Authors' objectives: Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid and is used to prevent acute gout flares in patients with gout. Observational and small interventional studies have suggested beneficial cardiovascular effects of allopurinol. To determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease. Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid (SUA) and is widely used in patients with gout to prevent acute gout flares. Xanthine oxidase promotes inflammation and atherosclerosis via the production of reactive oxygen species and xanthine oxidase levels are raised in several conditions including coronary artery disease. The role of SUA in cardiovascular (CV) disease is controversial, with some studies associating higher SUA levels with worse CV outcomes, but more recent genome-wide association studies suggest no major role of uric acid levels in determining CV outcomes. Some observational studies have suggested that allopurinol therapy may improve CV outcomes, while others have not found an association. Small interventional studies have shown that allopurinol therapy improves some CV parameters, including endothelial function, left ventricular hypertrophy, blood pressure, carotid intimal media thickness and arterial stiffness. Allopurinol therapy was also found to improve outcomes after acute coronary syndrome (ACS) in one study and to improve chest pain in patients with chronic stable angina with documented coronary artery disease in another. However, results have not been consistent across different studies. Before the ALL-HEART study, no large, randomised trial of the effects of allopurinol therapy on CV outcomes in patients with ischaemic heart disease (IHD) had been performed. Primary Does allopurinol therapy added to usual care improve major CV outcomes in patients aged over 60 years with IHD but no gout?

Authors' results and conclusions: From 7 February 2014 to 2 October 2017, 5937 participants were enrolled and randomised to the allopurinol arm (n = 2979) or the usual care arm (n = 2958). A total of 5721 randomised participants (2853 allopurinol; 2868 usual care) were included in the modified intention-to-treat analysis population (mean age 72.0 years; 75.5% male). There was no difference between the allopurinol and usual care arms in the primary endpoint, 314 (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years), hazard ratio 1.04 (95% confidence interval 0.89 to 1.21); p = 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, hazard ratio 1.02 (95% confidence interval 0.87 to 1.20); p = 0.77. The pre-specified health economic analysis plan was to perform a ‘within trial’ cost-utility analysis if there was no statistically significant difference in the primary endpoint, so NHS costs and quality-adjusted life-years were estimated over a 5-year period. The difference in costs between treatment arms was +£115 higher for allopurinol (95% confidence interval £17 to £210) with no difference in quality-adjusted life-years (95% confidence interval −0.061 to +0.060). We conclude that there is no evidence that allopurinol used in line with the study protocol is cost-effective. The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve cardiovascular outcomes compared to usual care in patients with ischaemic heart disease. We conclude that allopurinol should not be recommended for the secondary prevention of cardiovascular events in patients with ischaemic heart disease but no gout. From 7 February 2014 to 29 September 2017, 6134 patients consented to enrol in the trial and were assessed for eligibility. Also, 167 of the 6134 consented participants were not eligible and 30 others were not randomised. The final randomisation was completed on 2 October 2017. Of the 5937 randomised participants, 216 were excluded post randomisation from the mITT analysis population (184 did not meet the eGFR entry criteria once their screening blood results were available; 32 were later found to have not met all of the inclusion/exclusion criteria). Five thousand seven hundred and twenty-one participants (2853 in the allopurinol arm and 2868 in the usual care arm) were included in the mITT analysis population for the efficacy analysis. The population for safety analyses consisted of 2805 participants in the allopurinol arm (excluding the 48 participants in the allopurinol arm who never received any randomised therapy) and 2868 participants in the usual care arm. The mean duration of follow-up in the trial was 4.8 years. Two hundred and fifty-eight participants (9.0%) in the allopurinol group and 76 participants (2.6%) in the usual care group withdrew consent for all follow-up. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment. Baseline characteristics were well balanced in the two groups. The mean age at study entry was 72.0 years (SD 6.8), 4321 participants (75.5%) were male, 5676 (99.2%) were white and 1241 (21.7%) had a history of diabetes mellitus. The median duration of IHD at study entry was 10.1 years (IQR 5.1–16.1). Three thousand four hundred and sixty-four (60.5%) participants were recruited in England and 2257 (39.5%) participants in Scotland. The most commonly taken dose of allopurinol was 600 mg daily. In the 2447 participants in the allopurinol arm with both a baseline and 6-week SUA result, SUA fell from a mean of 0.34 (SD 0.08) mmol/l at baseline to a mean of 0.18 (SD 0.09) mmol/l 6 weeks after randomisation. Forty-five participants in the usual care arm started allopurinol therapy during follow-up (for clinical reasons, mainly gout). Primary and secondary outcomes There was no significant difference between the randomised treatment groups in the rates of the primary outcome or any of the secondary time-to-event outcomes. Three hundred and fourteen (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years) experienced a primary outcome, HR 1.04 (95% CI 0.89 to 1.21); p = 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, HR 1.02 (95% CI 0.87 to 1.20); p = 0.77. Results for the primary outcome were consistent across all pre-specified subgroups. In a supporting on-treatment analysis, results for the time-to-event clinical outcomes were broadly similar to those in the mITT analysis. There was limited evidence of any effect of allopurinol on quality-of-life outcomes, with no differences in EQ-5D-5L outcomes or Seattle angina questionnaire outcomes at the end of the first year or at the final visit, except for a nominally significant but only slightly greater fall in the physical domain score of the Seattle angina questionnaire at the end of the first year [treatment difference = 1.219 (95% CI 0.027 to 2.410); p = 0.045] in the allopurinol arm. The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve CV outcomes compared to usual care in patients with IHD. There were also no benefits on quality of life. There was no evidence that allopurinol used in line with the study protocol is cost-effective within the NHS system. We conclude that allopurinol should not be recommended for the secondary prevention of CV events in patients with IHD but no gout.

Authors' recommendations: Future research should explore other therapeutic options for the improvement of CV outcomes and quality of life in patients with IHD. Further exploration of the effects of allopurinol on CV outcomes in patients with co-existing IHD and clinical gout or hyperuricaemia could be considered (patients with gout were excluded from this study).

Authors' methods: Prospective, randomised, open-label, blinded endpoint multicentre clinical trial. Four hundred and twenty-four UK primary care practices. Aged 60 years and over with ischaemic heart disease but no gout. Participants were randomised (1 : 1) using a central web-based randomisation system to receive allopurinol up to 600 mg daily that was added to usual care or to continue usual care. The primary outcome was the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes were non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, all-cause mortality, hospitalisation for heart failure, hospitalisation for acute coronary syndrome, coronary revascularisation, hospitalisation for acute coronary syndrome or coronary revascularisation, all cardiovascular hospitalisations, quality of life and cost-effectiveness. The hazard ratio (allopurinol vs. usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis. The results may not be generalisable to younger populations, other ethnic groups or patients with more acute ischaemic heart disease. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment, but an on-treatment analysis gave similar results to the main analysis. Design and participants The ALL-HEART study was a prospective, randomised, open-label, blinded endpoint (PROBE) multicentre trial undertaken in patients with IHD. Participants were primarily recruited from 424 primary care practices via 18 regional centres in the UK, with a small number also referred into the study from secondary care centres. Eligible patients were aged 60 years or over, with a history of IHD [myocardial infarction (MI), angina or other evidence of IHD]. Exclusion criteria were: history of gout; known severe renal impairment [estimated glomerular filtration rate (eGFR) < 30 ml/minute/1.73 m2]; moderate-to-severe heart failure (HF) [New York Heart Association (NYHA) III–IV]; significant hepatic disease [e.g. alanine transaminase (ALT) > 3 × upper limit of normal, cirrhosis, ascites] (investigator opinion); currently taking part in another interventional clinical trial of an investigational medicinal product or medical device (or taken part in one within the last 3 months); previous allergy to allopurinol; previous serious adverse cutaneous (skin) reaction to any drug (e.g. Stevens–Johnson syndrome, toxic epidermal necrolysis, hospitalisation due to skin reaction to drug) (investigator opinion); already taking urate-lowering therapy (including allopurinol, febuxostat, sulfinpyrazone, benzbromarone, probenecid, rasburicase); taking azathioprine, mercaptopurine, ciclosporin or theophylline; malignancy (except non-metastatic, non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 5 years (investigator opinion). The exclusion criterion relating to renal impairment was originally ‘known renal impairment eGFR < 60 ml/minute/1.73 m2’ for patients recruited from the start of the trial (7 February 2014) until 4 April 2016 when an updated version of the protocol was implemented at all study sites to allow the inclusion of patients with moderate renal impairment in the study with the purpose of making the study results more generalisable. Fifty-two per cent of the target number of patients had been randomised by this date.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/11/36/41

Year Published: 2024

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/ATTM4092

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/ATTM4092

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk