Systematic Review and Meta-Analysis of Randomized Controlled Trials of Fuke Qianjin Tablet

Purpose The aim of the research was to evaluate the efficacy and safety associated with Fuke Qianjin tablet combined with conventional therapy in the treatment of pelvic inflammatory diseases and associated complications (endometritis) using a meta-analysis approach. Patients and Methods. We searched 8 electronic databases up to December 31, 2019, including PubMed, the Cochrane Library, Embase, Web of Science, CNKI, WanFang, VIP, and SinoMed. Eligible studies were clinical trials of Fuke Qianjin tablet combined with conventional therapy used in the treatment of acute pelvic inflammatory disease, chronic pelvic inflammatory disease, and endometritis. The meta-analysis was performed using STATA15 software. Results A total of 125 RCTs (n = 14,494) were shortlisted for the meta-analysis, which included 23 trials for acute pelvic inflammatory disease, 69 trials for chronic pelvic inflammatory disease, and 33 trials for endometritis. The overall analysis illustrated Fuke Qianjin tablet combined with conventional therapy was significantly more efficacious than conventional therapy alone across all types of antibiotics treatment for acute pelvic inflammatory disease (OR = 5.57, 95% CI 4.09–7.58, Z = 10.90, p=0.001), chronic pelvic inflammatory disease (OR = 4.70, 95% CI 4.07–5.42, Z = 21.21, p=0.001) and endometritis (OR = 5.09, 95% CI 4.03–6.43; Z = 13.63, p=0.001) in both primary endpoints and secondary endpoints. There is also a trend that Fuke Qianjin tablet combined with conventional therapy has lower adverse reaction rates than conventional therapy alone. Conclusion Fuke Qianjin tablet combined with conventional therapy showed better clinical efficacy in the treatment of acute pelvic inflammatory disease, chronic pelvic inflammatory disease, and endometritis. There were no obvious drug-related adverse reactions. Fuke Qianjin tablet presented advantages in shortening the remission time of clinical symptoms, reducing the concentration of serum inflammatory factors, improving endometrial thickness, menstruation, and reducing relapse rate.


Introduction
Pelvic inflammatory disease (PID), one of the most common infections in women of reproductive age, could lead to endometritis, oophoritis, salpingitis, tuboovarian abscess, peritonitis, and other complications [1][2][3][4]. Studies have shown that about 25% of PID patients will have long-term sequelae, including annexitis, irregular menstruation, infertility, ectopic pregnancy, or chronic pelvic pain [5]. Moreover, compared with those without PID, patients with PID had a 1.864 times higher risk of developing preterm labor and a 2.121 times higher risk of developing ectopic pregnancy [6]. Women with PID also have a 6%-8% risk of infertility [5]. Endometritis or complications of PID will further reduce endometrial receptivity and increase the risk of infertility. e prevalence of chronic endometritis in the general population is about 19% [7], and the prevalence of chronic endometritis in infertile patients is about 45% [8]. Studies have shown that effective treatment of endometritis can improve patient reproductive health [9]. A research reported on PID health economics showed that young women are willing to spend 1-2 years of life to prevent PID and its related sequelae [10]. PID has severely affected female reproductive health and has also caused a heavy economic burden. In the United States, the medical cost in treating a PID case is about US$3,200 [11], and the annual PID-related treatment cost on the US healthcare system adds to US$4.2 billion [12]. e current treatment methods for PID are mainly antibiotic treatment and surgical treatment. According to the guidelines [13] issued by CDC in 2015, PID treatment programs must provide empirical and broadspectrum coverage of possible pathogens. However, longterm, repeated use of antibiotics may lead to increasing antibiotic resistance of related pathogens [14]. According to the 2018 World Health Organization (WHO) report, pathogens showed high rates of quinolone resistance, increasing azithromycin resistance, and emerging resistance to extended-spectrum cephalosporins [15]. On the other end, surgical treatment is only carried out when drug treatment is ineffective or emergency symptoms appear. Surgery presents risk of intrauterine iatrogenic damage, and so, surgical treatment measures should be carefully considered specific to the conditions of patients [16].
Fuke Qianjin tablet is a pure Chinese medicine preparation approved by the National Medical Products Administration. It is widely used clinically to treat acute pelvic inflammatory disease, chronic pelvic inflammatory disease, and endometritis. In recent years, many researchers have performed evaluation of the clinical application of Fuke Qianjin tablets [17], but further evaluation is deemed necessary.
erefore, this study aims to comprehensively evaluate the efficacy and safety of Fuke Qianjin tablets and provide a basis for its application as a treatment for pelvic inflammatory disease.

Literature Search.
is study evaluated the clinical effectiveness and safety of Fuke Qianjin tablets in the treatment of acute pelvic inflammatory disease, chronic pelvic inflammatory disease, and endometritis. Synonyms of Fuke Qianjin tablets such as "Fuke Qianjin tablet," "Qianjin tablet," and "Qianjin" were used to search English databases. Chinese database search strategies and results are shown in Table 1. Additional, a manual search on chictr.org.cn (clinical trial database in China) was also done to identify potential unpublished studies.

Inclusion and Exclusion Criteria.
Eligible studies should have met the following criteria: (1) randomized controlled trials (RCTs) of Fuke Qianjin tablets published in China or internationally; (2) patients diagnosed with acute pelvic inflammatory disease, chronic pelvic inflammatory disease, or endometritis; (3) the intervention measures of the experimental group are Fuke Qianjin tablets alone or combined with conventional treatment; and (4) the study reported one or more of the following outcome indicators: the main outcome indicators such as total effective rate and incidence of adverse reactions, and secondary outcome indicators such as clinical symptom relief time, endometrial thickness, serum inflammatory factor concentration, menstrual recovery, and relapse rate.
Exclusion criteria were (1) nonpharmacological treatment-related studies, such as acupuncture, physical therapy, and hot compresses; (2) studies with repeated publications; (3) studies with completely missing data; and (4) studies with unclear interventions, unclear description of efficacy evaluation criteria, or statistical errors.

Quality Assessment.
Two authors independently evaluated the risk of bias of the included literature using the Cochrane Handbook which consists of seven domains [18]: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessments, incomplete outcome data, selective reporting, and other bias. For each domain, the risk of bias for each study was assessed according to three categories: low risk, high risk, or unclear risk. Disagreements encountered during the process were settled by a third author through discussion.

Data Extraction.
Two independent reviewers extracted the following data from the included studies using a standardized data extraction form. Data are connected with study characteristics (first author's name, the sample size of each group, and publication year), patient characteristics (age and course of the disease), treatment measures, outcome measures, and literature quality evaluation information. Any disagreement between the two reviewers was subject to a discussion or further inquiry from the third researcher.
pelvic inflammatory disease , and 33 for endometritis .
e full list of studies is illustrated in Tables 1-3.  (Table 4 and Figure 2).

Meta-Analysis of Fuke Qianjin
(2) Adverse Reaction. A total of 15 studies reported outcome of adverse reactions, in which 10 studies reported the specific data of 90 cases of adverse reactions. e difference of the incidence of the adverse reaction between the two groups was not statistically significant (OR � 0.71, 95% CI 0.45-1.10, Z � 1.55, p � 0.121). 5 studies reported no adverse events or mild adverse reactions which improved spontaneously (Table 4 and Figure 3).

Secondary Outcomes.
Comparisons in secondary outcomes were also made. Similar to the primary outcome, Fuke Qianjin tablets combined with antibiotics had better efficacy profiles in shortening the remission time of clinical symptoms and reducing serum inflammatory factor concentrations when compared with antibiotics alone, as shown in Table 5.

Publication Bias.
e publication bias test was performed on the total effective rate and incidence of adverse reactions, and the inverted funnel diagram (Figures 4(a) and 4(b)) was drawn, respectively. e results of the Harbord test showed that there were significant publication bias and small sample effect in the outcome of the total effective rate (t � 5.95, p � 0.001), and there were not significant publication bias and small sample effect in the outcome of the incidence of adverse reactions (t � −0.57, p � 0.583). e sensitivity analysis was carried out by using the trim and filled method. e point estimated value and 95% confidence interval of the summary effect OR before and after the implementation of the trim and fill method was 5.57 [4.09, 7.58] and 4.25 [3.18, 5.68], respectively. e differences between two of groups were still statistically significant (Z � 9.765, p � 0.001).
e iterative results show that 10 additional studies are needed to further enhance the stability of the research results.  (Table 4 and Figure 5).

Secondary Outcomes.
Comparisons in secondary outcomes were also made. Similar to the primary outcome, Fuke Qianjin tablets combined with antibiotics had better efficacy profiles in shortening the remission time of clinical symptoms and reducing serum inflammatory factor concentrations when compared with antibiotics alone, as shown in Table 5.

Publication Bias.
Perform the publication bias test on total effective rate and the incidence of adverse reactions, and the inverted funnel diagram (Figures 7(a) and 7(b)) was drawn, respectively. e inverted funnel plots of the 2 outcomes were substantially symmetric. e results of the Harbord test showed that there were no significant publication bias and small sample effect in the total effective rate (t � 0.11, p � 0.912) and adverse reaction rate (t � 0.96, p � 0.349). Screening based on title and abstract, and the following exclusion criteria.

Meta-Analysis of Fuke Qianjin
Further multiplex screening, excluding duplicate publications, those that did not meet specific standards, and those that satisfied the criteria without the required index text.
Acute PID (n = 23) Chronic PID (n = 69) Endometritis (n = 33)  Evidence-Based Complementary and Alternative Medicine          outcome. e results of the fixed-effect model showed that the combined group of Fuke Qianjin tablets had a better total effective rate of treating endometritis than the control group (OR � 5.09, 95% CI 4.03-6.43, Z � 13.63, p � 0.001). According to the specific intervention measures, the subgroup analysis showed that the combined group of Fuke Qianjin tablets had a better curative effect than the control group (Table 4 and Figure 8).

Evidence-Based Complementary and Alternative Medicine
(2) Adverse Reaction. In the included study, only 4 studies (a total of 427 participants) counted adverse reactions as part of the study. 3 studies reported no serious adverse reactions or no obvious adverse reactions, and 1 reported specific adverse reactions: there were 2 cases in the trial group (1 case of nausea and 1 case of gastrointestinal reaction); there were 3 cases in the control group (1 case of nausea, 1 case of vomiting, and 1 case of gastrointestinal reaction). ere was no significant difference in the incidence of adverse reactions between the two groups (p > 0.05).

Secondary Outcomes.
Comparisons in secondary outcomes were also made. Similar to the primary outcome, Fuke Qianjin tablets combined with antibiotics had better efficacy profiles in improving endometrial thickness, menstrual recovery, and relapse rate, as shown in Table 5.

Publication Bias.
Perform the publication bias test on total effective rate, endometrial thickness, menstrual normalization rate, and the incidence of irregular vaginal bleeding, and the inverted funnel diagram (Figures 9(a)-9(c)) was drawn, respectively. e results of the Harbord test showed that there were no significant publication bias and small sample effect in the total effective rate (t � 0.17, p � 0.859), endometrial thickness (t � 2.04, p � 0.060), menstrual normalization (t � −0.90, p � 0.39), and the incidence of irregular vaginal bleeding (t � 0.17, p � 0.867). e inverted funnel plots of the 3 outcomes were substantially symmetric.

Discussion
In recent years, some researchers have evaluated Fuke Qianjin tablets in the treatment of acute pelvic inflammation, chronic pelvic inflammation, and endometritis [17,[152][153][154]. It is considered that the clinical effect of Fuke Qianjin tablets combined with antibiotics is better than that of antibiotics alone, which is consistent with the conclusion of this study. e purpose of this study was to compare the efficacy and safety of gynecological Qianjin tablets combined with routine treatment in patients with pelvic inflammatory diseases. e results of this study showed that Fuke Qianjin tablets combined with conventional treatment have better efficacy outcomes for acute pelvic inflammatory disease, chronic pelvic inflammatory disease, and endometritis when compared to using antibiotics alone. Moreover, it can shorten the time of clinical symptom relief, reduce serum inflammatory factor concentration, improve endometrial thickness, improve menstruation, and reduce relapse rate. According to studies reports, the combined application of Fuke Qianjin tablets has no significant adverse reactions, suggesting a strong safety profile. e occurrence of pelvic inflammatory disease is not only related to a single bacterium. Studies have shown that 30-40% of pelvic inflammatory cases are caused by multibacterial infection [155]. erefore, it is necessary to provide broad-spectrum coverage of possible pathogens during treatment.
e results of the subgroup analysis showed that the efficacy of Fuke Qianjin tablets combined with antibiotics was not affected by antibiotic types. It demonstrated that Fuke Qianjin tablets are effective in the treatment of a variety of bacteria and have the therapeutic effect of broad-spectrum coverage. Evidence from the PEACH research suggests that short-term and long-term outcomes of oral and intravenous regimens are similar [156], so there is no subgroup analysis of antibiotic administration routes and courses in this study. In addition, two studies of Fuke Qianjin tablets compared with antibiotics (penicillin + metronidazole) showed that Fuke Qianjin tablet was more effective in the treatment of chronic pelvic inflammation. Due to the small number of literature included, more clinical studies need to be carried out to verify the clinical efficacy of Fuke Qianjin tablets alone.
Traditional Chinese medicine has multiple components, and its complexity means it has many potential targets. is makes it more difficult for bacteria to become resistant to it, which has a definite clinical advantage for PID. Fuke Qianjin tablet is extracted from herbs including Suberect spatholobus stem, Jin Ying Gen, Angelica sinensis, and Andrographis paniculata Nees. Suberect spatholobus stem has the effect of relaxing muscles and activating blood circulation; Jin Ying Gen has the effect of fixing essence and astringent intestines; Angelica sinensis has the effect of tonifying blood, harmonizing blood, regulating menstruation, and stopping bleeding; Andrographis paniculata Nees has the effect of cooling blood and detumescence, clearing heat, and detoxification. Related animal experiments and modern pharmacological studies [157][158][159][160][161] showed that Fuke Qianjin tablets may achieve the anti-inflammatory effect by regulating the concentration of serum TNF-α, NF-kB, IL-2, IL-6, and other factors to reduce the inflammatory response mediated by cellular inflammatory factors. It can also promote the production of IgA, IgG, and IgM [162], improve the body's immunity, play antibacterial and anti-inflammatory effects, and also improve the body's ability to resist infection. is demonstrated that in the future, due to the increasing resistance of pathogens to antibiotics,   Figure 5: Meta-analysis of total effective rate of chronic pelvic inflammatory disease. 16 Evidence-Based Complementary and Alternative Medicine traditional Chinese medicine may play a more important role in the treatment of PID anti-inflammatory. erefore, it is necessary to carry out a clinical study on the graded dose response of Fuke Qianjin tablets combined with antibiotics to explore whether the combined application can reduce the dose and frequency of antibiotics, so as to alleviate the situation of reduced efficacy due to increased antibiotic resistance.
Heterogeneity between studies is a key issue in metaanalysis. e existence of heterogeneity has an impact on the merger of research results and also directly affects the interpretation of meta-analysis results.
is research conducted a subgroup analysis and sensitivity analysis on the outcomes with high heterogeneity. rough a reexamination of studies with high heterogeneity and comparison with other studies, the stability of the sensitive   analysis results to determine the credibility of the research results and whether to retain the studies. In the meta-analysis of acute pelvic inflammatory disease, there was significant heterogeneity in some secondary outcome indicators, which was mainly caused by Zhao and Huang [29] and Fan [38]. e reverification of the two articles showed that the literature quality evaluation was moderately biased risk. After excluding the literature data, the result of meta-analysis was still significant, and the sensitivity analysis showed that the result was stable. In the meta-analysis of chronic pelvic inflammation, two secondary outcome indicators of the remission time of uterine pain and remission time of abdominal pain carried out subgroup analysis according to the course of treatment. e results showed that the heterogeneity significantly decreased, and the difference between the experimental group and the control group was still statistically significant. It can be considered that the results of meta-analysis of these two indicators were robust. Sensitivity analysis was performed on the two secondary outcome indicators of CRP and TNF-α concentration. e outcome indicator of TNF-α concentration has passed the sensitivity analysis, and the meta-analysis results of this indicator can be considered robust. e outcome indicator of CRP concentration in chronic pelvic inflammatory disease cannot pass the sensitivity analysis. It is considered that the reliability of the result of meta-analysis of this indicator was low, and the source of its heterogeneity needs to be further discussed.
is research still has certain limitations. First of all, affected by the quality of the original literature, only 2 articles of the original literature reported the specific   implementation of the blind method, and most of them did not report the specific implementation of the random method and the blind method, which may have some potential bias. Second, the subgroup analysis and sensitivity analysis of the secondary outcome indicators with heterogeneity showed that the results were robust. But the number of secondary outcome indicators reported in articles was very small, thereby potentially affecting the strength of the results. Finally, the clinical research of gynecological Fuke Qianjin tablets is only carried out across hospitals in China. e extrapolation of the results on an international scale maybe limited. In order to overcome the above limitations and verify the results of this study, additional high-quality randomized controlled trials that employ a larger sample size are required.

Conclusion
In order to systematically evaluate the efficacy of Fuke Qianjin tablets in the treatment of pelvic inflammatory diseases and endometritis, this study uses indicators such as total effective rate and incidence of adverse reactions to compare with the combined application of various conventional treatment programs. Results from 125 studies have been observed in the treatment of acute pelvic inflammatory disease, chronic pelvic inflammatory disease, and endometritis. Overall, these studies report positive effects of Fuke Qianjin tablets as adjuvant medication. In addition, the incidence of adverse reactions was not statistically different in the analyzed studies.
Data Availability e data generated or analyzed during this study are included within this published article. e data used to support the findings of this study have been deposited in the 7 electronic databases, including PubMed, e Cochrane Library, Web of science, CNKI, Wan Fang, VIP, and Sinomed.

Conflicts of Interest
e authors declare that they have no conflicts of interest.

Authors' Contributions
PJ was in charge of the main execution of the research and wrote the main part of the study. All authors contributed to data analysis and drafted and revised the article. Wentao supervised and instructed the study. All authors read and approved the final manuscript.