Title A systematic review of proton pump inhibitors for the treatment of adult patients with symptomatic gastroesophageal reflux disease or peptic ulcer disease. Review Question(s) Requested Requested by PSD 1. What is the comparative effectiveness of different proton pump inhibitors in patients with symptoms of gastroesophageal reflux disease? 2. What is the comparative effectiveness of different proton pump inhibitors in treating peptic (duodenal and gastric) ulcer? 3. What are the comparative safety and adverse events of different proton pump inhibitors in patients being treated for symptoms of gastroesophageal reflux disease and peptic ulcer? 4. Are there subgroups of patients based on demographics, other medications, or comorbidities (including nasogastric tubes and inability to swallow solid oral medication) for which a particular proton pump inhibitor or preparation is more effective or associated with fewer adverse effects? Drug The following five proton pump inhibitors (PPI) drugs will be reviewed 1. Esomeprazole (Nexium® and its generic equivalent) 2. Lansoprazole (Prevacid® and its generic equivalent) 3. Omeprazole* (Losec® and its generic equivalent) 4. Pantoprazole* sodium and magnesium (Pantoloc®, Panto IV and their generic equivalent and Tecta® 5. Rabeprazole* (Pariet® and its generic equivalent) Note: *Omeprazole, Pantoprazole and Rabeprazole have been identified as reference drugs by PSD. Esomeprazole and Lansoprazole will be compared to these three reference drugs. TABLE OF CONTENTS TABLE OF CONTENTS ..........................................................................................................................2 List of Tables ......................................................................................................................................4 List of figures .....................................................................................................................................6 ABBREVIATIONS .................................................................................................................................9 1 EXECUTIVE SUMMARY ............................................................................................................. 11 1.1 Background ..................................................................................................................... 11 1.2 Research Questions (according to Cochrane ‘PICOS’ format) ............................................. 11 1.3 Method ........................................................................................................................... 12 1.4 Results ............................................................................................................................. 12 1.5 Strengths of review .......................................................................................................... 19 1.6 Limitations of review ....................................................................................................... 19 1.7 Overall Summary of findings ............................................................................................ 20 1.8 Conclusions ..................................................................................................................... 23 2 INTRODUCTION........................................................................................................................ 24 2.1 Disease Prevalence and Incidence .................................................................................... 24 2.2 Standard of Therapy ........................................................................................................ 25 2.3 Drug ................................................................................................................................ 26 2.3.1 Drug characteristics: ............................................................................................................................ 26 2.4 Goals of Therapy .............................................................................................................. 27 2.5 Guidelines ....................................................................................................................... 27 3 OBJECTIVES AND METHODS: .................................................................................................... 31 3.1 Objectives requested (PICOS format) ................................................................................ 31 3.2 Methods: ......................................................................................................................... 32 3.2.1 Eligibility Criteria .................................................................................................................................. 32 3.2.2 Search strategy and findings ................................................................................................................ 33 3.2.3 Study selection ..................................................................................................................................... 33 3.2.4 Data extraction and synthesis .............................................................................................................. 33 3.2.5 Quality Assessment:............................................................................................................................. 34 3.2.6 Data synthesis ...................................................................................................................................... 35 3.2.7 Assessment of Publication bias ............................................................................................................ 35 3.2.8 Additional analyses .............................................................................................................................. 35 3.2.1 Sensitivity analyses .............................................................................................................................. 35 RESULTS .......................................................................................................................................... 36 3.3 Findings from the Literature ............................................................................................. 36 June 6th 2014 3.4 Trials meeting inclusion criteria are listed according to specific comparisons ..................... 41 3.4.1 Description of studies .......................................................................................................................... 48 3.4.2 Population ............................................................................................................................................ 50 3.4.3 Interventions ........................................................................................................................................ 52 3.4.4 Outcomes (primary and other outcomes) ........................................................................................... 54 3.4.5 Statistical Analysis ................................................................................................................................ 55 3.5 Patient Disposition ........................................................................................................... 55 3.6 Exposure to treatment ..................................................................................................... 57 3.6.1 Investigational products ...................................................................................................................... 57 3.6.2 Concomitant Medications.................................................................................................................... 57 3.7 Critical Appraisal .............................................................................................................. 58 3.7.1 Internal Validity ................................................................................................................................... 58 3.7.2 Other Sources of Bias ........................................................................................................................... 68 3.7.3 External validity ................................................................................................................................... 70 3.8 Results of Individual studies ............................................................................................. 71 3.8.1 Efficacy results from RCTs .................................................................................................................... 71 3.8.2 Subgroup analysis from included RCTs ................................................................................................ 88 3.8.3 Harms from RCTs ............................................................................................................................... 102 3.9 Comparative and overall safety of PPI drug class ............................................................ 121 3.10 Synthesis of Results ....................................................................................................... 131 4 DISCUSSION ........................................................................................................................... 141 4.1 Summary of Available Evidence ...................................................................................... 141 4.2 Interpretation of Results ...............................................................................................