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Early Heartburn Relief With Proton Pump Inhibitors: A Systematic Review and Meta-analysis of Clinical Trials

2005; Elsevier BV; Volume: 3; Issue: 6 Linguagem: Inglês

10.1016/s1542-3565(05)00023-6

1542-7714

K. McQuaid, Loren Laine,

Respiratory and Cough-Related Research

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 relief 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 relief at day 1–2. The sample size-weighted pooled proportions of patients with complete or sustained (7 consecutive days) relief 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 relief occurred in 0.31 (95% confidence interval [CI], 0.30–0.32), 0.49 (95% CI, 0.48–0.50), 0.55 (95% CI, 0.53–0.56), and 0.21 (95% CI, 0.20–0.22) of patients. Up to 37% of the heartburn relief achievable with 28 days of PPIs occurred on day 1. Placebo was significantly less effective than PPIs for 24-hour relief on day 1 (relative risk [RR], 0.41; 95% CI, 0.29–0.58), and single-dose PPI therapy was less effective than double-dose therapy (RR, 0.82; 95% CI, 0.74–0.92). Conclusions: Complete heartburn relief 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 relief on day 1 for placebo versus PPI was 0.41 [95% CI, 0.28–0.58]). Although PPIs might provide benefit from the first day of therapy, most patients will not have symptom relief with 1 or 2 days of PPI therapy. 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 relief 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 relief at day 1–2. The sample size-weighted pooled proportions of patients with complete or sustained (7 consecutive days) relief 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 relief occurred in 0.31 (95% confidence interval [CI], 0.30–0.32), 0.49 (95% CI, 0.48–0.50), 0.55 (95% CI, 0.53–0.56), and 0.21 (95% CI, 0.20–0.22) of patients. Up to 37% of the heartburn relief achievable with 28 days of PPIs occurred on day 1. Placebo was significantly less effective than PPIs for 24-hour relief on day 1 (relative risk [RR], 0.41; 95% CI, 0.29–0.58), and single-dose PPI therapy was less effective than double-dose therapy (RR, 0.82; 95% CI, 0.74–0.92). Conclusions: Complete heartburn relief 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 relief on day 1 for placebo versus PPI was 0.41 [95% CI, 0.28–0.58]). Although PPIs might provide benefit from the first day of therapy, most patients will not have symptom relief 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.1The Gallup OrganizationA Gallup Organization national surgery. The Gallup Organization, Inc, Princeton, NJ1988Google Scholar, 2van Pinxteren B. Numans M. Lau J. et al.Short-term treatment of gastroesophageal reflux disease a systematic review and meta-analysis of the effect of acid-suppressant drugs in empirical treatment and in endoscopy-negative patients.J Gen Intern Med. 2003; 18: 755-763Crossref PubMed Scopus (57) Google Scholar As assessed by several instruments, patients have reduced health-related quality of life in proportion to the frequency of heartburn.3Dent J. Brun J. Fendrick A.M. et al.An evidence-based appraisal of reflux disease management the Genval Workshop Report.Gut. 1999; 44: S1-S16Crossref PubMed Google Scholar Patient-directed therapy with antacids or over-the-counter low-dose histamine2-receptor antagonists might be recommended for the treatment of intermittent heartburn in the absence of other warning signs.4DeVault K.R. Castell D.O. The Practice Parameters Committee of the American College of GastroenterologyUpdated guidelines for the diagnosis and treatment of gastroesophageal reflux disease.Am J Gastroenterol. 1999; 94: 1434-1442Crossref PubMed Scopus (484) Google Scholar, 5Tytgat G.N. Review article management of mild and severe gastro-oesophageal reflux disease.Aliment Pharmacol Ther. 2003; 17: 52-56Crossref PubMed Google Scholar 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 histamine2-receptor antagonists or proton pump inhibitors.3Dent J. Brun J. Fendrick A.M. et al.An evidence-based appraisal of reflux disease management the Genval Workshop Report.Gut. 1999; 44: S1-S16Crossref PubMed Google Scholar, 4DeVault K.R. Castell D.O. The Practice Parameters Committee of the American College of GastroenterologyUpdated guidelines for the diagnosis and treatment of gastroesophageal reflux disease.Am J Gastroenterol. 1999; 94: 1434-1442Crossref PubMed Scopus (484) Google Scholar In most patients, the principal goal of therapy is relief of heartburn and other GERD-related symptoms.3Dent J. Brun J. Fendrick A.M. et al.An evidence-based appraisal of reflux disease management the Genval Workshop Report.Gut. 1999; 44: S1-S16Crossref PubMed Google Scholar, 4DeVault K.R. Castell D.O. The Practice Parameters Committee of the American College of GastroenterologyUpdated guidelines for the diagnosis and treatment of gastroesophageal reflux disease.Am J Gastroenterol. 1999; 94: 1434-1442Crossref PubMed Scopus (484) Google Scholar, 6Bytzer P. Goals of therapy and guidelines for treatment success in symptomatic gastroesophageal reflux disease.Am J Gastroenterol. 2003; 98: S31-S39Crossref PubMed Scopus (84) Google Scholar On the basis of their proven efficacy and superiority to histamine2-receptor antagonists for healing of erosive esophagitis and relief 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.3Dent J. Brun J. Fendrick A.M. et al.An evidence-based appraisal of reflux disease management the Genval Workshop Report.Gut. 1999; 44: S1-S16Crossref PubMed Google Scholar, 7Dekel R. Morse C. Fass R. The role of proton pump inhibitors in gastro-oesophageal reflux disease.Drugs. 2004; 64: 277-295Crossref PubMed Scopus (55) Google Scholar Despite the efficacy of proton pump inhibitors for long-term heartburn management, antacids and/or histamine2-receptor antagonists are generally recommended for acute symptom relief because of their faster time to acid neutralization or suppression.5Tytgat G.N. Review article management of mild and severe gastro-oesophageal reflux disease.Aliment Pharmacol Ther. 2003; 17: 52-56Crossref PubMed Google Scholar 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.8Maton P. Omeprazole.N Engl J Med. 1991; 324: 965-975Crossref PubMed Scopus (280) Google Scholar, 9Richardson P. Hawkey C. Stack W. Proton pump inhibitors pharmacology and rationale for use in gastrointestinal disorders.Drugs. 1998; 56: 307-335Crossref PubMed Scopus (240) Google Scholar 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 hours10Williams M.P. Sercombe J. Hamilton M.I. et al.A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24 hour intragastric acidity and plasma gastrin concentration in young healthy male subjects.Aliment Pharmacol Ther. 1998; 12: 307-334Crossref Scopus (191) Google Scholar, 11Hartmann M. Theiss U. Huber R. et al.Twenty-four hour intragastric pH profiles and pharmacokinetics following single and repeated oral administration of the proton pump pantoprazole in comparison to omeprazole.Aliment Pharmacol Ther. 1996; 10: 359-366Crossref PubMed Scopus (83) Google Scholar, 12Huang J.Q. Goldwater D.R. Thomson A.B. et al.Acid suppression in healthy subjects following lansoprazole or pantoprazole.Aliment Pharmacol Ther. 2002; 16: 425-433Crossref PubMed Scopus (35) Google Scholar, 13Florent C. Forestier S. Twenty-four hour monitoring of intragastric acidity comparison between lansoprazole 30 mg and pantoprazole 40 mg.Eur J Gastroenterol Hepatol. 1997; 9: 195-200Crossref PubMed Scopus (39) Google Scholar, 14Hatlebakk J.G. Review article gastric acidity—comparison of esomeprazole with other proton pump inhibitors.Aliment Pharmacol Ther. 2003; 17: 10-15Crossref PubMed Google Scholar (also see pharmacodynamic data listed in product labeling). It is therefore possible that proton pump inhibitors might yield symptomatic relief from heartburn within the first 24–48 hours of therapy. Several prior systematic reviews have assessed the overall efficacy of proton pump inhibitors for heartburn relief in GERD. However, none have looked specifically at heartburn relief within the first week, and none have examined the benefit of proton pump inhibitors for relief of heartburn in the first day or two of therapy.2van Pinxteren B. Numans M. Lau J. et al.Short-term treatment of gastroesophageal reflux disease a systematic review and meta-analysis of the effect of acid-suppressant drugs in empirical treatment and in endoscopy-negative patients.J Gen Intern Med. 2003; 18: 755-763Crossref PubMed Scopus (57) Google Scholar, 15Chiba N. De Gara C.J. Wilkinson J. et al.Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease a meta-analysis.Gastroenterology. 1997; 112: 1798-1810Abstract Full Text Full Text PDF PubMed Scopus (811) Google Scholar, 16Sharma N. Donnellan C. Preston C. et al.A systematic review of symptomatic outcomes used in oesophagitis drug therapy trials.Gut. 2004; 53: iv58-iv65Crossref PubMed Scopus (20) Google Scholar, 17van Pinxteren B. Numans M.E. Bonis P.A. et al.Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux-like symptoms and endoscopy negative reflux disease (Cochrane Review). John Wiley & Sons, Ltd, Chichester, UK2004Google Scholar We therefore conducted a systematic review to summarize, quantify, and compare the efficacy of proton pump inhibitors for the relief of heartburn within the first 24–48 hours of therapy in patients with GERD. 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 relief at day 1–2 of therapy. We searched the MEDLINE (1966–June 2004) and EMBASE (1980–June 2004) computerized bibliographic databases as well as bibliographies from previous systematic reviews.2van Pinxteren B. Numans M. Lau J. et al.Short-term treatment of gastroesophageal reflux disease a systematic review and meta-analysis of the effect of acid-suppressant drugs in empirical treatment and in endoscopy-negative patients.J Gen Intern Med. 2003; 18: 755-763Crossref PubMed Scopus (57) Google Scholar, 15Chiba N. De Gara C.J. Wilkinson J. et al.Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease a meta-analysis.Gastroenterology. 1997; 112: 1798-1810Abstract Full Text Full Text PDF PubMed Scopus (811) Google Scholar, 16Sharma N. Donnellan C. Preston C. et al.A systematic review of symptomatic outcomes used in oesophagitis drug therapy trials.Gut. 2004; 53: iv58-iv65Crossref PubMed Scopus (20) Google Scholar, 17van Pinxteren B. Numans M.E. Bonis P.A. et al.Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux-like symptoms and endoscopy negative reflux disease (Cochrane Review). John Wiley & Sons, Ltd, Chichester, UK2004Google Scholar 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, or gastroesophageal 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. 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 relief 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 histamine2-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 relief on day 1 or 2 of therapy by using a prespecified symptom assessment tool (eg, daily diary, interactive phone system, patient or physician 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 al18Jadad A.R. Moore R.A. Carroll D. Assessing the quality of reports of randomized clinical trials is blinding necessary?.Control Clin Trials. 1996; 17: 1-12Abstract Full Text PDF PubMed Scopus (14028) Google Scholar 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 relief (overall, daytime, nighttime) and sustained heartburn relief 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%. The proportion of patients with complete or sustained heartburn relief 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 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 relief 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 relief 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 χ2 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. No funding source had any role in the design, performance, analysis, or reporting of this systematic review.