Therapeutic Efficacy of Kangfuxin Liquid Combined with PPIs in Gastric Ulcer

Objective To evaluate the clinical efficacy and safety of Kangfuxin liquid (KFX) combined with proton pump inhibitors (PPIs) in the treatment of gastric ulcer (GU). Materials and Methods Electronic databases including PubMed, Wanfang, CNKI, VIP, Embase, Cochrane Library, and CBM were examined for appropriate articles without language limitations on key words before March 10, 2019. RevMan 5.3 software was applied to execute outcome assessment and finish the meta-analysis. Results 22 articles involving 2,024 patients with a gastric ulcer were selected. Total efficacy rate and efficacy rate of gastroscopy were significantly enhanced for the combination of KFX with PPIs compared to those of PPI treatment alone (OR = 6.95, 95% CI: 4.87, 9.91, P < 0.00001; OR = 2.96, 95% CI: 1.98, 4.42, P < 0.00001, respectively). Same results were found for different PPIs in combination on total efficacy rate, respectively. The combination also significantly reduced the adverse events (OR = 0.39, 95% CI: 0.22, 0.70, P=0.002). In addition, KFX combined with PPI could suppress the inflammation (MD = −6.11, 95% CI: −7.45, −4.77, P < 0.00001), reduce the recurrence rate (OR = 0.31, 95% CI: 0.14, 0.70, P=0.005), and enhance the clearance rate of Helicobacter pylori (HP, OR = 3.76, 95% CI: 1.80, 7.87, P=0.0004). It seemed like the combination would influence immune function by increasing levels of T-lymphocyte subsets CD4 and CD8 but not CD3 (MD = 2.40, 95% CI: 1.25, 3.55, P < 0.0001); MD = 25.72, 95% CI: 14.55, 36.90, P < 0.00001; MD = 0.72, 95% CI: −0.66, 2.09, P=0.31, respectively). Conclusion KFX combined with PPIs in treatment of patients with GU could improve the total efficacy rate and efficacy rate of gastroscopy and reduce adverse events and the recurrence rate. However, the results of this study should be handled with care due to the limitations. Several rigorous RCTs are in need to confirm these findings.


Introduction
Peptic ulcer (PU) is a common and prevalent disease worldwide. Infection of Helicobacter pylori (HP), nonsteroidal anti-inflammatory drugs (NSAIDs), and aspirin drug usage are considered to be the major causative factors of PU. Taking other medications including glucocorticoids, some antitumor drugs, and anticoagulant drugs is also inducements for PU, which cannot be neglected [1]. Prevalence rates of PU reach up to 5%-10% in 2009 [2] and continue to rise due to unhealthy lifestyle, drug usage, and diet custom. Gastric ulcer (GU) is one of the common types appearing mostly in middle-aged and elderly people [3].
Suppressing gastric acid production is the most important measure to relieve clinical symptoms and promote healing. Proton pump inhibitors (PPIs) are the initial therapy for GU [4]. e first generation PPIs includes omeprazole, pantoprazole, and lansoprazole. e second generation PPIs including esomeprazole, ilaprazole, and rabeprazole have faster onset time, longer action time, and fewer side effects. PPIs are the best drugs for treating acidrelated diseases in the last dozen years. e medication amount of PPIs in domestic hospitals of 16 key cities in China reached 4.5 billion yuan in 2016 with an increase of 6% over the previous year, and it still presents a rising trend [5]. But long-term use of PPIs can cause a series of new safety issues, such as adverse renal effects [6], hypomagnesaemia [7], increased risk of dementia [8], increased risk of infection and osteoporosis [9], fracture risk [10], vitamin B12 deficiency, occurrence or development of atrophic gastritis, interstitial nephritis, microscopic colitis, increased risk of serious skin allergy, and so on [11,12]. Combination with traditional Chinese medicine provides an alternative to improve the current situation of PPI usage. Kangfuxin liquid (KFX) is a Chinese patent medicine extracted from Periplaneta americana. China Food and Drug Administration (CFDA) approved it in 1998. As an animal medicine, amino acids are considered as the main ingredients which are used as quality control for preparation. Efficacy of KFX is described as promoting blood circulation, nourishing yin, and promoting granulation. For oral administration, it is used for gore block, stomach bleeding, gastric and duodenal ulcers, phthisis with yin deficiency, and aiding in the treatment of tuberculosis. For external application, it is used for treating incised wound, trauma, ulcers, fistula, burns, and bedsore. Amounts of clinical trials have demonstrated that KFX is beneficial to cure GU [13][14][15], which is also supported by animal experiments [16]. Previous meta-analysis confirmed that KFX combined with PPIs was superior to PPIs alone in the treatment of GU [17,18]. We provide an updated and extended meta-analysis with detailed information for efficacy ( Figure 1).

Methods and Program
2.1. Literature Retrieval Strategy. Keywords "kangfuxin (KFX)" [Title/Abstract] OR "Periplaneta americana" [Title/Abstract] AND "Gastric ulcer" [Title/Abstract] OR "peptic ulcer" [Title/Abstract] OR "digestive ulcer" [Title/ Abstract] OR "PPI" (including Esomeprazole, Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole) [Title/ Abstract] were used as search items in electronic databases including PubMed, Wanfang, CNKI, VIP, Embase, Cochrane Library, and CBM. Articles published before March 10, 2019, was examined without language limitations in order to obtain a comprehensive retrieval. All relevant articles were downloaded into EndNote software (version X7, omson Reuters, Inc., New York, USA) for further exploration. Duplicate records were integrated. Full-text review was performed while the title/abstract was thought to be thematic. e job above was executed by two investigators independently. Conflicts were resolved by consensus and discussion.

Inclusion and Exclusion Criteria.
Based on the suggestions of a gastroenterologist, we designed the inclusion criteria as follows: (1) [19], or carrying out gastroscopy. (2) All trials mentioned were confined as RCTs. (3) Patients in treatment groups received KFX solution combined with PPI while control groups received PPI alone. (4) e total efficacy rate was the least outcome measurement to be reported.
We also designed the exclusion criteria as follows: (1) References such as reviews, case reports, animal experiments, comments, and so on that are thought to be athematic. (2) e diagnostic standard in the statement was ambiguous. (3) Trials emphasized on other peptic ulcers but not gastric ulcer. (4) Trials mentioned other interventions of essential treatment to GU but not only PPI alone.

Characteristics of Study Assessment.
Information including methods, participants, interventions, and outcomes was extracted and arranged (Tables 1 and 2). Characteristics of included studies were assessed by two searchers independently according to the Cochrane Handbook for Systematic Reviews of Interventions [41]. Disagreement was resolved by the consensus. Risk of bias was evaluated as follows: random sequence generation (A, selection bias), allocation concealment (B, selection bias), blinding of participants and personnel (C, performance bias), blinding of outcome assessment (D, detection bias), incomplete outcome data (E, attrition bias), selective reporting (F, reporting bias), and other biases (G). ree levels were applied to judge the quality of each item. "Low risk" indicates description of methods or procedures was adequate while "high risk" means not adequate or incorrect and "unclear risk" means missing description.

Data
Analysis. Data analysis was performed using Review Manager 5.3 (Cochrane Collaboration). Outcome indices such as total efficacy rate and efficacy rate of gastroscopy were regarded as dichotomous variables and presented as the odds ratio (OR) with 95% confidence intervals (95% CI). Levels of inflammatory cytokines such as IL-6, TNF-α, and TGF-β1 and T-lymphocyte subsets including CD3, CD4, and CD8 were continuous variables which were presented as the mean difference (MD) with 95% CI. Q statistic and I 2 tests were applied to assess the heterogeneity among studies. A fixed-effects model was used to analyze data with low heterogeneity (P > 0.1 and I 2 ≤ 50%), while a random-effects model was used to analyze data with high heterogeneity (P < 0.1 or I 2 > 50%). Potential publication bias was revealed by funnel plots.

Characteristics of the Eligible Studies.
Six hundred eighty-eight articles were identified through database searching, in which 386 articles were removed as duplicates. Evidence-Based Complementary and Alternative Medicine disqualification. en, 187 articles remained for further fulltext review. 165 studies were excluded in this procedure for the following reasons: diagnosis in 86 articles was vague, 51 studies mentioned unfit interventions, 24 studies were single-arm designs, and 4 articles were the recurrence of the same trial. 22 studies 42] were included in quantitative synthesis finally ( Figure 2). Two thousand twenty-four patients with a gastric ulcer (1045 cases in the experimental group and 979 cases in the control group) were taken in this meta-analysis. e age of the patients ranged from 17 to 75 years, and there was no obvious difference in terms of age and sex between the two groups (Table 1). Trials were conducted between 2007 and 2017, and all were RCTs with a comparison between a combination of KFX solution and PPI and PPI treatment alone. 4 studies [20,21,22,23] reported the combination with esomeprazole, 5 with omeprazole [24][25][26][27]39], 3 with lansoprazole [28][29][30], 3 with rabeprazole [31][32][33], and 7 with pantoprazole [34-38, 40, 42]. e treatment duration ranged from 1 to 4 weeks, and 2 articles [24,40] reported a follow-up which ranged from half a year to 1 year. 10 trials [22,26,27,29,34,36,[38][39][40]42] reported adverse events and side effects. All trials reported a total efficacy rate in outcome measures, 15 studies [20-24, 27-32, 34, 35, 37, 38] reported the efficacy rate of gastroscopy, 3 studies [25,34,39] reported the clearance of HP, 2 studies [24,39] reported the recurrence rate, and 2 trials [29,34] reported the levels of inflammatory cytokines and T-lymphocyte subsets ( Table 2).

Quality of Included Trials Assessment.
According to the Cochrane risk of bias estimation, all trials mentioned a randomized allocation of participants while 1 trial used a wrong method, so the selection bias (A) on random sequence generation was considered to be "low risk." Detailed information on allocation concealment, blinding of participants and personnel, and blinding of outcome assessment of all studies was ambiguous even wrong, from which the selection bias (B) on allocation concealment, performance bias (C), and detection bias (D) were identified as "unclear risk." All experimental data included in articles were complete, so the attrition bias (E) and reporting bias (F) were considered to be low for 22 trials. ere was insufficient information to assess the existence of other significant risk of bias, so other bias (G) of included trials were determined as "unclear risk."  Evidence-Based Complementary and Alternative Medicine 3∼4 days while 2 points means every 2 days, and 3 points means each day. e aggregate score was further divided into three levels: excellent, efficacious, and inefficient. All studies reported the total efficacy rate. A meta-analysis of these trials using a fixed-effect model demonstrated that KFX combined with PPI treatment significantly improved the total efficacy rate in the treatment of gastric ulcers (OR � 6.95, 95% CI: 4.87, 9.91; P < 0.00001).
A fixed-effect model was applied to finish the abovementioned meta-analysis ( Figure 5).

Clearance Rate of HP.
Helicobacter Pylori (HP) was thought to be the mainly inducing factor of GU. 3 studies [25,34,39] provided the clearance rate of HP in clinical treatment. A fixed-effect model analysis proved that the combination of KFX and PPI treatment enhanced the clearance of HP significantly (OR � 3.76, 95% CI: 1.80, 7.87; P � 0.0004). No statistically significant heterogeneity was found among individual studies (P � 0.62, I 2 � 0%; Figure 9(b)).

Publication Bias.
A funnel plot was used to express publication bias. When the indices were provided by more than 9 cases, the publication was explored. In the present study, the funnel plot of combination of KFX and PPIs versus PPIs therapy alone on total efficacy rate and adverse events was applied. e plots were generally symmetric, suggesting that there was no obvious publication bias (Figures 10(a) and 10(b)).

Discussion
"No acid, no ulcer" said by Schwartz indicated that excessive gastric acid secretion and GU are highly related. PPIs are the very class of medicines that are invited to decrease gastric acid secretion via inhibiting the H + /K + -ATP pump of the parietal cell. United States Food and Drug Administration (FDA) approved the first PPI omeprazole in 1980s. Today, 5 other PPIs are also employed to treat a variety of acid-related conditions such as duodenal ulcers, gastric ulcers, and Helicobacter pylori eradication. PPIs are widely accepted to be the most effective treatment for symptom relief of gastrooesophageal reflux [43][44][45]. Due to its good effect and the growing number of PPIs available over-the-counter, market of PPIs booms rapidly. However, accompanied by continuous appearance of adverse effects we discussed earlier, some scholars expressed concern about unnecessary use of PPIs which is so high in their latest review [46]. e huge market sales in China suggest that the consumption of PPIs  Figure 4: Forest plot of the total efficacy rate in patients treated with KFX + different PPI and PPI alone. I 2 and P are the criteria for the heterogeneity test; ◆, pooled odds ratio; -■-, odds ratio; and 95% CI. 8 Evidence-Based Complementary and Alternative Medicine is very enormous [5]. Scholars in China also put an immense concern on overmedication of PPIs [11]. Actions should be taken to pull back PPIs to the road of rational drug use.
Periplaneta americana also known as cockroach is an insect of Blattodea recorded most early in "Sheng Nong's herbal classic." It was classified as middle grade. CFDA has  [47,48]. Recent meta-analysis conformed that KFX combined with PPIs was superior to PPIs alone in the treatment of GU in total efficacy rate [17,18]. Here, in this paper, we further affirmed these findings and report an extended result. Compared to PPIs therapy alone, combination with KFX exerted significant improvement in total efficacy rate and efficacy rate of gastroscopy (P < 0.00001, P < 0.00001, respectively). e combination also reduced the adverse events and the recurrence rate (P � 0.002, P � 0.005, respectively). It was also associated with a significant enhancement of HP clearance (P � 0.0004). e efficacy may be associated with relieving the inflammation of patients (P < 0.00001) but not boosting immunity (P � 0.12). Conclusions on recurrence rate, clearance of HP, inflammatory cytokines, and T-lymphocyte subsets are based on only two or three small-sample studies which should be treated with caution. We also performed a subgroup analysis on KFX combined with different PPIs on total efficacy rate. No obvious difference was found between PPIs though the second generation PPIs including esomeprazole and rabeprazole was claimed for having better affects. Firstly, we apologized  for the limitations of our work, but we also found an explanation in the methodologies of trials included. Most of the trials put a final assessment on improvement of total efficacy rate instead of interval evaluation that may lead to a different conclusion. ree articles [27,40,42] reported anaphylaxis, such as rash of PPIs, which reminds us that we should also pay attention to adverse reactions in short-term medication.
e US FDA issued a warning on all PPIs in 2010 stating that patients should use the lowest dose and shortest duration of PPI therapy due to the increased risks [46]. Combination with TCM should be taken into consideration for effect-enhancing and/or side effectmitigating. e current research is not registered, and there may be a small offset, but the meta-analysis was produced strictly in accordance with the process of systematic review. However, due to the low quality of clinic trials cited, the accuracy of the results in this paper will be affected to some extent and should be handled cautiously.  Figure 9: Forest plot of (a) the recurrence rate and (b) the clearance of HP in patients treated with KFX + PPI and PPI alone. I 2 and P are the criteria for the heterogeneity test; ◆, pooled odds ratio; -■-, odds ratio; and 95% CI.

Conclusion
ese findings indicate that the combination of KFX and PPIs may significantly improve the total efficacy rate and efficacy rate of gastroscopy and reduce clinical adverse events. Due to the small sample size and limitations of this study, we sound a cautious note that KFX combined with PPIs may relieve the inflammation of patients, boost immunity, reduce recurrence rate, and enhance the clearance of HP. However, our findings must be handled with care because of the low quality of clinic trials cited. Other rigorous and large-scale RCTs are in need to confirm these results.

Disclosure
Junbo Zou and Xiaofei Zhang are co-first authors.

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