Association of serum 25-hydroxyvitamin D concentrations with all-cause and cause-specific mortality among individuals with gout and hyperuricemia.

BACKGROUND: We aimed to probe the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with all-cause and cause-specific mortality among patients with gout and hyperuricemia (HUA). METHODS: The study included 1169 gout patients and 7029 HUA patients from the National Health and Nutrition Examination Survey (NHANES) 2007-2018 and 2001-2018, respectively. The association between serum 25(OH)D and mortality was evaluated by Cox proportional hazard and restricted cubic spline models. RESULTS: Among participants with gout and HUA, the weighted mean concentrations of serum 25(OH)D were 71.49 ± 30.09 nmol/L and 64.81 ± 26.92 nmol/L, respectively. Vitamin D deficiency occurred in 29.68% of gout patients and 37.83% of HUA patients. During 6783 person-years of follow-up among gout patients, 248 all-cause deaths occurred, among which 76 died from cardiovascular disease (CVD) and 49 died from cancer. 1375 HUA patients were recorded for all-cause mortality during 59,859 person-years of follow-up, including 427 CVD deaths and 232 cancer deaths. After multifactorial adjustment, per one-unit increment in natural log-transformed 25(OH)D was associated with lower risk of 55% all-cause mortality and 61% CVD mortality among gout patients, and a 45% reduced risk of cancer mortality among HUA patients. Restricted cubic splines showed a U-shaped relationship with all-cause and CVD mortality among HUA patients, with inflection points of 72.7 nmol/L and 38.0 nmol/L, respectively. The results were robust in subgroup and sensitivity analyses. CONCLUSIONS: Serum 25(OH)D was negatively linearly correlated with mortality among gout patients, whereas U-shaped correlated with mortality in HUA patients. These results indicate that adequate vitamin D status could prevent premature death.

Association of C-reactive protein with all-cause and cause-specific mortality in people with gout.

AIMS: To test the association of C-reactive protein (CRP) with all-cause and cause-specific mortality in people with gout. METHODS: This cohort study included 502 participants with gout from the National Health and Nutrition Examination Survey. Multivariate Cox regression analysis, subgroup analysis, and restricted cubic spline (RCS) analyses were utilized to examine the association of CRP levels with all-cause, cardiovascular, and cancer mortality. RESULTS: After adjusting for multiple variables, Cox regression analysis showed that compared with individuals in the lowest tertile of CRP levels, those in the middle and highest tertiles experienced increases in all-cause mortality risk of 74.2% and 149.7%, respectively. Similarly, the cancer mortality risk for individuals in the highest tertile of CRP levels increased by 283.9%. In addition, for each standard deviation increase in CRP, the risks of all-cause and cancer mortality increased by 25.9% and 35.4%, respectively (P < 0.05). Subgroup analyses demonstrated that the association between CRP levels and all-cause mortality remained significant across subgroups of age (≤ 60 and > 60 years), gender (male), presence or absence of hypertension, non-diabetes, cardiovascular disease, non-cardiovascular disease and non-cancer. Furthermore, the association with cancer mortality was significant in subgroups including males, those without hypertension and cancer, and those with or without diabetes. However, the association with cardiovascular mortality was only significant in the non-hypertension subgroup (P < 0.05). Nonlinear association of CRP with all-cause mortality and linear association with cancer mortality were also confirmed (P for nonlinearity = 0.008 and 0.135, respectively). CONCLUSIONS: CRP levels were associated with increased all-cause and cancer mortality among individuals with gout.

Allopurinol Initiation and All-Cause Mortality Among Patients With Gout and Concurrent Chronic Kidney Disease : A Population-Based Cohort Study.

BACKGROUND: Two recent randomized clinical trials of escalating doses of allopurinol for the progression of chronic kidney disease (CKD) reported no benefits but potentially increased risk for death. Whether the risk could occur in patients with gout and concurrent CKD remains unknown. OBJECTIVE: To examine the relation of allopurinol initiation, allopurinol dose escalation, and achieving target serum urate (SU) level after allopurinol initiation to all-cause mortality in patients with both gout and CKD. DESIGN: Cohort study. SETTING: The Health Improvement Network U.K. primary care database (2000 to 2019). PARTICIPANTS: Patients aged 40 years or older who had gout and concurrent moderate-to-severe CKD. MEASUREMENTS: The association between allopurinol initiation and all-cause mortality over 5-year follow-up in propensity score (PS)-matched cohorts was examined. Analysis of hypothetical trials were emulated: achieving target SU level (<0.36 mmol/L) versus not achieving target SU level and dose escalation versus no dose escalation for mortality over 5-year follow-up in allopurinol initiators. RESULTS: Mortality was 4.9 and 5.8 per 100 person-years in 5277 allopurinol initiators and 5277 PS-matched noninitiators, respectively (hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.93]). In the target trial emulation analysis, the HR of mortality for the achieving target SU level group compared with the not achieving target SU level group was 0.87 (CI, 0.75 to 1.01); the HR of mortality for allopurinol in the dose escalation group versus the no dose escalation group was 0.88 (CI, 0.73 to 1.07). LIMITATION: Residual confounding cannot be ruled out. CONCLUSION: In this population-based data, neither allopurinol initiation, nor achieving target SU level with allopurinol, nor allopurinol dose escalation was associated with increased mortality in patients with gout and concurrent CKD. PRIMARY FUNDING SOURCE: Project Program of National Clinical Research Center for Geriatric Disorders.

Mortality in Patients With Gout Treated With Allopurinol: A Systematic Review and Meta-Analysis.

OBJECTIVE: Urate-lowering therapy (predominantly allopurinol) is highly effective as a treatment for gout, but its wider long-term effects remain unclear. This systematic review and meta-analysis aimed to ascertain the association between mortality and the use of allopurinol in patients with gout. METHOD: Medline, Embase, CINAHL, and the Cochrane Library were searched from inception to August 2018. Articles eligible for inclusion used a cohort design and examined cardiovascular or all-cause mortality in patients diagnosed with gout and prescribed allopurinol. Information on study characteristics, design, sample size, and mortality risk estimates were extracted. Article quality was assessed using the Newcastle-Ottawa Scale. Included articles were described in a narrative synthesis and, where possible, risk estimate data were pooled. RESULTS: Four articles reported a hazard ratio (HR) risk estimate for all-cause mortality in patients with gout using allopurinol, and 2 of these also reported cardiovascular mortality. Two articles found allopurinol to be protective in patients with gout, 1 found no statistically significant association, and 1 found no statistically significant effect of escalation of allopurinol dosage on all-cause or cardiovascular-related mortality. Data pooling was possible for all-cause mortality and found no association between allopurinol use in patients with gout and all-cause mortality compared to patients with gout not using allopurinol (adjusted HR 0.80 [95% confidence interval 0.60-1.05]). CONCLUSION: There was no significant association between all-cause mortality and allopurinol use in people with gout. However, the number of included studies was small, suggesting that further studies are needed.

Educational inequalities in all-cause and cause-specific mortality among people with gout: a register-based matched cohort study in southern Sweden.

BACKGROUND: Gout is the most common inflammatory arthritis with a rising prevalence around the globe. While educational inequalities in incidence and prevalence of gout have been reported, no previous study investigated educational inequality in mortality among people with gout. The aim of this study was to assess absolute and relative educational inequalities in all-cause and cause-specific mortality among people with gout in comparison with an age- and sex-matched cohort free of gout in southern Sweden. METHODS: We identified all residents aged ≥30 years of Skåne region with doctor-diagnosed gout (ICD-10 code M10, n = 24,877) during 1998-2013 and up to 4 randomly selected age- and sex-matched comparators free of gout (reference cohort, n = 99,504). These were followed until death, emigration, or end of 2014. We used additive hazards models and Cox regression adjusted for age, sex, marital status, and country of birth to estimate slope and relative indices of inequality (SII/RII). Three cause-of-death attribution approaches were considered for RII estimation: "underlying cause", "any mention", and "weighted multiple-cause". RESULTS: Gout patients with the lowest education had 1547 (95% CI: 1001, 2092) more deaths per 100,000 person-years compared with those with the highest education. These absolute inequalities were larger than in the reference population (1255, 95% CI: 1038, 1472). While the contribution of cardiovascular (cancer) mortality to these absolute inequalities was greater (smaller) in men with gout than those without, the opposite was seen among women. Relative inequality in all-cause mortality was smaller in gout (RII 1.29 [1.18, 1.41]) than in the reference population (1.46 [1.38, 1.53]). The weighted multiple-cause approach generally led to larger RIIs than the underlying cause approach. CONCLUSIONS: Our register-based matched cohort study showed that low level of education was associated with increased mortality among gout patients. Although the magnitude of relative inequality was smaller in people with gout compared with those without, the absolute inequalities were greater reflecting a major mortality burden among those with lower education.

The net clinical benefits of febuxostat versus allopurinol in patients with gout or asymptomatic hyperuricemia - A systematic review and meta-analysis.

BACKGROUND AND AIMS: Systemic reviews and meta-analyses suggest hyperuricemia is a cardiovascular risk factor. The effects of xanthine oxidase inhibitors on cardiac outcomes remain unclear. We assessed the effects of febuxostat and allopurinol on mortality and adverse reactions in adult patients with hyperuricemia. METHODS AND RESULTS: PubMed and EMBASE were searched to retrieve randomized controlled trials of febuxostat and allopurinol from January 2005 to July 2018. The meta-analysis consisted of 13 randomized controlled trials with a combined sample size of 13,539 patients. Febuxostat vs. allopurinol was not associated with an increased risk of cardiac-related mortality in the overall population (OR: 0.72, 95% CI: 0.24-2.13, P = 0.55). Regarding adverse skin reactions, the patients receiving febuxostat had significantly fewer adverse skin reactions than those receiving allopurinol treatment (OR: 0.50, 95% CI: 0.30-085, P = 0.01). Compared with allopurinol, febuxostat was associated with an improved safety outcome of cardiac-related mortality and adverse skin reactions (OR: 0.72, 95% CI: 0.55-0.96, P = 0.02). The net clinical outcome, composite of incident gout and the safety outcome, was not different significantly in the patients receiving febuxostat or allopurinol (OR: 1.04, 95% CI: 0.76-0.1.42, P = 0.79). In sensitivity analyses, a borderline significance was found in the patients randomized to febuxostat vs. allopurinol regarding cardiac-related mortality (OR: 1.29, 95% CI: 1.00-1.67, P = 0.05) after the CARES study was included. CONCLUSION: Febuxostat vs. allopurinol was associated with the improved safety outcome and have comparable mortality and net clinical outcome in patients with hyperuricemia. REGISTRATION NUMBER: PROSPERO(CRD42018091657).

Comparing Cardiovascular Safety of Febuxostat and Allopurinol in the Real World: A Population-Based Cohort Study.

OBJECTIVE: To determine and compare the risk of cardiovascular events and mortality of febuxostat and allopurinol use. PATIENTS AND METHODS: We conducted a cohort study using the Taiwan National Health Insurance Research Database. New users of febuxostat and allopurinol between April 1, 2012 and December 31, 2015 were identified, and the two groups were 1:1 matched by propensity score, benzbromarone use history, renal impairment, and time of drug initiation. The risk of major adverse cardiovascular events (MACEs), venous thromboembolism (VTE), heart failure (HF) hospitalization, atrial fibrillation hospitalization, cardiovascular (CV) death, and all-cause mortality was assessed using Cox proportional hazards models. The dose-response relationship between xanthine oxidase inhibitor use and adverse CV outcomes were also determined. RESULTS: A total of 44,111 patients were included for each group, and all baseline covariates were well matched. Febuxostat users were at a significantly higher risk for HF hospitalization (hazard ratio [HR], 1.22; 95% CI, 1.13-1.33), atrial fibrillation hospitalization (HR, 1.19; 95% CI, 1.05-1.36), and CV death (HR, 1.19; 95% CI, 1.03-1.36) than allopurinol users, whereas no difference was found for the major adverse cardiac events composite endpoint, venous thromboembolism, myocardial infarction, ischemic stroke, and all-cause mortality. The elevated risk of HF hospitalization was consistent throughout the primary and sensitivity analyses. In addition, febuxostat increased the risk of adverse CV outcomes in a dose-dependent manner. CONCLUSION: The use of febuxostat, compared with allopurinol, was associated with a significantly increased risk of adverse CV events. Higher febuxostat doses had a greater impact. Further studies are needed to investigate the mechanisms linking febuxostat to adverse CV outcomes.

Crystal-proven gout patients have an increased mortality due to cardiovascular diseases, cancer, and infectious diseases especially when having tophi and/or high serum uric acid levels: a prospective cohort study.

OBJECTIVE: To investigate the cause-specific mortality and the possible involved clinical characteristics with increased mortality in a cohort of 700 patients with crystal-proven gout. The cause-specific mortality of gout was compared to the mortality of the general population. METHODS: Patients with arthritis referred for diagnosis were consecutively included in the Gout Arnhem-Liemers Cohort (GOAL). Joint fluid analysis was performed in all patients and only crystal-proven gout patients were included in this study. At inclusion clinical characteristics and laboratory values were collected. At follow-up patients who died were identified. Standardized mortality ratios (SMRs) were calculated for all-causes, cardiovascular diseases, cancer, and infectious diseases using indirect standardization methods for mortality outcomes and compared with the general population. The clinical characteristics of the patients who died were compared with those of the survivors and were analyzed by a logistic regression analysis to identify any associations with mortality. RESULTS: The study population at inclusion contained 573 (81.9%) men and 127 (18.1%) females with an average age of 62.0 (SD 13.4). During 3500 person-years from inclusion visit till 31 May 2016, in 700 gout patients, 66 deaths (27 cardiovascular deaths, 15 cancer-related deaths, 8 infectious deaths, 16 various other causes) occurred in this cohort. The all-cause standardized mortality ratio in gout patients was 2.21 (95% CI 1.68-2.74). In this cohort, gout patients had a higher SMR for death attributed to cardiovascular diseases (6.75; 95% CI 4.64-8.86), infectious diseases (4.66; 95% CI 1.51-7.82) and cancer (3.58; 95% CI 1.77-5.39). Corrected for confounders high serum uric acid levels (SUA; > 0,56 mmol/L), tophaceous gout, a history of peripheral vascular disease, myocardial infarction, and heart failure at the inclusion visit were associated with increased mortality during follow-up. CONCLUSION: Compared to the general population, gout patients have an increased association with all-cause disease mortality, especially attributed to cardiovascular diseases, cancer, and infectious diseases. This association is strongest in hyperuricemic (uric acid levels > 0,56 mmol/l) and tophaceous patients and in those with a history of peripheral vascular disease, myocardial infarction, and heart failure. Preventive measures like treatment of high SUA levels and treatment of cardiovascular risk factors need to be considered and evaluated.

Hyperuricemia and gout are associated with cancer incidence and mortality: A meta-analysis based on cohort studies.

The association between hyperuricemia or gout and cancer risk has been investigated in various published studies, but their results are conflicting. We conducted a meta-analysis to investigate whether hyperuricemia or gout was associated with the cancer incidence and mortality. Linear and nonlinear trend analyses were conducted to explore the dose-response association between them. The pooled relative risk (RR) and 95% confidence interval (CI) were used to evaluate cancer risk. A total of 24 articles (33 independent studies) were eligible for inclusion. When compared participants with the highest SUA (hyperuricemia) levels and those with the lowest SUA levels, the pooled RR was 1.08 (95% CI, 1.04-1.12), it was significantly associated among males but not among females (males, RR = 1.07; 95% CI, 1.03-1.11; females, RR = 1.06; 95% CI, 0.96-1.17). Hyperuricemia increased total cancer mortality (RR = 1.15; 95% CI, 1.05-1.26), but a significant association was observed in females rather than in males (females: RR = 1.26; 95% CI, 1.09-1.45; males, RR = 1.02; 95% CI, 0.80-1.30). Linear relationships of SUA levels with overall cancer incidence (p for nonlinearity = 0.238) and overall cancer mortality (p for nonlinearity = 0.263) were identified. However, 1 mg/dL increment in SUA levels was weakly significant in overall cancer incidence (RR = 1.01; 95% CI, 1.01-1.01) but not associated with overall cancer mortality (RR = 1.01; 95% CI, 0.99-1.03). Gout was significantly associated with increased cancer incidence (RR = 1.19; 95% CI, 1.12-1.25). In conclusion, Hyperuricemia or gout was associated with higher cancer incidence and mortality. Though a potential linear relationship between them was found, we'd better treat this result with caution.

Assessment of Cardiovascular Risk in Older Patients With Gout Initiating Febuxostat Versus Allopurinol: Population-Based Cohort Study.

BACKGROUND: Hyperuricemia and gout are associated with an increased risk of cardiovascular disease. Xanthine oxidase inhibitors, allopurinol and febuxostat, are the mainstay of urate-lowering treatment for gout and may have different effects on cardiovascular risk in patients with gout. METHODS: Using US Medicare claims data (2008-2013), we conducted a cohort study for comparative cardiovascular safety of initiating febuxostat versus allopurinol among patients with gout ≥65 years of age. The primary outcome was a composite end point of hospitalization for myocardial infarction or stroke. Secondary outcomes were individual end points of hospitalization for myocardial infarction, stroke, coronary revascularization, new and recurrent heart failure, and all-cause mortality. We used propensity score matching with a ratio of 1:3 to control for confounding. We estimated incidence rates and hazard ratios for primary and secondary outcomes in the propensity score-matched cohorts of febuxostat and allopurinol initiators. RESULTS: We included 24 936 febuxostat initiators propensity score-matched to 74 808 allopurinol initiators. The median age was 76 years, 52% were male, and 12% had cardiovascular disease at baseline. The incidence rate per 100 person-years for the primary outcome was 3.43 in febuxostat and 3.36 in allopurinol initiators. The hazard ratio for the primary outcome was 1.01 (95% CI, 0.94-1.08) in the febuxostat group compared with the allopurinol group. Risk of secondary outcomes including all-cause mortality was similar in both groups, except for a modestly decreased risk of heart failure exacerbation (hazard ratio, 0.94; 95% CI, 0.91-0.99) in febuxostat initiators. The hazard ratio for all-cause mortality associated with long-term use of febuxostat (>3 years) was 1.25 (95% CI, 0.56-2.80) versus allopurinol. Subgroup and sensitivity analyses consistently showed similar cardiovascular risk in both groups. CONCLUSIONS: Among a cohort of 99 744 older Medicare patients with gout, overall there was no difference in the risk of myocardial infarction, stroke, new-onset heart failure, coronary revascularization, or all-cause mortality between patients initiating febuxostat compared with allopurinol. However, there seemed to be a trend toward an increased, albeit not statistically significant, risk for all-cause mortality in patients who used febuxostat for >3 years versus allopurinol for >3 years. The risk of heart failure exacerbation was slightly lower in febuxostat initiators.

Allopurinol Dose Escalation and Mortality Among Patients With Gout: A National Propensity-Matched Cohort Study.

OBJECTIVE: Observational data suggest that hyperuricemia and gout are associated with increased mortality, while allopurinol use is associated with reduced mortality. In addition, the protective effect of allopurinol may be dose dependent. The aim of the current study was to determine whether allopurinol dose escalation is associated with cause-specific mortality in patients with gout. METHODS: In this 10-year observational, active-comparator study of US Veterans with gout who initiated treatment with allopurinol, propensity score matching, Cox proportional hazards models, and competing risks regression analyses were used to assess differences in cause-specific mortality between patients whose allopurinol dose was escalated (dose escalators) and those whose allopurinol dose was not escalated or was reduced (non-escalators) over a 2-year period. RESULTS: Among the 6,428 dose escalators and 6,428 matched non-escalators, there were 2,867 deaths during the observation period (40.4 deaths per 1,000 person-years). Dose escalators experienced an increase in all-cause mortality (hazard ratio [HR] 1.08, 95% confidence interval [95% CI] 1.01-1.17), with the effect sizes being similar for incidence of cardiovascular-related deaths (HR 1.08, 95% CI 0.97-1.21) and cancer-related deaths (HR 1.06, 95% CI 0.88-1.27), although neither reached statistical significance. Dose escalation to achieve the goal of lowering the serum urate (SU) level to <6.0 mg/dl was infrequent. At 2 years, 10% of dose escalators were receiving a final daily dose of >300 mg and 31% had achieved the SU goal. In a sensitivity analysis limited to dose escalators achieving the SU goal, there was a nonsignificant reduction of 7% in the hazard of cardiovascular-related mortality (HR 0.93, 95% CI 0.76-1.14). CONCLUSION: This is the largest study to date to investigate the effects of allopurinol use on mortality and is the first to use a rigorous active-comparator design. Dose escalation was associated with a small (<10%) increase in all-cause mortality, thus showing that a strategy of allopurinol dose escalation, which in current real-life practice is characterized by limited dose increases, is unlikely to improve the survival of patients with gout.

Change gout: the need for a new approach.

Gout is the most common form of inflammatory arthropathy and is caused by an excess of uric acid in the blood (hyperuricemia). It is a chronic, debilitating condition that gradually increases in severity and affects an increasing number of people. It has a wide spectrum of clinical manifestations and is related to serious kidney and cardiovascular conditions and to an increased risk of mortality. The negative perception of the disease, historically seen as related to a life of dissipation, has led to underestimating its impact and focusing the attention on the short-term treatment of acute attacks rather than on the long-term management of the condition without, consequently, preventing the most serious complications. The most recent scientific evidence and the increasing understanding of the physio-pathologic mechanisms responsible for hyperuricemia and gout reveal a very different reality, in which gout is a condition which is only minimally affected by lifestyle and mainly by increasingly better identified genetic factors. Appropriate doctor training and patient education, catalyzed by the renewed attention to this disease and to new treatment options which overcome the limits of therapies currently available, will help to break down current barriers to allow for its optimal management.

Cardiovascular Disease Prevalence in Patients with Osteoarthritis, Gout, or Both.

OBJECTIVE: Osteoarthritis (OA) and gout have each been associated with increased cardiovascular disease (CVD), but their relative impact is unknown. We compared CVD rates among patients with gout versus patients with OA and no gout (OA-only). METHODS: We identified male patients at the VA New York Harbor Healthcare System with gout (with or without concur - rent OA) and with OA-only between August 2007 and August 2008. For each group, we collected baseline demographic data and CVD risk factors. The primary outcome was a composite index (CV4) of any diagnosis of coronary artery disease (CAD), angina, myocardial infarction (MI), or coro- nary bypass surgery (CABG). Secondary outcomes included individual diagnoses within the CV4, CHF, and death. We subsequently divided the gout patients into those who did versus did not have concurrent diagnoses of OA (gout-only; gout+OA). Logistic regression was used to compare the associations of OA-only, gout-only, and gout+OA with CV outcomes. RESULTS: 1,280 gout subjects met inclusion criteria (983 gout- only and 297 gout+OA), along with 1,231 OA-only subjects. Gout subjects overall had more CVD risk factors at baseline, including hypertension, hyperlipidemia, and chronic kidney disease, versus OA-only. Compared with OA-only, gout subjects overall had increased rates of all outcomes except MI. Both the gout-only and gout+OA subgroups also had increased risk for all outcomes except MI, and CABG in the case of gout+OA subjects. After adjusting for traditional CVD risk factors, both gout-only and gout+OA subjects continued to have increased risk for multiple CVD outcomes. Gout+OA did not impart ad- ditional risk over gout-only for any outcome studied. CONCLUSION: Our data suggest that gout is associated with higher risk of CVD compared with OA, and that OA does not impart any additive CVD risk to patients who also have gout. Significance and Innovations: • In our dataset, gout subjects both with and without con- comitant OA had more cardiovascular disease (CVD) risk factors at baseline, and higher prevalence of CVD outcomes, than patients with OA only. • After adjusting for traditional CVD risk factors, gout-only and gout+OA subjects continued to have increased rates of multiple CVD outcomes, suggesting an intrinsic CVD risk to the diagnosis of gout, compared with OA. • These observations underline that gout patients represent a group at increased CVD risk, for whom both rheumatic disease management and CVD prevention need to be addressed.

Effect of allopurinol on all-cause mortality in adults with incident gout: propensity score-matched landmark analysis.

OBJECTIVE: To examine the association between allopurinol use and all-cause mortality for patients with incident gout. METHODS: We compared all-cause mortality in incident gout patients who received allopurinol for at least 6 months within the exposure window (1 year or 3 years) with those who did not, using the UK Clinical Practice Research Data-link. Landmark analysis was used to account for immortal time bias and propensity score matching was used to control for potential effects of known confounders. RESULTS: Of 23 332 incident gout patients identified, the propensity score-matched cohorts contained 1016 patients exposed to allopurinol on the date 1 year from diagnosis (landmark date) and 1016 allopurinol non-users. Over a median follow-up period of 10 years after the landmark date, there were 437 allopurinol users and 443 allopurinol non-users who died during follow-up. Allopurinol users and non-users had similar risk for all-cause mortality (hazard ratio 0.99; 95% CI 0.87, 1.12). In the 3-year landmark analysis, 3519 allopurinol users (1280 died) were compared with 3519 non-users (1265 died). The hazard ratio for all-cause mortality was 1.01 (95% CI 0.92, 1.09). CONCLUSION: This propensity score-matched landmark analysis in a population of incident gout patients in the UK primary care setting found a neutral effect on the risk of all-cause mortality. Our study provides reassurance about the prescription of allopurinol for gout patients early in their disease course to prevent untoward consequences of chronic uncontrolled hyperuricaemia. However, whether higher than the commonly used dose of allopurinol could influence mortality remains to be determined.

Allopurinol initiation and all-cause mortality in the general population.

BACKGROUND: Allopurinol is the most commonly used urate-lowering therapy, with rare but potentially fatal adverse effects. However, its impact on overall mortality remains largely unknown. In this study, we evaluated the impact of allopurinol initiation on the risk of mortality among individuals with hyperuricaemia and among those with gout in the general population. METHODS: We conducted an incident user cohort study with propensity score matching using a UK general population database. The study population included individuals aged ≥40 years who had a record of hyperuricaemia (serum urate level >357 µmol/L for women and >416 µmol/L for men) between January 2000 and May 2010. To closely account for potential confounders of allopurinol use and risk of death, we constructed propensity score matched cohorts of allopurinol initiators and comparators (non-initiators) within 6-month cohort accrual blocks. RESULTS: Of 5927 allopurinol initiators and 5927 matched comparators, 654 and 718, respectively, died during the follow-up (mean=2.9 years). The baseline characteristics were well balanced in the two groups, including the prevalence of gout in each group (84%). Allopurinol initiation was associated with a lower risk of all-cause mortality (matched HR 0.89 (95% CI 0.80 to 0.99)). When we limited the analysis to those with gout, the corresponding HR was 0.81 (95% CI 0.70 to 0.92). CONCLUSIONS: In this general population study, allopurinol initiation was associated with a modestly reduced risk of death in patients with hyperuricaemia and patients with gout. The overall benefit of allopurinol on survival may outweigh the impact of rare serious adverse effects.

Allopurinol therapy in gout patients does not associate with beneficial cardiovascular outcomes: a population-based matched-cohort study.

INTRODUCTION: Previous studies have shown an association between gout and/or hyperuricemia and a subsequent increase in cardiovascular disease (CVD) outcomes. Allopurinol reduces vascular oxidative stress, ameliorates inflammatory state, improves endothelial function, and prevents atherosclerosis progression. Accordingly, we tested the hypothesis that a positive association between allopurinol therapy in gout patients and future cardiovascular outcomes is present using a population-based matched-cohort study design. METHODS: Patients aged ≥40 years with newly diagnosed gout having no pre-existing severe form of CVD were separated into allopurinol (n = 2483) and non-allopurinol (n = 2483) groups after matching for age, gender, index date, diabetes mellitus, hypertension, hyperlipidemia, and atrial fibrillation. The two groups were also balanced in terms of uric acid nephrolithiasis, acute kidney injury, hepatitis, and Charlson comorbidity index. RESULTS: With a median follow-up time of 5.25 years, the allopurinol group had a modest increase in cardiovascular risk [relative risk, 1.20; 95% confidence interval (CI), 1.08-1.34]. A Cox proportional hazard model adjusted for chronic kidney disease, uremia, and gastric ulcer gave a hazard ratio (HR) for cardiovascular outcomes of 1.25 (95% CI, 1.10-1.41) in gout patients receiving allopurinol compared with the non-allopurinol group. In further analysis of patients receiving urate-lowering therapy, the uricosuric agent group (n = 1713) had an adjusted HR of 0.83 (0.73-0.95) for cardiovascular events compared with the allopurinol group. CONCLUSIONS: The current population-based matched-cohort study did not support the association between allopurinol therapy in gout patients with normal risk for cardiovascular sequels and beneficial future cardiovascular outcomes. Several important risk factors for cardiovascular disease, such as smoking, alcohol consumption, body mass index, blood pressure were not obtainable in the current retrospective cohort study, thus could potentially bias the effect estimate.

[Survival of gout patients].

AIM: To assess survival and lethal outcome risk fahctors in gout patients. MATERIAL AND METHODS: The study included 286 gout patients (246 males, 86% and 49 females, 14%) treated for gout in the Research Institute of Rheumatology from 2001 to 2006. From 2010 to May 2011 a telephone survey was made to obtain information about death of the above examinees. After the survey clinical condition of the dead patients was compared to that of survivors. RESULTS: Of 286 participants of the trial, 38 did not response. By information from the relatives, there were 31 (12.5%) lethal outcomes of 248 patients. A cause of death in 20 patients, irrespective of age, were cardiovascular complications, 6 patients died of cancer; one patient--of chronic renal failure, one--of infection, one--of trauma and 2 - of unknown cause. Median of age at death was 62.1 years, median of gout duration--12.8 years. 65% of the deceased patients had risk factors of cardiovascular complications (type 2 diabetes mellitus, coronary heart disease, acute myocardial infarction, stroke, chronic cardiac failure). Median of time since examination in the clinic to death was 4.3 years. CONCLUSION: Gout patients' mortality is high. 7-year survival was 85% in high overall mortality. 2/3 patients died of cardiovascular diseases. Survival of gout patients with normuricemia is the same ofthose with hyperuricemia. A high level of highly sensitive CRP is a factor of poor prognosis (death) for gout patients.

Impact of allopurinol use on urate concentration and cardiovascular outcome.

AIMS: To characterize patients with urate measurements by urate-lowering therapy (ULT) use and to study the impact of allopurinol treatment on cardiovascular and mortality outcomes. METHODS: A cohort study using a record-linkage database. The study included 7135 patients aged ≥60 years with urate measurements between 2000 and 2002 followed up until 2007. A Cox regression model was used. The association between urate levels, dispensed allopurinol and cardiovascular hospitalization and mortality was determined. RESULTS: Six thousand and forty-two patients were not taking ULT and 45.9% of those (2774 of 6042) had urate concentrations ≤6 mg dl(-1) . Among 1035 allopurinol users, 44.7% (45.6% for men and 43.3% for women) reached target urate concentration. There was no significant increased risk of cardiovascular events for allopurinol users when compared with non-ULT users [adjusted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.95-1.26] and the non-ULT group with urate >6 mg dl(-1) (adjusted HR 1.07, 95% CI 0.89-1.28). Within the allopurinol use cohort, cardiovascular event rates were 74.0 (95% CI 61.9-86.1) per 1000 person years for the 100 mg group, 69.7 (49.6-89.8) for the 200 mg group and 47.6 (38.4-56.9) for the ≥300 mg group. Compared with low-dose (100 mg) users, high-dose (≥300 mg) users had significant reductions in the risk of cardiovascular events (adjusted HR 0.69, 95% CI 0.50-0.94) and mortality (adjusted HR 0.75, 95% CI 0.59-0.94). CONCLUSIONS: Less than 50% of patients taking allopurinol reached target urate concentration. Higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality.