Global Definition of GERD

Introduction
Why is a new definition needed?
• No globally accepted terminology relating to GERD
• Confusion over symptoms and complications of

GERD, in primary care and other disciplines
• Confusion about Barrett's esophagus terminology
• Many proposed but unproven extra-esophageal

disorders
Vakil N et al. AJG 2006;101:1900-1920

Aim
To develop a definition and

classification for reflux disease that is
global in application and addresses the
needs of patients, physicians
(all disciplines) and regulators
Vakil N et al. AJG 2006;101:1900-1920

Needs assessment
Primary care physician survey
• Web-based needs assessment with Primary Care Physicians

• 352 predominantly community based primary care
physicians (77% community based)
• 18 countries
• 39% reported 'no definition of GERD was in place'
• Disorders related to GERD
– Esophageal Adenocarcinoma – 51%
– Asthma – 47%
– Cough – 74%
– Hoarseness – 51%
The Delphi Process
What is the Delphi process?
The Delphi technique may be characterized as a

method for structuring a group communication
process so that the process is effective in allowing a
group of individuals as a whole to deal with a
complex problem
Linstone H & Turoff M. The Delphi Process. www.is.njit.edu/pubs/delphibook/

Application of the Delphi process
Stage 1:
• Selection of the expert panel and non-voting chair
Stage 2:
• Submission, assessment and feedback
of the Delphi statements
Stage 3:
• Final analysis and conclusions
Delphi process: unique aspects
Anonymity
• Allows change of views without “loss of face”
Iteration
• A series of rounds with modification of statements,
allows members to change the statements to reflect
group opinion
Controlled feedback
• Each round analyzed by a non-voting central researcher
• Responses for the given statement are fed back to the
Delphi group
Working and Consensus Groups
Working Group
Consensus group 18 countries, 43 experts
Vakil N et al. AJG 2006;101:1900-1920

(Europe)
Denmark Sweden
United Kingdom Netherlands

Germany
Belgium
France
Italy
Vakil N et al. AJG 2006;101:1900-1920

(North America)
Canada
North America
Vakil N et al. AJG 2006;101:1900-1920

(Latin America)
Mexico
Brazil
Peru
Argentina
Vakil N et al. AJG 2006;101:1900-1920

(Asia and Australia)
Japan
China
Hong Kong
Australia
Vakil N et al. AJG 2006;101:1900-1920

Australia: Denmark: Netherlands:
John Dent Peter Bytzer Elly C Klinkenberg- Knol
Peter Katelaris
France: Peru:
Argentina: Jean-Francois Bergmann Carlos Zapata
Graciela Salis Marc-Andre Bigard
Jean-Paul Galmiche Sweden:
Belgium: Lars Agréus
Jan Tack Germany: Folke Johnsson
Joachim Labenz
Brazil: Peter Malfertheiner UK:
Joachim Prado Stephen Atwood
Italy: Janusz Jankowski
Canada: Gianfranco Delle Fave Roger Jones
David Armstrong Fabio Pace
Nigel Flook Vincenzo Stanghellini USA:
Paul Moayyedi Patricia Blount
Sander van Zanten Japan: Hashem El-Serag
Tsutomu Chiba Ronnie Fass
China: Hiroto Miwa David Johnson
Mainland Michio Hongo Peter Kahrilas
Fan Dai-ming Yoshikazu Kinoshita Harley Liker
Lin San-ren Joel Richter
Hong Kong Prateek Sharma
Benjamin Wong Nicholas J Talley
Mexico: Nimish Vakil (Chairman)
Francisco Martin Huerta Iga
Vakil N et al. AJG 2006;101:1900-1920
Consensus group
Demonstrated knowledge/expertise in GERD by:

• Participation in national or regional GERD Consensus
guidelines
• Interest in guideline development and dissemination
International representation
Diversity of views
• Experts on GERD and Barrett’s esophagus
• Primary care physicians
• Surgeons
Vakil N et al. AJG 2006;101:1900-1920

The Consensus Process
Consensus development process
3 Working Group meetings October 2003 – June 2004
Statements developed by Working Group September 2004
Working Group meeting

Vote 1 (baseline): Electronic November 2004

Vote 2: First Consensus Group meeting: evidence review January 2005

Vote 3: Electronic May 2005

Vote 4: Final Consensus Group meeting: evidence review June 2005
Vakil N et al. AJG 2006;101:1900-1920

Evaluating and Grading
the evidence
Systematic reviews
• Medline, Embase, Cochrane Trials register, CINALH
• Key words submitted by Working Group
• Search strings developed by librarians
• 1980 onwards including key meeting abstracts of

2004 and 2005
Vakil N et al. AJG 2006;101:1900-1920

Why did we use systematic reviews
of the literature?
• Systematic review orients the panel away from
clinical opinion to methodologically sound evidence
• Convincing to journal editors
• Systematic review of the literature offers the most

convincing method of assessing the evidence
Vakil N et al. AJG 2006;101:1900-1920

Definition of grades of evidence
• High: Further research is unlikely to change our

confidence in the estimate of effect
• Moderate: Further research is likely to have an
important impact on our confidence in the estimate of
effect and may change the estimate
• Low: Further research is likely to have an
important impact on our confidence in the estimate of
effect and is very likely to change the estimate
• Very low: Any estimate of effect is uncertain
GRADE Working Group BMJ;2004:328:1490–4

Voting scale for votes 3 and 4
1 Agree strongly
Agree 2 Agree with minor reservation
3 Agree with major reservation
4 Disagree with minor reservation

Disagree 5 Disagree with major reservation
6 Disagree strongly
Vakil N et al. AJG 2006;101:1900-1920

Voting summary
A priori consensus was classed as ≥67% agreement
Vote 1
(Baseline) Vote 2 Vote 3 Vote 4
% of statements that were agreed to

by more than 67% of the participants 86% 88% 94% 100%
% of statements that were agreed to

by more than 90% of the participants 40% 61% 83% 94%
Vakil N et al. AJG 2006;101:1900-1920

The Global Definition
of GERD
Definition of disease and syndrome
• Disease: A morbid entity characterized usually by

at least two of these criteria: recognized etiologic
agent(s), identifiable group of signs and symptoms,
or consistent anatomic alterations
• Syndrome: The aggregate of symptoms and signs

associated with any morbid process, and
constituting together the picture of the disease
Stedman’s Medical Dictionary (www.stedmans.com)

GERD is a condition which develops when the reflux
of gastric content causes troublesome symptoms
or complications
Esophageal Extraesophageal
Syndromes Syndromes
Symptomatic Syndromes with Established Proposed

Syndromes Esophageal Injury Associations Associations
Typical Reflux Reflux Esophagitis Reflux Cough Pharyngitis

Syndrome Reflux Stricture Syndrome Sinusitis
Reflux Chest Pain Barrett’s esophagus Reflux Laryngitis Idiopathic
Syndrome Syndrome
Esophageal Pulmonary Fibrosis
Adenocarcinoma Reflux Asthma Recurrent Otitis
Syndrome Media
Reflux Dental Erosion
Syndrome
Vakil N et al. AJG 2006;101:1900-1920

STATEMENT 1 Vote % Agree
Gastroesophageal Reflux Disease (GERD)

is a condition which develops when the reflux 100%
of stomach contents causes troublesome
symptoms and/or complications
Vakil N et al. AJG 2006;101:1900-1920

Gastroesophageal Reflux Disease is common

and its prevalence varies in different parts 100%
of the world
Vakil N et al. AJG 2006;101:1900-1920

STATEMENTS 3 & 4 Vote % Agree
Symptoms related to gastroesophageal reflux

become troublesome when they adversely 100%
affect an individual’s well-being
Reflux symptoms that are not troublesome

should not be diagnosed as Gastroesophageal 95%
Reflux Disease
Vakil N et al. AJG 2006;101:1900-1920

In population based studies, mild symptoms

occurring two or more days a week, 95%
or moderate/severe symptoms occurring more
than one day a week, are often considered
troublesome by patients
In clinical practice, the patient should

determine if their reflux symptoms 100%
are troublesome
Vakil N et al. AJG 2006;101:1900-1920

Clinical implications of statements 1–6
• Definition and criteria are patient-centered i.e.

patient determines if symptoms are troublesome
• Patients may meet diagnostic criteria based on

symptoms, if they are troublesome, or by evidence
of injury
– Over-diagnosis is prevented by the concept of

troublesome
– Severe symptoms that occur infrequently may
meet the criteria for a diagnosis
Vakil N et al. AJG 2006;101:1900-1920

Esophageal Syndromes:
Symptomatic
or complications
Syndromes Syndromes


Syndrome Syndrome
Syndrome Media
Syndrome
Vakil N et al. AJG 2006;101:1900-1920

Heartburn is defined as a burning

sensation in the retrosternal area 100%
(behind the breastbone)
Vakil N et al. AJG 2006;101:1900-1920

Regurgitation is defined as the perception

of flow of refluxed stomach content into the 100%
mouth or hypopharynx
Vakil N et al. AJG 2006;101:1900-1920

Heartburn and regurgitation are the

characteristic symptoms of the Typical 100%
Reflux Syndrome
Vakil N et al. AJG 2006;101:1900-1920

Gastroesophageal reflux is the most

common cause of heartburn 100%
Vakil N et al. AJG 2006;101:1900-1920

Heartburn can have a number of non-reflux

related causes. The prevalence of these 98%
is unknown.
Vakil N et al. AJG 2006;101:1900-1920

The Typical Reflux Syndrome can be diagnosed

on the basis of the characteristic symptoms, 100%
without diagnostic testing
Vakil N et al. AJG 2006;101:1900-1920

Non-erosive reflux disease is defined by the

presence of troublesome reflux-associated 100%
symptoms and the absence of mucosal breaks
at endoscopy
Vakil N et al. AJG 2006;101:1900-1920

Epigastric pain can be the major symptom

of Gastroesophageal Reflux Disease 91%
Vakil N et al. AJG 2006;101:1900-1920

Gastroesophageal Reflux Disease is frequently

associated with sleep disturbance 96%
Vakil N et al. AJG 2006;101:1900-1920

Night-time heartburn and sleep disturbance

reported by patients with Gastroesophageal 98%
Reflux Disease are substantially improved
by proton pump inhibitor therapy
or anti-reflux surgery
Vakil N et al. AJG 2006;101:1900-1920

Physical exercise may induce troublesome

symptoms of Gastroesophageal Reflux Disease 100%
in patients who have no or minimal symptoms
at other times (exercise-induced
gastroesophageal reflux)
Vakil N et al. AJG 2006;101:1900-1920

• Typical symptoms of heartburn and regurgitation are

sufficient to diagnose GERD if the symptoms are troublesome
to the patient
• Nocturnal reflux can cause sleep disturbance

• Epigastric pain is reported by many patients with GERD
and may be the major symptom
• Some patients have reflux related symptoms only with

physical exercise
• Non-erosive reflux disease falls into a symptomatic reflux

syndrome because no signs of esophageal injury are evident
Vakil N et al. AJG 2006;101:1900-1920

or complications
Syndromes Syndromes


Syndrome Syndrome
Syndrome Media
Syndrome
Vakil N et al. AJG 2006;101:1900-1920

Chest pain indistinguishable from

ischemic cardiac pain can be caused 100%
by Gastroesophageal Reflux Disease
Gastroesophageal reflux can cause episodes

of chest pain that resemble ischemic cardiac 98%
pain, without accompanying heartburn
or regurgitation
Vakil N et al. AJG 2006;101:1900-1920

Esophageal motor disorders can cause pain

that resembles ischemic cardiac pain by a 100%
mechanism separate from
gastroesophageal reflux
Gastroesophageal reflux is more frequently

a cause of chest pain than esophageal 100%
motor disorders
Vakil N et al. AJG 2006;101:1900-1920

• Patients with chest pain related to GERD may have

symptoms that resemble ischemic heart disease
• Heartburn and regurgitation may not be reported by

these patients
• Esophageal motor disorders are an unusual cause

of chest pain
Vakil N et al. AJG 2006;101:1900-1920

Esophageal Syndromes: Syndromes
with Esophageal Injury
or complications
Syndromes Syndromes


Syndrome Syndrome
Syndrome Media
Syndrome
Vakil N et al. AJG 2006;101:1900-1920

Esophageal complications of Gastroesophageal

Reflux Disease are Reflux Esophagitis, 84%
Haemorrhage, Stricture, Barrett’s esophagus
and Adenocarcinoma
Vakil N et al. AJG 2006;101:1900-1920

or complications
Syndromes Syndromes


Syndrome Syndrome
Syndrome Media
Syndrome
Vakil N et al. AJG 2006;101:1900-1920

Reflux Esophagitis is defined endoscopically

by visible breaks of the distal esophageal 100%
mucosa
Vakil N et al. AJG 2006;101:1900-1920

Mucosal breaks may be intermittently present

in patients with the Reflux Esophagitis 98%
Syndrome
Over a twenty year period, the severity

of Reflux Esophagitis does not increase 93%
in most patients
Vakil N et al. AJG 2006;101:1900-1920

Although heartburn frequency and intensity

correlate with the severity of mucosal injury, 95%
neither will accurately predict the severity
of mucosal injury in the individual patient
Vakil N et al. AJG 2006;101:1900-1920

or complications
Syndromes Syndromes


Syndrome Syndrome
Syndrome Media
Syndrome
Vakil N et al. AJG 2006;101:1900-1920

STATEMENTS 27, 28 & 29 Vote % Agree
A Reflux Stricture is defined as a persistent

luminal narrowing of the esophagus caused 100%
by Gastroesophageal Reflux Disease
The characteristic symptom of a stricture

is persistent troublesome dysphagia 100%
Dysphagia is a perceived impairment of

the passage of food from the mouth into 100%
the stomach
Vakil N et al. AJG 2006;101:1900-1920

Troublesome dysphagia is present when

patients need to alter eating patterns 96%
or report food impaction
Dysphagia is troublesome in a small proportion

of patients with Gastroesophageal Reflux Disease 100%
Persistent, progressive or troublesome

dysphagia is a warning symptom for stricture
or cancer of the esophagus and warrants 98%
investigation
Vakil N et al. AJG 2006;101:1900-1920

• Reflux Esophagitis is the most common

manifestation of esophageal injury
• A novel definition of regurgitation and

troublesome dysphagia is provided
• A novel definition for a stricture is provided
Vakil N et al. AJG 2006;101:1900-1920

or complications
Syndromes Syndromes


Syndrome Syndrome
Syndrome Media
Syndrome
Vakil N et al. AJG 2006;101:1900-1920

The term Barrett’s esophagus is variably

interpreted at the present time and lacks the 93%
clarity needed for clinical and scientific
communication about columnar metaplasia
of the esophageal mucosa
Vakil N et al. AJG 2006;101:1900-1920

Neither the frequency nor the severity

of heartburn is useful for prediction of the 98%
presence, type or extent of esophageal
columnar metaplasia
Vakil N et al. AJG 2006;101:1900-1920

Endoscopically Suspected Esophageal

Metaplasia (ESEM) describes endoscopic 98%
findings consistent with Barrett’s esophagus
that await histological evaluation
Vakil N et al. AJG 2006;101:1900-1920

Multiple, closely-spaced biopsies are necessary

to characterize endoscopically suspected 96%
esophageal metaplasia
Vakil N et al. AJG 2006;101:1900-1920

The description of endoscopically suspected

esophageal metaplasia should include a 100%
standardized measure of endoscopic extent
Vakil N et al. AJG 2006;101:1900-1920

When biopsies of endoscopically suspected

esophageal metaplasia show columnar 86%
epithelium it should be called Barrett’s
esophagus and the presence or absence of
intestinal metaplasia specified
Vakil N et al. AJG 2006;101:1900-1920

or complications
Syndromes Syndromes


Syndrome Syndrome
Syndrome Media
Syndrome
Vakil N et al. AJG 2006;101:1900-1920

Adenocarcinoma of the esophagus

is a complication of Gastroesophageal 100%
Reflux Disease
The risk of Adenocarcinoma of the esophagus

rises with increasing frequency and duration 96%
of heartburn
Vakil N et al. AJG 2006;101:1900-1920

Long-segment Barrett’s esophagus with

intestinal-type metaplasia is the most important 100%
identified risk factor for Esophageal
Adenocarcinoma
Vakil N et al. AJG 2006;101:1900-1920

• Resolved the international controversy on

Barrett’s esophagus by redefining it
• Introduced a new concept: Endoscopically

Suspected Esophageal Metaplasia (ESEM)
• ESEM eliminates the risk of an inappropriate

diagnosis of Barrett’s esophagus being applied to
an individual without esophageal metaplasia
• Recognised the lack of data on the risk of cancer

with gastric metaplasia in the esophagus
Vakil N et al. AJG 2006;101:1900-1920

Extra-esophageal Syndromes:
Established Associations
or complications
Syndromes Syndromes


Syndrome Syndrome
Syndrome Media
Syndrome
Vakil N et al. AJG 2006;101:1900-1920

Chronic cough, chronic laryngitis,

and asthma are significantly associated 93%
with Gastroesophageal Reflux Disease
Chronic cough, chronic laryngitis, and asthma

are usually multi-factorial disease processes and
gastroesophageal reflux can be an aggravating 98%
co-factor
Gastroesophageal reflux is rarely the sole cause

of chronic cough, chronic laryngitis, 95%
or asthma
Vakil N et al. AJG 2006;101:1900-1920

Potential causal mechanisms of Reflux Cough,

Reflux Laryngitis, and Reflux Asthma 96%
Syndromes include direct (aspiration) or indirect
(neurally mediated) effects of gastroesophageal
reflux
Vakil N et al. AJG 2006;101:1900-1920

In the absence of heartburn or regurgitation,

unexplained asthma and laryngitis are 84%
unlikely to be related to Gastroesophageal
Reflux Disease
Vakil N et al. AJG 2006;101:1900-1920

Medical and surgical treatment trials aimed at

improving presumed Reflux Cough, Reflux 98%
Laryngitis, and Reflux Asthma Syndromes by
treating Gastroesophageal Reflux Disease are
associated with uncertain and inconsistent
treatment effect
Vakil N et al. AJG 2006;101:1900-1920

The prevalence of dental erosion, especially on

the lingual and palatal tooth surfaces, is 96%
increased in patients with Gastroesophageal
Reflux Disease
Vakil N et al. AJG 2006;101:1900-1920

Extra-esophageal Syndromes:
Proposed Associations
or complications
Syndromes Syndromes


Syndrome Syndrome
Syndrome Media
Syndrome
Vakil N et al. AJG 2006;101:1900-1920

It is unclear whether gastroesophageal reflux is

a significant causal or exacerbating factor in the 100%
pathogenesis of sinusitis, idiopathic pulmonary
fibrosis, pharyngitis or recurrent otitis media
Vakil N et al. AJG 2006;101:1900-1920

It is unclear whether gastroesophageal reflux

plays a role in triggering apneic episodes 100%
in patients with obstructive sleep apnea
Vakil N et al. AJG 2006;101:1900-1920

• Recognised that reflux can be an aggravating

co-factor in extra-esophageal disorders
• Reflux is unlikely to be a factor in extra-esophageal

disorders if heartburn and regurgitation are absent
• Medical and surgical treatment trials have had

inconsistent success
• A number of proposed extra-esophageal disorders

have no high quality evidence to support a causal
association
Vakil N et al. AJG 2006;101:1900-1920

Acknowledgements
• Endorsement by the World Organisation of

Gastroenterology (WGO-OMGE):
“an important development in a critical area
of gastroenterology worldwide”
• Sponsor:
AstraZeneca Research and Development, Sweden
Vakil N et al. AJG 2006;101:1900-1920

Evaluation of the consensus process
Anonymous votes on the consensus process:
• 90% agreed that the voting process was fair and

that they had a chance to input adequately
• 92% agreed that the sponsor had not, in any way,

influenced their voting
Vakil N et al. AJG 2006;101:1900-1920

Conclusions
• A patient-centered global definition of GERD has

been developed with consensus from various
countries and has been endorsed by the World
Organization of Gastroenterology
• Adoption of a universally accepted terminology

which bridges cultures and countries and may
simplify disease management, allow collaborative
research and make studies more generalizable,
assisting patients, physicians and regulatory
agencies
Vakil N et al. AJG 2006;101:1900-1920

Conclusions
For practicing physicians, this definition and

classification
• Clarifies the criteria necessary for a diagnosis
of GERD
• Simplifies the classification of suspected and proven

Barrett’s esophagus
• Defines the state of our incomplete knowledge in

extraesophageal disorders
Vakil N et al. AJG 2006;101:1900-1920

Conclusions
For patients, the consensus statement provides
• Clarity on a diagnosis which is based on a patient-

centered definition of troublesome symptoms
• Assistance for patients by preventing an

inappropriate diagnosis of Barrett’s esophagus
• Clarification of the role of GERD in patients with

cough, hoarseness and wheezing may also help the
management of patients with these difficult
conditions
Vakil N et al. AJG 2006;101:1900-1920

Conclusions
Regulatory agencies may benefit from:
• An appropriate diagnosis of GERD that guides

management
• A uniform terminology and classification that is

applicable to clinical trials
• Ability to generalise data-sets across countries and

cultures globally
Vakil N et al. AJG 2006;101:1900-1920

Global Definition of GERD

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Introduction

Why is a new definition needed?

• No globally accepted terminology relating to GERD

• Confusion over symptoms and complications of

• Confusion about Barrett's esophagus terminology

• Many proposed but unproven extra-esophageal

Vakil N et al. AJG 2006;101:1900-1920

To develop a definition and

Vakil N et al. AJG 2006;101:1900-1920

• Web-based needs assessment with Primary Care Physicians

The Delphi technique may be characterized as a

Linstone H & Turoff M. The Delphi Process. www.is.njit.edu/pubs/delphibook/

Vakil N et al. AJG 2006;101:1900-1920

United Kingdom Netherlands

Vakil N et al. AJG 2006;101:1900-1920

Vakil N et al. AJG 2006;101:1900-1920

Vakil N et al. AJG 2006;101:1900-1920

Vakil N et al. AJG 2006;101:1900-1920

Demonstrated knowledge/expertise in GERD by:

Vakil N et al. AJG 2006;101:1900-1920

Statements developed by Working Group September 2004

Working Group meeting

Working Group meeting

Working Group meeting

Working Group meeting

Vakil N et al. AJG 2006;101:1900-1920

• Medline, Embase, Cochrane Trials register, CINALH

• Key words submitted by Working Group

• Search strings developed by librarians

• 1980 onwards including key meeting abstracts of

Vakil N et al. AJG 2006;101:1900-1920

• Convincing to journal editors

• Systematic review of the literature offers the most

Vakil N et al. AJG 2006;101:1900-1920

• High: Further research is unlikely to change our

GRADE Working Group BMJ;2004:328:1490–4

4 Disagree with minor reservation

Vakil N et al. AJG 2006;101:1900-1920

A priori consensus was classed as ≥67% agreement

% of statements that were agreed to

% of statements that were agreed to

Vakil N et al. AJG 2006;101:1900-1920

• Disease: A morbid entity characterized usually by

• Syndrome: The aggregate of symptoms and signs

Stedman’s Medical Dictionary (www.stedmans.com)

Symptomatic Syndromes with Established Proposed

Typical Reflux Reflux Esophagitis Reflux Cough Pharyngitis

Vakil N et al. AJG 2006;101:1900-1920

Gastroesophageal Reflux Disease (GERD)

Vakil N et al. AJG 2006;101:1900-1920

Gastroesophageal Reflux Disease is common

Vakil N et al. AJG 2006;101:1900-1920

Symptoms related to gastroesophageal reflux

Reflux symptoms that are not troublesome

Vakil N et al. AJG 2006;101:1900-1920

In population based studies, mild symptoms

In clinical practice, the patient should

Vakil N et al. AJG 2006;101:1900-1920

• Definition and criteria are patient-centered i.e.

• Patients may meet diagnostic criteria based on

– Over-diagnosis is prevented by the concept of

Vakil N et al. AJG 2006;101:1900-1920

Symptomatic Syndromes with Established Proposed