Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage

NSAIDs are among the most commonly used drugs worldwide and their beneficial therapeutic properties are thoroughly accepted. However, they are also associated with gastrointestinal (GI) adverse events. NSAIDs can damage the whole GI tract including a wide spectrum of lesions. About 1 to 2% of NSAID users experienced a serious GI complication during treatment. The relative risk of upper GI complications among NSAID users depends on the presence of different risk factors, including older age (>65 years), history of complicated peptic ulcer, and concomitant aspirin or anticoagulant use, in addition to the type and dose of NSAID. Some authors recently reported a decreasing trend in hospitalizations due to upper GI complications and a significant increase in those from the lower GI tract, causing the rates of these two types of GI complications to converge. NSAID-induced enteropathy has gained much attention in the last few years and an increasing number of reports have been published on this issue. Current evidence suggests that NSAIDs increase the risk of lower GI bleeding and perforation to a similar extent as that seen in the upper GI tract. Selective cyclooxygenase-2 inhibitors have the same beneficial effects as nonselective NSAIDs but with less GI toxicity in the upper GI tract and probably in the lower GI tract. Overall, mortality due to these complications has also decreased, but the in-hospital case fatality for upper and lower GI complication events has remained constant despite the new therapeutic and prevention strategies.

frequent being gastroesophageal refl ux (regurgitation and/or heartburn) and dyspeptic symptoms (including belching, epigastric discomfort, bloating, early satiety and postprandial nausea) [3]. Th e onset of these symptoms seems to vary depending on the type of NSAID. A meta-analysis of the available trials from the Cochrane collaboration concluded that COX-2 selective inhibitor (celecoxib) was associated with less sympto matic ulcers, endoscopically detected ulcers and discon tinu ations for GI adverse events compared with ns-NSAIDs (naproxen, diclofenac, ibuprofen and loxoprofen) [5]. Unfortunately, these symptoms are not predictive of the presence of mucosal injury. Approximately 50% of patients with symptoms have no mucosal lesions; how ever, >50% of users with serious peptic ulcer compli ca tions had no previous warning symptoms [3,6].
Th e most important upper GI side eff ects are the occurrence of symptomatic and/or complicated peptic ulcer. NSAID-related upper GI complications include bleeding, perforation and obstruction. About 1 to 2% of NSAID users experienced a serious complication during treatment. Case-control studies and a meta-analysis have shown that the average relative risk (RR) of developing uncomplicated or complicated peptic ulcer is fourfold and fi vefold in NSAIDs users compared with nonusers [7][8][9]. Th e risk is suggested to be higher during the fi rst month of treatment (RR, 5.7; 95% confi dence interval CI, 4.9 to 6.6), but remains elevated during the intake and 2 months after stopping therapy [8].
As we mentioned previously, in many cases the fi rst evidence of NSAID toxicity is a GI complication. Th at is the main reason to say that prevention therapies should be implemented based on the presence of risk factors and not after the occurrence of dyspeptic symptoms.

Risk factors for gastrointestinal complications
Th e main risk factors for NSAID-related GI compli cations (Table 1) are: older age (age ≥65 years, especially ≥70 years); prior uncomplicated or complicated ulcer; concomitant use of other drugs, including aspirin, other nonaspirin antiplatelet agents, anticoagulants, corticosteroids or selective serotonin reuptake inhibitors; severe illness; alcohol and tobacco use; and Heliobacter pylori infection [10]. H. pylori infection and NSAID use have synergistic eff ects on risk. A meta-analysis of 16 studies showed that the odds ratio for peptic ulcer in patients with both risk factors (H. pylori-positive NSAID use) was 61.1 (95% CI, 9.98 to 373)), compared with H. pylorinegative nonusers [11]. Some of these risk factors can be modifi ed. For example, two studies have showed that H. pylori eradication before starting NSAID therapy reduces the rate of peptic ulcer, but eradication in longterm NSAID users seems to be not eff ective in preventing peptic ulcer disease [12,13].

Are NSAIDs equally harmful to the upper gastrointestinal tract?
Based on current evidence, the RR of GI bleeding is not the same with the diff erent types of NSAIDs.

Traditional or nonselective NSAIDs
Traditional or ns-NSAIDs, including high dose of ASA, are considered the most GI harmful kind of NSAID. GI damage is dose dependent, and slow-release formulations and drugs with longer half-life also have greater toxicity. A recent Systematic Review and Meta-Analysis of Observational Studies (the SOS Project) confi rms variability in the risk of GI complications among individual NSAIDs as used in clinical practice. Th e RR ranged from <2 for aceclofenac, ibuprofen and celecoxib, between 2-4 for rofecoxib, meloxicam, nimesulide, sulindac, diclofenac and ketoprofen, and between 4 to 5 for tenoxicam, naproxen, difl unisal and indomethacin, and more than 5 for piroxicam, azapropazone and ketorolac [14]. Th ese diff erences may be attributed in part to the dose and formulations. For individual NSAIDs, data on the eff ect of dose and duration of use are still scant.

Selective cyclooxygenase-2 inhibitors
Th e identifi cation of the gene for the COX-2 isoenzyme in 1991 opened the door to development of NSAIDs that selectively inhibit COX-2. Th is isoenzyme expression can be induced by infl ammatory mediators in multiples tissues and can have an important role in the mediation of pain, infl ammation and fever. Selective COX-2 inhibitors inhibit this enzyme, but keep prostaglandin production via COX-1, which is involved in the maintenance of GI mucosal integrity. As a result, these drugs should in theory be safer than ns-NSAIDs for the development of upper GI complications, although COX-1 inhibition is not the only mechanism involved in GI toxicity.
A 2007 systematic review of randomized controlled trials (RCTs) showed that selective COX-2 inhibitors (celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) produced signifi cantly fewer ulcers (RR, 0.26; 95% CI, 0.23 to 0.30) and ulcer complications (RR, 0.39; 95% CI, 0.31 to 0.50) as well as better GI tolerability compared with ns-NSAIDs [15]. One should keep in mind that concomitant use of low-dose ASA for CV prophylaxis is frequent among NSAID users (approximately 20 to 25% in clinical trials), mainly in older people. Evidence from subgroup analyses of the systematic review above mentioned [15] and several RCTs (the CLASS [16], TARGET [17] and SUCCES-1 [18] studies) suggests that this benefi t might be reduced with the co-administration of low dose ASA. In spite of this, a meta-analysis of all available trials that include users of low-dose ASA combined with NSAIDs (traditional or selective) showed a lower GI complication risk in the group of selective COX-2 NSAID plus low-dose ASA users compared with ns-NSAID plus low-dose ASA users (RR, 0.72; 95% CI, 0.62 to 0.95) [19]. One should point out that these studies were nonrandomized trials and the data result from indirect comparisons.
Also of interest is a recent systematic review of RCTs that compare COX-2 inhibitors versus ns-NSAIDs plus proton pump inhibitors (PPIs) with regard to GI safety. Th e review involved 7,616 patients and concluded that COX-2 inhibitors reduce signifi cantly the risk of perforation, obstruction, and bleeding (RR, 0.38; 95% CI, 0.25 to 0.56; P <0.001) compared with ns-NSAIDs plus PPIs, but this benefi t was signifi cant only for high-risk and longterm users [20]. Selective COX-2 inhibitors are therefore as eff ective as ns-NSAIDs to relieve infl ammation but they can reduce NSAID-asso ciated GI toxicity. Th ese GI benefi ts of selective NSAIDs have to be balanced against the known CV risk, although CV toxicity is not exclusive of selective COX-2 NSAIDs. Rofecoxib (no longer in the market), etoricoxib and diclo fenac (among ns-NSAIDs) seem to have the worst CV profi les [21].

New NSAIDs compounds
Nitric oxide and hydrogen sulfi de are potent vasodilator molecules and increase mucosal protection, keeping its wholeness. Th is has led to the concept that coupling a NSAID and nitric oxide or hydrogen sulfi de molecules could overcome the negative eff ects produced by prostaglandin inhibition.
Th e nitric oxide-releasing NSAIDs, or COX-inhibiting nitric oxide donator, have been investigated as a potentially safer alternative to selective and ns-NSAIDs. Naproxcinod was the fi rst and only COX-inhibiting nitric oxide donator investigated in clinical trials, showing a slight improvement in GI tolerability compared with naproxen. Owing to the lack of outcome studies and potential side eff ects not yet fully evaluated, this compound has not obtained the green light to be commercial ized by offi cial drug agencies in Europe and the USA [22].
NSAIDs that release hydrogen sulfi de are being investigated in preclinical models.

Time trends of gastrointestinal complications and hospitalization due to them
Over the past decades, there have been signifi cant changes in the rate of hospitalizations due to GI complications. A 2004 multicenter study reported that rates of hospitalization for NSAID gastropathy fi rst increased from 0.6% per year in 1981 to a peak of 1.5% in 1992, and then decreased to 0.5% in 2000 [23]. Th e last change could be attributed to several factors: use of lower doses of NSAIDs, an increase in less toxic NSAID and PPI use, and decreased prevalence of H. pylori infection.
Looking at reported time trends for hospitalizations due to GI events (overall and not only NSAID-associated GI complications), we could say that hospitalizations owing to uncomplicated peptic ulcer are decreasing over time [24,25]. However, there were discrepancies concerning hospitalizations owing to complicated ulcers. Generally, studies that reported decreasing peptic ulcer bleeding rates were more recent and were population based. In this regard, it is interesting to highlight a Spanish study by Lanas and colleagues published in 2011 [26]. Th e authors showed that the incidence per 100,000 person-years of hospitalizations due to upper GI ulcer bleeding and perforations decreased over time (from 54.6 and 3.9 in 1996 (R 2 = 0.944) to 25.8 and 2.9 in 2005 (R 2 = 0.410), respectively). Of patients with upper GI events, 21% and 15% of patients with upper GI events were NSAID or antiplatelet users, respectively [27]. Th is tendency con trasted with a progressive and signifi cant increase in the incidence of hospitalizations due to lower GI compli ca tions (colonic diverticular and angiodysplasia bleeding, and a small increasing trend of intestinal perforations).

Nonsteroidal anti-infl ammatory drug-associated lower gastrointestinal damage
As we have pointed out above, the association of NSAID use with upper GI damage is well documented; however, the association with damage to the lower GI tract has not been widely studied and remains poorly characterized. NSAID-induced enteropathy has gained much attention due to the introduction of new diagnostic modalities such as capsule endoscopy (CE) and device-assist ed entero scopy, as well as the increased use of low-dose aspirin (ASA) and NSAIDs. A number of reports have suggested that NSAIDs also cause lower GI tract injury and complications. Th e clinical signifi cance and frequency of adverse events with ns-NSAIDs in the lower GI tract have been increasingly reported (Table 2).

Epidemiology
Recent publications have shown that the incidence of lower GI complications (including ulceration, bleeding, obstruction or perforation), many of them related to NSAID and ASA use, is increasing whereas the incidence of upper GI complications is decreasing [28] (Figure 1). Th e ratio of upper/lower complications was 4.1 in 1996 but decreased to only 1.4 in 2005 [27,28]. Current evidence suggests that NSAIDs increase the risk of lower GI bleeding and perforation to a similar extent as that seen in the upper GI tract [29].
Post-hoc analysis of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) trial concluded that lower GI events accounted for 40% of all serious GI events in patients on NSAIDs [30]. CE studies in healthy subjects taking either short-term or long-term NSAIDs have presented evidence of mucosal damage in the small bowel. Graham and colleagues performed a CE study in arthritic patients who had been using NSAIDs for at least 3 months and showed an incidence of small intestinal mucosal injury as high as 71% [31]. In healthy volunteers, Maiden and colleagues reported that slow-release diclofenac use for 2 weeks resulted in macroscopic injury to the small intestine in 68 to 75% of subjects [32]. In addition, Goldstein and colleagues reported that 2 weeks of naproxen plus omeprazole ingestion induced smallbowel mucosal breaks in 55% of volunteers [33].
Growing evidence indicates that ASA can also damage the lower GI tract. A systematic review reported an increase of fecal blood loss (0.5 to 1.5 ml/day) in lowdose ASA users (<325 mg) [34]. A study in healthy volunteers has shown that even enteric-coated ASA was associated with development of erosions and ulcers in 50% of volunteers [35]. Th e clinical signifi cance of these fi ndings is not yet clear.
Evidence suggests that COX-2 selective inhibitors are associated with fewer mucosal lesions of the small bowel than are ns-NSAIDs plus a PPI in CE studies performed in healthy subjects [36,37]. Th e Celecoxib versus Omeprazole and Diclofenac in Patients with Osteoarthritis and Rheumatoid Arthritis (CONDOR) trial reported recently that the risk of clinically signifi cant events from both the upper and lower GI tract were almost four times lower in at-risk osteoarthritis and rheuma toid arthritis patients treated with celecoxib 200 mg twice daily when compared with those receiving slow-release diclofenac 75 mg twice daily plus omeprazole 20 mg/day [38].

Subclinical and clinical pictures
Th e prevalence of NSAID-related lower GI adverse eff ects, including both clinical and subclinical manifestations, may exceed those detected in the upper GI tract and include a wide spectrum of lesions.

Anemia and blood loss
In long-term NSAID users, continuous and mild blood loss produced by NSAID enteropathy may result in iron defi ciency and anemia. No studies have been performed to determine the exact burden and clinical impact of this problem in patients taking NSAIDs or ASA. Furthermore, in many instances, there is no close relationship between demonstrable lesions on the upper GI tract and GI blood loss [39]. Morris and colleagues showed that 47% of NSAID users for rheumatoid arthritis with chronic iron defi ciency anemia who had negative gastroscopy and colonoscopy fi ndings had small-bowel ulcerations, and they concluded that this could be the reason for the development of anemia [40]. Moore and colleagues performed a systematic review including 1,162 subjects and found that most NSAIDs and ASA (325 mg) resulted in a small average increase in fecal blood loss of 1 to 2 ml/ day from about 0.5 ml/day at baseline [34]. Some individuals lost much more blood than average, 5% of those taking NSAIDs had daily blood loss ≥5 ml and 1% had dialy blood loss higher than 10 ml. For ASA at daily doses ≥1,800 mg, the rates of daily blood loss of 5 ml/day or 10 ml/day were 31% and 10%, respectively.

Infl ammation and increased permeability
Th e development of increased gut permeability and mucosal infl ammation are the most frequent abnormalities in NSAID users [41]. Increased gut permeability can be seen as soon as 12 hours after the ingestion of single doses of most NSAIDs, but it is not observed in NSAIDs without enterohepatic recirculation (nabumetone, ASA) [41][42][43][44]. Short-term studies with COX-2 selective inhibitors have shown that these agents do not increase intestinal permea bility [45,46]. Some studies have found that NSAIDs increase fecal calprotectin in rheumatoid arthritis or osteoarthritis patients taking NSAIDs [47].  Th ese tests have shown that intestinal infl ammation is present in 60 to 70% of patients taking NSAIDs and that, once established, it may be detected up to 1 to 3 years after the long-term NSAID use has been stopped. Small intestine permeability is necessary for the subsequent development of small intestine infl ammation, which is associated with blood and protein loss, but it is often silent [48].

Mucosal ulceration
CE and enteroscopic studies have shown that NSAID use induces erythema, mucosal hemorrhage, erosions and intestinal ulceration in the small bowel, confi rming previous autopsy data [49,50]. Some reports suggest that this type of lesion can be seen in up to 40% of rheumatic NSAIDs users [31,50]. Colonoscopy studies have also shown that NSAID intake is associated with isolated colonic ulcers, diff use colonic ulceration that could be associated with occult bleeding, major GI bleeding and/ or perforation [51][52][53].

Major complications
Lanas and colleagues reported in the early 1990s that 86% of patients admitted to hospital with lower GI bleeding had evidence of recent (<7 days) NSAID or ASA use [52,53], and a similar scenario was found later with intestinal perforation [53]. Recently, the presence of severe clinical side eff ects of the lower GI tract associated with NSAID use were confi rmed by post-hoc analysis of diff erent RCTs [54][55][56].
Current evidence shows contradictory results concerning the safety of COX-2 selective inhibitors because posthoc analyses of the Vioxx Gastrointestinal Outcomes Research (VIGOR) and MEDAL trials have reported diff erent results. In the VIGOR trial, lower GI events were as frequent as upper GI events, and the benefi ts of rofecoxib 50 mg/day over naproxen (500 mg twice daily) were present in both the upper and the lower GI tract, with a similar risk reduction of 50% and 60%, respectively [54]. However, in the MEDAL trial, although the incidence of lower GI events exceeded that seen in the upper GI tract (patients were advised to take PPIs if they had risk factors), there were no benefi ts of etoricoxib over diclofenac when looking at the incidence of lower GI complications [30]. CONDOR trial recently found that the risk of clinically signifi cant outcomes throughout the entire GI tract were lower in patients treated with celecoxib 200 mg twice daily compared with those patients taking slow-release diclofenac 75 mg twice daily plus omeprazole 20 mg/day [38]. Th e authors concluded the need to review the actual preventive strategies for chronic NSAID users.
Another clinical side eff ect associated with NSAID use in the lower GI tract is complicated diverticular disease. A systematic review found a positive association of compli cated diverticular disease with ns-NSAID use [57]. Wilcox and colleagues reported that the risk for lower GI bleeding among patients taking NSAIDs was 2.6 times higher compared with nonuse (95% CI, 1.7 to 3.9) [58]. Th e specifi c risk for diverticular bleeding was increased 3.4-fold (95% CI, 1.9 to 6.2) in NSAID users.

Nonsteroidal anti-infl ammatory drug-related mortality
Patients developing an upper and lower GI complication are at risk of dying [59]. Th is risk is probably higher in older people [60] and/or in people with co-morbidities and/or with large ulcers in the posterior duodenal bulb or on the lesser curvature. Th e reported peptic ulcer bleeding-related mortality rates range from 5 to 12%. Most studies from the United States, Europe, and Asia place that fi gure closer to 5% than to 12% [27,29,61].
A recent study published by Sonnenberg looking at the time trends of ulcer disease in a representative sample of six European countries concluded that the risk of death from gastric and duodenal ulcers increased among consecutive generations born during the second half of the nineteenth century until shortly before the turn of the century and then decreased in all subsequent generations [62]. Th e increase in NSAID consumption or intro duction of potent anti-secretory medications has not aff ected the long-term downward trends of ulcer mortality.
A recent Spanish population-based study looking at patients hospitalized because of GI adverse events between 1998 and 2006 reported that, overall, there was a statistically signifi cant decrease in the sex-standardized and age-standardized mortality rate owing to a decrease in the number of patients hospitalized because of GI events over time [27]. When stratifi ed by source, the decrease was not present in patients with lower GI events. However, the case fatality rate did not change over the study period for all types of GI complication events. One should note that the mean age of fatal cases remained constant during the study period. Th e authors concluded that the reduction observed in mortality associated with hospitalizations because of GI events was due to the observed decreased rate of upper GI events, probably associated with our ability to prevent those complications [15,63]. One should also highlight that recent publications note that most peptic ulcer bleedingrelated deaths are not a direct consequence of the bleed ing ulcer itself. Instead, mortality derives from cardiopulmonary conditions, multiorgan failure or terminal malignancy, suggesting that improving treat ments of the bleeding ulcer may aff ect mortality very little [64].
Recognition of these associations is essential for the improvement of therapeutic strategies that focus not only on the GI tract, but also on providing supportive care and preventing complications and key-organ failure. Th e identifi cation of non-GI risk factors associated with poor outcomes in peptic ulcer bleeding patients and a multidisciplinary approach for high-risk patients should help to reduce this outcome.

Key messages
• Th e presence of upper GI symptoms (dyspepsia and refl ux) is not predictive of the occurrence of GI complications. •

Competing interests
AL is consultant or has received research grants from AstraZeneca, Pfi zer, and Bayer. CS and CJG declare that they have no competing interests.

Declaration
This article has been published as part of Arthritis Research & Therapy Volume 15 Suppl 3, 2013: 'Gastroprotective NSAIDS' . The full contents of the supplement are available online at http://arthritis-research.com/ supplements/15/S3. The supplement was proposed by the journal and developed by the journal in collaboration with the Guest Editor. The Guest Editor assisted the journal in preparing the outline of the project but did not have oversight of the peer review process. The Guest Editor serves as a clinical and regulatory consultant in drug development and has served as such consultant for companies which manufacture and market NSAIDs including Pfi zer, Pozen, Horizon Pharma, Logical Therapeutics, Nuvo Research, Iroko, Imprimis, JRX Pharma, Nuvon, Medarx, Asahi. The articles have been through the journal's standard peer review process. Publication of this supplement has been supported by Horizon Pharma Inc. Duexis (ibuprofen and famotidine) is a product marketed by the sponsor.