What is/are the best oral anticoagulant/s for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation? Protocol Background and Rationale Importance of the health problem to the NHS Thrombosis followed by embolization to distant organs occurs in both arterial and venous circulation and these conditions can be treated or prevented by oral anticoagulant treatment. Venous thromboembolic disease Venous thromboembolic disease (VTE) (UK annual incidence 183 per 100,000) encompasses clot formation in deep veins of legs or pelvis (deep vein thrombosis (DVT; annual incidence 123 per 100,000), and their displacement to pulmonary arteries (pulmonary embolism (PE; annual incidence 60 per 100,000). Important risk factors for VTE include major surgery, particularly lower limb orthopaedic surgery and surgery for cancer, as well as hospitalization in acutely ill general medical patients (approximate incidence 15%). VTE costs the NHS £640 million and is responsible for approximately 30,000 (10%) deaths each year in hospitals in England. DVT is also an important cause of long-term morbidity, being a major risk factor for chronic leg ulceration. PE may also lead to long- term morbidity due to pulmonary hypertension. There is an approximately 30% risk of recurrence of VTE within 8 years. The risk of VTE during hospitalisation for surgical or medical treatment can be reduced by low molecular weight heparin (LMWH), fonaparinux or unfractionated heparin.1 Warfarin is the most frequently prescribed anticoagulant for the initial treatment and for the long-term secondary prevention of VTE in those deemed to be at high risk of recurrence. Atrial fibrillation and stroke Atrial fibrillation (AF) is the most common cardiac arrhythmia.2 The prevalence of AF roughly doubles with each decade of age, rising to almost 9% at age 80-90 years. Atrial fibrillation substantially increases (up to 5 times) the risk of thromboembolic stroke (annual incidence 114 per 100,000) due to blood pooling in the left atrium and systemic embolization to the brain. More than 20% of the 130,000 annual strokes in England and Wales are attributed to AF. Approximately 1/3 of stroke patients die in the first 10 days, 1/3 recover in 1 month and 1/3 have disabilities needing rehabilitation making stroke the leading cause of adult disability. Patients with thromboembolic stroke from AF have higher mortality, morbidity and hospital stay than patients with other stroke subtypes. Warfarin is an effective oral anticoagulant for the prevention of stroke in patients with AF.3 Although the incidence and mortality of stroke continue to fall in the UK, the underutilisation of anticoagulation in patients with AF at high-risk of stroke is a major gap in clinical care.4 Cost and limitations of warfarin anticoagulation A 2007 HTA report stated that approximately 950,000 people (2% of the GP population) in the UK are prescribed warfarin; increasing by about 10% per year 5. Warfarin related bleeding is one of the top 5 reasons for hospitalisation for adverse drug effects in England6, because of the narrow therapeutic index and numerous drug/dietary interactions. Although the acquisition cost of warfarin is only approximately £10 per patient per year, the requirement for therapeutic monitoring to ensure optimal efficacy and to reduce the risk of bleeding, through hospital-, primary care-, or pharmacist- based anticoagulation clinics, or by home-monitoring with anticoagulant clinic support, inflates the cost of warfarin treatment substantially. The estimated annual cost of managing patients on warfarin in the NHS in England and Wales is approximately £90 million.7 Partly because of the perception of the risk and inconvenience of warfarin treatment, a 2006 NICE report estimated that 46% of patients who should be on warfarin are not receiving it, and that many receiving anticoagulation are not in optimal therapeutic range.7 New oral anticoagulants Unlike warfarin, new oral anticoagulants dabigatran (a direct inhibitor of clotting factor II) and rivaroxaban, apixaban, edoxaban, otamixaban and betrixaban (factor X inhibitors), have rapid action and predictable dosing requirements, negating the need for therapeutic drug monitoring.8 However, the estimated annual acquisition cost per patient of new anticoagulants will remain substantially 1 What is/are the best oral anticoagulant/s for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation? higher than that of warfarin, until patent expiry (for example, 2020 for rivaroxaban). However, the higher acquisition cost may be offset by the reduced need for therapeutic monitoring through anticoagulation services, by increased effectiveness, or by improved safety. Nevertheless potential limitations of newer agents include class- and drug-specific cautions/contraindications, potential for sub-therapeutic dosing, lack of antidotes, added cost of maintaining stocks of numerous different anticoagulants and potential for prescribing errors due to unfamiliarity. Why this research is needed now Limitations of the evidence base (and shortfalls in previous attempts at evidence synthesis) make rational selection from the now wide range of available oral anticoagulants difficult for NHS commissioners, doctors and patients. Much of the existing NICE guidance in this area is limited to individual technology appraisals. Trials in this area have the following limitations: • We have identified no trials making direct comparisons of new oral anticoagulant drugs with one another. This limitation can be addressed through the use of network-meta-analysis to estimate the comparative efficacy and safety of agents, which have been tested against a common comparator, in this case warfarin • Differing rates of sub-therapeutic anticoagulation with warfarin within trials (indexed by the time spent in the therapeutic range) may have artificially inflated the apparent efficacy of newer agents. This limitation can be addressed so some extent by investigating the relation of average time in therapeutic range with efficacy, within network meta-analyses. Prior synthesis research in this area has the following limitations: • Absence of network meta-analysis of novel oral anticoagulants for certain therapeutic indications (e.g. acute treatment and secondary prevention of VTE) • Some meta-analyses preceded recently published, potentially influential trials • Failure to fully incorporate evidence on the adverse effects of oral anticoagulants by including data from all trials, irrespective of indication, to maximise power and provide the most robust evidence on the balance between benefit and harm. • The lack of cost-effectiveness analyses relevant to England and Wales. Thus, there is a need for an up-to-date comprehensive evidence synthesis of all competing treatments to inform the rational choice of a minimum set of oral anticoagulants needed by NHS hospitals for the main therapeutic indications to avoiding unnecessary over-stocking and to reduce the risk of prescription error due to unfamiliarity. Aims and objectives 1. Identify the most effective, safe and cost-effective oral anticoagulant for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and consider whether the evidence is consistent for both prevention and treatment, and across important patient subgroups (for example cancer surgery, hip and knee replacement, and hospital admission for acute medical illness). 2. Identify the most effective, safe and cost-effective anticoagulant for stroke prevention in atrial fibrillation, and consider whether the evidence is consistent across important patient subgroups (for example presence of comorbidities, age). 3. Identify optimal anticoagulation strategies for use by Trust Drugs and Therapeutics Committees, based on the best drug(s) for each of the main therapeutic indications. 4. Estimate the value of conducting further research on the cost-effectiveness of these drugs, for example by conducting a head-to-head trial of two or more new anticoagulants. 2 What is/are the best oral anticoagulant/s for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation? Methods Systematic review: Clinical effectiveness reviews Systematic reviews of randomised controlled trials addressing questions relevant to the study objectives will be undertaken in accordance with the Centre for Reviews and Dissemination (CRD) guidelines for undertaking systematic reviews38, and the Cochrane Handbook for Systematic Reviews of Interventions39 (as updated online during 2011: see www.cochrane-handbook.org). The following reviews will be carried out: 1. Oral anticoagulants for primary prevention of venous thromboembolic disease 2. Oral anticoagulants for treatment and secondary prevention of venous thromboembolic disease 3. Oral anticoagulants for prevention of stroke in atrial fibrillation The reviews have been registered in the PROSPERO database (http://www.crd.york.ac.uk/prospero), with registration numbers CRD42013005331, CRD42013005330 and CRD42013005324. Criteria for considering studies for the reviews Participants Review 1: Primary prevention of VTE Adults (>18 years) considered to be at high risk of VTE, including those with a medical condition (e.g. cancer, major trauma, stroke), or undergoing a surgical procedure (e.g. total knee or