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Update on the Approach and Management of

Dyspepsia Udom Kachintorn

Department of Medicine, Siriraj21 August 2010

The extent of investigation

Practical approachto dyspepsia

To decide

The treatmentThe treatmentwhich is mostwhich is mostappropriateappropriate

Dyspepsia

IBS

GERD

Chronic Constipation

†Corazziari E. Best Prac Res Clin Gastroenterol. 2004;18:613-631.‡Talley NJ et al. Am J Gastroenterol. 2003;98:2454-2459.

There is significant overlapamong GI disorders

�20-30% of GERD or IBS patients may have dyspeptic symptoms

�Diagnoses can shift from one disorder to another over time†

�Possible common pathophysiologicalmechanisms†‡

Rome III Definition of Dyspepsia

Symptom or set of symptoms that are

considered to originate from the

gastroduodenal region include–Epigastric pain / burning–Postprandial fullness–Early satiation–Bloating in the upper abdomen–Nausea–Vomiting –Belching

• Not include heartburnTack J, et al. Gastroenterology 2006; 130:1466-79.

Talley et al. Gastroenterology 2005

AGA Technical Review

Dyspeptic symptoms

Consider discontinuing NSAID, switching to another agent or adding PPI

Manage as GERD (acid suppression)

Depends on age & alarm symptoms

Dyspepsia*

Alarm features (at any age)

ReassureReassure

-Review medication/diet

-Manage appropriately

-Review medication/diet

-Manage appropriatelyEGD/Refer to GI

Non-response/RecurrentNon-response/Recurrent

*Rome III definition,

Uninvestigated

*Rome III definition,

Uninvestigated

Uncomplicated dyspepsia

without alarm features:

Consider

- Dietary advice

- Lifestyle modification

- Empirical treatment

Uncomplicated dyspepsia

without alarm features:

Consider

- Dietary advice

- Lifestyle modification

- Empirical treatment

Gastritis/Normal EGD

Structural diseases

eg. PU, cancer

Structural diseases

eg. PU, cancer

Manage as functional dyspepsia-Provide reassurance-Encourage lifestyle

Modification-Consider drug therapy

Treat

Appropriately

Treat

Appropriately

Refer to GI Specialist Thai Dyspepsia Guideline 2010

YesNo

Age of onset > 55Age of onset > 55

YesNot

Resolved

No

Resolved

Guideline Statements

ผูปวยที่ไมมีสัญญาณอันตราย ใหทบทวนการใชยา และอาหารที่อาจทําใหมีอาการปวดทอง ไมสบายทองบริเวณลิ้นป (dyspepsia)Evidence level : 3Grade of recommendation : C

Thai Dyspepsia Guideline 2010

ยาที่เปนสาเหตุของ dyspepsia

• NSAIDs และ ASA • Antibiotics : Penicillins, sulphonamides ,

macrolides, doxycycline, tetracycline • Hormone : Insulin, oral anti-diabetics, estrogen

supplement, oral corticosteroids• Cardiovascular drugs : Digoxin, calcium blockers• Potassium supplement • Musculoskeletal drugs : Alendronate• Theophylline

Bytzer P, et al. Aliment Pharmacol Ther 2000;14:1479-84.

Alarm Features

• Dysphagia

• Evidence of GI blood loss (Anemia /

hematemesis / melena)

• Persistent vomiting

• Unexplained weight loss

CangaCanga C, et al. C, et al. Am J Gastroenterol 2002;97(3):600-3.

Hammer J, et al. Gut 2004;53(5):666-72.

Positive predictive value LOW

Present in 10% of

But most do not • 13 upper GI cancer (0.5%)

• Only 1.5 % with dysphagiaand 1.5% with weight losshad a cancer

Danish prospective Danish prospective GP study (n=2,479):GP study (n=2,479):

have a serious have a serious diseasedisease

PC patients whoconsult

Alarm features are poor indicatorsAlarm features are poor indicatorsof serious diseaseof serious disease

Alarm features

Diagnostic Value of Alarm Symptoms for Diagnostic Value of Alarm Symptoms for UGI MalignancyUGI Malignancy

� Meta-analysis through Medline 1966-2003, Embase 1988-Jan 2005, Cochrane Jan 2005, CINAHL 1988-Jan 2005

� 15 studies total 57,363 pts, cancer 458 pts (0.8%)

Alarm Symptom Studies Pts/TotalCancer

cases

Sens (%)

(95% CI)

Spec (%)

(95% CI

Weight loss 8 3,219 / 48,499340

(0.7%)

49

(37-65)

84

(81-87)

Anemia 4 1,518 / 42,327190

(0.4%)

13

(8-20)

95

(92-97)

Dysphagia 5 1,217 / 9,646192

(2%)

39

(23-66)

85

(78-92)

Dysphagia for

esophageal

cancer

2 203 / 5,49293

(1.7%)

59

(37-94)

97

(92-100)

Vakil, N et al. Gastroenterol 2006;131:390-401.

Diagnostic Value of Alarm Symptoms Diagnostic Value of Alarm Symptoms for UGI Malignancyfor UGI Malignancy

�Meta-analysis through Medline search

� 17 cases studies (1,552 pts), 9 cohort studies (16,161 pts)

Alarm Symptom N Sens (%) Spec (%) PPV (%) NPV (%)

Dysphagia 7058 25 94 6.6 98.8

Anemia / bleeding 7248 17 90 4.6 97.5

Nausea / vomiting 1721 27 78 7.5 94.3

Weight loss 8178 24 93 7.9 97.9

Any alarm symptom 7655 75 79 5.9 99.4

Age >45, male,

anemia or bleeding3815 91 77 3 99.2

Fransen G, et al. Aliment Pharmacol Ther 2004;20:1054-52.

1:175 chance of missing malignancy

in patients without alarm symptoms

Role of age for alarm features

Cancers of upper GI tract are very low(PPV –low and NPV – high)

4 studies (USA and UK) cancer was rarely in patients under age of 55 years

Patients less than 55 years withoutalarm symptoms was at riskof the population per year

1 per million

Important patient informationbefore treatment

1

- Cancer or seriousconditions?- Symptomsinterfere with dailyand social activity- Which symptombother the most

2

- Reassurance,counseling andadvice- Investigations- Medications

Patients’ concern Patients’ expectations

Do all patients need medications?

Symptoms do not affectdaily activity:

* Need only reassurance.* Do not need medications.* Most of these patients don’tcome to see doctors.* If these patients come theyusually have special concernabout their symptoms.

Symptoms affect daily orsocial activity:

*They need treatmentor medications to relievetheir symptoms.

Patients with moderateto severe symptoms

Patients with mildsymptoms

Empirical therapy for uninvestigated dyspepsia

According to symptom subgroups (sensible approach)

Efficacy of pharmacological therapy for uninvestigated dyspepsia

Cochrane Review 2002PPI vs antacids, n=1186

RR=0.72 (95%CI, 0.64-0.80)PPI vs H2RA, n=1267

RR=0.64 (95%CI, 0.49-0.82)PPI vs cisapride, FU 8,14,52 wks

RR=0.95 (95%CI, 0.80-1.13)H2RA vs antacids, RR=0.86 (95%CI,0.35-2.11)

Conclusion: PPI is significantly better than H2RA and antacids

therapeutic gainH2RA and antacids 40%PPI and prokinetic 60%

DIAMOND Study: a primary-care-based RCT

AntacidsAntacids

H2RAH2RA

PPIPPI

StepStep--upupn=332n=332

SuccessSuccess

72%72%

Average Average

costcost

228 Euro228 Euro

StepStep--downdownn=313n=313

SuccessSuccess70%70%

Average Average costcost

245 Euro245 Euro

New onset dyspepsiaNew onset dyspepsia

•• Treatment success with stepTreatment success with step--up or stepup or step--down is similardown is similar•• StepStep--up strategy is more costup strategy is more cost--effective at 6 monthseffective at 6 months

OR=0.92,OR=0.92,

95%CI95%CI

0.70.7--1.31.3

P=0.0008P=0.0008

van van MarrewijkMarrewijk CJ, et al. Lancet 2009 CJ, et al. Lancet 2009

AGA Technical Review

Dyspepsia without GERD or NSAIDs

Age > 55 or alarm symptoms Age ≤ 55 No alarm symptoms

Test for H.pyloriTest for H.pylori

PPI trial 4-8

weeks

PPI trial 4-8

weeksTreat

For H. pylori

TreatFor H. pylori

PPI trial 4-8

weeks

PPI trial 4-8

weeks

Reassurance

Reassess diagnosis

Reassurance

Reassess diagnosis

Consider EGDConsider EGD

positivenegative

fails

fails

EGD

fails

Rationale for test & treat: positive patient have treatable pathology

Esophagitis

12%

DU 40%

Erosive duodenitis 2%

Deformed duodenium 1%

UBT +ve (n=182)UBT – ve (n=136)

Esophagitis 17%

GU 3%

DU 2%

McColl et al. Gut. 1997: 40: 302-6

"test and treat" vs prompt endoscopy

Mahadeva, S et al. Gut 2008

0

10

20

30

40

50

60

70

Very satisfied Satisfied Dissatisfied Very

dissatisfied

Percentage

UBT EGD

P<0.001

N=432, FU=12 monthsNo different in symptom change in both gr.More additional endoscopy in UBT( p=0.03)Medication consumption higher in EGD gr.(p<0.001)Cost of EGD approach higher than “test andtreat” (US$179 vs US$87, p<0.0001)

• N=1,547; meta-analysis, 1-yr follow up• There was little difference in symptom-resolution

or costs between the two strategies

HP test & treat vs. PPI for HP test & treat vs. PPI for initial management of dyspepsiainitial management of dyspepsia

• N=699, RCT in primary care, 1-yr follow up• Test & treat and PPI are equally cost-effective

in the management of dyspepsia

Delaney BC, et al. BMJ 2008

Ford AC, et al. Aliment Pharmacol Ther 2008

Guideline Statements

แนวทางการดูแลผูปวยอายุนอยที่มาดวย dyspepsia และไมมีสัญญาณอันตราย ไมวาจะเริ่มดวยการสองกลองตรวจทางเดินอาหารสวนตนกอน หรือการเลือกทดสอบและรักษาการติดเชื้อเฮลิโคแบคเตอร ไพลอไร โดยไมสองกลอง หรือการใหยาลดการหลั่งกรดกอน พบวาทําใหอาการ dyspepsia ดีขึ้นไมแตกตางกัน

Evidence level : 1

Grade of recommendation : AFord AC, et al. Ford AC, et al. Aliment Pharmacol Ther 2008;28:534-44.

Duggan AE, et al. Aliment Pharmacol Ther 2008;29:55-68.

Guideline Statements

การสองกลองตรวจทางเดินอาหารสวนตน (EGD) ในผูปวยอายุนอยทุกรายที่มาดวยปญหา dyspepsia และไมมสีัญญาณอันตราย เปนแนวทางที่ไมคุมคาทางเศรษฐกิจ

Evidence level : 4Grade of recommendation : D

Thai Dyspepsia Guideline 2010

Management of uninvestigated dyspeptic patients with no alarm features

Talley NJ, et al. Am J Gastroenterol 2005Talley NJ, et al. Am J Gastroenterol 2005

VakilVakil N. Dig N. Dig DisDis 20082008

DyspepsiaGastro-esophageal

reflux disease

Irritable bowel syndrome

Uninvestigated Investigated

Organic- Peptic ulcer (8-25%)

- Reflux esophagitis (3-15%)

- Gastric cancer (1-3%)

- NSAIDs gastropathy

Functional or NUD

60-90%

Postprandial distress

syndrome

Epigastric pain

syndrome

Tack J, Talley NJ, Camilleri M, et al. Gastroenterology 2006

Rome III definition of Dyspepsia and Functional dyspepsia

Treatment strategy

���� Non-drug therapy� Reassurance� Clear explanation� Explore psychological

factors/stress contributing to symptoms

� LSM

���� Remove precipitating cause when identified– Medications– Meals

• Types of food• Timing of meals• Too much food

���� Pharmacological therapy

PATHOPHYSIOLOGY OF FUNCTIONAL DYSPEPSIA:

Delayed gastric

emptying

dyspepsia with postprandial fullness,

nausea and vomiting

dyspepsia with postprandial pain,

belching

Hypersensitivity to

gastric distention

Impaired postprandial

fundus relaxation

dyspepsia with early satiety

and weight loss

Prokinetics,

tegaserod

Visceral analgesic

therapy: TCA,

tegaserod, SSRI

Fundus relaxing

therapy: tegaserod,

SSRI

Acid-related or

hypersensitivity

dyspepsia with postprandial pain,

nausea

Acid-suppressive

therapy: PPI, H2RA

PATHOPHYSIOLOGY PRESENTATIONS ESTABLISHED RX.

THERAPEUTIC IMPLICATIONS

Approach for Management of FD

Functional

Dyspepsia

(Ulcer-like)

EPS

Education/lifestyle modification

(Dysmotility-like)

PDS

Education/lifestyle modification

Test Hp

+_

Trial of acid suppression

Trial of prokinetic medication

Eradicate

Success Fail Success FailSuccess Fail

Re-evaluate and consider antidepressant

Specialist referral

lifestyle modifications

Functional

Dyspepsia

Mucosa protective

agents Acid inhibition

Prokinetics

Functionaldyspepsia

Carminatives

Anti-depressants

Anti-serotoninergics

Opioids

Prokinetics

Mucosal protectantsrebamipide

H.pylori eradication

Dietary

Pharmacological interventions forfunctional dyspepsia

-40%- 36%

-36%- 24%

4%- 20%

8%- 35%

18%- 45%t

95% CIRRR NNT

Prokinetics (n=3178) 33%* 4

H2RA (n=2,183) 23%* 8

PPIs (n=3347) 13%* 9

Antacid (n=109) -2%# NA

Sucralfate (n=246) 29%# NA

* significant more effective than placebo

# not statistically significant superior to placebo

t publication bias

Moayyedi et al. Cochrane Database Syst Rev. 2007

Eradication of H.pylori for functional dyspepsia

17 RCT, 3566 patientsFollow up 3-12 months

- Mean placebo response = 29%- Mean eradication response = 36%- RRR in H.pylori eradication compared

to placebo = 10% (95% CI=6%-14%) - NNT to cure one case of dyspepsia

=14 (95% CI = 10-25)

If there is a benefit, it is limited to a subgroup of patients

Moayyedi et al. Cochrane Database Syst Rev. 2007

Treatment options in FD

Efficacy versus placebo

Psychological intervention –

insufficient evidence

Spasmolytics –ineffective

Carminative –no scientific

evidence

Seroternergic modulators,

opioid-agonists –inconclusive

2nd/3rd-line options Enzyme

supplements –ineffective

Antidepressants – effective in

subset

Anti-depressants* Amitriptyline 10 mg hs1

2

3

4

H.pylori eradicationSerotonergic modulator

* TegaserodRebamipide

Treatment Options in Nonresponsive NUD

5 Intensify LSM

Re-evaluation6

Talley et al. Gastroenterology 2005

AGA Technical Review

Dyspeptic symptoms

Consider discontinuing NSAID, switching to another agent or adding PPI

Manage as GERD (acid suppression)

Depends on age & alarm symptoms

36

Rofecoxib Non-selective NSAIDs

Cumulative incidence of dyspeptic symptoms over 6 months%

0

10

20

30 p= 0.02

23.525.5

Langman et al 1999

Presence of dyspepsia after NSAID use

COX-2 inhibitors do cause dyspepsia

Meta-analysis: 39,605 patients

Drug Relative risk 95% CIof dyspepsia

Moore et al. Arthritis Res Ther 2005

Placebo 1.00 –

Celecoxib 1.30 1.08–1.60

Dyspepsia : relation to ulcer risk

The presence of dyspepsia does not predict the presence of mucosal lesions in patients taking NSAIDs

Sardinia Consensus, Am J Med 2001

NSAIDs-associated dyspepsia responds to acid suppression

The role of endoscopy in the management of NSAIDs dyspepsia is not established

Presence of dyspepsia soon after NSAID use

Presence of dyspepsia soon after NSAID use

Symptom only

(no anemia, weight loss)

Symptom only

(no anemia, weight loss)

Options:- Stop NSAID- Add PPI- Change to COXIB- Reduce dose of COXIB- COXIB+PPI

Options:- Stop NSAID- Add PPI- Change to COXIB- Reduce dose of COXIB- COXIB+PPI

Persistent dyspepsiaPersistent dyspepsia

Symptom +anemia, evidence of GI bleed

(overt, occult)

Symptom +anemia, evidence of GI bleed

(overt, occult)

ENDOSCOPYENDOSCOPY

No NSAID/COXIBNo NSAID/COXIB

Lanas A, et al. Chinese J Digest Dis 2006

1

2

3

4

Symptoms overlaps with GERD and IBS

Conclusion

Dyspepsia is a heterogenous syndrome, most are functional dyspepsia

Empiric therapy is usually justified over EGD

Target therapy at disturbed pathophysiologyin investigated patients

5 Value of EPS and PDS in directing therapy

6FD failing to respond to HP eradication and PPI: options limited, need reassurance, intensified LSM

Uninvestigated dyspepsiaUninvestigated dyspepsia

Hepato-biliary, Irritable bowel, GERD

Hepato-biliary, Irritable bowel, GERD

Clinical evaluation

Clinical evaluation

If<4 wks; dietary advice and observe, review medications

If<4 wks; dietary advice and observe, review medications

Manage accordinglyManage accordingly 1. Alarm features?2. Chronic NSAID user?3. Age > 40 yrs*

1. Alarm features?2. Chronic NSAID user?3. Age > 40 yrs*

Validated local H.pylori testValidated local H.pylori test

Positive Negative

H.pylori** eradicationH.pylori** eradication

EmpiricaltreatmentEmpiricaltreatment

Upper endoscopyUpper endoscopy

No

Yes

Structural diseases

Structural diseases

Manage accordingly

Manage accordingly

Nonulcer dyspepsiaNonulcer dyspepsia

1.EPS: antisecretory drugs2.PDS: prokenitic drugs3.Nonspecific:antiseceretory or prokenitic drugs

1.EPS: antisecretory drugs2.PDS: prokenitic drugs3.Nonspecific:antiseceretory or prokenitic drugs

Failure Failure

Follow-upSuccess

Success

Re-evaluate and consider another class of therapy

Failure

Specialist referral or additional option,eg.antidepressantsFailure

Success

*Age cut-off varies with age-specificincidence of gastric cancer in eachcountries (35-55 yrs)**In a country with high incidenceof gastric cancer, test-and-scopemay be appropriate

Algorithm for the management of patients with dyspepsia and NUD