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A novel ultra-low-volume regimen combining 1 L polyethylene glycol and linaclotide versus 2 L polyethylene glycol for colonoscopy cleansing in low-risk individuals: a randomized controlled trial
∗ Drs Zhang, Chen, and Tang contributed equally to this article.
Chen Zhang
Footnotes
∗ Drs Zhang, Chen, and Tang contributed equally to this article.
Affiliations
Department of Gastroenterology, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China
Department of Gastroenterology, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China
Department of Gastroenterology, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China
Department of Gastroenterology, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China
Department of Gastroenterology, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China
Reprint requests: Xiaobin Sun, MB, Department of Gastroenterology, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, Sichuan, China.
Department of Gastroenterology, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China
The single dose of 2 L polyethylene glycol (PEG) has shown high cleaning efficacy and tolerability in low-risk patients. However, the dosage of this regimen is still challenging for many patients. We investigated the efficacy and tolerability of a novel ultra-low-volume regimen using 1 L PEG and linaclotide (1 L PEG+L) versus a single dose of 2 L PEG in low-risk patients.
Methods
In this prospective, randomized, observer-blinded, multicenter study, low-risk adult patients scheduled for colonoscopy were enrolled and randomized (1:1) to receive the 1 L PEG+L regimen or the 2 L PEG regimen. The primary outcome was the effectiveness of bowel cleansing according to the Boston Bowel Preparation Scale. Secondary outcomes included cecal intubation rate, cecal insertion time, withdrawal time, polyp detection rate and adenoma detection rate, tolerability, adverse events, and willingness to repeat bowel preparation. The full analysis set (FAS) and per-protocol set (PPS) were used for statistical analyses.
Results
A total of 548 patients comprised the FAS, and 522 patients comprised the PPS. Noninferiority on adequate bowel cleansing of 1 L PEG+L vs 2 L PEG was established both in FAS (90.5% vs 91.6%, P = .644) and PPS (90.3% vs 92.4%, P = .390). There were no significant differences regarding the total score and each segment scores of the Boston Bowel Preparation Scale, cecal intubation rate, cecal insertion time, withdrawal time, polyp detection rate, and adenoma detection rate (all, P > .05). However, patients in the 1 L PEG+L group reported less nausea (7.7% vs 17.1%, P < .01) and vomiting (4.0% vs 10.9%, P < .01) and had a higher willingness to repeat bowel preparation (95.2% vs 82.2%, P < .01).
Conclusions
The regimen of 1 L PEG+L was not inferior to 2 L PEG on colon cleansing, with better tolerability and higher willingness to repeat the bowel preparation in a low-risk population. (Clinical trial registration number: ChiCTR2100053273.)
A safety and efficacy comparison of a new sulfate-based tablet bowel preparation versus a PEG and ascorbate comparator in adult subjects undergoing colonoscopy.
Same-day single dose of 2 liter polyethylene glycol is not inferior to the standard bowel preparation regimen in low-risk patients: a randomized, controlled trial.
High-volume polyethylene glycol (PEG)-based (3-4 L) regimens have been established as the standard regimens for bowel preparation in unselected patients.
To address these disadvantages, optimized methods using lower-volume PEG combined with additional bowel purgatives have been developed, which have shown comparable efficacy with better compliance compared with high-volume regimens.
2-Litre polyethylene glycol-citrate-simethicone plus bisacodyl versus 4-litre polyethylene glycol as preparation for colonoscopy in chronic constipation.
A new low-volume isosmotic polyethylene glycol solution plus bisacodyl versus split-dose 4 L polyethylene glycol for bowel cleansing prior to colonoscopy: a randomised controlled trial.
Several risk factors have been identified as predictors of colonoscopy preparation failure such as increasing age, constipation, diabetes mellitus, history of inadequate bowel preparation, and the use of narcotics and tricyclic antidepressants.
Although low-volume regimens seem to be less effective in such high-risk patients, they may be attractive alternatives for low-risk patients, who are relatively “easy-to-prepare.”
Because the awareness of colonoscopy for CRC screening is on the rise, more low-risk patients are likely to engage in colonoscopy screening. However, data are limited on the yield of bowel preparation among low-risk patients. One retrospective study was conducted in nonconstipated patients; another randomized controlled trial in patients without any risk factors suggested that 2 L PEG was noninferior to the standard split dose of 4 L PEG.
Same-day single dose of 2 liter polyethylene glycol is not inferior to the standard bowel preparation regimen in low-risk patients: a randomized, controlled trial.
Low-volume regimen without additional liquids or adjunctive agents versus standard bowel preparation in non-constipated patients: a propensity score matching analysis.
A further reduction in volume, without compromising bowel-cleansing efficacy, might represent a promising strategy to improve tolerability and compliance, especially in the easy-to-prepare population.
Linaclotide, an acid peptide guanylate cyclase-C agonist, which could increase luminal fluid secretion and mediate visceral analgesia, induces a laxative effect and improves abdominal symptoms.
Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety.
Another study also showed that 290 μg linaclotide combined with 2 L PEG was comparably effective and associated with better tolerability compared with 4 L PEG regimens.
Polyethylene glycol combined with linaclotide is an effective and well-tolerated bowel preparation regimen for colonoscopy: an endoscopist-blinded, randomized, controlled trial.
Based on these results, we hypothesized that the additional use of linaclotide may not only reduce the total volume of PEG while maintaining the desired efficacy but also improve patients’ experience during colonoscopy. Therefore, an ultra-low-volume bowel preparation regimen that combined 1 L PEG and linaclotide (1 L PEG+L) was developed in the current study to compare its efficacy and tolerability with those of 2 L PEG in low-risk patients.
Methods
Study design
This prospective, multicenter, randomized controlled, endoscopist-blinded, noninferiority trial was conducted at the endoscopic centers of The Third People’s Hospital of Chengdu, Sichuan Mianyang 404 Hospital, The Sixth People’s Hospital of Chengdu, and the People’s Hospital of Zhongjiang County in China from January 6, 2022, to April 30, 2022. The study was prospectively registered in the Chinese Clinical Trial Registry (ChiCTR2100053273, November 18, 2021). The protocol was approved by the Human Ethics Committees of the Third People’s Hospital of Chengdu (2021-S-199) on January 5, 2022.
Patients
Low-risk patients aged older than 18 years who were scheduled for colonoscopy were enrolled in this study. Patients were regarded as low risk if they had none of the following risk factors: constipation, body mass index (BMI) over 25 kg/m2, age older than 70 years, prior surgery of gastrectomy or colorectal resection, diabetes, Parkinson’s disease, history of stroke or spinal cord injury, and use of tricyclic antidepressants or narcotics. Exclusion criteria included patients with the following: (1) congestive heart failure (New York Heart Association functional class III or IV), (2) respiratory failure, (3) uncontrolled shock, (4) hemodynamic instability, (5) aortic aneurysm, (6) recent myocardial infarction or stroke, (7) severe coagulation dysfunction, (8) suspected bowel obstruction or perforation, (9) megacolon, (10) cirrhosis with moderate to severe ascites, (11) end-stage renal disease (dialysis or predialysis), (12) psychiatric diseases, and (13) pregnancy or lactation. Patients were also excluded if they were allergic to linaclotide or PEG or took prokinetic or laxative drugs within 1 week preceding the trial.
Randomization and blinding
After eligibility screening, consent, and baseline assessment, each patient was randomly allocated (1:1) to either the 1 L PEG+L group or the 2 L PEG group by opening a sealed opaque envelope containing their allocation. Randomization was performed by using a permuted block design, with randomly varying block sizes and stratified according to center. The envelopes were prepared and kept by an independent investigator who was not engaged in data collection or analysis. The investigators or endoscopists collecting the primary and secondary outcome data were blinded to participant allocation. To achieve this blinding, subjects were instructed not to disclose their study allocation to the endoscopists or investigators.
Bowel preparation regimens and colonoscopy
All patients were provided with standard verbal and written instructions and directed to have a low-residue diet the day before colonoscopy. Those in the 2 L PEG group were directed to consume 2 sachets of PEG (68.56 g, each bag containing 1.46 g of sodium chloride, 5.68 g of anhydrous sodium sulfate, 0.74 g of potassium chloride, 1.68 g of sodium bicarbonate, and 59 g of PEG 4000; Shenzhen Wanhe Pharmaceutical Co Ltd, Shenzhen, China) in 2 L of water between 9:00 am and 11:00 am on the day of the colonoscopy at a rate of 250 mL every 15 minutes. Those in the 1 L PEG+L group were instructed to take 290 μg linaclotide (Linzess, Ironwood Pharmaceuticals, Cambridge, Mass, USA) at 8:00 pm on the day before the procedure and another 290 μg of linaclotide at 9:00 am on the day of the procedure. They were then asked to consume one sachet of PEG dissolved in 1 L of water between 10:00 am and 11:00 am at the same rate. All colonoscopies were performed during the afternoon, 2 to 6 hours after preparation completion, and all patients received anesthesia with propofol during the colonoscopy.
Colonoscopy was performed by experienced endoscopists (more than 500 colonoscopies per year) who were blinded to group allocation. All examiners were previously trained in the proper use of the Boston Bowel Preparation Scale (BBPS) and provided standard examples of images for reference. All endoscopists were instructed to take endoscopic images of each colonic segment that were representative of the colonic cleansing level. The final BBPS scores were evaluated independently by 2 endoscopists, with disagreements resolved by consensus.
Outcome assessment
The primary outcome was the rate of adequate bowel preparation evaluated according to the BBPS, a validated instrument for colonoscopy-oriented research.
Colonoscopy preparation: polyethylene glycol with Gatorade is as safe and efficacious as four liters of polyethylene glycol with balanced electrolytes.
The BBPS was based on the summation of preparation scores from 3 segments of colon (right, transverse, and left colon) with each segment scored from 0 to 3 points. Bowel cleansing was adequate with a total score ≥6 and each segmental score ≥2; this was evaluated during the withdrawal phase, after sufficient washing and suctioning.
The secondary outcomes included total and each segment scores of BBPS, cecal intubation, cecal insertion time, withdrawal time, polyp detection rate, and adenoma detection rate (ADR).
The detailed definitions of the aforementioned parameters are presented in the supplementary material (available online at www.giejournal.org). In terms of each patient’s tolerability, they were asked about total feelings using a 6-point scale (0 denotes very good, 5 denotes not tolerated at all), adverse events potentially related to the bowel preparation (including nausea, vomiting, abdominal discomfort, and sleep disturbances), and willingness to repeat the preparation in the future.
Statistics and sample size
Based on retrospective data obtained from 5600 patients in our endoscopic center, the rate of adequate bowel preparation was estimated as 87% in low-risk patients with 2 L PEG (data not published). In our preclinical trial, we included 15 low-risk patients using the 1 L PEG+L regimen for bowel cleansing, suggesting 87% of adequate bowel preparation. To detect the noninferiority effect with a margin of 10%, the sample size was determined as 238 patients per group to have a significance level of .025 (one-side) and a power of 90%. Considering the blocked randomization and a dropout rate of 10%, we calculated that a total of 284 participants in each group were needed. Noninferiority was established when the one-sided 97.5% upper confidence limit for the difference did not exceed the noninferiority margin (10%).
Statistical analyses were performed by using the R system (R Core Team 2022, version 4.1.1; R Foundation for Statistical Computing, Vienna, Austria). Continuous variables are reported as mean ± standard deviation and analyzed with the Student t test or Mann-Whitney U test. Categorical variables are expressed as frequencies and percentages and were assessed by using the Pearson χ2 test or the Fisher exact test, as appropriate. A value of P < .05 was used for all statistical analysis.
The full analysis set (FAS) included all patients randomized to treatment, with the exception of patients who did not meet the inclusion criteria and who did not take any study drug. The detailed reasons for each participant who was excluded from FAS analysis are presented in Supplementary Table 1 (available online at www.giejournal.org). The per-protocol set (PPS) included participants who met the eligibility criteria, complied with the study protocol, and had available data for the primary end points. The analyses of the primary efficacy end points were conducted in the FAS and PPS. Exploratory subgroup analyses were performed based on the following characteristics: age, sex, BMI, history of surgery, stool frequency, and indications for colonoscopy.
Results
As presented in Figure 1, a total of 679 patients were screened for eligibility for the study, with 62 patients meeting the exclusion criteria and 49 not willing to participate in the study. Low-risk patients were randomized to treatment, equally distributed between the 2 study arms (n = 284 for each group). After excluding 20 patients (19 patients canceled or rescheduled their colonoscopy, 1 patient did not meet inclusion criteria), 275 participants in the 2 L PEG group and 273 in the 1 L PEG+L group were included in the FAS. Finally, 522 patients comprised the PPS, with 264 in the 2 L PEG group and 258 in the 1 L PEG+L group. Overall, demographic characteristics were well balanced between the groups (Table 1).
Figure 1Flow diagram of patients enrolled. PEG, Polyethylene glycol.
Overall, the 1 L PEG+L regimen achieved noninferior efficacy compared with 2 L PEG in terms of bowel cleansing (upper confidence interval for the difference, 6.03% and 7.08% in FAS and PPS, respectively). In FAS, the rate of adequate bowel preparation was 91.6% in the 2 L PEG group and 90.5% in the 1 L PEG+L group (P = .644). The data in PPS were 92.4% vs 90.3% (P = .390). In addition, mean total BBPS scores were not significantly different between the groups, with a mean ± standard deviation total score of 7.36 ± 1.18 vs 7.30 ± 1.30 (P = .521) in FAS and 7.37 ± 1.15 vs 7.26 ± 1.28 (P = .278) in PPS. No significant differences were noted in terms of right, transverse, and left segmental BBPS scores (all, P > .05) (Table 2).
Table 2Outcome of bowel preparation
Colonoscopy outcome
Full analysis set population
Per-protocol population
2 L PEG (n = 275)
1 L PEG + linaclotide(n = 273)
P value
2 L PEG (n = 264)
1 L PEG + linaclotide (n = 258)
P value
Primary end point
Adequate bowel preparation
251 (91.6)
247 (90.5)
.644
244 (92.4)
233 (90.3)
.390
Secondary end point
BBPS score, mean ± SD
Total score
7.36 ± 1.18
7.30 ± 1.30
.521
7.37 ± 1.15
7.26 ± 1.28
.278
Left colon
2.43 ± 0.57
2.43 ± 0.61
.910
2.44 ± 0.57
2.42 ± 0.61
.743
Transverse colon
2.66± 0.50
2.60 ± 0.54
.181
2.67± 0.49
2.59 ± 0.54
.085
Right colon
2.27 ± 0.55
2.26 ± 0.60
.838
2.27 ± 0.54
2.24 ± 0.59
.562
Cecal intubation rate
273 (99.3)
272 (99.6)
1.00
263 (99.6)
257 (99.6)
1.00
Cecal intubation time, mean ± SD, min
5.01 ± 2.65
4.84 ± 2.59
.451
4.97± 2.66
4.84 ± 2.64
.567
Withdrawal time, mean ± SD, min
7.04 ± 1.26
6.82 ± 0.88
.567
7.04 ± 1.26
6.82 ± 0.88
.567
Polyp detection rate
115 (41.8)
97 (35.5)
.131
110 (41.7)
93 (36.0)
.188
Adenoma detection rate
59 (21.5)
50 (18.3)
.357
56 (21.2)
48 (18.6)
.456
Values are n (%) unless otherwise defined.
PEG, Polyethylene glycol; BBPS, Boston Bowel Preparation Scale; SD, standard deviation.
Successful cecal intubation was achieved in 273 (99.3%) patients assigned to the 2 L PEG group and 272 (99.6%) patients allocated to the 1 L PEG+L group (P = 1.00) except for 2 patients with neoplasms in the ascending and descending colon, respectively, and 1 patient with melanosis coli. No statistically significant differences were observed in cecal intubation time (5.01 ± 2.65 minutes vs 4.84 ± 2.59 minutes, P = .451) or withdrawal time (7.04 ± 1.26 minutes vs 6.82 ± 0.88 minutes, P = .567). The polyp detection rates were 41.8% in the 2 L PEG group and 35.5% in the 1 L PEG+L group (P = .131). ADRs were 21.5% and 18.3% in the 2 L PEG group and 1 L PEG+L group (P = .357).
Adverse effects and tolerance
Overall, both bowel preparation regimens were well tolerated, with no serious adverse events in the study population. There was no significant difference between the 2 groups in terms of total feeling score (P > .05) (Table 3). However, the percentages of nausea and vomiting were much lower in the 1 L PEG+L group compared with the 2 L PEG group (7.7% vs 17.1%, P < .01 for nausea; 4.0% vs 10.9%, P < .01 for vomiting). The percentages of abdominal discomfort and other adverse events were comparable in the 2 groups (P > .05). Likewise, no significant difference was observed regarding sleep disturbance (4.7% vs 7.0%, P = .265). However, more patients in the 1 L PEG+L group expressed willingness to repeat the bowel preparation (95.2% vs 82.2%, P < .01).
Table 3Comparison of tolerability and adverse events
Exploratory subgroup analyses for adequate bowel preparation
The effects of the 2 regimens on adequate rate of bowel preparation were further analyzed in different subgroups. No significant differences were observed between the 2 regimens for all subgroups based on age, sex, BMI, history of surgery, stool frequency, and indications for colonoscopy (all, P > .05) (Table 4).
Table 4Exploratory subgroup analyses for adequate bowel preparation
This multicenter, randomized controlled trial recommended 1 L PEG+L as an alternative to the single-dose 2 L PEG regimen for low-risk individuals. Not only did the novel regimen show a high bowel cleansing efficacy, but it also improved patient tolerability and willingness to repeat bowel preparation.
Recent studies have suggested that low-volume bowel preparation regimens are as effective as high-volume regimens in nonselected populations.
An enhanced high-volume preparation for colonoscopy is not better than a conventional low-volume one in patients at risk of poor bowel cleansing: a randomized controlled trial.
The additional use of adjuvants (eg, ascorbic acid or bisacodyl) combined with 2 L PEG has been validated and recommended for routine bowel preparation, with comparable efficacy and higher tolerability.
However, the dosage of the 2 L regimen is still large to ingest. Several ultra-volume regimens were developed to further improve patients’ experience, based on either hyperosmotic solution or stimulant laxative. In a recent meta-analysis, ultra-low-volume bowel preparation using sodium picosulfate with magnesium citrate, 1 L PEG with ascorbate, sodium phosphate solution, or oral sulfate solution achieved adequate bowel preparation in 75.2%, 82.9%, 81.9%, and 92.1% of patients, respectively, which did not meet the quality standard of 90% as defined by the European Society of Gastrointestinal Endoscopy, with the exception of the oral sulfate solution.
In the current study, 1 L PEG+L was highly efficacious, achieving adequate bowel preparation in more than 90% of patients with a similar safety profile compared with that of 2 L PEG. Of note, the majority of these ultra-low-volume preparations did not release patients from drinking large volumes, which required extra liquids in addition to the laxatives to maintain hydration (usually 3-4 L of total liquids).
Lower volume of total liquids in the 1 L PEG+L regimens with 92.2% (238 of 258; data not shown) of patients drinking less than 2 L of total fluids represented a significant step toward “real” reduction of total liquids in ultra-low-volume approaches, which may further increase a patient’s cooperation.
Linaclotide, a minimally absorbed guanylate cyclase-C agonist, accelerated colonic transit and improved abdominal and bowel symptoms in patients with irritable bowel syndrome with constipation.
Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety.
In terms of its laxative effect, linaclotide has been used in bowel preparation for capsule endoscopy and colonoscopy to improve bowel cleansing with minimal side effects.
Polyethylene glycol combined with linaclotide is an effective and well-tolerated bowel preparation regimen for colonoscopy: an endoscopist-blinded, randomized, controlled trial.
Consistent with these results, our study also suggested that the combination of 1 L PEG with linaclotide displayed efficacy similar to that of 2 L PEG, with no serious adverse events. It is noted that the use of linaclotide shortened the first defection time after consuming PEG (22.66 ± 14.70 minutes vs 31.89 ± 21.06 minutes, P < .01) (Supplementary Table 2, available online at www.giejournal.org), which may contribute to the adequate preparation in the 1 L PEG+L group. Interestingly, it was expected that linaclotide would reduce abdominal discomfort during the colonoscopy preparation, but this was not seen. There was no significant difference in abdominal symptoms between the 2 groups, whereas nausea and vomiting were less frequent in the 1 L PEG+L group, which could be interpreted with the reduction of volume. According to Rao et al,
A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation.
Am J Gastroenterol.2012; 107 (quiz 1725): 1714-1724
linaclotide treatment improved spontaneous bowel movements within 24 hours of the first dose, whereas significant improvement in abdominal pain and bowel symptoms required at least 12 weeks. This may explain why a high-quality bowel cleansing without improvement in abdominal discomfort was observed in the 1 L PEG+L group.
The current study was restricted to low-risk patients who did not have risk factors for poor bowel cleansing. Previous studies have identified that constipation,
were risk factors for suboptimal bowel preparation. Patients with these conditions were excluded from this study. Given the growing awareness of colonoscopy for CRC screening, the proportion of low-risk individuals is increasing who may benefit from lower intensity of bowel cleansing compared with high-risk individuals. Recently, numerous studies have been conducted in high-risk patients to improve the bowel cleansing quality, whereas the current evidence in easy-to-prepare patients is scarce. One multicenter randomized controlled study suggested that a same-day single dose of 2 L PEG was not inferior to 4 L PEG (standard group) for low-risk patients.
Same-day single dose of 2 liter polyethylene glycol is not inferior to the standard bowel preparation regimen in low-risk patients: a randomized, controlled trial.
Same-day single dose of 2 liter polyethylene glycol is not inferior to the standard bowel preparation regimen in low-risk patients: a randomized, controlled trial.
which were slightly lower than the rates found in the current study. The discrepancy may be ascribed to the less restrictive diet regimen (nearly 10% of patients did not comply with the diet restriction) and the lower compliance rate (3%-7% of patients ingested less than 80% of the total solution) in the study by Kang et al.
Same-day single dose of 2 liter polyethylene glycol is not inferior to the standard bowel preparation regimen in low-risk patients: a randomized, controlled trial.
By contrast, we noted that nearly 99% (541 of 548) of patients followed the diet restrictions and 98% (536 of 548; data not shown) drank all required liquids in our study. Of note, consistent with the previous study,
Same-day single dose of 2 liter polyethylene glycol is not inferior to the standard bowel preparation regimen in low-risk patients: a randomized, controlled trial.
our study reported that 52.1% of patients were at low risk. Thus, we estimated that nearly one-half of patients undergoing colonoscopy would benefit from this novel ultra-low-volume regimen, which emphasized the importance of enhanced instructions, intensive diet restriction, and better compliance.
The overall ADRs in both groups of this study (ranging from 18.3%-21.5%) seemed to be lower than that recommended for an unselected colonoscopy population.
patient characteristics such as age, BMI, diabetes mellitus, and personal history of adenoma were risk factors associated with colorectal adenoma. The relatively low ADRs in the current study might be ascribed to data obtained from low-risk patients with a relatively younger age (about 45 years old), lower BMI (about 22 kg/m2), and fewer comorbidities (diabetes), which were similar to those reported in another study from low-risk patients.
Same-day single dose of 2 liter polyethylene glycol is not inferior to the standard bowel preparation regimen in low-risk patients: a randomized, controlled trial.
There are several strengths to the current study. First, our results have important clinical implications. Given the rising awareness and accessibility of colonoscopy for CRC screening, the percentage of screenings among low-risk individuals would be increased. The 1 L PEG+L regimen provided high-quality bowel cleansing with safety and better tolerability for easy-to-prepare patients, who might benefit more from less-intensive regimens. Second, the multicenter design and large sample size provided highly generalizable results. Third, the rigorous methodology, with concealment of randomization allocation until enrollment, and blinding of the endoscopists were used to reduce both conscious and unconscious bias. Fourth, the evaluation of the primary end point was based on the well-validated BBPS, which was performed by 2 independent blinded observers. The analyses based on FAS and PPS were consistent, which further support the validity of the results in our study.
Several limitations should be acknowledged. First, the regimen of this study was used for procedures performed in the afternoon, and its efficacy for morning procedures was uncertain. Second, we did not use a split-dose regimen for bowel cleansing, which was commonly used in high-volume preparations. However, it is still uncertain whether split dosing is feasible with ultra-low-volume fluids. In line with our study, van Riswijk et al
reported that the pooled efficacy of ultra-low-volume regimens with a same-day setting was nearly 90%, suggesting that a same-day regimen was a viable option that could be used in ultra-low-volume regimens. Third, there are currently no uniform criteria for low-risk populations. We used factors related to poor bowel preparation as exclusion criteria in this study based on high-quality randomized controlled trials, meta-analyses, and guidelines. Fourth, although our 1 L PEG+L regimen was an effective, well-tolerated, and safe solution for low-risk patients, several essential prerequisites were needed for its success, including enhanced instructions, strict diet restriction, and high adherence. In addition, further studies are needed to establish the optimal dosage and time of taking linaclotide for colonoscopy. Fifth, our analysis was restricted to low-risk individuals, and generalization of these findings to the general population should be made with caution. In fact, we tried but failed to statistically extrapolate our results to the population overall due to the current lack of sufficient information, which warrants further investigation.
In conclusion, this study showed similar bowel cleansing efficacy but better tolerability with a higher willingness to repeat bowel preparation for the 1 L PEG+L regimen compared with 2 L PEG in low-risk individuals, which indicated its potential as a first-choice regimen for an easy-to-prepare population. Future studies are warranted to establish the efficacy of ultra-low volume regimens for morning procedures or split-dose administration, which may extend the current evidence and provide more individualized strategies for low-risk individuals.
Acknowledgments
The statistical analyses were independently conducted by Qin Pan, West China School of Public Health. We thank Qin Pan for the assistance with statistical analyses. We thank all the patients, physicians, and nurses for their friendly participation.
Supplementary material
Definition of secondary outcomes
We defined the cecal intubation as successful insertion of the colonoscopy tip into the cecum. The cecal intubation rate was the percentage of successful insertion. Cecal insertion time was defined as the time from insertion into the rectum to the identification of the base of the cecum. Withdrawal time referred to the time spent on retracting the instrument from the cecum to the anus, excluding both tissue sampling and therapeutic procedures. The polyp detection rate was the proportion of patients undergoing colonoscopy who have at least one polyp, and the adenoma detection rate was defined as the percentage of patients undergoing colonoscopy who have at least one adenoma.
Supplementary Table 1Reasons for exclusion of each participant from the full analysis set
A safety and efficacy comparison of a new sulfate-based tablet bowel preparation versus a PEG and ascorbate comparator in adult subjects undergoing colonoscopy.
Same-day single dose of 2 liter polyethylene glycol is not inferior to the standard bowel preparation regimen in low-risk patients: a randomized, controlled trial.
2-Litre polyethylene glycol-citrate-simethicone plus bisacodyl versus 4-litre polyethylene glycol as preparation for colonoscopy in chronic constipation.
A new low-volume isosmotic polyethylene glycol solution plus bisacodyl versus split-dose 4 L polyethylene glycol for bowel cleansing prior to colonoscopy: a randomised controlled trial.
Low-volume regimen without additional liquids or adjunctive agents versus standard bowel preparation in non-constipated patients: a propensity score matching analysis.
Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety.
Polyethylene glycol combined with linaclotide is an effective and well-tolerated bowel preparation regimen for colonoscopy: an endoscopist-blinded, randomized, controlled trial.
Colonoscopy preparation: polyethylene glycol with Gatorade is as safe and efficacious as four liters of polyethylene glycol with balanced electrolytes.
An enhanced high-volume preparation for colonoscopy is not better than a conventional low-volume one in patients at risk of poor bowel cleansing: a randomized controlled trial.
A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation.
Am J Gastroenterol.2012; 107 (quiz 1725): 1714-1724
Disclosure: This work was supported by the National Natural Science Foundation of China (81902398) and foundation of Science & Technology Department of Sichuan Province (2021YJ0203). All authors disclosed no financial relationships.
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