IntroductionGout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and this is most often achieved with use of xanthine oxidase inhibitors, such as allopurinol. Febuxostat is the first new xanthine oxidase inhibitor since allopurinol and was licensed for use in 2008. The European Medicines Agency requested a postlicensing cardiovascular safety study of febuxostat versus allopurinol, which has been named the Febuxostat versus Allopurinol Streamlined trial (FAST).Methods and analysisFAST is a cardiovascular safety study using the prospective, randomised, open, blinded endpoint design. FAST is recruiting in the UK and Denmark. Recruited patients are aged over 60 years, prescribed allopurinol for symptomatic hyperuricaemia and have at least one additional cardiovascular risk factor. After an allopurinol lead-in phase where the dose of allopurinol is optimised to achieve European League against Rheumatism (EULAR) urate targets (serum urate <357 µmol/L), patients are randomised to either continue optimal dose allopurinol or to use febuxostat. Patients are followed-up for an average of 3 years. The primary endpoint is first occurrence of the Anti-Platelet Trialists’ Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are all cause mortality and hospitalisations for heart failure, unstable, new or worsening angina, coronary or cerebral revascularisation, transient ischaemic attack, non-fatal cardiac arrest, venous and peripheral arterial vascular thrombotic event and arrhythmia with no evidence of ischaemia. The primary analysis is a non-inferiority analysis with a non-inferiority upper limit for the HR for the primary outcome of 1.3.Ethics and disseminationFAST (ISRCTN72443728) has ethical approval in the UK and Denmark, and results will be published in a peer reviewed journal.Trial Registration numberFAST is registered in the EU Clinical Trials Register (EUDRACT No: 2011-001883-23) and International Standard Randomised Controlled Trial Number Register (ISRCTN No: ISRCTN72443728).

Despite the dif®culties involved in designing drug epidemiology studies, these studies are invaluable for investigating the unexpected adverse effects of drugs. The aim of this paper is to discuss various aspects of study design, particularly those issues that are not easily found in either textbooks or review papers. We have also compared and contrasted drug epidemiology with the randomized controlled trial (RCT) wherever possible. Drug epidemiology is especially useful in the many situations where the RCT is not suitable, or even possible. The study base has to be de®ned before the appropriate cohort of subjects is assembled. If all of the cases are identi®ed, then a referent sample of controls may be assembled by random sampling of the study base. If all of the cases cannot be assembled, a hypothetical secondary base may need to be created. Preferably, only new-users of the drug should be included, and the risk-ratio will be different for acute users and chronic users. Studies will usually only be possible when researching the unintended effects of drugs. It is dif®cult to study ef®cacy because of confounding by indication. In occasional circumstances it may be possible to study ef®cacy (examples are given). Discussion of the dangers of designing with generalisability in mind is provided. Additionally, the similarities in study design between drug epidemiology and the RCT are discussed in detail, as well as the designcharacteristics that cannot be shared between the two methods.

The Royal Infirmary, Edinburgh EH3 9YW 1 y-L-glutamyl-L-dopa (gludopa) was given by intravenous infusion to six healthy saltreplete men on two occasions, with and without pretreatment with (+)-sulpiride. 2 Gludopa increased sodium excretion, glomerular filtration rate and effective renal plasma flow whilst decreasing plasma renin activity. 3 (+)-sulpiride had no significant effect on baseline natriuresis, renal haemodynamics or plasma renin activity, but significantly attenuated the rise in sodium excretion, glomerular filtration rate and effective renal plasma flow produced by gludopa. 4 (+)-sulpiride abolished the acute fall in plasma renin activity seen with gludopa. 5 (+)-sulpiride raised serum prolactin concentration but did not affect the rise in urine dopamine excretion rate caused by gludopa. 6 Gludopa exerts its renal effects by stimulating specific dopamine receptors which are principally of the DA1 subtype.

1. The effect of oral lithium on the renal response to gamma‐L‐glutamyl‐ L‐dopa (gludopa, 25 micrograms kg‐1 min‐1) was investigated in seven normal males. 2. Gludopa at this dose produced an 800‐fold increase in urine dopamine excretion. It was natriuretic and suppressed plasma renin activity without altering blood pressure and pulse. 3. Lithium alone increased sodium excretion and stimulated plasma renin activity. However, it abolished the natriuresis produced by gludopa. 4. Gludopa did not significantly affect lithium clearance. 5. This study suggests that lithium interacts with dopamine at the proximal tubule and that the lithium clearance method is not suitable for investigating dopaminergic mechanisms in the kidney.