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Polyethylene glycol vs. sodium phosphate for bowel preparation: a treatment arm meta-analysis of randomized controlled trials

Juluri et al. BMC Gastroenterology 2011, 11:38 Polyethylene glycol vs. sodium phosphate forbowel preparation: A treatment arm meta-analysis of randomized controlled trials Ravi Juluri1*, George Eckert2 and Thomas F Imperiale3,4,5 Background: Results of meta-analyses of randomized trials comparing PEG and NaP are inconsistent and have notincluded trials comparing either or both preps to less traditional ones.
AIM: To perform a meta-analysis by treatment arm.
Methods: Using MEDLINE and EMBASE, we identified English-language trials published from 1990 to 2008 thatincluded PEG and/or NaP, and aggregated them by treatment arm into: 4 liter (L) PEG; 2 L PEG; split-dose PEG; two45 ml doses of NaP +/- adjunctive medication; and NaP tablets. We compared prep quality and the proportioncompleting the prep.
Results: Among 71 trials (patient N = 10,201), excellent prep quality was present in 34% (CI, 26-41%) for 4 L PEGalone; 39% (CI, 26-51%) for 2 L PEG; 37% (CI, 28-46%) for split-dose PEG; 42% (CI, 33-51%) for NaP solution; 44% (CI,38-51%) for NaP with adjunctive meds; and 58% (CI, 49-67%) for NaP tablets. Patients receiving NaP were morelikely to complete the prep (97% [CI, 96-98%] vs. 90% [CI, 87-92%] for 4L PEG alone); however, completion rates for2L PEG (98%) and split dose PEG (95%) were similar to NaP.
Conclusions: NaP tablets resulted in better prep quality and higher completion rates compared to other regimens.
In comparisons limited by sample size, split dose PEG was not statistically different from NaP solution forcompletion rate or prep quality.
Keywords: Colonoscopy Bowel preparation, Polyethylene Glycol, Sodium Phosphate Colyte; Schwarz Pharma, Milwaukee, WI, and MoviPrep; Colonoscopy is a well-established procedure for screen- Salix Pharmaceutical, Inc, Morrisville, NC) and sodium ing, diagnosis and treatment of colorectal disorders phosphate (NaP) tablets (Visicol and OsmoPrep Tablets; . For colonoscopy to be effective, adequate prepara- Salix Pharmaceuticals, Inc, Morrisville, NC), NaP solution tion of the bowel is required for visualization of the (Fleet Phospho-soda; C.B. Fleet Company, Inc, Lynchburg, colonic mucosa. To achieve this, a bowel preparation VA), are the most widely used agents for colon cleansing.
should be tolerable, safe, effective and convenient. Bowel Polyethylene glycol is an orally administered isotonic solu- preparation is considered to be the main obstacle for tion introduced in 1980 Since PEG is nondigestible patients undergoing colonoscopy [The aversion and nonabsorbable, it cleanses the colon by purging of toward bowel preparation may be related to its taste, intraluminal contents Because it is iso-osmolar with fluid volume ingested, or side effects such as nausea, plasma, the large volume of PEG does not result in signifi- bloating and vomiting.
cant fluid shifts. It has been shown to be highly effective Polyethylene glycol (PEG) (NuLYTELY, Half Lytely, and when taken as instructed (4L of PEG solution). However, GoLYTELY; Braintree Laboratories, Inc, Braintree, MA; the efficacy of standard 4 L PEG outside of clinical trials iscompromised by poor patient compliance. The largevolume and taste are the main factors that contribute to * Correspondence: 1Indiana University Health Physicians, Indianapolis, Indiana, USA poor patient compliance and tolerability , which led Full list of author information is available at the end of the article 2011 Juluri et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License ), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
Juluri et al. BMC Gastroenterology 2011, 11:38 to development of reduced volume PEG solution with or aggregated by treatment arm into one of the fol- without laxatives, sulfate-free, and flavored PEG solutions lowing groups: 1) 4 liter PEG +/- adjunctive medications (Half Lytely, NuLYTELY) in an attempt to reduce the sul- (e.g., dulcolax), 2) 2 liter PEG, 3) Split-dose PEG, 4) fate odor and improve taste [In some studies, split-dose NaP solution - two 45 ml doses +/- adjunctive medica- PEG has been more effective than standard 4L PEG tions, 5) NaP tablets. Disassembly of the trials into treat- ment arms was based on the determination that the Sodium phosphate (NaP), a buffered saline laxative, treatment arms were clinically homogeneous in compo- gained popularity as an alternative method for colonic sition. This determination was based on a qualitative preparation due to its smaller volume. Containing assessment of similarity of the trial populations, study monobasic sodium phosphate and dibasic sodium phos- settings, prep regimens, ratings of bowel prep quality, phate, NaP acts as an osmotic laxative, cleansing the and outcomes. All descriptive and quantitative data colon by drawing fluids into the gastrointestinal tract.
were extracted from the papers to an analytic database.
Several randomized trials and meta-analyses comparing If the data for the particular variable were not available, PEG and NaP have suggested that NaP is safe, better that variable was excluded from analysis and no tolerated, cost-effective, and equally or more effective assumption was made about the missing data.
. NaP tablets (Visicol ®) were designed toimprove the taste and reduce the volume required for Quantitative analysis bowel preparation. NaP tablets contain microcrystalline Descriptive data were extracted to determine clinical cellulose which can be deposited in the colon requiring similarity of the individual trials; extracted quantitative additional irrigation. A newer residue-free formulation data included the number of subjects in each treatment of sodium phosphate tablets (OsmoPrepTM) was intro- arms and those with each outcome. Discrepancies in duced to overcome this limitation.
data extraction were resolved in discussion. For pooling Previous meta-analyses, ] have included head- procedures, the extracted data were combined across to-head trials of PEG vs. NaP but have not included treatment arms rather than across individual trials. We trials comparing either or both of these preps to other, assumed the presence of clinical heterogeneity because less commonly used preps. The objective of this meta- of variation in factors that were not consistently analysis was to quantify and compare the effect of the described in each trial, such as prep timing, consump- two bowel preps on efficacy of and patient adherence to tion of additional liquids, and dietary instructions. We NaP vs. PEG for elective colonoscopy.
combined the data using the random effects modeldeveloped by DerSimonian-Laird [which adjusts for variation within treatment arms and provides a more Search Strategy and selection criteria conservative estimate an effect by providing wider confi- We searched the medical literature from January 1990 to dence intervals (CIs). We compared prep quality (excel- December 2008 using MEDLINE and EMBASE biblio- lent, good, fair, poor) and the percent of persons graphic databases and identified all relevant English lan- completing the prep using weighted, summary- level guage publications. The search strategy used the proportions and 95% CI. All analyses and calculations following MeSH terms: 1) colonoscopy, 2) polyethylene were done using r-meta library (version 2.14) for the glycol, 3) phosphates, 4) cathartics and 5) bowel prep.
statistical software R (version 2.5.1).
We limited these sets of articles to diagnostic and thera-peutic uses and to human studies published in English.
In addition, we hand-searched the reference lists of every Descriptive findings selected primary study for additional trials. The following One hundred seventy four abstracts were obtained from criteria were used to select studies for inclusion: 1) study 1990 through 2008 using MEDLINE and EMBASE; 50 design: randomized controlled trial (RCT), 2) patient were excluded as they were either published prior to population: adult patients undergoing elective colono- 1990 (n = 18), involved bowel preparation for non colo- scopy, 3) year of publication (1990-2008), 4) dosing and noscopy use (n = 11), were published in foreign lan- frequency schedules of PEG and NaP commonly used in guage (n = 8), or were non-randomized controlled trials clinical practice. We excluded duplicate trials, those that (n = 13). Of the 124 randomized controlled trials lacked categorical data on both prep quality and adher- included for full text review, 53 trials were excluded.
ence; review articles; editorials; and letters to the editor.
The number of articles and reasons for exclusion wereas follows: trials which included a pediatric population Assembling the treatment arms (n = 6); trials that did not include PEG or NaP (n = 24); The analysis compared on treatment arms rather than trials with no categorical data (n = 12); and trials with individual trials. Each trial was disassembled and non-traditional doses of either prep (e.g., single dose 3L Juluri et al. BMC Gastroenterology 2011, 11:38 or 6L PEG solutions regimen, single dose NaP (45 mL quality as "excellent or good", satisfactory (excellent or or 90 mL; n = 11) were excluded (Figure good), or unsatisfactory (fair or poor). These definitions For analysis, we included 71 randomized controlled were comparable to the individual quality components trials involving 10,201 patients.
of the four point scale for prep quality Trial aggregation by treatment arm resulted in the fol- The method of preparation of PEG and NaP were lowing prep arms: 4 liter PEG with and without adjunc- similar among the trials with some variation in the tim- tive medications (e.g., metoclopramide, dulcolax); 2 liter ing of prep consumption. Dietary recommendations the PEG; split-dose PEG; NaP solution - two 45 ml doses day before colonoscopy varied from regular to a clear with and without adjunctive medications; and NaP liquid diet for lunch to a full clear liquid diet in the eve- tablets. All low volume PEG trials (i.e., 2 liter) invariably ning. Co-interventions accompanying trials with 2 liter used an adjunctive medication such as bisacodyl (70%), PEG, 4 liter PEG with adjunctive medications, and NaP senna (20%), and magnesium citrate or ascorbic acid solution with adjunctive medications were either taken (10%). Trials that used split dose PEG regimen either separately and only rarely in combination with the study divided a 4 liter dose into 2 liter the day before and 2 preparation, and included magnesium citrate, metoclo- liter on the day of the procedure or divided a 3 liter pramide, psyllium, bisacodyl, cisapride, ascorbic acid, dose into 2 liter the day before and 1 liter the day of the senna, and simethicone.
Descriptive data for each treatment arm is shown in Quantitative findings Table Overall mean age was 58 years; 49% of the The proportion of persons with excellent prep quality study participants were men. At least 68 (95.7%) of 71 were 42.1% (CI, 33-51%) for NaP solution alone; 44.4% trials were investigator-blinded. The trials had compar- (CI, 38-51%) for NaP with adjunctive meds; 58.2% (CI, able study populations; individual trial inclusion criteria 49-67%) for NaP tablets; 33.7% (CI, 26-41%) for 4 liter consisted of patients with indications for screening or PEG alone; 38.7% (CI, 26-51%) for 2 literL PEG; and diagnostic colonoscopy. Exclusion criteria generally 37.2% (CI, 28-46%) for split-dose PEG (Table Based included congestive heart failure, recent myocardial on the criterion of minimal or no overlap of the 95% infarction, renal insufficiency, and cirrhosis with ascites.
CIs, NaP tablets resulted in a greater likelihood of All trials used comparable scales for rating bowel prep achieving an excellent quality prep than did all PEG quality [: excellent prep quality was defined as a small groups, while NaP solution was intermediate. All PEG volume of clear liquid or greater than 95% of surface groups were essentially equivalent with respect to prep seen; good prep quality was defined as large volume of clear liquid covering 5% to 25% of the surface but The composite measure of excellent or good quality greater than 90% of surface seen; fair prep quality was preparation was achieved by 76.3% (CI, 72-81%) of those defined as some semi-solid stool that could be suctioned who used NaP solution alone; by 68.7% (CI, 54-84%) of or washed away but greater than 90% of surface seen; those who used NaP solution with adjunctive medica- and poor prep quality was defined as: semi-solid stool tion; and by 87.8% (CI, 83-93%) of those who used NaP that could not be suctioned or washed away and less tablets (Table and Figure For the PEG treatment than 90% of the surface seen. A few trials defined prep subgroups, an excellent or good prep quality wasachieved by 71.5% (CI, 64-80%) for 4 liter PEG alone; in67.8% (CI, 49-87%) for 4 liter PEG with adjunctive med-ications; in 69.2% (CI, 58-81%) for 2 liter PEG; and in 66.4% (CI, 31-100%) for split-dose PEG. Use of NaPtablets was more likely to result in good or excellent 50 studies excluded: (<1990, non colonoscopy, non RCTs ; and quality prep than both NaP solution groups. When foreign language) compared to the PEG groups, NaP tablets were superior 124 randomized controlled to both 4 liter and 2 liter PEG groups and were superior trials for full text review 53 studies excluded: (pediatrics, to 4 liter PEG with adjunctive medications, with mini- non PEG or non- NaP, studies mally overlapping CIs. All comparisons that included with no categorical data and studies using nontraditional split-dose PEG resulted in significant overlap of the 95% CIs because of both the relatively small numbers of sub- 71 studies included for final jects in this group and the variation in results among the individual studies. Thus, while split-dose PEG was Figure 1 Flow chart diagram for the studies identified in the not statistically different from any of the other groups, the proportion of subjects with a good or excellent Juluri et al. BMC Gastroenterology 2011, 11:38 Table 1 Descriptive data for each prep treatment arm Prep Treatment Arm # of Treatment Arms Mean Age, y (range) NaP Solution alone NaP Solution with adjunctive meds 4L PEG with adjunctive meds quality prep was numerically lower than all groups and among the trials that included completion rates, NaP to a clinically-important degree as compared with NaP was more likely to be completed than PEG, with the exception of the split dose PEG regimen.
Prep completion rates are shown in Table and Fig- Previous meta-analyses of head-to-head trials of PEG ure . Patients who received NaP either alone in liquid vs. NaP have reported that sodium phosphate is more form or in tablet form were more likely to complete the effective, better tolerated, and less costly than PEG prep (97.3% [CI, 96-98%] and 97.2% [CI, 95-99] respec- . However, in 2007 a meta-analysis by Belsey et al tively, vs. 89.5% [CI, 87-92%] for PEG). However, com- reported that no single bowel preparation was consis- pletion rates for 2L PEG (98%) and split-dose PEG tently superior to others Both meta-analyses (95%) were similar to NaP.
excluded data from trials comparing either or both ofthese preps to other, less commonly used preps.
This analysis has strengths and limitations. One This meta-analysis examined 71 randomized controlled strength is the breadth of our search strategy and analy- trials that included NaP or PEG solution or both for sis, as we included studies that have been excluded in bowel preparation prior to elective, outpatient colono- other systematic reviews. Another strength is the clinical scopy. The findings indicate that NaP resulted in an homogeneity of the patient population studied: all excellent quality prep more often than PEG. Further, groups were comprised of outpatients undergoing elec- based on minimal or no overlap of the 95% CIs, NaP tive colonoscopy. Further, as best we could determine, tablets resulted in a greater likelihood of achieving an the study populations, even after re-assembly by treat- excellent quality prep than did all PEG groups, while ment arm, appear to be demographically and clinically NaP solution was in between. There was no difference comparable. Finally, the large sample size of this analysis in prep quality among the various PEG subgroups.
provides reasonable precision for most of the point esti- Among treatments arms where prep quality could be mates of effect for both efficacy and tolerability.
quantified as a composite of excellent or good, NaP With regard to limitations, the potential for clinical tablets (87.8%) were numerically superior to all other heterogeneity is always present when combining trials, forms of either prep. There was minimal overlap of the particularly for factors that were not measured. The 95% CI of NaP tablets with those of both NaP solution possibility of clinical heterogeneity appears to be low; to and 4 L PEG arms, both of which included adjunctive minimize its effects, we used a random effects model, medications. Despite an absolute difference of just over which accounts for heterogeneity by both providing a 21% between NaP tablets and split dose 4 L PEG that point estimate that is less weighted by the studies with favored NaP tablets, the CIs showed a large degree of larger sample sizes and resulting in wider confidence overlap, most likely due to the imprecision of the indivi- intervals. Several candidate factors may contribute to dual trial point estimate for split dose PEG. Finally, clinical and/or methodological heterogeneity among Table 2 Prep quality by treatment arm Prep Treatment Arm # of Treatment Arms % Excellent (95% CI) NaP Solution alone NaP Sol'n with adjunctive meds Juluri et al. BMC Gastroenterology 2011, 11:38 Table 3 Prep quality (Excellent/Good) and completion rates by treatment arm Prep Treatment Arm # of Treatment Arms % Good or Excellent (95% CI) % Prep Completed (95% CI) NaP Solution alone NaP Sol'n with adjunctive meds 4L PEG with adjunctive meds trials. One factor is variation in timing of bowel prep.
to and during the prep, which also were not uniform The time at which the bowel prep was started was not among the trials, and which ranged from a regular diet uniform among the trials ranging from 2:00 PM in the to a clear liquid diet for lunch and clear liquid diet in afternoon to 7:00 PM in the evening the day before the the evening.
scheduled procedure. This may have affected those A second limitation is the uncertain acceptability of patients undergoing colonoscopy in the afternoon by the "treatment-arm" method of doing meta-analysis.
affecting prep quality particularly in the right colon, While this method has been used previously for com- where intestinal chyme can accumulate, obscuring the paring treatments for rheumatoid arthritis for mucosa. Another factor potentially contributing to het- prevention of deep venous thrombosis following total erogeneity is the variation in dietary instructions prior hip replacement and for treatment of premature % Good or Excellent Figure 2 Forest plot of preparation quality by treatment arm.
Juluri et al. BMC Gastroenterology 2011, 11:38 Figure 3 Forest plot of preparation completion/acceptability.
labor its validity is less well established than is A third potential factor is the variation in definitions head-to-head meta-analysis where comparators are the of patient tolerance of the prep. While some trials same in all studies. Limiting the analysis to a head-to- defined patient tolerance by different parameters (e.g.
head comparison would not have allowed considera- completion rates, willingness to repeat the prep, palat- tion of evidence from trials where either NaP or PEG ability and adverse affects), others defined patient toler- was compared to another bowel preparation. An alter- ance as a single parameter and reported it as a single native to our "treatment-arm" approach is a mixed treatment comparison or "network" meta-analysis, In recent years, three reports have described 22 which is another way of quantitatively aggregating data patients who developed renal insufficiency due to across studies containing disparate comparators nephrocalcinosis that was temporally associated with use It allows comparison of multiple treatments, of NaP for colonoscopy prep, 4 of whom progressed to combining direct and indirect evidence in a single ana- end stage renal disease requiring dialysis The lysis. While head-to-head meta-analysis and network majority of these patients had co-morbid conditions meta-analysis of the same data have been compared such as diabetes mellitus, hypertension (treated with , there are no comparative analyses between net- angiotensin-converting enzyme inhibitors [ACE-I] or work and treatment-arm meta-analyses. In the absence angiotensin receptor blockers [ARBs] or diuretics), pre- of such comparative data, it remains uncertain which existing renal insufficiency, were elderly, or had small method is most appropriate for synthesizing quantita- bowel disease that resulted in calcium and vitamin D tive data, and under which circumstances the two malabsorption. Renal biopsies of many of the cases methods differ in results.
showed nephrocalcinosis with intra-tubular deposition Juluri et al. BMC Gastroenterology 2011, 11:38 of calcium-phosphate. The term for this pathologic con- dose PEG and NaP tablets would be useful in further dition is acute phosphate nephropathy (APN). The his- defining the relative efficacy of these two regimens.
topathology suggests that sodium phosphate ingestionleads to obstructive calcium-phosphate crystalluria fol-lowed by acute intra-tubular nephrocalcinosis. These reports have recently raised concerns that led Food and Supported by in part by NIH grant #DK K24 02756 (TFI).
Drug Administration to announce a safety alert in December 2008, stating that a boxed warning would be 1Indiana University Health Physicians, Indianapolis, Indiana, USA.
2 added to the labeling on prescription OSPs (Visicol and Department of Medicine, Division of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana, USA. 3Department of Medicine, Division of OsmoPrep) and recommending against use of over-the- Gastroenterology and Hepatology, Indiana University School of Medicine, counter OSPs for bowel preparation. Shortly after this Indianapolis, Indiana, USA. 4Regenstrief Institute, Inc, Indianapolis, Indiana, announcement, all over-the-counter NaP products were USA. 5Center of Excellence for Implementing Evidence-based Practice,Richard L. Roudebush VAMC, Indianapolis, Indiana, USA.
voluntarily removed from the market, with a subsequentsharp decline in use of NaP solution.
Authors' contributions Despite the FDA's action and resulting reaction, the RJ: carried out data collection, analysis and interpretation of the data,sequence alignment and drafting the manuscript. GE: carried out the published data suggest that absolute risk of APN is very statistical analysis and helped in drafting relevant statistical discussion in the low [Further, a recent systematic review and manuscript. TFI: carried out- analysis and interpretation of the data, meta-analysis of seven controlled studies (patient N = conceived of the analysis, participated in sequence alignment and finalapproval of the manuscript. All authors read and approved the final 14,520) of the effects of NaP versus comparator on kid- ney function showed that there is significant clinical het-erogeneity in the populations studied, study methods, Competing interestsThe authors declare that they have no competing interests.
definition of kidney injury, and results [Quantita-tively, the pooled odds ratio for kidney injury among Received: 4 June 2010 Accepted: 14 April 2011 Published: 14 April 2011 NaP-treated patients ranged from 1.08 (CI, 0.71-1.62) to1.22 (CI, 0.77-1.92). The investigators concluded that it Wexner SD, Beck DE, Baron TH, Fanelli RD, Hyman N, Shen B, Wasco KE, was not possible to discern whether there is a true asso- American Society of C, Rectal S, American Society for Gastrointestinal E, ciation between NaP and kidney injury.
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Pre-publication historyThe pre-publication history for this paper can be accessed here: doi:10.1186/1471-230X-11-38Cite this article as: Juluri et al.: Polyethylene glycol vs. sodiumphosphate for bowel preparation: A treatment arm meta-analysis ofrandomized controlled trials. BMC Gastroenterology 2011 11:38.
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