International Journal of Cardiology 177 (2014) 575–577

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Letter to the Editor

FGF 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studies☆,☆☆,★ Yunjun Xiao ⁎, Xianru Luo, Wei Huang, Jinzhou Zhang, Chaoqiong Peng Department of Nutrition and Food Hygiene, Shenzhen Center for Disease Control and Prevention, Shenzhen, China

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Article history: Received 18 August 2014 Accepted 21 August 2014 Available online 27 August 2014 Keywords: Cardiovascular disease Cohort studies Fibroblast growth factor 23 Meta-analysis

Dear Editor, We read Krupp et al.'s comment on our paper “Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studies” published in the April 2014 issue of International Journal of Cardiology [1,2]. The authors have raised several questions and good suggestions. In our study, we conducted a systematic literature search of PubMed through November 2013 for relevant articles that reported the association between FGF23 and risk of all-cause mortality and CVD events. Furthermore, we also used EMBASE, OVID, and Google Scholar to search relevant articles; majority of search results were same with the results of PubMed. Other articles did not meet inclusion criteria and were firstly eliminated. Hence we only employed the search results from PubMed. And search strings and the detailed eligible inclusion and exclusion criteria have been shown in our previous paper. With regard to the exclusion of the cohort studies such as the Framingham Heart Study and the Northern Manhattan Study, it may be explained that the Framing-

☆ Funding/support: None. ☆☆ Ethical review: Not applicable. ★ Statement of authorship: All authors have contributed to the critical revision of the manuscript for important intellectual content. ⁎ Corresponding author at: Department of Nutrition and Food Hygiene, Shenzhen Center for Disease Control and Prevention, 8 Longyuan Road, Nanshan District, 518055 Shenzhen, China. Tel.: +86 755 25617321; fax: +86 755 25500660. E-mail address: [email protected] (Y. Xiao).

http://dx.doi.org/10.1016/j.ijcard.2014.08.125 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

ham Heart Study did not report the association between FGF23 and mortality or CVD events. Although the Northern Manhattan Study reported the association between FGF23 and the risk of stroke, the study was published online in May 2014 after the publication of our study [3]. And the Heart and Soul Study has been included in our metaanalysis [4]. Furthermore, we had written a report on the meta-analyses according to the PRISMA statement and firstly submitted our manuscript as an original article to the Journal. However, finally, our paper could only be published in the form of a letter on the Journal. Hence, some sections such as abstract, assessment of study quality, and the limitations in previous submitted version of our paper were lacking in the published version. Now in this response letter, we have presented the quality assessment of the studies included in the meta-analysis [5]. Briefly, a 9-score system on the basis of the Newcastle–Ottawa Scale (NOS) was used to assess the quality of the included studies. Each study included in the meta-analysis was judged on three broad perspectives: the selection of the study cases, the comparability of the study populations and the ascertainment of either the exposure or outcome of interest. Two reviewers independently assessed each study quality. Differences and disagreements were resolved through discussion to come to an agreement. In this 9-score system, studies which scored greater or equal than 7 were considered to be of high quality. The assessment of study specific quality scores from NOS system were summarized in Table 1. In this total 9 point evaluation system, the median score of included studies was 8, with a range from 5 to 9, and 85.7% of the studies were identified as relatively of high-quality. To limit bias in the selection of included studies, we used broad inclusion criteria for studies that provided quantitative data on the risk for mortality or CVD events associated with FGF23, and then did sensitivity analyses according to differences between the studies and methodological study quality. Because the small sample and short follow-up may decrease the study quality, we excluded 6 studies among which sample sizes were less than 200 and duration of followup was less than one year [6–11]. Nevertheless, the inclusion of these studies still did not materially alter the overall combined risk estimate. Moreover, the association of FGF23 with risk of all-cause mortality persists and remains statistically significant in sensitivity and subgroup analyses based on various exclusion criteria and characteristics of populations. Substantial heterogeneity was observed among the studies of FGF23 and all-cause mortality, which was not surprising given the differences in characteristics of populations, measurement of FGF23, and adjustment

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Y. Xiao et al. / International Journal of Cardiology 177 (2014) 575–577

Table 1 Assessment of study quality included in the meta-analysis by Newcastle–Ottawa Scale (NOS). Source

Jean et al. [18] Parker et al. [4] Olauson et al. [19] Wolf et al. [20] Kendrick et al. [21] Isakova et al. [22] Arnlov et al. [12] Ix et al.[14] Nakano et al. [23] Baia et al. [24] Lee et al. [25] Westerberg et al. [13] Scialla et al. [15] Arnlov et al. [26]

Comparabilitya

Selection

Outcome

Total scores

1

2

3

4

5A

5B

6

7b

8c

– – – – – – * * – – – * – *

* * * * * * * * * * * * * *

* * * * * * * * * * * * * *

* * * * * * * * * * * * * *

* * * * * * * * * * * * * *

* * * * * * * * * * * * * *

– * – * * * * * * * * * * *

– * – * * * * * * * * * * *

* – – * – * – * – * * – * *

6 7 5 8 7 8 8 9 7 8 8 8 8 9

1 Representativeness of the exposed cohort; 2 selection of the non-exposed cohort; 3 ascertainment of exposure; 4 demonstration that outcome of interest was not present at start of study; 5 comparability of cohorts on the basis of the design or analysis; 6 assessment of outcome; 7 was follow-up long enough for outcomes to occur; 8 adequacy of follow up of cohorts. An asterisk represents one score. a Studies that controlled for age and traditional risk factors received one score, whereas studies that controlled for other important confounders received an additional score. b Study with follow-up time of N2 years was assigned one score. c Study with follow-up rate of N70% was assigned one score.

for confounding factors. Our sensitivity analyses suggest that 2 studies [12,13] conducted only in male participants probably contributed to the heterogeneity. When these 2 studies were excluded, no statistical heterogeneity was found among the remaining 10 studies. In addition to the difference in the sex of study population, these 2 studies also differed from others in some aspects. First, the participants of these 2 studies were community-based population as well as that of another study [14], whereas the subjects of other studies were kidney dysfunction patients, CAD or diabetes patients. The difference in participants of the studies may contribute to the difference of their results. Second, the difference in the measurement of FGF23 among the studies including intact and C-terminal FGF23 may also increase the possibility that chance accounted for their results. Subgroup analyses showed only weak evidence for statistical heterogeneity among the studies of C-terminal FGF23 and risk of all-cause mortality. However no statistical heterogeneity was observed among the studies of intact FGF23 and risk of all-cause mortality. Hence, the difference in the measurement of FGF23 may also partly account for the sources of heterogeneity. Our study has several limitations. First, a meta-analysis of prospective cohort studies should be interpreted with caution. Proof of a cause-effect relation between increased FGF23 levels and risk of allcause mortality or CVD events cannot be established by observational studies, even though it can provide useful information when only data from observational studies are available. To our knowledge, no randomized, controlled trial has studied the benefits of decreasing FGF23 levels in patients with CKD or CAD with regard to mortality or CVD events. Second, we found substantial heterogeneity among studies for the association between FGF23 and risk of all-cause mortality. Nevertheless, we were able to detect the major source of heterogeneity through the sensitivity and subgroup analyses. In addition, uncontrolled or unmeasured risk factors potentially produce biases. Although the selected studies were adjusted for a group of conventional cardiovascular risk factors, we still cannot rule out the possibility that residual confounding could affect the results because these factors do not explain all of the risk for mortality and CVD events. Furthermore, because current data in relation to FGF23 and specific CVD outcomes are sparse, subgroup analyses of the association between FGF23 and specific CVD outcomes should be interpreted with caution given the limited number of studies. Nevertheless, the results for FGF23 and heart failure were consistent [4,14,15]. Finally, although our graphical and statistical analyses showed that publication bias was unlikely, it cannot be excluded because the capacity to detect publication bias is reduced when meta-analyses are based on a

relatively small number of included studies [16,17]. Selective reporting of the outcomes in the cohorts cannot be excluded, either. In conclusion, by collecting and synthesizing data currently available, the meta-analysis suggests that FGF23 might be associated with high risk of cardiovascular disease. Further investigations are needed to establish whether decreasing FGF23 levels can reduce risk of mortality and cardiovascular events. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] Xiao Y, Luo X, Huang W, et al. Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: a meta-analysis of prospective cohort studies. Int J Cardiol 2014;174:824–8. [2] Krupp K, Madhivanan P. FGF23 and risk of all-cause mortality and cardiovascular events: a meta-analysis of prospective cohort studies. Int J Cardiol 2014;177:575–7. [3] Wright CB, Dong C, Stark M, et al. Plasma FGF23 and the risk of stroke: the Northern Manhattan Study (NOMAS). Neurology 2014;82:1700–6. [4] Parker BD, Schurgers LJ, Brandenburg VM, et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann Intern Med 2010;152:640–8. [5] Wells GA, Shea B, O'Connell D, et al. The Newcastle–Ottawa Scale (NOS) for assessing the quality of non-randomised studies in meta-analyses. http://www. ohri.ca/programs/clinical_epidemiology/oxford.htm. [Accessed 29 Apr 2004]. [6] Poss J, Mahfoud F, Seiler S, et al. FGF-23 is associated with increased disease severity and early mortality in cardiogenic shock. Eur Heart J Acute Cardiovasc Care 2013;2:211–8. [7] Seiler S, Reichart B, Roth D, et al. FGF-23 and future cardiovascular events in patients with chronic kidney disease before initiation of dialysis treatment. Nephrol Dial Transplant 2010;25:3983–9. [8] Holden RM, Beseau D, Booth SL, et al. FGF-23 is associated with cardiac troponin T and mortality in hemodialysis patients. Hemodial Int 2012;16:53–8. [9] Plischke M, Neuhold S, Adlbrecht C, et al. Inorganic phosphate and FGF-23 predict outcome in stable systolic heart failure. Eur J Clin Invest 2012;42:649–56. [10] Prie D, Forand A, Francoz C, et al. Plasma fibroblast growth factor 23 concentration is increased and predicts mortality in patients on the liver-transplant waiting list. PLoS One 2013;8:e66182. [11] Sugimoto H, Ogawa T, Iwabuchi Y, et al. Relationship between serum fibroblast growth factor-23 level and mortality in chronic hemodialysis patients. Int Urol Nephrol 2014;46:99–106. [12] Arnlov J, Carlsson AC, Sundstrom J, et al. Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Kidney Int 2012; 83:160–6. [13] Westerberg PA, Tivesten A, Karlsson MK, et al. Fibroblast growth factor 23, mineral metabolism and mortality among elderly men (Swedish MrOs). BMC Nephrol 2013;14:85.

Y. Xiao et al. / International Journal of Cardiology 177 (2014) 575–577 [14] Ix JH, Katz R, Kestenbaum BR, et al. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol 2012;60:200–7. [15] Scialla JJ, Xie H, Rahman M, et al. Fibroblast growth factor-23 and cardiovascular events in CKD. J Am Soc Nephrol 2014;25:349–60. [16] Egger M, Davey Smith G, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34. [17] Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088–101. [18] Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant 2009;24:2792–6. [19] Olauson H, Qureshi AR, Miyamoto T, et al. Relation between serum fibroblast growth factor-23 level and mortality in incident dialysis patients: are gender and cardiovascular disease confounding the relationship? Nephrol Dial Transplant 2010;25:3033–8. [20] Wolf M, Molnar MZ, Amaral AP, et al. Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol 2011;22:956–66.

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[21] Kendrick J, Cheung AK, Kaufman JS, et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J Am Soc Nephrol 2011;22:1913–22. [22] Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 2011;305: 2432–9. [23] Nakano C, Hamano T, Fujii N, et al. Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis. Bone 2012; 50:1266–74. [24] Baia LC, Humalda JK, Vervloet MG, et al. Fibroblast growth factor 23 and cardiovascular mortality after kidney transplantation. Clin J Am Soc Nephrol 2013;8:1968–78. [25] Lee JE, Gohda T, Walker WH, et al. Risk of ESRD and all cause mortality in type 2 diabetes according to circulating levels of FGF-23 and TNFR1. PLoS One 2013;8: e58007. [26] Arnlov J, Carlsson AC, Sundstrom J, et al. Serum FGF23 and risk of cardiovascular events in relation to mineral metabolism and cardiovascular pathology. Clin J Am Soc Nephrol 2013;8:781–6.

FGF 23 and risk of all-cause mortality and cardiovascular events: a meta-analysis of prospective cohort studies.

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