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Update on Bowel Preparation Agents: Considering Efficacy, Tolerability and Safety for Optimal Compliance

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PHYSICIAN PERSPECTIVE - Viewpoint based on current literature and presentations from the 19th Canadian Digestive Disease Week (CDDW) & 8th Annual CASL Winter Meeting

Toronto, Ontario / February 8-11, 2014

Guest Editors:
Stephen Vanner
Professor of Medicine and Physiology
Queen’s University
Kingston, Ontario 

Lawrence Hookey
Associate Professor of Medicine
Queen’s University
Kingston, Ontario

Introduction

The effectiveness of colonoscopy is highly dependent on good bowel preparation. This is especially true given that subtle lesions can give rise to colorectal cancer, not just large, more visible polyps. The development of more advanced imaging techniques likewise demands excellent visualization of the mucosa, not lesser degrees of it. Different cleansing agents are available to help patients achieve good bowel preparation. It is important to balance the efficacy and safety of an agent or regimen with the patient’s ability to tolerate the product, as patients who have difficulties with their initial experience are more likely to opt out of screening altogether. Maximizing the efficacy, tolerability and safety of bowel preparation is the focus of this report.

 

Good bowel preparation is essential to the efficacy and indeed the utility of colonoscopy. “Suboptimal cleaning leads to lower detection rates for bowel cancer, particularly in the case of smaller lesions,” noted authors Longcroft-Wheaton and Bhandari.1 When bowel preparation is suboptimal, irrigation and suction must also be applied to improve mucosal visualization. These procedures are costly in terms of the time and effort they take, and prolong the entire process. Keeping the patient and cost to healthcare in mind, even with a less optimum bowel preparation, one often moves forward with the procedure, sometimes needing to rebook the patient for an earlier follow-up.

In North America, two types of bowel-cleansing agents have prevailed: variations of large-volume lavage with osmotically balanced polyethylene glycol (PEG) solutions and small-volume lavage with osmotically active agents. Previously, sodium phosphate agents were commonly used because they required less volume to produce cathartic effects equal to PEG solutions. However, they have been associated with a rare but serious form of acute nephropathy and few gastroenterologists in North America continue to use them. A nonphosphate, low-volume, dual-action preparation containing sodium picosulfate and magnesium citrate (P/MC) has been used for decades outside of North America, and since 2005, in Canada.

Recent Trials with Sodium Picosulfate and Magnesium Citrate

In two pivotal multicentre head-to-head comparisons of the new vs. standard bowel cleansing agents, P/MC has been shown to be better tolerated and at least as safe and effective vs. comparator PEG controls.1,2 Over 1,200 patients were in these two trials. In SEE CLEAR I —(Safety and Efficacy of a Dual-Action, Low-Volume Preparation: An Evaluation of Colon Cleansing in Day Before and Split Dose Regimens)—Rex et al. compared P/MC to 2 litres of a PEG solution (2L PEG-3350) given with two 5 mg bisacodyl tablets.2

A higher proportion of patients at 84.2% in the P/MC arm had an overall colon cleansing rating of excellent or good compared with 74.4% of those randomized to the PEG-3350 plus bisacodyl tablets.

In SEE CLEAR II,3 investigators again compared the efficacy, safety, and tolerability of the same two preparations evaluated in SEE CLEAR I. The dosing regimen was the “day before dosing” (both P/MC sachets were taken at different times on the day before the colonoscopy).

As measured by the Aronchick scale, overall cleansing was judged to be successful in 83% of patients in the P/MC arm vs. approximately 80% in the 2L PEG-3350 plus bisacodyl tablets arm. The overall incidence of treatment-emergent adverse events (AEs) was similar in both SEE CLEAR I and SEE CLEAR II and incidence rates in both treatment arms were similar regardless of the bowel preparation used.

An independent review of 21 different studies1, including SEE CLEAR I and II, confirm individual study findings in which the use of P/MC was largely compared to other bowel cleansing agents. Overall, the authors of this review summarized their findings as follows: “P/MC provides good efficacy and safety while offering better tolerability and patient acceptance. Since good compliance is essential to ensure adequate cleansing… this review therefore suggests that the use of P/MC is likely to produce optimal results in a broad patient population.”

Figure 1. 

Tolerability

If efficacy of a bowel preparation is paramount for gastroenterologists, tolerability is paramount for patients. Our studies have shown that P/MC is better tolerated than oral sodium phosphate, recognized as one of the best tolerated preparations, particularly in comparison to large volume PEG solutions.5 In addition, in SEE CLEAR II, patient-reported acceptability and tolerability responses were significantly higher for P/MC compared with the 2L PEG-3350 plus bisacodyl tablets arm (P<0.0001). For example, almost 90% of patients receiving P/MC rated the regimen as “very easy” or “easy” to  consume compared to almost 40% of those taking the PEG-3350 plus bisacodyl tablets and a greater proportion would use the same regimen for a future colonoscopy (96% vs. 54.7%; P<0.0001) (Figure 1).

Split Dosing

Many have observed that there is a direct relationship between the quality of bowel preparation and the interval between the last dose of the agent taken and colonoscopy start time. Four to six hours before the start time appears to be the optimum interval and underlies the rationale for the split-dose regimens.

Regardless of the bowel cleansing agent used, split dosing is now, in fact, standard practice and the regimen should be used whenever possible to enhance patient tolerance and adherence.4 In one of our own studies, we examined whether a split dose of a picosulfate, magnesium oxide and citric acid solution given both the night before and the morning prior to the colonoscopy vs. only the night before (the traditional arm) increased bowel cleansing while maintaining tolerability and safety.

For the study, Flemming et al.6 randomized 123 patients to the traditional arm where patients consumed one sachet of the solution at 5 pm and another at 10 pm the night before their colonoscopy. Another 127 patients were assigned to the split-dose arm where they consumed one sachet at 7 pm the night before and the second 4 hours prior to their appointment. Overall, the same Ottawa Bowel Preparation Score (OBPS) was significantly better in the split-dose group than in the traditional-dose group (4.05 than 5.51; P<0.001). The benefit was greatest in right-sided colon cleansing (1.22 in the split-dose arm vs. 2.14 in the traditional arm; P<0.001) but was evident throughout. Split-dosing did not decrease tolerability, even for cases booked in the early morning.

Also at this meeting, Arya et al.7 reported factors that seemed to affect the quality of bowel preparation at our centre at Queen’s University, Kingston, Ontario. The quality of bowel preparation was poor in slightly over one-quarter of some 421 patients analyzed to date—a finding that is widely corroborated by other investigators.

Early analysis of our data showed that age, sex, and level of education did not appear to influence the quality of the bowel preparation. The choice of agent did not appear to affect the quality of bowel preparation either, although with many more patients projected to be enrolled in the analysis, this parameter could emerge as a significant factor. What has emerged is the fact that the more medications patients were taking, the greater the likelihood of a poor prep—possibly a signal of increasingly poor health and an inability to follow instructions as the number of medications rose. Another potential deterrent to completion of the purgative process is the need to drink only clear fluids the day prior to the procedure.

In a previously published randomized non-inferiority trial,8 we compared the standard clear-fluid diet and a low-residue breakfast eaten the day before colonoscopy. All subjects received a low-volume bowel preparation. For the clear-fluid diet group, the mean OBPS was 4.47 compared with 4.62 for the low-residue breakfast group. Both groups reported similar mean hunger intensity but overall satisfaction was higher among those permitted to have the low-residue breakfast, suggesting that this approach is likely to be preferred by patients. Results from this study were corroborated by a similar study presented at the CDDW this year.

In this study, Flemming et al.9 examined the effect that a low-residue breakfast had on bowel cleansing in patients using a PEG-based preparation prior to colonoscopy. A total of 105 patients were randomized to the low-residue breakfast arm followed by clear fluids and another 109 patients were randomized to clear fluids only. In the intent-to-treat group, although not the per protocol group, the criteria for non-inferiority of the low-residue breakfast arm were met even though there was no difference in the mean total OBPS between the two arms.

We concluded that the low-residue breakfast strategy was better tolerated by patients compared to clear fluids alone. This strategy can be used for colon cleansing with PEG-based preparations when physicians are concerned about their patient’s ability to tolerate bowel cleansing, particularly when combined with a split-dose regimen (i.e. 2L and 2L) which optimizes the efficacy and tolerability of the preparation.

Other preparations are available in Canada such as a combination product of 2 litres of PEG plus 15 mg of bisacodyl. Although a similar combination is commonly used in the United States, the dose of bisacodyl was reduced because of reports of ischemic colitis associated with the higher doses. In the United States the preparation now contains 5 mg of bisacodyl, a reduction from the earlier versions which used 20 and then 10 mg. Another PEG-reduced volume product recently available in Canada contains the combination of 2 litres of PEG and ascorbic acid. Studies to date also suggest good efficacy and tolerability although some patients may not prefer the taste.

Special Patient Populations

Data supporting the use of P/MC in children are far from robust but since tolerability in pediatric patients is a critical first step, it is worth noting several studies have evaluated the acceptability of P/MC in children. In one such study, Turner et al.10 randomized 83 subjects between 4 and 18 years of age to either P/MC taken in two doses—one the evening before and one the morning of the colonoscopy—or to a PEG-ELS solution, given over 4 hours the night before. Although no differences were found in effectiveness between the two agents as judged by the OBPS, patient questionnaire results indicated that 81% of the P/MC group were satisfied or very satisfied with the cleanout compared with 48% of the PEG-ELS group (P=0.001). A second study in children between the ages of 18 months and 16 years also showed that the use of P/MC and clear fluids proved to be superior to bisacodyl tablets and a phosphate enema in children undergoing colonoscopy even though bowel preparation was good or excellent in both groups.11

Being at increased risk, safety is also an important considering in selecting a bowel preparation agent for the elderly. This is not a trivial issue. For example, Ho et al.12 observed a SAE—defined as a composite of nonelective hospitalization, an emergency department visit or death within 7 days of colonoscopy—of between 24 to 28 per 1000 procedures in over 50,000 Ontario outpatients 66 years of age and older who received either a PEG or sodium picosulfate bowel cleansing agent, highlighting that all bowel preparations can potentially have serious side effects. Serious hyponatremia has been identified in rare cases with virtually every type of bowel preparation although elderly patients taking P/MC may be at a slightly increased risk according to the Ho study.

In another study of the elderly using P/MC, McLaughlin et al.13 observed no significant changes in serum urea, sodium, potassium or estimated glomerular filtration rate following colonoscopy preceded by a P/MC-based agent in a study of 72 frail elderly patients, over half of whom had comorbidities that might caution against the use of such an agent. Serum magnesium did increase slightly by 0.11 mmol/L in 14 patients without clinical sequelae; nevertheless, the authors still suggested P/MC be used with caution in the elderly with reduced renal function.

A subgroup of interest in for all endoscopists is the patients who had poor cleansing with their previous colonoscopy. One must consider factors like those above such as medication, diet and cleansing agent compliance (i.e., did they follow the instructions properly), but in the end we usually turn to split-dose PEG in these difficult-to-cleanse patients, with colonoscopy booked relatively early in the day. For those particularly challenging cases, the clear fluid restriction can be extended for several days and a stimulant laxative added for two days prior.

Summary

Given that approximately one-quarter of all colonoscopies consistently demonstrate patients clearly have difficulties in complying with the bowel preparation regimen as instructed, prescribing any cleansing agent cannot be done in a vacuum. Indeed, patients who are consistently reminded when and how to initiate the regimen and how to proceed with subsequent steps14 are much more likely to adhere to all steps of the process than those who are not. It thus falls to all of us to encourage patients to follow all necessary steps so that they can present to us with good to excellent preparatory results. 

 

References:

1.  Wheaton C, Bhandari P. Sodium Picosulphate/Magnesium Citrate as a bowel cleansing agent: A review of the evidence for efficacy, safety and tolerability. AGH 2013: September, 2013.
2. Rex DK et al. Split-dose administration of a dual-action, low-volume bowel cleanser for colonoscopy: the SEE CLEAR I study. Gastrointest Endosc 2013;78:132-41.
3. Katz PO et al. A dual-action, low-volume bowel cleanser administered the day before colonoscopy: Results from the SEE CLEAR II study. Am J Gastroenterol 2013;108: 401-9.
4. Sharara A et al. The modern bowel preparation in colonoscopy. Gastroenterol Clin N Am 2013;42:577-98.
5. Juluri R et al. Meta-analysis: randomized controlled trials of 4-L polyethylene glycol and sodium phosphate solution as bowel preparation for colonoscopy. Aliment Pharmacol Ther 2010 Jul;32(2):171-81.
6.Flemming JA et al. Split-dose picosulfate, magnesium oxide and citric acid solution markedly enhances colon cleansing before colonoscopy: a randomized controlled trial. Gastrointest Endosc 2012;75:537-44.
7. Arya A et al. Factors affecting the quality of bowel preparation: A single-centre prospective study. Abstract A88. CDDW 2014. Presented February 9, 2014.
8. Melicharkova A et al. A low-residue breakfast improves patients’ tolerance without impacting quality of low-volume colon cleansing prior to colonoscopy: A randomized trial. Am J Gastroenterol 2013;108:1551-5.
9. Flemming JA et al. Low residue breakfast has minimal effect on bowel cleansing while improving patient tolerance of polyethylene gycol based preparation for colonoscopy: a randomized non-inferiority trial. Abstract A73. CDDW 2014. Presented Feb. 9, 2014.
10. Turner D et al. Pico-Salax vs. PEG before colonoscopy in children. Endoscopy 2009; 41:1038-45.
11. Pinfield A, Stringer M. Randomised trial of two pharmacological methods of bowel preparation for day case colonoscopy. Arch Dis Child 1999;80:181-3.
12.Ho JM et al. Serious events in older Ontario residents receiving bowel preparations for outpatient colonoscopy with various comorbidity profiles: A descriptive, population-based study. Can J Gasterenterol 2012;26:436-40.
13.  McLaughlin P et al. Bowel preparation in CT colonography: electrolyte and renal function disturbances in the frail and elderly patients. Eur Radiol 2010;20:604-12.
14. Schlichting JA et al. Increasing Colorectal Cancer Screening in an Overdue Population: Participation and Cost Impacts of Adding Telephone Calls to a FIT Mailing Program. J Community Health 2014 Apr;39(2):239-47.

PH

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