SPECIAL REPORT. Aspirin and Risk of Gastroduodenal Complications

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7: 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 Podcast interview: see related article, Reimer C et al, on page 80 in Gastroenterology. Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are among the most commonly used medications worldwide. Their use is associated with significant gastroduodenal adverse effects, including dyspepsia, bleeding, ulcer formation, and perforation. Given their long-term use by millions of patients, there is a substantial impact at the population level of these complications. In this evidence-based review, we have endeavored to answer 12 commonly encountered questions in clinical practice that deal with the following: extent of the problem of NSAID/aspirin-induced gastroduodenal damage and its impact on public health; role of proton pump inhibitors (PPIs) in the primary prevention, healing, and secondary prevention of NSAID/aspirin-induced gastroduodenal ulceration as assessed by using endoscopic end points; role of PPIs in the prevention of adverse clinical outcomes related to NSAID/aspirin use; whether PPIs are effective in NSAID-induced dyspepsia; comparison of PPI co-therapy with selective cyclooxygenase-2 inhibitors for risk reduction of adverse clinical outcomes; role of PPIs in preventing rebleeding from aspirin clopidogrel therapy in high-risk patients; identifying high-risk patients who can benefit from PPI co-therapy; the role of other gastroprotective agents for prevention of NSAID/aspirin-induced gastroduodenal damage; and the cost-effectiveness of and limitations to the use of PPIs for prevention of gastroduodenal damage related to the use of NSAIDs or aspirin. We then summarized our recommendations on the use of PPIs for the clinical management of patients using NSAIDs or aspirin. To view this article s video abstract, go to the AGA s YouTube Channel. What Is the Extent of Nonsteroidal Anti-inflammatory Drug/Aspirin Toxicity and Its Impact on Public Health? Nonsteroidal Anti-inflammatory Drugs and Risk of Gastroduodenal Complications Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications. Nearly 30 million people worldwide take NSAIDs on a daily basis, and about 40% of them are older than 60 years. 1,2 The broad use of these drugs attests to their significant anti-inflammatory effect used for relieving pain in chronic arthritis and other acute and chronic musculoskeletal disorders. In fact, studies performed on patients with arthritis indicated that NSAIDs, when compared with high-dose acetaminophen (4000 mg daily), provide better pain control and functional outcomes and are preferred by the patients. 3 5 The benefits of NSAIDs, however, come at the cost of an increased risk for gastroduodenal adverse effects, ranging from dyspepsia and peptic ulcer disease to more serious and potentially life-threatening complications such as hemorrhage, obstruction, or perforation. 6 8 The gastroduodenal toxicity of NSAIDs has been attributed to blockade of the cyclooxygenase type-1 (COX- 1) mediated generation of cytoprotective prostanoids such as prostaglandin E 2 and prostacyclin. The highly selective inhibitors of COX-2 reportedly cause less gastrointestinal (GI) damage than nonselective NSAIDs, which inhibit both COX-2 and COX-1. 9,10 Not all users of NSAIDs experience endoscopic gastroduodenal damage, and this is not readily predicted by symptoms. Indeed, dyspepsia, a common occurrence in NSAID users, correlates poorly with ulcer development Asymptomatic endoscopic ulcers have been documented in up to 40% of longterm users. 2,8,16,17 Life-threatening complications such as bleeding, perforation, or obstruction occur with an annual incidence of 1.5% and might also be unheralded by symptoms. 16,18 The risk of developing serious gastroduodenal complications is 3 5 times higher in NSAID users compared with nonusers. 19 This risk might be highest just after the initiation of NSAIDs but, importantly, remains persistently increased during the entire duration of therapy. 11,13 15 Aspirin and Risk of Gastroduodenal Complications Low-dose aspirin (LDA) ( 325 mg) is being increasingly used as prophylaxis for cardiovascular disease, and many of these patients also take concomitant NSAIDs. Use of LDA alone increased the risk of upper GI bleeding in a dose-dependent manner, Abbreviations used in this paper: CI, confidence interval; COX, cyclooxygenase; GI, gastrointestinal; GPA, gastroprotective agent; H 2 RA, H 2 -receptor antagonist; LDA, low-dose aspirin; NSAID, nonsteroidal anti-inflammatory drug; OR, odds ratio; PPI, proton pump inhibitor; PUB, peptic ulcer bleeding; RCT, randomized controlled trial; RR, relative risk; RRR, relative risk reduction by the AGA Institute /09/$36.00 doi: /j.cgh

2 726 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 compared with both hospital and community controls. 20 Furthermore, the risk of ulcer bleeding in patients taking concomitant NSAIDs and LDA is almost double that of those taking either alone. 20 In a double-blind placebo-controlled study, the risk of gastroduodenal ulcer was significantly greater in patients taking naproxen and aspirin (27%) than in those who received the COX-2 inhibitor celecoxib plus aspirin (19%, P.016) or placebo plus aspirin (8%, P.001). 21 A study of patients with osteoarthritis who were taking enteric-coated aspirin (81 mg daily) showed that 7.3% of them exhibited endoscopic ulcers and erosions at 12 weeks. 22 Another study reported that among patients taking aspirin (100 or 325 mg daily) for more than 3 months, 48% of asymptomatic patients developed endoscopic ulcers or erosions. 23 Although it might improve drug tolerability, coated or buffered aspirin has not shown any benefit to decrease the incidence of GI complications. 24 In a prospective case-control study in Spain during , consecutive patients admitted to 4 hospitals with peptic ulcer bleeding (PUB) were evaluated for aspirin use. 25 After adjustment for potential confounders, it was found that LDA ( 300 mg daily) use was significantly associated with GI bleeding (odds ratio [OR], 6.5; 95% confidence interval [CI], ) and peptic ulceration (OR, 2.1; 95% CI, ). In addition, use of antisecretory medications was associated with significantly lower odds in patients taking LDA (OR, 0.4; 95% CI, ). 25 A meta-analysis of 22 randomized placebo-controlled trials including more than 57,000 patients showed that the pooled incidence of major GI bleeding in the placebo group was 0.12% per year, and LDA doubled that risk (relative risk [RR], 2.07; 95% CI, ). 26 Aspirin increased the risk of any major bleeding (GI or intracranial) by times relative to the placebo. When aspirin at a dose of 162 to 325 mg daily was compared with a dose of mg daily, there was no evidence of increased risk of bleeding. What Is the Role of Proton Pump Inhibitors in the Primary Prevention of Nonsteroidal Anti-inflammatory Drug/ Aspirin Induced, Endoscopically Detected Gastroduodenal Ulceration? Various proton pump inhibitors (PPIs), omeprazole, pantoprazole, lansoprazole, esomeprazole, rabeprazole, have emerged as effective and well-tolerated agents that protect the stomach and the duodenum during NSAID use. These agents inhibit the gastric H /K adenosinetriphosphatase by covalently binding to the cysteine residues of the proton pump and thus reduce the gastric acid secretion. The PPIs as a group have an excellent history of safety in patients with acid-related upper GI complaints. 27 Supplementary Table 1 summarizes studies on primary prevention of NSAID-induced GI damage with concomitant PPI therapy. Results of a meta-analysis that pooled the results of 5 randomized controlled trials showed that the use of PPIs was associated with a much lower risk of endoscopically identified gastric (RR, 0.40; 95% CI, ) and duodenal ulcers (RR, 0.19; 95% CI, ) when compared with placebo. 28 The overall rate of endoscopic ulcers was 14.5% with PPIs versus 35.6% in the placebo groups. Most of the trials to date have used such endoscopic findings as end points. In one of the earlier randomized controlled trials for prevention of NSAID-induced ulcers by Ekstrom et al, 29 omeprazole 20 mg was compared with placebo in patients with a history of dyspepsia or uncomplicated peptic ulcer disease who required continuous NSAID therapy. After 3 months, 4.7% of omeprazole-treated patients developed an ulcer compared with 16.7% of those randomized to receive placebo. The rates of dyspepsia were 15.3% with omeprazole compared with 35.6% in the placebo group, a 57% RR decrease with the PPI as compared with placebo. The remission rates at the end of the 3-month trial period were 74% and 48%, respectively. In a similar trial (OP- PULENT study), Cullen et al 30 studied patients with no more than mild dyspepsia who continued to take NSAIDs. At the end of 6 months, the probability of remaining free of endoscopic gastroduodenal ulcers or erosions or moderate to severe dyspeptic symptoms was 0.78 for omeprazole as compared with 0.53 for placebo (relative risk reduction [RRR], 32%; P.004). Patients receiving placebo developed 4 times (16.5% vs 3.6%) as many ulcers as those receiving omeprazole, and elderly patients in particular were less likely to remain free of NSAID-related gastroduodenal damage. A short trial compared omeprazole with placebo in primary prevention of endoscopic ulcers in patients with arthritis requiring indomethacin, diclofenac, or ketoprofen for pain control. 31 At the end of the trial, 100% of patients on omeprazole were gastric ulcer free as compared with 88% in the placebo arm (P.01). No difference was found in the rate of duodenal ulcer or dyspepsia. Another study that compared pantoprazole with placebo found the former to be superior for the prevention of NSAID-related ulcers. 32 This 12-week trial of pantoprazole 40 mg daily in arthritic patients requiring continuous NSAID treatment, half of whom had normal baseline mucosa and the other half had grade 0 2 gastroduodenal lesions, revealed that 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). In an interesting randomized parallel-group comparison, Pilotto et al 33 compared the effect of pantoprazole 40 mg daily for 1 month (n 34) with PPI-based triple drug therapy (n 35) for Helicobacter pylori (1 week) in elderly patients ( 60 years) who had symptoms or history of ulcers and required continuous NSAID treatment. At 1 month, on the basis of the severity of gastroduodenal damage determined endoscopically, 91% in the pantoprazole group versus 71% in the other group were in remission (P.05). The results of this study are clinically relevant because they demonstrate the protective effects of PPIs in high-risk elderly patients who are particularly vulnerable to gastroduodenal toxicity from NSAIDs used even for a shortterm course for ailments such as musculoskeletal pain. Stupnicki et al 34 compared pantoprazole 20 mg daily (n 257) with the prostaglandin-repleting drug misoprostol 400 g daily (n 258) in the prevention of NSAID-related lesions and symptoms in high-risk rheumatoid arthritis patients. After 6 months of therapy, the remission rates for pantoprazole were significantly higher than misoprostol (95% vs 86%, P.005) for preventing endoscopically detected gastroduodenal injury. Remission rates (defined as lack of endoscopic findings, GI symptoms, or adverse events) were also significantly higher with pantoprazole (89% vs 70%, P.001). It should be noted that the overall number of gastroduodenal lesions might have been

3 July 2009 PPI FOR NSAID OR ASPIRIN-INDUCED UGI DAMAGE 727 underestimated in this study because patients with 10 or more erosions evident at the 3-month endoscopy were withdrawn. Scheiman et al 35 published data from 2 identical, randomized, placebo-controlled trials, VENUS (United States, n 844) and PLUTO (international, n 585). Both trials involved highrisk (age 65 years or history of peptic ulcer disease within 5 years) ulcer-free patients who continued to take a nonselective NSAID or COX-2 inhibitor on a chronic basis. Esomeprazole (20 mg or 40 mg given once daily) was compared with placebo for the rate of ulcer development at 6 months. Remission rates at the end of the study period were 79.6% for placebo, 94.7% for esomeprazole 20 mg daily, and 95.3% for 40 mg daily (both P.001 as compared with placebo) in the VENUS study and 87.7% for placebo, 94.8% for esomeprazole 20 mg daily (P.018), and 95.6% for esomeprazole 40 mg daily (P.007) in PLUTO. When a pooled analysis was performed only for the COX-2 inhibitors from the above 2 studies, remission rates were 83.5% on placebo, 99.1% on esomeprazole 20 mg daily (P.001), and 95.9% on esomeprazole 40 mg daily (P.002). Both these trials demonstrated the effectiveness of a PPI in preventing GI damage from the long-term use of nonselective NSAIDs and COX-2 inhibitors in a high-risk population. Regula et al 36 reported the results of a randomized trial (n 595) that compared pantoprazole with omeprazole for prevention of gastroduodenal toxicity in high-risk patients continuing to take NSAIDs. At 6 months, patients in remission from therapeutic failure (defined as ulcer development/more than 10 erosions/ adverse events/severe GI symptoms) were 90% with pantoprazole 20 mg daily, 93% with pantoprazole 40 mg daily, and 89% with omeprazole 20 mg daily (all P NS), indicating that both these drugs provided highly effective, equivalent, and well-tolerated prophylaxis against NSAID-induced GI damage in high-risk patients. The recent ASTERIX trial of primary prevention of endoscopic gastroduodenal ulcers in patients requiring daily LDA ( mg) for secondary cardiovascular prevention showed that at 26 weeks, 5.4% in the placebo group versus 1.6% on esomeprazole 20 mg daily developed endoscopically detected ulcers. 37 The corresponding life-table estimates at 6 months were 6.2% versus 1.8% (RRR, 71%; P.001). A number of nonrandomized trials have demonstrated the beneficial effect of PPIs in NSAID users. A cohort study by Pilotto et al 38 looked at elderly patients who underwent an upper endoscopy and compared those taking NSAIDs or aspirin (n 676) with the ones who were not (n 2435). Furthermore, the usage of NSAIDs/aspirin was categorized as acute (7 30 days) or chronic ( 30 days). In both acute and chronic users, the prevalence of endoscopically detected ulcer(s) was assessed according to whether the patient had taken a PPI for at least 7 days before the endoscopy. Results showed that in the acute group, the OR of having an ulcer was 0.70 (95% CI, ), with an absolute risk reduction of 36.6% in patients who took a PPI versus those who did not. Similarly, in chronic users, the OR was 0.32 (95% CI, ), with an absolute risk reduction of 34.6%. The prevalence of H pylori infection was similar in the 2 cohorts. In a 26-month-long, nested casecontrol study of chronic NSAID users, Vonkeman et al 39 found that concomitant PPI therapy was associated with a reduced risk of NSAID-related complications (adjusted OR, 0.33; 95% CI, ; P.002). Are Proton Pump Inhibitors Effective in Secondary Prevention of Nonsteroidal Anti-inflammatory Drug/Aspirin Induced, Endoscopically Detected Gastroduodenal Ulceration? Supplementary Table 2 summarizes studies on secondary prevention of NSAID-induced gastroduodenal ulceration with concomitant PPI therapy. Secondary prevention, that is, prevention of repeat gastroduodenal damage in patients who already had such damage, is of utmost importance in people with healed NSAID-induced ulcers, because this is the group at highest risk of further gastroduodenal injury, including perforation and bleeding, if they continue to take NSAIDs. A decade ago, the OMNIUM trial demonstrated that maintenance treatment with omeprazole 20 mg daily (remission in 61%) reduced ulcer recurrence compared with both misoprostol 400 g daily (remission in 48%, P.001) and placebo (remission in 27%, P.001), and those patients who received omeprazole had fewer adverse events than those receiving misoprostol. 40 At the same time, another trial, the ASTRONAUT study, showed superiority of omeprazole 20 mg daily over ranitidine 300 mg daily in maintaining remission (72% vs 59%, P.004). 41 In a large double-blind study (n 401), Graham et al 42 compared 2 doses of lansoprazole with misoprostol 800 g daily and placebo in the prevention of relapse in patients with a history of endoscopically documented gastric ulcers who continued NSAID use and were known to be H pylori negative. They found that at the end of 12 weeks, the percentage of patients who were free from gastric ulcers was higher in both lansoprazole groups (80% in 15 mg daily and 82% in 30 mg daily) when compared with placebo (51%) but not when compared with the misoprostol group (93%). Notably, a significantly higher proportion of patients in the misoprostol group reported treatment-related adverse events or withdrew early from the study. There could be a few reasons why the remission percentages reported in this study were higher than those in other studies. First, the short duration of follow-up of 12 weeks significantly decreased the probability of relapse as compared with studies reporting 6-month or 12-month maintenance periods. Second, the primary end point included only gastric ulcer and not the presence of GI symptoms or adverse events, and last, to improve efficacy, the dose of misoprostol used in this study was high (800 g daily). This last factor leads to problems with compliance and translates into decreased clinical effectiveness when using misoprostol. Three trials published the results of secondary prevention of NSAID-induced GI damage as abstracts. In one, patients with healed gastric ulcers who continued to receive NSAIDs 43 exhibited remission in 66% in the pantoprazole 40 mg daily group, which was higher than in the omeprazole 20 mg daily group (55%, P.07) or misoprostol 400 g daily group (44%, P.02), after the 12 months. In another 6-month trial, patients with healed gastric or duodenal ulcer or multiple erosions who were continuing NSAID therapy 44 experienced significantly lower incidence of relapse and bleeding in the pantoprazole group compared with those in the omeprazole or ranitidine groups (P.05). In a third trial, patients with prior severe GI bleeding while on NSAIDs and who continued on NSAID treatment 45 reported significantly less treatment failures, defined as upper GI bleeding, symptomatic ulcer recurrence, or unrelieved GI symptoms, when treated with omeprazole 20 mg daily instead of misoprostol 800 g daily (4.4% vs 30.4%, P.02).

4 728 ARORA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 7 Are Proton Pump Inhibitors Effective in Preventing Nonsteroidal Antiinflammatory Drug Induced, Clinically Detected Gastrointestinal Complications? Although there is considerable evidence that PPI use prevents the development of NSAID-induced endoscopic lesions, it is not known how such use would reflect a reduction in the risk of clinically significant events such as GI hemorrhage or perforation. One relatively small clinical outcome study was done to assess the efficacy of PPIs for high-risk users of NSAIDs. 46 This study enrolled 150 H pylori positive patients who had a history of NSAID-related ulcer bleeding and needed continuous NSAID (naproxen) treatment. In this trial, 1 week of H pylori eradication therapy was compared with 6 months of PPI (omeprazole) use, and the latter was found to be associated with significantly lower probability of recurrent ulcer bleeding (18.8% vs 4.4%, P.005). In a case-control study of 2777 patients with endoscopically confirmed PUB matched to 5532 control subjects, Lanas et al 47 found that the use of PPIs reduced the risk of both NSAID-related PUB (adjusted RR, 0.33; 95% CI, ) and aspirin (all doses)-related PUB (adjusted RR, 0.30; 95% CI, ). A recently published study analyzed 363,037 person-years of follow-up data in Tennessee s Medicaid database for new peptic ulcer related hospitalizations related to nonselective NSAID or coxib use in a large cohort containing approximately 30% subjects with a history of upper GI disease. 48 They found that when compared with nonselective NSAID alone, the risk of peptic ulcer hospitalization was reduced by 39% (95% CI, 16% 56%) for nonselective NSAID any gastroprotective co-therapy (PPI, misoprostol, or double-dose H 2 -receptor antagonist [H 2 RA]), 40% (23% 54%) for coxib only, and 50% (28% 66%) for coxib gastroprotective co-therapy. Furthermore, the greatest risk reduction was seen with PPI co-usage with either a nonselective NSAID (54% [27% 72%]) or a coxib (50% [27% 66%]). 48 How Does Concomitant Proton Pump Inhibitor Use Compare With That of Selective Cyclooxygenase-2 Inhibitors as a Risk-Reduction Strategy? When compared with nonselective NSAIDs, COX-2 selective agents are associated with a reduced incidence of serious upper GI adverse events; hence, another strategy to reduce the risk of recurrent NSAID-associated ulcers would be to substitute the nonselective NSAID with a COX-2 inhibitor. Several recent studies have evaluated how these strategies compare with each other, especially in high-risk populations. Chan et al 49 randomized 287 NSAID users who had a recent episode of ulcer bleeding to treatment with celecoxib alone (400 mg daily) or diclofenac (75 mg daily) plus omeprazole (20 mg daily) for 6 months. They did not find a difference in the incidence of recurrent endoscopic gastroduodenal ulcer between the 2 groups (18.7% vs 25.6%, P.21). Of note, a small fraction of patients in each group took concomitant aspirin, herbal products, or were smokers. Treatment-induced significant dyspepsia, age 75 years, and comorbidity were found to independently predict ulcer recurrence. Accordingly, development of significant dyspepsia on therapy might be justified as indication for further endoscopic evaluation in high-risk patients. Lai et al 50 randomized 242 patients with healed NSAID-induced ulcer to treatment with celecoxib 200 mg daily or naproxen 750 mg daily plus lansoprazole 30 mg daily after eradicating H pylori. After a median follow-up of 24 weeks, the proportion of patients with ulcer recurrence was statistically similar in both groups (3.7% vs 6.3%, P NS). More patients receiving celecoxib developed dyspepsia (15% vs 5.7%, P.02). Advanced age ( 65) and concomitant illness were noted to be independent risk factors. A large ongoing trial (CONDOR) comparing the GI adverse events between celecoxib alone and diclofenac plus omeprazole in patients with arthritis at high risk of GI adverse effects will potentially provide further key data. 51 A more recent study by Chan et al 52 looked at patients with arthritis taking nonselective NSAIDs who presented to the hospital with upper GI bleeding (n 272) and showed that a strategy of combining celecoxib with a PPI (esomeprazole 20 mg) given twice daily yielded significantly better results compared with celecoxib alone (recurrent ulcer bleeding after 12 months: 0% vs 8.9%, P.001). Are Proton Pump Inhibitors Effective in Reducing Nonsteroidal Antiinflammatory Drug Induced Dyspepsia? In general, NSAID-induced, endoscopically detected gastroduodenal lesions cause few, if any, symptoms. In contrast, many NSAIDs, aspirin, and even acetaminophen might cause dyspeptic symptoms (such as epigastric discomfort and fullness, upper abdominal pain, nausea, and bloating), especially at high doses. Dyspepsia is a common adverse event of NSAID therapy and is the most common reason for drug discontinuation. 17 Yet there is little correlation between the dyspeptic symptoms sometimes seen with these drugs and underlying gastroduodenal erosions or ulcers or the risk of complications. Hawkey et al 53 conducted 2 multinational, randomized controlled trials to evaluate the efficacy of PPIs for the relief of NSAID-related symptoms (NASA1 and SPACE1). The patients studied had a chronic condition that required a nonselective NSAID, COX-2 inhibitor, high-dose aspirin ( 325 mg daily), or a combination of these for longer than 7 months; had no ulcers or erosive esophagitis at baseline; and were H pylori negative. Esomeprazole 20 mg daily or 40 mg daily given for 4 weeks was compared with placebo, and the change in patient-reported upper GI symptoms was assessed. Both these trials demonstrated significant improvement with both doses of esomeprazole as compared with placebo. This benefit was also seen when data were pooled for those only taking COX-2 inhibitors. Another study from the Netherlands used an uncontrolled observational study design (n 615) and showed a dramatic reduction in the prevalence of nonselective NSAID-related dyspepsia in elderly patients treated with concomitant pantoprazole at 20 mg per day, compared with those who did not receive pantoprazole. 54 Because there are limited direct comparison data assessing COX-2 inhibitors versus the combination of nonselective NSAID plus PPI, a meta-analysis to compare the rates of dyspepsia for these 2 common therapies in high-risk patients with arthritis showed that NSAID PPI affords greater risk reduction for dyspepsia than COX-2 inhibitors when compared with the common baseline of NSAIDs. 55

5 July 2009 PPI FOR NSAID OR ASPIRIN-INDUCED UGI DAMAGE 729 How Effective Are Proton Pump Inhibitors in Preventing Rebleeding From Aspirin Clopidogrel Therapy in High-Risk Patients? The aggressive antithrombotic therapy used in patients undergoing stent implantation, and particularly those with acute coronary syndromes, might precipitate or aggravate GI bleeding, and this risk increases with the number of antithrombotic agents used. The GI bleeding risk is 2.3-fold to 2.8-fold higher among clopidogrel users as compared with nonusers and is similar to aspirin and NSAIDs. 56 Furthermore, clopidogrel increases blood loss caused by NSAIDs 57 and synergistically causes GI bleeding in patients using aspirin, nonselective NSAIDs, or anticoagulants. 58 In a randomized controlled trial, Lai et al 59 enrolled 123 patients with ulcers who had used LDA for more than 1 month and had H pylori infection. After ulcer healing and H pylori infection eradication, patients were randomized to receive lansoprazole 30 mg daily aspirin 100 mg daily or placebo aspirin 100 mg daily for 12 months. After a median follow-up of 12 months, a significantly lower percentage in the lansoprazole group (1.6% vs 14.8%, adjusted hazard ratio, 9.6; 95% CI, ) had a recurrence of ulcer complications. In a randomized controlled trial, Chan et al 60 enrolled 320 patients with ulcer bleeding. After ulcer healing and H pylori eradication, patients were randomized in a 1:1 fashion to receive clopidogrel 75 mg placebo or aspirin 80 mg daily esomeprazole 20 mg twice daily. The cumulative incidence of recurrent ulcer bleeding after a 12-month period was 8.6% ( %) in the clopidogrel group versus 0.7% (0 2.0%) in the aspirin esomeprazole group. The absolute difference between the 2 groups was highly significant (P.001), thereby indicating superiority of aspirin given in combination with a twicedaily PPI (esomeprazole) over clopidogrel for secondary prevention of ulcer complications in patients needing antithrombotic therapy for cardiovascular disease prevention. It should be noted that the study population was predominantly male and Asian, which might limit its external validity. In another study, Lai et al 61 tested the hypothesis that a combination of aspirin and esomeprazole was as safe as clopidogrel; the latter is recommended for patients intolerant of aspirin who are in need of antithrombotic prophylaxis for their cardiovascular risk. This was essentially the same design as that of the study by Chan et al, 60 albeit with different doses of aspirin and esomeprazole. In this double-blind controlled trial, they randomized 170 patients who had developed ulcer bleeding after using LDA to receive esomeprazole 20 mg daily aspirin 100 mg daily versus clopidogrel 75 mg daily. This was done after healing of the ulcers and eradication of H pylori infection. After a median follow-up of 52 weeks, they found that the cumulative incidence of recurrent ulcer complication was 0% in the esomeprazole group versus 13.6% in the clopidogrel group (absolute difference, 13.6%; 95% CI, 6.3% 20.9%; P.002). This demonstrated the superiority of the combination of aspirin with a PPI (esomeprazole) over clopidogrel in the secondary prevention of ulcer complications and echoed the results of the study by Chan et al. However, it also shared the possible limitation of general applicability of their results because their study population was predominantly Asian men. In a single-blind, randomized controlled trial with endoscopic rather than clinical outcomes, Ng et al 62 recruited 129 patients with aspirin-induced peptic ulcer disease who were being treated with omeprazole 20 mg daily and randomized them to receive clopidogrel 75 mg daily versus continuing on LDA. Five patients in each group were excluded after randomization for various reasons. In the analysis after those exclusions, no difference was found in the treatment success (defined as no ulcers and 5 erosions at 8 weeks) between the 2 groups (90% in clopidogrel and 95% in aspirin group, P.337). There has been recent concern over whether PPIs decrease the effectiveness of concomitantly administered clopidogrel. One published study reported that omeprazole decreased the efficacy of clopidogrel on platelets as measured by the vasodilator stimulated phosphoprotein phosphorylation assay in the laboratory. 63 The American Heart Association, American College of Cardiology, and American College of Gastroenterology issued a joint statement concluding that there is no definite evidence to change clinical practice at this time. 64 Results of the ongoing COGENT 1 trial are expected to provide more answers to this question. 65 How Effective Are Proton Pump Inhibitors in Healing Nonsteroidal Anti-inflammatory Drug Induced Gastroduodenal Ulcers and Can Ulcers Heal by Proton Pump Inhibitor Therapy if Nonsteroidal Anti-inflammatory Drugs or Aspirin Are Continued? A common clinical dilemma revolves around the decision to interrupt NSAID therapy in patients with arthritis who are found to have ulcers or related complications. Should NSAID therapy be continued in conjunction with PPI co-therapy given for a healing intent? At the cost of patient s discomfort and pain, should NSAIDs be stopped and resumed after ulcer healing? To date, many trials have demonstrated the efficacy of PPIs in healing ulcers caused by NSAID use and their superiority over H 2 RA and misoprostol. Almost all of these trials have used endoscopic criteria for diagnosing the ulcers as well as documenting their healing (Supplementary Table 3). Furthermore, most of these studies were of 8-week duration. In one of the earlier trials, Bardhan et al 66 compared ulcer healing rates among patients with NSAID-induced gastric ulcer given lansoprazole 60 mg daily, lansoprazole 30 mg daily, or ranitidine 300 mg daily. They found healing rates to be comparable for the 2 doses of lansoprazole, both of which were superior to those of ranitidine. Similar conclusions were reached by Agrawal et al 67 in their study that compared lansoprazole 30 mg and 15 mg daily with ranitidine 300 mg daily. Bianchi-Porro et al 68 compared omeprazole 20 mg daily with sucralfate 4 g daily and found significantly better healing rate with the former (96% vs 78%). Massimo Claar et al 69 explored the healing rates between 2 different doses of omeprazole and demonstrated excellent healing of gastroduodenal ulcers with both 40 mg daily (88%) and 20 mg daily (96%), without any statistical difference between them. In the healing phase of the ASTRONAUT study, patients with NSAID-induced gastric or duodenal ulcers or with more than 10 mucosal erosions and requiring daily NSAID therapy were randomized to receive omeprazole 40 mg (n 187) or 20 mg (n 174) daily or ranitidine 300 mg daily (n 174) for 8 weeks. 41 The primary end points were treatment success (defined as absence of any ulcers, or a maximum of 5 erosions and

6 730 ARORA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 7 no more than mild dyspepsia), gastric ulcer healing, and duodenal ulcer healing. When compared with ranitidine, both dosage groups of omeprazole fared better. In another trial of similar design, the OMNIUM study, omeprazole 40 mg (n 315) and 20 mg (n 308) daily were compared with misoprostol 800 g daily (n 298). 40 This study used the same end points and duration of treatment as the ASTRONAUT study. When compared with misoprostol, there was no difference in treatment success rates in the patients randomized to receive omeprazole. However, when the healing rates for gastric ulcer and duodenal ulcer were considered separately, omeprazole was superior to misoprostol. More recently, Goldstein et al 70,71 published the results of 2 separate multicenter, randomized, double-blind trials that compared the healing rates of gastric ulcers induced by NSAID use. Esomeprazole 40 mg and 20 mg daily were compared with ranitidine 300 mg daily, given for 8 weeks, in patients with at least 1 documented gastric ulcer who required continuous NSAID treatment. In the first study (n 399), healing rates for both esomeprazole groups were superior to ranitidine (P.01). 71 However, in the more recently published study (n 410), no statistical difference was found between the groups, despite having the same design and equivalent sample sizes as the previous study, although the numeric results were similar. 70 The authors reported that the second trial was done to confirm and extend the findings of the previous trial. In a literature review of 7 clinical trials performed by Yeomans et al, 72 after 8 weeks treatment with ranitidine, gastric ulcer healing rates were 50% 74%, whereas duodenal ulcer healing ranged from 81% 84%, similar to sucralfate. However, 8-week gastric healing rates were 92% and 88% with esomeprazole 40 mg and 20 mg, respectively. For omeprazole, 8-week healing rates were 87% with omeprazole 40 mg and 84% with omeprazole 20 mg, and for lansoprazole the corresponding values were 73% 74% and 66% 69% for the 30-mg and 15-mg doses, respectively. Duodenal ulcer healing rates were 92% for omeprazole 20 mg (vs 81% for ranitidine). NSAID-associated gastric ulcers are more likely to heal when patients receive PPI co-therapy rather than ranitidine. How Can High-Risk Patients Be Identified for Concomitant Proton Pump Inhibitor Protective Co-therapy? Because symptoms do not predict endoscopic lesions or clinical complications in NSAID users, risk stratification of patients even before institution of NSAID therapy is essential. Various factors reported to increase the risk of NSAID-related GI complications are history of gastroduodenal ulcer or hemorrhage, age 65 years or older, prolonged use of high-dose NSAIDs, use of more than one NSAID, concomitant use of corticosteroids or anticoagulants, and serious comorbidities such as cardiovascular disease, renal or hepatic impairment, diabetes, or hypertension. 2,73 Out of all these, the most significant 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 mucosal integrity at the site of prior ulceration, given that ulcers tend to recur at their previous location. 60,76 The risk of ulceration is increased 4-fold when NSAIDs and corticosteroids are taken together, compared with no increased risk when taking corticosteroids alone. 77 A study of Medicaid enrollees aged 65 years and older found that the risk of peptic ulcer disease was increased 4 times in those taking NSAIDs compared with nonusers. 13 In another 6-month study, patients with advanced age, history of peptic ulcer, PUB, and cardiovascular disease had a 9% risk of a major GI complication. 16 In a metaanalysis of randomized controlled trials that compared the risk of GI complications in users versus nonusers of NSAIDs, the RRs for various NSAIDs were indomethacin 2.25 ( ), naproxen 1.83 ( ), diclofenac 1.73 ( ), piroxicam 1.66 ( ), tenoxicam 1.43 ( ), meloxicam 1.24 ( ), and ibuprofen 1.19 ( ). 78 Also noted was an increased risk with increasing dosage (dichotomized as high and low) of the NSAIDs. What Is the Role of Other Gastroprotective Agents for Prevention of Nonsteroidal Anti-inflammatory Drug/Aspirin Induced Gastrointestinal Damage? Primarily because of their lower costs, other gastroprotective agents (GPAs) have been investigated and used in the prevention and therapy of gastroduodenal NSAID damage, but overall, their clinical effectiveness has been inferior. Misoprostol prevents NSAID-induced gastric and duodenal ulcers and reduces the risk of life-threatening complications such as bleeding. 16,28,40,42,79 81 In a meta-analysis of patients receiving misoprostol along with NSAIDs versus placebo, the incidence of gastric ulcers decreased by 74% and that of duodenal ulcers by 53%. 28 The major limiting factor preventing widespread use as a protective agent is the high frequency of side effects of diarrhea, abdominal cramps, and nausea in up to 20% of those using it, thus limiting patient compliance. Several studies have compared PPIs and misoprostol for reducing the risk of NSAID-induced GI complications and have concluded that the 2 strategies offer equivalent efficacy. It should also be noted that some of the studies have evaluated dosages of drugs that are not comparable, eg, half-dose misoprostol versus full-dose omeprazole. Standard doses of H 2 RAs, such as ranitidine and famotidine, have a modest protective effect against duodenal ulcers during NSAID administration but offer no significant protection against gastric ulcers, which tend to be more of a problem in this population. 28,82 86 In a case-control study, Lanas et al 25 showed that use of an antisecretory therapy (PPI [taken by 8.3% of the patients] or H 2 RA [taken by 3.8% of the patients]) was associated with decreased odds (OR, 0.6; 95% CI, ) of upper GI bleeding in patients taking NSAIDs or aspirin. In a 24-week trial of primary prevention by using endoscopic end points in patients receiving NSAIDs daily, no difference was found in the incidence of gastric ulcers in patients receiving standard doses of famotidine (40 mg daily) compared with placebo (13% vs 20%). 86 However, gastric ulcer incidence was reduced (8%) in those receiving high doses (80 mg daily), and duodenal ulcer incidence was reduced with both the doses. What Is the Cost-Effectiveness of Proton Pump Inhibitors When Compared With Other Gastroprotective Agents? In a recently published cost-effectiveness analysis of PPI co-therapy in people taking long-term LDA, Saini et al 87 reported that PPI co-therapy at over-the-counter cost in average-

7 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 nonselective NSAID plus H 2 RA 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 costeffectiveness analysis, Spiegel et al 89 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 al 90 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 Bae 91 reported COX-2 inhibitor alone strategy to be the most cost-effective. Overall, it is unclear which strategy (NSAID H 2 RA, NSAID misoprostol, NSAID PPI, COX-2 alone, COX-2 PPI, etc.) is the most cost-effective for gastroprotection in patients requiring long-term NSAID use. This ambiguity is based in part on the relative paucity of data from clinical trials that directly compare these strategies and also on the changing costs and availability of these drugs. Furthermore, in many parts of the world, alternatives to PPIs, such as famotidine, ranitidine, and misoprostol, are off-patent and cheaper than even the generic PPIs. Thus, it is imperative to conduct cost-effectiveness analysis for different countries separately on the basis of the variable local costs of these drugs. Are There Any Limitations to the Use of Proton Pump Inhibitors? Because NSAID use is mostly long-term and frequently life-long, PPI co-therapy in NSAID users is also long-term. Figure 1. *High GI risk is mostly based on age 65 and history of ulcer or ulcer complication; alternatives to PPI include H 2 RA and misoprostol. Figure 2. *High GI risk is mostly based on age 65 and history of ulcer or ulcer complication; alternatives to PPI include H 2 RA and misoprostol. Given the widespread use of PPIs, there are concerns regarding possible overprescription and the resultant economic and potential health consequences. 92 In general, however, PPIs are well-tolerated in both short-term and long-term studies of patients with acid-related disorders. 93 Data from clinical trials show that the most common side effects associated with the use of PPIs are diarrhea, headache, dizziness, pruritus, and skin rash. These symptoms are usually mild to moderate and rarely require treatment discontinuation. A postmarketing surveillance program found that among more than 100,000 patients with acid-related disorders receiving pantoprazole, only 0.77% had any untoward events. 94 The PPIs undergo extensive hepatic metabolism via the cytochrome P450 system, although the specific enzymes involved in the metabolism of the various agents differ. Clinically significant 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 some but not all studies. 100 PPI, but not H 2 RA, use was associated with bacterial gastroenteritis with Campylobacter and Salmonella in a nested case-control study in the United Kingdom. 101 Hip fracture 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 pneumonia 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 patients 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 further, 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 complications. A population-based nested case-control study looked at the impact of adherence to GPA therapy in patients with at least 1 risk factor and using daily NSAIDs. 105 The study found that the risk of an NSAID-related upper GI complication

8 732 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 H 2 RAs 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. among NSAID users increased by 16% for every 10% decrease in adherence; the latter was defined as the proportion of NSAID treatment days covered by a GPA prescription. Discussion and General Conclusions Gastroduodenal damage related to NSAID and aspirin use is a significant problem, especially given the scale at which these drugs are used. Because the elderly population has been shown to be at high risk and this is the same population predominantly using NSAIDs/aspirin, it is increasingly likely that physicians would come across such patients and their attendant risks of ulcer bleeding and related complications. Risk factors predicting serious gastroduodenal damage in NSAID users are a history of gastroduodenal ulcer or hemorrhage, age 65 years or older, prolonged use of high-dose NSAIDs, use of more than one NSAID, concomitant use of corticosteroids or LDA, anticoagulants, and the presence of serious comorbidities. Among the various pharmacologic strategies used for the primary and secondary prevention of NSAIDinduced gastroduodenal damage in patients requiring ongoing NSAID treatment, PPI co-therapy has emerged as among the most clinically effective and best tolerated. No significant or consistent differences between PPIs with regard to clinical or endoscopic end points have been found in clinical studies, and the various members of the PPI class appear to be comparable. Figures 1 and 2 outline proposed strategies to be considered before initiation of long-term NSAID or aspirin use. The PPIs are effective in the healing and prevention of recurrence of ulcers in patients who are continuing with longterm NSAID therapy and might be the treatment of choice for these indications. A fixed combination of PPI with NSAID will likely improve patient compliance and convenience and thus reduce the population risk of NSAID-induced serious GI complications. Trials are underway to evaluate the former, 36,106 to compare a combination of NSAID and PPI with that of NSAID and misoprostol, 61 and to compare a combination of NSAID and H 2 RA versus NSAID alone. 107 In summary, in this evidence-based review, we have addressed some of the clinically important issues surrounding the use of PPIs for NSAID-related or aspirin-related gastroduodenal damage and have provided justification for the use of these agents (key points listed in Table 1). Further research is needed to address the efficacy of the various gastroprotective strategies by using clinical outcomes as end points. Supplementary Data Note: to access the supplementary materials accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at References 1. Lee M, Feldman M. The aging stomach: implications for NSAID gastropathy. Gut 1997;41: Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999;340: Case JP, Baliunas AJ, Block JA. Lack of efficacy of acetaminophen in treating symptomatic knee osteoarthritis: a randomized, double-blind, placebo-controlled comparison trial with diclofenac sodium. Arch Intern Med 2003;163: Pincus T, Koch G, Lei H, et al. Patient Preference for Placebo, Acetaminophen (paracetamol) or Celecoxib Efficacy Studies (PACES): two randomised, double blind, placebo controlled, crossover clinical trials in patients with knee or hip osteoarthritis. Ann Rheum Dis 2004;63: Pincus T, Koch GG, Sokka T, et al. A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee. Arthritis Rheum 2001;44: Fries JF, Miller SR, Spitz PW, et al. Identification of patients at risk for gastropathy associated with NSAID use. J Rheumatol 1990;20(Suppl): Smalley WE, Griffin MR, Fought RL, et al. Excess costs from gastrointestinal disease associated with nonsteroidal antiinflammatory drugs. J Gen Intern Med 1996;11: Stalnikowicz R, Rachmilewitz D. NSAID-induced gastroduodenal damage: is prevention needed? A review and metaanalysis. J Clin Gastroenterol 1993;17: Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis: VIGOR Study Group. N Engl J Med 2000;343: Micklewright R, Lane S, Linley W, et al. Review article: NSAIDs, gastroprotection and cyclo-oxygenase-ii-selective inhibitors. Aliment Pharmacol Ther 2003;17: Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: a meta-analysis. Ann Intern Med 1991; 115: Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994;343: Griffin MR, Piper JM, Daugherty JR, et al. Nonsteroidal antiinflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med 1991;114: Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non-steroidal antiinflammatory drugs: results of a collaborative meta-analysis. BMJ 1996;312: Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994;343: Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheuma-