Gout is caused by high levels of urate, which is a normal waste product but if too high, can remain as urate crystals inside joints. When a build-up of crystals is shed, it causes pain and swelling, called gout flares. People with flares can have a higher risk of heart attacks and strokes. It is not known if gout flares are also linked with heart failure and irregular heartbeat.
Medicines like allopurinol reduce urate and dissolve crystals, reducing gout flares. Anti-inflammatory medicines like colchicine also prevent gout flares. Whether these medicines also reduce the risk of heart attack and stroke in people with gout is unknown.
This study will find out if people treated with allopurinol who have well-controlled low levels of urate and those treated with colchicine also have the benefits of a lower risk of experiencing heart attack or stroke. It will also find out if gout flares are associated with other heart diseases such as irregular heartbeat and heart failure and if the use of medicines can help lower any increased risks.
The study will use clinical information from over 90 thousand people with gout. It will use routinely collected information from their general practice, hospital, and mortality records obtained from the Clinical Practice Research Datalink (CPRD) and linked to hospitalisation and mortality records.
This project will improve gout care by highlighting the adverse effects of gout flares on people’s health and the benefits of medicines that lower uric acid. Consequently, these results will improve gout treatment.
Background: People with gout have high cardiovascular disease risk. Long-term treat-to-target urate-lowering therapy (T2T-ULT) prevents gout flares. Whether lowering serum urate with T2T-ULT will prevent cardiovascular events has not been investigated. Additionally, whether gout flares are associated with arrhythmias and decompensated heart failure is unknown.
Objectives: The objectives are to evaluate among people with gout whether: [1] T2T-ULT that meets serum urate target recommended in NICE guidelines (i.e. <360 µmol/L) reduces cardiovascular event risk, [2] colchicine flare prophylaxis co-prescribed with ULT reduces cardiovascular event risk, and [3] whether gout flares are associated with subsequent cardiac arrhythmias, heart failure and are potential risks modified with well controlled urate levels from treatment with ULT and colchicine.
Methods: The study will be delivered in three parts.
Data source: Routinely collected healthcare data from the Clinical Practice Research Datalink (CPRD) linked with socioeconomic deprivation, hospitalisation and mortality records will be used.
Objective-1: Using a cohort of incident gout patients prescribed ULT for the first time, landmark analysis in a cohort study design will be used to compare hazard ratios of future cardiovascular events and rate ratio of number of healthcare utilizations for cardiovascular events in patients meeting and not meeting serum urate treatment target recommended in NICE guidelines within 12 months of the start of ULT.
Objective-2: Using the cohort of incident gout cases prescribed ULT for the first time, hazard ratios of cardiovascular events and rate ratio of the number of healthcare utilizations for cardiovascular events will be compared between those co-prescribed colchicine flare prophylaxis and age-sex-matched comparisons not co-prescribed colchicine flare prophylaxis in a cohort study.
Objective-3: Data from CPRD will be used to conduct two separate nested case-control studies and self-controlled case series analyses to investigate the association between gout flares and subsequent cardiac arrhythmias, and heart failure.
Outcomes:
Objective 1 (cardioprotective effect of ULT) and Objective 2 (cardioprotective effect of colchicine):
[a] incident cardiovascular event (primary-outcome),
[b] death due to cardiovascular events (secondary-outcome),
[c] number of primary-care consultations for cardiovascular events,
[d] number of hospitalizations for cardiovascular events.
Definition: primary care diagnosis of stroke and/or acute myocardial infarction, hospitalisation with a primary discharge diagnosis of stroke and/or acute myocardial infarction, death with stroke and/or acute myocardial infarction as the cause of death. Linkage across all databases will be used to improve case ascertainment as 25-50% of cardiovascular events are not recorded in at least one of the three data sources [3].
Objective 3 (gout flare and other cardiovascular events):
[a] cardiac arrhythmias (atrial fibrillation, ventricular tachycardia, ventricular fibrillation, atrioventricular blocks, bradyarrhythmias, placement of pacemaker).
Defined as primary care diagnosis of arrhythmias, hospitalisation with a primary discharge diagnosis of arrhythmias or death with arrhythmias as the cause of death.
[b] hospitalisation for decompensated heart failure, defined as primary discharge diagnosis of heart failure.
Abhishek Abhishek - Chief Investigator - University of Nottingham
Edoardo Cipolletta - Corresponding Applicant - University of Nottingham
Anthony Avery - Collaborator - University of Nottingham
Georgina Nakafero - Collaborator - University of Nottingham
Laila Tata - Collaborator - University of Nottingham
Mamas Mamas - Collaborator - Keele University
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation