Heartburn is a common symptom among adults in

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3: Early Heartburn Relief With Proton Pump Inhibitors: A Systematic Review and Meta-analysis of Clinical Trials KENNETH R. MCQUAID*, and LOREN LAINE *Veterans Affairs Medical Center and Department of Medicine, University of California San Francisco, San Francisco, California; and University of Southern California, Los Angeles, California Background & Aims: Proton pump inhibitors (PPIs) are often taken for short-term treatment of heartburn. We performed a systematic review of the efficacy of PPIs for heartburn within the first 1 2 days of therapy. Methods: Bibliographic databases were searched for clinical trials of PPIs in patients with heartburn that provided information about the proportion with heartburn at day 1 2. The sample size weighted pooled proportions of patients with complete or sustained (7 consecutive days) were calculated. Meta-analyses of randomized comparisons of PPIs were also performed. Results: Eighteen trials met inclusion criteria. At day 1 of PPI therapy, complete 24-hour, daytime, nighttime, and sustained heartburn occurred in 0.31 (95% confidence interval [CI], ), 0.49 (95% CI, ), 0.55 (95% CI, ), and 0.21 (95% CI, ) of patients. Up to 37% of the heartburn achievable with 28 days of PPIs occurred on day 1. Placebo was significantly less effective than PPIs for 24-hour on day 1 (relative risk [RR], 0.41; 95% CI, ), and single-dose PPI therapy was less effective than double-dose therapy (RR, 0.82; 95% CI, ). Conclusions: Complete heartburn for the entire day occurs in approximately 30% of patients after their first PPI dose and 9% of patients after their first placebo (RR for on day 1 for placebo versus PPI was 0.41 [95% CI, ]). Although PPIs might provide benefit from the first day of therapy, most patients will not have symptom with 1 or 2 days of PPI therapy. Heartburn is a common symptom among adults in the US, occurring at least once monthly in 25% 44% and daily in 5% 7% of the adult population. 1,2 As assessed by several instruments, patients have reduced health-related quality of life in proportion to the frequency of heartburn. 3 Patient-directed therapy with antacids or over-the-counter low-dose histamine 2 -receptor antagonists might be recommended for the treatment of intermittent heartburn in the absence of other warning signs. 4,5 Consensus expert opinion, however, is that heartburn occurring on 2 or more days per week is predictive of gastroesophageal reflux disease (GERD) that warrants medical attention and more aggressive acid suppression therapy with full-dose histamine 2 -receptor antagonists or proton pump inhibitors. 3,4 In most patients, the principal goal of therapy is of heartburn and other GERD-related symptoms. 3,4,6 On the basis of their proven efficacy and superiority to histamine 2 -receptor antagonists for healing of erosive esophagitis and of heartburn, proton pump inhibitors are recommended for the initial acute treatment of erosive and nonerosive GERD as well as empirical treatment of symptomatic (ie, uninvestigated) GERD. 3,7 Despite the efficacy of proton pump inhibitors for long-term heartburn management, antacids and/or histamine 2 -receptor antagonists are generally recommended for acute symptom because of their faster time to acid neutralization or suppression. 5 On the basis of their pharmacokinetic and pharmacodynamic properties, oral proton pump inhibitors administered once daily do not achieve maximal acid suppression for 4 days. 8,9 Nevertheless, studies measuring gastric acid secretion or intragastric ph in normal volunteers and patients with GERD demonstrate that administration of a single dose of a proton pump inhibitor begins to inhibit acid secretion within 1 2 hours, significantly reduces 24-hour gastric acidity, and increases intragastric ph 4 for up to 50% of the first 24 hours (also see pharmacodynamic data listed in product labeling). It is therefore possible that proton pump inhibitors might yield symptomatic from heartburn within the first hours of therapy. Several prior systematic reviews have assessed the overall efficacy of proton pump inhibitors for heartburn in GERD. However, none have looked specifically at heartburn within the first week, and none have examined the benefit of proton pump inhibitors for of heartburn in the first day or two of therapy. 2,15 17 We Abbreviations used in this paper: CI, confidence interval; GERD, gastroesophageal reflux disease; RR, relative risk by the American Gastroenterological Association /05/$30.00 PII: /S (05)

2 554 MCQUAID AND LAINE CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 6 therefore conducted a systematic review to summarize, quantify, and compare the efficacy of proton pump inhibitors for the of heartburn within the first hours of therapy in patients with GERD. Methods Searching We performed a systematic review of the medical literature for clinical trials of proton pump inhibitors in patients with GERD that provided information about the number or percentage of patients achieving complete heartburn at day 1 2 of therapy. We searched the MED- LINE (1966 June 2004) and EMBASE (1980 June 2004) computerized bibliographic databases as well as bibliographies from previous systematic reviews. 2,15 17 We did not search for abstracts, and we did not seek unpublished data from pharmaceutical companies or the US Food and Drug Administration. The MEDLINE search was conducted by combining the MESH terms (benzimidazoles, proton pumps/ antagonists and inhibitors, omeprazole, omeprazoles/analogs and derivatives) or the title words (esomeprazole, lansoprazole, pantoprazole, and rabeprazole) with the MESH terms (gastroesophageal reflux, heartburn, esophagitis, peptic or esophagitis); the search was limited to clinical trials. The EMBASE search was conducted by combining the terms benzimidazole derivative, proton pump inhibitor, esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole with the terms heartburn, reflux esophagitis, orgastroesophageal reflux and the restrictor Clinical trial. The searches were not limited by language. These strategies yielded 388 articles from MEDLINE and 973 titles from EMBASE. The 2 authors independently screened the titles and abstracts for eligibility. Study Selection The full text of published clinical trials that examined the efficacy of proton pump inhibitors (ie, esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole) in adults with acute heartburn, erosive esophagitis, nonerosive GERD, or symptomatic GERD was reviewed. Studies were eligible for inclusion if subjects were reported to have heartburn and/or symptomatic GERD at enrollment, and if sufficient information about heartburn assessment during the first 2 days of therapy was given. Studies that enrolled patients with erosive esophagitis but did not provide sufficient information about baseline heartburn were excluded. Because the focus of this systematic review was acute of heartburn with proton pump inhibitors in GERD, studies were excluded that addressed chronic maintenance, intermittent, or on demand therapy. In addition, studies in which GERD symptoms were reported to be refractory to standard or high-dose antisecretory therapy with histamine 2 -receptor antagonists or proton pump inhibitors were excluded, as were studies with less than 20 subjects per study arm. Uncontrolled trials were not excluded a priori from the analysis. Studies were only included that reported either the number or percentage of patients with complete heartburn on day 1 or 2 of therapy by using a prespecified symptom assessment tool (eg, daily diary, interactive phone system, patient or physician assessment). Data Abstraction and Validity Assessment The full text of selected articles was reviewed independently by the authors to confirm eligibility, assess study quality, and extract data by using a predesigned extraction form. Disagreement between reviewers was resolved by consensus. Clinical trials were scored for quality by using the criteria established by Jadad et al 18 on a scale of 0 5. The following data were extracted for each treatment arm: number of patients, study design, type of analysis (per protocol or intent to treat), treatment arms (medications, dosage, and duration), inclusion/exclusion criteria, method of symptom assessment, the number with baseline heartburn (overall, daytime, nighttime), and the number with complete heartburn (overall, daytime, nighttime) and sustained heartburn on days 1, 2, and 28. The primary outcome assessment was the number of patients at day 1 with heartburn resolution within the prior 24-hour period (overall, daytime, or nighttime). Secondary outcomes that were assessed were heartburn resolution on day 2 (overall, daytime, or nighttime) and sustained heartburn resolution on days 1 and 2. Sustained resolution is defined as the absence of heartburn in the prior 24-hour period that lasts for 7 consecutive days. In addition, we assessed the proportion of maximal benefit that could be achieved with therapy on day 1 or day 2 by dividing the proportion of patients with heartburn resolution at day 1 or day 2 by the proportion with heartburn resolution at day 28 (if day 28 data were available). The number of patients with heartburn resolution at day 28 was used as an estimate of the maximal benefit achievable with the therapy. For example, if 80% of patients had resolution at day 28 and 20% had resolution at day 1, the proportion of benefit that was achieved on day 1 was 25% (0.20/0.80). In many studies, heartburn resolution was depicted in graphic form as the percentage of patients with complete or sustained heartburn resolution. For these studies, each reviewer independently made an estimation of the percentage of patients achieving symptom resolution at day 1, 2, or 28, and a mean was taken of these 2 estimations. In most cases, both graphic estimations were within 1% and in all cases within 2%. Data Analysis The proportion of patients with complete or sustained heartburn at day 1 and day 2 of treatment with proton pump inhibitors and placebo was calculated separately by using sample size weighted pooling for each treatment subgroup. The 95% confidence intervals (CIs) were calculated for each pooled estimate. Pooled analyses were done separately for

3 June 2005 PPIS AND EARLY HEARTBURN RELIEF 555 day 1 and day 2 for individual proton pump inhibitors, combined proton pump inhibitors, and placebo. Comparisons between proton pump inhibitors and between proton pump inhibitors and placebo of the proportions of patients achieving complete or sustained of heartburn at day 1 were performed by using meta-analysis. Meta-analytic assessment was applied only when at least 2 studies provided head-to-head comparison of the same treatment arms for one of our predefined end points. The relative risk (RR) of heartburn for combined or individual proton pump inhibitors versus comparator proton pump inhibitors or placebo was calculated by using True Epistat software (Epistat Services, Henderson, TX) through statistical pooling of individual study estimates. Heterogeneity was calculated by using the 2 test with n 1 degrees of freedom, where n represented the number of studies in the analysis. Significant heterogeneity was defined as a P value of.10 or less. The RRs and 95% CIs were calculated by using a random effects model. Although the studies included had similar patient populations, study designs, and symptom assessment tools, the random effects model provides a more conservative estimation than a fixed effects model of the overall treatment response by incorporating between-study heterogeneity. Role of Funding Sources No funding source had any role in the design, performance, analysis, or reporting of this systematic review. Results Our search yielded 17 original articles (comprising 18 clinical trials) that met our inclusion and exclusion criteria and provided sufficient information to determine the number and proportion of patients with complete heartburn after 1 day of proton pump inhibitor therapy More than 21,000 patients with GERD were treated with proton pump inhibitors in these clinical trials. Heartburn was the primary outcome being assessed in 9 of the articles 19,22,23,25,27,28,31,32,34 ; however, heartburn within the first 2 days was the primary outcome assessment in only 2 studies. 22,31 The characteristics of the 18 clinical trials included in this systematic review are provided in Table 1. All studies but one 34 were randomized, controlled trials. Eight studies had a placebo control arm. Fifteen of the trials were double-blind, and 14 had a Jadad score of 3, reflecting good quality study design. Results of one unblinded, uncontrolled trial (with a Jadad score of 0) were included in the initial pooled analysis of daytime and nighttime heartburn ; however, a post hoc analysis excluding this study also was performed. 34 Because this study did not include a comparator, it was not included in the meta-analyses. Eleven trials enrolled patients with erosive esophagitis; 5 enrolled patients with nonerosive reflux disease (confirmed by endoscopy), and 2 enrolled patients with symptomatic GERD (without endoscopy). Heartburn symptoms on day 1 or day 2 of therapy were assessed by a written patient diary in 16 trials and by a telephone interactive voice response system in 2 trials. The studies selected for this review included treatment arms with omeprazole mg/d, esomeprazole mg/d, lansoprazole mg/d, and rabeprazole mg/d. No clinical trials with pantoprazole fulfilled our inclusion criteria. Antacids were permitted in all trials on an as needed basis for breakthrough symptoms for patients taking placebo or proton pump inhibitors; however, histamine 2 -receptor antagonists were not permitted. The primary outcome assessment in this review was the number and proportion of patients at day 1 of therapy with complete heartburn resolution during the daytime, nighttime, and/or entire 24 hours. Of the 16 trials that provided this information, 7 reported overall for the preceding 24 hours; 8 reported daytime and nighttime separately without reporting overall 24- hour ; and 1 reported overall 24-hour as well as daytime and nighttime. Three trials did not provide information about overall, daytime, or nighttime in the first 24 hours but did report the number of patients with sustained heartburn. Three trials reported sustained in addition to 24-hour or daytime and nighttime. Table 2 lists results of 24- hour, daytime, nighttime, and sustained heartburn for days 1, 2, and 28 for each study. Six articles were retrieved but excluded from the analysis Three of these studies provided information about complete of GERD symptoms (including heartburn, regurgitation, dysphagia, dyspepsia, bloating, belching, indigestion, abdominal pain, and nausea) within the first 1 2 days but did not provide separate information about heartburn Because the specific focus of our review was complete heartburn, we did not believe that the results of these 3 studies could be fairly compared or pooled with the other studies included in our analysis. In one of these studies, complete daytime or nighttime of GERD symptoms after 1 day of therapy was reported in 40% or 43% of patients treated with cimetidine 400 mg 4 times daily versus 40% or 50% of patients treated with omeprazole 20 mg/d. 36 Another study reported complete 24-hour from GERD symptoms during the first day of therapy in 3% of patients treated with ranitidine 300 mg twice daily versus 8% treated with omeprazole 20 mg/d. 38 A third study reported complete 24-hour in 30% of

4 556 MCQUAID AND LAINE CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 6 Table 1. Characteristics of Studies Included in Systematic Review Author, year reference Design Jadad score (0 5) Daily PPI dose (N) Placebo (N), H 2 RA (N) Symptom assessment tool Heartburn outcome Erosive esophagitis Adachi et al, Castell et al, Castell et al, Holtmann et al, Howden et al, Kahrilas et al, R, unblinded 2 Omeprazole 20 mg (30) Lansoprazole 30 mg (25) Rabeprazole 20 mg (30) R, DB 4 Lansoprazole 30 mg (2617) Esomeprazole 40 mg (2624) R, DB 2 Omeprazole 20 mg (418) Lansoprazole 15 mg (208) Lansoprazole 30 mg (402) R, DB 5 Omeprazole 40 mg (116) Rabeprazole 20 mg (118) R, DB 3 Lansoprazole 30 mg (143) Esomeprazole 40 mg (141) R, DB 4 Omeprazole 20 mg (624) Esomeprazole 20 mg (626) Esomeprazole 40 mg (621) R, DB 5 Omeprazole 20 mg (1209) Esomeprazole 40 mg (1216) R, DB 3 Omeprazole 20 mg (1746) Lansoprazole 30 mg (1748 R, SB 2 Omeprazole 20 mg (92) Ranitidine, metoclopramide Richter et al, Richter et al, Robinson et al, Robinson et al, Sontag et al, Non-erosive reflux disease Katz et al, Study #1 R, DB 5 Esomeprazole 20 mg (121) Esomeprazole 40 mg (123) Daily diary Daily diary 24-h 24-h Placebo (198) Daily diary Daytime and nighttime Daily diary Daily diary Daily diary Day and nighttime (1) 24-h (2) Day and nighttime 24-h Sustained Daily diary (1) 24-h (2) Sustained Daily diary (1) 24-h (2) Sustained Daily diary Day and nighttime Uncontrolled 0 Rabeprazole 20 mg (2449) IVRS Day and nighttime R, DB 4 Omeprazole 20 mg (93) Placebo (46) Daily diary Day and nighttime Omeprazole 40 mg (91) heartburn Study #2 R, DB 5 Esomeprazole 20 mg (113) Esomeprazole 40 mg (118) Miner et al, 28 R, DB 3 Rabeprazole 10 mg (64) 2002 Rabeprazole 20 mg (67) Richter et al, 31 R, DB 3 Lansoprazole 15 mg (80) 1999 Lansoprazole 30 mg (86) Richter et al, 32 R, DB 3 Omeprazole 10 mg (118) 2000 Omeprazole 20 mg (118) Symptomatic GERD Chey et al, R, DB 5 Lansoprazole 30 mg (1520) Esomeprazole 40 mg (1514) Johnsson et al, R, DB 4 Esomeprazole 20 mg bid (176) Esomeprazole 40 mg (171) Placebo (124) Daily diary Sustained Placebo (118) Daily diary Sustained Placebo (68) Daily diary Day and nighttime Placebo (43) Daily diary Day and nighttime Placebo (123) Daily diary 24-h IVRS (1) Sustained (2) Day and nighttime Placebo (92) Daily diary 24-h PPI, proton pump inhibitor; H 2 RA, histamine 2 -receptor antagonist; R, randomized; DB, double-blind; SB, single-blind; IVRS, interactive voice response system. patients treated with omeprazole 10 mg/d and 34% treated with omeprazole 20 mg/d during the first day of therapy. 37 Of the other 3 excluded studies, one provided information about adequate (but not complete) of GERD symptoms but not heartburn. 40 The other 2 provided information about the time to persistent from either GERD symptoms 39 or heartburn, 41 defined as the first day on which symptoms were absent and not reported on any subsequent days during the study. Because these definitions differed from our predefined end points and from the definition of complete heartburn used in all other included studies, these studies were excluded.

5 June 2005 PPIS AND EARLY HEARTBURN RELIEF 557 Table 2. Efficacy of Proton Pump Inhibitors for Heartburn Relief: Results of Individual Studies Study reference PPI N Day 1 (%) Day 2 (%) Day 28 (%) 24-Hour heartburn Adachi et al, Omeprazole 20 mg 30 2 (7) 10 (33) Lansoprazole 30 mg 25 2 (8) 6 (24) Rabeprazole 20 mg (33) 17 (57) Castell et al, Lansoprazole 30 mg (25) 837 (32) 1793 (69) Esomeprazole 40 mg (26) 932 (36) 1876 (71) Howden et al, Lansoprazole 30 mg (35) Esomeprazole 40 mg (27) Johnsson et al, Esomeprazole 20 mg (30) 82 (47) Esomeprazole 40 mg (26) 87 (51) Kahrilas et al, Omeprazole 20 mg (37) Esomeprazole 20 mg (38) Esomeprazole 40 mg (47) Richter et al, Omeprazole 20 mg (32) Esomeprazole 40 mg (45) Richter et al, Omeprazole 20 mg (25) Lansoprazole 30 mg (33) Richter et al, Omeprazole 10 mg (14) 25 (21) 59 (50) Omeprazole 20 mg (25) 45 (38) 91 (77) Total 13, (31) 2041 (35) 3819 (70) Daytime heartburn Castell et al, Omeprazole 20 mg (38) Lansoprazole 15 mg (43) Lansoprazole 30 mg (49) Chey et al, Lansoprazole 30 mg (46) Esomperazole 40 mg (45) Holtmann et al, Omeprazole 40 mg (46) 81 (70) Rabeprazole 20 mg (47) 93 (79) Howden et al, Lansoprazole 30 mg (42) Esomeprazole 40 mg (35) Miner et al, Rabeprazole 10 mg (27) 20 (31) Rabeprazole 20 mg (21) 22 (33) Richter et al, Lansoprazole 15 mg (45) Lansoprazole 30 mg (40) Robinson et al, Omeprazole 20 mg (20) 22 (24) 56 (61) Robinson et al, Rabeprazole 20 mg (62) 1665 (68) Sontag et al, Omeprazole 20 mg (16) 21 (23) 62 (67) Omeprazole 40 mg (16) 26 (29) 65 (71) Total (49) 1950 (63) 183 (66) Nighttime heartburn Castell et al, Omeprazole 20 mg (52) Lansoprazole 15 mg (49) Lansoprazole 30 mg (62) Chey et al, Lansoprazole 30 mg (48) Esomeprazole 40 mg (47) Holtmann et al, Omeprazole 40 mg (60) 95 (82) Rabeprazole 20 mg (62) 97 (82) Howden et al, Lansoprazole 30 mg (48) Esomeprazole 40 mg (42) Miner et al, Rabeprazole 10 mg (34) 30 (47) Rabeprazole 20 mg (36) 27 (40) Richter et al, Lansoprazole 15 mg (61) Lansoprazole 30 mg (51) Robinson et al, Omeprazole 20 mg (22) 24 (26) 57 Robinson et al, Rabeprazole 20 mg (68) 1885 (77) Sontag et al, Omeprazole 20 mg (24) 29 (31) 58 Omeprazole 40 mg (20) 26 (29) 66 Total (55) 2213 (72) 181 (66) (continued on following page)

6 558 MCQUAID AND LAINE CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 6 Table 2 (continued). Efficacy of Proton Pump Inhibitors for Heartburn Relief: Results of Individual Studies Study reference PPI N Day 1 (%) Day 2 (%) Day 28 (%) Sustained heartburn Chey et al, Lansoprazole 30 mg (17) 294 (20) Esomeprazole 40 mg (17) 300 (20) Kahrilas et al, Omeprazole 20 mg (23) 416 (67) Esomeprazole 20 mg (22) 439 (70) Esomeprazole 40 mg (30) 461 (74) Katz et al, Esomeprazole 20 mg (10) 16 (13) 58 (48) Esomeprazole 40 mg (19) 28 (23) 63 (51) Katz et al, Esomeprazole 20 mg (15) 25 (22) 64 (57) Esomeprazole 40 mg (19) 31 (26) 61 (52) Richter et al, Omeprazole 20 mg (20) 362 (30) 856 (71) Esomeprazole 40 mg (29) 462 (38) 913 (75) Richter et al, Omeprazole 20 mg (17) 1372 (79) Lansoprazole 30 mg (22) 1363 (78) Total 11, (21) 1518 (26) 6066 (73) PPI, proton pump inhibitor. Summary of Pooled Results of Heartburn Relief: Proton Pump Inhibitors Combined Table 3 lists the pooled results for day 1 and day 2 complete heartburn for the 24-hour period, the daytime or nighttime periods, and sustained for 7 consecutive days. After day 1 of therapy, the proportion of all patients treated with proton pump inhibitors who had complete for the entire 24-hour period was 0.31 (95% CI, ). After restricting the analysis to trials that enrolled patients with erosive esophagitis, the proportion with complete 24-hour heartburn was unchanged (0.31; 95% CI, ). On the basis of data from 2 studies, 25,32 the proportion of patients treated with placebo who had complete for the entire 24-hour period during day 1 was 0.09 (95% CI, ) and during day 2 was 0.09 (95% CI, ). The RR for day 1 heartburn with placebo versus proton pump inhibitors was 0.41 (95% CI, ). The 2 placebocontrolled studies provided no information about antacid usage during the first 2 days in the patients treated with placebo or proton pump inhibitors. The proportion of patients reporting complete heartburn with proton pump inhibitor therapy during the day 1 daytime (0.49; 95% CI, ) or nighttime (0.55; 95% CI, ) periods was higher than for the entire 24-hour period. A subset analysis of trials that enrolled patients with erosive esophagitis yielded higher proportions with day 1 daytime (0.52; 95% CI, ) and nighttime (0.60; 95% CI, ) heartburn than trials that enrolled patients with nonerosive reflux disease (daytime: 0.34 [95% CI, ] and nighttime: 0.47 [95% CI, ]). After post hoc elimination of one large, poor quality, uncontrolled, unblinded study from the pooled analysis, the proportion of patients treated with proton pump inhibitors with was lower for both daytime heartburn (0.42; 95% CI, ) and nighttime heartburn (0.48; 95% CI, ). 34 On the basis of summary data from 4 studies, the proportion of patients treated with placebo with day 1 daytime (0.16; 95% CI, ) or nighttime (0.27; 95% CI, ) complete heartburn appears to be lower than with proton pump inhibitors. 21,28,31,35 Two placebo-controlled studies provided information about antacid usage during day 1 of therapy. In one, antacids were used by 42% 50% of patients treated with proton pump inhibitors versus 73% of patients with placebo. 21 In another study, antacids were used by 47% of patients treated with lansoprazole versus 76% treated with placebo. 31 When heartburn resolution with proton pump inhibitor therapy at day 1 was compared to the maximal level of attained by day 28, the proportion of the maximal response achieved in the first 24-hour period was 0.37 (95% CI, ). The proportion of maximal achievable response for nighttime heartburn on day 1 was 0.33 (95% CI, ) and for daytime heartburn was 0.26 (95% CI, ). When day 1 and day 2 are compared, the proportion of patients treated with proton pump inhibitors with complete heartburn is increased on day 2 in the daytime, nighttime, and 24-hour periods, and the 95% CIs for the day 2 proportions do not overlap with day 1. The proportions of maximal achievable also increase from day 1 to day 2; however, the 95% CIs overlap for the daytime and nighttime assessments. Results for

7 June 2005 PPIS AND EARLY HEARTBURN RELIEF 559 Table 3. Heartburn Relief: Pooled Results of Combined Proton Pump Inhibitors Heartburn Number of studies pooled for each analysis reference Day 1: Responders/N pooled proportion (95% CI) Day 2: Responders/N pooled proportion (95% CI) Proportion of maximal attributable Day 1/28 Pooled proportion (95% CI) Day 2/28 Pooled proportion (95% CI) 24-h Day 1: 8 19,20,24 26,29,30, /13, / / /3819 Day 2: 4 19,20,25, Day 1/28: 2 20,32 ( ) ( ) ( ) ( ) Day 2/28: 2 20,32 Daytime Day 1: ,28,31, / / /183 69/183 Day 2: 5 23,28, Day 1/28: 2 33,35 ( ) ( ) ( ) ( ) Day 2/28: 2 33,35 Nighttime Day 1: ,28,31, / / /181 79/181 Day 2: 5 23,28, Day 1/28: 2 33,35 ( ) ( ) ( ) ( ) Day 2/28: 2 33,35 Sustained Day 1: 6 22,26,27,29, /11, / / /2015 Day 2: 4 22,27, Day 1/28: 5 26,27,29,30 ( ) ( ) ( ) ( ) Day 2/28: 3 27,29 these end points, however, were available for far fewer patients (183 and 181) than for any other end point, leading to wider CIs. Sustained heartburn was a secondary outcome assessment. The proportion of patients achieving complete heartburn resolution on day 1 or day 2 of proton pump inhibitor therapy that was sustained for at least 7 consecutive days was 0.21 (95% CI, ) and 0.26 (95% CI, ). As might be expected by this more rigorous definition, the proportion of patients achieving sustained heartburn with proton pump inhibitors was lower than the proportion achieving on individual days 1 and 2. A subset analysis of trials that enrolled patients with erosive esophagitis demonstrated higher day 1 sustained heartburn (0.22; 95% CI, ) than trials that enrolled patients with nonerosive reflux disease (0.16; 95% CI, ). The proportion of maximal sustained at day 28 that was achieved by day 1 was 0.30 (95% CI, ) and by day 2 was 0.46 (95% CI, ). On the basis of data from 2 studies, the proportion of patients treated with placebo that derived sustained heartburn at day 1 (0.01; 95% CI, ) or day 2 (0.02; 95% CI, ) was very low. 27 Subgroup Analysis of Pooled Results Data from different proton pump inhibitors were pooled and analyzed separately. At day 1 of therapy, complete 24-hour heartburn was reported in 0.29 (95% CI, ) of patients treated with omeprazole 20 mg/d and 0.29 of patients treated with lansoprazole 30 mg/d (95% CI, ). Esomeprazole 40 mg/d yielded slightly higher day 1 heartburn (0.34; 95% CI, ). When data pertaining to sustained heartburn for different proton pump inhibitors were analyzed, the same pattern was noted. The proportions of patients achieving sustained by day 1 with omeprazole 20 mg (0.19; 95% CI, ), lansoprazole 30 mg (0.20; 95% CI, ), and esomeprazole 20 mg (0.19; 95% CI, ) were lower than esomeprazole 40 mg/d (0.24; 95% CI, ). Subgroup analysis was also performed for daytime and nighttime heartburn with different proton pump inhibitors. The proportion of patients achieving daytime heartburn at day 1 with omeprazole 20 mg/d was 0.32 (95% CI, ), which was lower than the proportion with lansoprazole 30 mg/d (0.46; 95% CI, ) or esomeprazole 40 mg (0.44; 95% CI, ). On the basis of data from 3 studies, 1588 of 2634 patients treated with rabeprazole 20 mg/d (0.60; 95% CI, ) achieved complete daytime heartburn at day 1. However, this proportion is dominated by the inclusion of one large (N 2449) uncontrolled study 34 of poor methodologic quality (Jadad score, 0). Similar trends among the proton pump inhibitors are noted with day 1 nighttime heartburn. The proportion of patients achieving complete nighttime heartburn was 0.43 (95% CI, ) with omeprazole 20 mg/d, 0.51 (95% CI, ) with lansoprazole 30 mg/d, and 0.47 (95% CI, ) with esomeprazole 40 mg/d. Rabeprazole 20 mg/d again

8 560 MCQUAID AND LAINE CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 6 Table 4. Meta-analysis of Heartburn Relief at Day 1 Comparators: drug 1 vs drug 2 Number of studies reference Summary RR 95% CI Heterogeneity P value Day 1 24-h heartburn Placebo vs standard dose PPI 2 25, Omeprazole 20 mg vs standard dose PPI 419,26,29, Omeprazole 20 mg vs lansoprazole 30 mg 219, Omeprazole 20 mg vs esomeprazole 40 mg 226, Lansoprazole 30 mg vs esomeprazole 40 mg 220, Single-dose PPI vs double-dose PPI 226, Day 1 daytime heartburn Placebo vs standard dose PPI 421,28,31, Lansoprazole 30 mg vs esomeprazole 40 mg 222, Single-dose PPI vs double-dose PPI 421,28,31, Day 1 nighttime heartburn Placebo vs standard dose PPI 421,28,31, Lansoprazole 30 mg vs esomeprazole 40 mg 222, Single-dose PPI vs double-dose PPI 421,28,31, Day 1 sustained heartburn Placebo vs esomeprazole 40 mg Omeprazole 20 mg vs other PPIs combined 326,29, Omeprazole 20 mg vs esomeprazole 40 mg 226, PPI, proton pump inhibitor. yielded a higher proportion of patients with day 1 nighttime heartburn resolution (0.67, 95% CI, ), with the same caveat that this proportion is dominated by inclusion of one large uncontrolled study. Meta-analysis A sufficient number of comparative trials were identified to permit a meta-analysis of heartburn at day1(table 4). For 24-hour, daytime, nighttime, and sustained heartburn, placebo was inferior to combined proton pump inhibitors (omeprazole 20 mg/d, esomeprazole 20 or 40 mg/d, lansoprazole 15 or 30 mg/d, or rabeprazole 10 or 20 mg/d). For overall 24-hour heartburn at day 1, omeprazole 20 mg was inferior to combined comparator proton pump inhibitors (lansoprazole 30 mg, esomeprazole 20 and 40 mg, and rabeprazole 20 mg), with a summary RR 0.83 (95% CI, ). Although there was significant heterogeneity (P.004) of results among the trials included in this pooled random-effects estimate, the point estimates of all studies included were on the same side of unity, all favoring the comparator proton pump inhibitors over omeprazole 20 mg. When analyzed separately, omeprazole 20 mg was inferior to lansoprazole 30 mg (RR, 0.82; 95% CI, ) and esomeprazole 40 mg (0.78, 95% CI, ). By contrast, lansoprazole 30 mg achieved similar overall day 1 heartburn to esomeprazole 40 mg (RR, 1.03, 95% CI, ). Two studies compared single-dose to double-dose proton pump inhibitor therapy (omeprazole 10 vs 20 mg, esomeprazole 20 vs 40 mg). Single-dose therapy was significantly less effective at achieving overall 24-hour heartburn at day 1 than double-dose therapy (RR, 0.82; 95% CI, ). Meta-analysis of trials that assessed day 1 sustained heartburn yielded similar results. Omeprazole was inferior (RR, 0.80, 95% CI, ) to comparator proton pump inhibitors (esomeprazole 20 or 40 mg, lansoprazole 30 mg) and to esomeprazole 40 mg/d (RR, 0.78; 95% CI, ). Few trials compared proton pump inhibitors for daytime and nighttime heartburn, limiting metaanalysis. Lansoprazole 30 mg was similar to esomeprazole 40 mg for daytime (RR, 1.03; 95% CI, ) and nighttime (RR, 1.03, 95% CI, ). In trials comparing single-dose versus double-dose proton pump inhibitors (lansoprazole 15 vs 30 mg, rabeprazole 10 vs 20 mg, omeprazole 20 vs 40 mg), daytime and nighttime heartburn resolutions were not significantly different. Discussion Our systematic review found that acute proton pump inhibitor therapy yields complete heartburn in 31% (95% CI, 30% 32%) of patients at day 1 of treatment and 35% (95% CI, 33% 36%) of patients at day 2, whereas 9% (95% CI, 5% 14%) of patients treated with placebo had complete heartburn on day 1. Whether looking at 24-hour, sustained, daytime, or nighttime heartburn, 1 day of proton pump

9 June 2005 PPIS AND EARLY HEARTBURN RELIEF 561 inhibitor therapy achieves 26% 37% of the maximal attainable after 28 days. Taken in aggregate, these pooled results confirm that proton pump inhibitors afford complete heartburn after only 1 2 days of therapy in a subset of GERD patients; however, the majority continue to be symptomatic. The results of our analysis are consistent with the pharmacokinetic and pharmacodynamic properties of proton pump inhibitors. 8,9,14,42 48 A single oral dose of a proton pump inhibitor can achieve acid suppression, although maximal suppression occurs after multiple daily dosing. After a single oral dose all proton pump inhibitors are rapidly absorbed, reaching peak drug levels and acid suppression within 2 4 hours The bioavailability of proton pump inhibitors on day 1 varies widely, ranging from 30% (omeprazole 20 mg) to 80% (lansoprazole 30 mg); however, with repeated daily dosing, gastric acid inhibition increases during the first 5 days as a result of enhanced bioavailability (less destruction by gastric acid), increased drug concentrations (area under the curve), and progressive inactivation of H /K -ATPase molecules. The area under the curve for omeprazole 20 mg ( mol L 1 h 1 ) is also lower on day 1 than for lansoprazole ( mol L 1 h 1 ) or esomeprazole 40 mg ( mol L 1 h 1 ) A single dose of omeprazole 20 mg inhibits 25% 50% of day 1 24-hour intragastric acidity; however, after multiple daily dosing of omeprazole 20 mg, 24-hour acidity is decreased by 80% 97%. 8,47,48 Pharmacodynamic studies of intragastric ph measurements suggest that other proton pump inhibitors might be superior to omeprazole for suppression of acid secretion on day 1. Whereas a single dose of omeprazole 20 mg increases intragastric ph 4 for 25% of day 1, esomeprazole 40 mg or lansoprazole 30 mg increases intragastric ph 4 for 30% 60% of the 24-hour period After multiple daily dosing, omeprazole 20 mg, esomeprazole 40 mg, and lansoprazole 30 mg increase intragastric ph 4 for 50% 70% of the 24-hour period. In separate meta-analyses we found omeprazole 20 mg to be less effective than both lansoprazole 30 mg and esomeprazole 40 mg for achieving 24-hour or sustained heartburn during the first day of treatment. The apparent inferiority of omeprazole 20 mg compared with lansoprazole 30 mg and esomeprazole 40 mg for acute heartburn likely is attributable to lower dosage as well as the pharmacokinetic differences discussed above. By contrast, lansoprazole 30 mg and esomeprazole 40 mg resulted in similar daytime, nighttime, and 24-hour heartburn after 1 day of therapy. Because no studies of pantoprazole were included in this systematic review and because there are few head-to-head comparisons of rabeprazole with other agents (precluding meta-analysis), no conclusions can be drawn about speed of symptom with these agents relative to other proton pump inhibitors. There are several potential limitations of this systematic review. First, we did not seek to identify unpublished data. Our original literature search led to inclusion of a substantial number (eighteen) of clinical trials that had symptom assessment in more than 21,000 patients, allowing for a robust analysis. Second, although all of the studies included in this review enrolled patients with frequent heartburn, none provided specific information about the proportion of patients with heartburn on the day preceding treatment (day 0). Therefore, the actual proportion of symptom attributable to drug therapy versus natural symptom fluctuation is uncertain. Third, complete of heartburn in the first hours was not a primary end point in any of the studies included in this analysis. Information about these secondary end points was derived from patient diaries or interactive response systems and might not be completely accurate or reliable. Fourth, only one study included in this analysis included a histamine 2 -receptor antagonist as a comparator, precluding pooled or metaanalysis. 33 Although nonprescription formulations of histamine 2 -receptor antagonists are approved for the prevention and treatment of acute heartburn, the present analysis sheds no light on the relative efficacy of proton pump inhibitors to histamine 2 -receptor antagonists for acute heartburn. Another potential limitation of this analysis is that antacids were permitted on an as needed basis for heartburn symptoms in all studies. Although it might be argued that some of the therapeutic benefit observed in patients treated with placebo or proton pump inhibitors might be attributable to antacid therapy, this is unlikely. Because antacid use indicates that patients were symptomatic, patients taking antacids should not have been included as having complete heartburn (the focus of the present analysis). In conclusion, complete of heartburn for the entire day occurs in approximately 30% of patients after their proton pump inhibitor dose and 9% of patients after their first placebo dose (RR for on day 1 for placebo vs proton pump inhibitor, 0.41; 95% CI, ). Although proton pump inhibitors might provide benefit from the first day of therapy, most patients will not have symptom with 1 or 2 days of therapy.

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11 June 2005 PPIS AND EARLY HEARTBURN RELIEF 563 efficacy of pantoprazole vs. nizatidine in the treatment of erosive esophagitis: a randomized, active-controlled, double-blind study. Aliment Pharmacol Ther 2002;16: Scholten T, Gatz G, Hole U. Once-daily pantoprazole 40 mg and esomeprazole 40 mg have equivalent overall efficacy in relieving GERD-related symptoms. Aliment Pharmacol Ther 2003;18: Richter JE, Bochenek W. Oral pantoprazole for erosive esophagitis: a placebo-controlled, randomized clinical trial Pantoprazole US GERD Study Group. Am J Gastroenterol 2000;95: Hassan-Alin M, Andersson T, Bredberg E, et al. Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects. Eur J Clin Pharmacol 2000;56: Andersson T, Holmberg J, Rohss K, et al. Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole. Br J Clin Pharmacol 1998;45: Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases. J Pharm Assoc (Wash) 2000;40: Nexium prescribing information. Wilmington, DE: AstraZeneca, Inc, Prevacid prescribing information. Lake Forest, IL: Tap Pharmaceuticals, Prilosec prescribing information. Wilmington, DE: AstraZeneca, Inc, Bardhan KD, Muller-Lissner S, Bigard MA. Symptomatic gastrooesophageal reflux disease: double-blind controlled study of intermittent treatment with omeprazole or ranitidine. BMJ 1999; 318: Hatlebakk JG. Gastric acidity: comparison of esomeprazole with other proton pump inhibitors. Aliment Pharmacol Ther 2003; 17(Suppl 1): Rohss K, Lind T, Wilder-Smith C. Esomeprazole 40 mg provides more effective intragastric acid control than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with gastro-oesophageal reflux symptoms. Eur J Clin Pharmacol 2004;60: Blum RA, Shi H, Karol MD, et al. The comparative effects of lansoprazole, omeprazole, and ranitidine in suppressing gastric acid secretion. Clin Ther 1997;19: Miner P, Katz P, Chen Y, et al. Gastric acid control with esomeprazole, lansoprazole, pantoprazole, and rabeprazole: a five-way crossover study. Am J Gastroenterol 2003;98: Address requests for reprints to: Kenneth R. McQuaid, MD, GI Section 111-B-1, VA Medical Center, 4150 Clement St, San Francisco, CA Kenneth.mcquaid@med.va.gov; fax: Supported by a grant from Santarus.