Gout affects approximately 1 in 40 people and causes sudden flares of severe joint pain and swelling. Many people with gout experience recurrent flares. Gout is caused by high levels of urate in the blood. Long-term treatment of gout involves taking medication to lower urate levels, which reduces the risk of future flares.
Two medications are available to reduce urate levels: allopurinol and febuxostat. Allopurinol has been used for more than 50 years. However it is often given at too low a dose, or not at all, and around 1 in 20 people can’t take allopurinol due to side effects. An alternative, febuxostat, was authorised for use in 2008, and is potentially more effective for the treatment of gout. However, early research studies suggested febuxostat may increase the risk of heart attacks and strokes. Current guidance in the UK advises caution when using febuxostat in people with pre-existing heart disease or strokes.
Using the Clinical Practice Research Datalink (CPRD), we will form a group of patients with gout, who are given either febuxostat, allopurinol or nothing to find out two things.
• If the risk of heart attacks and strokes is bigger when people start taking febuxostat for gout than when they take allopurinol or no treatment?
• If people who have had a heart attack or stroke in the past, or those who have a high risk of them, are have a bigger chance of heart attacks or strokes when taking febuxostat than people given allopurinol or no treatment?
Gout affects 2.5% of adults in the UK and causes flares of severe joint pain and swelling. Flares can be prevented by urate lowering therapy (ULT), either allopurinol or febuxostat. The most-commonly prescribed ULT is allopurinol, however only one-third of people with gout receive treatment, only one-third of these receive a sufficient dose, and 5% have side-effects severe enough to stop therapy. Febuxostat is a newer alternative. However initial trials raised concerns that febuxostat was associated with an increased risk of cardiovascular events.
The Medicines and Healthcare products Regulatory Agency (MHRA) advises caution when using febuxostat in patients with prior major cardiovascular (CV) events. Gout is associated with CV events, hence a significant proportion of people who cannot tolerate allopurinol have no alternative treatment. It is therefore important to establish the cardiovascular safety of febuxostat.
Objectives:
1. Determine the risk of adverse major CV events following febuxostat treatment for gout in UK primary care, compared to treatment with allopurinol or no treatment.
2. Compare the incidence of major CV events between people initiating febuxostat, allopurinol, or no ULT in (1) people with gout but no CV events and low CV risk, or (2) those with increased CV risk but no events, and (3) those with a prior history of CV events.
The study will be undertaken using linked primary care and Hospital Episodes Statistics data.
Work-package 1
A retrospective cohort study will compare the incidence of major CV events using Cox proportional hazards regression between people with gout who initiate treatment with febuxostat, allopurinol or no ULT.
Work-package 2
A retrospective cohort study to compare the incidence of major CV events using Cox proportional hazards regression between people with gout who initiate treatment with febuxostat, allopurinol or no ULT, subcategorised by risk of cardiovascular disease at time of prescription.
Primary outcome:
Composite of first incidence of (MI; unstable angina; cerebrovascular accident (CVA); heart failure; revascularisation; death due to CV event.)
Secondary outcomes:
Non-fatal events considered separately (MI, unstable angina, CVA, heart failure, revascularisation); CV deaths
Richard Partington - Chief Investigator - Keele University
Richard Partington - Corresponding Applicant - Keele University
Christian Mallen - Collaborator - Keele University
Edward Roddy - Collaborator - Keele University
Mamas Mamas - Collaborator - Keele University
Payam Amini - Collaborator - Keele University
Sara Muller - Collaborator - Keele University
Subhashisa Swain - Collaborator - Keele University
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation