Peptic ulcer disease (PUD) is a huge problem in the United States. It is estimated that the cost of managing PUD is $5.65 billion dollars per year. This figure accounts for time out of work, hospitalization, and outpatient care excluding medication costs. The main risk factors leading to PUD include Helicobacter pylori infection, smoking, and the use of non-steroidal anti-inflammatory drugs (NSAIDs).¹
The NSAIDs make up one of the most commonly prescribed classes of medications worldwide.² There is a 25% chance that a chronic NSAID user will develop some type of ulcer disease while taking the medication. This is especially apparent in patients who chronically take oral non-selective NSAIDs. The risk of GI bleeds appears to be highest with ketorolac, and then in decreasing order, piroxicam, indomethacin (Indocin, others), naproxen (Aleve), ketoprofen, meloxicam (Mobic, others), diclofenac (Voltaren, Solaraze, others),³and ibuprofen (Advil, Motrin, others). The first 5 NSAIDs are more cyclooxygenase (COX)-1 selective, meloxicam and diclofenac are more COX-2 selective, and ibuprofen is nonselective.
Inhibition of COX-1, which is required to synthesize prostaglandins, may be the cause of NSAID-related gastrointestinal (GI) ulcers. Without the mucosal protective prostaglandins, stomach acid, bile salts, and enzymes may be more likely to cause direct damage.⁴ In recent years, pharmaceutical companies have produced COX-2-selective NSAIDs that are less toxic to the GI tract; however, this benefit must be weighed against a potentially heightened risk of cardiovascular problems. Celecoxib (Celebrex) is the only COX-2-selective product still on the market.
Who is At Risk?
Risk factors for an NSAID-related GI bleed include: previous GI bleed, age >60 years, concomitant use of an anticoagulant, corticosteroids, concomitant NSAIDs (including lose-dose aspirin), and cardiovascular disease. A separate factor that is harder to qualitatively determine is Helicobacter pylori infection.² The tests used to determine if a patient has a H. pylori infection include either a biopsy, or a breath, blood, or stool sample.⁵ In patients requiring long-term NSAID therapy, it is sometimes beneficial for patients to undergo testing to determine whether they have the infection. Eradication of the H. pylori infection has been found to be beneficial in preventing ulcers in patients requiring long-term NSAID therapy.³
Preventive Therapy
In patients who require chronic NSAID therapy but who may have an increased risk for ulcers, protective agents may be used concomitantly. The most common agents available for prevention of NSAID-related GI ulcers include misoprostol (Cytotec, others), histamine 2 receptor antagonists (H²RAs), and proton pump inhibitors (PPIs).²˒³
Misoprostol was the first agent approved for the prevention of NSAID-related ulceration. It is a synthetic prostaglandin E1 analog that is a potent inhibitor of gastric acid secretion. Unfortunately, this medication is associated with bothersome adverse events (AEs) and a frequent dosing schedule. The common AEs of misoprostol include GI cramping and diarrhea, and the medication must be taken 4 times a day, leading to reduced compliance.³ The average wholesale price for this medication is approximately $80 per month when it is taken as directed.⁶ Arthrotec, an agent released in 1997, combines diclofenac 50 mg or 75 mg and misoprostol 200 mcg into a single tablet.⁷ The average wholesale price for this product is approximately $260 per month.⁶
H²RAs (such as cimetidine [Tagamet, others], famotidine [Pepcid, others], and ranitidine [Zantac, others]) are gastroprotective due to their ability to inhibit the action of histamine on the parietal cells of the stomach, thereby reducing the amount of gastric acid produced.⁸ These medications are indicated to be taken twice daily and have a lower incidence of AEs compared to misoprostol.³ The average wholesale price of these medications is roughly $10 per month, depending on which agent is used.⁶ Recently, a newer agent Duexis (ibuprofen 800 mg and famotidine 26.6 mg) became available in the United States. This agent is intended to decrease the pill burden of the NSAID plus a protective agent,⁹ but it comes at a high price: the average wholesale price for this newer agent is approximately $800 per month.⁶
PPIs (such as omeprazole [Prilosec, others], esomeprazole [Nexium, others], lansoprazole [Prevacid, others], dexlansopraxole [Dexilant], pantoprazole [Protonix, others], and rabeprazole [Aciphex]) target a specific enzyme—hydrogen-potassiumadenosinetriphosphatase—to inhibit gastric acid secretion. Most PPIs are indicated to be taken once daily because of their long half-lives.¹⁰ The average wholesale price of a generic PPI, such as omeprazole, is approximately $20 per month, but the cost of a brand name product, such as Dexilant, may cost more than $180 for a month supply.⁶ In 2010, the FDA approved a new combination NSAID and PPI product called Vimovo. This product contains naproxen 375 mg or 500 mg in combination with esomeprazole 20 mg.¹¹ The average wholesale cost of this medication is $800 per month.⁶
How Effective Are These Products?
A Cochrane review conducted by Rostom et al included 41 randomized controlled trials that evaluated the effectiveness of misoprostol, H²RAs, or PPIs for the prevention of NSAID-induced GI ulceration.² The authors concluded that misoprostol significantly reduced the risk for ulceration compared to placebo. It found that misoprostol in doses of 800 mcg/day and 400 mcg/day reduced the risk of GI ulceration by 83% and 61%, respectively, when compared to placebo.
Koch et al also conducted a meta-analysis investigating H²RAs versus misoprostol for the prevention of ulcers. This study included 24 trials evaluating the efficacy of H²RAs compared to misoprostol and found misoprostol to be the more efficacious agent. The results of this study concluded that long-term use of misoprostol reduced the chance of a gastric ulcer by 13% (>4 wk) and short-term use (<2 wk) decreased the risk by 8%, whereas H²RAs did not reduce the risk. The risk of duodenal ulcers among long-term NSAIDs users was reduced by 3% with misoprostol and 2% with H²RAs.¹²
Leandro et al conducted a third meta-analysis that included 21 studies comparing misoprostol, H²RAs, and PPIs.13 They concluded that PPIs and misoprostol were both more effective than H²RAs for the prevention of NSAID-related GI ulceration. They also found that misoprostol was slightly more efficacious than PPIs but that misoprostol’s AEs and dosing schedule were problematic for patients. The study found that misoprostol, H²RAs, and PPIs reduced the risk of gastric ulceration by 69%, 38.3%, and 43%, respectively, and decreased duodenal damage by 22.3%, 13.2%, and 17.7%, respectively.
A study conducted by de Groot et al incorporated potential costs in Quality-Adjusted Life Years (QALYs) in the analysis of an NSAID/PPI single-tablet formulation, an NSAID/H²RA single-tablet formulation, and an NSAID/misoprostol single-tablet formulation, as well as an NSAID given separately in combination with misoprostol, an H²RA, or a PPI.¹⁴ The QALY value represents the cost saved and the cost associated with the quality of life yet to be lived. With respect to QALY, de Groot et al found that using NSAID and PPI agents, in separate formulations but in combination, was the most cost-effective method of preventing GI bleeds associated with NSAID use. The probability of the separate NSAID and PPI products being cost effective was 57%, compared to the probability with a separate NSAID plus H²RA products (17%) and the NSAID and PPI single tablet (13%). Misoprostol, combination misoprostol plus NSAID, and combination H²RA plus NSAID also were included in the analysis; however these options were not found to be cost effective.
Conclusion
For patients at risk of developing an NSAID-induced ulcer who require chronic NSAID therapy, a COX-2 selective agent may be considered in patients without cardiovascular risk. If a preventive therapy is required, misoprostol and PPIs have been found to be more effective than H²RAs. PPIs have a lower pill burden and fewer GI adverse effects compared to misoprostol, which has led to cost efficacy data supporting their use. When determining which agent is most suitable for a particular patient, the price, AEs, and efficacy all must be taken into consideration. Patient-specific factors related to adherence and insurance coverage of agents should be considered to determine the best preventive treatment option for that patient.