TECHNOLOGY OVERVIEW: PHARMACEUTICALS ISSUE 3.1 JUNE 1996 PHARMACEUTICAL MANAGEMENT OF PEPTIC ULCER DISEASE prepared by Ms. Christine Perras, BSc Phm Pharmaceutical Associate, CCOHTA and Dr. Nicolaas Otten, Pharm D. Coordinator, Pharmaceutical Assessment, CCOHTA This overview has been prepared by staff at the Canadian Coordinating Office for Health Technology Assessment (CCOHTA) and is based in part on a study commissioned by CCOHTA: Cost-effectiveness of alternative therapies for the long-term management of peptic ulcer disease conducted by Dr. Bernie O'Brien (McMaster University/St. Joseph's Hospital, Hamilton, Ontario), Mr. Ron Goeree (McMaster University/St. Joseph's Hospital, Hamilton, Ontario), Dr. Richard Hunt (McMaster University, Hamilton, Ontario), Ms. Joanne Wilkinson (McMaster University, Hamilton, Ontario), Dr. Mitchell Levine (McMaster University/St. Joseph's Hospital, Hamilton, Ontario), Dr. Andrew Willan (McMaster University, Hamilton, Ontario). The overview has been reviewed and accepted by CCOHTA's Scientific Advisory Panel. It does not necessarily reflect the opinions of the Panel, the Board of CCOHTA or the investigators.
Additional copies of Pharmaceutical Management of Peptic Ulcer Disease are available from CCOHTA. Vous pouvez aussi vous procurer la version française à l OCCETS. Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CCOHTA. Legal Deposit - 1996 National Library of Canada ISSN 1203-9012 Approximately 10% of the adult population will suffer from peptic ulcer disease (PUD) at some point in their life. Most individuals experiencing heartburn after eating, self-medicate with antacids, consulting a physician only if symptoms are not relieved. H 2 antagonists are usually prescribed as first line therapy, with ranitidine being the most widely prescribed. However, the use of omeprazole is increasing steadily due in part to increasing evidence of its efficacy, in combination with antimicrobials, for the eradication of Helicobacter pylori (H.pylori). A study commissioned by CCOHTA entitled Cost-effectiveness of alternative therapies for the long-term management of peptic ulcer disease 1 evaluates different drug treatment strategies available for the management of patients with PUD. Specifically, the study compares maintenance ranitidine to treatment of acute ulcer with omeprazole or ranitidine, as well as H.pylori eradication regimens. This overview attempts to put the findings of the commissioned study into clinical perspective.
CONCLUSIONS PHARMACEUTICAL MANAGEMENT OF PEPTIC ULCER DISEASE 1) All H 2 antagonists have similar ulcer healing rates. 2) There are too few studies available to evaluate differences between omeprazole and the new proton pump inhibitor (PPI) lansoprazole. 3) Of the two acute ulcer healing regimens (intermittent omeprazole and intermittent ranitidine), intermittent omeprazole is the most effective and the least costly option. 4) The H.pylori eradication regimens are more effective (increased rate of healing and decreased recurrences) than either treating only the acute ulcer episodes or providing maintenance ranitidine. In terms of direct health care costs, four of the six regimens cost less per patient per year and have better outcomes than maintenance ranitidine. 5) Of the H.pylori eradication regimens, ranitidine-bismuth triple therapy is the least expensive but also the least effective. Omeprazole in combination with two antibiotics decreases the time with ulcer by 12 to 13 days compared to the ranitidine-bismuth triple therapy but at an extra cost ranging from $64 to $108 per patient per year. 6) Study limitations include the use of efficacy data and expert opinions instead of effectiveness studies. Also, a Ministry of Health perspective is taken instead of a societal one. 7) The results of the commissioned study are comparable to those conducted in other countries 2,3,4 with H.pylori eradication regimens being the most effective therapy for PUD. Canadian Coordinating Office for Health Technology Assessment 1
INTRODUCTION PHARMACEUTICAL MANAGEMENT OF PEPTIC ULCER DISEASE Duodenal ulcers and gastric ulcers are the most common forms of peptic ulcer disease. It is estimated that approximately 10% of adults will have PUD at some point in their life. Individuals experiencing burning pain after eating will frequently self-medicate with over-the-counter (OTC) medications such as antacids. They will usually seek medical care when symptoms are persistent or no longer relieved by OTC medications. Standard treatment for PUD has traditionally been based on acid suppression using treatment modalities such as antacids, sucralfate, H 2 antagonists (eg.cimetidine), proton pump inhibitors (eg.omeprazole) and surgery. Evidence is accumulating showing that strategies aimed at eradicating H.pylori (eg.antimicrobials with acid suppressing drugs) produce favorable healing rates and greater reduction in rates of ulcer recurrences. Given that omeprazole's use is increasing steadily and that treatment strategies are changing due to our current knowledge of the role of H. pylori in PUD, it remains to be determined what is the best therapeutic modality. The commissioned study evaluates the different drug treatment strategies for the management of patients with confirmed and uncomplicated peptic ulcers. Specifically, the study compares maintenance ranitidine to treatment of acute ulcer with omeprazole or ranitidine, as well as H.pylori eradication regimens, and relates the findings in a pharmacoeconomic evaluation. The study also evaluates whether efficacy is different among the various H 2 antagonists as well as between the two available PPIs. EFFICACY/ EFFECTIVENESS There have been many clinical trials to date comparing the various treatment regimens used in the management of duodenal ulcers. Recently, focus has been on H.pylori eradication therapy. It is beyond the scope of this paper to present all relevant randomized clinical trials. The model used in the commissioned study is based on results obtained in randomized controlled trials and expert opinions in non-drug management. The primary outcome of interest is the amount of time the patient can be expected to be free from ulcer in one year. This amount of time is calculated based on the healing time and the likelihood of recurrences. Ulcer healing probabilities are obtained by pooling results of randomized controlled trials, specifically in adults with duodenal ulcer where healing is confirmed by endoscopy at set intervals. Weeks with ulcer per acute healing episode are derived from these probabilities (Table 1). H 2 antagonists, PPIs and six different eradication regimens are being compared. The different H 2 antagonists available are: cimetidine, famotidine, nizatidine and ranitidine. An evaluation done in the commissioned study shows that there is very little difference between these four drugs in terms of rates of healing and recurrences. Ranitidine is the most widely prescribed H 2 antagonist and is used in the base case analysis. Similarly, omeprazole is used instead of lansoprazole. Variations in the drug prices are addressed in sensitivity analyses. 2 Canadian Coordinating Office for Health Technology Assessment
PHARMACEUTICAL MANAGEMENT OF PEPTIC ULCER DISEASE TABLE 1: Ulcer Healing Probabilities and Weeks with Ulcer Drug Total daily dose % healed at 2 weeks % healed at 4 weeks % healed at 8 weeks # weeks with ulcer a Ranitidine 300mg -- 72% (CI b :67-76) 86% (CI:84-89) 3.4 a b Omeprazole 20mg 64% (CI:60-68) 87% (CI:85-89) time horizon is 8 weeks for ranitidine and 4 weeks for omeprazole CI denotes 95% confidence interval -- 1.85 Table 2 gives H.pylori eradication probabilities for strategies involving omeprazole and antibiotics (probabilities are based on results of a previously published meta-analysis 5 ) and for the ranitidinebismuth triple therapy (the probability of eradication is obtained by pooling the results of clinical trials). TABLE 2: H. pylori Eradication Probabilities Drug Regimen % Eradication omeprazole and amoxicillin (O+A) 61% (CI: 57-66) omeprazole and clarithromycin (O+C) 71% (CI: 66-76) omeprazole, amoxicillin and metronidazole (O+A+M) 84% (CI: 79-90) omeprazole, amoxicillin and clarithromycin (O+A+C) 85% (CI: 75-96) omeprazole, clarithromycin and metronidazole (O+C+M) 91% (CI: 88-94) ranitidine-bismuth triple therapy (ranitidine, bismuth subsalicylate, metronidazole and tetracycline; Ran-BMT) 86% (CI: 80-92) Probabilities of ulcer recurrence (Table 3) are determined from randomized double-blind trials in adults, diagnosed by endoscopy at 6 months, 12 months or both, for placebo, maintenance ranitidine therapy and pooled H.pylori eradication regimens. TABLE 3: Ulcer Recurrence Probabilities Drug Regimen % Recurrence a 0-6 months % Recurrence b 6-12 months a b c Placebo 56% (CI: 40-72) 18% (CI: 6-29) Ranitidine 150mg daily 12% (CI: 6-19) 12% (CI: 3-21) H.pylori eradication c -unsuccessful -successful 53% (CI: 36-69) 4% (CI: 0-11) 46% (CI: 31-61) 1% (CI: 0-10) probability of recurrence anytime during the first six months probability of recurrence in patients not experiencing a recurrence during the first six months some patients will remain positive for H.pylori following eradication treatment and as seen above, will be more likely to experience a recurrence Canadian Coordinating Office for Health Technology Assessment 3
PHARMACEUTICAL MANAGEMENT OF PEPTIC ULCER DISEASE A seven-year follow-up study 6 also showed a small probability of ulcer recurrence (3%) in patients who tested negative for H. pylori following eradication therapy, supporting the results of the meta-analysis. Evaluation of 35 trials revealed that 76% of ulcer recurrences are symptomatic. Only symptomatic recurrences are used in the model. PARAMETERS OF THE EVALUATION a) Perspective/Target Audience The perspective adopted reflects the target audience which is the Ministry of Health. In addition, physicians, formulary managers and patients may find the analysis to be relevant. b) Treatment Comparators Three therapeutic strategies are being compared. The drugs, dosages as well as length of therapy are described in detail in the section on costs. 1) Ulcer is healed with an H 2 antagonist or with a PPI. Maintenance therapy is not initiated. Recurrences are treated with the same agent as used previously. 2) Ulcer is healed with an H 2 antagonist followed by continuous half dose maintenance therapy with the same H 2 antagonist. Recurrences are treated with the same agent. 3) Ulcer is healed and H. pylori eradicated using one of six possible regimens: omeprazole and amoxicillin; omeprazole and clarithromycin; omeprazole, metronidazole and amoxicillin; omeprazole, amoxicillin and clarithromycin; omeprazole, clarithromycin and metronidazole; or, an H 2 antagonist and bismuth triple therapy. Recurrences are treated with an H 2 antagonist. c) Time Horizon The time horizon is a one-year period from the time of diagnosis of PUD. d) Cost Elements of Interest Direct costs accruing to the health care system are used. (See "Costs" below). COSTS Drug costs (Table 4) are obtained from the Ontario Drug Benefit Plan (best available price plus 10% pharmacy upcharge) or from a survey of local pharmacies for drugs not covered under the Ontario drug plan. 4 Canadian Coordinating Office for Health Technology Assessment
PHARMACEUTICAL MANAGEMENT OF PEPTIC ULCER DISEASE TABLE 4: Costs of Drug Regimens a Regimen Description Cost Intermittent ranitidine Intermittent omeprazole Maintenance ranitidine O+A O+C O+A+M O+A+C O+C+M treatment: ranitidine 150mg BID x 8 weeks maintenance: none treatment of recurrence: same as treatment treatment: omeprazole 20mg daily x 28 days maintenance: none treatment of recurrence: same as treatment treatment: ranitidine 150mg BID x 8 weeks maintenance: ranitidine 150 mg daily treatment of recurrence: same as treatment omeprazole 20mg BID x 14 days and amoxicillin 1g BID x 14 days; omeprazole 20mg daily on days 14-28. omeprazole 20mg BID x 14 days and clarithromycin 500mg TID x 14 days; omeprazole 20mg daily on days 14-28. omeprazole 20mg BID x 14 days and amoxicillin 1g BID x 7 days and metronidazole 500mg BID x 7 days; omeprazole 20mg OD on days 14 to 28. omeprazole 20mg BID x 14 days and clarithromycin 500mg BID x 7 days and amoxicillin 1g BID x 7 days; omprazole 20mg OD on days 14 to 28. omeprazole 20mg BID x 14 days and clarithromycin 500mg BID x 7 days and metronidazole 500mg BID x 7 days; omeprazole 20mg OD on days 14 to 28. $50.40 $0.00 $50.40 $71.96 $0.00 $71.96 $50.40 $0.45/day $50.40 $119.70 $257.88 $114.66 $163.80 $158.76 a Ran-BMT ranitidine 150mg BID x 56 days; bismuth subsalicylate 151mg QID on days 42 to 56 metronidazole 250mg QID on days 42 to 56 tetracycline 500mg QID on days 42 to 56. excludes dispensing fees; based on generic prices when generic drug is available $66.08 Note: All ulcer recurrences following treatment for H.pylori are treated with ranitidine 150mg twice daily for 8 weeks. Unit prices for health care resources utilized in the management of duodenal ulcers (excluding drugs) are based on costs obtained from the physician fee schedule for Ontario and from Chedoke-McMaster Hospital in Hamilton, Ontario. Based on clinical opinions obtained from an expert physician panel convened to identify resources used by patients presenting with symptoms of ulcer recurrences, it costs $180.16 and $361.06 per patient to treat first and second recurrences respectively in patients treated with intermittent omeprazole, intermittent ranitidine or maintenance ranitidine (excluding cost of drugs). For patients treated with one of eradication strategies, it costs $571.17 and $588.60 per patient to treat first and second recurrences respectively (excluding cost of drugs). Canadian Coordinating Office for Health Technology Assessment 5
PHARMACEUTICAL MANAGEMENT OF PEPTIC ULCER DISEASE RESULTS TABLE 5: Expected Outcomes and Total Costs in One Year Regimen Expected Weeks with Recurrences per 100 Ulcer per Patient a Patients b Expected Cost per Patient c Intermittent ranitidine 5.7 (CI: 4.9-6.6) 69 (CI: 43-95) $306 (CI: 228-390) Intermittent omeprazole 3.1 (CI: 2.6-3.6) 69 (CI: 43-95) $343 (CI: 259-432) Maintenance ranitidine 4.0 (CI: 3.6-4.4) 18 (CI: 7-30) $353 (CI: 326-383) O+A 2.4 (CI: 2.2-2.6) O+C 2.3 (CI: 2.1-2.5) O+A+M 2.1 (CI: 2.0-2.4) O+A+C 2.1 (CI: 2.0-2.3) O+C+M 2.0 (CI: 1.9-2.3) 28 (CI: 18-42) 22 (CI: 13-36) 14 (CI: 7-27) 13 (CI: 7-26) 10 (CI: 4-22) $387 (CI: 315-489) $482 (CI: 421-580) $292 (CI: 245-385) $337 (CI: 291-430) $306 (CI: 266-396) a b c Ran-BMT 3.8 (CI: 3.6-4.3) includes time with ulcer and time with recurrences symptomatic recurrences only 12 (CI: 6-25) includes all costs of treating an acute episode and any recurrences in one year $228 (CI: 186-317) Note: CI is 95% confidence interval based on a one-way sensitivity analysis on ulcer recurrence probabilities. 1) Cost The ranitidine-bismuth triple therapy combination (Ran-BMT) has the lowest cost per patient per year. The omeprazole-clarithromycin and the omeprazole-amoxicillin combinations (O+C and O+A) are the most expensive treatments even compared to the cost of omeprazole plus two antibiotics over one year. The reasons for the high cost are the higher recurrence rates and the difference in dosing (clarithromycin is given three times daily for 14 days in strategy O+C compared to twice daily for 7 days in strategies O+A+C and O+C+M). 2) Efficacy Time with ulcer: The eradication regimens combining omeprazole with two antibiotics (O+A+M, O+A+C and O+C+M) have the shortest times with ulcer. Recurrence rate: Omeprazole in combination with two antibiotics (O+A+M, O+A+C and O+C+M) as well as the ranitidine-bismuth triple therapy offer the lowest rate of recurrences. 6 Canadian Coordinating Office for Health Technology Assessment
PHARMACEUTICAL MANAGEMENT OF PEPTIC ULCER DISEASE Considering both time with ulcer and recurrence rate, omeprazole in combination with two antibiotics (O+A+M, O+A+C and O+C+M) show the greatest overall benefit. 3) Cost-effectiveness The cost-effectiveness analysis incorporates clinical outcomes and the costs associated with treating the ulcer and any recurrences in one year (Table 6). TABLE 6: Cost-effectiveness of all Regimens Relative to Maintenance Ranitidine Regimen Expected Cost per Patient in one Year Time-free from ulcer (weeks) C ($) E (weeks) Costeffectiveness Intermittent ranitidine Intermittent omeprazole Maintenance ranitidine $306 46.3-47 -1.7 lower cost but lower efficacy $343 48.9-10 0.9 D* $353 48.0 -- -- -- O+A $387 49.6 34 1.6 higher cost for higher effect O+C $482 49.7 129 1.7 higher cost for higher effect O+A+M $292 49.9-61 1.9 D* O+A+C $337 49.9-16 1.9 D* O+C+M $306 50.0-47 2.0 D* Ran-BMT $228 48.2-125 0.2 D* D*=dominant strategies: less cost for more effect, compared to maintenance ranitidine Of the two acute ulcer healing regimens (intermittent omeprazole and intermittent ranitidine), intermittent omeprazole is the most effective and the least costly option. All the H.pylori eradication regimens are more effective than treating only the acute ulcer episodes or using maintenance ranitidine strategy to prevent further ulcer. 4) Comparing the H.pylori eradication regimens! the omeprazole-antimicrobial combinations have similar disease-free periods;! the omeprazole-clarithromycin and the omeprazole-amoxicillin combinations are the most expensive options and the ranitidine-bismuth triple therapy is the least expensive option;! omeprazole in combination with two antibiotics decrease the time with ulcer by 12 to 13 days compared to the ranitidine-bismuth triple therapy but at an extra cost ranging from $64 to $108 per patient per year. Canadian Coordinating Office for Health Technology Assessment 7
PHARMACEUTICAL MANAGEMENT OF PEPTIC ULCER DISEASE Substituting maintenance ranitidine with ranitidine-bismuth triple therapy (Ran-BMT) results in cost-savings of $125,000 and 200 extra weeks of ulcer-free time per 1,000 patients in a one-year period. Using the omeprazole, amoxicillin and metronidazole combination (O+A+M) instead of maintenance ranitidine offers an additional 1,700 weeks of ulcer-free time per 1,000 patients in a one-year period but with lower costsavings of $61,000. Variations in drug prices across the different provinces do not alter the ranking of these options. 5) Study limitations: Clinical Randomized controlled trials require participants to be diagnosed by endoscopy or require a biopsy or test to determine their H.pylori status. In actual practice, a large proportion of patients presenting with epigastric pain will be treated empirically. Similarly, outcome of treatment may not always be confirmed by endoscopy or biopsy. Weeks with ulcer does not necessarily correlate to weeks with symptoms. Most patients enter an asymptomatic state (patient no longer suffers from epigastric pain) but are still not cured. The commissioned study does not consider patients with ulcers secondary to non steroidal antiinflammatory agents, patients with complicated ulcers such as bleeding ulcers, or ulcers extending into the esophagus, although these represent less than 10% of the ulcer patient population. The commissioned study does not consider the side effects associated with the different drugs. The commissioned study does not take patient compliance into consideration. Concerns have been raised that the H.pylori eradication regimens may be too complex for patients to follow. However, very few H.pylori eradication studies have evaluated patient compliance as part of the clinical trial. Resistance to antibiotics is a concern and has been linked to treatment failures in some studies. This problem may become more important with the increase use of antimicrobials in the treatment of PUD. Other therapeutic modalities are being considered (eg.h.pylori vaccines) to address this concern. 6) Study limitations: Economic The commissioned study uses a model based on data obtained from randomized controlled trials (rates of ulcer healing, recurrences and eradication) and on expert physicians' opinions (use of resources for ulcer recurrence) rather than studies based on actual clinical practice (effectiveness studies) to derive its findings. Due to patient selection and small sample size in some trials, randomized controlled trials results need to be interpreted with caution when extrapolated to the general population. The commissioned study takes a health care perspective and only includes direct costs. The impact on patients' lifestyle (eg.work absenteeism) and as such on society, is not evaluated. The cost associated with treating an ulcer and its recurrence (excluding drugs) are obtained from the Ontario physician fee schedule and an hospital in Hamilton, Ontario. These costs may not reflect those of other provinces or institutions. The commissioned study does not consider the costs associated with the management of complications. Although these are rare, they are usually expensive. 8 Canadian Coordinating Office for Health Technology Assessment
ENDNOTES PHARMACEUTICAL MANAGEMENT OF PEPTIC ULCER DISEASE 1 O'Brien, B., Goeree, R., Hunt, R., Wilkinson, J., Levine, M., Willan, A. (1996). Cost-effectiveness of alternative therapies for the long-term management of peptic ulcer disease. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA). 2 Sonnenberg, A., Townsend, W.F. (1995). Costs of duodenal ulcer therapy with antibiotics. Archives of Internal Medicine;155:922-928. 3 Unge, P., Jonsson, B., Stalhammar, N. (1995). The cost effectiveness of Helicobacter pylori eradication versus maintenance and episodic treatment in duodenal ulcer patients in Sweden. PharmacoEconomics;8(5):410-427. 4 Philips, C.,Moore, A. (1996). Implementing evidence-based medical interventions: the costeffectiveness of Helicobacter pylori diagnosis and eradication. British Medical Journal of Medical Economics;10:47-57. 5 Chiba, N., Wilkinson, J.M., Hunt, R.H. (1995). Clarithromycin or amoxicillin dual and triple therapies in H.pylori eradication: A meta-analysis. Gut;37:A31. 6 Forbes, G.M., Glaser, M.E., Cullen, D.J., Warren, J.R., Christiansen, K.J., Marshall, B.J. (1994) Duodenal ulcer treated with Helicobacter pylori eradication: seven-year follow-up. Lancet;343:258-260. Previous drafts of the technical document Cost-effectiveness of alternative therapies for the long-term management of peptic ulcer disease were reviewed by the Scientific Advisory Panel of CCOHTA: Dr. Andreas Laupacis Dr. David Feeny Dr. Lawrence Joseph Dr. Roy West Dr. Raisa Deber Dr. Heather Bryant Comments were also received from: Dr. Lloyd Sutherland Astra Pharma Inc. Eli Lilly Canada Janssen-Ortho Inc. Procter and Gamble Pharma Ottawa Civic Hospital McMaster University McGill University Memorial University University of Toronto University of Calgary University of Calgary CCOHTA would like to thank the above for their contributions. The complete report Cost-effectiveness of alternative therapies for the long-term management of peptic ulcer disease is available by contacting CCOHTA. Please address all enquiries and correspondence to: Publications, CCOHTA, 110-955 Green Valley Crescent, Ottawa, Ontario, Canada, K2C 3V4. Tel.: (613) 226-2553; Fax: (613) 226-5392; E-mail: pubs@ccohta.ca. Canadian Coordinating Office for Health Technology Assessment 9
Canadian Coordinating Office for Health Technology Assessment 110-955 Green Valley Crescent Ottawa, Ontario, Canada K2C 3V4