Title: Allopurinol and cardiovascular outcomes in patients with ischaemic heart disease
Funder: Chief Scientist Office, Scotland

Abstract: Design The study is a multi-centre, controlled, prospective randomised open-label, blinded endpoint (PROBE) trial of allopurinol up to 600mg daily vs no treatment added to usual therapy in patients aged 60 years and over with ischaemic heart disease (IHD). The aim is to establish whether allopurinol improves cardiovascular (CV) outcomes in this population. Primary care practice lists will be searched for suitable patients with IHD who will be invited to participate. At a screening visit, informed consent will be taken, inclusion and exclusion criteria checked and blood samples taken for baseline full blood count (FBC), urea and electrolytes (U+E), creatinine, eGFR and urate. Patients will be randomised via a web portal or interactive voice response system (IVRS) to either allopurinol or no drug to be given in addition to their usual medications. In patients who are randomised to allopurinol and have a screening visit eGFR =60mL/min/1.73m2, allopurinol will be started at 100-150mg daily for 2 weeks (100mg should be the usual starting dose; 150mg may be used as the starting dose in the event of a local shortage of 100mg tablets), then titrated to 300mg daily for 2 weeks, then titrated to 600mg daily if tolerated. In patients who are randomised to allopurinol and have a screening visit eGFR 30-59mL/min/1.73m2, allopurinol will be started at 100-150mg daily for 2 weeks, then titrated to 300mg daily if tolerated. In patients randomised to allopurinol, bloods will be taken for FBC, U+E, creatinine, eGFR and urate 6 weeks after starting study medication. Patients will be asked to report any adverse events, particularly rash (~1% incidence with allopurinol) and gout flares. Study medications will be prescribed by the GP. An eCRF and dedicated study web portal will be used to collect study data and aid pharmacovigilance reporting and trial management. Health technologies being assessed - Allopurinol up to 600mg daily Allopurinol is a xanthine oxidase inhibitor usually given in daily doses of 100-900mg to prevent gout. Xanthine oxidase promotes inflammation and atherosclerosis via the production of reactive oxygen species. Xanthine oxidase levels are raised in several conditions including coronary artery disease(1). Allopurinol has several beneficial effects in CV disease. Allopurinol improves endothelial function in patients with heart failure, type 2 diabetes and smokers, reduces left ventricular hypertrophy, increases exercise time in angina and reduces myocardial ischaemia-reperfusion injury. Allopurinol reduces oxidative stress and improves oxygen and energy supply to tissues. Allopurinol also reduces blood pressure, arterial stiffness and may reduce low density lipoprotein cholesterol levels and reduced CV events in patients with chronic kidney disease in one study. Observational studies suggest that allopurinol may improve CV outcomes. Higher doses of allopurinol (600mg) may be necessary to achieve some of these positive CV effects(2-4), which is why a dose of 600mg daily has been chosen for the current study for patients with normal renal function (screening visit eGFR >=60mL/min/1.73m2). A maximum dose of 300mg daily will be given to patients with screening visit eGFR 30-59mL/min/1.73m2. It is documented in the summary of product characteristics for allopurinol that in patients with severe renal impairment (creatinine clearance 10-20mL/min) a daily dose of 300mg allopurinol leads to equivalent levels of oxipurinol (the active metabolite of allopurinol) as a daily dose of 600mg allopurinol in patients with normal renal function (5). It has previously been demonstrated that 600mg allopurinol daily can be given safely in patients with angina(4). Setting Further additional interventions for patients with IHD are best tested in the real-life setting of patients already taking usual therapy. This is a pragmatic streamlined clinical trial within the primary care setting of the UK NHS. Follow-up will be by electronic record-linkage using unique identifiers to collect data on hospitalisations and mortality centrally without the need for study follow-up visits. This approach significantly reduces the cost of the trial. Target Population The study population is patients 60 years and over with IHD (angina or MI). Exclusions include patients with gout, renal impairment (eGFR <60mL/min/1.73m2), moderate to severe heart failure (NYHA III-IV), significant hepatic disease, already taking part in another clinical trial, allergy to allopurinol, previous serious adverse skin reaction to any drug, already taking urate lowering therapy, azathioprine, mercaptopurine, ciclosporin or theophylline. Sample size 5,215 patients need to be randomised to give 80% power to detect a 20% reduction in the primary CV endpoint for the intervention (allowing for 4% dropout for withdrawal of consent to follow up and for non-cardiovascular deaths). A 14% event rate over 4 years average follow-up has been estimated from previous trials in similar patient groups. The study will end when 631 adjudicated primary endpoints have occurred. Measurement of costs and outcomes The primary outcome will be the composite (APTC) CV endpoint of non-fatal MI, non-fatal stroke and CV death. It is necessary to use a composite endpoint in this type of trial as event rates for individual events would be too low. The APTC endpoint is well-established and non-subjective. Secondary outcomes will be: non-fatal MI, non-fatal stroke, CV death, all-cause mortality, all CV hospitalisations, hospitalisation for acute coronary syndrome (ACS), coronary revascularisation, hospitalisation for ACS or revascularisation, hospitalisation for heart failure, quality of life and cost-effectiveness of allopurinol. Record-linkage for events will be carried out at least once a year and potential endpoints will be investigated further by obtaining information from medical records. Endpoint packages will be adjudicated by an endpoint committee blinded to treatment allocation. Data analysis will be carried out according to a pre-determined data analysis plan. The primary analysis will be intention-to-treat. Results will be reported in peer-reviewed journals and at scientific meetings. The economic evaluation will estimate costs and benefits over a lifetime horizon using a Markov model approach. Using the cost perspective of the NHS and social services, it will take account of medicines cost, costs of monitoring, impact on hospital admissions (and associated costs after discharge). We will compare this to our estimate of the QALY gain from treatment to produce a net cost per QALY gained for adding allopurinol to usual care. Project timetables including recruitment rate: 3 month start-up phase to allow finalisation of regulatory approvals, development of the eCRF, web systems and training materials and staff recruitment. During this time, practices will be approached to take part in the study. The recruitment phase will last approximately 2 years with an average follow-up of around 4 years. The follow up period may be extended with appropriate approvals if this is necessary for the successful completion of the study. For example, this may happen if it takes longer than expected to include the necessary number of patients in the study or if the cardiovascular event rate is lower than expected. There will follow a period for finalisation of data collection by record linkage, data analysis and preparation of the final study reports. IHD is a common disease and recruitment will benefit from established primary care research networks. (1)Spiekermann S et al Circ 2003;107:1383-9. (2)George J et al Circ 2006;114:2508-16. (3)Guthikonda S et al Circ 2003:107:416-21. (4)Noman A et al Lancet 2010;375:2161-7. (5)Summary of product characteristics – allopurinol. https://www.medicines.org.uk/emc/medicine/25728 (accessed 22.7.15)

Lay abstract: Allopurinol is a medication that has been used for many years to prevent gout attacks. Allopurinol has been found to have several positive effects on the cardiovascular system, is inexpensive and is already widely used in certain patients. Ischaemic heart disease (angina or heart attack) is one of the most common causes of death in people in the UK and treatment of patients with ischaemic heart disease costs the NHS billions of pounds each year. In this study, we want to improve the treatment of patients with ischaemic heart disease. We want to investigate whether adding allopurinol up to 600mg daily to these patients’ usual medications will reduce their risk of having a stroke, heart attack or of dying due to cardiovascular disease. Patients attend their local primary care centre (general practice) to take part in the study. Patients are randomly allocated to receive allopurinol or no treatment in addition to their usual medications then are followed up for a period of around 4 years to count the number of heart attacks, strokes and cardiovascular deaths that occur. We will also record any instances of adverse side effects caused by allopurinol. The follow up period may be extended with appropriate approvals if this is necessary for the successful completion of the study. For example, this may happen if it takes longer than expected to include the necessary number of patients in the study or if fewer patients than expected have events like heart attacks or strokes. The numbers of events that occur in the different treatment groups will be compared to see if there is a benefit of adding allopurinol to their other treatment. Most of the follow up data will be collected electronically by accessing centrally held electronic records of hospital admissions and deaths which will make the study easier for patients and more cost-efficient. We will also measure quality of life and whether there is an economic benefit of using allopurinol in patients with ischaemic heart disease. The study was reviewed and approved by an ethics committee prior to starting. The team leading this study has a lot of experience in running large clinical studies of this type and have established good working research relations with hundreds of general practices. Because we have already established many of our systems and networks for doing this type of research study, we are able to ask for less funding than this size of study would normally cost. The results of this study could have major benefits for patients and result in significant cost savings for the NHS if allopurinol is found to be effective as it would be inexpensive and easy to introduce quickly to patient care within the UK.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR