A patient came to me recently with a list of her medications and their prices as quoted by her pharmacy. She had been taking most of the drugs for some time, but one was new: esomeprazole (Nexium, AstraZeneca). She had a long history of hoarseness and had recently developed a cough-both atypical symptoms of gastroesophageal reflux disease (GERD). After ruling out other possible causes, her physician diagnosed GERD and prescribed esomeprazole. At her pharmacy, the quoted price for a one-month supply of 30 capsules was more than $150-a cost equivalent to the combined costs of her other medications, most of which were available as generics. She told me she could not afford the new drug and asked, "What should I do?"
Esomeprazole, a proton pump inhibitor (PPI), is one of five in its drug class. Sold under the brand name Nexium, it's widely recognized by consumers as "the purple pill" and has been prescribed frequently since the U.S. Food and Drug Administration (FDA) approved it in 2001; more than 23 million prescriptions for Nexium were written in 2004. 1 Its predecessor, omeprazole (Prilosec, AstraZeneca), is now available in a generic form and, since June 2003, over the counter (Prilosec OTC, now manufactured by Procter and Gamble). The cost of over-the-counter omeprazole is significantly less than that of esomeprazole. I wanted to help my patient, but I needed to research this topic more before making a recommendation.
DIAGNOSIS AND MANAGEMENT OF GERD
GERD affects more than 61 million Americans at least once monthly, according to a survey cited by the American Gastroenterological Association (AGA). 2 It's estimated that from 25% to 35% of Americans will have GERD at some point in their lives, according to a literature review. 3 GERD may be diagnosed by the presence of typical symptoms (such as heartburn and acid reflux), atypical symptoms (such as chest pain, hoarseness, and chronic cough), or a combination of these, as well as by response to a trial of acid suppression therapy. 4 Erosive esophagitis, a complication, must be confirmed by endoscopy. Other possible complications of GERD are esophageal stricture; esophageal ulcer; and Barrett esophagus, a precursor of esophageal adenocarcinoma. 2 Patients presenting with signs of complicated GERD (such as gastrointestinal bleeding, dysphagia, weight loss, and vomiting) or with a history of symptoms lasting more than five years should be referred to a gastroenterologist for diagnosis. 4
According to updated guidelines issued by the American College of Gastroenterology, initial treatment should include lifestyle modifications (such as smoking cessation, dietary changes, and weight loss), although little evidence exists that such changes alone are effective. Antacids and histamine-2 receptor antagonists (H2 blockers) may help in milder cases of GERD. 5 But the disease tends to be chronic, and relapse is common; many patients require long-term, maintenance drug therapy. Research indicates that PPIs are a safe and effective means of acid suppression, achieving better gastric acid control for longer duration than do H2 blockers. 4, 6 They provide more rapid symptom relief and are more effective at healing damaged tissue. 5 For these reasons the use of PPIs in GERD management has become prominent.
THE PPIs
In 1989 omeprazole (Prilosec) was the first PPI to win FDA approval; it was followed by lansoprazole (Prevacid, TAP Pharmaceutical Products), rabeprazole (Aciphex, Eisai Inc.), and pantoprazole (Protonix, Wyeth-Ayerst). The newest PPI is esomeprazole (Nexium); it received FDA approval in 2001. 7
How they work.
All of the PPIs are approved for the treatment of GERD and erosive esophagitis. All act to inhibit stomach acid production by the proton pumps of parietal cells. PPIs are prodrugs, a class of drugs that are inactive until converted to a usable drug through metabolism. Because PPIs are activated by stomach acid, they're most effective when taken preprandially (in general, about 30 to 60 minutes before eating 4). Because their effect on proton pumps is irreversible, acid production is restored only when new proton pumps are made. Acid suppression may last as long as three days. 6
Of the PPIs, all except omeprazole are classified as pregnancy risk category B; omeprazole is pregnancy risk category C. (Omeprazole has been linked with increased fetal death rates in rats and rabbits, according to AstraZeneca's product literature, but no adequate and well-controlled studies in pregnant women have been performed. (For brief descriptions of the FDA's pregnancy categories, see http://www.fda.gov/fdac/features/2001/301_preg.html#categories.) Because the safety of the PPIs in human pregnancy has not been established, pregnant patients should be advised against their use. All are present in breast milk and should not be taken by nursing mothers. 6
Omeprazole versus esomeprazole.
For several reasons, this discussion focuses primarily on a comparison of omeprazole and esomeprazole. First, it appears that the five available PPIs have similar efficacy and safety profiles. A 2001 literature review by Berardi reported that differences in acid control among patients receiving omeprazole, lansoprazole, rabeprazole, or pantoprazole "have not resulted in clinically important differences in efficacy in patients with GERD." 6 A more recent review by Hellstrom and Vitols that included studies involving esomeprazole reached the same conclusion. 8 Moreover, there have been very few studies comparing one PPI to another at comparable dosages; a study cited by Hellstrom and Vitols, comparing esomeprazole to omeprazole, is a notable exception. 8
Finally, AstraZeneca's advertising has focused on establishing the superiority of Nexium, its most expensive PPI. Yet, among currently available PPIs, only Prilosec OTC offers significant cost savings. According to Red Book: Pharmacy's Fundamental Reference, the average wholesale price for a 30-day supply of Prilosec OTC 20 mg is about $20; a 30-day supply of a comparable dosage of any of the prescription brands costs between $114 and $150. 9 An informal comparison of retail prices at Internet and brick-and-mortar pharmacies, conducted by the author at this writing, yielded similar results.
Esomeprazole is the S-isomer of omeprazole, whereas omeprazole is a mixture of both S- and R-isomers. (Isomers are chemical compounds with identical molecular formulas but different spatial arrangements; the prefixes S and R- refer to these different arrangements.) Thus omeprazole and esomeprazole have slightly different pharmacokinetics, with esomeprazole demonstrating slightly greater bioavailability (68%) than omeprazole (65%) with continued daily dosing at 20 mg, according to studies cited by Berardi. 6 All PPIs are metabolized in the liver by a group of enzymes known as the cytochrome P-450 enzymes. Esomeprazole is metabolized less extensively than is omeprazole, 8 and this may account for its greater bioavailability. This difference may also account for some variation in their potential drug-drug interactions. For example, according to Berardi's review, esomeprazole doesn't significantly interact with phenytoin, warfarin, or diazepam, whereas omeprazole reduces the clearance of these three drugs, among others. 6
COMPARATIVE EFFICACY
Numerous studies have compared the efficacy of various PPIs in suppressing stomach acid production. The measure most often used for comparison is the number of hours stomach acid is maintained at a pH greater than 4. (Although there is no accepted ideal for stomach acid pH, studies cited in one review indicated that raising and maintaining gastric pH above 4 was essential to prevent mucosal injury and promote healing 10; the measure permits direct, objective comparison of results.) Hunt reviewed several studies that compared the effects of omeprazole and various H2 blockers. 10 Omeprazole 20 mg and 40 mg were shown to maintain pH greater than 4 for 15 to 21 hours, whereas standard and higher doses of the various H2 blockers did so for just four to eight hours. These results have been corroborated by later studies, and the superiority of PPIs to H2 blockers is accepted.
Other measures used to evaluate the efficacy of various PPIs include the 24-hour median pH value and the percentage of a 24-hour period that stomach acid pH is greater than 4. One study used subjects' reports, a subjective measure of resolution of heartburn symptoms, but it compared only esomeprazole 20 mg, 40 mg, and placebo. 11
Studies.
It's important to note that, with one exception, 12 all the studies discussed in this section were funded by AstraZeneca and were completed before esomeprazole was made available to the public. All of the studies reviewed here were confined to patients with GERD, with or without esophageal erosion, and all used once-daily dosing.
In one study by Lind and colleagues, 36 patients were randomized to receive esomeprazole 40 mg, esomeprazole 20 mg, or omeprazole 20 mg once daily, before breakfast; stomach acid pH was maintained at greater than 4 for 16.8 hours, 12.7 hours, and 10.5 hours, respectively. 13 The researchers concluded that esomeprazole was superior to omeprazole in gastric acid control. However, in all groups, gastric acid control was poor at 12 to 20 hours following the once daily dosing, suggesting that patient outcomes might improve with an additional dose before the evening meal, as the AGA recommends in cases of severe or resistant GERD. 2
In a study involving 2,425 patients with erosive esophagitis, Richter and colleagues compared esophageal healing at four and eight weeks in patients given either esomeprazole 40 mg or omeprazole 20 mg once daily; at eight weeks, 93.7% of those on esomeprazole and 84.3% of those on omeprazole were healed. 14 This study is often cited as evidence of the superiority of esomeprazole in esophageal healing, but it should be noted that doses were not comparable.
In the only study to use comparable dosages of esomeprazole and omeprazole (40 mg once daily), 114 patients with GERD received one or the other drug for five days. 15 During a 24-hour monitoring period on day 5, those taking esomeprazole maintained a gastric pH greater than 4 for a mean of 16.4 hours (68.4% of the time period), whereas those taking omeprazole did so for 14.9 hours (62% of the time period)-a mean difference of an additional 1.5 hours at higher gastric pH for the first group.
Kahrilas and colleagues studied 1,960 patients with erosive esophagitis, randomized to receive esomeprazole 40 mg, esomeprazole 20 mg, or omeprazole 20 mg, and found that at eight weeks healing rates were 94.1%, 89.9%, and 86.9%, respectively. 11 They concluded that esomeprazole was superior to omeprazole in "healing and symptom resolution." Miner and colleagues evaluated 34 patients given esomeprazole 40 mg, omeprazole 20 mg, or one of three other PPIs. 12 They found that on day 5, stomach acid pH was maintained at greater than 4 for a mean of 14 hours among patients taking esomeprazole and 11.8 hours for those taking omeprazole. They concluded that esomeprazole was more effective than standard doses of the other four PPIs, including omeprazole.
Limitations.
As mentioned earlier, all of the above studies were funded by AstraZeneca and were completed before esomeprazole was on the market. All showed minor but statistically significant results supporting superiority of esomeprazole. The possibility of publication bias must be considered.
Only the study by Rohss and colleagues compared equivalent doses of esomeprazole and omeprazole, and its small sample size limits its validity. 15 The statistics used to report results are based on mean pH values; they do not reflect the variations in individual response to treatment that can affect clinical outcomes. Finally, the studies discussed above and those discussed in the review articles below ranged in duration from five days to eight weeks. Patients with GERD typically continue taking a PPI for many months or years, and some require lifelong therapy. Studies of long-term PPI therapy may reveal whether a beneficial cumulative drug effect exists.
Reviews.
Several reviews and metaanalyses have included the studies described here, as well as others. A metaanalysis by Edwards and colleagues (two of the three authors are employed by AstraZeneca) concluded that studies showed that esomeprazole healed erosive esophagitis at significantly higher rates than did omeprazole. 16
But another metaanalysis performed in 2002 found that differences in outcomes for patients taking PPIs were dose related, not drug specific; the researchers concluded that "all PPIs appear to be clinically comparable," and that in clinical practice the choice of drug could be made based on other factors, including cost considerations. 17 Vakil and Fennerty reviewed 32 studies and stated that although claims have been made regarding the clinical efficacy of different PPIs, "there are as yet insufficient data to establish superiority of any one agent." 18
A 2004 literature review by Hellstrom and Vitols acknowledged that esomeprazole was somewhat more effective than the other four PPIs at inhibiting acid production, but stated, "the clinical gain of these findings seems marginal and studies demonstrating clinical importance are lacking." 8 In fact, all the reviews discussed here concluded that, with regard to PPI efficacy, statistically significant results were not shown to have clinical significance. Hellstrom and Vitols concluded, "in the clinical setting, all proton pump inhibitors have a similar potency and the same inherent capacity to inhibit acid secretion." 8
THE OTC OPTION
There is no clear evidence establishing the clinical superiority of esomeprazole over omeprazole or any of the other PPIs. However, when relative costs are considered, the case for recommending over-the-counter omeprazole becomes strong. In the January 2004 issue of the Johns Hopkins Medical Letter Health After 50, Prilosec OTC was called "one of the most effective medications available for heartburn." 19 The authors recommended its use by patients with simple heartburn who are self-treating without physician consultation, advising those with chronic or atypical symptoms of GERD to seek medical attention. In approving the over-the-counter drug, the FDA stated, "the availability of Prilosec OTC will help reduce costs and expand the availability of treatment options for millions of Americans." 20
In most cases, patients can safely take over-the-counter omeprazole for management of chronic heartburn and gastroesophogeal reflux disease. Esomeprazole may have some advantage over omeprazole in the treatment of erosive esophagitis.
Nursing implications.
It's appropriate for nurses to provide evidence-based patient education and counseling on medications. Patients who are prescribed a PPI should be advised to ask their primary care provider whether over-the-counter omeprazole is an acceptable alternative to reduce costs. Primary care providers should ask about their patients' cost considerations. Lower medication costs may facilitate long-term maintenance therapy, thus helping to prevent disease progression and complications.
In most cases, patients can safely take over-the-counter omeprazole for management of chronic heartburn and GERD. Esomeprazole may have some advantage over omeprazole in the treatment of erosive esophagitis. Warnings should be given about contraindications during pregnancy and lactation, as well as potential drug-drug interactions. Encourage patients to discuss specific concerns with their primary care provider and their pharmacist.
One recent observational study found an "increased risk of community-acquired pneumonia" among patients using PPIs and H2 blockers. 21 This effect may be a result of increased stomach pH, which is the goal of therapy. Most pathogenic bacteria are killed in a low pH environment. Risk was greatest in vulnerable populations, including children, the elderly, and people who had asthma or chronic obstructive pulmonary disease or were immunocompromised. Risk was higher for patients taking PPIs than for those taking H2 blockers, was dose dependent, and was higher during the first 30 days of therapy. The researchers concluded that acid-suppressive drugs should be used in vulnerable populations "only when necessary and with the lowest possible dose."
For effective GERD management, communication between the primary care provider and the patient is essential. Ask patients whether they have insurance and discuss any financial (or other) barriers to having prescriptions filled. Encourage patients to ask questions and voice concerns, including those regarding the cost of prescriptions and the effectiveness of lesser-known brands or generic drugs compared to well-known or heavily advertised brands.
TALKING WITH PATIENTS ABOUT PRESCRIPTION COSTS
Questions nurses might ask include:
* Do you have insurance that covers your prescription costs?
* Do you have any concerns about the cost of your medications?
* Would you like me to talk to your [doctor, NP] about helping you save money on medications?
REFERENCES