Dovepress events, occurring in 5%–20% of NSAID-treated patients, include dyspepsia, diarrhea, and other gastric disturbances. Dyspeptic symptoms do not always correlate with develop- ment of ulcers, which in many cases have no discernible symptoms.5,13 Although associated with lower morbidity and mortality than perforations, ulcers, and bleeds, dyspeptic symptoms are distressing to many patients, frequently lead- ing to costly symptomatic therapies and diagnostic studies, and may negatively affect adherence.13 Current measures to reduce the risk of gastrointestinal events when using oral NSAID therapy include concomitant use of agents such as misoprostol, as well as agents from the proton pump inhibitor class to suppress NSAID-associated increases in gastric acid secretion.13 Data from comparative studies have demonstrated that proton pump inhibitors are therapeutically superior to misoprostol, a prostaglandin E1 analog, for this purpose.13,18 A strong evidence base exists for use of proton pump inhibitors with NSAIDs to protect against both short-term and long-term gastrointestinal effects.13 For example, in one study in which a proton pump inhibitor was added to naproxen plus low-dose (cardioprophylactic) aspirin, endoscopic findings were comparable with those in patients on treatment with celecoxib plus low-dose aspirin.19 However, long-term use of proton pump inhibitors is also associated with risks, including a dose-related increase in risk of osteoporotic hip fractures among older adults.20 As with other multidrug regimens, the addition of a proton pump inhibitor to NSAID-based therapy increases the cost to the patient, as well as the risk of nonadherence.5,21 Nonadherence to proton pump inhibitors among patients receiving oral NSAID therapy is particularly problematic, because the most serious gastric adverse events associated with oral NSAID therapy are often asymptomatic.5,13 Patients with no symp- toms may assume that the proton pump inhibitor is unneces- sary and may be more likely to be noncompliant, when they may be at high risk for gastrointestinal bleeding. In addition to direct drug costs and adherence, gas- tropathy adds increased costs to the health care system.22 It is estimated that more than 100,000 hospitalizations and 10,000–20,000 deaths each year in the US can be attributed to NSAID-related complications.23 The costs of excess hos- pitalizations have been estimated at $4 billion annually,24 not to mention the indirect costs of NSAID gastropathy, such as lost productivity.25 Oral NSAIDs are likely to have more cost associated with adverse events than topical NSAIDs.26 In a randomized trial by Castelnuovo et al comparing the cost- effectiveness of topical and oral ibuprofen for knee pain, the total cost of drugs was lower in the topical group. The initial Clinical Interventions in Aging 2011:6 Nonsteroidal anti-inflammatory drug gastropathy lower cost of oral NSAID therapy was displaced by the higher cost of other drugs to treat gastrointestinal and cardiovascular side effects.27 Rahme et al conducted a literature review to summarize data that evaluated the direct costs of NSAID- related gastrointestinal adverse effects worldwide. The results showed that the events attributable to nonselective NSAIDs were substantial and that their costs far exceeded the cost of the nonselective NSAID itself.28 The level of gastrointestinal risk varies with the specific oral NSAID used. Agents with long half-lives, such as piroxicam, are associated with greater risk of gastrointesti- nal bleeding and perforation because, in the face of lower renal excretion in the elderly, cumulative systemic NSAID exposure is much greater over time.29 Patient factors also modulate risk, in that older adults, especially those with a history of ulcers or concurrent use of aspirin, steroids, or anticoagulants, are at increased risk for these gastrointestinal events.5,8 The shrunken gastric microvasculature in older individuals increases their risk for ulcer bleeds, even in the absence of other risk factors.5 The risk of gastrointestinal adverse events can be reduced by the use of COX-2 selective agents, although their selectivity and impact on overall risk diminishes at increased doses.30,31 In addition, these agents are themselves associated with adverse effects, such as an increased risk of thrombotic cardiovascular events.32,33 Cardiovascular adverse events Both COX-2 selective and nonselective oral (systemic) NSAIDs confer significant cardiovascular risks, although these events occur far less frequently compared with gastropathy.2,12,34 It has been postulated that the cardio- vascular effects of NSAIDs result from an imbalance between the effects of thromboxane and prostacyclin on the endothelium.8 Based on the relative rates of cardiovascular adverse events with oral NSAIDs, five characteristics have emerged as key mediators of cardiovascular risk potential, ie, COX-2 selectivity, dose, longer plasma half-life, effect on blood pressure, and interaction with concomitant aspirin that may potentially reduce the cardioprotective (antiplatelet) effects of the drug.34 Rofecoxib, a COX-2 selective agent, was withdrawn from the global market in 2004 after it was shown to increase the risk of acute myocardial infarction and other cardiovascular events significantly.8 Level of risk varies among the oral NSAIDs that remain on the market, including nonselective NSAIDs. Data from a study that evaluated cardiovascular outcomes in Medicare patients who were receiving oral NSAID therapy demonstrated that, among the nonselective submit your manuscript | www.dovepress.com Dovepress 127