The Current State of Bowel Preps: A Messy Affair

1
The Current State of Bowel Preps A Messy
Affair
2007 Fellows Pathophysiology Seminars
Phramacologics in Gastroenterology

• Jason N. Rogart, M.D.
• Section of Digestive Diseases
• Yale University School of Medicine
• March 16, 2007

2
OUTLINE

• Why should we care about bowel preps?
• Pharmacology of common bowel preps
• Which prep is the best?
• The future of bowel preps

3
Outline

• Why should we care about bowel preps?
• Pharmacology of common bowel preps
• Which prep is the best?
• The future of bowel preps

4
Colonoscopy in the U.S.

• 14 million colonoscopies in 2002
• Up from 4 million in 2000, ½ million in 1998
• lt50 of the population is getting screened
• 25 inadequate preps (range 9-67)1
• Waste of time and resources for physician
• Discomfort and inconvenience to patient

1 Hsu and Imperiale, GIE, 1998
5
Prep Quality Matters

• Higher adenoma detection rates in cleaner colons1
  
• 2.79 vs. 1.90 lesions/pt in better prepped group
• Higher cecal intubation rates2
• 90 vs. 71 (good vs. poor prep)
• More difficult procedure in poor preps3

1 Chiu et al., Am J Gastro, 2006 2 Froehlich et
al, GIE, 2005 3 Harewood et al, GIE 2003
6
Poor PrepsMore Costly, Less Efficient

• Increases the direct cost of colonoscopy by
  12-22 1
• Pts. will get repeat procedures sooner
• Results in longer procedure time
• 7-11 of time spent washing/suctioning 1
• 5 minutes longer in poor vs. good prep 2

1 Rex et al., Am J Gastro, 2002 2 Froehlich et
al, GIE, 2005
7
Adverse Effects

• Oral lavage solutions (e.g. Golytely)
• Nausea, vomitting, bloating
• Aspiration
• Saline Laxatives (e.g. Phospha-soda)
• Dehydration
• Sodium retention and volume overload
• Hyperphosphatemia

8
What Is the Ideal Prep?The Holy Grail

• Simple instructions
• Work rapidly
• Reliable cleansing
• No gross or histologic alteration of mucosa
• Easily tolerated
• minimal dietary restriction
• Safe
• Inexpensive

No available prep meets all these requirements!
9
OUTLINE

• Why should we care about bowel preps?
• Pharmacology of common bowel preps
• Which prep is the best?
• The future of bowel preps

10
The Evolution of Bowel Preps
Dietary restrictions Cathartics Enemas
Fleets Phosphasoda
Rectal lavage?
Golytely
NaP tablets
1960
1970
1980
1990
2000
Nulytely
Combo preps
High-volume electrolyte lavage
Senna
Mag Citrate
Dulcolax
Prokinetics
11
The Evolution of Endoscopy
HDTV DBE NBI Confocal AFI OCT
Hirschowitz fiberoptic gastroscope
CCD video-endoscopes
ERCP
1960
1970
1980
1990
2000
EUS
Chromo High mag
f.o. colonoscope panendoscope
NOTES
12
Classes of Bowel Preps

• Stimulant Laxatives
• Senna, bisacodyl, castor oil
• Hyperosmotic laxatives
• Mannitol, sorbitol, lactulose
• Oral lavage solutions
• Golytely, Nulytely
• Saline laxatives
• Fleet Phospha-soda (NaP)
• Visicol (NaP) tablets
• Magnesium citrate

13
Stimulant Laxatives

• Senna anthraquinone derivative
• activated by colonic bacteria
• has direct effect on intestinal mucosa
• Bisacodyl (dulcolax)
• poorly absorbed diphenylmethane
• Promote fluid secretion into intestinal lumen
• Increase peristalasis
• Not very effective by themselves

14
Hyperosmotic Laxatives

• Mannitol, Lactulose, Sorbitol
• Nonabsorbable carbohydrates
• Draw water into intestinal lumen
• Bowel distension stimulates evacuation
• Problem risk of explosion during
  electrosurgical procedures
• Fermented by bacteria to hydrogen and
  methane gasses

15
All solutions worth their salt need a name. We
call ours Golytely.

• -Davis et al., 1980

16
Golytely

• Polyethylene glycol electrolyte solution (PEG-ES)
• Contains (mEq/L) Na 125, SO4 40, CL 35, HCO3
  20, K 10, PEG 60g iso-osmotic
• Created to improve tolerance and safety over
  existing preps at the time
• Large volume balanced electrolyte solutions
  caused weight gain, volume overload, electrolyte
  shifts
• Cathartics/enemas- dehydration, electrolyte
  shifts
• 48-72 hrs of dietary restrictions
• Mannitol- explosive
• Preferred by patients1

1Thomas et al., Gastro, 1982
17
Golytely Development, cont.
Test Solutions
Net water and electrolyte movement
() net secretion, (-) net absorption
Davis et al., Gastro, 1980
18
Golytely Development, cont.
Solution E PEG 4000 substituted for mannitol
Net water and electrolyte movement
Davis et al., Gastro, 1980
() net secretion, (-) net absorption
19
Golytely Its Actually the Sulfate

• Sodium absorption is active (against an
  electrochemical gradient)
• Reduced when sulfate (a poorly absorbed anion) is
  substituted for chloride
• Result is near net zero water and sodium movement
• PEG non-absorbable
• Isonatremic solutions of NaSO4 (without PEG) are
  hypo-osmotic to plasma
• Added to create iso-osmotic solution
• Mannitol worked, but is fermentable

Davis et al., Gastro, 1980
20
Nulytely

• Created to improve salty, rotten-egg taste of
  Golytely
• Sulfate removed, more PEG added, and minor
  electrolyte adjustments made
• No signif diff. in net movement of water, Na, or
  Cl-
• Less K and HCO3- than Golytely

Fordtran, et al., Gastro, 1990
21
Nulytely Relies on Na gradient

• Low sodium solution creates a concentration
  gradient
• Reduces Na absorbtion
• Rate of Na absorbtion is balanced by rate of
  passive Na secretion (down conc. gradient)
• More PEG prevents water absorption
• Cleansing equivalent to Golytely
• Conflicting data regarding taste preference

Fordtran, et al., Gastro, 1990
22
PEG-ES Adverse Effects

• Terrible taste
• Nausea
• Vomitting
• Aspiration (rare)
• 4 cases of Boerhaaves Syndrome 1
• Abdominal cramps, bloating
• Sleep loss
• Volume overload (rare)
• Case reports pancreatitis, colitis, cardiac
  dysrythmia, SIADH

1 Aljanabi et al., ANZ J Surg, 2004
23
Fleet Phospha-Soda

• Oral NaP bufferred solution
• Saline laxative
• 2.4g monobasic 0.9g dibasic NaP
• Flavored or unflavored
• Dose 45cc x 2 (or 45 cc 30cc)
• 1990 better tolerated, cheaper, better cleansing
  than Golytely1

1 Vanner et al., Am J Gastro, 1990
24
NaP Hyperosmotic Effect

• Poorly absorbed phosphate ions
• fluid accumulation
• bowel distension
• stimulation of stretch receptors
• Increase in peristalasis
• Onset and duration of action1
• 1st dose, lt2 hrs in 84 avg. 4.6 hrs
• 2nd dose lt1 hr in 98 avg. 2.9 hrs (83lt4h,
  87lt5h)

1 Linden and Waye, GIE, 1999
25
NaP Tablets

• Active ingredients same as Fleet
• Two 90-minute dosing regimens, 12 hrs apart
• Evening before 3 tablets 8oz water every 15
  minutes for total of 20 tabs
• Day of (3-5 hrs pre) repeat (8-12 tabs may be
  equally effective)
• Equal colon cleansing w/ fewer side effects c/w
  PEG
• phase III trials
• Unclear if equally effective or better tolerated
  than aqueous NaP
• Problem microcrystalline cellulose (binder)
  leaves residue on mucosa
• Decreased amts in newer preps
• Gingerale may facilitate removal
• Similar safety profile as Fleet

FDA approved in 2000
26
Adverse Effects of NaP

• Unpalatable taste
• Nausea
• Fluid shifts
• Initially fluid retention
• Dehydration, Orthostasis
• Mucosal changes 3-4
• Erosions, apthoid lesions, ulcers
• Histology e.g. focal inflammation or hemorrhage,
  edema of LP, mucosal hyperemia
• May not want to use in patients with IBD, diarrhea

Watts et al., GIE, 2002
27
NaP Electrolyte Abnormalities

• Rarely clinically significant
• Hyperphosphatemia 40
• If severe, may have 33 mortality rate
• Nephrocalcinosis/acute phosphate nephropathy
• Hypocalcemia (5)
• Tonic-clonic seizures ,tetany
• Hypokalemia (20)
• Hypernatremia

Contraindicated in renal failure, CHF,
decompensated cirrhosis, ileus, baseline
electrolyte abnormalities. Caution in elderly,
children.
28
Outline

• Why should we care about bowel preps?
• Pharmacology of common bowel preps
• Which prep is the best?
• The future of bowel preps

29
Cost
July, 2005
ASGE Consensus document, 2006
30
1998 Meta-Analysis

• 8 RCTs, 1286 pts, PEG vs. NaP (1990-1996)
• NaP better
• More likely to complete prep (RR 0.23 NNT7)
• excellent prep quality (RR 1.72, NNT 5)
• No difference
• acceptable prep quality
• Cost comparison PEG 8 more expensive
• Cost of prep, of repeat procedures for poor
  prep
• Probabilities derived from single study

Hsu and Imperiale, GIE, 1998
31
2006 Meta-Analysis

• 23 RCTs, 1990-2005- 6459 patients
• 18 compared NaP to PEG
• NaP better than PEG in 9, PEG better than NaP in
  1
• 5 compared combinations of various agents
• Limitations due to variability in
• Prep doses
• Prep timing
• Bowel prep quality grading scales
• Dietary restrictions and fluid intake

Tan and Tjandra, Colorectal Disease, 2006
32
Phospha-soda more effective than PEG-ES
OR of acceptable prep 0.75 for NaP (CI 0.65-0.88,
p0.0004)
Tan and Tjandra, Colorectal Disease, 2006
33
More patients complete NaP
94.4 NaP vs. 71 PEG-ES OR 0.16 for NaP
Tan and Tjandra, Colorectal Disease, 2006
34
No difference in overall adverse events
PEG more abd pain, OR 1.67 (plt.01) NaP more
dizziness, OR 2.0 (plt0.01)
Tan and Tjandra, Colorectal Disease, 2006
35
NaP more hypokalemia, hyperphosphatemia, and
hypocalcemia
Not clinically significant
Tan and Tjandra, Colorectal Disease, 2006
36
Adjuvant Medications

• Flavoring may not improve tolerance
• Prokinetics
• Cisapride, tegaserod dont improve quality or
  tolerance
• Reglan may reduce nausea/bloating
• Enemas no additional benefit
• Senna little data may allow lower volume
• Magnesium Citrate may have some benefit
• Bisacodyl may allow lower volumes of prep

37
High Dose Senna

• Not discussed in ASGE Consensus Document
• Safety data is limited
• Inferior prep quality vs. aqueous NaP 1-2
• Conflicting results on tolerance and side effects
• Superior to 4L PEG in prep quality and side
  effects 3
• Better quality likely reflective of higher
  compliance
• But signif. more abd. pain (21 mod., 6 severe)

1 Unal et al., Acta Gastroenterol Belg, 1998 2
Kositchaiwat et al., World J Gastro, 2006 3
Radaelli et al, Am J Gastro, 2005
38
Magnesium Citrate

• Hyperosmotic saline laxative renal excretion
• PreRx with 300cc 2 hrs before 4L of PEG 1
• improved overall prep quality (minimally)
• decreased colonic liquid (less PEG ingested)
• 2L PEG Mg Citrate vs. 4L PEG 2
• Reduced volume better overall prep quality,
  patient satisfaction and symptoms less liquid
  stool aspirated
• But no difference in of excellent/good preps!

1 Sharma et al., GIE, 1997 2 Sharma et al., GIE,
1998
studied at VA- all men
39
Bisacodyl can reduce PEG volume
plt0.05
40
Outline

• Why we should care about bowel preps
• Pharmacology of bowel prep agents
• Which prep is the best- the data
• The future of bowel preps

41
Progress?
Stimulant laxatives
Rectal Lavage
Oral Lavage
Saline Laxatives
42
The Future

• Tailoring prep for specific patient populations
• Timing is critical
• The perfect combination
• Patient education on prep instructions
• Totally new pharmacologic agents
• Retrograde preps

43
Predictors of Inadequate Prep

modifiable
1 Ness et al., Am J Gastro, 2001 2 Froehlich et
al, GIE, 2005
3 Taylor et al., Am J Gastro, 2001 4 Harewood et
al., Am J Gastro, 2004
44
Is TIMING the Key?

• Timing of prep ingestion varies between studies
  and between institutions
• Stricter dietary control is required if prep is
  taken the day before the procedure
• Prep passes more rapidly to colon than food
• overnight shedding of residual fecal material
  from small bowel to colon is often a problem
• Afternoon colonoscopies have higher failure rates
  than morning in pts who receive PEG the night
  before 1

1Sanaka et al., Am J Gastro, 2006
45
4L PEG the morning of procedure is better than
afternoon before
Church, Dis Col Rect, 1998
46
4L PEG the morning of procedure is better than
afternoon before
all plt0.0001
Church, Dis Col Rect, 1998
47
Split-dose PEG without dietary restriction is
better than whole dose with dietary restriction

• 141 pts randomized, endoscopist-blinded
• Group A liquid diet 4L PEG 6-10pm
• Group B 2L PEG, 7-9pm and 2L PEG day-of
• reg. diet until 630pm, then water only

p0.011
p lt0.001
Aoun et al., GIE, 2005
48
½ Fleet phospha-soda in morning is better than
day-before preps
p lt.001 for all
Plt.001
NaP ½ day-of
NaP ½ day-of
PEG
NaP day before
PEG
NaP day before
Frommer, Dis Col Rect, 1997
49
Longer interval between NaP doses is better




NaP, 24h
NaP, 12h
NaP, 6h
PEG
12 and 24h better than 6h and PEG (plt0.05)
Rostom et al., GIE 2006
50
Morning or Split-Dose PEG is equivalent to Fleet
Phospha-soda

• Poon et al., 2002
• 2L PEG vs. 90mL NaP (morning)
• No differences in overall prep quality, pt
  tolerance
• Minimally better cecal prep in NaP
• Huppertz-Hauss et al., 2005, Vliegen, 2006
• 4L PEG given in AM for PM procedures or night
  before for morning procedures
• 90mL NaP (split 12hrs apart) 2nd bottle given
  in AM for PM procedures
• No differences in prep quality or side effects

ngt200
51
Patient Education

• Patient compliance is suboptimal
• Patients overestimate the quality of their own
  prep1
• Only 50 accurate for excellent prep
• Marketing has focused on improving ease of use
  and instruction clarity
• We need to do more

1 Harewood et al., Am J Gastro, 2004
52
New Product MoviPrep

• 2L PEG-ES with ascorbic acid and sodium ascorbate
  (laxative in high doses)
• Two possible regimens
• 2L night before 1L clears
• 1L night before ? 1L morning of 500cc clears
• Comparable efficacy and side effects vs. Golytley
• Greater patient satisfaction

FDA approved 8/06
Kastenberg, ACG Las Vegas 2006
53
Pulsed Rectal Lavage
Avitar 2000 Bowel Evacuation System

• Infusion of short pulses of warm tap water
• 25 ml/s x 5g (20-30 min.)
• Mag citrate night before
• Compared to 4L PEG (7pm)
• No significant difference in prep quality but
  trend favored PEG
• Disadvantages costly, skilled nursing,
  embarrassing
• May be useful for
• Nonambulatory patients
• Pts. who cant tolerate oral prep

Chang et al., GIE, 1991
54
Hydrotherapy- 2006
Prep Quality by segment
Patient Tolerance






plt0.001
Fiorito et al., ACG Las Vegas, 2006
55
Exercise improves Prep Quality

• 383 patients randomized to walk or rest
• Evening before 5mg bisacodyl and a liquid dinner
  
• Day-of at hospital 250mL PEG q10min., 3L total
• Only healthy pts lt80yo (ASA I or II) included
• 41 vs. 25 had excellent/good prep
• Subgroup analysis favored nonobese pts lt65 yo
  without h/o abd surgery

plt0.05
Kim et al., Am J Gastro, 2005
56
Concluding thoughts

• We need more and better research!
• Timing is critical
• For afternoon procedures, half the prep should be
  taken in the morning
• For morning procedures, take prep in
  evening/night, not afternoon
• Patient compliance is important
• Patients prefer lower volumes of prep
• The prep is worse than the procedure
• We need to do better to increase the of
  population screened and to increase our adenoma
  detection rates, especially when we face
  competition from CTC, capsule, etc.

57
The End.

• Thanks to Dr. Uzma Siddiqui