NSAIDs-induced gastrointestinal damage. Review

Non-steroidal anti-inflammatory drugs (NSAIDs), along with analgesics, are the most widely prescribed medication in the world. However, NSAIDs cause numerous side effects, being the gastrointestinal (GI) events the most common ones with an increase of risk of serious GI complications between 2.5- and 5-fold, as compared with individuals not taking NSAIDs. Factors that increase the risk for serious events in NSAID-using patients include a history of ulcer or ulcer complications, advanced age (=or>65 years), the use of high-dose NSAIDs, more than one NSAID, anticoagulants or corticosteroid therapy. If NSAID therapy is required, we must balance GI and cardiovascular risk and the therapy should be prescribed at the lowest possible dose and for the shortest period of time. The use of NSAID without gastroprotective co-therapy is considered appropriate in patients<65 years, not taking aspirin and having no GI history. In patients with GI risk factors, but no cardiovascular risk, coxibs or NSAIDs plus proton pump inhibitor (PPI) or misoprostol are valid options. Patients with a history of ulcer bleeding should receive coxib plus PPI therapy and should be tested and treated for Helicobacter pylori infection. Coxib therapy has better GI tolerance than traditional NSAIDs and PPI therapy is effective both in treatment and prevention of NSAID-induced dyspepsia and should be considered in patients who develop dyspepsia during NSAID or coxib therapy.     

NSAID‐induced gastrointestinal damage: Current clinical management and recommendations for prevention

Gastrointestinal toxicity is a common adverse effect of traditional non‐steroidal anti‐inflammatory drugs (NSAIDs) and patients at risk should receive prevention therapies. Selective cyclooxygenase‐2 (COX‐2) inhibitors (coxibs) are safer to the gastrointestinal tract than traditional NSAIDs. Current prevention strategies in patients who need NSAIDs should also take into account the presence of cardiovascular risk factors, as coxibs and probably most traditional NSAIDs increase the incidence of serious cardiovascular events. Patients without risk factors should be treated with traditional NSAIDs, whereas patients at risk may receive cotherapy with a proton pump inhibitor (PPI) or misoprostol, or a coxib alone. However, patients with a previous bleeding ulcer should receive the combination of a coxib plus a PPI, and Helicobacter pylori should be tested for and treated if present. Coxib and NSAID therapy should be prescribed with caution in patients with increased cardiovascular risk and should be prescribed at the lowest possible dose and for the shortest period of time. These patients will probably be treated with low‐dose aspirin or other antiplatelet agents, which puts them at increased risk of upper gastrointestinal complications. The risk of gastrointestinal toxicity with combined therapy of aspirin and coxib may be lower than that with traditional NSAIDs plus aspirin, but all these patients may benefit from PPI cotherapy. When the lower gastrointestinal tract is of concern, coxib instead of NSAID therapy should be considered. Coxib therapy has better gastrointestinal tolerance than traditional NSAIDs and PPI therapy is effective both in the treatment and prevention of NSAID‐induced dyspepsia and should be considered in patients who develop dyspepsia during NSAID or coxib therapy.     

NSAID-induced gastrointestinal damage: current clinical management and recommendations for prevention

Gastrointestinal toxicity is a common adverse effect of traditional non-steroidal anti-inflammatory drugs (NSAIDs) and patients at risk should receive prevention therapies. Selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) are safer to the gastrointestinal tract than traditional NSAIDs. Current prevention strategies in patients who need NSAIDs should also take into account the presence of cardiovascular risk factors, as coxibs and probably most traditional NSAIDs increase the incidence of serious cardiovascular events. Patients without risk factors should be treated with traditional NSAIDs, whereas patients at risk may receive cotherapy with a proton pump inhibitor (PPI) or misoprostol, or a coxib alone. However, patients with a previous bleeding ulcer should receive the combination of a coxib plus a PPI, and Helicobacter pylori should be tested for and treated if present. Coxib and NSAID therapy should be prescribed with caution in patients with increased cardiovascular risk and should be prescribed at the lowest possible dose and for the shortest period of time. These patients will probably be treated with low-dose aspirin or other antiplatelet agents, which puts them at increased risk of upper gastrointestinal complications. The risk of gastrointestinal toxicity with combined therapy of aspirin and coxib may be lower than that with traditional NSAIDs plus aspirin, but all these patients may benefit from PPI cotherapy. When the lower gastrointestinal tract is of concern, coxib instead of NSAID therapy should be considered. Coxib therapy has better gastrointestinal tolerance than traditional NSAIDs and PPI therapy is effective both in the treatment and prevention of NSAID-induced dyspepsia and should be considered in patients who develop dyspepsia during NSAID or coxib therapy.     

NSAIDs and the gastrointestinal tract

NSAIDs incur significant gastrointestinal (GI) side effects. The complication risk increases with history of peptic ulcer or older age. Helicobacter pylori infection and cardioprotective aspirin have independent and additive risks in the presence of NSAID use. NSAID enteropathy is increasingly recognized. Cardiovascular and GI risk stratification and H. pylori infection testing should be done before initiating NSAIDs. An NSAID combined with a proton pump inhibitor (PPI) is comparable to cyclooxygenase (COX)-2 inhibitors for gastroprotection, but for high-risk patients, COX-2 plus PPI should be considered. Aspirin and COX-2 inhibitors are associated with reduced colon adenoma risk, but higher dose and longer duration of treatment with aspirin appears effective. Hence, patients at high risk of colorectal cancer (with significant family or personal history of premalignant adenoma) must be identified, and cardiovascular and GI risk must be assessed before using these agents as chemopreventive drugs.     

The David Y. Graham lecture: use of nonsteroidal antiinflammatory drugs in a COX-2 restricted environment

Recent evidence suggests that both cyclooxygenase-2 (COX-2) inhibitors and nonselective NSAIDs, with the possible exception of naproxen, increase cardiovascular (CV) hazard. Clinicians should assess not only patients' GI risk but also their CV risk before prescribing these drugs. Patients with low CV risk can be managed according to their GI risk—low-risk patients (without risk factors) receive nonselective NSAIDs, medium risk patients (1–2 risk factors) receive COX-2 inhibitors or nonselective NSAIDs plus a proton pump inhibitor (PPI) or misoprostol, whereas high-risk patients (multiple risk factors, previous ulcer complications, or concomitant anticoagulants) receive a COX-2 inhibitor plus a PPI or misoprostol. Among patients with high CV risk ( e.g. , prior cardiothrombotic events) who require NSAIDs, naproxen is preferred. These patients should receive a prophylactic PPI or misoprostol because the risk of ulcer bleeding is substantially increased with concomitant use of naproxen and low-dose aspirin. Substitution of clopidogrel for aspirin is not recommended in patients at risk for upper GI bleeding who require antiplatelet therapy. Patients with high GI and high CV risk should avoid NSAIDs and COX-2 inhibitors. If antiinflammatory analgesics are required, the choice of therapy depends on the relative importance of GI and CV risks of individual patients. Combination of naproxen, low-dose aspirin, and a PPI or misoprostol is recommended if CV risk is the major concern ( e.g. , recent myocardial infarction). In contrast, combination of low-dose COX-2 inhibitor, low-dose aspirin, and a PPI or misoprostol is preferred if GI risk outweighs CV risk ( e.g. , recent ulcer bleeding and stable CV disease).     

Proton pump inhibitor co-therapy with nonsteroidal anti-inflammatory drugs--nice or necessary?

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory, analgesic, and anti-pyretic effects, whereas low-dose aspirin (also an NSAID) is used for cardiovascular prophylaxis. The main concern limiting use of these drugs is their gastrointestinal (GI) toxicity. GI side effects include ulcers (found at endoscopy in 15%-30% of patients using NSAIDs regularly), complications such as upper GI bleeding (annual incidence of 1.0%-1.5%), and development of upper GI symptoms such as dyspepsia (occurring in up to 60% of patients taking NSAIDs). Histamine-2 receptor antagonists are not effective at preventing NSAID-induced gastric ulcers when used at standard doses, although they can decrease upper GI symptoms. Misoprostol effectively decreases NSAID-induced ulcers and GI complications but is used infrequently in the United States-perhaps because of issues of compliance (multiple daily doses) and side effects (eg, diarrhea, dyspepsia). Once-daily proton pump inhibitor (PPI) therapy also decreases the development of NSAID-associated ulcers and recurrent NSAID-related ulcer complications; it also decreases upper GI symptoms in NSAID users. In patients using aspirin, the addition of a cyclooxygenase-2-specific inhibitor appears to significantly increase GI risk to the level of a nonselective NSAID; aspirin plus a nonselective NSAID appears to increase GI risk still higher. Patients taking low-dose aspirin who have risk factors for GI complications (including concomitant nonselective NSAID therapy) should receive medical co-therapy, such as a PPI.     

Minimizing complications from nonsteroidal antiinflammatory drugs: cost-effectiveness of competing strategies in varying risk groups

OBJECTIVE: To appraise the cost-effectiveness of competing therapeutic strategies in patient cohorts eligible for aspirin prophylaxis with varying degrees of gastrointestinal (GI) and cardiovascular risk. METHODS: Cost-effectiveness and cost-utility analyses were performed to evaluate 3 competing strategies for the management of chronic arthritis: 1) a generic nonselective nonsteroidal antiinflammatory drug (NSAID(NS)) alone; 2) NSAID(NS) plus a proton pump inhibitor (PPI); and 3) a cyclooxygenase 2-selective inhibitor (coxib) alone. Cost estimates were from a third-party payer perspective. The outcomes were incremental cost per ulcer complication avoided and incremental cost per quality-adjusted life year (QALY) gained. Sensitivity analysis was performed to evaluate the impact of varying patient GI risks and aspirin use. RESULTS: In average-risk patients, the NSAID(NS) + PPI strategy costs an incremental 45,350 US dollars per additional ulcer complication avoided and 309,666 US dollars per QALY gained compared with the NSAID(NS) strategy. The coxib strategy was less effective and more expensive than the NSAID(NS) + PPI strategy. Sensitivity analysis revealed that the NSAID(NS) + PPI strategy became the dominant approach in patients at high risk for an NSAID adverse event (i.e., patients taking aspirin with > or =1 risk factor for a GI complication). CONCLUSION: Generic nonselective NSAIDs are most cost-effective in patients at low risk for an adverse event. However, the addition of a PPI to a nonselective NSAID may be the preferred strategy in patients taking aspirin or otherwise at high risk for a GI or cardiovascular adverse event.     

Primer: managing NSAID-induced ulcer complications--balancing gastrointestinal and cardiovascular risks

Ulcer complications associated with the use of NSAIDs, in high-risk patients, are often caused by a failure to identify patients' risk factors, concomitant use of aspirin or multiple NSAIDs, and underutilization of gastroprotective agents. Current data suggest that cyclo-oxygenase 2 (COX2) inhibitors and some nonselective NSAIDs increase the risk of myocardial infarction. Physicians must, therefore, take into account both the gastrointestinal and the cardiovascular risks of individual patients when prescribing NSAIDs. In patients with a low cardiovascular risk, NSAIDs can be prescribed according to the level of gastrointestinal risk. Patients with a moderate gastrointestinal risk (one or two risk factors) should receive a COX2 inhibitor or an NSAID plus a PPI or misoprostol. Patients with more than two gastrointestinal risk factors or prior ulcer complications require the combination of a COX2 inhibitor and a PPI. Patients with a high cardiovascular risk (e.g. coronary heart disease or an estimated 10-year cardiovascular risk greater than 10%) should receive prophylactic aspirin and combination therapy with a PPI or misoprostol irrespective of the presence of gastrointestinal risk factors. Naproxen is the preferred NSAID because it is not associated with excess cardiovascular risk. Patients with a high cardiovascular risk and a very high gastrointestinal risk should avoid using NSAIDs or COX2 inhibitors.     

Prevention of NSAID-induced ulcers

Opinion statement Cyclooxygenase-2 (COX-2) selective inhibitors were developed as gastrointestinal (GI) safer alternatives to nonselective NSAIDs—providing equivalent analgesic and anti-inflammatory efficacy. Their GI sparing is impaired by concomitant aspirin use, and concerns regarding adverse cardiovascular effects have emerged. Risk factors for NSAID-related complications include a history of ulcer disease or bleeding, concomitant corticosteroid or anticoagulant therapy, use of high-dose or multiple NSAIDs (including low-dose aspirin), advanced age, and certain chronic diseases. If an NSAID must be used in a patient at risk, the lowest-risk NSAID should be used with, in many cases, cotherapy to reduce the risk for ulcers. COX-2 drugs have been associated with a significantly higher risk of vascular events than placebo or naproxen. This increase may be shared by nonselective NSAIDs and appears to be medication-and dose-dependent. Prostaglandin depletion is a central mechanism for NSAID ulcer development, and replacement therapy with misoprostol reduces NSAID toxicity; however, it is rarely used due to side effects. The acid suppression provided by traditional doses of histamine 2-receptor antagonists (H₂RAs) does not prevent most NSAID-related gastric ulcers. Despite a single study demonstrating that H₂RAs at double the dose may be effective, studies comparing such high doses with misoprostol or proton pump inhibitors (PPIs) for preventing NSAID ulcers are not available. PPIs are effective at single daily doses, do not demonstrate tachyphylaxis, and are superior to H₂RAs and misoprostol in reducing ulcers and NSAID-associated dyspepsia. NSAID choice should be predicated by an assessment of an individual’s cardiovascular and GI risk. For those with competing cardiovascular and GI risks, the tradeoffs between reducing adverse GI events (COX-2 inhibitor instead of a nonselective NSAID) must be explicitly weighed against concerns about cardiovascular side effects (naproxen instead of other agents). Considering cost is appropriate because it may not be feasible to recommend the “safest” regimen in every circumstance. The cost effectiveness of risk-reducing therapies is intimately tied to the patient’s underlying risk. For those at highest GI risk, using a PPI and a low-dose COX-2 inhibitor seems appropriate for those without high cardiovascular risk. For patients whose cardiovascular risk parallels or exceeds GI concerns, naproxen with a PPI is recommended when non-NSAID approaches fail.     

Acid-NSAID/aspirin interaction in peptic ulcer disease

The presence of gastric acid plays a critical role in the mechanisms of NSAIDs/aspirin-associated gastric and duodenal mucosal injury and ulceration. The role of gastric acid and its relationship to NSAIDs/aspirin in mucosal damage, ulcer and ulcer complications continues to be an important concern because of the increasing worldwide use of NSAIDs and aspirin. Acid suppression continues to be an important prevention strategy for NSAID-associated gastric and duodenal ulcer and ulcer complications. While a coxib or an NSAID and PPI in combination are considered to have comparable safety profiles, the evidence from direct comparisons in high-risk patients is limited, and the cardiovascular safety of coxibs and NSAIDs remains a concern especially in patients with a high risk of cardiovascular disease. An evaluation of individual gastrointestinal and cardiovascular risks and benefits, selection of the most appropriate NSAID and dose for each particular patient should always be emphasized. Twice daily PPI is more appropriate to protect a patient who is taking NSAIDs twice daily. PPI co-therapy is still recommended in patients receiving dual antiplatelet treatment, although conflicting results have been reported about adverse drug interactions between PPIs and clopidogrel.     

Gastro-duodenal protection in an era of cyclo-oxygenase-2-selective nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective and necessary for the relief of pain and inflammation in patients with arthritis. NSAIDs are however also associated with an increased risk for ulceration in the stomach and in the duodenum, and many NSAID users experience bothersome dyspeptic symptoms during continued NSAID therapy. PPIs like omeprazole, have been shown to heal and to prevent ulcers and dyspeptic symptoms during continued NSAID therapy, and during continued NSAID therapy the prostaglandin analogue, misoprostol, has been shown to reduce the risk for ulcer complications. The COX-2 selective NSAID, rofecoxib, is in comparison with naproxen, a non-selective NSAID, associated with fewer clinically important upper gastrointestinal events. The incidence of myocardial infarctions seems, however, to be lower with naproxen than with rofecoxib, and this is expected to lead to low-dose aspirin use in rofecoxib users at risk for cardiovascular events. Co-administration of the COX-2 selective NSAID, celecoxib, and low-dose aspirin, is associated with the same risk for upper gastrointestinal ulcer complications alone and combined with symptomatic ulcers, as the non-selective NSAIDs, ibuprofen and diclofenac. A proton pump inhibitor (PPI) should be used for healing of NSAID-associated ulcers, and a PPI or misoprostol should be considered for prevention of ulceration in non-selective NSAID users at risk for ulceration. The experience with COX-2 selective NSAIDs is still limited, and it remains to be studied whether subpopulations of COX-2 selective NSAID users will benefit from gastro-duodenal protection.     

Gastrointestinal and cardiovascular risks of nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed but can have serious gastrointestinal (GI) and cardiovascular side effects, which have led to the withdrawal of some of these drugs and continuing uncertainty about the best approach to patients requiring NSAID therapy, particularly in those with GI or cardiovascular risk factors. To define the risks to the GI and cardiovascular systems associated with NSAID therapy, we have undertaken a series of systematic reviews of original articles published between January 1995 and December 2006. In this article we describe the mechanisms and patterns of GI and cardiovascular side effects in NSAID-taking patients and identify a range of drug and patient factors that contribute to an increased risk of adverse events. We conclude that NSAID therapy should not be started unless it is essential, and that Helicobacter pylori eradication should be considered in patients at increased GI risk. We discuss the use of gastroprotective agents and provide practical advice to help physicians assess and balance both cardiovascular and GI risks and benefits in their prescribing decisions.     

Recommendations for the appropriate use of anti-inflammatory drugs in the era of the coxibs: defining the role of gastroprotective agents.

Treatment with anti-inflammatory drugs and the analgesic efficacy of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are compromised by a two- to fourfold increased risk of gastrointestinal complications. This increased risk has resulted in an increasing use of the new selective cyclooxygenase-2 inhibitors or coxibs, which, in clinical trials and outcomes studies, reduced gastrointestinal adverse events by 50% to 65% compared with conventional NSAIDs. However, the coxibs are not available to all patients who need them, and NSAIDs are still widely used. Moreover, treatment with a coxib cannot heal pre-existing gastrointestinal lesions, and cotherapy with an anti-secretory drug or mucosal protective agent may be required. This paper addresses the management of patients with risk factors for gastrointestinal complications who are taking NSAIDs and makes recommendations for the appropriate use of 'gastroprotective' agents (GPAs) in patients who need to take an NSAID or a coxib. When economically possible, a coxib alone is preferable to a conventional NSAID plus a GPA to minimize exposure to potential gastrointestinal damage and avoid unnecessary dual therapy. Patients at high risk require a GPA in addition to a coxib.     

A COX-2-specific inhibitor plus a proton-pump inhibitor: is this a reasonable approach to reduction in NSAIDs' GI toxicity?

The two prevailing approaches to decrease risks of nonsteroidal anti-inflammatory drug (NSAID)-associated gastrointestinal (GI) events are the use of a COX-2 inhibitor or co-therapy with a proton-pump inhibitor (PPI). A major limitation of each approach is that, in patients at the highest risk for NSAID-induced ulcers, neither treatment is effective when used as a stand-alone strategy. An important question is whether combination therapy with a COX-2 inhibitor plus a PPI has improved GI safety compared to a traditional NSAID plus a PPI. This study evaluated high GI risk patients who were taking, along with their NSAID or COX-2 inhibitor, either the PPI, esomeprazole, or the placebo. It confirms that our current approach of adding PPIs to reduce NSAIDs' ulcer risks is an effective strategy. However, this study did not show a safety advantage for using a COX-2 inhibitor instead of a traditional NSAID in high GI risk patients who take PPIs. Thus, there continues to be no prospective data to support a GI benefit of COX-2 inhibitor plus a PPI over traditional NSAID plus a PPI in high-risk patients.     

Channeling and prevalence of cardiovascular contraindications in users of cyclooxygenase 2 selective nonsteroidal antiinflammatory drugs

OBJECTIVE: To assess use and channeling of cyclooxygenase 2 selective inhibitors (coxibs) over time and to estimate the percentage of coxib users with cardiovascular contraindications. METHODS: The study population comprised all coxib and nonselective nonsteroidal antiinflammatory drug (NSAID) users in the Integrated Primary Care Information project between January 2000 and December 2004. The prevalence of risk factors for NSAID-related upper gastrointestinal ulcer complications, cardiovascular disease, and cerebrovascular disease at the start of treatment was compared between users of coxibs and users of nonselective NSAIDs. RESULTS: The study population included 72,841 nonselective NSAID users and 10,739 coxib users. The prevalence of risk factors for NSAID-related gastrointestinal complications was higher in coxib users than nonselective NSAID users (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 1.10-1.26). Similarly, the prevalence of prior cardiovascular disease was higher in coxib users than in nonselective NSAID users (OR 1.35, 95% CI 1.28-1.43). Channeling of coxibs to patients with NSAID-related gastrointestinal risk factors declined after 2001 but increased again in 2004, whereas the channeling of coxibs to patients with cardiovascular disease remained constant. Less than 15% of all coxib users had history of ischemic coronary or cerebrovascular disease. Among coxib users with increased risk for NSAID-related gastrointestinal disorders, 27% had history of ischemic coronary or cerebrovascular disease. CONCLUSION: This study demonstrates that coxibs were preferentially prescribed to patients with risk factors for NSAID-related gastrointestinal disorders and/or cardiovascular diseases. Only one-quarter of coxib users with increased risk for NSAID-related gastrointestinal complications had cardiovascular conditions compatible with recent European safety contraindications for coxibs.