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Update on the Approach and Management of Dyspepsia

21 August 2010

Udom Kachintorn
Department of Medicine, Siriraj

Practical approach to dyspepsia

To decide

The extent of investigation

The treatment which is most appropriate

There is significant overlap among 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 pathophysiological mechanisms

Chronic Constipation
Dyspepsia

IBS GERD

Corazziari

Talley

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

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 heartburn
Tack J, et al. Gastroenterology 2006; 130:1466-79.

AGA Technical Review

Talley et al. Gastroenterology 2005

Dyspeptic symptoms

Manage as GERD (acid suppression)

Consider discontinuing NSAID, switching to another agent or adding PPI

Depends on age & alarm symptoms

Dyspepsia*
Yes Yes

*Rome III definition, Uninvestigated

Alarm features (at any age)

EGD/Refer to GI
Age of onset > 55
Not

No

-Review medication/diet Resolved -Manage appropriately

No Gastritis/ Normal EGD Structural diseases eg. PU, cancer Uncomplicated dyspepsia without alarm features: Consider - Dietary advice - Lifestyle modification - Empirical treatment Non-response/Recurrent

Resolved

Manage as functional dyspepsia -Provide reassurance -Encourage lifestyle Modification -Consider drug therapy

Treat Appropriately

Reassure

Refer to GI Specialist

Thai Dyspepsia Guideline 2010

Guideline Statements
(dyspepsia) Evidence level : 3 Grade of recommendation : C
Thai Dyspepsia Guideline 2010

 dyspepsia
NSAIDs 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
Canga C, et al. Am J Gastroenterol 2002;97(3):600-3. Hammer J, et al. Gut 2004;53(5):666-72.

Alarm features are poor indicators of serious disease

Present in 10% of PC patients who consult But most do not have a serious disease

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

Alarm features

13 upper GI cancer (0.5%) Only 1.5 % with dysphagia and 1.5% with weight loss had a cancer

Positive predictive value LOW

Diagnostic Value of Alarm Symptoms for UGI 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 Weight loss Anemia Dysphagia Dysphagia for esophageal cancer Studies 8 4 5 Pts/Total 3,219 / 48,499 1,518 / 42,327 1,217 / 9,646 Cancer cases 340 (0.7%) 190 (0.4%) 192 (2%) 93 (1.7%) Sens (%) Spec (%) (95% CI) (95% CI 49 (37-65) 13 (8-20) 39 (23-66) 59 (37-94) 84 (81-87) 95 (92-97) 85 (78-92) 97 (92-100)

203 / 5,492

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

Diagnostic Value of Alarm Symptoms for UGI Malignancy

Meta-analysis through Medline search 17 cases studies (1,552 pts), 9 cohort studies (16,161 pts)
Alarm Symptom Dysphagia Anemia / bleeding N 7058 7248 Sens (%) 25 17 Spec (%) 94 90 PPV (%) 6.6 4.6 NPV (%) 98.8 97.5

1:175 Nausea / vomiting

Weight loss

chance of27 missing malignancy94.3 1721 78 7.5 in patients without alarm symptoms
8178 7655 3815 24 75 91 93 79 77 7.9 5.9 3 97.9 99.4 99.2

Any alarm symptom Age >45, male, anemia or bleeding

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

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 without alarm symptoms was at risk 1 per million
of the population per year

Important patient information before treatment

- Cancer or serious conditions? - Symptoms interfere with daily and social activity - Which symptom bother the most

- Reassurance, counseling and advice - Investigations - Medications Patients expectations

Patients concern

Do all patients need medications?

Symptoms do not affect daily activity:
* Need only reassurance. * Do not need medications. * Most of these patients dont come to see doctors. * If these patients come they usually have special concern about their symptoms.

Symptoms affect daily or social activity: *They need treatment or medications to relieve their symptoms.

Patients with mild symptoms

Patients with moderate to severe symptoms

Empirical therapy for uninvestigated dyspepsia According to symptom subgroups (sensible approach)

Efficacy of pharmacological therapy for uninvestigated dyspepsia

Cochrane Review 2002 PPI 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 gain H2RA and antacids 40% PPI and prokinetic 60%

DIAMOND Study: a primary-care-based RCT

New onset dyspepsia Step-up

n=332 Success 72% Average cost 228 Euro PPI H2RA

Step-down
n=313 Success 70% Average cost 245 Euro
OR=0.92, 95%CI 0.7-1.3

Antacids

P=0.0008

Treatment success with step-up or step-down is similar Step-up strategy is more cost-effective at 6 months
van Marrewijk 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.pylori

negative positive

PPI trial 4-8 weeks fails

fails

Treat
For H. pylori
fails
PPI trial 4-8 weeks

EGD

Reassurance Reassess diagnosis Consider EGD

Rationale for test & treat: positive patient have treatable pathology

Esophagitis 12%
DU 2%

Esophagitis 17%
GU 3%
Deformed duodenium 1%

DU 40%

Erosive duodenitis 2%

UBT ve (n=136)

UBT +ve (n=182)

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

"test and treat" vs prompt endoscopy

N=432, FU=12 months No 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 and treat (US$179 vs US$87, p<0.0001)
P<0.001

70 60

Percentage

50 40 30 20 10 0

UBT

EGD

Very satisfied

Satisfied

Dissatisfied

Very dissatisfied

Mahadeva, S et al. Gut 2008

HP test & treat vs. PPI for initial 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

N=1,547; meta-analysis, 1-yr follow up There was little difference in symptom-resolution or costs between the two strategies
Ford AC, et al. Aliment Pharmacol Ther 2008

Guideline Statements dyspepsia dyspepsia Evidence level : 1 Grade of recommendation : A

Ford AC, et al. Aliment Pharmacol Ther 2008;28:534-44. Duggan AE, et al. Aliment Pharmacol Ther 2008;29:55-68.

Guideline Statements

(EGD) dyspepsia Evidence level : 4 Grade of recommendation : D

Thai Dyspepsia Guideline 2010

Management of uninvestigated dyspeptic patients with no alarm features

Talley NJ, et al. Am J Gastroenterol 2005 Vakil N. Dig Dis 2008

Rome III definition of Dyspepsia and Functional dyspepsia

Gastro-esophageal reflux disease

Dyspepsia

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

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

Epigastric pain syndrome

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: THERAPEUTIC IMPLICATIONS

PATHOPHYSIOLOGY Delayed gastric emptying

PRESENTATIONS

ESTABLISHED RX. Prokinetics, tegaserod Fundus relaxing therapy: tegaserod, SSRI Visceral analgesic therapy: TCA, tegaserod, SSRI Acid-suppressive therapy: PPI, H2RA

dyspepsia with postprandial fullness, nausea and vomiting dyspepsia with early satiety and weight loss

Impaired postprandial fundus relaxation

Hypersensitivity to gastric distention

dyspepsia with postprandial pain, belching

Acid-related or hypersensitivity

dyspepsia with postprandial pain, nausea

Approach for Management of FD

Functional Dyspepsia

EPS
(Ulcer-like)

PDS
(Dysmotility-like)

Education/lifestyle modification

Test Hp

Education/lifestyle modification

+
Eradicate

_
Trial of acid suppression Fail Trial of prokinetic medication

Success

Success

Fail

Success

Fail

Re-evaluate and consider antidepressant

Specialist referral

Prokinetics
Mucosa protective H.pylori agents eradication

Acid inhibition

Functional Functional dyspepsia Dyspepsia

Mucosal protectants rebamipide

Prokinetics

Carminatives Anti-depressants Anti-serotoninergics Opioids

Dietary

lifestyle modifications

Pharmacological interventions for functional dyspepsia

RRR Prokinetics (n=3178) H2RA (n=2,183) PPIs (n=3347) Antacid (n=109) Sucralfate (n=246) 33%* 23%* 13%* -2%# 29%#

95% CI 18%- 45%t 8%- 35% 4%- 20% -36%- 24% -40%- 36%

NNT 4 8 9 NA 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 patients Follow 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
Spasmolytics ineffective Psychological intervention insufficient evidence Carminative no scientific evidence

Seroternergic modulators, opioid-agonists inconclusive

2nd/3rd-line options

Enzyme supplements ineffective

Antidepressants effective in subset

Treatment Options in Nonresponsive NUD

1 2 3 4 5 6

Anti-depressants * Amitriptyline 10 mg hs H.pylori eradication Serotonergic modulator * Tegaserod Rebamipide Intensify LSM Re-evaluation

AGA Technical Review

Talley et al. Gastroenterology 2005

Dyspeptic symptoms

Manage as GERD (acid suppression)

Consider discontinuing NSAID, switching to another agent or adding PPI

Depends on age & alarm symptoms

Presence of dyspepsia after NSAID use

Cumulative incidence of dyspeptic symptoms over 6 months %
30
23.5 p= 0.02 25.5

20

10

Rofecoxib

Non-selective NSAIDs Langman et al 1999 36

COX-2 inhibitors do cause dyspepsia

Meta-analysis: 39,605 patients Drug Placebo Celecoxib Relative risk of dyspepsia 1.00 1.30 95% CI 1.081.60

Moore et al. Arthritis Res Ther 2005

Dyspepsia : relation to ulcer risk

The presence of dyspepsia does not predict the presence of mucosal lesions in patients taking NSAIDs NSAIDs-associated dyspepsia responds to acid suppression The role of endoscopy in the management of NSAIDs dyspepsia is not established
Sardinia Consensus, Am J Med 2001

Presence of dyspepsia soon after NSAID use

Symptom only (no anemia, weight loss) Options:- Stop NSAID - Add PPI - Change to COXIB - Reduce dose of COXIB - COXIB+PPI Symptom +anemia, evidence of GI bleed (overt, occult)

ENDOSCOPY

No NSAID/COXIB Persistent dyspepsia

Lanas A, et al. Chinese J Digest Dis 2006

Conclusion
1 2 3 4 5 6
Dyspepsia is a heterogenous syndrome, most are functional dyspepsia Symptoms overlaps with GERD and IBS Empiric therapy is usually justified over EGD Target therapy at disturbed pathophysiology in investigated patients Value of EPS and PDS in directing therapy
FD failing to respond to HP eradication and PPI: options limited, need reassurance, intensified LSM

Algorithm for the management of patients with dyspepsia and NUD

Uninvestigated dyspepsia
Clinical evaluation 1. Alarm features? 2. Chronic NSAID user? 3. Age > 40 yrs* No Yes

Hepato-biliary, Irritable bowel, GERD Manage accordingly

If<4 wks; dietary advice and observe, review medications *Age cut-off varies with age-specific incidence of gastric cancer in each countries (35-55 yrs) **In a country with high incidence of gastric cancer, test-and-scope may be appropriate

Validated local H.pylori test Positive H.pylori** eradication Failure Negative Empirical treatment Failure Structural diseases Success Manage accordingly

Upper endoscopy Nonulcer dyspepsia 1.EPS: antisecretory drugs 2.PDS: prokenitic drugs 3.Nonspecific:antiseceretory or prokenitic drugs Failure Re-evaluate and consider another class of therapy Success Failure Specialist referral or additional option,eg.antidepressants

Success Follow-up