Drawing the parallels between efficacy and safety of Omeprazole with respect to other PPIs for acid peptic disorders

Omeprazole is an effective proton pump inhibitor for treating acid peptic disorders and prevents bleeding risk, with good tolerability, superiority over placebo, and comparable effectiveness to other PPIs for heartburn and ulcer healing.

Acid peptic disorders (APDs) are a set of conditions manifesting in the form of gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), dyspepsia and gastritis. A global survey of 206 countries in 2019 reported 309.38 million APDs.

GERD: It is characterized by gastric acid reflux into the esophagus causing a sensation of heartburn, nausea, chest pain and chronic cough. The prevalence of GERD has been reported to be 7% to 52% worldwide and from 8% to 30% in India. GERD is further characterized into 3 categories i.e.,

Non-erosive reflux disease (NERD): More common, Prevalence rate; ~70%

Erosive esophagitis (EO): Prevalence rate; 10-30%

Barrett’s esophagitis (BE): It is a result of intestinal metaplasia of the esophagus. A systematic review confirmed the prevalence of endoscopic BE to be 7.8% and histologically confirmed BE to be 1.3 % using clinical trial data across 41 Asian countries.

PUD: It is caused by Helicobacter pylori infection or is NSAID induced. This condition is characterized by the development of ulcers in the lining of the stomach and esophagus. Dyspepsia: It is characterized by chronic pain in epigastric region. A comprehensive study across 40 countries from the year 1990-2022 estimated the global pooled prevalence of dyspepsia to be 8.4%.

Gastritis: It manifests in the form of inflammatory lesions in the mucosal lining of the stomach and can be classified as erosive and non-erosive.

Suggested Treatments for APDs:

• Proton pump inhibitors: PPIs have demonstrated their effectiveness as the first line of therapy to treat acid peptic diseases (APDs). PPIs are recommended as the primary therapy for APDs according to The World Gastroenterology Organization guidelines. The first PPI to hit the market was Omeprazole, which was followed by pantoprazole, lansoprazole, and rabeprazole. They suppress gastric acid secretion by inhibiting H+K+-ATPase.
• Antacids: They provide rapid relief by partial neutralization of gastric acid and inhibition of proteolytic enzyme pepsin. Examples include calcium carbonate, sodium bicarbonate, aluminum hydroxide and magnesium hydroxide.
• H2-receptor antagonists: Although not superior to PPIs, they decrease the production of stomach acid by acting as inverse agonists. Examples include ranitidine, cimetidine, nizatidine and famotidine, all of which reduce the tonic activation rate of the H2 receptor.
• Mucosal protective agents: Basic compounds like Sucralfate (aluminum salt of sucrose octa-sulfate), Bismuth (salt of salicylic acid).
• Prostaglandins analogs: These are employed for the prevention of NSAID induced ulcers. Examples include; Arbaprostil, misoprostol (FDA approved), Rioprostil and Enprostil.

Omeprazole: Drug of choice for various gastrointestinal disorders:

Omeprazole, with a documented safety record of over 30 years, is approved for treating acid-related conditions and effectively manages dyspepsia, as well as healing and preventing NSAID-associated ulcers in the stomach and duodenum.

Omeprazole, a proton pump inhibitor, is a weak base with a pKa of 4.0. After being absorbed in the intestine, it travels through the bloodstream and reaches the parietal cells of the stomach. Omeprazole is not charged at a pH of 7 and can cross cell membranes. However, in the secretory canaliculus of actively secreting gastric parietal cells, where the drug is exposed to a pH of less than 2, Omeprazole becomes protonated and is converted to the active form, a sulfenamide that reacts covalently with the sulfhydryl groups of cysteine residues on the extracellular surface of the alpha subunit of the H(+)/K(+)-ATPase and inhibits the activity of the enzyme (Figure 1B).

RATIONALE BEHIND RESEARCH

There is a large gap in the determination of the most effective and safe PPI. Furthermore, nothing is known about the comparative evaluation of PPIs for various APD disorders.

OBJECTIVE

This study aimed to investigate the effectiveness and safety of Omeprazole with respect to other PPIs for different types of APDs, such as NERD, EO, etc. based on the different randomized controlled trials (RCTs).

Literature search

To identify prospective RCTs comparing Omeprazole to other PPIs or placebo, PubMed, Google Scholar and the China National Knowledge Infrastructure (CNKI) databases were searched from database inception to 30th March 2023.  A combination of specific keywords; ‘GERD’ AND ‘Omeprazole’ AND ‘randomized controlled trial OR cross-over' AND ‘efficacy’ AND NOT ‘prokinetics’ OR NOT ‘alginate’ was used as the search strategy for PubMed. Additionally, reference lists, authors, reviews, meeting abstract websites and https:// clinicaltrials.gov for unpublished trials were used as grey literature resources. The translation and review of articles in languages other than English was also conducted.

Inclusion criteria

This systematic review (following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses ([PRISMA 2020] guidelines) encompassed the following studies:

• RCTs with prospective parallel groups or cross-over design with at least two weeks washout period in children.
• Adult subjects with diagnosis of APDs including GERD, NERD, OE, upper gastrointestinal (GI) ulcers, GI bleeding, and presence or absence of H. pylori.
• Interventions: Omeprazole (oral or IV) for at least 4 weeks (later revised to at least one week) compared to other types of PPIs (Esomeprazole (ESO), Ilaprazole (ILA), lansoprazole (LAN), Pantoprazole (PAN), Rabeprazole (RAB), or placebo).
• Study outcomes: Measurement of improvement of APD symptoms.  

Exclusion criteria

• Nonhuman studies, case reports, early phase 1 (safety) or 2 (mechanism of action, dose ranging, formulation, kinetics) studies.
• Validation of measurement tools for APD, no control group and ill-defined interventions.
• Additional details omitted included reviews, meta-analysis, duplicate reports, no comparisons of interest and no relevant outcomes.
• Other disorders with similar symptoms, such as chronic cough, asthma, laryngitis, Zollinger-Ellison syndrome, primary motility disorder, esophageal structure, Barrett's esophagus or upper GI malignancy.
• PPI treatment less than 1-week, non-PPI comparison groups (prokinetics, H2 receptor antagonists, surgery, alginates, or potassium competitive acid blockers) and those lacking original quantitative data.

Study Selection and Data extraction

The study titles and abstracts were separately evaluated by two reviewers, LV and PM. Data from all full-text articles data were extracted and reviewed individually using a predesigned data extraction form, following standard systematic review and meta-analysis methods.

PICO data was extracted which included:

1. Study Population (age and country)
2. Intervention (type of PPI or controls used, daily doses, formulation, duration, and follow-ups)
3. Comparisons (type of control group either placebo or open and unblinded)
4. Evaluation of outcomes such as improvement in APD symptoms, scores, ulcer or erosion healing rates, time to ulcer healing, pH > 4 for 24 hours by the end of the treatment, and percent remaining in remission.

Data and Statistical Analysis

To be included in the meta-analysis, studies required at least two RCTs or cross-over trials with a common outcome measure by control type (placebo or the same type of PPI). Stata software version 16 was used to generate forest plots and conduct statistical analysis. For significant heterogeneity levels (I2 ≥ 50%), meta-analysis was conducted using Bayesian random effects models, otherwise fixed-effect models were used.

Dichotomous outcomes were assessed using relative risks (RRs) with 95% confidence intervals (CI), and continuous outcomes using standardized mean differences (SMD) with 95% CI. Outcomes were categorized by APD type: NERD, EO, or ulcers (significance threshold of p ≤ 0.05). Heterogeneity among trials was assessed with the I² statistic.

Data on study design, quality, setting, and H. pylori status were collected to identify potential confounders. For any lacking information, the authors were contacted. Assessment of publication bias was performed using funnel plots and Egger's test. The Cochrane Q test was used for subgroup analysis to pinpoint sources of heterogeneity. Sequential sensitivity analysis showed no outcome dependence on any single trial.

Risk of Bias and Quality assessment

The review of each RCT involved independent scoring by coauthors using standard methods. The risk of bias (RoB) was assessed using the RoB 2.0 tool and graded as low, high or some concerns for five types of bias: randomization process; deviations from intended interventions; missing outcome data; measurement of outcome; and selection of reported result.

Study outcomes

Primary Outcomes

1. Improvement in NERD symptoms: Measured as overall improvement cure and improvement of specific APD symptoms such as pain, nausea, heartburn, etc. The remission frequency, esophageal pH improvement, pH of more than 4 for 24 hours at the end of treatment, heartburn and composite laryngeal score and visual analogue scales for symptom severity.
2. Healing of erosive ulcers: Included reduction of ulcer size by >50% and presence or absence of inflammation

Secondary Outcome

Information was gathered about length of hospital stay, cost-effectiveness, nocturnal acid breakthrough, and safety (adverse events).

Outcomes

Study and participant characteristics:

• Adults in the 16–85 age range.
• Erosive ulcers were observed in 61% of patients, NERD in 23% patients and EO in 16% patients.
• Study size: 19 to 2,645 patients were enrolled per trial.48% of the trails were double-blinded, 45% were open trials and 7% were single blinded. Distribution of trials according to geographic region was Asia (52%), Europe (32%), USA, (6%) and mixed countries (10%). Participant dropout over time or attrition rates were low (25%) in 61% of the trials and high (32%) in one trial.
• Interventions: Omeprazole was compared to placebo in 19% of the trials, esomeprazole in 7%, ilaprazole in 13%, lansoprazole in 10%, pantoprazole in 2% and rabeprazole in 10% of the trials.
• Omeprazole was administered at a dose of 20mg/d but was also administered at 10-40 mg/d in some of the RCTs.
• The most common duration for Omeprazole treatment was 4 weeks but also ranged from 10 days to 8 weeks in some of the RCTs.

Study quality:

Each RCT was independently reviewed and scored for quality and risk of bias using the RoB 2.0 tool. Disagreements were resolved by discussion or a third reviewer. A summary table was created, and study quality was assessed in low-risk trials.

Out of the 31 randomized trials, 68% had low risk of bias and 32% had high risk of bias.

Effect of intervention on the outcome:

• Of the included trial, 4606 patients were treated with Omeprazole.
• Omeprazole 20 mg/day healed 77% of erosive disease cases and 59% of NERD cases.
• Symptom resolution was higher for erosive disease at 2 and 4 weeks (74% and 92.3%) than for NERD (44% and 65%).
• Erosive disease patients reported fewer nocturnal acid breakthroughs (57%) than NERD patients (32%).
• H. pylori was eradicated in 87% of trials with Omeprazole in people with erosive condition.
• For heartburn: Omeprazole was efficient in reducing heartburn by 2.5 times compared to placebo (RR = 2.47, p < 0.001). 
• Symptom relief: Omeprazole had significantly higher rates of overall symptom improvement compared to placebo. This PPI was equally effective compared to esomeprazole.
• Healing of ulcers: The healing rates of Omeprazole were comparable to those of pantoprazole, ilaprazole, and rabeprazole. Omeprazole was more effective in healing ulcers and erosions than lansoprazole and caused less nausea compared to pantoprazole.
• As per two trials, 78% of patients were satisfied with treatment.
• Fewer rescue medications were needed compared to other treatments.
• Omeprazole was well tolerated, though more adverse events were reported in erosive disease than in NERD.
• Omeprazole (20 mg/d) was most cost-effective (89.6 Indian rupees) as compared to other PPIs (300-900 Indian rupees). 

This systematic review highlights the role of Omeprazole as an effective treatment for curing the symptoms caused by APDs. This meta-analysis incorporated extensive literature search of articles previously not included due to translation or journal access issues. Moreover, unlike other meta-analysis which studied the effect on only one type of APD, this study incorporates a comprehensive approach towards separate analysis of all PPIs on different types of APDs.

It was discovered that Omeprazole proved to be significantly effective for heartburn relief and displayed signs of overall improvement as compared to placebo. Its efficacy was found to be equivalent to other types of PPIs. Omeprazole was found to outperform lansoprazole in resolving ulcers. However, Edwards et al. reported that the efficacy of esomeprazole in ulcer healing and heartburn relief was significantly better than its racemate; Omeprazole.

A network meta-analysis (62 RCTs) conducted by Dean et al. concluded that PPIs were superior to H2RAs or placebo in healing duodenal ulcers. Another network meta-analysis (23 RCTs) conducted by Barberio et al. confirmed that Omeprazole was effective over esomeprazole in healing the symptoms of NERD.

It has also been established that Omeprazole (20mg/day) provided quick relief from the symptoms in long-term NSAIDs users. All the PPIs, including Omeprazole, have also been found efficient in preventing bleeding caused by NSAIDs. Omeprazole proved to be the most cost-effective of all PPIs in India (89.6 rupees/patient) as well as in a study of Chinese patients with duodenal ulcers (USD $5.30/patient).

Omeprazole had an extremely low chance of side effects (well-tolerable). Merely 11% of the participants reported minor symptoms such as headaches or diarrhoea. Omeprazole has been extensively validated in 1200 clinical trials and 400 million patient treatment courses worldwide. It is a clinically approved medication for the treatment of dyspepsia and gastro-esophageal ulcers with a very well documented long-term safety profile for over 30 years.