitral stenosis, mostly related to rheumatic heart disease, were excluded from randomized trials of NOACs, so for this proposal, non-valvular atrial fibrillation will refer to patients with atrial fibrillation without these conditions [7]. For countries with moderate to high prevalence of rheumatic heart disease, history of rheumatic disease, acute rheumatic fever, or cardiac murmurs, an echocardiogram should be performed to determine if the patient has rheumatic heart disease-related AF [32], based on the World Heart Federation guideline for diagnosis of rheumatic heart disease [33]. Currently an ongoing trial is testing the efficacy and safety rivaroxaban for rheumatic heart disease-related AF [34].

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8.4. Likely impact of treatment on the disease NOACs reduce risk of stroke and systemic embolism, mortality, and bleeding in patients with non-

valvular AF. A 2016 modelling analysis evaluated possible trends of ischaemic stroke and death rates in AF patients comparing the scenario of unchanged oral anticoagulant use (45% of patients on VKA; 55% on NOACs) to a scenario of relative increase in NOAC use. In East Asia, NOACs uptake to 90% would help preventing 206,315 ischaemic strokes and 139,353 deaths over the period of 20 years from 2031 to 2050 when compared to the scenario of unchanged use of oral anticoagulants [35]. Similarly in Europe, the introduction of NOACs in 2010 has been estimated to have led to >88,000 fewer strokes, thromboembolisms, and deaths each year. If the prevalence rate of use of edoxaban were to increase from 11% in 2013 to 75% in 2030, then an additional 12,000 cases of stroke, thromboembolism, and death would be avoided annually [36]. 9. Review of benefits: summary of evidence of comparative effectiveness. 9.1. Summary of evidence of comparative effectiveness in RCTs

The efficacy and safety of each NOAC versus warfarin in preventing stroke and systemic embolism in non-valvular AF patients have been investigated in individual pivotal RCTs: the RE-LY [37], ROCKET-AF [3], J-ROCKET AF [4], ARISTOTLE [25], ENGAGE AF-TIMI 48 [6] trials. Please refer to Section 5 in this proposal for the NOAC and dose(s) investigated in each trial.

The overall efficacy and safety of NOACs versus warfarin in preventing stroke and systemic embolism in

non-valvular AF patients have been summarized in numerous systematic reviews and meta-analysis. For instance, Ruff et al. published a meta-analysis of 4 of the 5 RCTs [38]. We herein update the meta-analysis by adding data from the J-ROCKET AF trial [4]. In the 5 RCTs (59,819 patients), NOACs significantly reduced the risk of stroke and systemic embolism compared with warfarin in NVAF patients (RR 0.80, 95% CI 0.71-0.91; p=0.0003; Figure 3). A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Evidence Profile table for the effects of NOACs versus warfarin in preventing stroke and systemic embolism in RCTs is attached in Annex 1. The quality of evidence is high for NOACs in preventing stroke and systemic embolism compared to warfarin, given that the evidence was based on RCTs with low risk of bias with no downgrading for study limitations, indirectness of evidence, imprecision, heterogeneity, nor publication bias.

Figure 3. Forest plot showing the effect of NOACs versus warfarin in preventing stroke and systemic embolism in non-valvular AF patients based on data from 5 RCTs.

9.2. Summary of evidence of comparative effectiveness in real-world practice We also systematically searched in the literature and summarized existing evidence on the efficacy and safety of NOACs versus vitamin K antagonists in preventing stroke and systemic embolism in non-valvular AF patients in unselected populations (also known as real-world data). The primary efficacy outcome was stroke and systemic embolism, and the primary safety outcome was major bleeding as defined in each study. 9.2.1. Methods: Search strategy, study screening and selection

In September 2018, we searched PubMed and OVID (covering major databases of evidence-based medicine reviews, EMBASE, and MEDLINE), as well as the China Academic Journals Full-text Database and the Virtual Health Library Regional Portal for relevant primary studies and systematic reviews with full-text articles published in any language since 1 January 2009 until 13 September 2018. Briefly, the search terms

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included non-vitamin k antagonist anticoagulants (NOAC), dabigatran, rivaroxaban, apixaban, edoxaban, vitamin k antagonist (VKA), warfarin, and nonvalvular atrial fibrillation (NVAF). We also manually searched references in pertinent review articles. The PICO structure for the analysis was:

Population: Patients with non-valvular AF Intervention: NOACs Comparison: VKA Outcome: Efficacy - stroke and systemic embolism; Safety – major bleeding

Inclusion criteria for a primary study were as follows: 1) studies reporting real-world data with a sample

size >1,000 participants; 2) any NOAC compared with VKAs (predominantly warfarin) in the efficacy and safety of preventing stroke and systemic embolism in NVAF patients. Studies reporting real-world data in our research included cohort studies, prospective registries, and retrospective analyses of insurance claims and electronic health records.

We reviewed the records retrieved from literature search to eliminate duplications and irrelevant articles, and selected the studies for qualitative and quantitative synthesis. For studies reporting data regarding the same NOAC in obviously overlapping study populations (in the same country/region), the one with the largest sample size or longest recruiting period was included for analysis. For an article with doubt regarding whether or not to be included in qualitative or quantitative analysis, agreement was achieved among three authors (X.L., E.Z., A.K.). 9.2.2 Methods: Data extraction and synthesis

We extracted relevant data from the primary studies and synthesized the data in Cochrane Review Manager (version 5.3). Random-effects models were used to estimate the efficacy and safety of each and all NOACs versus VKA (warfarin) in treating NVAF patients, presented in risk ratios (RR) and the 95% confidence intervals (CI). Publication bias of the primary studies was assessed by visual inspection of the funnel plot. Between-study heterogeneity was tested by the Cochran’s Q (χ2) and I2 statistics. Two-sided p values <0.05 and <0.10 were considered statistically significant, in estimation of the RRs, and between-study heterogeneity, respectively. Heterogeneity was not considered substantial when I2<50%. Summaries of evidence and assessment of evidence quality were conducted using the GRADE tool (https://gdt.gradepro.org/app).

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9.2.3 Results: Study selection and description Figure 4 shows the flow chart for study screening and selection.

Figure 4. Flow chart for study screening.

Overall, 50 studies reported real-world data from a large range of countries, including (in alphabetical order): Canada (1 study) [39], Denmark (5 studies) [40-44], France (1 study) [45], Germany (1 study) [46], Hong Kong (1 study) [47], Israel (1 study) [48], Italy (2 studies) [49, 50], Japan (3 studies) [51-53], Malaysia (1 study) [54], New Zealand (1 study) [55], Norway (1 study) [56], South Korea (2 studies) [57, 58], Sweden (2 studies) [59, 60], Taiwan (4 studies) [61-64], the United Kingdom (1 study) [65], and the United States (11 studies) [66-75]. Other studies reported relevant real-world data in >1 countries or regions, as an individual study [30, 76] or as a systematic review [77-86]. Data were mostly from high- or middle-high-income countries or regions, while there were relatively less data from LMICs.

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9.2.4 Results: Efficacy of NOACs versus VKA (predominantly warfarin) Of the 23 studies included in quantitative data synthesis, 12 studies reporting real-world data (n=520,859

patients) were analyzed for the primary efficacy outcome (stroke and systemic embolism; Figure 5). In these studies, NOACs were associated with a reduced risk of stroke and systemic embolism compared with warfarin in patients with non-valvular AF (RR 0.79, 95% CI 0.71-0.89; p<0.001). No apparent publication bias was observed by visual inspection of the funnel plot. There was substantial between-study heterogeneity (I2= 87%; p<0.001) for the effect of NOACs versus warfarin in preventing stroke and systemic embolism in patients with non-valvular AF in studies reporting real-world data. There were also significant between-study heterogeneities in meta-analysis below of the effects of each NOAC versus warfarin. Some of the key factors that would explain the heterogeneity are the definitions used to assign events, time of follow-up, study setting, and age of patients in each study.

Figure 5. Forest plot showing the efficacy of NOACs versus warfarin in preventing stroke and systemic embolism in patients with non-valvular AF based on data from studies reporting real-world data.

A GRADE Evidence Profile table for the effects of NOACs versus warfarin in preventing stroke and systemic embolism in real-world practice is attached in Annex 2; the quality of evidence is very low, given that the evidence was based on observational studies with heterogenous findings (I2=87%), but there was no downgrading for indirectness of evidence nor imprecision among these studies.

We also compared the efficacy of each NOAC versus VKAs (predominantly warfarin) separately in real-

world practice (Figures 6-8). In each comparison, the NOAC was associated with a significant lower risk of stroke and systemic embolism than warfarin, except that no real-world data were available regarding the associations between edoxaban versus warfarin and risks of stroke and systemic embolism. These data are reassuring that the application of NOACs into routine clinical practice show a similar direction and magnitude of effect as seen in randomized trials.

The GRADE Evidence Profile tables for the effects of each NOAC versus warfarin among patients with

non-valvular AF in studies reporting real-world data in preventing stroke and systemic embolism are attached in Annex 3-5. The quality of evidence is very low for dabigatran, rivaroxaban and apixaban, respectively, given that the evidence was based on observational studies with heterogenous findings (I2=86%, 82%, 91%), but there was no downgrading due to indirectness of evidence nor imprecision among these studies.

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Figure 6. Forest plot showing the effect of dabigatran versus warfarin in preventing stroke and systemic embolism in NVAF patients based on data from studies reporting real-world data.

Figure 7. Forest plot showing the effect of rivaroxaban versus warfarin in preventing stroke and systemic embolism in NVAF patients based on data from studies reporting real-world data.

Figure 8. Forest plot showing the effect of apixaban versus warfarin in preventing stroke and systemic embolism in NVAF patients based on data from studies reporting real-world data. Results are similar with previous systematic reviews and meta-analyses [38, 86, 87]. 10. Review of harms and toxicity: summary of evidence of safety 10.1 Summary of evidence of safety in RCTs

As outlined in Section 9, the efficacy and safety of each NOAC versus warfarin in preventing stroke and systemic embolism in patients with non-valvular AF have been investigated in individual pivotal randomized trials, and the overall effects of NOACs versus warfarin have been reported in previous systematic reviews and meta-analyses. We updated the meta-analysis by Ruff et al. [38] by adding data from the J-ROCKET AF trial [4]. In the 5 RCTs (59,776 patients), NOACs were associated with a significantly lower risk of major bleeding compared with warfarin in NVAF patients (RR 0.86, 95% CI 0.74-0.99; p=0.04; Figure 9). A GRADE Evidence Profile table for the association between NOACs versus warfarin and risk of major bleeding in RCTs is attached in Annex 1; the quality of evidence is moderate, given that the evidence was based on RCTs with low risk of bias but inconsistent findings (I2=77%).

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Figure 9. Forest plot showing the risks of major bleeding in non-valvular AF patients treated with NOACs versus warfarin based on data from 5 RCTs. 10.2. Summary of evidence of safety in real-world practice

The methods for literature search, study screening and selection, data synthesis, and evidence quality assessment are described in Section 9. 10.2.1. Results: Safety of NOACs versus VKA (predominantly warfarin)

Of the 23 studies included in quantitative data synthesis, 17 studies reporting real-world data (n=622,720 patients) were analyzed for the primary safety outcome (major bleeding; Figure 10). In these studies, NOACs were associated with a lower risk of major bleeding compared with warfarin in NVAF patients (RR 0.72, 95% CI 0.64-0.80; p<0.001). No apparent publication bias was observed by visual inspection of the funnel plot. A GRADE Evidence Profile table for the associations between NOACs versus warfarin and risks of major bleeding in studies reporting RWD is attached in Annex 2; the quality of evidence is very low, given that the evidence was based on observational studies with substantial heterogeneity (I2=90%), but there was no downgrading due to indirectness of evidence nor imprecision among these studies. Similar to the efficacy outcome, the direction and magnitude of the safety signal for NOACs compared with warfarin is similar in both randomized and non-randomized studies, which is reassuring for their widespread use.

Figure 10. Forest plot showing the risks of major bleeding in patients with non-valvular AF treated with NOACs versus warfarin based on data from RCTs and studies reporting real-world data.

We also compared the safety of each NOAC versus VKAs (predominantly warfarin) separately in real-world practice (Figures 11-14). In each comparison, the risk of major bleeding associated with the NOAC was lower than in warfarin. The GRADE Evidence Profile tables for the associations between each NOAC versus warfarin and the risks of major bleeding in RCTs and in studies reporting RWD are attached in Annex 3-6. The quality of evidence is very low for dabigatran, rivaroxaban and apixaban, respectively, given that the evidence was based on observational studies with heterogenous findings (I2=79%, 91%, 77%), but there was no downgrading for indirectness of evidence nor imprecision among these studies. The quality of evidence is

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moderate for edoxaban given that the evidence was based on observational studies with consistent findings without downgrading for indirectness of evidence nor imprecision among these studies.

Figure 11. Forest plot showing the risks of major bleeding in patients with non-valvular AF treated with dabigatran versus warfarin based on data from studies reporting real-world data.

Figure 12. Forest plot showing the risks of major bleeding in patients with non-valvular AF treated with rivaroxaban versus warfarin based on data from studies reporting real-world data.

Figure 13. Forest plot showing the risks of major bleeding in patients with non-valvular AF treated with apixaban versus warfarin based on data from a pivotal RCT and studies reporting real-world data.

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Figure 14. Forest plot showing the risks of major bleeding in patients with non-valvular AF treated with edoxaban versus warfarin based on data from studies reporting real-world data. Results are similar with previous systematic-reviews and meta-analyses [38, 85-87]. 10.3. Safety of NOACs in elderly

A major public concern is the anticoagulation of elderly AF patients. Data from Prevention of thromboembolic events – European Registry in Atrial Fibrillation (PREFER-AF) registry shows anticoagulation is better than no anticoagulation for elderly > 75 years patients with net clinical benefit increasing among all aging subgroups [88]. A 2016 review by authors from McMaster University, including data from RCTs subgroups of patients over 75 years old, showed safety and efficacy of NOACs, except increased risk of bleeding with dabigatran at the higher (150 mg versus 110 mg) dose [89]. A whole country analysis of elderly AF patients from Taiwan demonstrated that NOACs as the best alternative for this population [90], and a US Medicare claims analysis from patients >75 years demonstrated apixaban had lower rates of stroke and bleeding than warfarin [91].

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10.4. List of adverse effects not related to bleeding For NOACs adverse effects not related to bleeding are presented in Tables 2-5. Table 2. Dabigatran, discontinuation of study drug, adverse events, and liver function according to treatment group from the RE-LY trial* [37].

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Table 3. Rivaroxaban adverse events from the ROCKET-AF trial* [3].

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Table 4. Apixaban adverse events and liver function tests from the ARISTOTLE trial [25].

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Table 5. Edoxaban, discontinuation of study-drug and adverse effects from the ENGAGE AF-TIMI trial [6].

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11. Summary of available data on comparative cost and cost-effectiveness of the medicine. Table 6. Cost of NOACs per month in USD.

Country Costs per month in USD (if without insurance) Dabigatran Etexilate Rivaroxaban Apixaban Edoxaban

UK 150 mg twice daily: $64.91

20 mg once daily: $68.73

2,5 mg twice daily: $72.54

60 mg once daily: $67.55

USA 150mg twice daily: $300 (average retail price); $30-79 (if buying from international online pharmacies)

20mg once daily: $527 (average retail price); $47-195 (if buying from international online pharmacies)

5mg twice daily: $445 (average retail price); $64-192 (if buying from international online pharmacies)

60mg once daily: $397 (average retail price)

India 110 mg twice daily: $60.73 150 mg twice daily: $60.73

10 mg once daily: $57.19

5 mg twice daily: $61.08

Chile 150 mg twice daily: $67.51

20 mg once daily: $66.49

5 mg twice daily: $71.35

N/A

Argentina 150 mg twice daily: $121.22

20 mg once daily: $97.57

5 mg twice daily: $88.32

N/A

Brazil 150 mg twice daily: $76.78

20 mg once daily: $77.63

5 mg twice daily: $76.68

60 mg once daily: $66.96

China 110mg twice daily: $175 150mg twice daily: $222

20mg once daily: $742 5mg twice daily: $370 N/A

In other parts of this proposal, we reported the efficacy and safety of NOACs for stroke prevention among

patients with non-valvular AF. A key aspect for long term oral treatments is adherence, and food-drug and drug-drug interactions, necessary INR checking make VKAs a much less preferable class of drugs. Moreover, patients with non-valvular AF prefer NOACS over VKAs (see section 8.1). As a new group of drugs, their cost was expected to be higher than current treatment; however, different studies were developed to assess if the direct cost of replacing VKAs for NOACs would be offset by health costs related to stroke, bleeding, and their consequences.

A comprehensive 2016 systematic review (SR) of cost effectiveness analyses by Liberato and Marchetti [92] concluded that NOACS are cost effective in several countries, independent of their health system, direct costs of NOACs and VKAs, and costs of diseases. These authors defined a drug as cost effective when the incremental cost effectiveness ratio was below the willingness to pay value. For a critical appraise they used the International Society for Pharmacoeconomics and Outcome Research (ISPOR) checklist, and the mean ISPOR score was 33 (high quality). Most studies used a conventional Markov decision analysis model, and the rate of events was gathered from the RCTs of NOACs. We updated the systematic review (Annex 7), including 64 cost effectiveness analyses from 28 high- and middle-income countries from around the world. Most of them used same criteria, but newer cost effectiveness analyses from USA include costs from healthcare resource use and real world data from health systems to determine rate of stroke and bleeding rather than data solely from randomized trials. All studies to date demonstrate that NOACs are a cost effective strategy [93-156].

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12. Summary of regulatory status and market availability of the medicine. Table 7. Indicated, approved and licensed as anticoagulant for patients with non-valvular AF (yes, no). Regulatory authority Dabigatran Rivaroxaban Apixaban Edoxaban Food and Drug Administration (USA)

Yes Yes Yes Yes

European Medicines Agency (Europe)

Yes Yes Yes Yes

Therapeutic Goods Administration (Australia)

Yes Yes Yes No

Pharmaceuticals and Medical Devices Agency (Japan)

Yes Yes No Yes

Health Canada Yes Yes Yes Yes Argentina (ANMAT) Yes Yes Yes No Brazil (ANVISA) Yes Yes Yes No Mexico (COFEPRIS) Yes Yes Yes No China (CFDA) Yes Yes Yes No India Yes Yes Yes No Nigeria Yes Yes Yes Yes Bangladesh Yes Yes Yes No Nepal Yes No No No

13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia).

The British Pharmacopoeia Dabigatran: No Rivaroxaban: No Apixaban: No Edoxaban: No The International Pharmacopoeia Dabigatran: No Rivaroxaban: No Apixaban: No Edoxaban: No The United States Pharmacopoeia Dabigatran: No Rivaroxaban: No Apixaban: No Edoxaban: No The European Pharmacopoeia Dabigatran: No Rivaroxaban: No Apixaban: No Edoxaban: No

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