Table 7.

Cost-effectiveness of On-demand PPI Treatment.

Author	Year	Methodology	Outcome	Conclusion	Limitation
Wahlqvist et al10 (UK)	2002	• Patient and model: Markov model evaluates the cost-effectiveness of on-demand treatment with esomeprazole (20 mg) compared with the 2 omeprazole treatment strategies (intermittent and conventional care). The time frame of the analysis was 6 months and the model was made with a cycle length of 2 weeks. The timing of relapses, drug prescriptions, visits, and endoscopies were taken into account for each Markov cycle. • Patient management assumptions: Patient management assumptions used in the analysis were based mainly on a UK physician survey (involving 10 gastroenterologists and 15 general physicians) of patient management in clinical practice. • Effectiveness: The number of expected relapses per patient was used as the effectiveness measure in the cost-effectiveness analysis. • Unit costs and sensitivity analysis: Drug costs were calculated with regard to consumed medication during the study period. • The number of expected relapses per patient was used as the effectiveness measure in the cost-effectiveness analysis. Two clinical trials investigating the efficacy and safety of on-demand treatment with esomeprazole 20 mg for symptom control in patients with GERD without esophagitis. • Both studies were multicentered, randomized, double-blind, parallel group, 6-month comparative studies of esomeprazole 20 mg with placebo. Patients were instructed to take the study tablets when required to control symptoms. Patients in these 2 studies were also provided with antacids as rescue medication. The primary efficacy variable was “discontinuation due to unwillingness to continue” (due to insufficient control of heartburn, adverse events, or other reasons). In the first study, patients were randomized in equal proportions to on-demand treatment with esomeprazole 20 mg (n = 170) or placebo (n = 172). • In the second study, patients were randomized in proportions 2:1 to on-demand treatment with esomeprazole 40 mg (n = 293), esomeprazole 2 0 mg (n = 282), or placebo (n = 146). • Otherwise, both studies had essentially identical study protocols and were carried out at about the same point in time, with both doses of esomeprazole giving similar results. • To assess the proportion of patients relapsing during on-demand treatment with esomeprazole 20 mg, results were pooled as if the 2 studies were one large study in the current analysis. • The frequency of tablet intake was estimated in the clinical studies using Medical Event Monitoring System devices (Aardex Ltd, Switzerland) fitted to the drug containers, which recorded each time the container was opened. A pooled analysis on the average number of esomeprazole 20 mg tablets taken per patient each day was also carried out to estimate drug consumption during on-demand treatment.	• Cost-effectiveness analysis: The results indicate that the on-demand esomeprazole strategy is the most effective while being cost saving compared with either of the omeprazole strategies. • The results of the cost-effectiveness analysis in terms of expected direct medical costs per patient and expected number of relapses per patient. • The expected number of relapses per patient during on-demand therapy with esomeprazole 20 mg was 0.10. Using the “lower limit” for a probability of relapse during no drug treatment (47%, ie, placebo results from the clinical studies) resulted in 0.57 expected relapses per patient in the intermittent omeprazole strategy and 0.47 relapses in the conventional care omeprazole strategy. • Furthermore, the esomeprazole strategy incurred 16% lower direct medical costs than the intermittent omeprazole strategy and 34% lower costs compared with the conventional care omeprazole strategy. • The corresponding figures when using a 75% “upper limit” probability of relapse during no drug treatment were 1.12 relapses per patient in the intermittent omeprazole strategy and 0.75 in the conventional care omeprazole strategy. When considering the upper limit, the cost reduction by using the on-demand esomeprazole strategy increased to 57% compared with the intermittent omeprazole strategy and 61% compared with the conventional care omeprazole strategy. Thus, the results indicate that the on-demand esomeprazole strategy is the most effective while being cost saving compared with either of the omeprazole strategies. • Sensitivity analysis: The results indicate a cost saving of 26% to 55% still being made with the on-demand esomeprazole strategy (where direct medical costs were US$79.67), compared with a “low-dose” conventional care strategy.	• The data clearly demonstrate that on-demand esomeprazole 20 mg therapy is associated with significantly better effectiveness and lower costs than a strategy consisting of intermittent 4-week treatment courses of omeprazole 20 mg once daily.	• The endpoint used in this primary care study (symptoms of any severity on at least 2 days during the previous week) may not correspond to a definition of relapse in clinical practice.
Szucs et al13 (Switzerland)	2009	• Open-label, randomized, multicenter study comparing the 2 long-term management options with esomeprazole 20 mg—continuous daily or on-demand treatment during 26 weeks—in endoscopically uninvestigated patients seeking primary care in Switzerland for symptoms suggestive of GERD who demonstrated complete relief of symptoms after an initial treatment of 4 weeks with esomeprazole 40 mg. • Patients found to meet all the inclusion criteria and none of the exclusion criteria at the end of the initial treatment course were randomized in equal proportions to continuous treatment with esomeprazole 20 mg 4 times a day or on-demand treatment with esomeprazole 20 mg. For the randomization, a centrally compiled, computer-generated list was used, which was based on a block size of 4. Each site received a kit consisting of a list of randomization numbers and sealed randomization envelopes for 4 patients. The investigator was instructed to consecutively allocate the lowest available randomization number, but open the randomization envelopes containing the information on the allocated treatment group only at randomization. It had been planned that each site would recruit 4 patients (or an exact multiple of 4). Each patient in the continuous treatment arm was instructed to take 1 tablet once daily. • In the on-demand arm, the patient was instructed to take one tablet daily if needed for the relief of heartburn and to stop when the heartburn is adequately controlled. The study drugs were packed in bottles, and every patient received in total 2 bottles of 100 tablets esomeprazole 20 mg free of charge. The distribution schedule of the study drugs from general practitioner to patient was at the discretion of the general practitioner, ie, the treating physician decided when to distribute study drugs and whether to distribute them all at once or at several occasions. Compliance was determined by counting the tablets returned by the patient.	• The patients in the on-demand group experienced slightly more frequently GERD symptoms than those in the continuous group. At the end of the 6-month maintenance phase, 94% of the patients in the on-demand group and were classified as “satisfied” (score = 1-4) with their treatment, whereas 74% of the patients were reported to be “very satisfied” (score = 1-2), Wilcoxon rank sum test (score = 1-7): P < .056. • The difference of the adjusted mean direct medical costs between the treatment groups was CHF 88.72 (95% CI: CHF 41.34-153.95) in favor of the on-demand treatment strategy (Wilcoxon rank sum test: P < .0001). The mean number of clinic visits to the investigator for any reason required per patient was 0.52 (SD = 0.663) for those in the on-demand group. • Adjusted direct nonmedical costs and the productivity loss were similar in both treatment groups during the 6-month maintenance phase. Hence, health care payers will obtain net savings by implementing the use of on-demand esomeprazole. • These results confirm that the maintenance therapy through 6 months with respect to patients’ satisfaction and symptom control, defined no need for change of therapy, can be performed with a continuous, as well as by an on-demand schedule using esomeprazole 20 mg daily. The treatment with continuous esomeprazole was more efficient than the on-demand therapy with regard to remission of heartburn. • The adjusted direct medical costs of a 6-month on-demand treatment with esomeprazole 20 mg in patients with GERD were significantly lower compared with a continuous treatment with esomeprazole 20 mg once a day.	• The data clearly demonstrate that on-demand esomeprazole 20 mg therapy is associated with significantly better effectiveness and lower costs than a strategy consisting of intermittent 4-week treatment courses of omeprazole 20 mg once daily.	• The endpoint used in this primary care study (symptoms of any severity on at least 2 days during the previous week) may not correspond to a definition of relapse in clinical practice.
Gerson et al7 (USA)	2000	• On-demand PPI Arm: Empirical treatment with an 8-week course of PPI therapy administered on demand when GERD symptoms reoccur. Patients in this group require at most three 8-week courses (24 weeks) of medication per year. Patients failing on-demand therapy (recurrence of symptoms earlier than 2 months without medication) receive continuous PPI therapy, and endoscopy is performed only if symptoms recur on daily PPI therapy.	• The researchers had done a decision analysis on on-demand PPI strategy in which the empirical treatment with an 8-week course of PPI therapy administered on demand when GERD symptoms recur. Patients in this group require at most three 8-week courses (24 weeks) of medication per year. Patients failing on-demand therapy (recurrence of symptoms earlier than 2 months without medication) receive continuous PPI therapy, and endoscopy is performed only if symptoms recur on daily PPI therapy. • On-demand PPI strategy is the most cost-effective approach with discounted incremental cost-effectiveness ratio of US$20 934 per QALY gained by patient with mild to severe GERD symptoms and $379 223 per QALY gained for patient with mild GERD symptoms. On-demand PPI was dominant with an incremental cost-effectiveness ratio of $2197/QALY gained.	• On-demand PPI strategy is the most cost-effective approach	• An analysis of lifetime costs—not known how long patient can expect symptomatic relief. • Only few of the prior studies used QALYs as a utility measurement, and obtained their estimates through a modified Delphi process. • Prior models did not allow patients to switch from H2RAs to PPIs without endoscopy, often did not include the option of Nissen fundoplication, or sent patients without response to PPI for a Nissen without consideration of promotility therapy. • None of the models included patients with nonerosive disease.

Note. PPI = proton pump inhibitor; GERD = gastroesophageal reflux disease; CHF = congestive heart failure; CI = confidence interval; QALYs = quality-adjusted life in years; H₂RAs = histamine 2 receptor antagonists.