Pharmacoeconomics - Determiniation of the Cost-Effectiveness of Helicobacter Pylori Eradication

Effectiveness of Helicobacter Pylori Eradication In 1994, the National Institutes of Health Consensus Panel on Helicobacter pylori (HP) in peptic ulcer disease (PUD) recommended HP eradication in patients who test positive for HP and who have new or recurrent gastric or duodenal ulcers or require maintenance acid-suppressive therapy for PUD. The guidelines did not, however, recommend HP eradication in the absence of detection of infection with HP, even in patients with persistent symptoms. Also, the role of HP infection in nonulcer dyspepsia (NUD) is controversial. In the middle 1990s, HP infection was blamed for 80% to 90% of the symptoms and “misery” of ulcers. Some advocated the use of HP eradication therapy without obtaining definitive evidence of HP infection. By 19981999, however, the evidence was conclusive that only about 20% to 25% of NUD patients with HP infection when treated with effective HP eradication therapy reported symptomatic relief at 1 year. A randomized controlled trial of 337 patients with NUD found that eradication of HP was 90% at 4 to 6 weeks in the treatment group versus 2% in the placebo group. The treatment group received a 2-week, twice-daily regimen of 20 mg omeprazole, 1,000 mg amoxicillin, and 500 mg clarithromycin (OAC). At the 12-month follow-up, the rate of successful treatment (defined as no more than mild pain or discomfort centered in the upper abdomen [a score of 0 or 1] was 50% in the placebo group versus 46% in the treatment group during the 7 days prior to the final 12-month visit. Treatment was considered a failure if the patient had taken medication for dyspepsia, other than antacids, in the 30-day period prior to the last visit. Equally important, there was no significant difference in the rate of successful treatment (relief of symptoms) at 12 months between patients who were HP-negative (48%) versus HP-positive (49%). The accumulated evidence shows that the relationship between symptoms in NUD and HP infection is not predictable, and the eradication of HP does not necessarily cure the disease as measured by symptoms. Complete relief of symptoms occurred in 28% of the oral triple therapy patients and 23% of placebo patients. Perhaps as few as 20% of patients with NUD will benefit from HP eradication. There is apparently much that we still do not know about NUD, heartburn symptoms, and HP infection. For example, the duration (durability) of symptoms of NUD appears to be a factor in the effectiveness of HP eradication regimens as measured by relief of symptoms. One study found that 27% of NUD patients who had reported symptoms for less than 5 years reported relief of symptoms after HP eradication compared to 12% for the subgroup of NUD patients who had reported having NUD symptoms for 5 years or more. Some might argue that the truth about the value of HP eradication lies in the definition of the disease—NUD, PUD, or heartburn. Managed care pharmacists who work in disease management will appreciate the observations of gastroenterologists participating in clinical practice improvement projects who describe NUD, heartburn, and gastroesophageal reflux disease as a “brag bag of symptoms.” The article by Fairman and Motheral in this issue of the Journal tackles a difficult and complex subject area, validation of predictive decision-analytical models that are, by definition, models, and not actual observations. As pointed out by Zafar Hakim, PhD, one of the reviewers of this manuscript, models are simplifications of clinical practice and will never be able to capture the richness and diversity of clinical practice. Models will never yield completely accurate predictions of costs or other outcomes. Equally important, one might question the use of any HP eradication recipe given the apparent fact that HP eradication relieves problematic symptoms in only 1 in 5 NUD patients. This context also includes the predictable rate of HP reinfection and recurrence of dyspeptic symptoms in one fourth to one third of NUD patients at the 2-year follow-up. Furthermore, heartburn and NUD symptoms are often manageable without drug intervention and the avoidance of symptom triggers such as spicy foods, fatty foods, alcohol, cigarettes, heavy meals, large body mass, or eating too close to bedtime. Previously in the Journal, Kozma, Dickson, Mullenix, and Reeder presented results of pharmacoeconomic (PE) modeling of the relative merit of HP eradication versus usual care (antisecretory therapy) for peptic ulcer disease and suggested that a prior history of ulcer is necessary to make empiric HP eradication cost effective. Readers will note that the article by Fairman and Motheral examines assumptions inherent in early PE models applied to HP eradication recipes, oral tripe therapy with BMT (bismuth, metronidazole, tetracycline), and dual therapy comprised of a PPI with either amoxicillin or clarithromycin. Triple and quadruple drug therapies are generally preferred today, often in 1-week regimens rather than the 2-week regimens common in the 1990s. Recipes of 3 antibiotics with a PPI for as few as 5 days (the MACLOR study) have been shown to eradicate HP infection in 86% to 89% of patients. The purpose of the article by Fairman and Motheral is not evaluation of PE analyses of state-of-the-art HP eradication recipes. Rather, the point is that assumptions employed in PE models require validation using actual health plan experience when these data become available. In the case of the 2 PE models evaluated by Fairman and Motheral, the BMT model with lower direct drug cost was found to be the most cost effective using actual health plan data, contrary to the PE model prediction. When HP eradication is pursued, there may be a role for clinical pharmacists in delivering maximum value. A gastrointestinal clinic operated by clinical pharmacists was shown to attain 100% patient adherence to HP eradication regimens and no patients resumed acid-suppression therapy at 1-month follow-up. A separate study showed that clinical pharmacist intervention with prescribers could increase the utilization of the BMT oral triple therapy regimen with either 2 weeks of a proton pump inhibitor (PPI) or 4 weeks of an H2-receptor antagonist (as recommended in 1998 by the American College of Gastroenterology) from 0% of all HP-eradication regimens to EDITORIAL SUBJECTS—IN THIS ISSUE


ss Pharmacoeconomics-Determination of the Cost-Effectiveness of Helicobacter Pylori Eradication
In 1994, the National Institutes of Health Consensus Panel on Helicobacter pylori (HP) in peptic ulcer disease (PUD) recommended HP eradication in patients who test positive for HP and who have new or recurrent gastric or duodenal ulcers or require maintenance acid-suppressive therapy for PUD. 1 The guidelines did not, however, recommend HP eradication in the absence of detection of infection with HP, even in patients with persistent symptoms. Also, the role of HP infection in nonulcer dyspepsia (NUD) is controversial. In the middle 1990s, HP infection was blamed for 80% to 90% of the symptoms and "misery" of ulcers. 2 Some advocated the use of HP eradication therapy without obtaining definitive evidence of HP infection. By 1998By -1999, however, the evidence was conclusive that only about 20% to 25% of NUD patients with HP infection when treated with effective HP eradication therapy reported symptomatic relief at 1 year. 3,4 A randomized controlled trial of 337 patients with NUD found that eradication of HP was 90% at 4 to 6 weeks in the treatment group versus 2% in the placebo group. 5 The treatment group received a 2-week, twice-daily regimen of 20 mg omeprazole, 1,000 mg amoxicillin, and 500 mg clarithromycin (OAC). At the 12-month follow-up, the rate of successful treatment (defined as no more than mild pain or discomfort centered in the upper abdomen [a score of 0 or 1] was 50% in the placebo group versus 46% in the treatment group during the 7 days prior to the final 12-month visit. Treatment was considered a failure if the patient had taken medication for dyspepsia, other than antacids, in the 30-day period prior to the last visit. Equally important, there was no significant difference in the rate of successful treatment (relief of symptoms) at 12 months between patients who were HP-negative (48%) versus HP-positive (49%). The accumulated evidence shows that the relationship between symptoms in NUD and HP infection is not predictable, and the eradication of HP does not necessarily cure the disease as measured by symptoms. Complete relief of symptoms occurred in 28% of the oral triple therapy patients and 23% of placebo patients. Perhaps as few as 20% of patients with NUD will benefit from HP eradication.
There is apparently much that we still do not know about NUD, heartburn symptoms, and HP infection. For example, the duration (durability) of symptoms of NUD appears to be a factor in the effectiveness of HP eradication regimens as measured by relief of symptoms. One study found that 27% of NUD patients who had reported symptoms for less than 5 years reported relief of symptoms after HP eradication compared to 12% for the subgroup of NUD patients who had reported having NUD symptoms for 5 years or more. 6 Some might argue that the truth about the value of HP eradication lies in the definition of the disease-NUD, PUD, or heartburn. Managed care pharmacists who work in disease management will appreciate the observations of gastroenterologists participating in clinical practice improvement projects who describe NUD, heartburn, and gastroesophageal reflux disease as a "brag bag of symptoms." 7 The article by Fairman and Motheral in this issue of the Journal tackles a difficult and complex subject area, validation of predictive decision-analytical models that are, by definition, models, and not actual observations. As pointed out by Zafar Hakim, PhD, one of the reviewers of this manuscript, models are simplifications of clinical practice and will never be able to capture the richness and diversity of clinical practice. 8 Models will never yield completely accurate predictions of costs or other outcomes. Equally important, one might question the use of any HP eradication recipe given the apparent fact that HP eradication relieves problematic symptoms in only 1 in 5 NUD patients. This context also includes the predictable rate of HP reinfection and recurrence of dyspeptic symptoms in one fourth to one third of NUD patients at the 2-year follow-up. 9 Furthermore, heartburn and NUD symptoms are often manageable without drug intervention and the avoidance of symptom triggers such as spicy foods, fatty foods, alcohol, cigarettes, heavy meals, large body mass, or eating too close to bedtime. 10 Previously in the Journal, Kozma, Dickson, Mullenix, and Reeder presented results of pharmacoeconomic (PE) modeling of the relative merit of HP eradication versus usual care (antisecretory therapy) for peptic ulcer disease and suggested that a prior history of ulcer is necessary to make empiric HP eradication cost effective. 11 Readers will note that the article by Fairman and Motheral examines assumptions inherent in early PE models applied to HP eradication recipes, oral tripe therapy with BMT (bismuth, metronidazole, tetracycline), and dual therapy comprised of a PPI with either amoxicillin or clarithromycin. Triple and quadruple drug therapies are generally preferred today, often in 1-week regimens rather than the 2-week regimens common in the 1990s. Recipes of 3 antibiotics with a PPI for as few as 5 days (the MACLOR study) have been shown to eradicate HP infection in 86% to 89% of patients. 12 The purpose of the article by Fairman and Motheral is not evaluation of PE analyses of state-of-the-art HP eradication recipes. Rather, the point is that assumptions employed in PE models require validation using actual health plan experience when these data become available. In the case of the 2 PE models evaluated by Fairman and Motheral, the BMT model with lower direct drug cost was found to be the most cost effective using actual health plan data, contrary to the PE model prediction.
When HP eradication is pursued, there may be a role for clinical pharmacists in delivering maximum value. A gastrointestinal clinic operated by clinical pharmacists was shown to attain 100% patient adherence to HP eradication regimens and no patients resumed acid-suppression therapy at 1-month follow-up. 13 A separate study showed that clinical pharmacist intervention with prescribers could increase the utilization of the BMT oral triple therapy regimen with either 2 weeks of a proton pump inhibitor (PPI) or 4 weeks of an H2-receptor antagonist (as recommended in 1998 by the American College of Gastroenterology) from 0% of all HP-eradication regimens to

Editorial Subjects-In This Issue
61%. 14 The pharmacist intervention produced a 31% average savings for all HP eradication by increasing the utilization of the lower-cost BMT regimen and reducing utilization (from 74% to 26%) of the higher-cost OAC (omeprazole, amoxicillin, and clarithromycin) regimen. Cost-effectiveness might also be achieved via 1-week HP eradication recipes with PPI pantoprazole. Seven-day regimens including either twice-daily pantoprazole 40 mg, amoxicillin 1,000 mg, and clarithromycin 500 mg ("PAC7") or twice-daily pantoprazole 40 mg, bismuth subcitrate 108 mg 4 times daily, tetracycline 500 mg 4 times daily, and metronidazole 200 mg 3 times daily and 400 mg at night ("PBMT7") produced similar HP eradication rates, 78% and 82%, respectively, both superior in clinical outcome to 69% HP eradication achieved with 14 days of BMT without PPI. 15 As is often the case in medicine, the challenge is to identify those patients who are most likely to benefit from the intervention (sensitivity) and exclude those patients unlikely to benefit from the intervention (specificity). Long-term use of acid-suppression therapy, histamine-2 receptor antagonists (H2RAs) in the 1980s to the end of the 1990s and supplanted by PPIs in the middle 1990s, can be expensive and a drain on the financial resources of health plans. Introduction of generic cimetidine, followed by generic ranitidine, famotidine, and nizatidine, reduced the average annual cost of H2RA therapy from nearly $1,000 per patient to less than $250 per patient. The introduction of generic omeprazole at year-end 2002 had not by mid-2003 reduced significantly the average annual PPI cost of nearly $1,500 per patient per year, before copayment.
A study of 1,007 patients on long-term H2RA therapy (defined as 6 months or more) found that PUD was the most common indication for H2RA prescribing (42%). PUD was found in 58% of patients receiving long-term H2RA drug therapy who had their HP serology tested and were HP-positive. 16 While two thirds (67%) of the patients reported improvement in quality of life following HP eradication, and H2RA use was reduced, there is no guarantee that PUD patients treated with an HP-eradication recipe will discontinue use of H2RA or PPI drug therapy. The findings noted above, in which clinical pharmacist intervention in an HP-eradication intervention was associated with no resumption of acid suppression therapy at 1-month follow-up, need validation over a longer follow-up period. It is entirely possible that HP eradication, achieved at any incremental cost as measured in total prescription drug expenditures, results in some relief of symptoms in a majority of patients on long-term acid-suppression therapy.
For managed care organizations in 2003, the direct drug cost at discounted prices, before member copayment or pharmacy dispensing fees, was about $44 for quadruple therapy for 7 days with PBMT7 or $102 for 7 days with triple therapy PAC7, compared with about $250 for the commercial packaging of 14 days of therapy with lansoprazole, amoxicillin, and clarithromycin. 17 Avoidance of even 1 month of therapy with a PPI in 1 of 2 patients treated with PBMT7 or PAC7 would cover the direct drug cost of most HP eradication recipes. For patients with PUD, HP infection is present in 85% to 95% of patients, and eradicating HP is effective in healing the ulcers. 18 For patients with NUD, the relative risk reduction for persistent dyspeptic symptoms (the same or worse) at 3 to 12 months following HP eradication is 9% compared with placebo, and the number needed to treat is 15 NUD patients to obtain 1 case of cured dyspepsia. 19 The cost to obtain 1 dyspeptic-free NUD patient with PBMT7, the lowest-cost therapy, is therefore $660 in 2003 dollars versus $1,530 for PAC7 or $3,750 for the commercial package of lansoprazole, amoxicillin, and clarithromycin.
ss Formulary Management Methods and Pharmacoeconomics Twenty years ago, 40% of hospitals stocked a single drug product to represent a therapeutic category, and 31% of hospitals allowed automatic therapeutic interchange performed by pharmacists. 20 In calendar year 2002, 88% of hospitals with greater than 100 beds employed therapeutic interchange as part of formulary management. 21 Cost-effectiveness analysis is a fundamental part of determining the value of drug therapy compared with the cost, or the value-for-money equation. Yet, most pharmacy and medical directors involved in drug formulary decisions of pharmacy and therapeutics (P & T) committees apparently have an inadequate understanding of basic terms and methods of pharmacoeconomics (PE). A survey conducted in 1999 and reported in the March/April 2000 issue of the Journal 22 found that (a) while most pharmacy and medical directors involved in drug formulary decisions believed that their P & T committees understood pharmacoeconomics, only 17% felt that their committee understood pharmacoeconomics completely and (b) most terms in pharmacoeconomics were not well understood, e.g., 71% of respondents reported inadequate understanding of qualityadjusted life year, 78% conjoint analysis, 88% the Markov model, and 95% league tables. There is also distrust of pharmacoeconomic data, perhaps since most pharmacoeconomic analyses are sponsored by manufacturers of the products that are the subject of the PE analyses. 23 In addition to apparent poor understanding of PE terms and methods and distrust of PE data among decision makers, bias in PE studies is unavoidable, creating a ripe opportunity for mistrust. PE studies use economic data applied to an inferred association between one or more independent variables and a dependent variable. 24 The PE researcher has control over the selection of economic data, inclusion criteria, range of independent variables, and the dependent variable. Selection bias is a potential source of error in any study, and a common threat is nonrandom, nonresponse data or otherwise nonrandom missing data. For example, using medical claims data will show a lower incidence of diagnoses of depression than would patient chart data, which would have a lower incidence of diagnoses of