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Background

Functional dyspepsia (FD) is reported in as high as 30% adult population in India [1]. It is defined according to Rome IV criteria by one or more of the followings: postprandial fullness, early satiation, epigastric pain, and epigastric burning that are unexplained after a routine clinical evaluation and in the absence of an identifiable organic disease, during the last 3 months, with onset at least 6 months before [2].

The causal relationship between Helicobacter pylori (H. pylori) and superficial gastritis has been established. But whether H. pylori is responsible for symptoms of FD is a topic of debate [3]. Studies have reported various estimates of association between H. pylori eradication and improvement of dyspeptic symptoms [4,5,6]. There is scarcity of large randomized controlled studies and the available studies have great heterogeneity. Early meta-analyses concluded no benefit of H. pylori eradication on symptom relief in FD [7], while later meta-analyses showed some benefit [8]. This may be due to stringent criteria used in earlier studies to define response and lack of standard definition of FD used in these studies. The contradictory outcomes of various meta-analyses indicate that there is no compelling evidence of the benefit of eradication of H. pylori in patients of FD.

It has been suggested that a “test-and-treat” strategy for H. pylori is preferable in populations with infection rates higher than 10% in the community [9]. Kyoto Consensus proposes treatment of H. pylori in H. pylori–positive dyspepsia and makes a retrospective diagnosis of H. pylori-associated dyspepsia if there is sustained relief after 6–12 months [10].

However, a Cochrane Database Systematic Review did not find significant evidence to favor this approach [11]. Some studies have shown marginal cost-effectiveness in treating patients with non-ulcer dyspepsia (NUD) [9]. On the other hand, patients with FD with H. pylori infection have been found to have higher antibiotic resistance as compared to patients with peptic ulcer disease [12].

There is lack of enough data on H. pylori eradication for FD in India. We conducted a prospective randomized trial to study the benefit of eradicating H. pylori in patients with FD as compared to standard medical treatment only. We hypothesized that H. pylori eradication would provide additional benefit as compared to standard medical treatment for symptom relief in H. pylori–positive FD.

Methods

Study characteristics and participants

This was a single-center, open-label, prospective randomized controlled study. The study was done at Sir Ganga Ram Hospital, New Delhi, a tertiary center in northern India, between September 2017 and May 2019. Requisite ethical clearance from institutional ethical committee was obtained before the initiation of the study. The trial was registered in Protocol Registration and Results System (NCT04697641).

Consecutive adult (>18 years age) patients with FD (ROME IV criteria) who were H. pylori positive were included in the study. Pregnant and lactating females; children and adolescents; those with predominant symptoms of heartburn, irritable bowel syndrome, history of peptic ulcer, upper gastrointestinal (GI) tract surgery, biliary colic, and allergies to study medication; those who received previous eradication therapy for H. pylori; patients who received antibiotics or bismuth during 4 weeks before enrolment, proton pump inhibitors (PPI) 2 weeks before enrolment, and histamine-2 receptor blockers in the week before enrolment; patients on drugs which have interactions with anti-H. pylori drugs (Annexure 1); or those unable to answer the study questionnaires were excluded from the study. Those with uncontrolled diabetes mellitus (hemoglobin A1c [HbA1c] > 9 mmol/mol) and uncontrolled thyroid status (thyroid-stimulating hormone [TSH] > 10 mIU/L or < 0.5 mIU/L) were further excluded after investigations.

Evaluation

All patients underwent routine investigations including complete hemogram, liver function tests, renal function tests, TSH, urine analysis, fasting and postprandial blood sugar levels, HbA1c, and ultrasound abdomen. All patients underwent upper GI endoscopy. Those with esophagitis, peptic ulcer, polyp, or mass lesion were excluded. H. pylori infection was diagnosed when both rapid urease test (RUT) (Halifax Research Laboratory, Kolkata, India) and H. pylori stool antigen test (SAT) by immunochromatography were positive [13, 14].

Symptom assessment

The Global Overall Symptom (GOS) scale was used for symptom assessment in the study population [15]. The symptoms were self-reported on a 7-point Likert scale ranging from 1 = no problem to 7 = a very severe problem (Annexure 2). Those with moderate to high intensity (>2 on GOS) symptoms were included in the study. Patients were also asked to rate the severity of 10 specific upper GI symptoms (specific symptom subtypes [SSS] using the same 7-point Likert scale as for the GOS scale: epigastric pain, epigastric discomfort, heartburn, acid regurgitation, upper abdominal bloating, excessive belching, nausea, early satiety, postprandial fullness, and other epigastric symptoms) (Annexure 3). SSS was used for dividing participants into two symptom subgroups: predominantly epigastric pain syndrome (EPS)—if first four symptom score was higher; and predominantly postprandial distress syndrome (PDS)—if last six symptom score was higher. Although there is significant overlap in patients with EPS and PDS as is shown in a previous study [16], this was an arbitrary division based on predominant symptoms.

Randomization and intervention

Subjects were randomized into two groups based on computer-generated randomization.

The group allocation was concealed in a sealed opaque envelope and opened at randomization. Participants allotted to group 1 received H. pylori eradication therapy in the form of 14 days of clarithromycin 500 mg twice a day, amoxicillin 1000 mg twice a day, and pantoprazole 40 mg twice a day followed by 6 more weeks of pantoprazole 40 mg once daily. Prokinetics before meals (levosulpiride 25 mg, acotiamide 100 mg, itopride 50 mg) were given as and when required for PDS. Participants allotted to group 2 received the standard of care treatment for FD. They received PPI (pantoprazole 40 mg or equivalent) for 8 weeks and/or prokinetics before meals (levosulpiride 25 mg, acotiamide 100 mg, itopride 50 mg) when required in patients with PDS. Both the recipients and investigators were aware of the therapy given.

Follow-up

The first follow-up was at 12 weeks, 4 weeks after completion of the 8-week treatment. At this follow-up, participants were asked to rate their symptoms over the preceding week and GOS reduction by at least 2 and GOS < 2 was considered symptom relief and taken as treatment success. Patients who were lost to follow-up were included in the intention-to-treat analysis with negative outcome. H. pylori SAT was done at this follow-up. A positive H. pylori SAT was taken as failure of H. pylori eradication. In the case of patients who did not undergo these tests, the status was defined as unknown.

The second follow-up was 6 months after completion of the 8-week treatment. GOS was administered and H. pylori SAT was repeated. All participants were allowed medications for symptom relief over these 6 months and adverse events were noted.

Outcome measures

Primary outcome

Treatment success was defined as absence of symptoms or minimal symptoms (GOS score < 2 and reduction by at least 2 points), 6 months after treatment.

Secondary outcomes

• Efficacy of H. pylori eradication therapy defined as stool H. pylori antigen negative at 4 weeks after treatment.

• Rate of H. pylori reinfection defined as stool H. pylori antigen positivity at 6 months in those who were negative at 4 weeks.

Statistical analysis

Sample size was calculated assuming the rate of treatment success to be 40% in the group assigned to receive H. pylori eradication therapy and 20% in the group assigned to receive standard of care alone [17]. Considering this study to be binary outcome superiority trial, 158 H. pylori–positive patients were required to have 80% chance of detecting an increase in the primary outcome measure from 20% in the standard medical treatment group to 40% in the eradication group. Analysis of data was done using Statistical Package for the Social Sciences (SPSS) version 22 (IBM, New York, USA). Continuous variables were presented as mean and SD. Categorical variables were presented as proportions.

Two-sample t tests were used to compare the mean values of variables considered continuous in the treatment and placebo groups. Chi-square tests were used to analyze categorical variables. Multivariate analysis was done in variables found significant on univariate analysis to asses predictors of response. Intention-to-treat analyses included all patients who received at least one dose of medication and who were H. pylori positive at entry.

Results

  1. 1.

    Patient recruitment and characteristics

A total of 715 patients with dyspepsia for more than 3 months were screened. Of them, 287 were excluded because they had predominantly reflux symptoms, consumed medications prohibited in the study, or had received H. pylori eradication treatment. Twenty-four were excluded due to biochemical abnormalities (HbA1c >9%, TSH >10, abnormal liver function test [LFT]), 33 due to cholelithiasis on ultrasonography (USG), and 42 for endoscopic abnormalities. The remaining 329 participants were diagnosed as FD, of whom 76 were H. pylori negative. Fifty-one patients were further excluded as they had GOS ≤ 2.

The remaining 202 patients were diagnosed as H. pylori–positive FD and were randomized into two study groups of 101 each. Fifteen (7 in group 1; 8 in group 2) patients were lost to follow-up at the first follow-up, while at the second follow-up visit 27 more participants (14 in group 1; 13 in group 2) were lost to follow-up. A total of 160 participants (80 in each group) completed the study (Fig. 1). Of the 202 patients who were randomized, 105 (52%) were males. The mean age of the participants was 41.8 years (SD 9.1 years). Ninety-nine patients had EPS and 103 had PDS. The mean GOS score was 4.168 (SD 0.84, range 3–6). Each group had 101 participants; baseline demographic, biochemical parameters, and GOS scores were comparable in both the groups (p >0.05; Table 1).

  1. 2.

    Primary outcome

    Fig. 1
    figure 1

    Flow chart showing various exclusion criteria applied, randomization, and follow-up of patients enrolled in the study

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    Table 1 Comparison of baseline characteristics in those who received Helicobacter pylori eradication (group 1) and those who received standard medical treatment (group 2). BMI body mass index, CAD coronary artery disease, EPS epigastric pain syndrome, PDS post-prandial distress syndrome, AST aspartate aminotransferase, ALT alanine aminotransferase, ALP alkaline phosphatase, GGT gamma-glutamyl transferase
    Full size table

At 6 months follow-up, 63 patients achieved treatment success, 32 from group 1 and 31 from group 2. This difference was insignificant on both per protocol and intention-to-treat analysis (p=1.000; Fig. 2). The mean GOS score at 6 months was 2.51 in group 1 and 2.52 at 6 months follow-up; 63 patients achieved treatment success, 32 from group 1 and in group 2 (p = 0.937) (Fig. 2).

  1. 3.

    Predictors of response

    Fig. 2
    figure 2

    Comparison of treatment success in those who received H. pylori eradication (group 1) versus those who received standard medical treatment (group 2)

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Patients achieving and not achieving treatment success did not have significant difference in H. pylori eradication therapy and H. pylori positive status (p-value 0.871 and 0.870, respectively). On univariate analysis, type of symptom presentation (EPS or PDS) was the only factor significantly different in those who had treatment success or not. 38/80 (47.5%) patients with EPS and 25/80 (31.3%) PDS patients had treatment success (p=0.035). Age, gender, body mass index (BMI), H. pylori eradication therapy, or H. pylori status were not significantly different on univariate analysis (Tables 1 and 2). Patients with EPS and PDS had similar proportion of those treated for H. pylori (47.5% and 52.4% respectively, p = 0.574) and those who achieved eradication (63% and 59% respectively, p = 0.653).

Table 2 Comparison of parameters in those who achieved treatment success and those who did not
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Secondary outcomes

Prevalence of H. pylori in FD in our study was 76.89% (253 of 329 patients with FD).

Efficacy of H. pylori eradication therapy was 74.5% (94 patients in group 1 who completed first follow-up, 70 were H. pylori stool antigen negative). During the first follow-up, a total of 73 (70 in group 1, 3 in group 2) patients had cleared H. pylori infection. Of them, 19 had stool H. pylori antigen positivity at second follow-up. Thus, H. pylori reinfection rate in our study was 26.02% (Figs. 1 and 2).

Discussion

This is a single-center, open-label randomized trial comparing the efficacy of H. pylori eradication in symptom relief in patients with FD as compared to standard of care. There was no difference in symptom relief (treatment success) at 6 months in patients who received H. pylori treatment as compared to those who received standard therapy.

We used a standard inclusion criteria (ROME IV criteria) to reduce heterogeneity [18, 19]. Patients with significant symptom scores on validated scales were included in the study to maintain homogeneity and reduce bias. A follow-up of 6 months ensured adequate time for the effect of H. pylori eradication to become evident, as was observed in a previous study by Verdu et al. [20]. Three large RCTs from other countries by Talley et al., Blum et al., and Koskenpato et al. and an Indian study by Sodhi et al. also concluded that eradication of H. pylori does not lead to resolution of symptoms of FD [4, 17, 21, 22]. While Sodhi et al. used Rome II definition of FD, we used Rome IV definition. Repeat endoscopy and biopsy were done by Sodhi et al., while we used non-invasive H. pylori SAT on follow-up.

On the contrary, western studies by Mccoll et al. and Mazzoleni et al.; Asian studies by Gwee et al., Kim et al., and Yamada et al.; and an Indian study by Dhali et al. found significant improvement of symptoms after H. pylori eradication [23,24,25,26,27,28]. The criteria used to define response in these studies varied and included 50% reduction or partial response as a type of response [24]. This difference in western and Asian studies might be due to higher prevalence of H. pylori in Asian populations. The prevalence of H. pylori infection in FD patients in our study was 76.89%. This is higher than in other studies, which have shown prevalence of H. pylori in FD ranging from 30% to 70% [17, 22, 26, 28,29,30,31,32]. Important studies on the effect of H. pylori eradication in patients with FD are summarized in Table 3.

Table 3 Studies evaluating outcomes of Helicobacter pylori eradication in functional dyspepsia. NA not available
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Inclusion of patients with significant reflux symptoms may also confound the results. In our study, we included patients with FD as defined by ROME IV criteria and we defined treatment success by stringent criteria. Our study had similar number of patients with EPS and PDS (49% EPS; 51% PDS) as compared to a study by Gwee et al. who had predominantly EPS patients [27].

We could not comment on status of gastritis as histopathological evaluation was not a part of our study; however, it has been shown earlier that there is a strong relationship between H. pylori eradication and resolution of gastritis [29]. But whether this resolution of gastritis results in symptom improvement is still controversial.

The efficacy of H. pylori eradication treatment in our study was 77.6%. This rate was lower as compared to an Indian study by Dhali et al. [28] and the other studies by Blum et al. Koskenpato et al., and Talley et al. [17, 21, 29].. A recent study from India has shown similar rates of H. pylori eradication as in our study [22]. We used triple therapy for 14 days, which has been proven to be efficacious and equivalent to sequential therapy for H. pylori eradication. A suboptimal efficacy of this regimen could be due to the resistance patterns of H. pylori in our country [34, 35]. There were 3 participants in group 2 who cleared H. pylori infection despite not receiving eradication therapy. Prolonged use of PPI in them might have caused decreased levels of infection, which might not have been detected by laboratory tests.

Analysis revealed that patients with EPS were more likely to achieve treatment success than PDS (47.5% vs. 31.3%; p-value 0.035). Other factors like H. pylori eradication treatment, gender, age of patient, comorbidities like diabetes mellitus and hypertension, smoking status, or tobacco chewing did not affect the likelihood of getting symptom resolution. Our results are in concordance with studies by Tsuda et al. and Suzuki et al. which showed that the response of patients with EPS symptoms was better [30, 33]. Of the 73 patients who had H. pylori clearance at the first follow-up, 19 (26.02%) were H. pylori positive at 6 months follow-up. This could be due to reinfection or recrudescence of H. pylori infection. Data from western and South East Asian countries show a very low rate of reinfection [36,37,38]. Whereas, reports from the Indian subcontinent and other developing countries show reinfection rates after successful H. pylori eradication in the range of 5% to 15% [39, 40].

The limitations of our study are as follows: this was a single-center study, which may limit external validation of the results. Although, published literature does not show variation in FD prevalence across geographical areas in India. We excluded patients who had previous H. pylori eradication treatment and those who had recent PPI use in order to homogenize entry criteria and reduce the effect of referral bias.

This was a non-blinded study as standard medications were used in both groups and this may affect results of the study. However, responses were recorded using an elaborate tool, thus minimizing such bias. Another potential limitation is that in patients who were given H. pylori eradication therapy, no prokinetic was used in them. This was done to maintain homogeneity and assess the effect of H. pylori eradication. Patients with FD have psychiatric comorbidities and we did not do separate psychological assessment of patients. However, these patients would have been evenly distributed in both the groups. Similarly patients with other potential confounders like smoking were included but they were equally distributed in both the groups and did not affect response. Another limitation of our study is that we used triple therapy for H. pylori eradication; however, we did not have local antibiotic resistance profiles as we did not culture H. pylori. But this is a commonly used regimen in our country and results of this study can be applied widely. Biopsy was not done to assess gastritis; however, correlation of biopsy and symptom relief was not part of our study. Both groups had similar rate of attrition and number of participants who completed the study was more than the number needed for adequately powered study.

In conclusion,  this prospective study, the prevalence of H. pylori in FD was76.89% and efficacy of H. pylori eradication therapy was 74.5%. H. pylori eradication therapy was not found superior to standard medical treatment for symptom relief in FD.