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We read the letter by Battaggia et al. [1] commenting our systematic review and meta-analysis on the association between hyperuricemia (HU) and coronary heart disease (CHD) incidence and mortality [2], and we thank the authors for giving us the opportunity to better explain and emphasize some important points of our work. In our study, we updated the literature search and reviewed available observational prospective cohort studies about the relationship between HU and future CHD incidence and mortality in the CHD-free population that fulfilled well-defined selection criteria, including the explicit definition of the urate threshold above which the risk, if present, became clinically important. Regarding the CHD incidence, which is the outcome preferentially considered by Battaggia et al., our meta-analysis showed a slight but significant (p = 0.003) increase of CHD risk [risk ratio (RR) = 1.206 (1.066–1.364)] in hyperuricemic subjects, becoming more evident in hyperuricemic women [RR = 1.446 (1.323–1.581)]. Based on these results, Battaggia et al. conclude that the main message of our study was that the treatment of HU should be included in the therapeutic strategies to reduce the CHD risk. We would like to clarify, however, that we never wrote this recommendation anywhere in the text. On the contrary, we believe that, for many reasons, the message of our paper is just opposite to what these authors have deduced. First, it should be noted that the primary studies included in our meta-analysis are all observational, meaning that they are designed to investigate risk factors (defined as distinct volume categories) and not interventions or the need for promoting therapeutic strategies [3]. Second, we clearly stated that further specifically designed trials are needed to confirm the meta-analysis outcome because of the low number of retrieved trials fulfilling inclusion criteria and the significant heterogeneity found among them (I2 statistic, ~65%). Finally, in our opinion, our results have the merit to revaluate down the stronger statistical significance obtained in some previous meta-analyses on the association between HU and future cardiovascular disease mortality, raising therefore further perplexity about a possible treatment focused on HU. If one wishes to find a practical indication from our results, they might just suggest promoting more surveillance in subjects with HU, mainly if women, through, e.g. diet modification without necessarily resorting to drugs. Battaggia et al. evaluated our meta-analysis by using the AMSTAR checklist [4], obtaining a medium/low methodological quality. In particular, they considered 4/11 items fully satisfied, 3/11 not satisfied and 4/11 uncertain. As the AMSTAR questionnaire asks reviewers to answer “Yes”, “No”, “Can’t answer” or “Not applicable”, we are a little surprised about the final judgment because they declare uncertainty in answering to more than one-third of questions. It has been already reported that some items of AMSTAR are difficult to interpret and theoretically hinder an accurate assessment [5]. Furthermore, the reliability of AMSTAR checklist as a tool to assess quality of systematic reviews of observational studies is prone to several criticisms, and assessors should be aware of this as well as to consider that speculations on the need for primary prevention programs according to observational data may be useless [6]. Even if not explicitly mentioning AMSTAR checklist, we reported the poor applicability of some AMSTAR items to our meta-analysis. For instance, AMSTAR item 7 (critical appraisal of included studies) is difficult to apply in order to obtain the true methodological quality of primary studies included in our metaanalysis [5]. As a matter of fact, there is no gold standard *Corresponding author: Federica Braga, Research Centre for Metrological Traceability in Laboratory Medicine (CIRME), University of Milan, Via G.B. Grassi 74, Milano, Italy, Phone: +39 02 39042766, E-mail: federica.braga@unimi.it Simona Ferraro, Sara Pasqualetti and Mauro Panteghini: Research Centre for Metrological Traceability in Laboratory Medicine (CIRME), University of Milan, Milan, Italy

Reply to: Hyperuricemia does not seem to be an independent risk factor for coronary heart disease