Evidence review for pharmacological interventions to reduce progression to dysplasia or cancer

Evidence review for pharmacological interventions to reduce progression to dysplasia or cancer

Barrett’s oesophagus and stage 1 oesophageal adenocarcinoma

Evidence review B

NICE Guideline, No. 231

London: National Institute for Health and Care Excellence (NICE); 2023 Feb.

ISBN-13: 978-1-4731-5008-9

1. Pharmacological interventions to reduce progression to dysplasia or cancer

1.1. Review question

For adults with Barrett’s oesophagus, what is the clinical and cost effectiveness of pharmacological interventions (such as antacids, aspirin, H2 receptor antagonists, proton pump inhibitors) in reducing progression to dysplasia or cancer?

1.1.1. Introduction

For people with Barrett’s Oesophagus, medical management with pharmacological interventions is routinely used. Pharmacological interventions have been associated with a reduction in the risk of cancer progression, but there remains a debate with regards risk versus benefit of aspirin. It is important to understand how beneficial these agents are in preventing progression of Barrett’s and this review aims to find out the clinical and cost effectiveness of these medications in reducing progression to dysplasia or cancer.

1.1.2. Summary of the protocol

For full details see the review protocol in Appendix A.

Table 1

PICO characteristics of review question.

1.1.3. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

Two RCTs were included in the review ¹^, ² these are summarised in Table 2 below. Both the studies included people with low grade dysplasia in Barrett’s oesophagus.

One study compared three different Proton Pump Inhibitors (PPI) pantoprazole, lansoprazole, or omeprazole, examining the degree of dysplasia after one year of follow up. The second study compared high dose vs low dose PPI and aspirin vs no aspirin on a sample of participants randomised to four different groups using a 2x2 factorial design to receive either high or low dose PPI with or without aspirin. Participants were followed up for a median of 8.9 years and outcomes included all-cause mortality, oesophageal adenocarcinoma, and high-grade dysplasia. Evidence from these studies is summarised in the clinical evidence summary below (Table 3).

No relevant clinical studies examining antacids, NSAIDs, H2 receptor antagonists or statins were identified.

See also the study selection flow chart in Appendix C, study evidence tables in Appendix D, forest plots in Appendix E and GRADE tables in Appendix F.

1.1.4.2. Excluded studies

See the excluded studies list in Appendix H.

1.1.5. Summary of studies included in the effectiveness evidence

Table 2

Summary of studies included in the evidence review.

See Appendix D for full evidence tables.

1.1.6. Summary of the effectiveness evidence

Table 3

Clinical evidence summary: High dose PPI compared to Low dose PPI for Barrett’s Oesophagus.

Table 4

Clinical evidence summary: Aspirin compared to no Aspirin for Barrett’s Oesophagus.

Table 5

Clinical evidence summary: Pantoprazole compared to Lansoprazole for Barrett’s Oesophagus.

Table 6

Clinical evidence summary: Lansoprazole compared to Omeprazole for Barrett’s Oesophagus.

Table 7

Clinical evidence summary: Pantoprazole compared to Omeprazole for Barrett’s Oesophagus.

See Appendix F for full GRADE tables.

1.1.7. Economic evidence

1.1.7.1. Included studies

No health economic studies were included.

1.1.7.2. Excluded studies

No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in Appendix G.

1.1.8. Summary of included economic evidence

There was no economic evidence found.

1.1.9. Economic model

This area was prioritised for new cost-effectiveness analysis. However, original economic modelling was not conducted due to a lack of robust clinical evidence.

1.1.10. Unit costs

Relevant unit costs are provided below to aid consideration of cost effectiveness.

Table 8

Unit cost of drugs.

1.1.11. The committee’s discussion and interpretation of the evidence

1.1.11.1. The outcomes that matter most

To understand the clinical effectiveness of pharmacological interventions in reducing progression to dysplasia or cancer, the committee considered the outcomes of mortality (including all-cause mortality), health related quality of life, progression from non-dysplastic to low grade dysplasia, progression to any grade of dysplasia, progression to high grade dysplasia or cancer and adverse events. All outcomes in this review were equally important in decision making and were therefore rated as critical by the committee.

Evidence was identified for the outcomes of mortality (all-cause and cause-specific mortality), progression to low-grade dysplasia, progression to high-grade dysplasia and oesophageal adenocarcinoma and serious adverse events. No evidence was identified for the outcome of health-related quality of life.

1.1.11.2. The quality of the evidence

Evidence from two RCTs meeting the review protocol was identified, with one RCT examining the clinical effectiveness of three different PPIs (pantoprazole, lansoprazole, or omeprazole) and one RCT comparing high dose to low dose PPI and aspirin to no aspirin.

No relevant clinical studies examining the clinical effectiveness of antacids, NSAIDs, H2 receptor antagonists or statins for the outcomes prespecified were identified.

For the comparisons of different PPIs (pantoprazole, lansoprazole, or omeprazole), there was evidence for the outcomes of low and high-grade dysplasia, the quality of which was very low. Evidence was downgraded for risk of bias that was due to limited information regarding the methodology, analysis, and patient characteristics. Evidence was also downgraded due to population indirectness as the study included participants who had dysplasia at baseline and imprecision in the effect estimates with confidence intervals being very wide.

The quality of the evidence for high vs low dose PPI and aspirin vs no aspirin was low for the outcomes of cause-specific mortality and oesophageal adenocarcinoma due to very serious imprecision with the confidence intervals being very wide and moderate for the outcomes of all-cause mortality, high-grade dysplasia, due to serious imprecision based on the confidence interval around the effect estimates. The quality of the evidence for the outcome of serious adverse events was high for the high vs low dose PPI comparison and moderate for the aspirin vs no aspirin comparison, the latter being downgraded due to serious imprecision.

1.1.11.3. Benefits and harms

No relevant clinical studies on antacids, NSAIDs, H2 receptor antagonists or statins were identified and in the included evidence on PPIs and aspirin there was no comparison between drug classes.

The evidence comparing different PPIs showed no clinically important difference for any PPI (pantoprazole, lansoprazole, or omeprazole) over the other. The committee noted that because the evidence comparing different PPIs was from an underpowered RCT and was of very low quality with very wide confidence intervals it was not possible to draw conclusions regarding the effect estimates. The committee also noted that the length of follow up (1 year) in the study was too short for any clinically important change to occur. The committee agreed that the evidence for different PPIs was too limited both in terms of quantity and quality to base any recommendations on.

Evidence comparing high dose PPI with low dose PPI, also showed there was no clinically important difference across the outcomes examined. However, the committee noted that although the absolute effects did not meet the thresholds for clinical importance, the direction of the effect favoured high dose PPI over low dose PPI for the outcome of all-cause mortality. The committee noted this was also the case for most of the other outcomes examined except for serious adverse events. Despite not reaching the threshold for clinical importance, the committee emphasised that a higher dose of PPI was not associated with a higher number of adverse events or cases of all-cause mortality. The committee discussed that, although treatment with PPI might have chemo-preventive effects against oesophageal adenocarcinoma compared to no treatment, this would be difficult to demonstrate within a clinical trial setting as a placebo-controlled trial is not feasible as most people with Barrett’s oesophagus need treatment with PPI. There was consensus that the current evidence did not support a recommendation for the use of PPIs in preventing progression to dysplasia and oesophageal cancer.

For the comparison of aspirin with no aspirin, evidence showed no clinically important difference across the outcomes examined. The committee noted that despite not meeting thresholds for clinical importance, the point estimates for all-cause mortality and high-grade dysplasia favoured aspirin compared to no aspirin. However, there was a greater number of serious adverse events with aspirin compared to no aspirin. Although the effect was not clinically important, the committee noted this was in line with their experience as a greater number of adverse events such as bleeding, is likely to be seen in people treated with aspirin compared to no aspirin. The committee emphasised that in the current trial, the lack of a clinically important effect favouring no aspirin in terms of adverse events could be attributed to a protective effect from PPIs taken by people in both the aspirin and no aspirin groups.

The committee discussed that although there is some effect observed in terms of all-cause mortality and high-grade dysplasia in both the comparisons of high vs low dose PPI and aspirin vs no aspirin, the length of follow up, despite being 8.5 years, may not have been sufficient to capture progression to high-grade dysplasia. Therefore, the lack of a clinically important effect within the duration of this study did not allow the committee to draw conclusions, as they noted based on their experience that it may take longer for pharmacological interventions to act on cancer risk. The committee agreed that there was no sufficient evidence to recommend aspirin as a chemo-preventive treatment for Barrett’s oesophagus. Considering their clinical experience that was in line with evidence showing a greater number of adverse events associated with aspirin, the committee concluded a recommendation should be made against offering aspirin to prevent progression of dysplasia or and cancer.

The committee agreed that, based on the current limited evidence base (coming from one study and showing no clinically important results), the use of neither high dose PPI nor Aspirin can be recommended.

The committee agreed that PPI treatment is widely used for symptom control for patients with Barrett’s oesophagus but not for chemoprevention. They noted, the current evidence does not justify a recommendation for high dosage PPI but agreed based on clinical experience that acid-suppressant medication such as PPI should be offered to all patients to control symptoms of gastro-oesophageal reflux, although the dose should be reviewed regularly to prevent potential long-term side effects such as bone fractures, infections, and electrolyte disturbances. They agreed to cross reference to the recommendations on managing gastro-oesophageal reflux disease in the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults.

1.1.11.4. Cost effectiveness and resource use

There are recurrent costs and side effects associated with drug treatments, but they might be justified by improved quality of life through symptom control or through reduced progression of disease.

No economic evaluations were identified for this question.

The clinical evidence for aspirin versus no aspirin suggested no clinically important benefit, with an increase in serious adverse events with aspirin, though this was clinically unimportant. Overall, the committee decided there was insufficient clinical evidence to inform the cost effectiveness of aspirin as a chemo-preventative agent in Barrett’s.

The clinical evidence for PPIs suggested a trend towards improved survival with high dose PPI versus low dose PPI with a clinically unimportant difference in serious adverse events. The committee did not think the evidence was strong enough to show if high-dose PPIs are effective for chemoprevention, and therefore their cost effectiveness is uncertain.

1.1.12. Recommendations supported by this evidence review

This evidence review supports recommendation 1.2.2.

1.1.13. References

1.: Babic Z, Bogdanovic Z, Dorosulic Z, Petrovic Z, Kujundzic M, Banic M et al. One year treatment of Barrett’s oesophagus with proton pump inhibitors (a multi-center study). Acta Clinica Belgica. 2015 70(6):408–413 [PubMed: 26790552]

2.: Jankowski JAZ, de Caestecker J, Love SB, Reilly G, Watson P, Sanders S et al. Esomeprazole and aspirin in Barrett’s oesophagus (AspECT): A randomised factorial trial. Lancet. 2018 392(10145):400–408 [PMC free article: PMC6083438] [PubMed: 30057104]

3.: National Institute for Health and Care Excellence. Developing NICE guidelines: the manual [updated January 2022]. London. National Institute for Health and Care Excellence, 2014. Available from: http://www.nice.org.uk/article/PMG20/chapter/1%20Introduction%20and%20overview

Appendices

Appendix A. Review protocols

Review protocol for pharmacological interventions to reduce progression to dysplasia or cancer (PDF, 189K)

Health economic review protocol (PDF, 132K)

Appendix B. Literature search strategies

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual.³

For more information, please see the Methodology review published as part of the accompanying documents for this guideline.

B.1. Clinical search literature search strategy (PDF, 165K)

B.2. Health Economics literature search strategy (PDF, 140K)

Appendix H. Excluded studies

Clinical studies

Table 16

Studies excluded from the clinical review.

Health Economic studies

Published health economic studies that met the inclusion criteria (relevant population, comparators, economic study design, published 2006 or later and not from non-OECD country or USA) but that were excluded following appraisal of applicability and methodological quality are listed below. See the health economic protocol for more details.

None.

Final

Evidence review underpinning recommendation 1.2.2 in the NICE guideline

National Institute for Health and Care Excellence

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK595771PMID: 37816096

Table 1PICO characteristics of review question

Population	Adults, 18 years and over, with non-dysplastic Barrett’s oesophagus and low-grade dysplasia in Barrett’s oesophagus
Interventions	Antacids NSAIDs Aspirin H2 receptor antagonists Proton Pump Inhibitors Statins (e.g., simvastatin)
Comparisons	Each other Within class comparison Combination therapy (e.g., PPI + Aspirin combination vs. singular medicine) Low dose vs. high dose of medication (same medication) No treatment
Outcomes	Mortality (including all-cause mortality) Health related quality of life Progression from non-dysplastic to low grade dysplasia Progression to any grade of dysplasia Progression to high grade dysplasia or cancer Adverse events (e.g., bleeding)
Study design	RCT SR of RCT’s Published NMAs and IPDs will be considered for inclusion.

Table 2Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Babic 2015 ¹

PPI medication:

Pantoprazole (N = 54) dose of 40mg twice a day during 10weeks

Lansoprasole (N = 36) dose of 30mg twice a day during 10 weeks, then 30mg once a day to the end of the study

Omeprazole (N = 30) dose of 40mg twice a day for 10weeks, then 40mg once a day

Patients with Barrett’s oesophagus diagnosed by endoscopy and histological analysis of the tissue biopsy specimen

N=120 mean age (SD): 52.3 (14.4) years

Croatia

Indefinite dysplasia

Low-grade dysplasia

High-grade dysplasia

Follow up: 1 year

One patient in each Treatment group showed worsening and progression to higher grade of dysplasia at baseline.

Jankowski 2018 ²

High or low dose PPI with or without aspirin.

High dose PPI: Esomeprazole (40 mg capsules twice daily; n=1270)

low dose (20 mg capsules once daily; n=1265).

Aspirin (300 mg in the UK, 325 mg in Canada; n=1138)

No aspirin (n=1142).

Study comparison groups:

1): High dose PPI vs low dose PPI (in each group there was an approximately equal number of people who did or did not receive aspirin)

2): Aspirin vs no aspirin (in each group there was an approximately equal number of people who received high and low dose PPI medication)

People aged ≥18 years with circumferential Barrett’s oesophagus of at least 1 cm in length (≥C1M1) or a tongue of Barrett’s oesophagus of at least 2 cm in length (≥C0M2), irrespective of the presence now or historically of histologically proven intestinal metaplasia.

Countries: England, Scotland, Wales, and Northern Ireland, and one in McMaster Health Sciences Centre, Hamilton, ON, Canada

All-cause mortality

Cause-specific mortality

High-grade dysplasia

Oesophageal adenocarcinoma

Serious adverse events(Blood and lymphatic system disorders, cardiac disorders, ear and labyrinth disorders, endocrine disorders, eye disorders, gastrointestinal disorders, general disorders and administration site conditions, hepatobiliary disorders, immune system disorders, infections and infestations, injury, poisoning, and procedural complications investigations, metabolism and nutrition disorders, musculoskeletal and connective tissue disorders, neoplasms benign, malignant, and unspecified (including cysts and polyps, nervous system disorders, psychiatric disorders, renal and urinary disorders, respiratory, thoracic, and mediastinal disorders, skin and subcutaneous tissue disorders, vascular disorders)

Follow up: Median 8.9 years

Participants in the AspECT trial were randomised using a 2×2 factorial design to receive high or low dose PPI with or without aspirin.

Results were reported separately for the comparisons of low vs high dose PPI and aspirin vs no aspirin.

Table 3Clinical evidence summary: High dose PPI compared to Low dose PPI for Barrett’s Oesophagus

Outcomes

№ of participants

(studies)

Follow-up

Certainty of the evidence

(GRADE)

Relative effect

(95% CI)

Anticipated absolute effects

Risk with Low dose PPI

Risk difference with High dose PPI

All-cause mortality

2535

(1 RCT)

⨁⨁⨁◯

Moderate^a

RR 0.75

(0.57 to 0.99)

83 per 1,000

21 fewer per 1,000

(36 fewer to 1 fewer)

Cause-specific mortality

2535

(1 RCT)

⨁⨁◯◯

Low^a

RR 0.66

(0.27 to 1.62)

9 per 1,000

3 fewer per 1,000

(7 fewer to 6 more)

Oesophageal Adenocarcinoma

2535

(1 RCT)

⨁⨁◯◯

Low^a

RR 0.97

(0.63 to 1.49)

32 per 1,000

1 fewer per 1,000

(12 fewer to 16 more)

High-grade dysplasia

2535

(1 RCT)

⨁⨁⨁◯

Moderate^a

RR 0.74

(0.51 to 1.09)

47 per 1,000

12 fewer per 1,000

(23 fewer to 4 more)

Serious adverse events

2535

(1 RCT)

⨁⨁⨁⨁

High

RR 1.00

(0.87 to 1.13)

265 per 1,000

0 fewer per 1,000

(34 fewer to 34 more)

a: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs (default MIDs for dichotomous outcomes: 0.8 and 1.25)

Table 4Clinical evidence summary: Aspirin compared to no Aspirin for Barrett’s Oesophagus

Outcomes

№ of participants

(studies)

Follow-up

Certainty of the evidence

(GRADE)

Relative effect

(95% CI)

Anticipated absolute effects

Risk with no Aspirin

Risk difference with Aspirin

All-cause mortality

2280

(1 RCT)

⨁⨁⨁◯

Moderate^a

RR 0.81

(0.60 to 1.10)

79 per 1,000

15 fewer per 1,000

(32 fewer to 8 more)

Cause-specific mortality

2280

(1 RCT)

⨁⨁◯◯

Low^a

RR 1.00

(0.38 to 2.66)

7 per 1,000

0 fewer per 1,000

(4 fewer to 12 more)

Oesophageal Adenocarcino ma

2280

(1 RCT)

⨁⨁◯◯

Low^a

RR 1.00

(0.63 to 1.59)

31 per 1,000

0 fewer per 1,000

(11 fewer to 18 more)

High-grade dysplasia

2280

(1 RCT)

⨁⨁⨁◯

Moderate^a

RR 0.68

(0.45 to 1.02)

48 per 1,000

15 fewer per 1,000

(26 fewer to 1 more)

Serious adverse events

2280

(1 RCT)

⨁⨁⨁◯

Moderate^a

RR 1.17

(1.02 to 1.35)

238 per 1,000

40 more per 1,000

(5 more to 83 more)

a: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs (default MIDs for dichotomous outcomes: 0.8 and 1.25)

Table 5Clinical evidence summary: Pantoprazole compared to Lansoprazole for Barrett’s Oesophagus

Outcomes

№ of participants

(studies)

Follow-up

Certainty of the evidence

(GRADE)

Relative effect

(95% CI)

Anticipated absolute effects

Risk with Lansoprazole

Risk difference with Pantoprazole

Low-grade dysplasia

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

RR 0.67

(0.04 to 10.32)

28 per 1,000

9 fewer per 1,000

(27 fewer to 259 more)

High-grade dysplasia

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

RR 0.67

(0.04 to 10.32)

28 per 1,000

9 fewer per 1,000

(27 fewer to 259 more)

a: Downgraded by 1 increment as the evidence was at high risk of bias due to limited information regarding the methodology, analysis and participant characteristics

b: Downgraded by 1 increment due to the study including a partially indirect population with a small number of people having dysplasia at baseline

c: Downgraded by 2 increments as the confidence interval crossed both MIDs (default MIDs for dichotomous outcomes: 0.8 and 1.25)

Table 6Clinical evidence summary: Lansoprazole compared to Omeprazole for Barrett’s Oesophagus

Outcomes

№ of participants

(studies)

Follow-up

Certainty of the evidence

(GRADE)

Relative effect

(95% CI)

Anticipated absolute effects

Risk with Omeprazole

Risk difference with Lansoprazole

Low-grade dysplasia

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

RR 0.83

(0.05 to 12.77)

33 per 1,000

6 fewer per 1,000

(32 fewer to 392 more)

High-grade dysplasia

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

RR 0.83

(0.05 to 12.77)

33 per 1,000

6 fewer per 1,000

(32 fewer to 392 more)

a: Downgraded by 1 increment as the evidence was at high risk of bias due to limited information regarding the methodology, analysis and participant characteristics

b: Downgraded by 1 increment due to the study including a partially indirect population with a small number of people having dysplasia at baseline

c: Downgraded by 2 increments as the confidence interval crossed both MIDs (default MIDs for dichotomous outcomes: 0.8 and 1.25)

Table 7Clinical evidence summary: Pantoprazole compared to Omeprazole for Barrett’s Oesophagus

Outcomes

№ of participants

(studies)

Follow-up

Certainty of the evidence

(GRADE)

Relative effect

(95% CI)

Anticipated absolute effects

Risk with Omeprazole

Risk difference with Pantoprazole

Low-grade dysplasia

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

RR 0.56

(0.04 to 8.57)

33 per 1,000

15 fewer per 1,000

(32 fewer to 252 more)

High-grade dysplasia

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

RR 0.56

(0.04 to 8.57)

33 per 1,000

15 fewer per 1,000

(32 fewer to 252 more)

a: Downgraded by 1 increment as the evidence was at high risk of bias due to limited information regarding the methodology, analysis and participant characteristics

b: Downgraded by 1 increment due to the study including a partially indirect population with a small number of people having dysplasia at baseline

c: Downgraded by 2 increments as the confidence interval crossed both MIDs (default MIDs for dichotomous outcomes: 0.8 and 1.25)

Table 8Unit cost of drugs

Resource	Unit costs	Source
Antacids	£30.75	Prescription Cost Analysis 2020/21
Aspirin	£1.20
H2 receptor antagonists	£15.62
Proton pump inhibitors	£2.31
Statins	£1.82

Table 16Studies excluded from the clinical review

Study	Reason for exclusion
(2020) Erratum: correction: argon plasma coagulation for Barrett’s esophagus with low-grade dysplasia: a randomized trial with long-term follow-up on the impact of power setting and proton pump inhibitor dose (Endoscopy (2020)). Endoscopy [PubMed: 33003211]	- Full text paper not available
(2018) Erratum: esomeprazole and aspirin in Barrett’s oesophagus (AspECT): a randomised factorial trial (The Lancet (2018) 392(10145) (400-408), (S0140673618313886) (10.1016/S0140-6736(18)31388-6)). Lancet 392(10164): 2552 [PMC free article: PMC6083438] [PubMed: 30057104]	- Duplicate reference Summary of paper included in the review
Attwood, S. E., Lundell, L., Hatlebakk, J. G. et al. (2008) Medical or surgical management of GERD patients with Barrett’s esophagus: the LOTUS trial 3-year experience. Journal of Gastrointestinal Surgery 12(10): 1646–54; discussion 1654 [PubMed: 18709511]	- Comparator in study does not match that specified in this review protocol Comparing pharmacological treatment with anti-reflux surgery
Caldwell, M. T. P., Byrne, P. J., Walsh, T. N. et al. (1996) A randomized trial on the effect of acid suppression on regression of Barrett’s oesophagus. Gastroenterology 110(4): a074	- Full text paper not available
Chen, Y., Sun, C., Wu, Y. et al. (2021) Do proton pump inhibitors prevent Barrett’s esophagus progression to high-grade dysplasia and esophageal adenocarcinoma? An updated meta-analysis. Journal of Cancer Research & Clinical Oncology 147(9): 2681–2691 [PubMed: 33575855]	Systematic review of non-randomized studies
de Bortoli, N., Martinucci, I., Piaggi, P. et al. (2011) Randomised clinical trial: twice daily esomeprazole 40 mg vs. pantoprazole 40 mg in Barrett’s oesophagus for 1 year. Alimentary Pharmacology & Therapeutics 33(9): 1019–27 [PubMed: 21385192]	- Outcome not relevant to protocol Assessing scoring of Ki67, COX-2 expression, apoptotic staining and oesophageal pH-metry
Eslami, L. and Nasseri-Moghaddam, S. (2013) Meta-analyses: does long-term PPI use increase the risk of gastric premalignant lesions?. Archives of Iranian Medicine 16(8): 449–58 [PubMed: 23906249]	- Outcome not relevant to this review protocol Assessing the incidence of (pre)malignant gastric lesions
Falk, G. W., Buttar, N. S., Foster, N. R. et al. (2012) A combination of esomeprazole and aspirin reduces tissue concentrations of prostaglandin E(2) in patients with Barrett’s esophagus. Gastroenterology 143(4): 917–26.e1 [PMC free article: PMC3458136] [PubMed: 22796132]	- Outcome not relevant to protocol Assessing PGE2 concentrations in Barrett’s mucosa
Faybush, E. M. and Sampliner, R. E. (2005) Randomized trials in the treatment of Barrett’s esophagus. Diseases of the Esophagus 18(5): 291–7 [PubMed: 16197527]	- Systematic review including interventions not relevant to the protocol Comparing different therapeutic modalities e.g. Anti-reflux surgery, argon plasma coagulation, photodynamic therapy
Frazzoni, M., Manno, M., De Micheli, E. et al. (2007) Efficacy in intra-oesophageal acid suppression may decrease after 2-year continuous treatment with proton pump inhibitors. Digestive and liver disease 39(5): 415–421 [PubMed: 17379591]	- Outcome not relevant to protocol Assessing oesophageal acid exposure
Hoffman, A., Kiesslich, R., Vieth, M. et al. (2007) Influence of acid suppression with Esomeprazole on the length and area of Barrett’s oesophagus without intra-epithelial neoplasia - a prospective, randomised studye. Zeitschrift fur gastroenterologie 45(8): 742	- Study not reported in English
Husain, N. S. and El-Serag, H. B. (2018) Chemoprevention of Barrett’s oesophagus: a step closer with PPIs and aspirin. Nature Reviews Clinical Oncology 15(12): 728–730 [PubMed: 30237519]	- Review article but not a systematic review
Kantor, E. D., Onstad, L., Blount, P. L. et al. (2012) Use of statin medications and risk of esophageal adenocarcinoma in persons with Barrett’s esophagus. Cancer Epidemiology, Biomarkers & Prevention 21(3): 456–61 [PMC free article: PMC3297725] [PubMed: 22241250]	- Study design not relevant to this review protocol Prospective cohort study
Klaus, A. and Hinder, R. A. (2000) Medical therapy versus antireflux surgery in Barrett’s esophagus: what is the best therapeutic approach?. Digestive Diseases 18(4): 224–31 [PubMed: 11356994]	- Review article but not a systematic review
Lanas, A., Ortego, J., Sopeña, F. et al. (2004) Effects of prolonged treatment with an inhibitor of COX-2 in cell proliferation in patients with Barrett’s esophagus. Preliminary results of a multicenter, randomized, controlled trial. Gastroenterologia y hepatologia 27(3): 186–187	- Study not reported in English
Li, H.; Zhang, Z. Y.; Wang, T. G. (1999) Function of omeprazole in including reversibility of Barrett’s esophagus mucosa. Chinese journal of digestion 19(4): 279–280	- Full text paper not available
Li, L., Cao, Z., Zhang, C. et al. (2021) Risk of esophageal adenocarcinoma in patients with Barrett’s esophagus using proton pump inhibitors: A systematic review with meta-analysis and sequential trial analysis. Translational Cancer Research 10(4): 1620–1627 [PMC free article: PMC8798809] [PubMed: 35116488]	- Study design not relevant to this review protocol Review of non-randomized studies
Li, Y. M., Li, L., Yu, C. H. et al. (2008) A systematic review and meta-analysis of the treatment for Barrett’s esophagus. Digestive Diseases & Sciences 53(11): 2837–46 [PubMed: 18427992]	- Systematic review not relevant to the protocol Includes studies with interventions comparing different therapeutic modalities e.g.: Anti-reflux surgery, argon plasma coagulation, photodynamic therapy
Manifold, D. K., Marshall, R. E., Anggiansah, A. et al. (2000) Effect of omeprazole on antral duodenogastric reflux in Barrett oesophagus. Scandinavian Journal of Gastroenterology 35(8): 796–801 [PubMed: 10994616]	- Outcome not relevant to protocol Assessing oesophageal acid exposure, gastric alkaline shift and duodeno-gastric reflux
Ortiz, A., Martinez De Haro, L. F., Parrilla, P. et al. (1996) Conservative treatment versus antireflux surgery in Barrett’s oesophagus: Long-term results of a prospective study. British Journal of Surgery 83(2): 274–278 [PubMed: 8689188]	- Comparator in study does not match that specified in this review protocol Comparing pharmacological treatment with anti-reflux surgery
Parrilla, P., Martinez de Haro, L. F., Ortiz, A. et al. (2003) Long-term results of a randomized prospective study comparing medical and surgical treatment of Barrett’s esophagus. Annals of Surgery 237(3): 291–8 [PMC free article: PMC1514316] [PubMed: 12616111]	- Comparator in study does not match that specified in this review protocol Comparing pharmacological treatment with anti-reflux surgery
Peters, F. T. M., Ganesh, S., Kuipers, E. J. et al. (1997) Regression of Barrett’s oesophagus during omeprazole: a randomized double-blinded study. European journal of gastroenterology & hepatology 9(suppl12): a39	- Conference abstract
Peters, F. T., Ganesh, S., Kuipers, E. J. et al. (1999) Endoscopic regression of Barrett’s oesophagus during omeprazole treatment; a randomised double blind study. Gut 45(4): 489–94 [PMC free article: PMC1727665] [PubMed: 10486353]	- Outcome not relevant to protocol Assessing regression of Barrett’s oesophagus
Sampliner, R. E. (1994) Effect of up to 3 years of high-dose lansoprazole on Barrett’s esophagus. American Journal of Gastroenterology 89(10): 1844–8 [PubMed: 7942680]	- Study design not relevant to this review protocol – Non-randomized study
Singh, S., Singh, A. G., Singh, P. P. et al. (2013) Statins are associated with reduced risk of esophageal cancer, particularly in patients with Barrett’s esophagus: a systematic review and meta-analysis. Clinical Gastroenterology & Hepatology 11(6): 620–9 [PMC free article: PMC3660516] [PubMed: 23357487]	- Systematic review not relevant to the protocol; including on-randomized studies included
Sontag, S. J., Schnell, T. G., Chejfec, G. et al. (1997) Lansoprazole heals erosive reflux oesophagitis in patients with Barrett’s oesophagus. Alimentary Pharmacology & Therapeutics 11(1): 147–56 [PubMed: 9042987]	- Outcome not relevant to protocol - Assessing healing rate
Sopeña, F., Fernández, A., Ortego, J. et al. (2006) Final results of a 6-month randomized controlled trial on the effects of rofecoxib, a selective inhibitor of COX-2 in patients with Barrett’s esophagus. Gastroenterologia y hepatologia 29: 156	- Study not reported in English
Spechler, S. J.; Barker, P. N.; Silberg, D. G. (2009) Clinical trial: intragastric acid control in patients who have Barrett’s oesophagus-comparison of once- and twice-daily regimens of esomeprazole and lansoprazole. Alimentary Pharmacology & Therapeutics 30(2): 138–45 [PubMed: 19438416]	- Outcome not relevant to protocol Assessing intragastric pH control
Spechler, S. J., Sharma, P., Traxler, B. et al. (2006) Gastric and esophageal pH in patients with Barrett’s esophagus treated with three esomeprazole dosages: a randomized, double-blind, crossover trial. American Journal of Gastroenterology 101(9): 1964–71 [PubMed: 16848802]	- Outcome not relevant to protocol Assessing 24-h, intragastric and distal intra-oesophageal pH
Triadafilopoulos, G. (2000) Proton pump inhibitors for Barrett’s oesophagus. Gut 46(2): 144–146 [PMC free article: PMC1727807] [PubMed: 10644301]	- Full text paper not available Editorial
Wassenaar, E. B. and Oelschlager, B. K. (2010) Effect of medical and surgical treatment of Barrett’s metaplasia. World Journal of Gastroenterology 16(30): 3773–9 [PMC free article: PMC2921088] [PubMed: 20698039]	- Review article but not a systematic review
Weinstein, W. M., Lieberman, D., Lewin, D. N. et al. (1996) Omeprazole-induced regression of Barrett’s oesophagus: a 2 year randomized controlled double blind trial. Gastroenterology 110(4): a294	- Full text paper not available
Wilson, H., Mocanu, V., Sun, W. et al. (2021) Fundoplication is superior to medical therapy for Barrett’s esophagus disease regression and progression: a systematic review and meta-analysis. Surgical Endoscopy 18: 18 [PubMed: 34008109]	- Comparator in study does not match that specified in this review protocol Comparing pharmacological treatment with anti-reflux surgery
Zhang, J.; Wu, H.; Wang, R. (2021) Effect of nonsteroidal anti-inflammatory drugs on Barrett’s esophagus risk: a systematic review and meta-analysis. Clinics & Research in Hepatology & Gastroenterology 45(3): 101552 [PubMed: 33268293]	- Systematic review used as source of primary studies review of non-randomised studies

Evidence review for pharmacological interventions to reduce progression to dysplasia or cancer

1. Pharmacological interventions to reduce progression to dysplasia or cancer

1.1. Review question

1.1.1. Introduction

1.1.2. Summary of the protocol

1.1.3. Methods and process

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

1.1.4.2. Excluded studies

1.1.5. Summary of studies included in the effectiveness evidence

1.1.6. Summary of the effectiveness evidence

1.1.7. Economic evidence

1.1.7.1. Included studies

1.1.7.2. Excluded studies

1.1.8. Summary of included economic evidence

1.1.9. Economic model

1.1.10. Unit costs

1.1.11. The committee’s discussion and interpretation of the evidence

1.1.11.1. The outcomes that matter most

1.1.11.2. The quality of the evidence

1.1.11.3. Benefits and harms

1.1.11.4. Cost effectiveness and resource use

1.1.12. Recommendations supported by this evidence review

1.1.13. References

Appendices

Appendix A. Review protocols

Appendix B. Literature search strategies

Appendix C. Effectiveness evidence study selection

Appendix D. Effectiveness evidence

Appendix E. Forest plots

Appendix F. GRADE tables

Appendix G. Economic evidence study selection

Appendix H. Excluded studies

Clinical studies

Health Economic studies

Table 1PICO characteristics of review question

Table 2Summary of studies included in the evidence review

Table 3Clinical evidence summary: High dose PPI compared to Low dose PPI for Barrett’s Oesophagus

Table 4Clinical evidence summary: Aspirin compared to no Aspirin for Barrett’s Oesophagus

Table 5Clinical evidence summary: Pantoprazole compared to Lansoprazole for Barrett’s Oesophagus

Table 6Clinical evidence summary: Lansoprazole compared to Omeprazole for Barrett’s Oesophagus

Table 7Clinical evidence summary: Pantoprazole compared to Omeprazole for Barrett’s Oesophagus

Table 8Unit cost of drugs

Table 16Studies excluded from the clinical review