Serendipity: How the search for meaning of serum uric acid might lead to the repurposing of an old drug in patients with cardiovascular disease

In the January edition of the journal, Lazzeroni et al. examined the relationship between serum uric acid (sUA) and clinical outcome in patients who had undergone cardiac surgery. Over six years of observation an impressive (almost) linear relationship was found between sUA level measured at baseline and all-cause mortality, cardiovascular death and major adverse cardiac and cerebrovascular events (MACCEs). Further, it was demonstrated that in the 20% of patients with a sUA 360 mmol/l (6mg/dl) the annual all-cause mortality was 5%/year and cardiovascular mortality was 2.5%/year, both more than twice that of patients with sUA< 360 mmol/l. Whilst the strength of the relationship between sUA and all-cause mortality, cardiovascular death and MACCEs in this study is consistent with other reports in patients with cardiovascular disease and cancer, the clinical implications are far from clear. Mendelian randomization studies avoid the bias inherent in non-randomized cohort studies and have confirmed that sUA is only causal in diseases associated with abnormal UA metabolism and not causal in atherosclerosis, hypertension or diabetes. It would appear therefore that other than its use in the assessment and treatment of patients with disordered uric acid metabolism, sUA will likely remain ‘a measure in search of clinical relevance’: it is not causal; it is not a marker of disease activity; it is not a proven therapeutic target in any other disease; and it may not tell us more about a patient’s outcome than the composite of other commonly used clinical and biochemical markers of prognosis. In contrast, the link between gout and atherosclerosis is of more interest. Specifically, recent understanding of the ‘importance and symmetry’ of crystal-induced inflammation mediated via the IL-1b pathway in both gout and atherosclerosis indicates that drugs that inhibit the IL-1b pathway, such as canakinumab and colchicine, may be of value in the treatment of both diseases. However, this is where the link between gout and atherosclerosis ends, for whilst lowering sUA is effective for secondary prevention in gout in the same way as lowering low-density lipoprotein is effective for secondary prevention of atherosclerosis, there is no evidence that lowering sUA will be effective for secondary prevention in cardiovascular disease. To be clear, atherosclerosis is not gout. This conclusion is disappointing as is it leads to the realization that the tantalizing idea of ‘simply joining the dots’ to support the thesis that lowering sUA can reduce a patient’s risk of cardiovascular death and disability is simply not tenable. Despite this reality, there is an increasing body of evidence, albeit mixed and indirect, supporting the prospect that allopurinol might reduce the risk of heart failure and atherosclerotic events. Although no convincing or plausible mechanism for these cardiovascular benefits has been described, there are increasing calls to ‘push the envelope and square the circle’ by performing a study to determine whether allopurinol has important off-target effects that can truly modify the natural history of cardiovascular disease. Given the low cost, widespread availability and known long-term tolerability and safety of allopurinol perhaps such a trial would be of value if it was well designed, adequately powered and used an appropriate dose of therapy. Based upon observations to date, a prospective event driven trial of placebo versus allopurinol 300mg daily (seemingly the most effective dose) in high risk patients with cardiovascular disease could definitively answer the question in a relatively short time as it would only