Carla J. Gargallo

Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely prescribed medication in the world. Their main benefit derives from their anti-inflammatory and analgesic effect, but the use of these agents is not innocuous since they mainly increase the risk of gastrointestinal (GI) and cardiovascular complications compared with non-NSAID users. NSAIDs injures the upper and lower gut by depleting COX-1 derived prostaglandins and causing topical injury to the mucosa. The risk of upper GI complications varies, depending on the presence of one or more risk factors. Among them, the three main risk factors are prior history of peptic ulcer, the single most important risk factor, age, the most common, and concomitant aspirin use, due to their GI and cardiovascular implications. Those individuals at-risk should be considered for alternatives to NSAID therapy and modifications of risk factors. If NSAID therapy is required, patients at risk will need prevention strategies including co-therapy of NSAID with gastroprotectants (PPI or misoprostol) or the prescription of COX-2 selective inhibitors. The probable introduction of NO-NSAIDs in the market in the near future may open a new therapeutic option for patients with hypertension who need NSAIDs.

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.

Aspirin, cyclooxygenase inhibition and colorectal cancer

Colorectal cancer (CRC) is the third most common type of cancer worldwide. Screening measures are far from adequate and not widely available in resource-poor settings. Primary prevention strategies therefore remain necessary to reduce the risk of developing CRC. Increasing evidence from epidemiological studies, randomized clinical trials and basic science supports the effectiveness of aspirin, as well as other non-steroidal anti-inflammatory drugs, for chemoprevention of several types of cancer, including CRC. This includes the prevention of adenoma recurrence and reduction of CRC incidence and mortality. The detectable benefit of daily low-dose aspirin (at least 75 mg), as used to prevent cardiovascular disease events, strongly suggests that its antiplatelet action is central to explaining its antitumor efficacy. Daily low-dose aspirin achieves complete and persistent inhibition of cyclooxygenase (COX)-1 in platelets (in pre-systemic circulation) while causing a limited and rapidly reversible inhibitory effect on COX-2 and/or COX-1 expressed in nucleated cells. Aspirin has a short half-life in human circulation (about 20 minutes); nucleated cells have the ability to resynthesize acetylated COX isozymes within a few hours, while platelets do not. COX-independent mechanisms of aspirin have been suggested to explain its chemopreventive effects but this concept remains to be demonstrated in vivo at clinical doses.

Interaction between Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs and/or low-dose aspirin use: Old question new insights

Previous reports clearly demonstrated that Helicobacter pylori (H. pylori) infection, nonsteroidal anti-inflammatory drugs (NSAID) or low dose aspirin (ASA) use significantly and independently increased the risk for the development of peptic ulcer disease. Today, the presence of H. pylori infection associated with low dose ASA and/or NSAID use in the same patient is becoming more frequent and therefore the potential interaction between these factors and the consequences of it has important implications. Whether NSAID intake in the presence of H. pylori infection may further increase the risk of peptic ulcer carried by the presence of only one risk factor is still a matter of debate. Studies on the interaction between the two risk factors yielded conflicting data and no consensus has been reached in the last years. In addition, the interaction between H. pylori infection and low-dose ASA remains even more controversial. In real clinical practice, we can find different clinical scenarios involving these three factors associated with the presence of different gastrointestinal and cardiovascular risk factors. These huge variety of possible combinations greatly hinder the decision making process of physicians.

Is NSAIDs-related gastrointestinal damage preventable?

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are some of the most commonly used drugs worldwide; however, they are not innocuous. The spectrum of upper gastrointestinal (GI) tract damage caused by NSAIDs has been well established, and strategies to prevent this have been widely studied and implemented. Removing modifiable risk factors, the selection of less toxic NSAIDs and treatment with gastroprotective drugs, if necessary, are the main strategies employed. However, injury of the NSAIDs‐related lower GI tract remains poorly characterized. In the last decade, there has been an increasing interest in this field and the search for effective preventive treatments is under way. Use of cyclooxygenase‐2 inhibitor, prostaglandin, antibiotic or drugs that are not yet commercially available such as nitric oxide‐releasing and hydrogen sulfide (H2S)‐releasing NSAIDs compounds seem to reduce lower GI injury, but more evidence are needed before any of them are recommended in high‐risk patients.

Balancing the risk and benefits of low-dose aspirin in clinical practice.

Antiplatelet agents are widely used in primary and secondary prevention of cardiovascular events. The scientific evidence has provided strong support for the benefits of aspirin in decreasing the risk of cardiovascular events in a wide range of pathologies. The relatively rare occurrence of major bleeding complications should not be underestimated, mainly due to its high morbi-mortality. The assessment of both gastrointestinal risk and cardiovascular benefits of low-dose aspirin for any individual patient may be difficult in clinical practice. In this review, we summarize the evidence supporting the efficacy of aspirin and the risks of side effects due to hemorrhagic complications. This article proposes a unifying framework for application to help the clinician in the decision making process of individuals who have different risk of cardiovascular and bleeding events with different examples. Finally, new developments in the field directed towards individualized risk assessment strategies are described.

Gastrointestinal lesions and complications of low-dose aspirin in the gastrointestinal tract

Low dose aspirin (ASA) use has been associated with a wide range of adverse side effects in the upper gastrointestinal (GI) tract, which range from troublesome symptoms without mucosal lesions to more serious toxicity, including ulcers, GI bleeding, perforation and even death. Upper GI symptoms in low dose ASA users are common but often careless or misinterpreted and they are not always related to the presence of mucosal injury. Usually, low dose ASA related ulcers are reasonably small and asymptomatic, and probably heal over a period of weeks to a few months. But, the real clinical problem occurs when the ulcer results in a GI complication (mostly bleeding). The estimated average excess risk of symptomatic or complicated ulcer related to low dose ASA is five cases per 1000 ASA users per year. Death is the worst outcome of GI complications in low dose ASA users, but data about this aspect are scarce. Current evidence indicates that low dose ASA can damage the lower GI tract also, but the real size of the problem is still unknown.

Prevention and Treatment of NSAID Gastropathy

Opinion statementNonsteroidal anti-inflammatory drug (NSAID) treatment will be necessary as part of our therapeutic armamentarium for many years to come. Therefore, safe prescription is mandatory in order to prevent adverse events. In the last two decades, new strategies and new drugs have been developed to reduce NSAID-associated upper gastrointestinal (GI) adverse events. Although the implementation of guidelines into clinical practice takes time, several studies have shown a recent and profound decrease in hospitalizations due to upper GI complications, which has been linked to widespread use of proton pump inhibitors (PPIs), better NSAID prescription, and decreased prevalence of Helicobacter pylori infection. This is encouraging.Safe NSAID prescription should be straightforward since the most relevant aspects are clinical in nature. Before issuing any prescription, three key questions should be considered:1) Is NSAID treatment necessary for this patient?2) What cardiovascular (CV) and GI risk factors does this patient have?3) What is the most suitable NSAID for this patient?GI and CV risk are easy to estimate, and we know that these risks are not the same for all NSAIDs. Selective cyclooxygenase (COX)-2 inhibitors, like celecoxib at usual doses, carry the lowest GI risk and are the best option in patients with moderate/high GI risk without high CV risk. Gastroprotective therapy (PPI as the drug of choice) should be considered if a non-selective NSAID is prescribed. For those at the highest risk, a combination of PPI plus a coxib is the best option. Also, eradication of H. pylori infection in patients with previous peptic ulcer or in NSAID-naïve users must be considered. Naproxen is the best option in patients with high CV risk and low/moderate GI risk.Patients taking aspirin represent a real challenge for treatment, since interaction with frequently prescribed NSAIDs (e.g. ibuprofen/naproxen) may alter its antiplatelet effect, representing a potential clinical problem. Switching treatment (e.g. taking aspirin before NSAID dosing) may not be an alternative since interaction may persist, especially when taking enteric-coated aspirin. Changing NSAID treatment to diclofenac/celecoxib/etoricoxib may also not be an option in patients with high or previous CV event history. Under these circumstances, careful prescription should be considered at the individual patient level.When dyspepsia develops in an NSAID user, PPI co-therapy plus reduction of the NSAID dose or a change in the type of NSAID are valid alternatives, but clinical experience shows that, for some patients, stopping NSAID therapy may be the only option. After a bleeding episode, most patients can be managed with alternative therapy to NSAIDs, but if needed, a coxib plus a PPI and H. pylori eradication is a safe alternative.

Drug-related damage of the ageing gastrointestinal tract

Drug use increases with age and the elderly is at increased risk of adverse drug reactions. Gastrointestinal adverse effects are one of the most often reported. Serious event are mostly caused by NSAIDs and/or aspirin which are the most widely prescribed medications in the world. NSAIDs and/or aspirin use are associated with complications from both the upper and the lower gastrointestinal tract. The risk of these complications depends on presence of risk factors, and age is the most frequent and relevant one. At-risk patients should be on prevention strategies including the use of the lowest effective dose, co-therapy with a gastroprotective agents or use of a COX-2 selective agent. Treatment of Helicobacter pylori infection is beneficial in patients starting therapy with these agents, especially in the presence of ulcer history. The best strategy to prevent lower GI complications has yet to be defined.

Management of low-dose aspirin and clopidogrel in clinical practice: a gastrointestinal perspective

Low-dose aspirin, alone or combined with other antiplatelet agents, is increasingly prescribed for cardiovascular prevention. However, the cardiovascular benefits should be evaluated together with the gastrointestinal risks. Low-dose aspirin is associated with upper and lower gastrointestinal injury, although lower gastrointestinal effects are poorly characterized. This gastrointestinal risk differs among antiplatelets drugs users. The most important risk factors are history of peptic ulcer, older age, and concomitant use of non-steroidal anti-inflammatory drugs or dual antiplatelet therapy. Effective upper gastrointestinal prevention strategies are available and should be used in at-risk patients taking low-dose aspirin or clopidogrel. Proton pump inhibitors seem to be the best gastroprotective agents, whereas the benefits of Helicobacter pylori eradication are still unclear. Low-dose aspirin has additional effects in the gastrointestinal tract. A large body of evidence indicates that it can protect against different cancers, in particular colorectal cancer. This effect could modify the future indications for use of low-dose aspirin and the risk–benefit balance.