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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:725–735

SPECIAL REPORT

Proton Pump Inhibitors for Gastroduodenal Damage Related to


Nonsteroidal Anti-inflammatory Drugs or Aspirin: Twelve Important
Questions for Clinical Practice

GAURAV ARORA,* GURKIRPAL SINGH,*,‡ and GEORGE TRIADAFILOPOULOS*


*Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford; and ‡Institute of Clinical Outcomes Research and Education,
Palo Alto, California

effect used for relieving pain in chronic arthritis and other acute
Podcast interview: www.gastro.org/cghpodcast; and chronic musculoskeletal disorders. In fact, studies performed
see related article, Reimer C et al, on page 80 on patients with arthritis indicated that NSAIDs, when compared
in Gastroenterology. with high-dose acetaminophen (4000 mg daily), provide better
pain control and functional outcomes and are preferred by the
Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are patients.3–5 The benefits of NSAIDs, however, come at the cost of
among the most commonly used medications worldwide. Their an increased risk for gastroduodenal adverse effects, ranging from
use is associated with significant gastroduodenal adverse effects, dyspepsia and peptic ulcer disease to more serious and potentially
including dyspepsia, bleeding, ulcer formation, and perforation. life-threatening complications such as hemorrhage, obstruction,
Given their long-term use by millions of patients, there is a sub- or perforation.6 – 8 The gastroduodenal toxicity of NSAIDs has
stantial impact at the population level of these complications. In been attributed to blockade of the cyclooxygenase type-1 (COX-
this evidence-based review, we have endeavored to answer 12 com- 1)–mediated generation of cytoprotective prostanoids such as
monly encountered questions in clinical practice that deal with the prostaglandin E2 and prostacyclin. The highly selective inhibitors
following: extent of the problem of NSAID/aspirin-induced gas- of COX-2 reportedly cause less gastrointestinal (GI) damage than
troduodenal damage and its impact on public health; role of nonselective NSAIDs, which inhibit both COX-2 and COX-1.9,10
proton pump inhibitors (PPIs) in the primary prevention, healing, Not all users of NSAIDs experience endoscopic gastroduo-
and secondary prevention of NSAID/aspirin-induced gastroduo- denal damage, and this is not readily predicted by symptoms.
denal ulceration as assessed by using endoscopic end points; role Indeed, dyspepsia, a common occurrence in NSAID users, cor-
of PPIs in the prevention of adverse clinical outcomes related to relates poorly with ulcer development.11–15 Asymptomatic en-
NSAID/aspirin use; whether PPIs are effective in NSAID-induced doscopic ulcers have been documented in up to 40% of long-
dyspepsia; comparison of PPI co-therapy with selective cyclooxy- term users.2,8,16,17 Life-threatening complications such as
genase-2 inhibitors for risk reduction of adverse clinical outcomes; bleeding, perforation, or obstruction occur with an annual
role of PPIs in preventing rebleeding from aspirin ⫾ clopidogrel incidence of ⬃1.5% and might also be unheralded by symp-
therapy in high-risk patients; identifying high-risk patients who toms.16,18 The risk of developing serious gastroduodenal com-
can benefit from PPI co-therapy; the role of other gastroprotective plications is 3–5 times higher in NSAID users compared with
agents for prevention of NSAID/aspirin-induced gastroduodenal nonusers.19 This risk might be highest just after the initiation
damage; and the cost-effectiveness of and limitations to the use of of NSAIDs but, importantly, remains persistently increased
PPIs for prevention of gastroduodenal damage related to the use during the entire duration of therapy.11,13–15
of NSAIDs or aspirin. We then summarized our recommendations
on the use of PPIs for the clinical management of patients using Aspirin and Risk of Gastroduodenal
NSAIDs or aspirin. Complications
To view this article’s video abstract, go to the AGA’s Low-dose aspirin (LDA) (ⱕ325 mg) is being increasingly
YouTube Channel. used as prophylaxis for cardiovascular disease, and many of these
patients also take concomitant NSAIDs. Use of LDA alone in-
What Is the Extent of Nonsteroidal creased the risk of upper GI bleeding in a dose-dependent manner,
Anti-inflammatory Drug/Aspirin Toxicity
and Its Impact on Public Health? Abbreviations used in this paper: CI, confidence interval; COX, cyclo-
Nonsteroidal Anti-inflammatory Drugs and oxygenase; GI, gastrointestinal; GPA, gastroprotective agent; H2RA,
Risk of Gastroduodenal Complications H2-receptor antagonist; LDA, low-dose aspirin; NSAID, nonsteroidal

N
anti-inflammatory drug; OR, odds ratio; PPI, proton pump inhibitor;
onsteroidal anti-inflammatory drugs (NSAIDs) are PUB, peptic ulcer bleeding; RCT, randomized controlled trial; RR, rel-
among the most commonly prescribed medica- ative risk; RRR, relative risk reduction.
tions. Nearly 30 million people worldwide take NSAIDs on a daily © 2009 by the AGA Institute
basis, and about 40% of them are older than 60 years.1,2 The broad 1542-3565/09/$36.00
use of these drugs attests to their significant anti-inflammatory doi:10.1016/j.cgh.2009.03.015
726 ARORA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 7

with up to 4-fold increased odds at a dose of 300 mg/day, when In one of the earlier randomized controlled trials for preven-
compared with both hospital and community controls.20 Further- tion of NSAID-induced ulcers by Ekstrom et al,29 omeprazole
more, the risk of ulcer bleeding in patients taking concomitant 20 mg was compared with placebo in patients with a history of
NSAIDs and LDA is almost double that of those taking either dyspepsia or uncomplicated peptic ulcer disease who required
alone.20 In a double-blind placebo-controlled study, the risk of continuous NSAID therapy. After 3 months, 4.7% of omepra-
gastroduodenal ulcer was significantly greater in patients taking zole-treated patients developed an ulcer compared with 16.7%
naproxen and aspirin (27%) than in those who received the COX-2 of those randomized to receive placebo. The rates of dyspepsia
inhibitor celecoxib plus aspirin (19%, P ⫽ .016) or placebo plus were 15.3% with omeprazole compared with 35.6% in the pla-
aspirin (8%, P ⬍ .001).21 A study of patients with osteoarthritis cebo group, a 57% RR decrease with the PPI as compared with
who were taking enteric-coated aspirin (81 mg daily) showed that placebo. The remission rates at the end of the 3-month trial
7.3% of them exhibited endoscopic ulcers and erosions at 12 period were 74% and 48%, respectively. In a similar trial (OP-
weeks.22 Another study reported that among patients taking aspi- PULENT study), Cullen et al30 studied patients with no more
rin (100 or 325 mg daily) for more than 3 months, 48% of than mild dyspepsia who continued to take NSAIDs. At the end
asymptomatic patients developed endoscopic ulcers or erosions.23 of 6 months, the probability of remaining free of endoscopic
Although it might improve drug tolerability, coated or buffered gastroduodenal ulcers or erosions or moderate to severe dys-
aspirin has not shown any benefit to decrease the incidence of GI peptic symptoms was 0.78 for omeprazole as compared with
complications.24 0.53 for placebo (relative risk reduction [RRR], 32%; P ⫽ .004).
In a prospective case-control study in Spain during 1995– Patients receiving placebo developed 4 times (16.5% vs 3.6%) as
1998, consecutive patients admitted to 4 hospitals with peptic many ulcers as those receiving omeprazole, and elderly patients
ulcer bleeding (PUB) were evaluated for aspirin use.25 After in particular were less likely to remain free of NSAID-related
adjustment for potential confounders, it was found that LDA gastroduodenal damage.
(ⱕ300 mg daily) use was significantly associated with GI bleed- A short trial compared omeprazole with placebo in primary
ing (odds ratio [OR], 6.5; 95% confidence interval [CI], 2.0 –21.2) prevention of endoscopic ulcers in patients with arthritis re-
and peptic ulceration (OR, 2.1; 95% CI, 1.0 – 4.1). In addition,
quiring indomethacin, diclofenac, or ketoprofen for pain con-
use of antisecretory medications was associated with signifi-
trol.31 At the end of the trial, 100% of patients on omeprazole
cantly lower odds in patients taking LDA (OR, 0.4; 95% CI,
were gastric ulcer–free as compared with 88% in the placebo
0.2– 0.9).25 A meta-analysis of 22 randomized placebo-con-
arm (P ⬍ .01). No difference was found in the rate of duodenal
trolled trials including more than 57,000 patients showed that
ulcer or dyspepsia. Another study that compared pantoprazole
the pooled incidence of major GI bleeding in the placebo group
with placebo found the former to be superior for the prevention
was 0.12% per year, and LDA doubled that risk (relative risk
of NSAID-related ulcers.32 This 12-week trial of pantoprazole
[RR], 2.07; 95% CI, 1.61–2.66).26 Aspirin increased the risk of
40 mg daily in arthritic patients requiring continuous NSAID
any major bleeding (GI or intracranial) by 1.7–2.1 times relative
treatment, half of whom had normal baseline mucosa and the
to the placebo. When aspirin at a dose of ⬎162 to 325 mg daily
other half had grade 0 –2 gastroduodenal lesions, revealed that
was compared with a dose of 75–162 mg daily, there was no
evidence of increased risk of bleeding. 72% were ulcer-free as compared with 59% in the placebo group.
Furthermore, this protective effect was stronger in the patients
with normal gastric mucosa at baseline (82% vs 55%, P ⫽ .036).
What Is the Role of Proton Pump In an interesting randomized parallel-group comparison,
Inhibitors in the Primary Prevention of Pilotto et al33 compared the effect of pantoprazole 40 mg daily
Nonsteroidal Anti-inflammatory Drug/ for 1 month (n ⫽ 34) with PPI-based triple drug therapy (n ⫽
Aspirin–Induced, Endoscopically 35) for Helicobacter pylori (1 week) in elderly patients (⬎60 years)
Detected Gastroduodenal Ulceration? who had symptoms or history of ulcers and required continu-
Various proton pump inhibitors (PPIs), omeprazole, ous NSAID treatment. At 1 month, on the basis of the severity
pantoprazole, lansoprazole, esomeprazole, rabeprazole, have of gastroduodenal damage determined endoscopically, 91% in
emerged as effective and well-tolerated agents that protect the the pantoprazole group versus 71% in the other group were in
stomach and the duodenum during NSAID use. These agents remission (P ⬍ .05). The results of this study are clinically
inhibit the gastric H⫹/K⫹–adenosinetriphosphatase by co- relevant because they demonstrate the protective effects of PPIs
valently binding to the cysteine residues of the proton pump in high-risk elderly patients who are particularly vulnerable to
and thus reduce the gastric acid secretion. The PPIs as a group gastroduodenal toxicity from NSAIDs used even for a short-
have an excellent history of safety in patients with acid-related term course for ailments such as musculoskeletal pain.
upper GI complaints.27 Stupnicki et al34 compared pantoprazole 20 mg daily (n ⫽
Supplementary Table 1 summarizes studies on primary pre- 257) with the prostaglandin-repleting drug misoprostol 400 ␮g
vention of NSAID-induced GI damage with concomitant PPI daily (n ⫽ 258) in the prevention of NSAID-related lesions and
therapy. Results of a meta-analysis that pooled the results of 5 symptoms in high-risk rheumatoid arthritis patients. After 6
randomized controlled trials showed that the use of PPIs was months of therapy, the remission rates for pantoprazole were
associated with a much lower risk of endoscopically identified significantly higher than misoprostol (95% vs 86%, P ⫽ .005) for
gastric (RR, 0.40; 95% CI, 0.32– 0.51) and duodenal ulcers (RR, preventing endoscopically detected gastroduodenal injury. Re-
0.19; 95% CI, 0.09 – 0.37) when compared with placebo.28 The mission rates (defined as lack of endoscopic findings, GI symp-
overall rate of endoscopic ulcers was 14.5% with PPIs versus toms, or adverse events) were also significantly higher with
35.6% in the placebo groups. Most of the trials to date have pantoprazole (89% vs 70%, P ⬍ .001). It should be noted that
used such endoscopic findings as end points. the overall number of gastroduodenal lesions might have been
July 2009 PPI FOR NSAID OR ASPIRIN-INDUCED UGI DAMAGE 727

underestimated in this study because patients with 10 or more Are Proton Pump Inhibitors Effective in
erosions evident at the 3-month endoscopy were withdrawn. Secondary Prevention of Nonsteroidal
Scheiman et al35 published data from 2 identical, random- Anti-inflammatory Drug/Aspirin–Induced,
ized, placebo-controlled trials, VENUS (United States, n ⫽ 844) Endoscopically Detected
and PLUTO (international, n ⫽ 585). Both trials involved high- Gastroduodenal Ulceration?
risk (age ⱖ65 years or history of peptic ulcer disease within 5 Supplementary Table 2 summarizes studies on second-
years) ulcer-free patients who continued to take a nonselective ary prevention of NSAID-induced gastroduodenal ulceration
NSAID or COX-2 inhibitor on a chronic basis. Esomeprazole with concomitant PPI therapy. Secondary prevention, that is,
(20 mg or 40 mg given once daily) was compared with placebo prevention of repeat gastroduodenal damage in patients who
for the rate of ulcer development at 6 months. Remission rates already had such damage, is of utmost importance in people
at the end of the study period were 79.6% for placebo, 94.7% for with healed NSAID-induced ulcers, because this is the group at
esomeprazole 20 mg daily, and 95.3% for 40 mg daily (both P ⬍ highest risk of further gastroduodenal injury, including perfo-
.001 as compared with placebo) in the VENUS study and 87.7% ration and bleeding, if they continue to take NSAIDs. A decade
for placebo, 94.8% for esomeprazole 20 mg daily (P ⫽ .018), and ago, the OMNIUM trial demonstrated that maintenance treat-
95.6% for esomeprazole 40 mg daily (P ⫽ .007) in PLUTO. ment with omeprazole 20 mg daily (remission in 61%) reduced
When a pooled analysis was performed only for the COX-2 ulcer recurrence compared with both misoprostol 400 ␮g daily
inhibitors from the above 2 studies, remission rates were 83.5% (remission in 48%, P ⫽ .001) and placebo (remission in 27%,
on placebo, 99.1% on esomeprazole 20 mg daily (P ⬍ .001), and P ⬍ .001), and those patients who received omeprazole had
95.9% on esomeprazole 40 mg daily (P ⫽ .002). Both these trials fewer adverse events than those receiving misoprostol.40 At the
demonstrated the effectiveness of a PPI in preventing GI dam- same time, another trial, the ASTRONAUT study, showed su-
periority of omeprazole 20 mg daily over ranitidine 300 mg
age from the long-term use of nonselective NSAIDs and COX-2
daily in maintaining remission (72% vs 59%, P ⫽ .004).41
inhibitors in a high-risk population.
In a large double-blind study (n ⫽ 401), Graham et al42
Regula et al36 reported the results of a randomized trial (n ⫽
compared 2 doses of lansoprazole with misoprostol 800 ␮g
595) that compared pantoprazole with omeprazole for prevention
daily and placebo in the prevention of relapse in patients with
of gastroduodenal toxicity in high-risk patients continuing to take a history of endoscopically documented gastric ulcers who
NSAIDs. At 6 months, patients in remission from therapeutic continued NSAID use and were known to be H pylori–negative.
failure (defined as ulcer development/more than 10 erosions/ They found that at the end of 12 weeks, the percentage of
adverse events/severe GI symptoms) were 90% with pantoprazole patients who were free from gastric ulcers was higher in both
20 mg daily, 93% with pantoprazole 40 mg daily, and 89% with lansoprazole groups (80% in 15 mg daily and 82% in 30 mg
omeprazole 20 mg daily (all P ⫽ NS), indicating that both these daily) when compared with placebo (51%) but not when com-
drugs provided highly effective, equivalent, and well-tolerated pro- pared with the misoprostol group (93%). Notably, a signifi-
phylaxis against NSAID-induced GI damage in high-risk patients. cantly higher proportion of patients in the misoprostol group
The recent ASTERIX trial of primary prevention of endo- reported treatment-related adverse events or withdrew early
scopic gastroduodenal ulcers in patients requiring daily LDA from the study. There could be a few reasons why the remission
(75–325 mg) for secondary cardiovascular prevention showed percentages reported in this study were higher than those in
that at 26 weeks, 5.4% in the placebo group versus 1.6% on other studies. First, the short duration of follow-up of 12 weeks
esomeprazole 20 mg daily developed endoscopically detected significantly decreased the probability of relapse as compared
ulcers.37 The corresponding life-table estimates at 6 months with studies reporting 6-month or 12-month maintenance pe-
were 6.2% versus 1.8% (RRR, 71%; P ⬍ .001). riods. Second, the primary end point included only gastric ulcer
A number of nonrandomized trials have demonstrated the and not the presence of GI symptoms or adverse events, and
beneficial effect of PPIs in NSAID users. A cohort study by last, to improve efficacy, the dose of misoprostol used in this
Pilotto et al38 looked at elderly patients who underwent an study was high (800 ␮g daily). This last factor leads to problems
upper endoscopy and compared those taking NSAIDs or aspi- with compliance and translates into decreased clinical effective-
rin (n ⫽ 676) with the ones who were not (n ⫽ 2435). Further- ness when using misoprostol.
Three trials published the results of secondary prevention of
more, the usage of NSAIDs/aspirin was categorized as acute
NSAID-induced GI damage as abstracts. In one, patients with
(7–30 days) or chronic (⬎30 days). In both acute and chronic
healed gastric ulcers who continued to receive NSAIDs43 exhibited
users, the prevalence of endoscopically detected ulcer(s) was
remission in 66% in the pantoprazole 40 mg daily group, which
assessed according to whether the patient had taken a PPI for at
was higher than in the omeprazole 20 mg daily group (55%, P ⫽
least 7 days before the endoscopy. Results showed that in the
.07) or misoprostol 400 ␮g daily group (44%, P ⫽ .02), after the 12
acute group, the OR of having an ulcer was 0.70 (95% CI, months. In another 6-month trial, patients with healed gastric or
0.24 –2.04), with an absolute risk reduction of 36.6% in patients duodenal ulcer or multiple erosions who were continuing NSAID
who took a PPI versus those who did not. Similarly, in chronic therapy44 experienced significantly lower incidence of relapse and
users, the OR was 0.32 (95% CI, 0.15– 0.67), with an absolute bleeding in the pantoprazole group compared with those in the
risk reduction of 34.6%. The prevalence of H pylori infection was omeprazole or ranitidine groups (P ⬍ .05). In a third trial, patients
similar in the 2 cohorts. In a 26-month-long, nested case- with prior severe GI bleeding while on NSAIDs and who continued
control study of chronic NSAID users, Vonkeman et al39 found on NSAID treatment45 reported significantly less treatment fail-
that concomitant PPI therapy was associated with a reduced ures, defined as upper GI bleeding, symptomatic ulcer recurrence,
risk of NSAID-related complications (adjusted OR, 0.33; 95% or unrelieved GI symptoms, when treated with omeprazole 20 mg
CI, 0.17– 0.67; P ⫽ .002). daily instead of misoprostol 800 ␮g daily (4.4% vs 30.4%, P ⫽ .02).
728 ARORA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 7

Are Proton Pump Inhibitors Effective randomized 242 patients with healed NSAID-induced ulcer to
in Preventing Nonsteroidal Anti- treatment with celecoxib 200 mg daily or naproxen 750 mg
inflammatory Drug–Induced, Clinically daily plus lansoprazole 30 mg daily after eradicating H pylori.
Detected Gastrointestinal After a median follow-up of 24 weeks, the proportion of pa-
Complications? tients with ulcer recurrence was statistically similar in both
Although there is considerable evidence that PPI use groups (3.7% vs 6.3%, P ⫽ NS). More patients receiving cele-
prevents the development of NSAID-induced endoscopic le- coxib developed dyspepsia (15% vs 5.7%, P ⫽ .02). Advanced age
sions, it is not known how such use would reflect a reduction in (ⱖ65) and concomitant illness were noted to be independent
the risk of clinically significant events such as GI hemorrhage or risk factors. A large ongoing trial (CONDOR) comparing the GI
perforation. One relatively small clinical outcome study was adverse events between celecoxib alone and diclofenac plus
done to assess the efficacy of PPIs for high-risk users of omeprazole in patients with arthritis at high risk of GI adverse
NSAIDs.46 This study enrolled 150 H pylori–positive patients effects will potentially provide further key data.51 A more recent
who had a history of NSAID-related ulcer bleeding and needed study by Chan et al52 looked at patients with arthritis taking
continuous NSAID (naproxen) treatment. In this trial, 1 week nonselective NSAIDs who presented to the hospital with upper
of H pylori eradication therapy was compared with 6 months of GI bleeding (n ⫽ 272) and showed that a strategy of combining
PPI (omeprazole) use, and the latter was found to be associated celecoxib with a PPI (esomeprazole 20 mg) given twice daily
with significantly lower probability of recurrent ulcer bleeding yielded significantly better results compared with celecoxib
(18.8% vs 4.4%, P ⫽ .005). In a case-control study of 2777 alone (recurrent ulcer bleeding after 12 months: 0% vs 8.9%, P ⬍
patients with endoscopically confirmed PUB matched to 5532 .001).
control subjects, Lanas et al47 found that the use of PPIs
reduced the risk of both NSAID-related PUB (adjusted RR, 0.33;
95% CI, 0.27– 0.39) and aspirin (all doses)-related PUB (adjusted Are Proton Pump Inhibitors Effective
RR, 0.30; 95% CI, 0.20 – 0.44). A recently published study ana- in Reducing Nonsteroidal Anti-
lyzed 363,037 person-years of follow-up data in Tennessee’s inflammatory Drug–Induced Dyspepsia?
Medicaid database for new peptic ulcer–related hospitalizations In general, NSAID-induced, endoscopically detected
related to nonselective NSAID or coxib use in a large cohort gastroduodenal lesions cause few, if any, symptoms. In contrast,
containing approximately 30% subjects with a history of upper many NSAIDs, aspirin, and even acetaminophen might cause
GI disease.48 They found that when compared with nonselective dyspeptic symptoms (such as epigastric discomfort and full-
NSAID alone, the risk of peptic ulcer hospitalization was re- ness, upper abdominal pain, nausea, and bloating), especially at
duced by 39% (95% CI, 16%–56%) for nonselective NSAID ⫹ any high doses. Dyspepsia is a common adverse event of NSAID
gastroprotective co-therapy (PPI, misoprostol, or double-dose therapy and is the most common reason for drug discontinu-
H2-receptor antagonist [H2RA]), 40% (23%–54%) for coxib only, ation.17 Yet there is little correlation between the dyspeptic
and 50% (28%– 66%) for coxib ⫹ gastroprotective co-therapy. symptoms sometimes seen with these drugs and underlying
Furthermore, the greatest risk reduction was seen with PPI
gastroduodenal erosions or ulcers or the risk of complications.
co-usage with either a nonselective NSAID (54% [27%–72%]) or
Hawkey et al53 conducted 2 multinational, randomized con-
a coxib (50% [27%– 66%]).48
trolled trials to evaluate the efficacy of PPIs for the relief of
NSAID-related symptoms (NASA1 and SPACE1). The patients
How Does Concomitant Proton Pump studied had a chronic condition that required a nonselective
Inhibitor Use Compare With That of NSAID, COX-2 inhibitor, high-dose aspirin (⬎325 mg daily), or
Selective Cyclooxygenase-2 Inhibitors a combination of these for longer than 7 months; had no ulcers
as a Risk-Reduction Strategy? or erosive esophagitis at baseline; and were H pylori–negative.
When compared with nonselective NSAIDs, COX-2– Esomeprazole 20 mg daily or 40 mg daily given for 4 weeks was
selective agents are associated with a reduced incidence of compared with placebo, and the change in patient-reported
serious upper GI adverse events; hence, another strategy to upper GI symptoms was assessed. Both these trials demon-
reduce the risk of recurrent NSAID-associated ulcers would be strated significant improvement with both doses of esomepra-
to substitute the nonselective NSAID with a COX-2 inhibitor. zole as compared with placebo. This benefit was also seen when
Several recent studies have evaluated how these strategies com- data were pooled for those only taking COX-2 inhibitors. An-
pare with each other, especially in high-risk populations. Chan other study from the Netherlands used an uncontrolled obser-
et al49 randomized 287 NSAID users who had a recent episode vational study design (n ⫽ 615) and showed a dramatic reduc-
of ulcer bleeding to treatment with celecoxib alone (400 mg tion in the prevalence of nonselective NSAID-related dyspepsia
daily) or diclofenac (75 mg daily) plus omeprazole (20 mg daily) in elderly patients treated with concomitant pantoprazole at 20
for 6 months. They did not find a difference in the incidence of mg per day, compared with those who did not receive panto-
recurrent endoscopic gastroduodenal ulcer between the 2 prazole.54
groups (18.7% vs 25.6%, P ⫽ .21). Of note, a small fraction of Because there are limited direct comparison data assessing
patients in each group took concomitant aspirin, herbal prod- COX-2 inhibitors versus the combination of nonselective
ucts, or were smokers. Treatment-induced significant dyspepsia, NSAID plus PPI, a meta-analysis to compare the rates of dys-
age ⱖ75 years, and comorbidity were found to independently pepsia for these 2 common therapies in high-risk patients with
predict ulcer recurrence. Accordingly, development of signifi- arthritis showed that NSAID ⫹ PPI affords greater risk reduc-
cant dyspepsia on therapy might be justified as indication for tion for dyspepsia than COX-2 inhibitors when compared with
further endoscopic evaluation in high-risk patients. Lai et al50 the common baseline of NSAIDs.55
July 2009 PPI FOR NSAID OR ASPIRIN-INDUCED UGI DAMAGE 729

How Effective Are Proton Pump patients with aspirin-induced peptic ulcer disease who were
Inhibitors in Preventing Rebleeding being treated with omeprazole 20 mg daily and randomized
From Aspirin ⴞ Clopidogrel Therapy in them to receive clopidogrel 75 mg daily versus continuing on
High-Risk Patients? LDA. Five patients in each group were excluded after random-
ization for various reasons. In the analysis after those exclu-
The aggressive antithrombotic therapy used in patients
sions, no difference was found in the treatment success (defined
undergoing stent implantation, and particularly those with
as no ulcers and ⱕ5 erosions at 8 weeks) between the 2 groups
acute coronary syndromes, might precipitate or aggravate GI
(90% in clopidogrel and 95% in aspirin group, P ⫽ .337).
bleeding, and this risk increases with the number of antithrom-
There has been recent concern over whether PPIs decrease
botic agents used. The GI bleeding risk is 2.3-fold to 2.8-fold
the effectiveness of concomitantly administered clopidogrel.
higher among clopidogrel users as compared with nonusers and
One published study reported that omeprazole decreased the
is similar to aspirin and NSAIDs.56 Furthermore, clopidogrel
efficacy of clopidogrel on platelets as measured by the vasodi-
increases blood loss caused by NSAIDs57 and synergistically
lator–stimulated phosphoprotein phosphorylation assay in the
causes GI bleeding in patients using aspirin, nonselective
laboratory.63 The American Heart Association, American Col-
NSAIDs, or anticoagulants.58
lege of Cardiology, and American College of Gastroenterology
In a randomized controlled trial, Lai et al59 enrolled 123
issued a joint statement concluding that there is no definite
patients with ulcers who had used LDA for more than 1 month
evidence to change clinical practice at this time.64 Results of the
and had H pylori infection. After ulcer healing and H pylori
infection eradication, patients were randomized to receive lan- ongoing COGENT–1 trial are expected to provide more answers
soprazole 30 mg daily ⫹ aspirin 100 mg daily or placebo ⫹ to this question.65
aspirin 100 mg daily for 12 months. After a median follow-up
of 12 months, a significantly lower percentage in the lansopra- How Effective Are Proton Pump
zole group (1.6% vs 14.8%, adjusted hazard ratio, 9.6; 95% CI, Inhibitors in Healing Nonsteroidal
1.2–76.1) had a recurrence of ulcer complications. Anti-inflammatory Drug–Induced
In a randomized controlled trial, Chan et al60 enrolled 320 Gastroduodenal Ulcers and Can Ulcers
patients with ulcer bleeding. After ulcer healing and H pylori Heal by Proton Pump Inhibitor Therapy
eradication, patients were randomized in a 1:1 fashion to re- if Nonsteroidal Anti-inflammatory
ceive clopidogrel 75 mg ⫹ placebo or aspirin 80 mg daily ⫹ Drugs or Aspirin Are Continued?
esomeprazole 20 mg twice daily. The cumulative incidence of A common clinical dilemma revolves around the deci-
recurrent ulcer bleeding after a 12-month period was 8.6% sion to interrupt NSAID therapy in patients with arthritis who
(4.1–13.1%) in the clopidogrel group versus 0.7% (0 –2.0%) in the are found to have ulcers or related complications. Should
aspirin ⫹ esomeprazole group. The absolute difference between NSAID therapy be continued in conjunction with PPI co-ther-
the 2 groups was highly significant (P ⫽ .001), thereby indicat- apy given for a healing intent? At the cost of patient’s discom-
ing superiority of aspirin given in combination with a twice- fort and pain, should NSAIDs be stopped and resumed after
daily PPI (esomeprazole) over clopidogrel for secondary preven- ulcer healing? To date, many trials have demonstrated the
tion of ulcer complications in patients needing antithrombotic efficacy of PPIs in healing ulcers caused by NSAID use and their
therapy for cardiovascular disease prevention. It should be superiority over H2RA and misoprostol. Almost all of these
noted that the study population was predominantly male and trials have used endoscopic criteria for diagnosing the ulcers as
Asian, which might limit its external validity. well as documenting their healing (Supplementary Table 3).
In another study, Lai et al61 tested the hypothesis that a Furthermore, most of these studies were of 8-week duration. In
combination of aspirin and esomeprazole was as safe as clopi- one of the earlier trials, Bardhan et al66 compared ulcer healing
dogrel; the latter is recommended for patients intolerant of rates among patients with NSAID-induced gastric ulcer given
aspirin who are in need of antithrombotic prophylaxis for their lansoprazole 60 mg daily, lansoprazole 30 mg daily, or raniti-
cardiovascular risk. This was essentially the same design as that dine 300 mg daily. They found healing rates to be comparable
of the study by Chan et al,60 albeit with different doses of for the 2 doses of lansoprazole, both of which were superior to
aspirin and esomeprazole. In this double-blind controlled trial, those of ranitidine. Similar conclusions were reached by
they randomized 170 patients who had developed ulcer bleed- Agrawal et al67 in their study that compared lansoprazole 30 mg
ing after using LDA to receive esomeprazole 20 mg daily ⫹ and 15 mg daily with ranitidine 300 mg daily. Bianchi-Porro et
aspirin 100 mg daily versus clopidogrel 75 mg daily. This was al68 compared omeprazole 20 mg daily with sucralfate 4 g daily
done after healing of the ulcers and eradication of H pylori and found significantly better healing rate with the former (96%
infection. After a median follow-up of 52 weeks, they found vs 78%). Massimo Claar et al69 explored the healing rates be-
that the cumulative incidence of recurrent ulcer complication tween 2 different doses of omeprazole and demonstrated excel-
was 0% in the esomeprazole group versus 13.6% in the clopi- lent healing of gastroduodenal ulcers with both 40 mg daily
dogrel group (absolute difference, 13.6%; 95% CI, 6.3%–20.9%; (88%) and 20 mg daily (96%), without any statistical difference
P ⫽ .002). This demonstrated the superiority of the combination between them.
of aspirin with a PPI (esomeprazole) over clopidogrel in the sec- In the healing phase of the ASTRONAUT study, patients
ondary prevention of ulcer complications and echoed the results of with NSAID-induced gastric or duodenal ulcers or with more
the study by Chan et al. However, it also shared the possible than 10 mucosal erosions and requiring daily NSAID therapy
limitation of general applicability of their results because their were randomized to receive omeprazole 40 mg (n ⫽ 187) or 20
study population was predominantly Asian men. mg (n ⫽ 174) daily or ranitidine 300 mg daily (n ⫽ 174) for 8
In a single-blind, randomized controlled trial with endo- weeks.41 The primary end points were treatment success (de-
scopic rather than clinical outcomes, Ng et al62 recruited 129 fined as absence of any ulcers, or a maximum of 5 erosions and
730 ARORA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 7

no more than mild dyspepsia), gastric ulcer healing, and duo- aged 65 years and older found that the risk of peptic ulcer
denal ulcer healing. When compared with ranitidine, both dos- disease was increased 4 times in those taking NSAIDs compared
age groups of omeprazole fared better. In another trial of with nonusers.13 In another 6-month study, patients with ad-
similar design, the OMNIUM study, omeprazole 40 mg (n ⫽ vanced age, history of peptic ulcer, PUB, and cardiovascular
315) and 20 mg (n ⫽ 308) daily were compared with misopros- disease had a 9% risk of a major GI complication.16 In a meta-
tol 800 ␮g daily (n ⫽ 298).40 This study used the same end analysis of randomized controlled trials that compared the risk
points and duration of treatment as the ASTRONAUT study. of GI complications in users versus nonusers of NSAIDs, the
When compared with misoprostol, there was no difference in RRs for various NSAIDs were indomethacin 2.25 (1.00 –5.08),
treatment success rates in the patients randomized to receive naproxen 1.83 (1.25–2.68), diclofenac 1.73 (1.21–2.46), piroxi-
omeprazole. However, when the healing rates for gastric ulcer cam 1.66 (1.14 –2.44), tenoxicam 1.43 (0.40 –5.14), meloxicam
and duodenal ulcer were considered separately, omeprazole was 1.24 (0.98 –1.56), and ibuprofen 1.19 (0.93–1.54).78 Also noted
superior to misoprostol. was an increased risk with increasing dosage (dichotomized as
More recently, Goldstein et al70,71 published the results of 2 high and low) of the NSAIDs.
separate multicenter, randomized, double-blind trials that com-
pared the healing rates of gastric ulcers induced by NSAID use.
What Is the Role of Other
Esomeprazole 40 mg and 20 mg daily were compared with
Gastroprotective Agents for Prevention
ranitidine 300 mg daily, given for 8 weeks, in patients with at
of Nonsteroidal Anti-inflammatory
least 1 documented gastric ulcer who required continuous
Drug/Aspirin–Induced Gastrointestinal
NSAID treatment. In the first study (n ⫽ 399), healing rates for
Damage?
both esomeprazole groups were superior to ranitidine (P ⬍
.01).71 However, in the more recently published study (n ⫽ 410), Primarily because of their lower costs, other gastropro-
no statistical difference was found between the groups, despite tective agents (GPAs) have been investigated and used in the
having the same design and equivalent sample sizes as the prevention and therapy of gastroduodenal NSAID damage, but
previous study, although the numeric results were similar.70 overall, their clinical effectiveness has been inferior. Misopros-
The authors reported that the second trial was done to confirm tol prevents NSAID-induced gastric and duodenal ulcers and
and extend the findings of the previous trial. reduces the risk of life-threatening complications such as bleed-
In a literature review of 7 clinical trials performed by Yeo- ing.16,28,40,42,79 – 81 In a meta-analysis of patients receiving miso-
mans et al,72 after 8 weeks’ treatment with ranitidine, gastric prostol along with NSAIDs versus placebo, the incidence of
ulcer healing rates were 50%–74%, whereas duodenal ulcer heal- gastric ulcers decreased by 74% and that of duodenal ulcers by
ing ranged from 81%– 84%, similar to sucralfate. However, 53%.28 The major limiting factor preventing widespread use as
8-week gastric healing rates were 92% and 88% with esomepra- a protective agent is the high frequency of side effects of
zole 40 mg and 20 mg, respectively. For omeprazole, 8-week diarrhea, abdominal cramps, and nausea in up to 20% of those
healing rates were 87% with omeprazole 40 mg and 84% with using it, thus limiting patient compliance. Several studies have
omeprazole 20 mg, and for lansoprazole the corresponding compared PPIs and misoprostol for reducing the risk of
values were 73%–74% and 66%– 69% for the 30-mg and 15-mg NSAID-induced GI complications and have concluded that the
doses, respectively. Duodenal ulcer healing rates were 92% for 2 strategies offer equivalent efficacy. It should also be noted
omeprazole 20 mg (vs 81% for ranitidine). NSAID-associated that some of the studies have evaluated dosages of drugs that
gastric ulcers are more likely to heal when patients receive PPI are not comparable, eg, half-dose misoprostol versus full-dose
co-therapy rather than ranitidine. omeprazole. Standard doses of H2RAs, such as ranitidine and
famotidine, have a modest protective effect against duodenal
ulcers during NSAID administration but offer no significant
How Can High-Risk Patients Be
protection against gastric ulcers, which tend to be more of a
Identified for Concomitant Proton
problem in this population.28,82– 86 In a case-control study, La-
Pump Inhibitor Protective Co-therapy?
nas et al25 showed that use of an antisecretory therapy (PPI
Because symptoms do not predict endoscopic lesions or [taken by 8.3% of the patients] or H2RA [taken by 3.8% of the
clinical complications in NSAID users, risk stratification of patients]) was associated with decreased odds (OR, 0.6; 95% CI,
patients even before institution of NSAID therapy is essential. 0.4 – 0.8) of upper GI bleeding in patients taking NSAIDs or
Various factors reported to increase the risk of NSAID-related aspirin. In a 24-week trial of primary prevention by using endo-
GI complications are history of gastroduodenal ulcer or hem- scopic end points in patients receiving NSAIDs daily, no difference
orrhage, age 65 years or older, prolonged use of high-dose was found in the incidence of gastric ulcers in patients receiving
NSAIDs, use of more than one NSAID, concomitant use of standard doses of famotidine (40 mg daily) compared with pla-
corticosteroids or anticoagulants, and serious comorbidities cebo (13% vs 20%).86 However, gastric ulcer incidence was reduced
such as cardiovascular disease, renal or hepatic impairment, (8%) in those receiving high doses (80 mg daily), and duodenal
diabetes, or hypertension.2,73 Out of all these, the most signif- ulcer incidence was reduced with both the doses.
icant risk factor is a history of a serious ulcer complication,
which increases the likelihood of a subsequent event by as high
as 13.5-fold.9,11,13,16,74,75 This risk might be related to attenuated What Is the Cost-Effectiveness of Proton
mucosal integrity at the site of prior ulceration, given that Pump Inhibitors When Compared With
ulcers tend to recur at their previous location.60,76 The risk of Other Gastroprotective Agents?
ulceration is increased 4-fold when NSAIDs and corticosteroids In a recently published cost-effectiveness analysis of PPI
are taken together, compared with no increased risk when co-therapy in people taking long-term LDA, Saini et al87 re-
taking corticosteroids alone.77 A study of Medicaid enrollees ported that PPI co-therapy at over-the-counter cost in average-
July 2009 PPI FOR NSAID OR ASPIRIN-INDUCED UGI DAMAGE 731

risk patients and at prescription cost in high-risk patients was


found to be cost-effective. An economic modeling analysis from
the United Kingdom, published in 2006, suggested that nonse-
lective NSAID plus H2RA or nonselective NSAID plus PPI are
the most cost-effective strategies for avoiding endoscopic ulcers
in patients requiring long-term NSAID therapy.88 In a cost-
effectiveness analysis, Spiegel et al89 reported nsNSAID ⫹ PPI
therapy to be cost-effective and better than COX-2 inhibitor alone
strategy in average-risk patients. In high-risk patients, the
NSAID ⫹ PPI therapy was clearly the dominant strategy. In a
qualitative analysis, Hur et al90 suggested that although COX-2
selective inhibitors might have a better GI complication profile, the
increased risk of cardiovascular events and greater cost needed to
be addressed when comparing these agents with a combination of
NSAID and PPI. In 2005, Yun and Bae91 reported COX-2 inhibitor
alone strategy to be the most cost-effective.
Overall, it is unclear which strategy (NSAID ⫹ H2RA, NSAID ⫹
Figure 2. *High GI risk is mostly based on age ⬎65 and history of ulcer
misoprostol, NSAID ⫹ PPI, COX-2 alone, COX-2 ⫹ PPI, etc.) is or ulcer complication; alternatives to PPI include H2RA and misoprostol.
the most cost-effective for gastroprotection in patients requir-
ing long-term NSAID use. This ambiguity is based in part on
the relative paucity of data from clinical trials that directly Given the widespread use of PPIs, there are concerns regarding
compare these strategies and also on the changing costs and possible overprescription and the resultant economic and po-
availability of these drugs. Furthermore, in many parts of the tential health consequences.92 In general, however, PPIs are
world, alternatives to PPIs, such as famotidine, ranitidine, and
well-tolerated in both short-term and long-term studies of pa-
misoprostol, are off-patent and cheaper than even the generic
tients with acid-related disorders.93 Data from clinical trials
PPIs. Thus, it is imperative to conduct cost-effectiveness anal-
show that the most common side effects associated with the use
ysis for different countries separately on the basis of the variable
of PPIs are diarrhea, headache, dizziness, pruritus, and skin rash.
local costs of these drugs.
These symptoms are usually mild to moderate and rarely require
treatment discontinuation. A postmarketing surveillance program
Are There Any Limitations to the Use found that among more than 100,000 patients with acid-related
of Proton Pump Inhibitors? disorders receiving pantoprazole, only 0.77% had any untoward
Because NSAID use is mostly long-term and frequently events.94 The PPIs undergo extensive hepatic metabolism via the
life-long, PPI co-therapy in NSAID users is also long-term. cytochrome P450 system, although the specific enzymes involved
in the metabolism of the various agents differ. Clinically signifi-
cant drug-drug interactions remain uncommon. The PPIs do not
require dose adjustment in the healthy elderly or in patients with
renal or hepatic disease.95,96
Recent data from observational cohort and case-control
studies of patients on long-term PPI therapy have indicated
certain potential risks. Clostridium difficile–associated disease was
found to have a higher association with PPI use in some97–99 but
not all studies.100 PPI, but not H2RA, use was associated with
bacterial gastroenteritis with Campylobacter and Salmonella in a
nested case-control study in the United Kingdom.101 Hip frac-
ture risk with long-term PPI use was shown to be increased in
1 study, but another study with the same database concluded
that there was no increased risk.102 Community-acquired pneu-
monia was noted to have a higher incidence in current users of
PPIs in a study from the Netherlands,103 and another study with
a United Kingdom database found increased incidence in pa-
tients who started a PPI within 30 days before the diagnosis of
pneumonia but not in longer-term current users.104 Although
such studies remain hypothesis-generating and will require fur-
ther, more robust confirmatory evidence, they have created
safety concerns among users and prescribers.
It is important to emphasize that simply prescribing GPAs is
not sufficient to fully prevent NSAID-induced upper GI com-
plications. A population-based nested case-control study looked
at the impact of adherence to GPA therapy in patients with at
Figure 1. *High GI risk is mostly based on age ⬎65 and history of ulcer least 1 risk factor and using daily NSAIDs.105 The study found
or ulcer complication; alternatives to PPI include H2RA and misoprostol. that the risk of an NSAID-related upper GI complication
732 ARORA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 7

Table 1. Key Points


Concomitant PPI use reduces the risk of development of NSAID-induced endoscopic lesions such as ulcers.
Concomitant PPI use is strongly recommended for high-risk NSAID users.
It is not known whether concomitant PPI use reduces the risk of clinically significant GI events such as hemorrhage and perforation.
PPI co-therapy in high-risk NSAID users is equivalent to COX-2 therapy in preventing NSAID-induced endoscopic lesions.
Concomitant PPI use might be superior to COX-2 therapy in minimizing incident dyspepsia in NSAID users.
PPI use is effective as secondary prevention of ulcer complications in patients needing antithrombotic therapy with aspirin or clopidogrel.
As alternatives to PPIs, misoprostol and H2RAs can be used in the prevention of NSAID-related ulcers and their complications, and their use
is cost-effective.
PPI co-therapy is effective in the healing and prevention of recurrence of ulcers in patients maintained on long-term NSAID therapy.

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German post-marketing surveillance (PMS) program. Gastroen- Address requests for reprints to: George Triadafilopoulos, MD, DSc,
terology 1997;112(Suppl 4):A138. Clinical Professor of Medicine, Division of Gastroenterology and Hepa-
95. Lew EA. Review article: pharmacokinetic concerns in the selec- tology, Stanford University School of Medicine, Alway Building, Room
tion of anti-ulcer therapy. Aliment Pharmacol Ther 1999; M 211, 300 Pasteur Drive, MC: 5187, Stanford, California 94305-
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96. Radhofer-Welte S. Pharmacokinetics and metabolism of the
proton pump inhibitor pantoprazole in man. Drugs Today (Barc) Conflicts of interest
1999;35:765–772. The authors disclose the following: Dr Triadafilopoulos has received
97. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium speakers’ honoraria and consulting fees from Astra-Zeneca, LLP,
difficile diarrhea among hospital inpatients prescribed proton Takeda, NicOx SA, Horizon Therapeutics, Inc, and Pfizer, Inc. Dr Singh
pump inhibitors: cohort and case-control studies. CMAJ 2004; donates all his speaker fees and honoraria to research. Dr Arora
171:33–38. discloses no conflicts.
98. Akhtar AJ, Shaheen M. Increasing incidence of Clostridium dif-
ficile-associated diarrhea in African-American and Hispanic pa- Funding
tients: association with the use of proton pump inhibitor ther- This project was supported in part by an unrestricted educational
apy. J Natl Med Assoc 2007;99:500 –504. grant from Astra-Zeneca Pharmaceuticals. The Institute of Clinical
99. Dial S, Delaney JA, Barkun AN, et al. Use of gastric acid-suppres- Outcomes Research and Education (ICORE), Palo Alto, CA has received
sive agents and the risk of community-acquired Clostridium diffi- grant support from the following organizations in the past 3 years:
cile-associated disease. JAMA 2005;294:2989 –2995. Astra Zeneca, Pfizer, Novartis, Centocor, and Nycomed.
July 2009 PPI FOR NSAID OR ASPIRIN-INDUCED UGI DAMAGE 735.e1

Supplementary Table 1. Primary Prevention of NSAID or Aspirin Use-Related Gastroduodenal Damage With PPIs (Endoscopic
and Clinical Outcomes)
First author (y)ref Study type Study population Study groups Duration Primary end point Results

Yeomans [ASTERIX study], Randomized, double-blind, High-risk (age ⬎60 y), Esomeprazole 20 mg daily 26 weeks Ulcer development 5.4% on placebo vs 1.6% on
(2008)37 placebo-controlled ulcer-free patients (n ⫽ 493) vs placebo esomeprazole; 6.2% vs
requiring daily LDA (n ⫽ 498) 1.8% (P ⬍ .001) by life-
table estimates at
6 months
Scheiman [VENUS study], Randomized, double-blind, High-risk ulcer-free NSAID/COX-2 vs NSAID/ 6 months Ulcer development Ulcer development: 20.4%
(2006)35 placebo-controlled patients requiring COX-2 ⫹ esomeprazole on placebo, 5.3% on
(United States) NSAIDs or COX-2 20 mg (n ⫽ 281) or 40 esomeprazole 20 mg
inhibitors mg (n ⫽ 282) daily or (P ⬍ .001) and 4.7% on
placebo (n ⫽ 281) esomeprazole 40 mg
(P ⬍ .001)
Scheiman [PLUTO study] Randomized, double-blind, High-risk ulcer-free NSAID/COX-2 vs NSAID/ 6 months Ulcer development Ulcer development: 12.3%
(2006)35 placebo-controlled patients requiring COX-2 ⫹ esomeprazole on placebo, 5.2% on
(international) NSAIDs or COX-2 20 mg (n ⫽ 195) or 40 esomeprazole 20 mg
inhibitors mg (n ⫽ 198) daily or (P ⫽ .018) and 4.4% on
placebo (n ⫽ 192) esomeprazole 40 mg
(P ⫽ .007)
Scheiman [pooled analysis Randomized, double-blind, High-risk ulcer-free COX-2 vs COX-2 ⫹ 6 months Ulcer development Ulcer development: 16.5%
for COX-2 from VENUS placebo-controlled patients requiring esomeprazole 20 mg on placebo, 0.9% on
and PLUTO studies] COX-2 inhibitors or 40 mg daily or esomeprazole 20 mg
(2006)35 placebo (total (P ⬍ .001) and 4.1% on
n ⫽ 400) esomeprazole 40 mg
(P ⫽ .002)
Regula (2006)36 Randomized, double-blind, Rheumatic disease; Pantoprazole 20 mg once 6 months Endoscopic Remission: 90% vs 93% vs
parallel-group high-risk; daily (n ⫽ 196) vs findings, severe 89% (all P ⫽ NS)
comparison study continuous NSAIDs pantoprazole 40 mg GI symptoms,
once daily (n ⫽ 199) AEs
vs omeprazole 20 mg
once daily (n ⫽ 200)
Stupnicki (2003)34 Randomized, double-blind, High-risk arthritis Pantoprazole 20 mg once 6 months Endoscopic Remission: pantoprazole
multicenter, parallel- (⬎55 y age); daily (n ⫽ 257) vs findings, severe 89% vs misoprostol 70%
group comparison continuous NSAID misoprostol 200 ␮g GI symptoms, (P ⬍ .001)
study treatment twice a day (n ⫽ 258) AEs
Pilotto (2000)33 Randomized, parallel- Symptoms and/or a Pantoprazole 40 mg daily 1 month Endoscopically Remission: 91% vs 71%
group comparison history of ulcer; (n ⫽ 34) vs PPI-based determined (P ⬍ .05)
study elderly (⬎60 y); triple drug therapy severe
continuous NSAID (n ⫽ 35) gastroduodenal
treatment damage
Bianchi Porro (2000)32 Randomized double blind Outpatients with RA Pantoprazole 40 mg daily 12 weeks Endoscopic ulcer; Free of endoscopic ulcer:
placebo-controlled or OA on NSAIDs (n ⫽ 70) vs placebo AE pantoprazole: 72% vs
(diclofenac, (n ⫽ 34) placebo: 59% (82% vs
ketoprofen, or 55%, P ⫽ .036 when only
indomethacin) for considering patients with
at least 8 weeks normal baseline mucosa)
with grade 0–2
endoscopic
gastroduodenal
lesions
Cullen [OPPULENT study] Randomized double-blind, Continuous NSAID Omeprazole 20 mg daily 6 months Endoscopic Probability of remaining free
(1998)30 placebo-controlled, (any) use; not (n ⫽ 83) vs placebo ulcers/erosion of the end points: 0.78
parallel-group study having more than (n ⫽ 85) or moderate– for omeprazole vs 0.53
mild dyspepsia severe for placebo, P ⫽ .004
dyspeptic
symptoms
Bianchi Porro (1998)31 Randomized, double-blind, Arthritis; requiring Omeprazole 20 mg once 3 weeks Endoscopic Gastric ulcer-free: 100% in
placebo-controlled indomethacin, daily (n ⫽ 50) vs findings omeprazole groups vs
diclofenac, or placebo (n ⫽ 53) 88% in placebo group
ketoprofen (P ⬍ .01); no difference
in duodenal ulcer rate or
dyspepsia rate
Ekstrom (1996)29 Randomized, placebo- History of dyspepsia Omeprazole 20 mg daily 3 months Endoscopic ulcers 4.7% for omeprazole vs
controlled or uncomplicated (n ⫽ 85) vs placebo 16.7% for placebo
peptic ulcer; (n ⫽ 90)
continuous NSAID
treatment
Pilotto (2004)38 Cohort study Elderly; on aspirin PPI (omeprazole 20 mg or At least 7 Endoscopic ulcer Acute group: OR, 0.70 (95%
(low dose/regular lansoprazole 30 mg or days CI, 0.24–2.04), ARR,
dose) or NSAID pantoprazole 40 mg or 36.6%; chronic group:
(nimesulide, esomeprazole 40 mg) OR, 0.32 (95% CI,
ketorolac, taken for at least 7 0.15–0.67), ARR, 34.6%
piroxicam, days before EGD
diclofenac,
ketoprofen) acutely
(7–30 days,
47.3%) or
chronically (⬎30
days, 52.7%)
735.e2 ARORA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 7

Supplementary Table 1. Continued


First author (y)ref Study type Study population Study groups Duration Primary end point Results

Vonkeman (2007)39 Nested case-control Chronic NSAID users For cases, n ⫽ 104 and 26 months NSAID-related complications Concomitant PPI therapy
study for controls, n ⫽ 284 requiring hospitalization associated with reduced
risk for NSAID-related
complications (adjusted
OR, 0.33 (95% CI, 0.17–
0.67, P ⫽ .002)
Lanas (2007)47 Case-control study Upper GI bleeding Adjusted RR of PUB in n/a PUB For NSAID-related PUB:
(confirmed by patients taking PPI adjusted RR, 0.33 (95%
endoscopy) (cases ⫽ 239, CI, 0.27–0.39) and for
compared with controls ⫽ 732) aspirin users (all doses):
controls adjusted RR, 0.30 (95%
CI, 0.20–0.44)
Spiegel (2006)55 Meta-analysis Chronic arthritis NSAID vs NSAID ⫹ PPI n/a Dyspepsia (epigastric pain, ARR, 9%; RRR, 66% with
patients and COX-2 vs NSAID dyspepsia, nausea) NSAID ⫹ PPI vs NSAIDs;
ARR, 3.7%; RRR, 12%
with coxibs vs NSAIDs.
Conclusion: NSAID ⫹ PPI
better for dyspepsia
reduction
Rostom (2002)28 Meta-analysis Adults taking NSAIDs PPI use vs placebo Variable Endoscopic ulcer detection For duodenal ulcer: PPI vs
for more than 3 placebo: RR, 0.19 (95%
weeks CI, 0.09–0.37), P ⬍.001;
for gastric ulcer: PPI vs
placebo: RR, 0.40 (95%
CI, 0.32–0.51), P ⬍
.001)

AEs, adverse events; RA, rheumatoid arthritis; OA, osteoarthritis; EGD, esophagogastroduodenoscopy; ARR, absolute risk reduction.
July 2009 PPI FOR NSAID OR ASPIRIN-INDUCED UGI DAMAGE 735.e3

Supplementary Table 2. Secondary Prevention of NSAID or Aspirin Use-Related Gastroduodenal Damage With PPIs
(Endoscopic and Clinical Outcomes)
First author (y)ref Type of study Study population Study groups Duration Primary end point Results

Chan (2007)52 Double-blind randomized Healed ulcers after PUB, Celecoxib 200 mg BID ⫹ 12 months Recurrent ulcer bleeding 0% vs 8.9% (P ⬍ .001),
controlled trial H pylori negative, esomeprazole 20 mg adverse effects
taking nonselective daily (n ⫽ 137) vs similar in both
NSAIDs before, given celecoxib 200 mg groups
celecoxib after ulcer BID ⫹ placebo (n ⫽
healing 136)
Lai (2005)50 Randomized controlled Healed NSAID ulcer after Celecoxib 200 mg daily 24 weeks Recurrent ulcer Primary end point:
trial complications; H. (n ⫽ 120) vs complications celecoxib 3.7% vs
pylori eradicated naproxen 750 mg NSAID ⫹ PPI 6.3%
daily ⫹ lansoprazole (P ⫽ NS); for
30 mg daily (n ⫽ dyspepsia: celecoxib
122) 15.0% vs NSAID ⫹
PPI 5.7% (P ⫽ .02)
Chan (2004)49 Randomized, double- Healed ulcer after Diclofenac 75 mg BID ⫹ 6 months Recurrent ulcer Recurrent ulcer in:
blind NSAID-ulcer bleeding; omeprazole 20 mg celecoxib: 18.7% vs
H pylori negative; daily (n ⫽ 106) vs diclofenac ⫹
continuous NSAID celecoxib 200 mg BID omeprazole: 25.6%,
use (n ⫽ 116) P ⫽ .21
Graham (2002)42 Randomized, double- History of endoscopic Misoprostol 800 ␮g daily 12 weeks Endoscopic gastric Gastric ulcer-free at 12
blind, active and gastric ulcer; long- (134), lansoprazole ulcers weeks: lansoprazole
placebo-controlled term NSAID use; H 15 mg (136), 15 mg, 80%;
pylori negative. lansoprazole 30 mg lansoprazole 30 mg,
(133), placebo (134) 82%; misoprostol,
93%; placebo, 51%
(lansoprazole groups
vs placebo, P ⬍
.001; 15 vs 30 mg,
P ⫽ NS).
Compliance:
lansoprazole groups:
90% vs misoprostol
73%, P ⬍ .001
Olteanu (2000)43 Randomized, parallel- Healed gastric ulcer; Pantoprazole 40 mg 12 months Not specified. Remission: 66% vs 55%
groups comparison continuous NSAID once daily (n ⫽ 40) (P ⫽ NS) vs 44%
study treatment vs omeprazole 20 mg (P ⫽ .02)
once daily (n ⫽ 40)
vs misoprostol 200
␮g BID (n ⫽ 40)
Jensen (2000)45 Prospective, High-risk patients Omeprazole 20 mg BID Not Treatment failure: upper Treatment failure:
randomized, parallel- (previous severe GI (n ⫽ 23) vs available GI bleeding, omeprazole 4.4% vs
group bleeding while on misoprostol 200 ␮g symptomatic ulcer misoprostol 30.4%
NSAIDs); continuous QID (n ⫽ 23) recurrence, or (P ⫽ .02)
NSAID treatment unrelieved upper GI
symptoms
Kujundzic (2000)44 Randomized, parallel- Healed gastric or Pantoprazole 20 mg 6 months Endoscopic findings Lower rate of relapse
groups comparison duodenal ulcer or once daily vs (ulcer, ⬎10 erosions, with pantoprazole as
study erosions; continuous omeprazole 20 mg bleeding) compared with
NSAID treatment; H. once daily vs omeprazole or
pylori eradicated ranitidine 150 mg BID ranitidine (all P ⬍
(total n ⫽ 489) .05)
Hawkey [OMNIUM study] Randomized, double- No ulcers, ⬍5 erosions, Omeprazole (20 mg 6 months Endoscopic ulcers, Patients in remission at
(1998)40 blind, placebo- no more than mild daily, n ⫽274); withdrawals, AEs 6 months: 61% for
controlled, dyspepsia; misoprostol (200 ␮g omeprazole vs
international continuous NSAID BID, n ⫽ 296); misoprostol 48%
therapy placebo (n ⫽ 155) (P ⫽ .001); placebo
27% (P ⬍ .001
compared with
omeprazole and
misoprostol)
Yeomans [ASTRONAUT study] Randomized, controlled, No ulcers, ⬍5 erosions, Omeprazole 20 mg (n ⫽ 6 months Endoscopic ulcers Remission: 72% for
(1998)41 double-blind, no more than mild 210) vs ranitidine omeprazole vs 59%
international dyspepsia; 150 mg BID (n ⫽ for ranitidine (P ⫽
continuous NSAID 215) .004)
therapy

BID, twice a day; QID, 4 times a day; AEs, adverse events.


735.e4 ARORA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 7

Supplementary Table 3. PPIs for the Healing of NSAID or Aspirin Use-Related Gastroduodenal Damage
First author (y)ref Study type Study population Study groups Duration Primary end point Results

Goldstein (2007)70 Multicenter, randomized, At least 1 gastric ulcer; need Esomeprazole 40 mg daily 8 weeks Absence of gastric ulcer Healing rates: esomeprazole
double-blind, double- for continuous NSAID (n ⫽ 133) vs 40 mg, 85.7% (79.8%–
dummy, parallel-group (selective or nonselective) esomeprazole 20 mg 91.7%); esomeprazole
trial therapy daily (n ⫽ 138) vs 20 mg, 84.8% (78.8%–
ranitidine 300 mg daily 90.8%); ranitidine, 76.3%
(n ⫽ 139) (69.2%–83.3%) (no
difference between
groups)
Goldstein (2005)71 Multicenter, randomized, At least 1 gastric ulcer; need Esomeprazole 40 mg daily 8 weeks Absence of gastric ulcer Healing rates: esomeprazole
double-blind, parallel- for continuous NSAID (n ⫽ 129) vs 40 mg, 91.5% (86.7%–
group trial (selective or nonselective) esomeprazole 20 mg 96.3%); esomeprazole 20
therapy daily (n ⫽ 138) vs mg, 88.4%
ranitidine 300 mg daily (83.1%–93.7%);
(n ⫽ 132) ranitidine, 74.2%
(66.8%–81.7%) (P ⬍ .01
compared with both
esomeprazole groups)
Agrawal (2000)67 Prospective, double- At least 1 gastric ulcer; need Lansoprazole 30 mg daily 8 weeks Healing of ulcer Healing rates: compared
blind, double-dummy, for continuous NSAID (n ⫽ 73) vs with ranitidine 300 mg at
multicenter, parallel- (selective or nonselective) lansoprazole 15 mg 53%, lansoprazole 15
group study therapy daily (n ⫽ 71) vs mg, 69% (P ⬍ .05) and
ranitidine 300 mg daily lansoprazole 30 mg, 73%
(n ⫽ 70) (P ⬍ .01)
Hawkey [OMNIUM study] Randomized, double- Gastric or duodenal ulcer or Omeprazole 40 mg daily 8 weeks Treatment success Treatment success:
(1998)40 blind, international ⬎10 erosions in patients (n ⫽ 315) vs (absence of ulcers, omeprazole 40 mg, 75%
trial needing daily NSAID omeprazole 20 mg up to 5 erosions, (P ⫽ .24); omeprazole 20
therapy daily (n ⫽ 308) vs and no more than mg, 76% (P ⫽ .37); and
misoprostol 800 ␮g mild dyspepsia); misoprostol, 71%
daily (n ⫽ 298) gastric ulcer healing; (referent). Gastric ulcer
duodenal ulcer healing: omeprazole 40
healing mg, 80% (P ⫽ .14);
omeprazole 20 mg, 87%
(P ⫽ .004); and
misoprostol, 73%
(referent). Duodenal ulcer
healing: omeprazole 40
mg, 89% (P ⬍ .001);
omeprazole 20 mg, 93%
(P ⬍ .001); and
misoprostol, 77%
(referent).
Yeomans [ASTRONAUT study] Randomized, controlled, Gastric or duodenal ulcer or Omeprazole 40 mg daily 8 weeks Treatment success Treatment success:
(1998)41 double-blind, ⬎10 erosions in patients (n ⫽ 187) vs (absence of ulcers, omeprazole 40 mg, 79%
international needing daily NSAID omeprazole 20 mg up to 5 erosions, (P ⬍ .001); omeprazole
therapy daily (n ⫽ 174) vs and no more than 20 mg, 80% (P ⬍ .001);
ranitidine 300 mg daily mild dyspepsia); and ranitidine, 63%
(n ⫽ 174) gastric ulcer healing; (referent). Gastric ulcer
duodenal ulcer healing: omeprazole 40
healing mg, 87% (P ⬍ .001);
omeprazole 20 mg, 84%
(P ⬍ .001); and
ranitidine, 64% (referent).
Duodenal ulcer healing:
omeprazole 40 mg, 88%
(P ⫽ .17); omeprazole 20
mg, 92% (P ⫽ .03); and
ranitidine, 81% (referent).
Massimo Claar (1998)69 Randomized, double- Patients on daily NSAIDs Omeprazole 40 mg daily 8 weeks Healing of ulcer Healing rates: omeprazole
blind (diclofenac, ketoprofen, (n ⫽ 79) vs 40 mg, 88% (79%–95%);
indomethacin, or omeprazole 20 mg omeprazole 20 mg,
naproxen) for OA or RA daily (n ⫽ 77) 96.2% (89%–99%), P ⫽
and with endoscopically NS
proven gastroduodenal
ulcer
Bianchi Porro (1998)68 Randomized, single-blind Patients with arthritis or Omeprazole 20 mg daily 8 weeks Healing of ulcer Healing rates: omeprazole
arthrosis and NSAID- (n ⫽ 50) vs sucralfate 96% vs sucralfate 78%
related gastric or 4 g daily (n ⫽ 48) (P ⫽ .01)
duodenal ulcer
Bardhan (1994)66 Randomized, double- Endoscopically confirmed Lansoprazole 60 mg daily 8 weeks Healing of ulcer Healing rates: lansoprazole
blind, parallel-group, gastric ulcer (n ⫽ 73) vs 60 mg, 97.3%;
multicenter trial lansoprazole 30 mg lansoprazole 30 mg,
daily (n ⫽ 71) vs 98.6%; ranitidine 300
ranitidine 300 mg daily mg, 91.4% (P ⫽ .08)
(n ⫽ 70)

OA, osteoarthritis; RA, rheumatoid arthritis.

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