The incidence of peptic ulcer disease has declined due to the discovery of effective acid suppressive therapy and the eradication of Helicobacter pylori, but it continues to be an important clinical disorder due to the increasingly widespread use of NSAIDs and low-dose aspirin. Ulcers are found on upper gastrointestinal endoscopy in up to one-third of regular NSAID users, and every year about 1–2% of these patients develop a symptomatic ulcer and ulcer complications . Apart from gastrointestinal risks, all NSAIDs with the possible exception of naproxen also carry potential cardiovascular hazard . Recommendations on the use of NSAIDs according to individual patients' gastrointestinal and cardiovascular risks have therefore become a recent focus of discussion amongst health care physicians and many consensus bodies [3•]. Current evidence indicates that a cyclooxygenase (COX)-2-selective NSAID and a proton pump inhibitor (PPI) provide the best gastric protection . In patients with high gastrointestinal risk on aspirin, PPI cotherapy is recommended . In the last 12 months, further advances have been achieved in many aspects of NSAID use; these include a better understanding of the pathogenesis of NSAID-induced gastrointestinal injury, which could potentially lead to new gastroprotective derivatives, the introduction of new surrogate endpoints to assess gastrointestinal effects of NSAIDs not only in the upper gastrointestinal tract but also in the mid- and lower gastrointestinal tract, the potential role of histamine H2 antagonists in the prevention of peptic ulcers in NSAID users, and further refinement of strategies balancing the gastrointestinal and cardiovascular risk of NSAIDs. Furthermore, as we accumulate more data regarding the potential interaction between PPI and clopidogrel, new recommendations for healthcare providers and patients have been proposed. This brief review summarizes key research articles in the last year aimed at addressing the above issues. For a more comprehensive overall review of the topic, readers are referred to recent published reviews and updated practice guidelines [6–9].
Types of NSAIDs and their related gastrointestinal and cardiovascular risks
Physicians prescribing NSAIDs are currently confronted with the challenge of balancing not only the analgesic and anti-inflammatory potency against the gastrointestinal toxicity, but also the cardiovascular risk for an individual patient in relation to the widely contrasting cardiovascular effects of different classes of NSAIDs. A recent Spanish study showed that the risks of gastrointestinal complications from NSAIDs vary according to the type of NSAIDs and the dosage administered. In a systematic review of nine observational studies published between 2000 and 2008, compared with NSAIDs with a shorter half-life, those with a long half-life or slow-release formulation were associated with an overall higher risk of gastrointestinal complications. For instance, relative risk of upper gastrointestinal bleeding or perforation was 4.50 for traditional NSAIDs and 1.88 for celecoxib [10•], whereas rofexoxib increased the risk of ulcer bleeding by more than four-fold compared with placebo in a colorectal adenoma chemoprevention trial . NSAID-associated upper gastrointestinal toxicity is likely to be the result of two pharmacologic characteristics: exposure to the drug and the sparing of COX-1 activity. Both COX-2 selective and nonselective NSAIDs increase the risk of cardiovascular events, suggesting that the mechanism of cardiovascular toxicity is not solely explained by unopposed COX-2 inhibition. In the randomized double-blind MEDAL study of 23 504 patients with osteoarthritis and rheumatoid arthritis, etoricoxib showed comparable efficacy and similar cardiovascular risk to diclofenac but had a better gastrointestinal tolerability profile . Overall, factors including the dose and duration of NSAIDs, and the patient's baseline cardiovascular and gastrointestinal risks, can contribute to the magnitude of adverse effects of NSAIDs.
Mechanisms of NSAID-induced gastrointestinal toxicities
NSAIDs induce gastrointestinal cytotoxicity through the inhibition of COX enzyme activity, which has been well established. Recently, novel pathways, independent of COX inhibition, have been identified for some NSAIDs. Investigators from Texas showed that the cytotoxicity induced by NSAIDs may relate, in part, to their ability to bind and disrupt cell membranes. In vitro, exposure of gastric epithelial cells to different concentrations of NSAIDs resulted in altered cell membrane permeability with profound and rapid changes in cell morphology and cell size on confocal microscopy, suggesting that cytotoxicity and biological actions of NSAIDs are mediated by the cell membrane and not dependent on COX [13•]. In a separate series of elegant experiments by the Duke Medical team, mast-cell-deficient KitW-sh/W-sh (Sash) mice, wild-type and tumour necrosis factor (TNF)-deficient mice were given three different NSAIDs and examined for the presence of gastrointestinal ulceration. Significantly more mast-cell-deficient Sash mice developed gastric ulcers and gastric outlet obstruction (83 and 70%, respectively) when exposed to a non-COX-specific NSAID, piroxicam, compared with both wild-type (31 and 0%) and TNF-deficient mice (36 and 9%). Reconstitution of mast cells reverses ulcer susceptibility, independent of TNF, suggesting that the ulcerogenic effect of piroxicam may relate to inhibition of cell proliferation. Thus mast cells may play a critical role in the repair of NSAID-induced gastric epithelial injury . The renin angiotensin system may also play an important role in the development of upper gastrointestinal mucosal injury induced by low-dose aspirin. Patients treated with angiotensin-1 receptor blockers or angiotensin-converting enzyme inhibitors and low-dose aspirin have a reduced risk of peptic ulcers or ulcer bleeding . New mechanisms associated with NSAID-induced gastric ulcers and bleeding could lead to novel treatments for gastric damage induced by these drugs, and eventually more sophisticated risk management.
Composite endpoints to assess NSAID-related gastrointestinal risk
NSAIDs are known to cause stomach, small-bowel and colonic damage . Compared with NSAID-related upper gastrointestinal toxicity, the risk of NSAIDs on the lower gastrointestinal tract has been less well characterized. Nonetheless, with the emergence of technologies such as wireless capsule endoscopy and double balloon enteroscopy, growing evidence suggests that NSAIDs not only cause damage to the upper gastrointestinal tract but also can affect the lower gastrointestinal tract. Until recently, there has been no endpoint that evaluates serious gastrointestinal events in the entire gastrointestinal tract. A new composite that measures damage to the gastrointestinal tract known as Clinically Significant Upper and Lower Gastrointestinal Events in patients receiving NSAIDs has recently been proposed. This endpoint extends the traditional bleeding, perforation and obstruction assessment of upper gastrointestinal complications to events in the small and large bowel. For example, ‘clinically significant anaemia of presumed occult gastrointestinal origin’ including possible small-bowel blood loss has now been included as an endpoint. Although this assessment may be limited by the lack of confirmation of small-bowel blood loss because a diagnosis for a fall in haemoglobin is usually based on clinical judgement and the exclusion of other causes of anaemia, it is anticipated that, by providing clinicians with a descriptive tool for adverse events throughout the gastrointestinal tract, this composite endpoint can potentially become the gold standard for evaluating the gastrointestinal effects of a range of therapies .
Risk factors for NSAID-related complications
Risk factors for NSAID-related gastrointestinal complications include advanced age, a previous gastrointestinal event, higher dose of NSAIDs, the concomitant use of anticoagulants or corticosteroids, and cardiovascular disease . Low-dose aspirin is also associated with a definite risk of peptic ulcer and upper gastrointestinal bleeding, although how this risk compares with that of other NSAIDs is unclear. In a systematic review of 48 studies published between 1990 and 2009, the risk for upper gastrointestinal bleeding was increased by two-fold to three-fold with the use of low-dose aspirin. This risk was further increased in patients taking concomitant NSAIDs (three-fold), and in those with a previous history of ulcer (2.1-fold to four-fold) or upper gastrointestinal bleeding (4.4-fold to 8.7-fold). The concomitant use of low-dose aspirin with anticoagulants or NSAIDs further increased this bleeding risk [18•]. When the incidence of gastroduodenal ulcers in placebo arms of NSAID trials over the last three decades was examined, previous gastrointestinal events and concurrent treatment with low-dose aspirin or corticosteroids was associated with increasing peptic ulcers and gastrointestinal bleeding in placebo arms .
Data on whether the dose and/or duration of aspirin influence the risk of gastrointestinal bleeding have been limited and inconsistent. In a recent population-based study of 87 680 female nurses with no history of gastrointestinal bleeding or ulcers followed over a period of 24 years, regular aspirin users (at least two 325 mg tablets/week) had a relative risk of 1.42 in developing gastrointestinal bleeding compared with aspirin nonusers. A dose-dependent effect of aspirin on the risk of gastrointestinal bleeding regardless of the length of aspirin use was observed and increasing duration of aspirin use did not increase bleeding risk. Attempts to use the lowest effective dose in both short-term and long-term users may minimize these adverse effects .
Two meta-analyses showed that concurrent H. pylori infection increased the risk of peptic ulcer bleeding in NSAID users [21,22]. NSAIDs and H. pylori synergistically induce duodenal ulcers . Conversely, Hart et al. recently showed that H. pylori infection may partially protect against aspirin-induced gastric erosions. One potential explanation could be that H. pylori results in loss of parietal cells and reduction in the stomach's ability to produce acid, and, as acid acts as a cofactor in aspirin or NSAID-induced gastroduodenal damage, reduction in acid protects against gastric injuries. On the basis of findings from a recent observational study from Japan, female patients older than 70 years of age on low-dose aspirin had a significantly increased risk for the development of peptic ulcers (odds ratios of 8.44) and a significantly shorter time to diagnosis of aspirin-associated peptic ulcer when compared with males. It was speculated that the gradual drop in female sex hormones postmenopause in women coupled with reduced gastric mucosal defenses may be responsible for this increased risk .
Strategies to reduce NSAID-associated gastrointestinal and cardiovascular risks
Given the vast number of people taking NSAIDs for arthritis and prophylactic aspirin for cardiovascular events, any modulation of risk factors for NSAID-induced injury will be important. A recent Spanish study showed that most patients requiring NSAIDs had high prevalence of gastrointestinal and cardiovascular risk factors. In a series of 3265 consecutive patients with osteoarthritis, more than 80% of patients were at increased gastrointestinal risk and over half of the patients had a high cardiovascular risk [26,27].
Two main strategies have been employed to prevent the development of gastrointestinal mucosal injury in NSAID users: cotherapy with a high-dose H2 antagonist, a PPI, or a synthetic prostaglandin analogue, misoprostol; or substitution of a traditional NSAID with a COX-2 inhibitor. Patients with no gastrointestinal risk factors should receive traditional NSAIDs. Patients with gastrointestinal risks may receive either NSAID with PPI/misoprostol or a celecoxib alone. For patients with high gastrointestinal risk factors who need NSAIDs, including those with a prior bleeding ulcer, or on concurrent anticoagulant therapy, COX-2 inhibitor plus a PPI provide the most promising gastrointestinal protection . In these patients, H. pylori should be tested for and treated if present. Patients with a high cardiovascular risk but lower gastrointestinal risk should receive naproxen with a PPI/misoprostol. Patients with both high gastrointestinal and cardiovascular risks should be considered for alternative therapies to traditional NSAIDs or celecoxibs. Although COX-2 inhibitor plus a PPI provide the most promising gastrointestinal protection in patients at high risk of ulcer bleeding, fewer than 50% of NSAID users with gastrointestinal risk factors were given protective cotherapy, even when prescribers were reminded and cost was not an issue . Additional strategies including effective educational tools aimed at both prescribers and patients are likely to be needed to improve adherence to recommendations.
In patients with low or medium risk of gastrointestinal bleed, it is currently unclear whether COX-2 inhibitors alone will be as good as, if not better than, a nonselective NSAID plus PPI. Moreover, current guidelines recommend the use of COX-2 selective NSAIDs or nonselective NSAIDS plus a PPI to reduce the likelihood of upper gastrointestinal adverse events, but do not account for adverse events beyond the duodenum. To address this gap in clinical knowledge, a multicentre randomized controlled trial was recently conducted at 196 centres across 32 countries which randomized 4484 patients with osteoarthritis or rheumatoid arthritis to 6 months of treatment with either celecoxib 200 mg twice daily or diclofenac sustained-release 75 mg twice daily plus omeprazole 20 mg once daily. This is the first trial with predefined composite endpoints including gastroduodenal, small-bowel or large-bowel haemorrhage or perforation, gastric-outlet obstruction and anaemia. Patients taking diclofenac plus omeprazole were more likely to suffer upper or lower gastrointestinal damage (3.8 versus 0.9%, respectively) and to have clinically significant upper and lower gastrointestinal events, than patients on celecoxib (81 versus 10 events, respectively). This difference in the primary endpoint was related mainly to anaemia. More symptomatic ulcers were found in the diclofenac plus PPI group than in the celecoxib group (11 versus five). The study was limited by the 6-month duration of treatment; hence the results cannot be extrapolated to long-term celecoxib or diclofenac treatment. Longer follow-up will also be necessary to assess the true cardiovascular risk of the drugs. Nevertheless, the results have great relevance to clinical practice because they showed the importance of a haemoglobin drop associated with NSAID use, even when the patient is asymptomatic [29••].
In a recent double-blind randomized study, 880 Asian patients who suffered from osteoarthritis or rheumatoid arthritis with minimal risk factors were randomized to celecoxib 100 mg twice daily or diclofenac 50 mg twice daily. The incidence of gastric ulcers was significantly lower in patients on celecoxib compared with those on diclofenac (0.5 versus 3.6%) at 3 months. These observations suggest that ulcers develop over a short period of time, and that low-dose celecoxib is associated with a modest reduction in the incidence of gastric ulcers as early as 3 months [30•].
H2 antagonist therapy for the prevention of peptic ulcers
With the recent concern over the safety of PPI and the risk of interaction of PPI with clopidogrel, an alternative treatment option, including the use of H2 antagonist therapy, has been proposed. H2 antagonists were effective in the prevention and treatment of aspirin-induced peptic ulcers in Japanese patients . It is, however, unknown whether H2 antagonist cotherapy is as effective as PPI in reducing aspirin-induced gastrointestinal injury. Famotidine has been shown to reduce the development of duodenal but not gastric ulcers in patients using NSAIDs [32••,33]. The recent FAMOUS (famotidine for the prevention of peptic ulcers in patients receiving conventional NSAIDs) trial reported that famotidine 20 mg twice daily can reduce the development of oesophagitis, gastric and duodenal ulcers by 80% in an average-risk population on aspirin, when compared with placebo. No patients with H. pylori developed ulcers whilst on famotidine, and no interaction of famotidine with clopidogrel was observed [32••]. In contrast, a separate study from Hong Kong showed that high-dose famotidine (40 mg twice daily) was inferior to pantoprazole (20 mg daily) in the prevention of gastroduodenal ulcers in patients at high risk of aspirin-related ulcers. Recurrent symptomatic or bleeding ulcers (20 versus 0%) and gastrointestinal bleeding (7.7 versus 0%) were more common in patients on famotidine than in those on pantoprazole [34••].
Continuation of NSAID postendoscopic therapy in upper gastrointestinal bleed
Whether aspirin should be continued after endoscopic haemostasis in patients who had peptic ulcer bleeding whilst taking low-dose aspirin for cardiovascular or cerebrovascular diseases has been unclear. In a recent randomized, placebo-controlled trial from our centre, early resumption of aspirin following endoscopic haemostasis increased the risk for recurrent bleeding at 1 month (10 versus 5%), but potentially reduced all-cause mortality rates (1 versus 10%). Although larger trials are needed to confirm our findings, early resumption of low-dose aspirin with PPI in patients with peptic ulcer bleed and cardiovascular disease should be seriously considered. One potential strategy will be to resume aspirin at 3–5 days after index bleed or stabilization. Despite rapid clearance of aspirin from the circulation when discontinued, permanent inactivation of the platelets' COX activity on prostaglandin synthesis implies that antiplatelet effects of aspirin may last for at least a few days, and continue to confer a protective cardiovascular effect . Future studies should aim to address the optimal time to restart antiplatelet therapy after endoscopic haemostasis [36•].
Interaction between antiplatelets and proton pump inhibitors
An American joint consensus report recommends the use of prophylactic PPI in patients receiving aspirin plus clopidogrel to reduce gastrointestinal bleeding . Recently, some [38–40], but not all [41–45], observational studies have shown that some PPIs can reduce the efficacy of the antiplatelet activity of clopidogrel, leading to an increased risk of cardiovascular events (odds ratio 1.25–1.5). Clopidogrel is an inactive prodrug that is metabolized to its active component by P450 enzymes. It was hypothesized that PPI competitively inhibits the hepatic cytochrome P450 enzyme, CYP2C19, resulting in less inhibition of platelet aggregation and increased risk of myocardial infarction and coronary stent thrombosis in clopidogrel users . The use of PPI was also associated with either death or rehospitalization due to acute coronary syndrome . Both the United States Food and Drug Administration (FDA) [47,48] and the European Medicines Agency (EMEA)  have announced that PPI should be avoided in patients on clopidogrel. This recommendation has not been supported by prospective trials of PPI–clopidogrel interaction on cardiovascular adverse outcomes . Preliminary data from a randomized double-blind controlled trial of omeprazole versus placebo in clopidogrel and aspirin users, terminated early due to bankruptcy of the sponsor before reaching target sample size, demonstrated no difference in cardiovascular events between the two groups [51•]. Patients taking clopidogrel and PPI had a significant decrease in gastrointestinal complications. In support of this observation, a large retrospective cohort study using automated data from the Tennessee Medicaid program showed that the concurrent use of PPI in patients with coronary heart disease on clopidogrel was associated with fewer hospitalizations for gastroduodenal bleeding, with no increase in serious cardiovascular disease, compared with non-PPI users [52••].
In clinical practice, when faced with a patient on clopidogrel for high risk of coronary stent thrombosis who needs a PPI, one strategy to eliminate this potential negative interaction will be to administer PPI and clopidogrel at different times of the day. Both PPI and clopidogrel have relatively short half-lives of 1–2 and 4–6 h, respectively. Thus separation of 12–15 h between the two drugs should theoretically prevent any competitive inhibition of CYP metabolism and avoid any unwanted clinical effects. We suggest taking PPI before breakfast and clopidogrel after dinner. There is currently no convincing evidence to show that one PPI is clearly different from another, so switching between PPIs may not be sufficient to avoid the potential risk. Alternatively, H2 antagonist can be used instead of a PPI. Although H2 antagonist decreases endoscopic ulcers, there are no randomized trials to document that this therapy reduces gastrointestinal bleeding in aspirin users .
Novel gastroprotective derivatives to prevent NSAID-related intestinal injury
Several novel approaches to develop gastrointestinal-sparing NSAIDs have been explored, with promising preclinical and clinical results. Transdermal phosphatidylcholine has shown promise, and COX-inhibiting nitric oxide donators have demonstrated a favourable gastrointestinal profile in some but not all patients. A novel hydrogen sulphide-releasing NSAID derivative, which has similar anti-inflammatory effects to NSAIDs but with markedly reduced gastrointestinal toxicity, has been identified by researchers from Canada. A cytoprotective agent, rebamipide, was superior to placebo for the prevention of diclofenac-induced small intestinal mucosa injury , whereas geranylgeranylacetone failed to prevent aspirin-induced small-bowel mucosa injury in healthy volunteers .
Our understanding of the therapeutic combinations associated with NSAID-induced upper and lower gastrointestinal damage is expanding, as is our knowledge of the therapies that hold promise to prevent it. Guidelines recommend that selection of NSAID therapy should be driven by consideration of both cardiovascular and gastrointestinal effects of treatment. Gastrointestinal complications associated with the use of NSAIDs, in high-risk patients, are often caused by the concomitant use of aspirin or multiple NSAIDs, a failure to identify patients' risk factors and the underutilization of gastroprotective agents. Gastroprotection includes the use of PPI in patients at high risk of gastrointestinal bleeding and the eradication of H. pylori in patients with previous ulcer history. In high-risk patients, communication between gastroenterologists, cardiologists and primary care physicians may sometimes be necessary to weigh the ischaemic and bleeding risk in an individual patient. In average risk patients on NSAIDs, famotidine appears to be a good alternative to PPI. A new mechanism of NSAID-induced injury has been developed, and novel therapeutic approaches to gastrointestinal protection against NSAIDs are currently under investigation. Current evidence does not support the conclusion that PPI reduces the efficacy of clopidogrel, and more controlled studies are necessary to confirm this potential association.
No funding has been received for the publications. Francis K.L. Chan has received paid lecture fees from Pzifer, Takeda and Astrazeneca.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 673–674).
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. Unfortunately, this study was prematurely stopped before adequate sample size due to bankruptcy of the sponsor.
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