Kangfuxin (Periplaneta americana) Lotion for adjunctive treatment of ulcerative colitis: A systematic review and meta-analysis of randomized controlled trials

Xin-Lin Li; Ya-Jing Zhang; Bao-Yong Lai; Rui-Xue Hu; Nan-Qi Zhao; Mei Han; Jian-Ping Liu

doi:10.4103/wjtcm.wjtcm_11_18

ORIGINAL ARTICLE

Year : 2018 | Volume : 4 | Issue : 3 | Page : 77-84

Kangfuxin (Periplaneta americana) Lotion for adjunctive treatment of ulcerative colitis: A systematic review and meta-analysis of randomized controlled trials

Xin-Lin Li, Ya-Jing Zhang, Bao-Yong Lai, Rui-Xue Hu, Nan-Qi Zhao, Mei Han, Jian-Ping Liu
Center for Evidence Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China

Date of Submission	22-May-2018
Date of Acceptance	13-Aug-2018
Date of Web Publication	10-Oct-2018

Correspondence Address:
Jian-Ping Liu
Center for Evidence Based Chinese Medicine, Beijing University of Chinese Medicine, 11 North 3^rd East Road, Chaoyang, Beijing 100029
China

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/wjtcm.wjtcm_11_18

Abstract

Objective: The objective of the study is to investigate the effect of Kangfuxin lotion as adjunctive therapy for treating ulcerative colitis (UC) through a systematic review and meta-analysis of randomized controlled trials (RCTs). Materials and Methods: RCTs comparing Kangfuxin lotion with no treatment, placebo, western medications or combination therapy for treatment of UC were included in this study. Two English and three Chinese electronic databases were searched. All searches ended in December 2017. Data and quality assessment carried out respectively. RevMan 5.2 software (Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) was used to analyze with effect estimate presented as mean difference (MD), risk ratio (RR) and 95% confidence interval (CI). Results: Fifteen trials with 1050 participants were included in this review. Overall, 13 trials were eligible for meta-analysis. Kangfuxin lotion combined with Mesalazine was better than Mesalazine on clinical cure rate (RR 1.45, 95% CI 1.24–1.70, 7 trials), recurrence rate of UC (RR 0.22, 95% CI 0.07–0.72, 2 trials), or endoscopic mucosal recovery (RR 8.05, 95% CI 2.64–24.57, 2 trials). And Kangfuxin lotion combined with triple live bacteria tablets (Bifidobacterium-Lactobacillus- Streptococcus thermophilus)was superior with regard to symptoms remission rate (RR 5.36, 95% CI 1.73–16.60, 3 trials), endoscopic disease activity score (MD − 2.30, 95% CI − 2.64–−1.96, 1 trial). There were no reports on the serious adverse events of Kangfuxin lotion. Conclusion: Kangfuxin lotion as adjunctive treatment appears more effective than medications alone on clinical cure rate, recurrence rate, endoscopic mucosal recovery and improvement rate of related symptoms.

Keywords: Kangfuxin lotion, meta-analysis, randomized controlled trials, systematic review, ulcerative colitis

How to cite this article:
Li XL, Zhang YJ, Lai BY, Hu RX, Zhao NQ, Han M, Liu JP. Kangfuxin (Periplaneta americana) Lotion for adjunctive treatment of ulcerative colitis: A systematic review and meta-analysis of randomized controlled trials. World J Tradit Chin Med 2018;4:77-84

How to cite this URL:
Li XL, Zhang YJ, Lai BY, Hu RX, Zhao NQ, Han M, Liu JP. Kangfuxin (Periplaneta americana) Lotion for adjunctive treatment of ulcerative colitis: A systematic review and meta-analysis of randomized controlled trials. World J Tradit Chin Med [serial online] 2018 [cited 2023 Dec 1];4:77-84. Available from: https://www.wjtcm.net/text.asp?2018/4/3/77/243017

Introduction

Ulcerative colitis (UC) is caused by an abnormal immune response by body due to mistaken identity food, bacteria, and other materials in the intestine for foreign or invading substances by immune system.^[1] However, the etiology remains unknown. The large intestine is inflamed and ulcerated. Meanwhile, it can cause diarrhea, abdominal pain, rectal bleeding and fever. The pathogenesis of the disease is multifactorial and involves environmental, genetic and immunological factors.^[2] The clinical course is characterized by periods of remission or exacerbation, which may occur spontaneously or in response to treatment.^[3] Patients with UC have some common symptoms, such as bleeding, diarrhea and abdominal pain.^[4]

The incidence of UC has increased in several regions of the world over the past few years. The rate of developed countries is relatively stable or even declining. However, the number of cases has increased in developing regions, such as Asia, Latin America and Eastern Europe. What's more, the incidence of UC in different age was increasing, especially among children and adolescents.^[5] Currently, the treatment mainly used the western medicine, such as salicylates, which mainly treated mild and moderate UC patients; hormone drugs, which was used to treat severe and explosive type. There were also some auxiliary symptomatic treatments, for example, antibiotics, calcium antagonists and hyperbaric oxygen therapy.^[6] However, patients tended to obtain some discomfort symptoms when they received different kinds of western medicine, such as nausea, vomiting, abdominal pain, headache and insomnia.

Traditional Chinese medicine holds the idea that UC belongs to the disease category of “chronic diarrhea” and “spouting bleeding from anus”. The disease is mainly in the intestinal tract, and lesions involves multiple organs.^[7] There were some herbal medicine, such as Tongxieyaofang, would be suitable to treat UC.^[8] Moreover, herbal medicine also owns some advantages, such as less adverse drug reaction and good effect.^[9] While patients were reluctant to turn to Chinese doctors because of the bad taste and infusion of Chinese medicine. Kangfuxin lotion is extracted from America periplaneta,^[10] which can avoid the shortcomings of Chinese medicine. Moreover, in recent years, there is an increasing trend in using Kangfuxin lotion (patent medicine approved on April 30, 2010) as a prescription to treat UC. What's more, Kangfuxin lotion had the function of detoxification, eliminating blood stasis, softening masses and dispelling water swelling. In this study, we aim to systematically analyze Kangfuxin lotion as adjunctive therapy for treating UC.

Materials and Methods

Inclusion criteria

We included parallel randomized controlled trials (RCTs) of Kangfuxin lotion alone compared with no treatment, placebo or western medications in patients with UC. In addition, we also included combined therapy with Kangfuxin lotion and other western medicine compared with western medicine alone. Participants could be any age, sex or ethnic origin. There was no limitation to the UC stage. UC had to be diagnosed according to fiber colonoscopy and recognized criteria. Outcome measures were related to two parts. Main outcome measures referred to clinical cure rate (clinical symptoms disappeared completely), clinical remission rate (part of symptoms improved) and recurrence rate. Secondary outcome measures were endoscopic mucosal recovery, therapeutic effect of improving abdominal pain, diarrhea, pus and blood stool, and adverse drug reactions (related to treatment). Duplicate publications were excluded from the study. Publications in all languages were eligible.

Search strategy

We searched for eligible studies at the China Network Knowledge Infrastructure (CNKI; 1979–2017), Chinese VIP Information (1989–2017), WanFang Database (1995–2017), PubMed (1966–2017), and Cochrane Library (Issue 1, 2017). Meanwhile, we searched relevant comments on previously published series for potentially usable information. All searches ended in December 2017. The search terms included “UC” combined with “Kangfuxin lotion” “Kangfuxinye” or “Kangfuxin Liquid”.

Studies screening

Two authors (Li XL and Zhang YJ) assessed studies for eligibility against the inclusion criteria independently. And, any inconsistency in this process was resolved by the third person (Liu JP).

Data extraction

Two of three authors (Lai BY, Hu RX and Zhao NQ) evaluated all articles by title and abstract independently. According to self-designed data extraction form, two authors extracted information including study characteristics such as studies design, sample size, method for statistical analysis, inclusion and exclusion criteria, baseline characteristics of participants, interventions, treatment duration, outcome measures, and adverse events. The classification of outcome was confirmed as clinical cure, the symptoms remission and ineffectiveness through prediscussion. Any disagreement was resolved through discussion.

Quality assessment

Two authors (Li XL and Zhang YJ) applied the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0)^[11] to assess the methodological quality of the included studies. Seven items were judged as “low risk”, “high risk” or “unclear risk”. The items included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. Any disagreement was resolved by discussion with the third author (Liu JP).

Data analysis

Data were summarized using risk ratio (RR) with 95% confidence interval (CI) for binary outcomes. Continuous data was expressed as mean difference (MD) with 95% CI. Meta-analysis was used if the studies had acceptable homogeneity of study design, participants, interventions, control and outcome measures. Statistical heterogeneity was tested by examining I².^[11] It indicated the possibility of statistical heterogeneity if I² > 50%. Both a fixed-effect model and a random-effect model were used if there was a possibility of statistical heterogeneity among the studies. A fixed-effect model (I² < 50%) was used for meta-analysis. Subgroup analysis was conducted to determine the evidence for the different inventions. A funnel plot was applied to detect the publication bias.

Results

Description of studies

After primary searching in five databases, 673 studies were identified. The reasons for exclusion were obvious ineligibility. A total of 230 studies were excluded as studies duplication, and 139 studies were irrelevant to the treatment of UC. Then, we retrieved full-text papers of 304 studies for further identification. Through screened full text, we finally included 15 studies^{[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26]} [Figure 1].

Figure 1: Flow chart of study selection

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All of 15 RCTs were conducted in China and published in Chinese. The 15 studies involved a total of 1050 participants. The participants were aged 5–67 years old, and the treatment duration was from 2 to 8 weeks. All studies were two-arm design. The included studies applied national criteria for diagnosing UC. The interventions of the therapy group included the combination of Kangfuxin lotion and Mesalazine, Sulfasalazine (SASP), Xilei power and triple live bacteria tablets (Bifidobacterium-Lactobacillus- Streptococcus thermophilus). Meanwhile, the control group received usual care, Mesalazine, SASP, Xilei power and triple live bacteria tablets alone.

Kangfuxin lotion were administered by oral and enema. The characteristics of included randomized controlled studies that Kangfuxin lotion for adjunctive treatment of UC were listed in [Table 1].

Table 1: Characteristics of included randomized controlled studies that Kangfuxin lotion for adjunctive treatment of ulcerative colitis

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Methodological quality

According to our predefined quality assessment criteria, one^[18] included trial was evaluated as low risk of bias. While nine trials were evaluated as high risk of bias. The other five trials^{[21],[23],[24],[25],[26]} were an unclear risk of bias because the authors could not be contacted through E-mail or phone [Figure 2]. The sample size varied from 39 to 132 participants. Only 4 trials^{[13],[18],[23],[26]} described randomization procedure (random number table). Two trials did not report randomization, so that were assessed as high risk. Other trials did not report the aspect of randomization clearly so we assessed them as unclear bias. Most included studies did not report adequate allocation concealment except one clinical trial.^[18] 5 trials^{[12],[13],[16],[20],[22]} blinded participants. And only one trial blinded both participants and assessors.^[18] None of the included trials used intention-to-treat analysis. All trials were consistent with the number of participants randomized and reported. So for attrition bias, the trials were assessed as low risk of bias. For reporting bias, protocols were unavailable for most studies except one clinical trial.^[18] Hence, we had to check the methods and results sections. All trials reported outcome measurements in accordant with the method part described.

Figure 2: Risk of bias summary: review author's judgments about each methodological quality items for each included study

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Effect estimates

Eight trials^{[12],[15],[17],[19],[20],[21],[22],[25]} tested Kangfuxin lotion combined with Mesalazine versus Mesalazine alone for treating UC. Three trials^{[13],[24],[26]} compared the combination therapy of Kangfuxin lotion and triple live bacteria tablets with triple live bacteria tablets alone. Meanwhile, two trials^[14],[16] compared the combination of Kangfuxin lotion and SASP with SASP alone for treating UC.

One trial^[18] observed the comparison between Kangfuxin lotion combined with Xilei power and Xilei power. Another one^[23] tested the effect of the combination therapy of Kangfuxin lotion plus Mesalazine and triple live bacteria tablets. However, one trial could not perform a meaningful meta-analysis. Due to the insufficient number of the included trials in one meta-analysis, we could not perform a meaningful funnel plot analysis. Results of meta-analysis were listed in [Table 2] (estimate effect of included studies in meta-analysis).

Table 2: Estimated effect sizes of included randomized studies in systematic review

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Effect of intervention

Clinical cure rate

When clinical symptoms disappeared totally, it was defined clinical cure. Seven trials evaluating Kangfuxin lotion combined with Mesalazine provided information on clinical cure rate. And, we used fixed model to analysis because the heterogeneity was I²< 50%. In meta-analysis, Kangfuxin lotion combined with Mesalazine was superior to Mesalazine alone on clinical cure rate (RR 1.45, 95% CI 1.24–1.70, 516 participants, 7 trials). The other three trials applied to different inventions provided information on clinical cure rate. Three trials, which used the combination therapy that Kangfuxin lotion and SASP, Xilei power, or triple live bacteria tablets plus Mesalazine separately as inventions, showed no statistical difference compared to SASP^[14] (RR 1.63, 95% CI 0.74–3.59, 104 participants, 1 trial), Xilei power^[18] (RR 2.00, 95% CI 0.58–6.91, 40 participants, 1 trial), and triple live bacteria tablets plus Mesalazine^[23] (RR 1.33, 95% CI 0.54–3.29, 50 participants, 1 trial) alone on clinical cure rate.

Symptoms remission rate

Symptoms remission showed that the symptoms had clinical improvement or disappearance of some symptoms basically. There were eight trials using Kangfuxin lotion combined with Mesalazine as inventions. In this meta-analysis, fixed model was used due to low statistical heterogeneity. There had no difference between Kangfuxin lotion combined with Mesalazine and Mesalazine alone on symptoms remission rate (RR 0.73, 95% CI 0.48–1.11, 596 participants, 8 trials). Meta-analysis of three trials showed that the therapy of Kangfuxin lotion combined with triple live bacteria tablets was better than triple live bacteria tablets alone related to symptoms remission rate (RR 5.36, 95% CI 1.73–16.60, 206 participants, 3 trials).

And, another two trials provided information on symptoms remission rate, which used Kangfuxin lotion combined with SASP versus SASP alone. Random model was used due to high statistical heterogeneity. Through analysis, the result showed no difference between groups, either (RR 2.35, 95% CI 0.53–10.29, 164 participants, 2 trials). Meanwhile, two trials applied different inventions showed that no difference was found between groups, which applied Kangfuxin lotion with Xilei power^[18] (RR 1.24, 95% CI 0.34–4.46, 40 participants, 1 trial), triple live bacteria tablets plus Mesalazine^[23] (RR 1.40, 95% CI 0.45–4.35, 50 participants, 1 trial) separately.

Recurrence rate

There were two trials^[15],[21] involving Kangfuxin lotion combined with Mesalazine compared with Mesalazine alone. Fixed model was used due to low statistical heterogeneity. There was significantly effective for reducing the recurrence rate of UC when applied the combination therapy that Kangfuxin lotion combined with Mesalazine (RR 0.22, 95% CI 0.07–0.72, 128 participants, 2 trials). Moreover, another one trial^[16] showed an advantage of Kangfuxin lotion combined with SASP on reducing recurrence rate (RR 0.25, 95% CI 0.07–0.91, 48 participants, 1 trial). However, no difference was found on improving recurrence rate between the combination therapy that Kangfuxin lotion plus Xilei power compared with Xilei power^[18] (RR 1.00, 95% CI 0.13–7.89, 40 participants, 1 trial).

Endoscopic mucosal recovery rate

Meta-analysis showed that Kangfuxin lotion combined with Mesalazine was superior to Mesalazine alone^[12],[22] for endoscopic mucosal recovery (RR 8.05, 95% CI 2.64–24.57, 192 participants, 2 trials). The trial^[13] showed the Kangfuxin lotion with triple live bacteria tablets was superior to triple live bacteria tablets alone on endoscopic disease activity score (12 points) (MD − 2.30, 95% CI 2.64–1.96, 68 participants, 1 trial).

There was another trial,^[23] which used Kangfuxin lotion combined with Mesalazine plus triple live bacteria tablets, showed no difference compared with Mesalazine plus triple live bacteria tablets alone (RR 3.63, 95% CI 0.66–20.11, 50 participants, 1 trial). Meanwhile, Kangfuxin lotion combined with Xilei power also showed no difference compared with Xilei power for endoscopic mucosal recovery (RR 6.33, 95% CI 0.67–60.16, 40 participants, 1 trial).

Improvement rate of abdominal pain, diarrhea, pus, and blood stool

There were two trials reported improvement rate of abdominal pain, diarrhea, pus and blood stool, which applied Kangfuxin lotion combined with different inventions, such as SASP and Xilei power. One trial^[14] evaluated therapeutic effect of Kangfuxin lotion with SASP was superior to SASP alone on improving abdominal pain (RR 4.71, 95% CI 2.05–10.85, 104 participants, 1 trial), diarrhea (RR 4.63, 95% CI 2.03–10.58, 104 participants, 1 trial), and pus and blood stool (RR 2.33, 95% CI 1.02–5.28, 104 participants, 1 trial).

And another trial,^[18] which applied Kangfuxin lotion combined with Xilei power as inventions, showed no difference compared with Xilei powder alone on the aspect of improving abdominal pain (RR 4.75, 95% CI 0.48–46.91, 40 participants, 1 trial), diarrhea (RR 2.25, 95% CI 0.36–13.97, 40 participants, 1 trial), and pus and blood stool (RR 3.86, 95% CI 0.67–22.11, 40 participants, 1 trial).

Adverse events

Five trials mentioned information about adverse events. There were different adverse events reported in the treatment group, which applied combination therapy of Kangfuxin lotion and Mesalazine. The adverse events involved nausea^[19] (n = 3 patients), vomit^[15] (n = 1 patient), and fecal occult blood^[17] (n = 5 patients). The control group applying Mesalazine alone involved nausea^[19] (n = 5 patients) and fecal occult blood^[17] (n = 6 patients). There were two trials applied Kangfuxin lotion with triple live bacteria tablets as intervention, which adverse events included dizzy^[13],[24] (n = 4 patients), nausea^[13],[24] (n = 4 patients), headache^[13],[24] (n = 2 patients) in treatment group. And in control group, there were dizzy^[13],[24] (n = 4 patients), nausea^[13],[24] (n = 2 patients), and headache^[13],[24] (n = 2 patients). All studies measured outcomes at the end of the treatment. No studies reported long-term follow-up after the treatment.

Discussion

This review provided information that the combined therapy of Kangfuxin lotion with other medicine, such as Mesalazine, SASP, triple live bacteria tablets and Xilei power. Kangfuxin lotion combined with Mesalazine was effective on clinical cure rate, recurrence rate of UC, or endoscopic mucosal recovery. And Kangfuxin lotion combined with triple live bacteria tablets was better than triple live bacteria tablets alone with regard to clinical remission rate, endoscopic mucosal recovery. Meanwhile, SASP with Kangfuxin lotion as adjunctive therapy showed more effective than SASP alone on the aspect of improving recurrence rate, abdominal pain, diarrhea, and pus and blood stool.

Through screening the database, there was few studies analyzing the effect of Kangfuxin lotion systematically. Most studies just evaluated curative effect through clinical studies. The study just made up this insufficient. But there were some limitations of this review. The methodological quality of the included studies was generally poor. According to the analysis of the methodological reporting, only three included studies mentioned the detailed method of randomization, although the other studies just mentioned that the participants were randomly grouped. Almost all studies did not refer to blinding methods. Furthermore, the intervention group included several kinds of western medicine. Several studies used two or more drugs as combination therapy. Although this could enrich treatment, this nonuniform approach also reduced the comparability of the included studies.

Through subgroup meta-analysis, the results showed that the combination therapy of Kangfuxin lotion might improve the symptoms. However, there were some disadvantages, such as the small sample size and unclear or high risk of bias of the current included trials. And no study applied placebo as comparison, we cannot evaluate the effect of Kangfuxin lotion. Hence, we suggest that placebo can be applied as control invention for evaluating the effect of Kangfuxin lotion in the future studies. Meanwhile, this review suggests that the evidence on the use of herbal medicine for UC is insufficient. The available data indicates that Kangfuxin lotion and the combination therapy with herbal medicine and western medication, might improve symptoms of UC. Further high-quality studies of sufficient sample size are needed to assess the effectiveness of herbal medicine in treating UC. Randomization methods need to be reported with more rigorous details. Researchers should adhere to the standards of CONSORT^[27] for trial reporting. And details of methods and results should be fully addressed.

Conclusion

Kangfuxin lotion as adjunctive therapy appears to be effective for improving UC on clinical cure rate, symptoms remission rate, recurrence rate, endoscopic mucosal recovery, improvement rate of abdominal pain, diarrhea, pus and blood stool. However, further larger and rigorously designed studies are warranted due to insufficient methodological rigor in the included studies.

Financial support and sponsorship

This work was supported by Capacity Building in Evidence-based Chinese Medicine and Internationalization Project (1000061020008).

Conflicts of interest

There are no conflicts of interest.

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