CVD were increased by approximately 30% among
subjects with gout compared with healthy controls
(10.3 per 1000 person-years vs 8.0 per 1000 person-
years).
The results from the MRFIT study have been
confirmed by those of another large observational
survey, the Third National Health and Nutrition
Examination Survey (NHANES III), 9 which assessed
the association between gout and cardiovascular
mortality in the US population. The multivariable
risk of CV mortality was increased by 46% in those
with gout compared with those without gout (95%
CI 1.07–2.00). A further large-scale observational
study investigated the relation between a self-
reported history of gout and the risk of death and
MI in 51,297 males with and without history of
CHD and participants of the Health Professionals
Follow-Up for CVD (1.38; 95% CI 1.15–1.66) and
CHD (1.55; 95% CI 1.24–1.93) despite an extensive
adjustment including almost all the possible
confounding risk and dietary factors. The relative
risk of cardiovascular events was largely comparable
and highly significant in patients regardless of
the history of CHD. Finally, comparable results
have been reported by another study where a 39%
increase in the relative risk of MI was also reported
in women with gout (95% CI 1.20–1.61) compared
with controls. 19 The evidence reported by of all
these studies suggest the generalisability of the
observational data to a large population of patients
with gout that must be considered at a very high-
risk and subject to a careful evaluation of early CV
involvement in addition to control of serum urate
levels and well-known CV risk factors.
The association between gout and cardiovascular
mortality and morbidity has been specifically
investigated in the Asian population, and reports
very similar results. Teng and colleagues 20 assessed
the link between gout and CHD mortality in a
prospective cohort of the Singapore Chinese Health
Study. In agreement with previous observations,
subjects with gout had a higher risk of CHD death
(hazard ratio (HR) 1.38; 95% CI 1.10–1.73) compared
with subjects without gout. The association was
significant in males and females, but the risk
estimates for women were higher (HR 1.71; 95% CI
1.12–2.60), probably because of the age range of the
population (45–74 years) including pre-menopausal
subjects. A significant increase in the relative risk
of CVD mortality was also observed in a large
sample of the gout population of Taiwan compared
with normo-uricaemic controls (HR 1.97; 95% CI
1.08–3.59). 21 Another study of individuals in Taiwan 22
found similar results in terms of CVD mortality
among the individuals with gout (HR 1.10: 95% CI
1.07–1.13) with a large relative risk (RR) in patients
with normal renal function, thereby excluding the
involvement of renal disease in the association
between hyperuricemia and cardiovascular disease.
Gout and heart failure
Heart failure is a growing global epidemic but
particularly in industrialised countries. Prevention
and treatment of heart failure is one of the most
important targets of CV treatment and this implies
the correct management of all the possible risk
factors including serum uric acid and gout. Heart
failure is typically associated with an over-expression
of xanthine oxidase that could be responsible for an
increased production of uric acid that can largely
contribute to the prevalence of hyperuricaemia and
gout in patients with left ventricular dysfunction
regardless of deterioration of renal function. 23 An
association between high levels of urate and heart
Table 1
Summary of randomised clinical trials in the field of urate-lowering treatment and
cardiovascular disease
CV field Intervention Primary outcomes ClinicalTrials.gov/status
Blood pressure (BP) control Febuxostat vs allopurinol Clinic BP and ambulatory
blood pressure monitoring
(ABPM) NCT0171622; terminated
(unable to enroll
participants)
Coronary endothelial dysfunction Febuxostat vs placebo Coronary flow NCT01763996; completed
BP control Febuxostat vs placebo ABPM NCT01496469; completed
Exercise tolerance in chronic angina Febuxostat vs placebo Exercise tolerance testing
(ETT) NCT01549977; terminated
Vascular structure and function (FORWARD) Febuxostat vs allopurinol Carotid–femoral pulse
wave velocity EudraCT 2014-5567-33
enrollment closed
New-onset metabolic syndrome (FAST) Febuxostat vs placebo Insulin resistance and
features of metabolic
syndrome NCT01654276; ongoing
BP and cardiovascular (CV) complications (CARES) Febuxostat vs allopurinol MACE NCT01101035; ongoing
Treatment of coronary heart disease (ALL-HEARTY) Allopurinol vs placebo MACE EudraCT 2013-003559-39
Cerebrovascular protection (XILO-FIST) Allopurinol vs placebo White matter protection NCT0212218; starting
recruitment
Major CV disease (FREED) Febuxostat vs placebo MACE NCT01984749; ongoing
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