GASTROPROTECTION WITH PROTON PUMP INHIBITORS (PPI)IN THE SETTING OF STEROID USE

Taleen Karnieg, BSc. PharmD(c)

Outline• Corticosteroids• Proposed Mechanism of PUD• Evidence of Steroid-Induced PUD & Complications• Current Recommendations• Evidence Supporting PPI Use in Patient on Steroids• Guidelines for Prevention of NSAID-Related GI

Complications• PPIs

• Side Effects• Appropriateness• Economic Burden

CaseXY is a 60F PMHx: Not significant HPI: ear fullness and asymmetric hearing loss Diagnosis: idiopathic asymmetric hearing loss Medications:Prednisone 60mg daily x 14 daysValacyclovir x 14 days (possible shingles)Omeprazole x 14 days (ulcer prophylaxis)

Corticosteroids• Effective treatment for a number of diseases • Side effects (SEs) from long-term treatment

• Hypertension• Adrenal suppression• ↑ risk of infections• Osteoporosis• Peptic ulcer disease (PUD)

• Prophylaxis (ppx)

Proposed Mechanism of PUD

BicarbonateProstaglandins

Mucus productionBlood flow to

mucosa

Protective Factors

H. PyloriGastric acid

PepsinNSAIDs

Aggressive Factors

BicarbonateProstaglandins

Mucus productionBlood flow to

mucosa

Protective Factors

H. PyloriGastric acid

PepsinNSAIDs

Aggressive Factors

Proposed Mechanism of Steroid-Induced PUD

Biosynthesis of prostaglandins Mucus productionGastric BicarbonateAngiogenesis

Evidenceof Steroid-Induced PUD & Complications

Author Type of Evidence n Main Results:Conn et al. 1976

Meta-analysis (prospective, randomized, placebo-controlled, double-blind)

3558 No difference in ulcer risk in corticosteroids over placebo

Messer et al. 1983

Meta-analysis (71 randomized, controlled trials)

5961 Relative risk (RR) of 2.3 (CI 1.4 – 3.7)

Piper et al. 1991

Nested case-controlled study

1415 Ulcer risk was only increased in concurrent users of NSAIDs: • RR 1.1 for corticosteroid alone• RR 14.6 for corticosteroid & NSAIDs

Evidenceof Steroid-Induced PUD & Complications

Author Type of Evidence

n Main Results:

Narum et al. 2014

Meta-analysis (159 randomized, double-blind, placebo-controlled)

33 253 Corticosteroids ↑ risk of GI bleeds or perforation by 40%The risk was increased for hospitalised patients.

Tseng et al. 2015

Case-crossover study

8894 Short-term (7–28 days) exposure to glucocorticoids is significantly associated with peptic ulcer bleeding; Risk is dose-dependent and ↑ when nonselective NSAIDs or aspirin are used concurrently

Physicians’ Opinion• Agreed that ppx was required for a patient taking 60 mg

prednisone for COPD exacerbation• 72% attending physicians• 56% residents

• 69% of physicians prescribed stress ulcer ppx (SUP) to over 25% of patients in the non-ICU setting • Fear of upper GI bleeding• Potential for legal repercussion

Koczka et al. 2013

EvidenceSupporting PPI Use in Patients on Steroids• Controversial

Current RecommendationsAuthor Type of

EvidenceRecommendation/Evidence

Guillamon-degui et al. 2008

Guidelines (level III recommendation for steroids)

Risk factors for SUP: • Prolonged mechanical ventilation• Coagulopathy OR ≥2 of:• Multiple injuries• Spinal cord injury• Injury severity score greater than 15• Acute renal failure• Requirement of high-dose corticosteroids

Ben-Menachem et al. 1994

RCT (single blind)

~40-50% of patients on high dose corticosteroidsNo significant (NS) differences found for transfusion requirements, duration of ICU stay, and mortality rates among placebo, sucralfate, & cimetidinePpx not warranted

Timothy et al. 1993

RCT (open-label) ~9-16% of patients on high dose corticosteroidsNS difference in stress ulceration developed between sucralfate (8%), cimetidine bolus (13%), and cimetidine infusion (12%) groups. Corticosteroid use not a risk factor for stress ulceration

Current RecommendationsAuthor Type of Evidence Recommendation/Evidence

Dorlo et al. 2013

Meta-analysis (consensus)

PUD is a rare complication of steroid therapy (0.4-1.8%)• No indication for routine ppx with PPIs• Indication for the combination of NSAIDs + steroids

Liu et al. 2013 Guidelines (consensus)

Consider PPIs for GI protection in steroid users at ↑risk of GI bleeding or PUD, such as those: • Using NSAIDS• Hx of ulcers• Hx of GI bleeding• Serious comorbidities (i.e., advanced cancer)

Concomitant NSAID & Corticosteroids

Several guidelines recommend PPI ppx in the setting of concomitant NSAID and corticosteroid use

Guidelines for Prevention of NSAID-Related GI Complications

Pts at ↑risk of GI toxicity secondary to NSAID therapy

High Risk

Hx of a previously complicated ulcer, especially recent

Multiple (>2) risk factors

Moderate Risk

Age (>65 years)

High dose NSAID therapy

Previous Hx of uncomplicated ulcer

Concurrent use of aspirin (including low-dose), corticosteroids, or anticoagulantsLow Risk

No risk factors

Lanza et al. 2009

Guidelines for Prevention of NSAID-Related Complications

CV Risk GI RiskLow Moderate High

Low NSAID alone (the least ulcerogenicNSAID at the lowest effective dose)

NSAID+ PPI/misoprostol

Alternative therapy if possible or COX-2Inhibitor + PPI/misoprostol

High (low-dose aspirin required)

Naproxen + PPI/misoprostol

Naproxen + PPI/misoprostol

Avoid NSAIDs or COX-2 inhibitors. Usealternative therapy

Lanza et al. 2009

ASTRONAUTAuthor Design Population Results

ASTRONAUT Randomized, double-blind, international

• 18-85 yo• NSAID • ≤10 mg

prednisolone or equivalent

Healing Phase:80% omeprazole 20mg79% omeprazole 40mg63% ranitidine

Maintenance Phase:72% remission omeprazole 20mg59% remission ranitidine

Omeprazole 20 mg daily

Omeprazole 40 mg daily

Ranitidine 150 mg BID

4-8 wks

Omeprazole 20 mg daily

Ranitidine 150 mg BID

6 mo

Healing Phase Maintenance Phase

OMNIUMAuthor Design Population Results

OMNIUM Randomized, double-blind, placebo-controlled, international

• 18-85 yo• NSAID• ≤10 mg

prednisolone or equivalent

Healing Phase:76% omeprazole 20mg75% omeprazole 40mg71% misoprostol

Maintenance Phase:61% remission omeprazole48% remission misoprostil27% placebo

Omeprazole 20mg daily

Omeprazole 40mg daily

Misoprostil 200mcg QID

4-8 wks

Omeprazole 20mg daily

Misoprostil 200mcg BID

6 mo

Healing Phase Maintenance Phase

VENUS & PLUTOAuthor Design Population Results

VENUSPLUTO

Randomized, double-blind, placebo-controlled

• ≥60 yo• GU/DU• Stable NSAID/COX-2

inhibitors• No ulcers• H. pylori –• No GIB/ perforation

within 6 mo of study

GU & DU rates, ITT (PP):17% (17%) placebo5.2% (6.1%) esomeprazole 20 mg4.6% (3.9%) esomeprazole 40 mg

Subgroup (COX2-inhibitors):16.5% placebo0.9% esomeprazole 20 mg4.1% esomeprazole 40 mg

PlaceboEsomeprazole 20mg dailyEsomeprazole 40mg daily

6 mo

Is There a Concern with PPI Use?

Potential Side Effects of PPI Use• Clostridium difficile • ↑ risk of pneumonia• ↑ risk of fractures• Hypomagnesemia• Iron and B12 malabsorption• Interaction with clopidogrel

Inappropriate PPI Use• 26.8% - 71% patients on medicine wards were placed on

GI ppx

• 56% - 69% of patients received GI ppx with no indications

• 54% - 58% of patients receiving inappropriate GI ppx were discharged with acid suppressive medications

• Only 33% - 37.1% received GI ppx with appropriate indications

Grube et al., 2007.

Financial Burden• Heidelbaugh and Inadomy in 2006

– 22% of 1,769 patients received inappropriate GI ppx– 54% discharged home with PPIs– Estimated annual cost of inappropriate GI ppx was > $111,000

• Wadobia et al in 1997– 45 of 88 ICU patients received inappropriate GI ppx– $5,084.31 for inpatient and $8,619.75 for outpatient

Bottom Line• Corticosteroid use alone is not a valid indication for PPI

ppx• Attention given to patient-specific factors• NSAID + concomitant corticosteroid use can potentially

warrant ppx based on risk stratification• PPIs are associated with inappropriate use, financial

burden, undesirable SEs – cautious in use

Case ContinuedDay 6: developed fevers and chills and had several episodes of non-bloody emesis and diarrhea. Day 8: developed a red, blotchy, intensely pruritic cutaneous eruption throughout the body. Day 9: taken by ambulance to the hospital,Temp = 39°C,pulse = 102 beats per minute, respiratory rate = 18 breaths per minute,dry mucous membranesImproved after a few hours on IVFBiopsy test results = dermatologic drug reaction.The distribution of the cutaneous eruption was consistent with the classic dermatologic drug reaction caused by a PPI The dermatology department was consulted and confirmed PPI-related dermatologic drug reaction as the most likely etiology. She was treated with hydroxyzine. Her cutaneous eruption and pruritus improved and she was discharged after a 2-day hospitalization.

References• Ben-Menachem, et al. Prophylaxis for stress-related gastric hemorrhage in the medical intensive care unit. Ann Intern Mecidine.

1994;121:568-575.• Conn HO, Blitzer BL. Nonassociation of adrenocorticosteroid therapy and peptic ulcer. N Engl J Med. 1976;294(9):473-479.• Messer J, Reitman D, Sacks HS, Smith H, Jr., Chalmers TC. Association of adrenocorticosteroid therapy and peptic-ulcer disease. N

Engl J Med. 1983;309(1):21-24.• Piper JM, Ray WA, Daugherty JR, Griffin MR. Corticosteroid use and peptic ulcer disease: Role of nonsteroidal anti-inflammatory

drugs. Ann Intern Med. 1991;114(9):735-740.• Hernandez-Diaz S, Rodriguez LA. Steroids and risk of upper gastrointestinal complications. Am J Epidemiol. 2001;153(11):1089-

1093.• Narum et al. Corticosteroid and risk of gastrointestinal bleeding: a systematic review and meta-analysis. BMJ Open 2014;4:e004587.• Teseng et al. Short-term use of glucocorticoids and risk of peptic ulcer bleeding: a nationwide population-based case-crossover

study. Aliment Pharmacol Ther 2015; 42: 599–606.• Koczka et al. Physicians’ Opinions of Stress Ulcer Prophylaxis: Survey Results from a Large Urban Medical Center. Dig Dis Sci

(2013) 58:777–781.• Liu et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy, Asthma

& Clinical Immunology 2013, 9:30• Lanza et al. Guidelines for Prevention of NSAID-Related Ulcer Complications. Am J Gastroenterol 2009; 104:728 – 738.• Yeomans ND , Tulassay Z , Juhasz L et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal anti-in

ammatory drugs. Acid Suppression Trial: Ranitidine vs. Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group . N Engl J Med 1998 ; 338 : 719 – 26.

• Hawkey CJ , Karrasch AJ , Szczepanski L e t al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal anti-in ammatory drugs. Omeprazole vs. Misoprostol for NSAID-Induced Ulcer Management (OMNIUM) Study Group . N Engl J Med 1998 ; 338 : 727 – 34 .

• Scheiman JM , Yeomans ND , Talley NJ et al. Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors . Am J Gastroenterol 2006 ; 101 : 701 – 10.

• Grube RR and May DB, “Stress ulcer prophylaxis in hospitalized patients not in internsive care units”. Am J Health-Syst Pharm. Vol 64 Jul 1, 2007.

Trial ASTRONAUTDesign Randomized double-blind, international (73 centers in 15 countries)

Population Inclusion Healing Phase: 18-85 yo; NSAID >specified therapeutic doses (no max dose)min(mean)=50 mg (113 mg) of diclofenac, 50 mg (111 mg) of indomethacin, and 500 mg (775 mg) of naproxen taken for any diagnosis ; ≤10 mg prednisolone or equivalent; Endoscopy conducted: ulcers that were 3 mm or more in diameter, more than 10 erosions in the stomach, and more than 10 erosions in the duodenum. Erosions were assessed with the modified Lanza scale; H. pylori + = ~40-50%

Inclusion Maintenance Phase: therapeutic doses of NSAID ≥5days/week; no concurrent erosive or ulcerative reflux esophagitis, no abnormalities in the laboratory tests regarded as clinically important by the investigator; H. pylori + = ~45%

Exclusion: neck instability that would compromise endoscopy, concurrent erosive or ulcerative esophagitis, pyloric stenosis, major active gastrointestinal bleeding, or disorders that might modify the absorption of study drugs

Treatment Arms

Healing Phase:• Omeprazole 20 mg daily • Omeprazole 40 mg daily • Ranitidine 150 mg BID Maintenance Phase:• Omeprazole 20 mg daily • Ranitidine 150 mg BID

Treatment success

Healing Phase: Disappearance of ulcer, presence of <5 erosions in the stomach, <5 erosions in the duodenum, and not more than mild dyspeptic symptoms

Treatment failure

Maintenance Phase: gastric or duodenal ulcer, >10 erosions in the stomach, >10 erosions in the duodenum, moderate or severe symptoms of dyspepsia, or adverse events resulting in the discontinuation of treatment.

Results Healing Phase:80% omeprazole 20 mg/day79% omeprazole 40 mg/day63% ranitidine 150 mg BIDMaintenance Phase:72% remission omeprazole 20 mg/day59% remission ranitidine 150 mg BID

6-8 wks

6 mo

Trial OMNIUMDesign Randomized, double-blind, international (93 centers in 14 countries)

Population Inclusion Healing Phase: 18-85 yo; continuous NSAID >predetermined minimal doses (no max dose)min(mean)=50 mg (129 mg) for diclofenac, 100 mg (137 mg) for ketoprofen, and 500 mg (844 mg) for naproxen taken for any diagnosis; ≤10 mg of prednisolone (or equivalent); endoscopy conducted: ulcers that were 3 mm or more in diameter in the stomach, duodenum, or both, >10 gastric erosions , >10 duodenal erosions. Erosions were assessed with the modified Lanza scale; H. pylori + = ~11-15%; smoker = 6-8%

Inclusion Maintenance Phase: therapeutic doses of NSAID ≥5days/week; no concurrent erosive or ulcerative reflux esophagitis, no abnormalities in the laboratory tests regarded as clinically important by the investigator; smoker = 6-14%; H. pylori + = 14-24%

Exclusion: concurrent reflux esophagitis at stage 3 or 4 according to the Savary–Miller classification, clinically important UGIB, pyloric stenosis, a history of gastric surgery, or gastrointestinal disorders that might impair the absorption of the study drugs

Treatment Arms

Healing Phase:Omeprazole 20 mg/dayOmeprazole 40 mg/dayMisoprostil 200 mcg QIDMaintenance Phase:Omeprazole 20 mg/dayMisoprostil 200 mcg BIDPlacebo

Treatment success

Healing Phase: absence of ulcers in the stomach or duodenum and the presence of <5 gastric erosions, <5 duodenal erosions, and not more than mild symptoms of dyspepsia.

Treatment failure

Maintenance Phase: an ulcer, >10 gastric erosions, >10 duodenal erosions, at least moderate symptoms of dyspepsia, or adverse events resulting in the discontinuation of treatment. Relapse of all ulcers, larger ulcers, gastric ulcers, duodenal ulcers, and erosions and the quality of life.

Results Healing Phase:76% omeprazole 20 mg/day; 75% omeprazole 40 mg/day; 71% misoprostil 200 mcg QIDS ↑healing rates of gastric ulcer omeprazole 20mg (87%) vs. misoprostil (73%)S ↑ healing rates of duodenal ulcers omeprazole 20mg (93%) &40mg (89%) vs. misoprostol (77%)S ↑healing rates of erosions alone misoprostol (87%) vs. omeprazole 20mg (77%) &40mg (79%)S ↑ SE misoprostil (59%) vs. omeprazole 20mg (48%)/40mg (46%)Maintenance Phase:61% remission omeprazole; 48% remission misoprostil; 27% placebo

6-8 wks

6 mo

Trial VENUS & PLUTODesign Randomized, double-blind, placebo-controlled, 110 centers in US (VENUS) 56 centers in 11 countries (PLUTO)

Population Inclusion: ≥60 yo; stable NSAIDs or COX-2 inhibitors within 4 wks of endoscopy; hx of GU/DU within 5yrs before study; no ulcers; H. pylori –; no GIB or perforation within 6 mo of study; H. pylori + = ~7-15%

Exclusion: evidence of esophagitis, esophageal stricture or Barrett’s esophagus, gastric outlet obstruction, previous UGI surgery (except for simple ulcer closure), or significant disease affecting other bodily systems. For the 2 wks before baseline endoscopy, patients who needed concomitant corticosteroids, or had used a PPI, prostaglandin analogue, or a daily H2-receptor antagonist (< daily use was permitted during this period) were also ineligible for study entry.

Treatment Arms

Esomeprazole 20 mg/dayEsomeprazole 40 mg/dayPlacebo

Treatment outcomes

Primary: proportion of patients w/o GU or DU @6moSecondary: NASAID-associated upper GI symptoms within 1 wk of visit

Results GU & DU rates, ITT (PP):17% (17%) placebo5.2% (6.1%) esomeprazole 20 mg4.6% (3.9%) esomeprazole 40 mg

Sub-group (COX2-inhibitors):16.5% placebo0.9% esomeprazole 20 mg4.1% esomeprazole 40 mg

Sub-group (NSAIDs):17.1% placebo6.8% esomeprazole 20 mg4.8% esomeprazole 40 mg