Criticism: The NexiumÒ advertisement appeals to our desire for power
The headline ‘Experience the power – feel the relief’ does indeed appeal to the doctor’s desire for power. Doctors desire treatments that are highly effective. This is a perfectly reasonable desire, and one that patients with GERD would also reflect in the attributes they seek in a medicine for their condition.
This is not the case; significant differences in pharmacokinetics exist between NexiumÒ and omeprazole, and the results of several clinical trials indicate that NexiumÒ is more effective than clinically appropriate and currently recommended doses both of omeprazole and other PPIs.
· While esomeprazole (NexiumÒ) is the S-isomer of omeprazole, it is not just ‘double-dose’ omeprazole. Drug chirality can have considerable clinical significance, as has been reviewed in depth by Hutt and Tan (1996).1 Indeed, there are numerous examples of differences in activity between pairs of isomers, which may be sufficiently great that they are marketed for different indications (dextropropoxyphene, for example, is used as an analgesic, while the other isomer levopropoxyphene, is an antitussive for the treatment of cough). Esomeprazole has an advantageous metabolism compared with omeprazole2 which results in a greater area under the plasma concentration-time curve (AUC) than that obtained for omeprazole or the R-isomer at the same dose3. It is the AUC value that determines how much of each PPI reaches the parietal cell and is a major factor in determining the control of gastric acid that is achieved. As a result of these differences in metabolism and bioavailability, NexiumÒ was accepted as a new chemical entity.
· For each of the PPIs on the market, the dose that was chosen for clinical use is the one that maximises efficacy while still maintaining good tolerability. This is why the recommended dose of NexiumÒ is 40 mg once daily, of omeprazole is 20 mg once daily, of lansoprazole is 30 mg once daily etc. The different PPIs are not equivalent on a per milligram basis and cannot be compared in that way. Although they are members of the same class of drugs, they are different molecules with different optimum doses. It is misleading to suggest in Adwatch (and, stated more explicitly, in your letter to the Lancet) that the doses of comparator drugs used in the NexiumÒ trials were inappropriately low.
· In the management of acid-related diseases, it is the level of acid control achieved that is critical. With NexiumÒ, 40 mg once daily, the intragastric pH is controlled above 4 for significantly longer during each 24-hour period compared with omeprazole, 20 mg once daily, double-dose omeprazole, 40 mg once daily, lansoprazole, 30 mg once daily, pantoprazole, 40 mg once daily, and rabeprazole, 20 mg once daily.4, 5 This greater acid control achieved with NexiumÒ compared with all other PPIs has been shown to translate into a significantly greater clinical effect in the management of GERD compared with omeprazole,6, 7 lansoprazole8, 9 and pantoprazole.10
· The dose of omeprazole used in the NexiumÒ studies was chosen because:
– omeprazole, 20 mg once daily, was the ‘gold standard’ for the treatment of GERD at that time
– clinical trials with all the other PPIs had used omeprazole, 20 mg once daily, as the main comparator
– 90% of patients treated with omeprazole received a dose of 20 mg once daily
– this was the advice given by the regulatory authorities.
· The dose-response curve for omeprazole is relatively flat between 20 and 40 mg, therefore increasing the dose to 40 mg is likely to have a smaller clinical effect than replacing with NexiumÒ, 40 mg.
Criticism: The difference in the percentage of esophagitis patients healed with NexiumÒ, 40 mg, compared with lansoprazole, 30 mg, is too small to be clinically significant.
The overall superiority of NexiumÒ over lansoprazole (used at clinically appropriate doses) in esophagitis becomes more impressive when the results in healing and maintenance of healing are investigated in patients with moderate to severe disease.
· The therapeutic gain in healing of reflux esophagitis at 4 and 8 weeks with NexiumÒ, 40 mg once daily, compared with lansoprazole, 30 mg once daily, is around 4% across all severities of disease.8 This difference, while statistically significant, may at first glance seem of limited value. However, when healing data are subgrouped according to the pre-treatment Los Angeles (LA) Grade of esophagitis, NexiumÒ is shown to heal more consistently across all grades of disease, whereas the efficacy of lansoprazole declines to a greater extent with disease severity. Thus, the therapeutic gain in 8-week healing rate with NexiumÒ compared with lansoprazole was 11% in Grade C esophagitis (88% versus 77%) and 17% in Grade D esophagitis (81% versus 64%).8 Confidence that healing is effective across all grades of esophagitis is particularly important in a situation where a patient is being managed symptomatically and the severity of any underlying esophagitis is unknown. In addition, NexiumÒ achieved sustained resolution of heartburn faster and in more patients compared with lansoprazole.8
· NexiumÒ, 20 mg once daily, is also significantly more effective than lansoprazole, 15 mg once daily, in maintaining patients with healed reflux esophagitis in long-term remission.9 At 6 months, 83% of NexiumÒ-treated patients were in remission, compared with 74% of those taking lansoprazole. Again, NexiumÒ achieved consistently high remission rates across all pre-treatment LA Grades of esophagitis, whereas the efficacy of lansoprazole declined with increasing baseline disease severity. Remission rates for baseline LA Grades A, B, C and D for NexiumÒ and lansoprazole were 87% versus 84%, 83% versus 72% (p<0.01), 75% versus 61% (p<0.05) and 77% versus 50% (p<0.05), respectively. In addition, significantly more NexiumÒ-treated patients were free of heartburn, acid regurgitation and epigastric pain after 6 months compared with those taking lansoprazole.9
· The benefit of these therapeutic gains with NexiumÒ over lansoprazole has been demonstrated by a model that compared two management strategies: short-term treatment with NexiumÒ, 40 mg once daily, for healing, followed by maintenance treatment with NexiumÒ, 20 mg once daily, for 6 months to prevent relapse; or short-term treatment with lansoprazole, 30 mg once daily, followed by maintenance therapy with lansoprazole 15 mg once daily for 6 months.11 This showed that, for every 100 patients with reflux esophagitis treated using the NexiumÒ strategy, an additional 11 patients would be expected to be in remission at 6 months compared with lansoprazole. In patients with more severe esophagitis (LA Grades C and D) the benefit would be even more marked, and an additional 22 patients would be expected to be in remission with NexiumÒ.
Criticism: The advertisement does not compare NexiumÒ with other alternatives
By its very nature a journal advertisement cannot present all the available information. In fact NexiumÒ has been shown to compare very favourably against all other PPIs with which it has been compared. It has not been compared against H2-receptor antagonists or a treatment strategy based on lifestyle changes because these are already known to be less effective than PPIs in the management of GERD.
· NexiumÒ has been compared with omeprazole, which has been the standard comparator for all other PPIs, and with lansoprazole (as described above), and has been shown to be significantly more effective than both of these other PPIs in the management of GERD.6-9
· NexiumÒ has also been compared with pantoprazole in the healing of reflux esophagitis, and has been shown to be significantly more effective.10 At 4 weeks, 80.9% of patients were healed with NexiumÒ, 40 mg once daily, compared with 74.5% of those taking pantoprazole, 40 mg once daily (p<0.0001). This means that, in clinical practice, for every 100 patients treated, an additional 8–9 patients would be healed after 4 weeks with NexiumÒ compared with pantoprazole. As with lansoprazole, the efficacy of pantoprazole declined with increasing pre-treatment severity of disease. Thus, in patients with grade C and D esophagitis, the healing rates with pantoprazole were 60.1% and 40.2%, respectively at 4 weeks, compared with 71.1% and 61.4%, respectively, with NexiumÒ (p<0.01 for both comparisons). NexiumÒ also achieves faster resolution of heartburn compared with pantoprazole. A maintenance study with NexiumÒ versus pantoprazole is on-going.
· It is true that Caro et al.12 have shown in their meta-analysis that there is no difference between standard doses of omeprazole, lansoprazole, pantoprazole and rabeprazole in the acute and maintenance treatment of GERD. Only NexiumÒ has provided a significant advance over the other PPIs. The clinical advance provided by NexiumÒ has been confirmed by a more recent systematic meta-analysis of head-to-head studies that have compared esophagitis healing rates at 4 and 8 weeks with standard doses of NexiumÒ, 40 mg once daily, lansoprazole, 30 mg once daily, pantoprazole, 40 mg once daily, and rabeprazole, 20 mg once daily, versus omeprazole, 20 mg.13 The results show that Nexium is the only PPI that provides significantly greater healing rates than omeprazole at these time points.
· As yet, there has been no study that provides a direct comparison of NexiumÒ with rabeprazole in GERD. On a global scale, rabeprazole is currently the least prescribed of all the PPIs (IMS data), and new therapeutic options are tested against the current treatment standard (i.e. for PPIs, omeprazole). In line with this, comparative trials with rabeprazole have, as with all the other PPIs, been conducted versus omeprazole. However, as control of gastric acid secretion with NexiumÒ is more effective compared with rabeprazole,4, 14, 15 it seems likely that NexiumÒ would also be clinically more effective in the management of GERD (as has proven to be the case with the other three PPIs).
· As far as we are aware, no PPI has ever been compared with lifestyle changes. The Genval Guidelines on the management of GERD judged lifestyle changes to be of such low efficacy that they were rejected as a primary therapy for all patients.16 Indeed, there appear to be no data showing a positive effect of such measures on the healing of esophagitis. While it may be of value to check that individual patients are not exposing themselves to potentially important exacerbating factors, the guidelines recommend the use of appropriate drug therapy.
· It is normal practice to compare a new drug with the therapy that is currently the most effective drug available in the indication at that time. Omeprazole, rather than ranitidine, was therefore the comparator for all the PPIs that followed. There are many studies that show the inadequacy of the H2-receptor antagonists in healing reflux esophagitis and in resolving GERD symptoms. The meta-analysis by Chiba et al.17, for example, found that the overall proportion of reflux esophagitis patients healed with a PPI was 83.6% and 77.4% were symptom-free, compared with 51.9% and 47.6%, respectively with an H2-receptor antagonist. Thus, prescribing therapy with an H2-receptor antagonist would result in around half of all patients remaining unhealed and a similar proportion still suffering symptoms.
Criticism: Many people with peptic ulcers are better treated with H. pylori bacteria eradication therapy.
· Agreed, if H. pylori infection is the cause of the disease. The only indication that NexiumÒ has in peptic ulcer disease is for use along with appropriate antibiotics in the eradication of H. pylori.18, 19
References
1. Hutt A, Tan S. Drug chirality and its clinical significance. Drugs 1996;52 (Suppl 5):1-12.
2. Äbelö A, Andersson T, Antonsson M, Naudot A, Skånberg I, Weidolf L. Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. Drug Metabol Disp 2000;28:966-972.
3. Andersson T, Bredberg E, Sunzel M, Antonsson M, Weidolf L. Pharmacokinetics (PK) and effect on pentagastrin stimulated peak acid output (PAO) of omeprazole (O) and its 2 optical isomers, S-omeprazole/esomeprazole (E) and R-omeprazole (R-O). In: Abstract book from 7th World Conference on Clinical Pharmacology and Therapeutics, Florence, Italy, July 15–20,2000;241:abstract 935.
4. Miner P, Katz P, Chen Y, Sostek M. Esomeprazole 40 mg provides more effective intragastric acid suppression at steady state than standard doses of other proton pump inhibitors. Gastroenterology 2003;124 Suppl 1:A229.
5. Röhss K, Hasselgren G, Hedenström H. Effect of esomeprazole 40 mg vs omeprazole 40 mg on 24-hour intragastric pH in patients with symptoms of gastroesophageal reflux disease. Dig Dis Sci 2002;47:954-958.
6. Kahrilas P, Falk G, Johnson D, Schmitt C, Collins D, Whipple J, et al. Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux esophagitis patients: a randomized controlled trial. Aliment Pharmacol Ther 2000;14:1249-1258.
7. Richter J, Kahrilas J, Johanson J, Maton P, Breiter J, Hwang C, et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol 2001;96:656-665.
8. Castell D, Kahrilas P, Richter J, Vakil N, Johnson D, Zuckerman S, et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol 2002;97:575-583.
9. Lauritsen K, Devière J, Bigard M-A, Bayerdörffer E, Mózsik G, Murray F, et al. Esomeprazole 20 mg and lansoprazole 15 mg in maintaining healed reflux esophagitis: Metropole study results. Aliment Pharmacol Ther 2003;17:333-341.
10. Labenz J on behalf of the EXPO study group, Keeling N, Eklund S. A comparison of esomeprazole 40 mg once-dail and pantoprazole 40 mg once-daily for the healing of reflux esophagitis. Gut 2003;52 Suppl VI:A241.
11. Lind T, Junghard O, Lauritsen K. Esomeprazole and lansoprazole in the management of patients with oesophagitis (RO): combining results from two clinical studies. J Gastroenterol Hepatol 2002;17:A1024.
12. Caro J, Salas M, Ward A. Healing and relapse rates in gastroesophageal reflux disease treated withe the newer proton pump inhibitors lansoprazole, rabeprazole, and pantoprazole compared with omeprazole, ranitidine and placebo: evidence from randomized clinical trials. Clinl Ther 2001;23:998-1017.
13. Edwards S, Lind T, Lundell L. Systematic review of proton pump inhibitors for the acute treatment of reflux esophagitis. Aliment Pharmacol Ther 2001;15.
14. Wilder-Smith C, Claar-Nilsson C, Hasselgren G, Röhss K. Esomeprazole 40 mg provides faster and more effective acid control than rabeprazole 20 mg in patients with symptoms of GERD. J Gastroenterol Hepatol 2002;17 (Suppl):A612.
15. Röhss K, Claar-Nilsson C, Jansson L. Esomeprazole 20 mg provides more effective acid control than rabeprazole 10 mg following repeated drug administration. Scand J Gastroenterol 2002;37 Suppl 235:A61.
16. Dent J, Brun J, Fendrick A, Fennerty M, Janssens J, Kahrilas P, et al. on behalf of the Genval Workshop Group. An evidence-based appraisal of reflux disease management - the Genval Workshop Report. Gut 1999;44 Suppl 2:S1-S15.
17. Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology 1997;112:1798-1810.
18. Tulassay Z, Kryszewski A, Dite P, Kleczkowski D, Rudzinski J, Bartuzi Z, et al. One week of treatment with esomeprazole-based triple therapy eradicates Helicobacter pylori and heals patients with duodenal ulcer disease. European J Gastroenterol Hepatol 2001;13:1457-1465.
19. Veldhuyzen van Zanten S, Lauritsen K, Delchier J-C, Labenz J, Martin de Argila C, Lind T, et al. One-week triple therapy with esomeprazole, a new proton pump inhibitor, provides effective eradication of Helicobacter pylori in duodenal ulcer disease. Aliment Pharmacol Ther 2000;14:1605-1611.