Reinforced education improves the quality of bowel preparation for colonoscopy: An updated meta-analysis of randomized controlled trials

Background and aims Inadequate bowel preparation (BP) is an unfavorable factor that influence the success of colonoscopy. Although standard education (SE) given to patients are proved useful to avoid inadequate BP. Studies concerning the effects of reinforced education (RE) on the quality of BP were inconsistent. The aim of this updated meta-analysis of randomized controlled trial was to compare the quality of BP between patients receiving RE in addition to SE and those receiving SE alone. Methods MEDLINE, EMBASE, Web of Science and the Cochrane Library were systemically searched to identify the relevant studies published through April 2019. The primary outcome was the rate of adequate BP. Subgroup analyses were conducted. Secondary outcomes included BP score, adenoma detection rate (ADR), polyp detection rate (PDR), insertion time, withdrawal time, adverse events, >80% purgative intake and diet compliance. Dichotomous variables were reported as odds ratio (OR) with 95% confidence interval (CI). Continuous data were reported as mean difference (MD) with 95%CI. Pooled estimates of OR or MD were calculated using a random-effects model. Statistical heterogeneity was accessed by calculating the I2 value. A P value less than 0.05 was considered significant. Results A total of 18 randomized controlled trails (N = 6536) were included in this meta-analysis. Patients who received RE had a better BP quality than those only receiving SE (OR 2.59, 95%CI: 2.09–3.19; P<0.001). A higher ADR (OR 1.35; 95%CI: 1.06–1.72; P = 0.020) and PDR (OR 1.24, 95%CI: 1.02–1.50; P = 0.030), shorter insertion (MD -0.76; 95%CI: -1.48-(-0.04); P = 0.040) and withdrawal time (MD -0.83; 95%CI: -1.83-(-0.28); P = 0.003), less nausea/vomiting (OR 0.78; 95%CI: 0.64–0.97; P = 0.020) and abdominal distension (OR 0.72; 95%CI: 0.68–0.92; P = 0.020) were achieved in the RE group. More patients had >80% purgative intake (OR 2.17; 95%CI, 1.09–4.32; P = 0.030) and were compliant with diet restriction (OR 2.38; 95%CI: 1.79–3.17; P<0.001) in the RE group. Conclusion RE significantly improved BP quality, increased ADR and PDR, decreased insertion and withdrawal time and adverse events.


Introduction
Screening colonoscopies have been shown to decrease colorectal cancer incidence and mortality [1,2]. High quality of bowel preparation (BP) is an essential factor of the success of colonoscopy. According to European Society of Gastrointestinal Endoscopy (ESGE) guideline, a �90% minimum standard for adequate BP was recommended [3]. However, about 18%-30.5% of the patients had an inadequate prepared colon in clinical practice [4,5]. Inadequate BP leads to a higher rate of missed polyps or adenomas, increased healthcare cost, prolonged total procedural time and cancelled procedures [6][7][8]. According to recommendations from the US multi-society task force on colorectal cancer, patients should be provided with education instructions for all components of the colonoscopy preparation and emphasize the importance of compliance [9]. The latest ESGE guideline also recommended the use of enhanced instructions for BP [10].
In an effort to improve BP quality, researchers realized that regular oral or written instructions were insufficient and have focused on the strengthening of the instructions to patients before colonoscopy. In the early stage, additional explanations by a senior gastroenterologist were used to explain to patients according to their incorrect questionnaires [11]. Then, pictures [12], cartoon visual aids [13], booklets [14,15] and even videos [16] were applied. With the development of economy and technology and the popularization of digital devices, phone call [17,18], short message service [19,20], smart phone applications [21,22], social media [23] and online video [24] were employed to reinforce patients' education. However, the conclusions were inconsistent.
Four previous meta-analysis [25][26][27][28] have been published to systemically compare the adequacy of BP among patients receiving enhanced instructions and standard education. The design and search strategies of these studies were different. Chang et al's study [25] was the first meta-analysis determining the effect of educational intervention on BP quality. Although 9 RCTs (n = 2885) were included, three of them were abstracts. Desai et al [28] enrolled 6 studies, which only detected smartphone applications on BP quality compared with standard education (n = 810). Kurlander et al [26] enrolled 7 studies with full articles (n = 2660), however, two of them were not RCTs. In 2017, our team made comparisons of BP quality between patients receiving enhanced instructions plus regular instructions and regular instructions alone [27]. 8 RCTs (n = 3795) with full texts were enrolled. However, the literature search time were up to 2015. In the past 4 years, additional 10 high-quality clinical trials have been published [14, 16, 19-21, 24, 29-32]. The results, however, seemed to be conflicting. Therefore, here we further performed an updated meta-analysis to evaluate the influence of reinforced educations on the improvement of BP quality other outcomes.

Study selection
The included studies were required to fulfill the following inclusion criteria: 1, study design: RCTs with full text; 2, study participants: patients �18 years old who underwent colonoscopy including both hospitalized patients and outpatients; 3, the primary or secondary outcomes included the rate of adequate BP; 4, study design: patients in the intervention group received reinforced educations by a certain of tool based on standard instruction, while patients in the control group received standard instructions; 5, there should be a qualified scale evaluating the degree of cleansing of colon. SE meant oral instructions, written instructions or oral plus written instructions associated with bowel preparation, which was provided by physicians or nurses before colonoscopy. The contents of SE included diet restriction, the time and methods of drinking purgatives. RE referred to additional, enhanced instructions based on SE, which was realized by providing some certain of methods or tools. The contents of SE and RE were generally the same.

Study outcomes
The primary outcome was the rate of adequate bowel preparation. For the evaluation of BP quality, 5 BP scales were used, including Boston Bowel Preparation Scale (BBPS) [33], Ottawa Bowel Preparation Scale (OBPS) [34], Universal Preparation Assessment Scale (UPAS) [11], Harefield Cleansing Scale (HCS) [35] and Aronchick scale [36]. The adequacy of BP was defined by BBPS score �5, OBPS score <6, UBPS score <3 or HCS grade A or B. The secondary outcomes included BBPS or OBPS scores, adenoma or polyp detection rate (ADR or PDR), insertion time, withdrawal time and adverse events, >80% purgative intake and diet compliance.

Data extraction
The studies were retrieved and the data were assessed and extracted by two investigators (Li X and Wang Z) independently, which was then summarized. Conflicts and disagreements were resolved by discussion or consulting a third investigator. Among each eligible study, the following data were extracted: author, year of publication, country, study design, blinding, number of patients allocated to each group, detailed information of interventions and controls, primary and secondary endpoints, BP scale, purgatives, diet restriction and other detailed information undergoing colonoscopy including insertion time, withdrawal time, ADR, PDR, purgative use, diet restrictions and so on.

Quality assessment
Study quality was evaluated by modified Jadad's score [37,38] (S2 Table), with 1-3 points being regarded as low quality and 4-7 points as high quality. Two studies used a nonrandom component in the sequence generation progress. Since patients were impossible to be blinded to instruction methods, all trials were single blinded to endoscopists, which may cause methodological impairment.

Statistical analysis
All statistical analyses were performed using Review Manager (Revman, version 5.2) and Stata (version 12.0). If data from both intention-to-treat and per-protocol analyses were presented, the former were extracted and analyzed. Dichotomous data, including the rates of adequate bowel preparation, ADR or PDR, adverse events and diet compliance etc., were reported as odds ratio (OR) with 95% confidence interval (CI). Continuous data, including BBPS, OBPS, insertion and withdrawal time, were reported as mean difference (MD) with 95%CI. Pooled estimates of OR or MD were calculated using a random-effects model, in which both withinstudy and between-study variations were considered [39]. Subgroup analysis were conducted according to the types of RE (communicable or not), evaluation tool (BBPS or OPBS), indication (screening or mixed) and preparation method (4L PEG, split-dose or low-volume laxatives). Statistical heterogeneity was accessed by calculating the I 2 value, with substantial heterogeneity defined as I 2 greater than 50%, as described previously. A P value less than 0.05 was considered significant. Publication bias was assessed by visual inspection of a funnel plot using Review Manager and was detected by Stata software.

Characteristics of the selected trials
The characteristics of 18 included studies were summarized in Table 1. A total of 6536 patients were enrolled. The pooled rete of adequate bowel cleansing was 81.0%, with 87.3% in the intervention group and 74.4% in the control group. Only two studies were multicenter studies [19,23], the rest of which were conducted by single center. 17 trials' primary endpoint was BP quality, while one trial's primary endpoint was adherence with instruction [31]. Among all studies, secondary endpoints included: BP score, ADR or PDR, insertion time, withdrawal time etc.
There were some differences among these studies. Firstly, the quality of BP was evaluated by five scales. Secondly, methods that patients receiving REs were different (S1 Table). Thirdly, the type, volume and drinking methods of purgatives and diet restrictions were different.
For patients, one study [11] enrolled patients �40 years old and two studies [13,21] �20, while the rest studies enrolled candidates with age �18 years old. Most trials took outpatients into consideration. One study only enrolled hospitalized patients [14] and patient type was unclear in other two [11,17]. Furthermore, five studies [11-13, 16, 17] only enrolled patients undergoing screening colonoscopy, while the others enrolled patients with mixed indications of colonoscopy, including screening, diagnosis and surveillance except one not reporting [31].

Primary outcome: BP quality
As the primary outcome, the rates of BP quality were analyzed by all 18 studies (N = 6536) ( Fig  2)

Sensitivity analysis
For the primary endpoint, the I2 value of heterogeneity was 53%. Sensitivity analysis was conducted with the extraction of study one by one. It showed that after extracting Calderwood's study and Back's study, the I2 changed to 30% and 44% separately, while after the extraction of other studies one by one, all I2 values were >50%.

Publication bias
The funnel plots performed by Revman that was asymmetric (S14 Fig). Begg's test was conducted by Stata and the funnel plot showed no significant publication bias was found (P = 0.950) (S15 Fig).

Discussion
Colonoscopy is an important preventive, diagnostic, and therapeutic modality, and its efficacy is closely associated with BP quality. Even though recommended by US Multi-society Task Force on Colorectal Cancer [9], standard oral or written instructions of BP before colonoscopy may still not be effective enough to ensure quality of BP, which leads to about 1/3 patients had inadequate BP [4,41], far lower than the recommendation of a �90% minimum standard for adequate BP by ESGE guideline [3]. Therefore, investigators were hoping to improve BP quality through the enhancement of patients' education and multiple qualified RCTs have been conducted and reported. Apart from standard oral or written education, the reinforced education method is often more understandable, accessible or readable, which may improve patients' knowledge of BP, give patients a reminder before procedure and enable them to be more compliant with the instructions.
This updated meta-analysis including 18 qualified RCTs (N = 6536) with appropriate and variable reinforced educational methods, revealed that compared with SE, RE improves the quality of BP for colonoscopy (87.3% vs. 74.4%; P<0.001). For secondary outcomes, patients receiving RE had a better BP score, a higher ADR and PDR, shorter insertion time and withdrawal time, less nausea/vomiting and abdominal distension. Although the primary outcome was similar to the four previous systemic review and meta-analyses, this updated meta-analysis conducted some new conclusions in secondary outcomes: 1) RE improved both ADR and PDR, which firstly demonstrated that patients receiving RE had a higher PDR in the form of systemic review and meta-analysis; 2) patients in the RE group had a shorter insertion time; 3) less nausea/vomiting and abdominal distension were achieved in the RE group. In addition, this updated meta-analysis had the biggest sample size and the greatest number of qualified RCTs, which also included more kinds of reinforced education methods.
Among the included studies, RE methods or tools were variable. Desai et al [28] analyzed patients receiving RE by means of smartphone applications, which concluded that as a novel educational tool, smartphone application could achieve better bowel cleansing. However, in three studies, patients could not communicate with medical practitioners when met some problems during BP period. In subgroup analysis of this meta-analysis, we divided RE tools into two kinds: communicable tools and non-communicable tools. Four studies used communicable tools, including a social media application (WeChat) [20,23] and telephone call [17,18]. Through the communicable tools, patients could communicate with physicians or nurses if they had any questions about bowel preparation during the procedure of instruction or met problems during the preparation. However, patients using non-communicable tools for communication are indirect and medical practitioners cannot receive feedbacks from patients until BP finished.
This meta-analysis also showed that patients receiving RE had both shorter insertion time and withdrawal time which was different from our previous meta-analysis [27]. Although both BP examine (e.g adenoma, polyp and other colon disease) and BP evaluation were conducted when withdrawing, a colonoscopist may have a better visual when inserting colonoscopy, which could decrease insertion time. Generally, most discomforts for patients undergoing colonoscopy happened in insertion period, thus, to some extent, the decreasing of insertion time could relieve patient's pain and improve their willingness of colonoscopy.
In the past few years, several rating scales have been developed to evaluate the quality of BP, including BBPS [33], OBPS [34], UPAS [11], HCS [35], Aronchick scale [36] etc. BBPS is thought to be the best in clinical practice with high intra-and inter-observer reliability and good correlation with colonoscopic findings [9]. In this meta-analysis, BBPS was used in eight studies and OBPS in six studies. The subgroup analysis showed patients in EI group both had better BP quality no matter which evaluating methods (BBPS or OBPS) were used. For the secondary outcome of BBPS and OBPS scores, patients in RE also showed a better BBPS score.
Adverse events were reported in six studies [12,17,18,20,23,30]. This meta-analysis firstly demonstrated that patients receiving RE had less nausea/vomiting or less abdominal distension, which is different from Guo et al's [27]. According to our conclusion, there was no difference between two groups with regard to abdominal pain and no heterogeneity (I 2 = 0%) of found in abdominal pain by sensitivity analysis. However, adverse events were influenced by some factors. Firstly, various purgatives were used, including 4L PEG in single [32] and splitdose [12,14,16,23,24,30], 3L PEG [20], 2L PEG [15, 17-19, 22, 29]. Secondly, nausea and vomiting were combined for analysis in three studies [12,18,23] and analyzed separately in two studies [17,20]. Thirdly, some detailed information was not provided in these studies, such as drinking speed, time interval between starting taking purgative and adverse events happening. Further studies may control and eliminate these interference factors.
Although our finding confirms the effectiveness of RE in BP, there are some limitations and several areas worth further investigation. Firstly, only two studies were conducted by multicenter, the rest of which were carried out in single center. Secondly, owing to the superiorities and weaknesses of different tools of educations, the head-to-head comparison of different RE methods needs to be further investigated. It is possible that a combination use of two or more means of RE methods could achieve better BP quality. Thirdly, for the patients with high risk factors associated with inadequate BP (e.g the elderly, BMI �25 or constipation), adequate BP is less likely to be achieved. RE for such patients may be even more significant for a better BP quality. Further work needs to be done to investigate the impacts of RE in these patients. Fourthly, patients with younger age, without comorbidities (especially constipation, diabetes, Parkinson disease and spine injury) or medications (especially tricyclic antidepressant (TCA) and possibly calcium channel blockers (CCB) and those with higher education level represent an relatively "easy-to-prepare" group [44]. It is interesting to investigate whether these patients may achieve adequate bowel preparation even without RE. Unfortunately, among the 18 studies focusing on investigating the effects of RE on BP quality, none reported the results of bowel preparation in low-risk patients. Further studies are needed to investigate the effects RE on BP quality in the "easy to-prepare" population. Fifthly, among the 5 scales used for the evaluation of BP quality, only BBPS [33,45] and OBPS [23,34] were validated for the inter-and intraobserver consistence. Uncertainty of the results may exist with the uses of other 3 invalidated scales. Last but not the least, to evaluate the effects of RE in different conditions, several subgroup analyses were performed. Although significant differences were found in most of the analyses (P<0.001). The power of the subgroup analyses may be not sufficient. The capabilities of subgroup analyses to detect meaningful differences between studies is often limited, thus it should be cautioned to explain the results.
In summary, this updated meta-analysis indicated that compared with SE, RE could significantly improve BP quality, increase ADR and PDR, decrease insertion time and withdrawal time and reduce adverse events of nausea/vomiting and abdominal distension. Therefore, in addition to SE, RE before colonoscopy should be recommended for patients undergoing BP.