Background Men with gout have been found to have an increased risk of acute myocardial infarction (AMI), but no corresponding data are available among women.
Objective To evaluate the potential independent association between gout and the risk of AMI among elderly women, aged ≥65 years.
Methods A population-based cohort study was conducted using the British Columbia Linked Health Database and compared incidence rates of AMI between 9642 gout patients and 48 210 controls, with no history of ischaemic heart disease. Cox proportional hazards models stratified by gender were used to estimate the relative risk (RR) for AMI, adjusting for age, comorbidities and prescription drug use.
Results Over a 7-year median follow-up, 3268 incident AMI cases, were identified, 996 among women. Compared with women without gout, the multivariate RRs among women with gout were 1.39 (95% CI 1.20 to 1.61) for all AMI and 1.41 (95% CI 1.19 to 1.67) for non-fatal AMI. These RRs were significantly larger than those among men (multivariate RRs for all AMI and non-fatal AMI, 1.11 and 1.11; p values for interaction, 0.003 and 0.005, respectively).
Conclusion These population-based data suggest that women with gout have an increased risk for AMI and the magnitude of excess risk is higher than in men.
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Gout is a common and painful inflammatory arthritis affecting up to 9% and 6% of elderly men and women, respectively.1 Studies have reported that men with gout have an increased risk of coronary heart disease (CHD), independent of other cardiovascular risk factors.2 3 A recent meta-analysis showed a larger effect of hyperuricaemia on CHD risk in women than men.4 While this suggests that the impact of gout may be stronger among women than men, no relevant data are available. Thus, we investigated the association between gout and risk of acute myocardial infarction (AMI) among elderly women (≥65 years) in British Columbia (BC), Canada. We focused on elderly subjects because complete BC PhamaCare prescription coverage is limited to this group, and gout occurs predominantly after the menopause among women.
The BC Linked Health Database is a health data resource covering the entire province (2005 population, 4.3 million) and contains integrated longitudinal data on healthcare visits, hospitalisations and drug prescriptions.5 From the BCLHD, we created the BC Musculoskeletal Cohort of approximately 3.5 million subjects with any musculoskeletal diagnosis between 1991 and 2004.6 This cohort study consists of 9642 subjects with gout (3890 women) and 48 210 controls (19 450 women) matched (1:5 ratio) by age, sex, date of gout diagnosis (index date) and length of medical record. Prevalent cases of gout or ischaemic heart disease recorded in the first 3 years were excluded.
We ascertained gout using International Classification of Diseases 9th Revision (ICD-9) codes (274.x). Validation studies of these codes have reported positive predictive values ranging from 61% in a US managed care setting7 to 100% in US Veterans Affairs rheumatology clinic setting.8 In our cohort, gout incidence rates (per 1000 person-years) in age categories 65–84 and ≥85 years were 5.7 and 6.5 among men, and 2.5 and 2.9 among women,6 respectively, corresponding with estimates in the General Practice Research Database.9
From hospitalisation data, we identified incident AMI outcomes using ICD-9 codes (410.x). Validity of these codes are well-established with positive predictive values up to 95%.10 Incidence rates of AMI per 1000 person-years in this cohort were 6.7 and 10.7 for women and men, respectively, consistent with Canadian estimates.11
Subjects were followed up from baseline (index date for gout cases; matched date for controls) to AMI, deregistration from medical service plan, death or end of study (31 March 2004), whichever came first. We used Cox proportional hazards models, stratified by gender, to estimate the relative risk (RR) of AMI in multivariate analyses (PROC PHREG; SAS Institute, Cary, North Carolina, USA), adjusting for age, comorbid conditions (hypertension, diabetes, chronic obstructive pulmonary disease and hyperlipidaemia), Charlson comorbidity score12 and monthly prescription drug use (non-steroidal anti-inflammatory drugs, aspirin, glucocorticoids, statins, anticoagulants, hormone replacement therapy and diuretics) as time-dependent covariates. We tested the significance of the interaction by gender with a likelihood ratio test. All p values were two-sided.
Over a 7-year median follow-up, we identified 3268 incident AMI cases, 996 among women. Baseline characteristics of women and men according to history of gout are shown in table 1.
In unadjusted analyses, gout was associated with a higher risk of AMI (RR=1.67; 95% CI, 1.45 to 1.93) among women (table 2). After adjusting for age, comorbidities and prescription drug use, the multivariate RR was 1.39 (95% CI 1.20 to 1.61). This RR among women was significantly larger than that among men (multivariate RR=1.11; 95% CI 0.99 to 1.23; p value for interaction, 0.003). A significant gender difference with similar RRs was seen for non-fatal, but not fatal, AMI events.
In this population-based study of elderly Canadians, we found a 39% increased risk for AMI among women with gout. This association was independent of age, comorbidities and use of prescription drugs, and was significantly stronger than that among men. These findings fill the gap in knowledge about the relation between gout and AMI among women.
Gender differences in serum uric acid levels13 14 and perhaps uric acid metabolism13 may explain the stronger risk of AMI associated with gout among women than among men. Serum urate levels in men are about 1 mg/dl higher than in women during adulthood, although levels in women increase around the natural menopause.13 14 Thus, the relative physiological impact of having gout or a certain level of hyperuricaemia may be stronger among women than men. Furthermore, reports have shown higher mean uric acid levels among female patients with gout.13 14 It is conceivable that a higher level of uric acid among women with gout could lead to a higher impact on the risk of AMI compared with men. Similar to previous studies,13 14 we found higher frequencies of diuretic use and hypertension among women with gout. However, frequencies of these factors were also higher among women without gout and the differential gender impact on AMI risk persisted even after adjusting for these covariates.
Our findings expand on previous studies showing an independent impact of gout on AMI risk in men, including the Multiple Risk Factor Intervention Trial2 15 and Health Professionals Follow-up Study.3 Although the Framingham Heart Study attempted to evaluate the impact of gout in both men and women, only one incident AMI case among women precluded meaningful analyses.16 A Taiwanese study showed that the frequency of gouty attacks was associated with electrocardiographic evidence of AMI in women, but its cross-sectional design barred establishment of temporal relations.17
There are several potential mechanisms for the associations observed. The contribution of hyperuricaemia to cardiovascular disease risk has been postulated based on patho-physiological mechanisms, including vascular smooth muscle cell proliferation and inflammation and platelet adhesiveness and aggregation.18 Correspondingly, a recent meta-analysis found an independent impact of hyperuricaemia on CHD risk.4 Inflammation associated with gout may also have a role in potential mechanisms, including promotion of atherogenesis and thrombogenesis, similar to other inflammatory arthritides associated with cardiovascular disease.15 19 20
Study strengths and limitations deserve comment. We used a population-based cohort of Canadian women and men, thus findings are likely to be applicable to the general population. Because we used diagnostic codes to define gout, some misclassification of diagnosis is inevitable. However, any non-differential misclassification would probably have biased estimates towards the null and it remains conceivable that the associations are stronger with more specific case definitions for gout. Nevertheless, the gender ratios of incidence rates for both gout and AMI in this cohort were similar to published estimates,9 11 indicating that the possibility of differential ascertainment between men and women is unlikely. Thus, if the association between gout and AMI exists as shown in prospective studies among men,2 3 15 then our comparison employing the same definition of gout in both genders leads to a conclusion that the association is stronger among women. Nevertheless, confirmation of our findings using more specific case definitions of gout would be valuable. Our administrative data precluded adjustment for lifestyle factors for AMI such as smoking. However, because smoking is not an independent risk factor for gout exposure, findings will probably persist even with adjustment, as was the case in previous studies.
In conclusion, this population-based study suggests that women with gout have an increased risk for AMI, and the magnitude of excess risk is higher than for men. These findings provide support for the aggressive management of cardiovascular risk factors for male and female patients with gout.
Competing interests MADV receives training support from the Canadian Arthritis Network/The Arthritis Society, the Michael Smith Foundation for Health Research and the Canadian Institutes of Health Research. MMR receives training support from the Canadian Arthritis Network/The Arthritis Society. VB receives postdoctoral training fellowship support from the Canadian Arthritis Network/The Arthritis Society. HKC has received research funding from TAP Pharmaceuticals for other research projects. In addition, HKC has received honoraria from, and serves as a consultant to, TAP Pharmaceuticals and Savient.
Funding This work was supported in part by grants from the National Institute of Health (AR047785).
Ethics approval This study was conducted with the approval of the University of British Columbia.
Provenance and peer review Not commissioned; externally peer reviewed.
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