Peptic Ulcer DiseasePeptic Ulcer Disease

Byron Cryer, MDByron Cryer, MD

Dallas VA Medical CenterDallas VA Medical Center

University of Texas Southwestern Medical University of Texas Southwestern Medical SchoolSchool

H . pyloriH . pylori eradication should confer a benefit in all eradication should confer a benefit in all of the following diseases of the following diseases exceptexcept::

1. Active gastric ulcer

2. Past history of duodenal ulcer

3. GERD

4. MALT Lymphoma

Question 1

Question 2Question 2 Which of the following agent (s) are effective in

decreasing NSAID ulcer complications (such as bleeding, perforation, and gastric outlet obstruction) in patients with rheumatoid arthritis?

(A) H2-receptor antagonists

(B) Sucralfate(C) Proton-pump inhibitors(D) Misoprostol(E) All of the above

H2-blockers are likely to be effective in which H2-blockers are likely to be effective in which situation?situation?

1. Treatment of bleeding ulcer2. Reduction of requirement for blood

transfusion after endoscopic treatment of ulcers

3. In combination with clarithromycin and amoxcillin for H. pylori eradication

4. Treatment of MALT Lymphoma5. None of the above

Question 3

Differential Diagnosis of DyspepsiaDifferential Diagnosis of Dyspepsia•Peptic Ulcer DiseasePeptic Ulcer Disease•Related to infection with Related to infection with Helicobacter pyloriHelicobacter pylori•Related to use of nonsteroidal anti-inflammatory drugsRelated to use of nonsteroidal anti-inflammatory drugs

•Gastroesophageal reflux disease (GERD)Gastroesophageal reflux disease (GERD)

•Biliary tract diseaseBiliary tract disease•CholelithiasisCholelithiasis•CholecystitisCholecystitis

•PancreatitisPancreatitis

•CancerCancer

•Nonulcer dyspepsiaNonulcer dyspepsia

Pathogenesis of Peptic Ulcer DiseasePathogenesis of Peptic Ulcer Disease

H. pyloriH. pylori NSAIDsNSAIDs

Alterations in mucosal Alterations in mucosal defense mechanismsdefense mechanisms

UlcerationUlceration

SmokingSmoking AcidAcidPepsinPepsin

Etiologies of Gastric or Duodenal UlcersEtiologies of Gastric or Duodenal Ulcers

Very Common:Very Common:•Helicobacter pyloriHelicobacter pylori•Nonsteroidal Anti-inflammatory DrugsNonsteroidal Anti-inflammatory Drugs

Less Common:Less Common:•Gastric malignancy (adenocarcinoma or lymphoma)Gastric malignancy (adenocarcinoma or lymphoma)•Stress ulcerationStress ulceration•Viral infections (HSV-type 1 or CMV)Viral infections (HSV-type 1 or CMV)

Uncommon or Rare:Uncommon or Rare:•Zollinger-Ellison syndromeZollinger-Ellison syndrome•Cocaine-induced ulcersCocaine-induced ulcers•CrohnCrohn’s disease’s disease•Systemic mastocytosisSystemic mastocytosis•Myeloproliferative disorders with basophiliaMyeloproliferative disorders with basophilia•Idiopathic (non-Idiopathic (non- H.pyloriH.pylori) hypersecretory duodenal ulcer) hypersecretory duodenal ulcer•Abdominal radiotherapyAbdominal radiotherapy•Hepatic artery infusion of 5-flurouracilHepatic artery infusion of 5-flurouracil

HSV = Herpes Simplex VirusHSV = Herpes Simplex VirusCMV = CytomegalovirusCMV = Cytomegalovirus

Helicobacter pyloriHelicobacter pylori

• Most common human bacterial infectionMost common human bacterial infection• Infection is life longInfection is life long• Elicits a robust inflammatory responseElicits a robust inflammatory response• Associated with:Associated with:

Asymptomactic, healthy individualsAsymptomactic, healthy individualsPeptic Ulcer DiseasePeptic Ulcer DiseaseAtrophic GastritisAtrophic GastritisGastric AdenocarcinomaGastric AdenocarcinomaGastric LymphomaGastric Lymphoma

Eradication of Eradication of H. pyloriH. pylori and Duodenal Ulcer and Duodenal Ulcer RecurrenceRecurrence

Huang J, et al. Am J Gastro. 1996;91:1914.

0

20

40

60

80

100

0 6 12 18 24

% i

n r

emis

sio

n

Months

H. pylori - positive H. pylori - negative

Relationship of Relationship of H. pylori H. pylori to Gastric Cancerto Gastric Cancer

H. pyloriH. pylori

Chronic Active Superficial GastritisChronic Active Superficial Gastritis

Chronic Atrophic GastritisChronic Atrophic Gastritis

Chronic Atrophic Gastritis Chronic Atrophic Gastritis with Intestinal Metaplasiawith Intestinal Metaplasia

DysplasiaDysplasia

Gastric AdenocarcinomaGastric Adenocarcinoma

Gastric LymphomaGastric Lymphoma• H. pyloriH. pylori infections will cause varying infections will cause varying

degrees of gastric lymphoid degrees of gastric lymphoid infiltration:infiltration: H. pyloriH. pylori

Dense Lymphoid InfitrateDense Lymphoid Infitrate

Lymphoid FolliclesLymphoid Follicles

Gastric Low-Grade B-Cell Lymphoma (MALToma)Gastric Low-Grade B-Cell Lymphoma (MALToma)

What is the Relationship Between What is the Relationship Between H. pyloriH. pylori and Functional Dyspepsia?and Functional Dyspepsia?

Cochrane Systematic Review of Randomized, Controlled Trials of Cochrane Systematic Review of Randomized, Controlled Trials of H. H. pyloripylori Eradication in Functional Dyspepsia Eradication in Functional Dyspepsia

.60 1 1.66

Study % Weight Risk ratio (95% CI)

0.92 (0.81,1.03) Blum 14.9

0.85 (0.77,0.93) McColl 16.3

0.95 (0.81,1.11) Koelz 8.2

0.97 (0.85,1.11) Talley(Orchid) 12.3

1.07 (0.86,1.34) Talley(USA) 8.4

0.91 (0.70,1.18) Miwa 3.6

0.88 (0.77,0.99) Malfertheiner 22.3

0.83 (0.68,1.00) Varannes 10.0

0.86 (0.60,1.24) Froehlich 4.0

0.91 (0.86,0.96) p<0.0001 Overall (95% CI)

Favors eradication Favors placebo

Heterogeneity χ2 = 7.1 (df=8) p=0.53

Moayyedi P, et al. BMJ. 2000;321:659.

H. pyloriH. pylori Treatment Treatment

• PPI triple therapy preferred 1st line ~ 85% effective– PPI + clairthromycin 500 mg + amoxicillin 1 gm all BID

– Substitute metronidazole 500 mg only if penicillin allergic– Duration 10-14 days– Antibiotic resistance can influence results

• Quadruple therapy 1st line of re-treatment (BMT & PPI)– Treat for 2 weeks and use 500 mg metronidazole

Peura DA in Therapy of Digestive Disorders. 2nd ed. Elsevier; in press.

Most Recent United States Guidelines for Most Recent United States Guidelines for Management of Management of H. pyloriH. pylori

• Test only if Rx planned

• Treat when test positive• Use effective Rx• F/U testing limited (changed with availability of non-invasive testing)

Active or past ulcer YES

MALT lymphoma YES

Gastric cancer NO

GERD/Long term PPIs NONUD +Dyspepsia +NSAIDs alone +

Spectrum of NSAID-InducedSpectrum of NSAID-InducedGI Mucosal InjuryGI Mucosal Injury

Upper GIUpper GI• • GERD GERD • • Subepithelial petechialSubepithelial petechial

hemorrhages hemorrhages• • ErosionsErosions• • UlcersUlcers

– – Stomach > duodenumStomach > duodenum

• • BleedingBleeding

– – Stomach Stomach ≈≈ duodenum duodenum

• • Perforations/obstruction

Small IntestineSmall Intestine•• UlcersUlcers

• • StricturesStrictures• • DiaphragmsDiaphragms• • EnteropathyEnteropathy

ColonColon

•• ColitisColitis

• • UlcersUlcers

• • StricturesStrictures

• • Diverticular bleedDiverticular bleed

or perforation or perforation

• • CollagenousCollagenous

colitis colitis

• • Relapse of IBDRelapse of IBD

COX-1COX-1 COX-2COX-2

ProstaglandinsProstaglandins ProstaglandinsProstaglandins

Arachidonic acidArachidonic acid

ProtectionProtectionof gastric mucosaof gastric mucosa HemostasisHemostasis

Mediation of pain,Mediation of pain,inflammation, and feverinflammation, and fever

COX-2 inhibitor

Nonspecific NSAIDs

NSAIDs Mechanism of ActionNSAIDs Mechanism of Action

Adapted from Cryer B. Chapter 23. In: Sleisenger & Fordtran’s Gastrointestinal and Liver Disease. 7th ed. 2002:410.

Endoscopic Photograph of GastropathyEndoscopic Photograph of Gastropathy

Endoscopic PhotographEndoscopic Photographof Gastric Ulcerof Gastric Ulcer

SSTRATEGIESTRATEGIES FORFOR T TREATINGREATING NSAID-INSAID-INDUCEDNDUCED U ULCERSLCERS

• Discontinue NSAID

• Heal ulcer with acid suppression1,2

• Prevent ulcer recurrence2

– Eradicate Helicobacter pylori if present– GI prophylaxis if NSAIDs continued– Consider use of COX-2 specific inhibitor

or non-NSAID analgesic1. Scheiman. Curr Treatment Options Gastroenterol. 1999;2:205–213.2. Wolfe, et al. N Engl J Med. 1999;340:1888–1899.

Prevention of Ulcer DiseasePrevention of Ulcer Disease

High Risk PatientsHigh Risk Patients Prophylaxis TreatmentProphylaxis TreatmentHistory of peptic ulcerHistory of peptic ulcer MisoprostolMisoprostol::Concomitant anticoagulantConcomitant anticoagulant 100 100 µµg BID, advance tog BID, advance toConcomitant corticosteroidsConcomitant corticosteroids 200 200 µµg BID as tolerated g BID as tolerated

Significant co-morbiditiesSignificant co-morbiditiesHigh doses of NSAIDsHigh doses of NSAIDs Proton Pump InhibitorProton Pump Inhibitor::Combinations of > 1 NSAIDCombinations of > 1 NSAIDOlder Age ( i.e., > 75 y.o.)Older Age ( i.e., > 75 y.o.) COX-2 InhibitorCOX-2 Inhibitor

Low Risk PatientsLow Risk Patients No prophylaxis neededNo prophylaxis needed

NSAIDsNSAIDs• The decision for prophylaxis against NSAID-induced ulcer The decision for prophylaxis against NSAID-induced ulcer

needs to be made at the time the NSAID is started.needs to be made at the time the NSAID is started.

Risk Factors forRisk Factors forSerious GI Adverse Events with NSAIDs:Serious GI Adverse Events with NSAIDs: Relative RisksRelative Risks

Rodriguez. Lancet. 1994; Guttham. Epidemiology. 1997; Shorr. Arch Intern Med. 1993; Piper. Ann Intern Med. 1991.

00 5 10 15

4.44.4 (2.0-9.7) (2.0-9.7)

12.712.7 (6.3-25.7) (6.3-25.7)

2.92.9 (2.2-3.8) (2.2-3.8)

5.85.8 (4.0-8.6) (4.0-8.6)

5.65.6 (4.6-6.9) (4.6-6.9)

3.13.1 (2.5-3.7) (2.5-3.7)

1.61.6 (1.4-2.0) (1.4-2.0)

13.513.5 (10.3-17.7) (10.3-17.7)

Corticosteroid useCorticosteroid use

Anticoagulant useAnticoagulant use

Low dose NSAIDLow dose NSAID

High dose NSAIDHigh dose NSAID

Age 70-80Age 70-80

Age 60-69Age 60-69

Age 50-59Age 50-59

Prior bleedPrior bleed

Relative RiskRelative Risk

4.96.4

0

5

10

15

20

25

30

35

% r

e-b

leed

at

6-m

on

ths

19

26

0

5

10

15

20

25

30

35

6-m

on

th c

um

ula

tive

in

cid

ence

of

ulc

er (

%)

p = NS

p = NS

n = n = 143 144 116 106

Prevention of Recurrent Ulcer Bleeding in High Risk PatientsPrevention of Recurrent Ulcer Bleeding in High Risk Patients

Celecoxib 200 mg BID + placeboDiclofenac 75 mg BID + Omeprazole 20 mg QD

INITIAL STUDY GROUP 1 FOLLOW-UP STUDY GROUP 2

1Chan et al. N Engl J Med. 2002;347:2104.2Chan et al. DDW. 2004;A103404.

Patients with prior ulcer bleed on NSAID; ulcer healed and H. pylori – negative or eradicated prior to randomization

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

All PatientsAll Patients NSAID Naïve PatientsNSAID Naïve Patients00

1.21.2

Patients Not Taking AspirinPatients Not Taking Aspirin

0.50.5

1.01.0

1.51.5

2.02.0

All PatientsAll Patients NSAID Naïve PatientsNSAID Naïve Patients00

Patients Taking AspirinPatients Taking Aspirin

2.52.5

p = 0.68p = 0.68

p < 0.05p < 0.05

p = 0.97p = 0.97

p < 0.05p < 0.05

5/22105/2210

19/252619/2526

3/13733/1373

16/159716/1597

6/3296/3299/5839/583

5/3675/3678/5208/520

An

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in

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, %

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%A

nn

ual

ized

in

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ence

, %

AA

BB

EtodolacEtodolacNaproxenNaproxen

EtodolacEtodolacNaproxenNaproxen

Rates of Clinically Significant Upper GI Events Rates of Clinically Significant Upper GI Events

Weideman RA et al. Gastroenterology 2004;127:1322-1328Weideman RA et al. Gastroenterology 2004;127:1322-1328

10.210.2

0 1 2

Type of DrugType of Drug

NSAIDsNSAIDs

COX-2 InhibitorsCOX-2 Inhibitors

ASA 100 mg/dayASA 100 mg/day

NSAID + low-dose ASANSAID + low-dose ASA

COX-2 + low-dose ASACOX-2 + low-dose ASA

Adjusted Relative Risk (95% CI)Adjusted Relative Risk (95% CI)

5.05.0

3 4 5 6 7 8 9

1.31.3

2.42.4

9.59.5

COX-2 Inhibitors: Less Risk for Upper GI COX-2 Inhibitors: Less Risk for Upper GI Bleeding Compared With Other NSAIDsBleeding Compared With Other NSAIDs

Lanas A, et al. DDW Abstract 629. 2005.

10

Anti-Platelet TherapiesAnti-Platelet Therapies

• AspirinAspirin

• ADP Receptor AntagonistsADP Receptor AntagonistsClopidogrel (Plavix)Clopidogrel (Plavix)Ticlopidine (Ticlid)Ticlopidine (Ticlid)

• Glycoprotein IIb / IIIa InhibitorsGlycoprotein IIb / IIIa InhibitorsTicofiban (Aggrastat)Ticofiban (Aggrastat)Abciximab (ReoPro)Abciximab (ReoPro)Eptifibatid (Integrilin)Eptifibatid (Integrilin)

Knight, C. J Heart 2003;89:1273-1278Knight, C. J Heart 2003;89:1273-1278

Pathways of Platelet Activation and their Pathways of Platelet Activation and their Pharmacologic InhibitionPharmacologic Inhibition

Clopidogrel vs. Aspirin plus PPIClopidogrel vs. Aspirin plus PPIfor Prevention of Upper GI Bleedingfor Prevention of Upper GI Bleeding

• 320 pts with history of bleeding ulcer320 pts with history of bleeding ulcer• All All H. pyloriH. pylori negative negative• Randomized to:Randomized to:

– Clopidogrel 75 mg daily (n=161)Clopidogrel 75 mg daily (n=161)– Aspirin + esomeprazole 20 mg BID (n=159)Aspirin + esomeprazole 20 mg BID (n=159)

• Followed for 12-months for rates of recurrent major Followed for 12-months for rates of recurrent major GI bleeding (upper and lower GI tract)GI bleeding (upper and lower GI tract)

Chan, F. K.L. et al. N Engl J Med 2005;352:238-244Chan, F. K.L. et al. N Engl J Med 2005;352:238-244

Chan, F. K.L. et al. N Engl J Med 2005;352:238-244

Cumulative Incidence of Recurrent Ulcer BleedingCumulative Incidence of Recurrent Ulcer Bleeding with Clopidogrel and with Aspirin plus Esomeprazolewith Clopidogrel and with Aspirin plus Esomeprazole

Upper GI Clinical Events with Clopidogrel + AspirinUpper GI Clinical Events with Clopidogrel + Aspirin

Percent with Ulcer

Hsu et al., DDW 2010

Time

Sur

viva

l pro

babi

lity

0 50 100 150 200

1.0

0

1885 1761 1479 1089 986 951 577 533 515 260 231[trt=Placebo]1873 1762 1526 1111 1025 987 611 565 531 250 215[trt=Treated]

trt=Placebo

trt=Treated

0.9

0

Log Rank p-value = 0.000382Placebo Survival at 180 Days = 0.971 (0.961; 0.981)Treated Survival at 180 days = 0.989 (0.982; 0.996)

Kaplan-Meier curves for proton pump inhibitor vs. placebo for composite GI endpoint at 180 days following randomization

Omeprazole 20 mg q day (n=1885)

Placebo (n= 1873)

All patients received:Clopidogrel 75 mg + ASA 75-325 mg/day

Bhatt DL, Cryer BL, Contant CF et al, N Engl J Med. 2010 Nov 11;363(20):1909-17.

Upper GI Event Rate 2.92% = placebo1.09% = omeprazoleHR = 0.3495% CI (0.18, 0.63)p = 0.0007

Alarm FeaturesAlarm Features(Indications for Early Endoscopy)(Indications for Early Endoscopy)

• New onset symptoms after age 50 yearsNew onset symptoms after age 50 years• AnorexiaAnorexia• DysphagiaDysphagia• Gross or occult gastrointestinal bleedingGross or occult gastrointestinal bleeding• Unexplained anemiaUnexplained anemia• Weight lossWeight loss• Significant vomitingSignificant vomiting• Upper GI barium study suspicious for cancerUpper GI barium study suspicious for cancer

Complicated UlcersComplicated Ulcers

Primary TherapiesPrimary Therapies:: Bleeding UlcersBleeding Ulcers Endoscopic TherapyEndoscopic Therapy

Perforated UlcersPerforated Ulcers Surgical TherapySurgical Therapy

Secondary TherapiesSecondary Therapies: : Medical TherapiesMedical Therapies::- H- H22-Receptor Antagonists-Receptor Antagonists

- Proton Pump Inhibitors- Proton Pump Inhibitors- - H. pylori H. pylori TreatmentsTreatments- NSAIDs / ASA- NSAIDs / ASA

Upper GI BleedingUpper GI Bleeding

GI Bleeding — Common CausesGI Bleeding — Common Causes

• Gastric or duodenal ulcer– Helicobacter pylori (H. pylori)– NSAIDs

• Erosive esophagitis• Mallory-Weiss tear• Esophageal or gastric varices• Arterio-venous malformation (AVM)• Stress gastropathy

Cook DJ, et al. N Engl J Med. 1998;338:791-797.Cook DJ, et al. Crit Care Med. 1999;27:2812-2817.

GI BleedGI Bleed

• Minor Bleeding– Hematemesis– ‘Coffee ground’ emesis– Hematochezia– Melena

GI BleedGI Bleed

• Major Bleeding = Minor Bleeding plus:– Decrease in systolic blood pressure > 20mm Hg– Heart rate increase > 20– Decrease in Hgb > 2g/dL in which transfusion

does not boost Hgb > 2g/dL

Cook DJ, et al. N Engl J Med. 1998;338:791-797.Cook DJ, et al. Crit Care Med. 1999;27:2812-2817.

Management of Upper GI BleedingManagement of Upper GI Bleeding

Prevention of:Stress gastropathy

Treatment of:Gastric or duodenal ulcer

Erosive esophagitis

Mallory-Weiss tear

Esophageal or gastric varices

AVM

Stress gastropathy

Stress Ulcer BleedingStress Ulcer Bleeding

• Patients admitted to an ICU demonstrate endoscopic evidence of GI damage within 24 hours of admission.

• Historically, GI bleeding occurs in approximately 15% of ICU patients without prophylactic therapy.

• Current, incidence of clinically significantly bleeding is 1.5% .

Stress UlcerationStress Ulceration

Risk Factors for Stress Ulcer Bleeding

Acute respiratory failure/mechanical vent patients (>48hrs) Coagulopathy Shock Severe burns (>30% BSA) Significant intracranial bleeding or trauma Spinal injury (immobilization >24 hrs) GI bleed within 12 weeks Multiple organ failure High dose corticosteroid therapy Long-term NSAID use

Cook DJ, et al. N.Engl. J Med. 1998;338:791-7.Cook DJ, et al. Crit Care Med. 1999;27:2812-7.

Management of Upper GI BleedingManagement of Upper GI Bleeding

Prevention of:Stress gastropathy

Treatment of:Gastric or duodenal ulcer

Erosive esophagitis

Mallory-Weiss tear

Esophageal or gastric varices

AVM

Stress gastropathy

Causes of Acute Upper GI BleedingCauses of Acute Upper GI Bleeding

Dallal HJ, Palmer KR. BMJ. 2001;323:1115.

GI BleedingGI Bleeding

• Overall Management– Maintenance of hemodynamic stability– Nasogastric Lavage– Endoscopy with hemostasis– Blood products if necessary– Surgery if necessary – Antisecretory medications

Stigmata of Bleeding Stigmata of Bleeding Risks of Re-bleeding and PrevalenceRisks of Re-bleeding and Prevalence

Dot23%

Clot13%

Bleeder7%

NBVV8%

Clean base49%

0

10

20

30

40

50

60

Active bleeder NBVV Clot Dot Clean base

Ris

k o

f re

ble

edin

g (

%)

Adapted from Katschinski B et al. Dig Dis Sci 1994;39:706.

PREVALENCE

Randomized Controlled Comparison of I.V. PPI and Randomized Controlled Comparison of I.V. PPI and Placebo in Bleeding Peptic UlcerPlacebo in Bleeding Peptic Ulcer

4.2

6.7

2.54.2

20

22.5

7.5

10

0

5

10

15

20

25

Re-bleedingin 3 days

Re-bleedingin 30 days

Surgery 30-daymortality

Pati

en

ts (

%)

Omeprazole 80 mg I.V. bolus+ 8 mg/hr infusion for 72hours (n = 120)

Placebo by I.V. infusion for72 hours (n = 120)

Lau et al. N Engl J Med. 2000;343:310.

All patients had actively bleeding vessel or non bleeding visible vessel (NBVV) All patients had actively bleeding vessel or non bleeding visible vessel (NBVV) and received endoscopic therapyand received endoscopic therapy

**

* p <0.001 vs. placebo

H . pyloriH . pylori eradication should confer a benefit in all eradication should confer a benefit in all of the following diseases of the following diseases exceptexcept::

1. Active gastric ulcer

2. Past history of duodenal ulcer

3. GERD

4. MALT Lymphoma

Question 1

Question 2Question 2 Which of the following agent (s) are effective in

decreasing NSAID ulcer complications (such as bleeding, perforation, and gastric outlet obstruction) in patients with rheumatoid arthritis?

(A) H2-receptor antagonists

(B) Sucralfate(C) Proton-pump inhibitors(D) Misoprostol(E) All of the above

H2-blockers are likely to be effective in which H2-blockers are likely to be effective in which situation?situation?

1. Treatment of bleeding ulcer2. Reduction of requirement for blood

transfusion after endoscopic treatment of ulcers

3. In combination with clarithromycin and amoxcillin for H. pylori eradication

4. Treatment of MALT Lymphoma5. None of the above

Question 3

Cardiovascular Thrombotic Events with Cardiovascular Thrombotic Events with Clopidogrel + AspirinClopidogrel + Aspirin

Omeprazole 20 mg q day (n=1885) Placebo (n= 1876)

Time

Su

rviv

al p

roba

bili

ty

0 50 100 150 200

1.0

0

1885 1762 1474 1082 981 945 575 528 502 250 218[trt=Placebo]1876 1753 1512 1100 1008 966 598 551 510 242 205[trt=Treated]

trt=Placebotrt=Treated

0.9

0

Log Rank p-value = 0.979Placebo Survival at 180 Days = 0.943 (0.927; 0.96)Treated Survival at 180 days = 0.951 (0.936; 0.966)

Kaplan-Meier Plot of Cardiovascular Events by TreatmentKaplan-Meier curves for proton pump inhibitor versus placebo for the composite cardiovascular endpoint at 180 days following randomization.

All patients received:Clopidogrel 75 mg + ASA 75-325 mg/day

Bhatt DL, Cryer BL, Contant CF et al, N Engl J Med. 2010 Nov 11;363(20):1909-17.

Primary Composite CV Endpoint :• Cardiovascular death• Myocardial infarction• Revascularization• Stroke

CV Event Rate 4.88% = omeprazole 5.67% =placeboHR = 0.9995% CI (0.68, 1.44)p = 0.96