Effect of febuxostat on blood pressure in hyperuricemic patients

Abstract Background: Increasing evidence connects serum uric acid (sUA) with hypertension. Previous studies on the efficacy of febuxostat on blood pressure (BP) in hyperuricemic patients have provided conflicting results. Thus, we aim to perform a systematic review and meta-analysis to investigate the efficacy of febuxostat on BP. Methods: Five electronic databases (included The Cochrane Library, MEDLINE, Embase, Web of Science, and Cochrane Central Register of Controlled Trials) will be searched. Randomized controlled trials will be included if they recruited hyperuricemic participants for assessing the effect of febuxostat on BP versus control (placebo, no treatment, and other therapeutic agents). The primary outcome will be BP, secondary outcomes will be sUA, serum creatinine, and estimated glomerular filtration rate. Relevant literature search, data extraction, and quality assessment will be performed by 2 researchers independently, and the third researcher will be involved in a discussion for any disagreements. All analyses will be performed based on the Cochrane Handbook for Systematic Reviews of Interventions. Stata 12.0 software will be used for statistical analysis. The effect size of dichotomous data will be measured using the odds ratio , and the effect size of continuous data will be measured using the standardized mean difference. And 95% confidence intervals will be calculated. Heterogeneity will be tested by χ2-based Cochran Q statistic and I2 statistic. Sensitivity analysis and subgroup analysis will be used to observe changes in the pooled effect size and heterogeneity between included studies, to assess the reliability and stability of the pooled results. The funnel plot and Egger's and Begg's tests will be used to judge publication bias, and the trim and fill method will be used to correct the funnel asymmetry caused by publication bias. P < .05 will be considered to indicate a statistically significant result. Results: This systematic review and meta-analysis will be to assess the efficacy of febuxostat on BP. Conclusions: Our findings will show the effect of febuxostat on BP in hyperuricemic patients. And such a study may find a new therapeutic option for hypertensive patients and assist clinicians and health professionals make clinical decisions. Ethics and dissemination: This study is a protocol for systematic review and meta-analysis of the effect of febuxostat on BP in hypertensive patients. This systematic review and meta-analysis will be published in a journal and disseminated in print by peer-review. INPLASY registration number: INPLASY202050031.


Introduction
Aging is a natural process which is generally along with a decline in the physiological function of the body, as a result of the susceptibility to age-associated diseases will be increased. For example, cardiovascular disease, dementia, osteoporosis, diabetes, hypertension, and stroke are age-induced diseases. [1,2] Aging brings several diseases together will produce destructive effects on human society and breakdowns the entire health care system and economy. [1,2] It is well known that aging is an inevitable physiological process, but we can delay senecence by various therapy. [1] The potential mechanisms remain to be researched after many decades, and the oxidative stress and free radical accumulation theories stand out the most in the multiple theories related with aging. The antioxidant system declines as a growth of age, giving rise to destruction of the balance between radical oxygen species emergence and erasure issuing in oxidative cellular damage. [3] Compared with other organs, postmitotic tissues such as the brain, heart and skeleton muscle are more susceptible to aging. [4] Additionally oxidative stress, aging is also intimately related with issuing in structural and functional flaws in the immune system. [5] The 1 of the primary feature of aging is piecemeal loss of cognition, with exhibition of descending logical thinking, memory and spacial abilities. The aging of cerebral is the primary cause of cognitive obstacle. [6] The anti-aging interventions includes anti-aging medicine, herb, and Health Qigong. The anti-aging medicine according to mechanism include Calorie restriction mimetics, Activation of PY is the first authors.
Ethics approval is not required for this study does not involve human data. AMP protein kinase, Inhibition of growth hormone/insulin like growth factor-1 axis, Inhibition of mammalian target of rapamycin, Activation of the sirtuin pathway, Hormonal replacement, Gut microbiota, Vitamin D. [7] The herb for antiaging include Cistanches, [8] Ganoderma Lucidum [9] and so on. Health Qigong, containing Baduanjin, Wuqinxi, Yijinjing, Liuzijue and TaiChi, are traditional Chinese exercise, that are deemed to not only enhance the antioxidant capacity of the body but also regulate immune function. Previous researches have showed that Health Qigong has fine effects for anti-aging, including regulate mental and physical health, [10][11][12][13][14] and ageassociated diseases. [15][16][17] Due to these strength of Health Qigong,doctors recommend using Health Qigong to increase vigor and vitality as well as prolong lifespan.
Although Health Qigong is widely applied to anti-aging increasing, system reviews and meta-analysis of Health Qigong are few. Therefore, we will perform a systematic review of randomized clinical trials summarizing the existing evidence and assessing the effectiveness and safety of Health Qigong for anti-aging.

Methods
The protocol of the systematic review and meta-analysis has been registered in the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY), the registration number is INPLASY202090017. It will be based on the guidelines of Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA-P).
2.1. Inclusion criteria for study selection 2.1.1. Type of studies. Only the RCTs of Health Qigong for anti-aging will be included in this study, without placing the constraint on publication status and writing language. Studies without sufficient information about the randomized method or process, the animal mechanism studies, qualitative studies, uncontrolled trials and reviews and case reports will be excluded.

Type of participants.
Subjects aged 45 to 75 years, who do not exercising daily and have no major disease will be selected. There will be no restriction on gender, race, or nation.

Type of interventions.
Our systematic review and metaanalysis will be conducted based on the RCTs that solely apply Health Qigong intervention in the experimental group and placebo or other nonpharmacological therapies in the control group. The control group has the following forms: keep previous exercise habit, restrict any exercise etc. Health Qigong include Baduanjin, Wuqinxi, Yijinjing, Liuzijue and TaiChi.   The complete PubMed search strategy is in Table 1 and will be modified and used in other electronic databases.

Searching other resources.
We will investgate the preplanned, ongoing, and unpublished studies by searching Google Scholar, Baidu Scholar, the International Clinical Trials Registry Platform and the Chinese Clinical Trial Registry.
2.3. Data collection and analysis 2.3.1. Selection of studies. Two researchers(Han Li, Shuang Ouyang) will be individual into 2 groups, and each group will independently scan the titles and abstracts. After deleting repetitive and irrelevant articles, the 2 groups will set up 2 lists of potential studies which will be verified against each other by superintendent(Chaohui Tang) to make a preliminary list. Next authentication of eligible articles from the preliminary list will be accomplished by 2 researchers (Haiyang Cai, Jing Wu) through using the preplanned inclusion/exclusion criteria. When divergence appear another researchers(Peng Yu) will make a judgment. The selection procedure is fully described in a PRISMA flow chart (Fig. 1). 2.3.2. Data extraction. Two researchers (Han Li, Shuanng Ouyang) will independently work for data extraction, they will collect the undermentioned data: (1) basic characteristics, including the first author, publication year, sample size, trial location, age, geographic population, health status, duration and follow-up, frequency, intensity, Health Qigong style, control intervention. (2) (2)primary outcomes and secondary outcomes as the information showed before will also be included, including the antioxidant capacity, the immune function and cardiocerebrovascular function.
The results will be double-verified by a another researcher (Qingsong Huang). If the data is missing or unclear, the corresponding author will be contacted.

Risk of bias assessment.
We will according to the Cochrane Handbook(V.5.1.0) [18] of Systematic Reviews of Interventions, and the risk of bias (ROB) of the included studies will be assessed by 2 researchers(Haiyang Cai, Jing Wu) independently using the Cochrane risk of bias assessment tool.
The domains pertinent to ROB including random sequence generation, allocation concealment, blinding of participants and therapist, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The ROB for each domain will be rated as"low risk," "high risk," or "unclear risk." 2.3.4. Data synthesis. The meta-analysis will be performed by using the Review Manager V.5.3 (RevMan 5.3)software. We will describe the effect size with the risk Ration for dichotomous data, and the mean deference for continuous data.95% of the confidence interval will beused as an effective size for the combined analysis.
2.3.5. Assessment of heterogeneity. We will calculate the heterogeneity by using the Chi-square and I 2 statistic, which describes the percentage of variability in the effect estimates. I 2 statistic (I 2 values of 0% to 40% being interpreted as "might not be important";30% to 60%: may represent moderate heterogeneity;50% to 90%: may represent substantial heterogeneity; and 75% to 100%: represents considerable heterogeneity). For more detailed explanation on potential heterogeneity among involved studies, we may also conduct subgroup analyses or metaregression.
2.3.6. Analysis of subgroups. If we have a sufficient number of RCTs for inclusion in the review, we will carry out the subgroups when the heterogeneity is high. Subgroup analysis will be carried out based on the type of control interventions, type of Health Qigong, exercise frequency and duration.
2.3.7. Sensitivity analysis. We will conduct the sensitivity analysis to assess the robustness of bias on results and the sources of heterogeneity. We will delete the data of certain study 1 by 1 by comparing the recombined date with original date,and then focus on the changes merged size effects and heterogeneity.
2.3.8. Assessment of reporting biases. If there are more than 10 studies are included in the review, we will build funnel plots to appraise the reporting bias. There are 2 results, it means no reporting bias existed when the funnel is symmetrical, or it means reporting bias when the funnel is dissymmetry.
2.3.9. Confidence in cumulative evidence. We will assess the quality of evidence by using the GRADE system. The following 5 factors will be considered: risk of bias, inconsistency, directness, inaccuracy, and reporting bias. Four levels will be geaded of quality of evidence: high, moderate, low or very low.

Discussion
Aging is an unavoidable natural physiological process, but aging brings several diseases together will produce destructive effects on human society and breakdowns the entire health care system and economy. [1,2] Hence, it is necessary to find effective non-drug therapies to anti-aging. Health Qigong, as a traditional Chinese excercise, has a remarkable effect on improving immune function and the antioxidant capacity of the body. However, there is still no systematic review clearly demonstrating the role of Health Qigong for anti-aging. The results of this study will identify whether Health Qigong can delay senescence and related laboratory indicators of antiaging, which will present an evidence for Health Qigong in applications. The small quantity of related literature and the high heterogeneity of different Health Qigong styles used in the research may attract limitations to this study. If there is enough randomized controlled double-blind experimental research, we will accomplish a subgroup analysis to identify specific Health qigong programs and exercise time. In addition, Health Qigong has a widely application in Asia, peculiarly China, but it is not well accepted in other parts of the world, so publication bias will also be considered.
In conclusion, this study will investigate the efficacy and safety of Health Qigong as a treatment of anti-aging.