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Humans have a very limited ability to metabolize UA&#44; which must be eliminated via the intestines and kidneys to maintain homeostasis&#46; Intestinal bacteria degrade a third and the kidneys excrete the remainder&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Around 10&#37; of the population will have documented hyperuricemia at least once in their lives&#46; Most such episodes do not require further investigation or treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However&#44; hyperuricemia is associated with gout&#44; hypertension&#44; diabetes&#44; chronic renal failure &#40;CRF&#41; &#40;uric acid nephropathy&#41; and urolithiasis&#44; as well as with increased risk for cardiovascular disease&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The role of hyperuricemia as a risk factor is the subject of debate&#44; as to whether it contributes independently to the pathophysiology of cardiovascular disease or is an epiphenomenon resulting from concomitant conditions such as hypertension&#44; renal disease or metabolic syndrome&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The treatment of choice for hyperuricemia is allopurinol&#44; which reduces the formation of UA by inhibiting xanthine oxidase and improves endothelial function&#46; The latter is an early manifestation of vascular injury and contributes to the development of atherosclerosis&#46; Cardiovascular disease remains the leading cause of death in Portugal&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and so treating hyperuricemia could play an important role in reducing cardiovascular risk&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The aim of this study is to review the evidence on the effect of treatment with allopurinol in patients with hyperuricemia on reducing cardiovascular events&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">MEDLINE&#44; the Cochrane Library&#44; Bandolier&#44; DARE&#44; CMA Infobase&#44; National Guideline Clearinghouse&#44; and NHS Evidence were searched using the MeSH terms &#8220;uric acid&#8221;&#44; &#8220;cardiovascular diseases&#8221; and &#8220;allopurinol&#8221;&#46; The search was limited to guidelines&#44; meta-analyses&#44; systematic reviews&#44; randomized controlled trials &#40;RCT&#41;&#44; cohort studies &#40;CS&#41; and case-control studies &#40;CCS&#41; published between January 2002 and December 2013 in Portuguese and English&#46; Related articles were also considered&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">We included studies on adults with hyperuricemia treated with allopurinol at different doses compared with placebo&#44; analyzing reduction of fatal and non-fatal cardiovascular outcomes and all-cause mortality&#46; Repeated articles and those that did not meet the inclusion criteria &#40;studies of transplanted patients&#44; cancer patients under chemotherapy and&#47;or radiotherapy&#44; and those with congenital heart disease&#41; were excluded&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Level of evidence and strength of recommendation were graded according to the definitions used by the European Society of Cardiology&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><p id="par0045" class="elsevierStylePara elsevierViewall">Of the 46 articles found&#44; 41 were excluded on the grounds of repetition or failure to fulfill the inclusion criteria&#46; Five publications were thus selected&#58; one RCT&#44; three CS and one CCS&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Randomized controlled trial</span><p id="par0050" class="elsevierStylePara elsevierViewall">In the RCT by Goicoechea et al&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; after 24 months of treatment with 100 mg allopurinol serum UA levels fell from 7&#46;8&#177;2&#46;1 mg&#47;dl to 6&#46;0&#177;1&#46;2 mg&#47;dl &#40;p&#61;0&#46;001&#41; but remained stable in the control group &#40;7&#46;3&#177;1&#46;6 mg&#47;dl at baseline and 7&#46;5&#177;1&#46;7 mg&#47;dl at 24 months&#41; &#40;p&#61;0&#46;016 between groups and time period&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">After a mean follow-up of 23&#46;4&#177;7&#46;8 months&#44; 22 patients had suffered a cardiovascular event&#58; 15 in the control group and seven in the allopurinol group&#46; These were eight cases of congestive heart failure&#44; seven ischemic coronary events&#44; five strokes&#44; one peripheral arterial disease&#44; and one arrhythmia&#46; Kaplan&#8211;Meier survival analysis showed that patients in the allopurinol group had lower cardiovascular risk than those in the control group &#40;log rank&#58; 4&#46;24&#59; p&#61;0&#46;039&#41;&#46; Diabetes &#40;p&#61;0&#46;004&#41;&#44; elevated C-reactive protein &#40;p&#61;0&#46;031&#41; and previous coronary disease &#40;p&#61;0&#46;005&#41; increased the risk&#46; Allopurinol treatment decreased the risk of cardiovascular events by 71&#37; &#40;p&#61;0&#46;026&#41;&#46; Twenty-two patients from the control group and 12 from the allopurinol group were hospitalized &#40;p&#61;0&#46;032&#41;&#46; Allopurinol treatment reduced the risk of hospitalization by 62&#37; in a Cox regression model that included age&#44; glomerular filtration rate&#44; presence of diabetes&#44; and coronary disease &#40;hazard ratio 0&#46;378 &#91;0&#46;154&#8211;0&#46;927&#93;&#59; p&#61;0&#46;033&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Level of evidence B was attributed since this was a clinical trial with a sizable sample &#40;113 patients&#41;&#44; not double-blinded&#44; with an adequate follow-up period and a dropout rate of 13&#37; &#40;six in the treatment group and nine in the control group&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Cohort studies &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Struthers et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a> performed a cohort study of 1760 patients with chronic heart failure &#40;HF&#41; divided into four groups&#58; &#40;1&#41; those who had never received allopurinol&#59; &#40;2&#41; recent &#40;&#60;4 years&#41; low dose allopurinol group &#40;&#60;299 mg&#41;&#59; &#40;3&#41; longstanding &#40;&#8805;4 years&#41; low dose allopurinol group&#59; &#40;4&#41; longstanding high dose allopurinol group &#40;&#8805;300 mg&#41;&#46; The study endpoints were all-cause mortality&#44; cardiovascular mortality&#44; and emergency cardiovascular hospitalization&#46; Longstanding high dose allopurinol group mortality &#40;relative risk &#91;RR&#93; 0&#46;59&#44; 95&#37; confidence interval &#91;CI&#93; 0&#46;37&#8211;0&#46;95&#41; and hospitalizations for cardiovascular disease were reduced&#44; while mortality was higher in the longstanding low dose allopurinol group &#40;RR 2&#46;04&#44; 95&#37; CI 1&#46;48&#8211;2&#46;81&#41;&#46; This study was attributed level of evidence B&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">The 2011 cohort study by Wei et al&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a> assessed the impact of allopurinol treatment on cardiovascular events and all-cause mortality outcomes in patients aged &#8805;60 years who were followed for at least five years up to December 2007&#46; The study endpoints were nonfatal myocardial infarction &#40;MI&#41;&#44; nonfatal stroke and cardiovascular and all-cause mortality&#46; There were 7135 study subjects&#44; of whom 14&#46;5&#37; &#40;n&#61;1035&#41; were taking allopurinol and 6042 &#40;84&#46;7&#37;&#41; were not under urate-lowering therapy&#46; Patients taking allopurinol were divided into three groups&#58; low-dose &#40;100 mg&#47;day&#41;&#44; 200 mg&#47;day and high-dose &#40;&#8805;300 mg&#47;day&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">No significant difference was observed in the rate of cardiovascular events between patients treated with allopurinol and those not receiving urate-lowering therapy and with UA &#8805;6 mg&#47;dl &#40;adjusted hazard ratio &#91;HR&#93; 1&#46;07&#44; 95&#37; CI 0&#46;89&#8211;1&#46;28&#41;&#44; while in the high-dose allopurinol group&#44; cardiovascular events and all-cause mortality were reduced with higher doses &#40;&#8805;300 mg&#47;day&#41; compared to the low-dose group &#40;100 mg&#47;day&#41; &#40;adjusted HR 0&#46;75&#59; 95&#37; CI 0&#46;59&#8211;0&#46;94&#41;&#46; This effect was not influenced by UA levels&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The results of the study show that high-dose allopurinol reduces cardiovascular events and all-cause mortality irrespective of the level of CV risk&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The main strengths of the study are that it was a population-based cohort study with a large sample size and the fact that possible confounding factors such as comorbidities and concomitant drug treatment were taken into account&#46; Compliance with medication was monitored through dispensed prescribing data&#44; the follow-up was long with a low estimated loss to follow-up&#44; and the outcomes were patient-oriented&#46; The main limitations were that the investigators did not confirm whether participants actually took the medication prescribed&#44; and that there may have been changes in allopurinol dosage after UA measurement&#44; which was only performed once&#46; The study was therefore attributed level of evidence B&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The aim of the 2009 cohort study by Wei et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">9</span></a> was to explore the long-term effect of allopurinol on mortality and cardiovascular hospitalizations in HF patients&#46; The study outcomes were all-cause mortality&#44; cardiovascular mortality and cardiovascular disease recurrence &#40;hospitalization with a primary diagnosis of angina&#44; MI&#44; HF&#44; stroke or transient ischemic attack&#41;&#46; Patients were divided into three groups according to allopurinol exposure during the study period&#58; non-users&#44; prevalent users &#40;who had at least one prescription of allopurinol during the screening period&#41;&#44; and incident users &#40;who did not receive any allopurinol prescriptions during the screening period but received at least one prescription of allopurinol after the screening period&#46; Allopurinol users were further divided&#58; prevalent users according to cumulative dosage during the screening period&#58; low-dose group &#40;&#60;18<span class="elsevierStyleHsp" style=""></span>400 mg&#41;&#44; medium-dose group &#40;18<span class="elsevierStyleHsp" style=""></span>400&#8211;44<span class="elsevierStyleHsp" style=""></span>800 mg&#41; and high-dose group &#40;&#62;44<span class="elsevierStyleHsp" style=""></span>800 mg&#41;&#44; and incident users as high and low-dose exposure based on the dose of the first prescription &#40;&#60;299 mg&#47;day or &#8805;300 mg&#47;day&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">A total of 4785 HF patients &#40;4260 non-users&#44; 267 incident users and 258 prevalent users&#41; were studied between 1993 and 2002&#46; Median follow-up was 4&#46;8 years&#46; Multivariate analysis adjusted for social deprivation&#44; medication and comorbidities was performed&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In patients receiving low-dose allopurinol in the incident group&#44; there was an increase in risk of all-cause mortality &#40;adjusted HR 1&#46;6&#59; 95&#37; CI&#44; 1&#46;26&#8211;2&#46;03&#41;&#59; cardiovascular mortality &#40;adjusted HR 1&#46;70&#59; 95&#37; CI&#44; 1&#46;29&#8211;2&#46;23&#41; and cardiovascular recurrence &#40;adjusted HR 1&#46;44&#44; 95&#37; CI&#44; 1&#46;01&#8211;2&#46;07&#41; compared with non-users&#46; These results may be explained by the fact that subjects who are prescribed allopurinol have high UA&#44; which is a risk factor for cardiovascular disease&#46; High-dose allopurinol use was associated with a lower risk of all-cause mortality compared with low-dose allopurinol use &#40;adjusted HR 0&#46;65&#44; 95&#37; CI 0&#46;42&#8211;0&#46;99&#41;&#46; This may be due to the effect of allopurinol on endothelial function&#44; the benefits showing a steep dose-response curve&#46; However&#44; high dose did not significantly reduce risk for cardiovascular recurrence and cardiovascular mortality compared to low dose in the prevalent users group &#40;adjusted HR 0&#46;93&#44; 95&#37; CI 0&#46;56&#8211;1&#46;53 and adjusted HR 0&#46;64&#44; 95&#37; CI 0&#46;39&#8211;1&#46;04&#44; respectively&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">This study was classified as level of evidence B&#46; It was a population-based cohort study with a large sample size and some possible confounding factors such as comorbidities were taken into account&#46; Compliance with medication was monitored through dispensed prescribing&#44; the follow-up period was long with complete follow-up&#44; and the outcomes were patient-oriented&#46; However&#44; there was no information on other prescribed medication&#44; particularly losartan&#44; or on UA levels&#46; Furthermore&#44; the diagnosis of renal disease was made on the basis of creatinine level only&#44; the investigators did not confirm whether participants actually took the allopurinol prescribed&#44; and the two groups of allopurinol users were only similar in terms of comorbidities&#46; There was inconsistency in the methods used to estimate the level of exposure to allopurinol&#44; and when calculating risks&#44; high and low doses were considered&#44; with no data being presented on medium-dose users in the prevalent use group&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Case-control study &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;</span><p id="par0110" class="elsevierStylePara elsevierViewall">Thanassoulis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">10</span></a> carried out a case-control study in 25<span class="elsevierStyleHsp" style=""></span>090 patients with HF aged &#8805;66 years&#46; The primary outcome of a composite measure of HF readmission &#40;52&#46;9&#37;&#41; and all-cause mortality &#40;47&#46;1&#37;&#41; was experienced by 14<span class="elsevierStyleHsp" style=""></span>327 cases&#46; The control group was selected randomly to up to 10 controls for each case&#46; Allopurinol use was divided into two durations of current use&#58; new users &#40;&#8804;30 continuous days&#41; and continuous users &#40;&#62;30 continuous days&#41; and exposure was also dichotomized by daily dose &#40;&#8804;100 mg&#47;d and &#62;100 mg&#47;d&#41;&#46; Previous allopurinol users were considered unexposed&#44; since the physiologic effect of allopurinol is relatively short after drug cessation&#46; A remote history of gout was defined as a diagnosis of gout in the last five years&#44; and acute gout as a primary diagnosis of gout within 60 days of the event date&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">There was no statistically significant association between allopurinol use and HF readmissions or death &#40;adjusted rate ratio 1&#46;02&#59; 95&#37; CI&#44; 0&#46;95&#8211;1&#46;10&#44; p&#61;0&#46;55&#41;&#44; but allopurinol was associated with reduced HF readmissions or death &#40;adjusted rate ratio 0&#46;69&#59; 95&#37; CI&#44; 0&#46;60&#8211;0&#46;79&#44; p&#60;0&#46;001&#41; among patients with a history of gout&#46; No significant differences in effect were detected among men and women treated with allopurinol&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">As this was a case-control study&#44; it was attributed level of evidence B&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0125" class="elsevierStylePara elsevierViewall">According to the best and most recent evidence available&#44; prolonged treatment with high doses of allopurinol may be associated with reduced cardiovascular morbidity and mortality in at-risk populations &#40;class of recommendation IIa&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">This conclusion is supported by the fact that in all the selected studies performed in at-risk patients &#40;Goicoechea et al&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a> on patients with chronic renal disease&#44; Wei et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">9</span></a> and Struthers et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a> in patients with HF&#44; and Thanassoulis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">10</span></a> in patients with HF and gout&#41;&#44; cardiovascular outcomes were reduced by high-dose rather than low-dose allopurinol&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">It should be borne in mind that these studies differ in their methodology&#44; with bias arising from UA measurements&#44; lack of data on patients&#8217; lifestyles &#40;particularly alcohol consumption&#41; and body mass index&#44; selection bias &#40;with heterogeneity in terms of age and comorbidities&#41;&#44; and differing dosages&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">According to the European Society of Cardiology &#40;ESC&#41; 2012 guidelines on diagnosis and treatment of heart failure&#44; hyperuricemia and gout are common in HF and may be caused or aggravated by diuretic treatment&#46; Hyperuricemia is associated with a worse prognosis in HF with reduced ejection fraction&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">11</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Previous evidence has suggested that high-dose allopurinol may be associated with reduced risk of mortality and cardiovascular events through its pathophysiological pathway&#44; since higher doses of allopurinol are associated with improvement in endothelial function and may also improve cardiac structure&#46; These two mechanisms are noteworthy because both endothelial function and cardiac function are independent predictors of mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">10</span></a> According to the 2013 ESC guidelines on the management of stable coronary artery disease&#44; allopurinol has anti-anginal properties&#59; in a randomized crossover study of 65 patients with stable angina&#44; allopurinol 600 mg&#47;day increased times to ST-segment depression and to chest pain&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">12</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Although side effects of allopurinol treatment are beyond the scope of this article&#44; none were reported in the selected studies&#46; However&#44; serious side-effects do occur&#44; particularly Stevens-Johnson syndrome&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Patients with CRF develop hyperuricemia as glomerular filtration rate falls&#46; In Goicoechea et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a> progression of CRF was slower in patients under allopurinol treatment&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Treatment of asymptomatic hyperuricemia is still the subject of debate&#59; the risks and benefits should be carefully assessed before beginning urate-lowering therapy&#46; Methodologically rigorous research is required&#44; with greater statistical power and adjustment for confounding factors&#44; to assess the effect of therapy with allopurinol in reducing fatal and non-fatal cardiovascular events in patients with and without risk&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Ethical disclosures</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Protection of human and animal subjects</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Confidentiality of data</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Right to privacy and informed consent</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article&#46; The corresponding author is in possession of this document&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflicts of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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            1 => "Cardiovascular diseases"
            2 => "Allopurinol"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">High levels of uric acid &#40;UA&#41; have been associated with cardiovascular &#40;CV&#41; disease&#44; but its role as an independent risk factor is the subject of debate&#46; Treating hyperuricemia may be useful in reducing CV risk&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To review the evidence on the effect of treatment with allopurinol in patients with hyperuricemia on reducing CV events&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We searched medical databases for randomized controlled trials &#40;RCT&#41;&#44; cohort studies &#40;CS&#41; and case-control studies &#40;CCS&#41;&#44; meta-analyses&#44; systematic reviews and guidelines&#44; published between January 2002 and December 2013 in Portuguese and English&#46; Level of evidence &#40;LE&#41; and strength of recommendation were graded according to the definitions used by the European Society of Cardiology&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Out of 46 articles&#44; one RCT&#44; three CS and one CCS were included&#46; In the RCT&#44; treatment with allopurinol decreased CV events in patients with moderate chronic renal failure by 71&#37; compared to controls &#40;LE B&#41;&#46; In one CS&#44; patients treated with high doses had a greater reduction in CV events compared to low doses &#40;LE B&#41;&#46; The other two CS&#44; in patients with heart failure &#40;HF&#41;&#44; found similar benefits in patients treated with high doses of allopurinol &#40;LE B&#41;&#46; In the CCS&#44; in patients with HF and a history of gout&#44; treatment with allopurinol reduced HF admission and all-cause mortality &#40;LE B&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0030">Discussion and Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Prolonged treatment with high doses of allopurinol may be associated with a reduction in morbidity and mortality in high CV risk populations &#40;class of recommendation IIa&#41;&#46; More studies evaluating the effect of therapy with allopurinol in reducing CV events in patients with and without risk are needed&#46;</p>"
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        "titulo" => "Resumo"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0040">Introdu&#231;&#227;o</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">N&#237;veis elevados de &#225;cido &#250;rico &#40;AU&#41; t&#234;m sido associados a doen&#231;a cardiovascular &#40;<span class="elsevierStyleSmallCaps">CV</span>&#41;&#44; mas o papel deste como fator de risco independente &#233; controverso&#46; O tratamento da hiperuricemia pode ser relevante na abordagem do risco CV&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Objetivo</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Rever a evid&#234;ncia do tratamento com alopurinol&#44; em doentes com hiperuricemia&#44; na redu&#231;&#227;o de eventos cardiovasculares&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Metodologia</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Pesquisa de ensaios cl&#237;nicos controlados aleatorizados &#40;ECA&#41;&#44; estudos coorte &#40;EC&#41; e caso-controlo &#40;CC&#41;&#44; meta-an&#225;lises&#44; revis&#245;es sistem&#225;ticas e normas de orienta&#231;&#227;o&#44; publicados entre janeiro&#47;2002 e dezembro&#47;2013&#44; em bases de dados cient&#237;ficas&#46; O n&#237;vel de evid&#234;ncia e a for&#231;a de recomenda&#231;&#227;o foram atribu&#237;dos de acordo com escalas pr&#233;-definidas pela Sociedade Europeia de Cardiologia&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">De 46 artigos foram inclu&#237;dos um ECA&#44; tr&#234;s EC e um CC&#46; No ECA o tratamento com alopurinol <span class="elsevierStyleItalic">versus</span> grupo controlo diminuiu em 71&#37; os eventos cardiovasculares em doentes com insufici&#234;ncia renal cr&#243;nica moderada &#40;LE B&#41;&#46; Num dos EC&#44; doentes tratados com doses altas tiveram uma redu&#231;&#227;o mais significativa do risco de eventos CV &#40;LE B&#41;&#46; Os outros dois EC realizados em doentes com insufici&#234;ncia card&#237;aca &#40;IC&#41; verificaram benef&#237;cios id&#234;nticos em doentes tratados com doses elevadas de alopurinol &#40;LE B&#41;&#46; No estudo CC&#44; em doentes com IC e hist&#243;ria de gota o tratamento com alopurinol reduziu internamentos&#47;mortalidade por IC &#40;LE B&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0060">Discuss&#227;o</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">O tratamento prolongado com doses elevadas de alopurinol pode estar associado a uma redu&#231;&#227;o da morbimortalidade CV em popula&#231;&#245;es de risco &#40;Classe de Recomenda&#231;&#227;o IIa&#41;&#46; S&#227;o necess&#225;rios mais estudos que avaliem os efeitos da terap&#234;utica com alopurinol na diminui&#231;&#227;o de eventos CV em doentes sem risco&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Guedes M&#44; Esperan&#231;a A&#44; Pereira AC&#44; Rego C&#46; Qual o efeito da redu&#231;&#227;o da hiperuricemia nos eventos cardiovasculares&#63; Revis&#227;o baseada na evid&#234;ncia&#46; Rev Port Cardiol&#46; 2014&#59;33&#58;727&#8211;732&#46;</p>"
      ]
    ]
    "multimedia" => array:3 [
      0 => array:7 [
        "identificador" => "tbl0005"
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        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">CV&#58; cardiovascular&#59; GFR&#58; glomerular filtration rate&#59; LE&#58; level of evidence&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aims and methods&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Goicoechea et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">To study the effect of allopurinol treatment on renal disease progression&#44; CV events and hospitalization for any cause113 patients with GFR &#60;60 ml&#47;minAllopurinol 100 mg&#47;day &#40;n&#61;57&#41; vs&#46; control &#40;n&#61;56&#41;Outcomes&#58; hospitalizations&#44; CV events&#44; end-stage renal disease requiring dialysis therapy&#44; mortalityDuration&#58; 24 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">86&#46;7&#37; completed the trial &#40;51 vs&#46; 47&#41;Allopurinol treatment reduced CV events by 71&#37; and hospitalizations by 62&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab600499.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Randomized controlled trial&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">CV&#58; cardiovascular&#59; HF&#58; heart failure&#59; LE&#58; level of evidence&#59; MI&#58; myocardial infarction&#59; UA&#58; uric acid&#59; y&#58; years&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Aims and methods&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">LE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Struthers et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">To examine whether different doses of allopurinol are associated with any alteration in CV and all-cause mortality and CV hospitalizations1760 patients with chronic HFFour groups&#58; &#40;1&#41; those who had never received allopurinol&#59; &#40;2&#41; recent &#40;&#60;4 years&#41; low dose allopurinol group &#40;&#60;299 mg&#41;&#59; &#40;3&#41; longstanding &#40;&#8805;4 years&#41; low dose allopurinol group&#59; &#40;4&#41; longstanding high dose allopurinol group &#40;&#8805;300 mg&#41;&#46;Outcomes&#58; all-cause and CV mortality and CV hospitalizationDuration&#58; 4 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Possible reduction in CV mortality only with high-dose allopurinolLow-dose allopurinol may be insufficient to treat hyperuricemia and was associated with increased mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Wei et al&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">To study the impact of allopurinol treatment on cardiovascular events and all-cause mortality7135 patients aged &#8805;60 yearsAllopurinol &#40;n&#61;1035&#41; vs&#46; no treatment &#40;n&#61;6042&#41;Allopurinol 100 mg &#40;low dose&#41; vs&#46; 200 mg vs&#46; &#8805;300 mg &#40;high dose&#41;Follow-up&#58; 5&#8211;8 yearsOutcomes&#58; non-fatal stroke and MI&#44; CV and all-cause mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No difference in CV events between allopurinol and no treatmentNo difference in CV events between allopurinol and no treatment with UA &#8805;6 mg&#47;dlIncreased CV risk in the non-treatment group with increased UA levelReduced CV risk in the allopurinol group independent of UA level and dependent on allopurinol doseSignificant reduction in CV events and all-cause mortality in the high-dose vs&#46; low-dose allopurinol groups&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Wei et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">9</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">To assess whether allopurinol affects mortality and CV hospitalizations in patients with HF4785 HF patientsAllopurinol group&#58;Prevalent users &#40;prescribed in 1st 180 days after discharge&#44; n&#61;258&#41;&#58; cumulative low dose &#60;18<span class="elsevierStyleHsp" style=""></span>400 mg&#44; medium dose &#40;18<span class="elsevierStyleHsp" style=""></span>400&#8211;44<span class="elsevierStyleHsp" style=""></span>800 mg&#41; and high-dose &#40;&#62;44<span class="elsevierStyleHsp" style=""></span>800 mg&#41;Incident users &#40;prescribed &#8805;180 days after discharge&#44; n&#61;267&#41;&#58; &#60;299 mg&#47;day &#40;low dose&#41; vs&#46; &#8805;300 mg&#47;day &#40;high dose&#41;Non-treatment group &#40;n&#61;4260&#41;Median follow-up&#58; non-treatment 4&#46;9 y&#59; incident 5 y&#44; prevalent 3&#46;1 yOutcomes&#58; all-cause mortality&#44; CV mortality&#44; CV recurrence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alopurinol <span class="elsevierStyleItalic">vs</span>&#46; treatmentLow dose&#58;&#8211; incident group&#58; increased all-cause and CV mortality and CV recurrence&#8211; prevalent group&#58; increased CV mortalityHigh dose&#58; no effect on CV riskHigh dose&#58; no effect on CV riskHigh vs&#46; low dose&#58;&#8211; prevalent group&#58; reduced all-cause mortality&#8211; prevalent vs&#46; incident groups&#58; no difference in effect on CV risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab600500.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Cohort studies&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">HF&#58; heart failure&#59; LE&#58; level of evidence&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aims and methods&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thanassoulis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">To determine whether gout and allopurinol use are associated with HF outcomesCases &#40;n&#61;14<span class="elsevierStyleHsp" style=""></span>327&#41;&#58;HF readmission &#40;52&#46;9&#37;&#41;All-cause mortality &#40;47&#46;1&#37;&#41;Controls &#40;n&#61;143<span class="elsevierStyleHsp" style=""></span>225&#41;Exposure&#58;Allopurinol&#58; Duration of use &#8804;30 days&#44; &#62;30 daysDose &#8804;100 mg&#47;day&#44; &#62;100 mg&#47;dayGout&#58; remote &#60;5 years&#44; acute &#60;60 daysOutcomes<span class="elsevierStyleItalic">&#58;</span> HF readmission and all-cause mortalityDuration&#58; median 2&#46;1 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No association between allopurinol use and outcomesAllopurinol treatment in patients with a history of gout reduced HF readmissions and mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab600501.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Case-control study&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:12 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Asymptomatic hyperuricemia&#46; Literature review current through"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M&#46;A&#46; Becker"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:1 [
                        "fecha" => "2012"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Asymptomatic hyperuricemia&#58; to treat or not to treat"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46;E&#46; Dincer"
                            1 => "P&#46;D&#46; Dincer"
                            2 => "D&#46;J&#46; Levinson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Cleve Clin J Med"
                        "fecha" => "2002"
                        "volumen" => "69"
                        "paginaInicial" => "594"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12184468"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Uric acid balance&#46; Literature review current through"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M&#46;A&#46; Becker"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:1 [
                        "fecha" => "2012"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
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Evidenced-Based Cardiology
What is the effect on cardiovascular events of reducing hyperuricemia with allopurinol? An evidence-based review
Qual o efeito da redução da hiperuricemia nos eventos cardiovasculares? Revisão baseada na evidência
Marta Guedesa,
Corresponding author
martasguedes@gmail.com

Corresponding author.
, Ana Esperançaa, Ana Cristina Pereirab, Catarina Regoa
a Unidade de Saúde Familiar Nova Via, ACeS Espinho/Gaia, Valadares, Portugal
b Unidade de Saúde Familiar Amorosa XXI, ACeS Alto Ave Guimarães/Vizela/Terras de Basto, Guimarães, Portugal
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        "titulo" => "Qual o efeito da redu&#231;&#227;o da hiperuricemia nos eventos cardiovasculares&#63; Revis&#227;o baseada na evid&#234;ncia"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Based upon the solubility limit of urate in body fluids&#44; hyperuricemia is defined as uric acid &#40;UA&#41; concentrations exceeding 7 mg&#47;dl &#40;416 &#956;mol&#47;l&#41;&#44; as measured by automated enzymatic methods&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">UA is produced in the liver and is the final product of purine metabolism&#46; Since most UA is the result of this process&#44; diet is a significant source of UA precursors&#46; The catabolic steps that generate UA from free nucleic acids and purine nucleotides include degradation of the intermediates hypoxanthine and xanthine&#44; the latter being oxidized to UA in successive reactions catalyzed by xanthine oxidase&#46; Humans have a very limited ability to metabolize UA&#44; which must be eliminated via the intestines and kidneys to maintain homeostasis&#46; Intestinal bacteria degrade a third and the kidneys excrete the remainder&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Around 10&#37; of the population will have documented hyperuricemia at least once in their lives&#46; Most such episodes do not require further investigation or treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However&#44; hyperuricemia is associated with gout&#44; hypertension&#44; diabetes&#44; chronic renal failure &#40;CRF&#41; &#40;uric acid nephropathy&#41; and urolithiasis&#44; as well as with increased risk for cardiovascular disease&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The role of hyperuricemia as a risk factor is the subject of debate&#44; as to whether it contributes independently to the pathophysiology of cardiovascular disease or is an epiphenomenon resulting from concomitant conditions such as hypertension&#44; renal disease or metabolic syndrome&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The treatment of choice for hyperuricemia is allopurinol&#44; which reduces the formation of UA by inhibiting xanthine oxidase and improves endothelial function&#46; The latter is an early manifestation of vascular injury and contributes to the development of atherosclerosis&#46; Cardiovascular disease remains the leading cause of death in Portugal&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and so treating hyperuricemia could play an important role in reducing cardiovascular risk&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The aim of this study is to review the evidence on the effect of treatment with allopurinol in patients with hyperuricemia on reducing cardiovascular events&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">MEDLINE&#44; the Cochrane Library&#44; Bandolier&#44; DARE&#44; CMA Infobase&#44; National Guideline Clearinghouse&#44; and NHS Evidence were searched using the MeSH terms &#8220;uric acid&#8221;&#44; &#8220;cardiovascular diseases&#8221; and &#8220;allopurinol&#8221;&#46; The search was limited to guidelines&#44; meta-analyses&#44; systematic reviews&#44; randomized controlled trials &#40;RCT&#41;&#44; cohort studies &#40;CS&#41; and case-control studies &#40;CCS&#41; published between January 2002 and December 2013 in Portuguese and English&#46; Related articles were also considered&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">We included studies on adults with hyperuricemia treated with allopurinol at different doses compared with placebo&#44; analyzing reduction of fatal and non-fatal cardiovascular outcomes and all-cause mortality&#46; Repeated articles and those that did not meet the inclusion criteria &#40;studies of transplanted patients&#44; cancer patients under chemotherapy and&#47;or radiotherapy&#44; and those with congenital heart disease&#41; were excluded&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Level of evidence and strength of recommendation were graded according to the definitions used by the European Society of Cardiology&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><p id="par0045" class="elsevierStylePara elsevierViewall">Of the 46 articles found&#44; 41 were excluded on the grounds of repetition or failure to fulfill the inclusion criteria&#46; Five publications were thus selected&#58; one RCT&#44; three CS and one CCS&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Randomized controlled trial</span><p id="par0050" class="elsevierStylePara elsevierViewall">In the RCT by Goicoechea et al&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; after 24 months of treatment with 100 mg allopurinol serum UA levels fell from 7&#46;8&#177;2&#46;1 mg&#47;dl to 6&#46;0&#177;1&#46;2 mg&#47;dl &#40;p&#61;0&#46;001&#41; but remained stable in the control group &#40;7&#46;3&#177;1&#46;6 mg&#47;dl at baseline and 7&#46;5&#177;1&#46;7 mg&#47;dl at 24 months&#41; &#40;p&#61;0&#46;016 between groups and time period&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">After a mean follow-up of 23&#46;4&#177;7&#46;8 months&#44; 22 patients had suffered a cardiovascular event&#58; 15 in the control group and seven in the allopurinol group&#46; These were eight cases of congestive heart failure&#44; seven ischemic coronary events&#44; five strokes&#44; one peripheral arterial disease&#44; and one arrhythmia&#46; Kaplan&#8211;Meier survival analysis showed that patients in the allopurinol group had lower cardiovascular risk than those in the control group &#40;log rank&#58; 4&#46;24&#59; p&#61;0&#46;039&#41;&#46; Diabetes &#40;p&#61;0&#46;004&#41;&#44; elevated C-reactive protein &#40;p&#61;0&#46;031&#41; and previous coronary disease &#40;p&#61;0&#46;005&#41; increased the risk&#46; Allopurinol treatment decreased the risk of cardiovascular events by 71&#37; &#40;p&#61;0&#46;026&#41;&#46; Twenty-two patients from the control group and 12 from the allopurinol group were hospitalized &#40;p&#61;0&#46;032&#41;&#46; Allopurinol treatment reduced the risk of hospitalization by 62&#37; in a Cox regression model that included age&#44; glomerular filtration rate&#44; presence of diabetes&#44; and coronary disease &#40;hazard ratio 0&#46;378 &#91;0&#46;154&#8211;0&#46;927&#93;&#59; p&#61;0&#46;033&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Level of evidence B was attributed since this was a clinical trial with a sizable sample &#40;113 patients&#41;&#44; not double-blinded&#44; with an adequate follow-up period and a dropout rate of 13&#37; &#40;six in the treatment group and nine in the control group&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Cohort studies &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Struthers et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a> performed a cohort study of 1760 patients with chronic heart failure &#40;HF&#41; divided into four groups&#58; &#40;1&#41; those who had never received allopurinol&#59; &#40;2&#41; recent &#40;&#60;4 years&#41; low dose allopurinol group &#40;&#60;299 mg&#41;&#59; &#40;3&#41; longstanding &#40;&#8805;4 years&#41; low dose allopurinol group&#59; &#40;4&#41; longstanding high dose allopurinol group &#40;&#8805;300 mg&#41;&#46; The study endpoints were all-cause mortality&#44; cardiovascular mortality&#44; and emergency cardiovascular hospitalization&#46; Longstanding high dose allopurinol group mortality &#40;relative risk &#91;RR&#93; 0&#46;59&#44; 95&#37; confidence interval &#91;CI&#93; 0&#46;37&#8211;0&#46;95&#41; and hospitalizations for cardiovascular disease were reduced&#44; while mortality was higher in the longstanding low dose allopurinol group &#40;RR 2&#46;04&#44; 95&#37; CI 1&#46;48&#8211;2&#46;81&#41;&#46; This study was attributed level of evidence B&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">The 2011 cohort study by Wei et al&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a> assessed the impact of allopurinol treatment on cardiovascular events and all-cause mortality outcomes in patients aged &#8805;60 years who were followed for at least five years up to December 2007&#46; The study endpoints were nonfatal myocardial infarction &#40;MI&#41;&#44; nonfatal stroke and cardiovascular and all-cause mortality&#46; There were 7135 study subjects&#44; of whom 14&#46;5&#37; &#40;n&#61;1035&#41; were taking allopurinol and 6042 &#40;84&#46;7&#37;&#41; were not under urate-lowering therapy&#46; Patients taking allopurinol were divided into three groups&#58; low-dose &#40;100 mg&#47;day&#41;&#44; 200 mg&#47;day and high-dose &#40;&#8805;300 mg&#47;day&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">No significant difference was observed in the rate of cardiovascular events between patients treated with allopurinol and those not receiving urate-lowering therapy and with UA &#8805;6 mg&#47;dl &#40;adjusted hazard ratio &#91;HR&#93; 1&#46;07&#44; 95&#37; CI 0&#46;89&#8211;1&#46;28&#41;&#44; while in the high-dose allopurinol group&#44; cardiovascular events and all-cause mortality were reduced with higher doses &#40;&#8805;300 mg&#47;day&#41; compared to the low-dose group &#40;100 mg&#47;day&#41; &#40;adjusted HR 0&#46;75&#59; 95&#37; CI 0&#46;59&#8211;0&#46;94&#41;&#46; This effect was not influenced by UA levels&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The results of the study show that high-dose allopurinol reduces cardiovascular events and all-cause mortality irrespective of the level of CV risk&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The main strengths of the study are that it was a population-based cohort study with a large sample size and the fact that possible confounding factors such as comorbidities and concomitant drug treatment were taken into account&#46; Compliance with medication was monitored through dispensed prescribing data&#44; the follow-up was long with a low estimated loss to follow-up&#44; and the outcomes were patient-oriented&#46; The main limitations were that the investigators did not confirm whether participants actually took the medication prescribed&#44; and that there may have been changes in allopurinol dosage after UA measurement&#44; which was only performed once&#46; The study was therefore attributed level of evidence B&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The aim of the 2009 cohort study by Wei et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">9</span></a> was to explore the long-term effect of allopurinol on mortality and cardiovascular hospitalizations in HF patients&#46; The study outcomes were all-cause mortality&#44; cardiovascular mortality and cardiovascular disease recurrence &#40;hospitalization with a primary diagnosis of angina&#44; MI&#44; HF&#44; stroke or transient ischemic attack&#41;&#46; Patients were divided into three groups according to allopurinol exposure during the study period&#58; non-users&#44; prevalent users &#40;who had at least one prescription of allopurinol during the screening period&#41;&#44; and incident users &#40;who did not receive any allopurinol prescriptions during the screening period but received at least one prescription of allopurinol after the screening period&#46; Allopurinol users were further divided&#58; prevalent users according to cumulative dosage during the screening period&#58; low-dose group &#40;&#60;18<span class="elsevierStyleHsp" style=""></span>400 mg&#41;&#44; medium-dose group &#40;18<span class="elsevierStyleHsp" style=""></span>400&#8211;44<span class="elsevierStyleHsp" style=""></span>800 mg&#41; and high-dose group &#40;&#62;44<span class="elsevierStyleHsp" style=""></span>800 mg&#41;&#44; and incident users as high and low-dose exposure based on the dose of the first prescription &#40;&#60;299 mg&#47;day or &#8805;300 mg&#47;day&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">A total of 4785 HF patients &#40;4260 non-users&#44; 267 incident users and 258 prevalent users&#41; were studied between 1993 and 2002&#46; Median follow-up was 4&#46;8 years&#46; Multivariate analysis adjusted for social deprivation&#44; medication and comorbidities was performed&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In patients receiving low-dose allopurinol in the incident group&#44; there was an increase in risk of all-cause mortality &#40;adjusted HR 1&#46;6&#59; 95&#37; CI&#44; 1&#46;26&#8211;2&#46;03&#41;&#59; cardiovascular mortality &#40;adjusted HR 1&#46;70&#59; 95&#37; CI&#44; 1&#46;29&#8211;2&#46;23&#41; and cardiovascular recurrence &#40;adjusted HR 1&#46;44&#44; 95&#37; CI&#44; 1&#46;01&#8211;2&#46;07&#41; compared with non-users&#46; These results may be explained by the fact that subjects who are prescribed allopurinol have high UA&#44; which is a risk factor for cardiovascular disease&#46; High-dose allopurinol use was associated with a lower risk of all-cause mortality compared with low-dose allopurinol use &#40;adjusted HR 0&#46;65&#44; 95&#37; CI 0&#46;42&#8211;0&#46;99&#41;&#46; This may be due to the effect of allopurinol on endothelial function&#44; the benefits showing a steep dose-response curve&#46; However&#44; high dose did not significantly reduce risk for cardiovascular recurrence and cardiovascular mortality compared to low dose in the prevalent users group &#40;adjusted HR 0&#46;93&#44; 95&#37; CI 0&#46;56&#8211;1&#46;53 and adjusted HR 0&#46;64&#44; 95&#37; CI 0&#46;39&#8211;1&#46;04&#44; respectively&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">This study was classified as level of evidence B&#46; It was a population-based cohort study with a large sample size and some possible confounding factors such as comorbidities were taken into account&#46; Compliance with medication was monitored through dispensed prescribing&#44; the follow-up period was long with complete follow-up&#44; and the outcomes were patient-oriented&#46; However&#44; there was no information on other prescribed medication&#44; particularly losartan&#44; or on UA levels&#46; Furthermore&#44; the diagnosis of renal disease was made on the basis of creatinine level only&#44; the investigators did not confirm whether participants actually took the allopurinol prescribed&#44; and the two groups of allopurinol users were only similar in terms of comorbidities&#46; There was inconsistency in the methods used to estimate the level of exposure to allopurinol&#44; and when calculating risks&#44; high and low doses were considered&#44; with no data being presented on medium-dose users in the prevalent use group&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Case-control study &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;</span><p id="par0110" class="elsevierStylePara elsevierViewall">Thanassoulis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">10</span></a> carried out a case-control study in 25<span class="elsevierStyleHsp" style=""></span>090 patients with HF aged &#8805;66 years&#46; The primary outcome of a composite measure of HF readmission &#40;52&#46;9&#37;&#41; and all-cause mortality &#40;47&#46;1&#37;&#41; was experienced by 14<span class="elsevierStyleHsp" style=""></span>327 cases&#46; The control group was selected randomly to up to 10 controls for each case&#46; Allopurinol use was divided into two durations of current use&#58; new users &#40;&#8804;30 continuous days&#41; and continuous users &#40;&#62;30 continuous days&#41; and exposure was also dichotomized by daily dose &#40;&#8804;100 mg&#47;d and &#62;100 mg&#47;d&#41;&#46; Previous allopurinol users were considered unexposed&#44; since the physiologic effect of allopurinol is relatively short after drug cessation&#46; A remote history of gout was defined as a diagnosis of gout in the last five years&#44; and acute gout as a primary diagnosis of gout within 60 days of the event date&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">There was no statistically significant association between allopurinol use and HF readmissions or death &#40;adjusted rate ratio 1&#46;02&#59; 95&#37; CI&#44; 0&#46;95&#8211;1&#46;10&#44; p&#61;0&#46;55&#41;&#44; but allopurinol was associated with reduced HF readmissions or death &#40;adjusted rate ratio 0&#46;69&#59; 95&#37; CI&#44; 0&#46;60&#8211;0&#46;79&#44; p&#60;0&#46;001&#41; among patients with a history of gout&#46; No significant differences in effect were detected among men and women treated with allopurinol&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">As this was a case-control study&#44; it was attributed level of evidence B&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0125" class="elsevierStylePara elsevierViewall">According to the best and most recent evidence available&#44; prolonged treatment with high doses of allopurinol may be associated with reduced cardiovascular morbidity and mortality in at-risk populations &#40;class of recommendation IIa&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">This conclusion is supported by the fact that in all the selected studies performed in at-risk patients &#40;Goicoechea et al&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a> on patients with chronic renal disease&#44; Wei et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">9</span></a> and Struthers et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a> in patients with HF&#44; and Thanassoulis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">10</span></a> in patients with HF and gout&#41;&#44; cardiovascular outcomes were reduced by high-dose rather than low-dose allopurinol&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">It should be borne in mind that these studies differ in their methodology&#44; with bias arising from UA measurements&#44; lack of data on patients&#8217; lifestyles &#40;particularly alcohol consumption&#41; and body mass index&#44; selection bias &#40;with heterogeneity in terms of age and comorbidities&#41;&#44; and differing dosages&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">According to the European Society of Cardiology &#40;ESC&#41; 2012 guidelines on diagnosis and treatment of heart failure&#44; hyperuricemia and gout are common in HF and may be caused or aggravated by diuretic treatment&#46; Hyperuricemia is associated with a worse prognosis in HF with reduced ejection fraction&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">11</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Previous evidence has suggested that high-dose allopurinol may be associated with reduced risk of mortality and cardiovascular events through its pathophysiological pathway&#44; since higher doses of allopurinol are associated with improvement in endothelial function and may also improve cardiac structure&#46; These two mechanisms are noteworthy because both endothelial function and cardiac function are independent predictors of mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">10</span></a> According to the 2013 ESC guidelines on the management of stable coronary artery disease&#44; allopurinol has anti-anginal properties&#59; in a randomized crossover study of 65 patients with stable angina&#44; allopurinol 600 mg&#47;day increased times to ST-segment depression and to chest pain&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">12</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Although side effects of allopurinol treatment are beyond the scope of this article&#44; none were reported in the selected studies&#46; However&#44; serious side-effects do occur&#44; particularly Stevens-Johnson syndrome&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Patients with CRF develop hyperuricemia as glomerular filtration rate falls&#46; In Goicoechea et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a> progression of CRF was slower in patients under allopurinol treatment&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Treatment of asymptomatic hyperuricemia is still the subject of debate&#59; the risks and benefits should be carefully assessed before beginning urate-lowering therapy&#46; Methodologically rigorous research is required&#44; with greater statistical power and adjustment for confounding factors&#44; to assess the effect of therapy with allopurinol in reducing fatal and non-fatal cardiovascular events in patients with and without risk&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Ethical disclosures</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Protection of human and animal subjects</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Confidentiality of data</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Right to privacy and informed consent</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article&#46; The corresponding author is in possession of this document&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflicts of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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            4 => "Resultados"
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              "identificador" => "sec0020"
              "titulo" => "Randomized controlled trial"
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            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Cohort studies &#40;Table 2&#41;"
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              "titulo" => "Case-control study &#40;Table 3&#41;"
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              "titulo" => "Protection of human and animal subjects"
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              "titulo" => "Confidentiality of data"
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              "identificador" => "sec0055"
              "titulo" => "Right to privacy and informed consent"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2014-02-15"
    "fechaAceptado" => "2014-06-12"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec368081"
          "palabras" => array:3 [
            0 => "Uric acid"
            1 => "Cardiovascular diseases"
            2 => "Allopurinol"
          ]
        ]
      ]
      "pt" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palavras-chave"
          "identificador" => "xpalclavsec368080"
          "palabras" => array:3 [
            0 => "&#193;cido &#250;rico"
            1 => "Doen&#231;as cardiovasculares"
            2 => "Alopurinol"
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">High levels of uric acid &#40;UA&#41; have been associated with cardiovascular &#40;CV&#41; disease&#44; but its role as an independent risk factor is the subject of debate&#46; Treating hyperuricemia may be useful in reducing CV risk&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To review the evidence on the effect of treatment with allopurinol in patients with hyperuricemia on reducing CV events&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We searched medical databases for randomized controlled trials &#40;RCT&#41;&#44; cohort studies &#40;CS&#41; and case-control studies &#40;CCS&#41;&#44; meta-analyses&#44; systematic reviews and guidelines&#44; published between January 2002 and December 2013 in Portuguese and English&#46; Level of evidence &#40;LE&#41; and strength of recommendation were graded according to the definitions used by the European Society of Cardiology&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Out of 46 articles&#44; one RCT&#44; three CS and one CCS were included&#46; In the RCT&#44; treatment with allopurinol decreased CV events in patients with moderate chronic renal failure by 71&#37; compared to controls &#40;LE B&#41;&#46; In one CS&#44; patients treated with high doses had a greater reduction in CV events compared to low doses &#40;LE B&#41;&#46; The other two CS&#44; in patients with heart failure &#40;HF&#41;&#44; found similar benefits in patients treated with high doses of allopurinol &#40;LE B&#41;&#46; In the CCS&#44; in patients with HF and a history of gout&#44; treatment with allopurinol reduced HF admission and all-cause mortality &#40;LE B&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0030">Discussion and Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Prolonged treatment with high doses of allopurinol may be associated with a reduction in morbidity and mortality in high CV risk populations &#40;class of recommendation IIa&#41;&#46; More studies evaluating the effect of therapy with allopurinol in reducing CV events in patients with and without risk are needed&#46;</p>"
      ]
      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0040">Introdu&#231;&#227;o</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">N&#237;veis elevados de &#225;cido &#250;rico &#40;AU&#41; t&#234;m sido associados a doen&#231;a cardiovascular &#40;<span class="elsevierStyleSmallCaps">CV</span>&#41;&#44; mas o papel deste como fator de risco independente &#233; controverso&#46; O tratamento da hiperuricemia pode ser relevante na abordagem do risco CV&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Objetivo</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Rever a evid&#234;ncia do tratamento com alopurinol&#44; em doentes com hiperuricemia&#44; na redu&#231;&#227;o de eventos cardiovasculares&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Metodologia</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Pesquisa de ensaios cl&#237;nicos controlados aleatorizados &#40;ECA&#41;&#44; estudos coorte &#40;EC&#41; e caso-controlo &#40;CC&#41;&#44; meta-an&#225;lises&#44; revis&#245;es sistem&#225;ticas e normas de orienta&#231;&#227;o&#44; publicados entre janeiro&#47;2002 e dezembro&#47;2013&#44; em bases de dados cient&#237;ficas&#46; O n&#237;vel de evid&#234;ncia e a for&#231;a de recomenda&#231;&#227;o foram atribu&#237;dos de acordo com escalas pr&#233;-definidas pela Sociedade Europeia de Cardiologia&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">De 46 artigos foram inclu&#237;dos um ECA&#44; tr&#234;s EC e um CC&#46; No ECA o tratamento com alopurinol <span class="elsevierStyleItalic">versus</span> grupo controlo diminuiu em 71&#37; os eventos cardiovasculares em doentes com insufici&#234;ncia renal cr&#243;nica moderada &#40;LE B&#41;&#46; Num dos EC&#44; doentes tratados com doses altas tiveram uma redu&#231;&#227;o mais significativa do risco de eventos CV &#40;LE B&#41;&#46; Os outros dois EC realizados em doentes com insufici&#234;ncia card&#237;aca &#40;IC&#41; verificaram benef&#237;cios id&#234;nticos em doentes tratados com doses elevadas de alopurinol &#40;LE B&#41;&#46; No estudo CC&#44; em doentes com IC e hist&#243;ria de gota o tratamento com alopurinol reduziu internamentos&#47;mortalidade por IC &#40;LE B&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0060">Discuss&#227;o</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">O tratamento prolongado com doses elevadas de alopurinol pode estar associado a uma redu&#231;&#227;o da morbimortalidade CV em popula&#231;&#245;es de risco &#40;Classe de Recomenda&#231;&#227;o IIa&#41;&#46; S&#227;o necess&#225;rios mais estudos que avaliem os efeitos da terap&#234;utica com alopurinol na diminui&#231;&#227;o de eventos CV em doentes sem risco&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Guedes M&#44; Esperan&#231;a A&#44; Pereira AC&#44; Rego C&#46; Qual o efeito da redu&#231;&#227;o da hiperuricemia nos eventos cardiovasculares&#63; Revis&#227;o baseada na evid&#234;ncia&#46; Rev Port Cardiol&#46; 2014&#59;33&#58;727&#8211;732&#46;</p>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">CV&#58; cardiovascular&#59; GFR&#58; glomerular filtration rate&#59; LE&#58; level of evidence&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aims and methods&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Goicoechea et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">To study the effect of allopurinol treatment on renal disease progression&#44; CV events and hospitalization for any cause113 patients with GFR &#60;60 ml&#47;minAllopurinol 100 mg&#47;day &#40;n&#61;57&#41; vs&#46; control &#40;n&#61;56&#41;Outcomes&#58; hospitalizations&#44; CV events&#44; end-stage renal disease requiring dialysis therapy&#44; mortalityDuration&#58; 24 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">86&#46;7&#37; completed the trial &#40;51 vs&#46; 47&#41;Allopurinol treatment reduced CV events by 71&#37; and hospitalizations by 62&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Randomized controlled trial&#46;</p>"
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      1 => array:7 [
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">CV&#58; cardiovascular&#59; HF&#58; heart failure&#59; LE&#58; level of evidence&#59; MI&#58; myocardial infarction&#59; UA&#58; uric acid&#59; y&#58; years&#46;</p>"
          "tablatextoimagen" => array:1 [
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Aims and methods&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">LE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Struthers et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">To examine whether different doses of allopurinol are associated with any alteration in CV and all-cause mortality and CV hospitalizations1760 patients with chronic HFFour groups&#58; &#40;1&#41; those who had never received allopurinol&#59; &#40;2&#41; recent &#40;&#60;4 years&#41; low dose allopurinol group &#40;&#60;299 mg&#41;&#59; &#40;3&#41; longstanding &#40;&#8805;4 years&#41; low dose allopurinol group&#59; &#40;4&#41; longstanding high dose allopurinol group &#40;&#8805;300 mg&#41;&#46;Outcomes&#58; all-cause and CV mortality and CV hospitalizationDuration&#58; 4 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Possible reduction in CV mortality only with high-dose allopurinolLow-dose allopurinol may be insufficient to treat hyperuricemia and was associated with increased mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Wei et al&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">To study the impact of allopurinol treatment on cardiovascular events and all-cause mortality7135 patients aged &#8805;60 yearsAllopurinol &#40;n&#61;1035&#41; vs&#46; no treatment &#40;n&#61;6042&#41;Allopurinol 100 mg &#40;low dose&#41; vs&#46; 200 mg vs&#46; &#8805;300 mg &#40;high dose&#41;Follow-up&#58; 5&#8211;8 yearsOutcomes&#58; non-fatal stroke and MI&#44; CV and all-cause mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">No difference in CV events between allopurinol and no treatmentNo difference in CV events between allopurinol and no treatment with UA &#8805;6 mg&#47;dlIncreased CV risk in the non-treatment group with increased UA levelReduced CV risk in the allopurinol group independent of UA level and dependent on allopurinol doseSignificant reduction in CV events and all-cause mortality in the high-dose vs&#46; low-dose allopurinol groups&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Wei et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">9</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">To assess whether allopurinol affects mortality and CV hospitalizations in patients with HF4785 HF patientsAllopurinol group&#58;Prevalent users &#40;prescribed in 1st 180 days after discharge&#44; n&#61;258&#41;&#58; cumulative low dose &#60;18<span class="elsevierStyleHsp" style=""></span>400 mg&#44; medium dose &#40;18<span class="elsevierStyleHsp" style=""></span>400&#8211;44<span class="elsevierStyleHsp" style=""></span>800 mg&#41; and high-dose &#40;&#62;44<span class="elsevierStyleHsp" style=""></span>800 mg&#41;Incident users &#40;prescribed &#8805;180 days after discharge&#44; n&#61;267&#41;&#58; &#60;299 mg&#47;day &#40;low dose&#41; vs&#46; &#8805;300 mg&#47;day &#40;high dose&#41;Non-treatment group &#40;n&#61;4260&#41;Median follow-up&#58; non-treatment 4&#46;9 y&#59; incident 5 y&#44; prevalent 3&#46;1 yOutcomes&#58; all-cause mortality&#44; CV mortality&#44; CV recurrence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Alopurinol <span class="elsevierStyleItalic">vs</span>&#46; treatmentLow dose&#58;&#8211; incident group&#58; increased all-cause and CV mortality and CV recurrence&#8211; prevalent group&#58; increased CV mortalityHigh dose&#58; no effect on CV riskHigh dose&#58; no effect on CV riskHigh vs&#46; low dose&#58;&#8211; prevalent group&#58; reduced all-cause mortality&#8211; prevalent vs&#46; incident groups&#58; no difference in effect on CV risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">HF&#58; heart failure&#59; LE&#58; level of evidence&#46;</p>"
          "tablatextoimagen" => array:1 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Aims and methods&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thanassoulis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">To determine whether gout and allopurinol use are associated with HF outcomesCases &#40;n&#61;14<span class="elsevierStyleHsp" style=""></span>327&#41;&#58;HF readmission &#40;52&#46;9&#37;&#41;All-cause mortality &#40;47&#46;1&#37;&#41;Controls &#40;n&#61;143<span class="elsevierStyleHsp" style=""></span>225&#41;Exposure&#58;Allopurinol&#58; Duration of use &#8804;30 days&#44; &#62;30 daysDose &#8804;100 mg&#47;day&#44; &#62;100 mg&#47;dayGout&#58; remote &#60;5 years&#44; acute &#60;60 daysOutcomes<span class="elsevierStyleItalic">&#58;</span> HF readmission and all-cause mortalityDuration&#58; median 2&#46;1 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No association between allopurinol use and outcomesAllopurinol treatment in patients with a history of gout reduced HF readmissions and mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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Article information
ISSN: 21742049
Original language: English
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Revista Portuguesa de Cardiologia (English edition)
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