Cardiovascular disease takes 17.9 million lives each year. This is 31% of all deaths worldwide, making it the most common cause of death. Despite lifestyle changes and medical interventions, patients remain at high risk of fatal and non-fatal cardiovascular events. Therefore new therapeutic strategies are necessary.
Allopurinol and colchicine, two commonly used drugs for the treatment of gout, have recently been linked to a possible reduction of cardiovascular disease. The potential underlying mechanism for colchicine lies in its anti-inflammatory activity while allopurinol might reduce oxidative stress, resulting in less damage to cells. Allopurinol also might have blood pressure lowering effects.
Despite the proven cardiovascular benefits of colchicine, two important questions remain. Firstly, the combined benefit of allopurinol and colchicine together has not been studied before. Reducing vascular inflammation (colchicine) and lowering oxidative stress / hypertension (allopurinol) might result in an even greater reduction of cardiovascular disease than either drug alone. Secondly, in particular for colchicine, the time that is needed to obtain a clear benefit and the duration of cardioprotection after stopping the drug remains to be sorted out.
Therefore, the aims of this study are as following: (1) to investigate the effect of combined use of allopurinol + colchicine versus colchicine alone, (2) to assess time to obtain cardiovascular benefit and (3) the effect of drug ending patterns in relation to cardiovascular disease in adult patients with gout.
Cardiovascular disease (CVD) takes 17.9 million lives each year, which comprises 31% of all deaths, making it the leading cause of death worldwide. Despite lifestyle changes and medical interventions, patients remain at high risk of cardiovascular events. Therefore novel therapeutic strategies are necessary.
Allopurinol and colchicine, two widely used treatments for gout, have recently been linked to a possible improvement of cardiovascular outcomes. The potential underlying mechanism for colchicine lies in the reduction of vascular inflammation and for allopurinol through the reduction of oxidative stress and blood pressure lowering effects. Indeed, two randomized controlled trials confirmed the cardiovascular benefits of colchicine. For allopurinol, evidence is limited to observational data suggesting a reduction of CVD and mortality, especially in patients with high uric acid.
Despite the confirmed cardiovascular benefits of colchicine, two important knowledge gaps remain. Firstly, the combined cardiovascular value of allopurinol and colchicine together has not been studied before. A multimodal approach of reducing vascular inflammation (colchicine) and diminishing oxidative stress / hypertension (allopurinol) might procure synergism on cardiovascular outcomes. Secondly, in particular for colchicine, the time to benefit and duration of cardioprotection after drug cessation remains to be elucidated.
Therefore, the aims of this study are twofold: (1) to evaluate combined use of allopurinol + colchicine versus colchicine alone and (2) to assess time to cardiovascular benefit and drug cessation patterns in relation to major adverse cardiovascular events (MACE) in adult patients with gout.
In this observational cohort study, hazard ratios for MACE will be calculated among combined colchicine + allopurinol users versus colchicine-monotherapy users. In addition, hazard ratios will be stratified by duration of use/time since cessation in order to calculate time to benefit and temporal effects after drug cessation. Time-dependent cox proportional hazards models will be used, adjusted for potential confounders using propensity score matching.
A composite outcome of MACE is our primary outcome of interest and is defined as: Myocardial infarction; stroke, and all-cause mortality. For myocardial infarction and stroke, READ codes will be used (see Appendix I and II).
- Chief Investigator -
Jeroen Houwen - Corresponding Applicant - University Medical Centre Utrecht
Toine Egberts - Collaborator - Utrecht University