Objective: To compare a Helicobacter pylori “test and treat” strategy with prompt endoscopy in young Asians with dyspepsia.
Methods: A randomised, prospective study was carried out on uninvestigated dyspeptics aged <45 years in a single (academic) primary care centre. Patients were randomised to either a [13C]urea breath test (UBT) or prompt endoscopy (oesophagogastroduodenoscopy (OGD) and followed-up for 12 months.
Results: 432 patients (mean (SD) age 30 (8) years, male 46%, ethnicity: Malays 33.3%, Chinese 30.6%, Indians 34.7%) were randomised to UBT (n = 222) or OGD (n = 210). 387 (89.6%) patients completed the study. At 12 months, there was no difference in symptom change (measured by the Leeds Dyspepsia Questionnaire) between the two groups, but more patients were very satisfied (40.0% vs 21.6%, p<0.0001) in the OGD group. More additional endoscopy was performed in the UBT group (25 vs 10, p = 0.03), but medication consumption was higher in the OGD group (proton pump inhibitor 3.6 (8.8) vs 2.0 (7.5) weeks, p<0.001; H2 receptor antagonist 5.3 (9.7) vs 3.9 (9.2) weeks, p = 0.017; prokinetics 1.4 (4.7) vs 0.4 (2.5) weeks, p<0.001) and no differences in medical consultation were noted. The median cost of the initial prompt endoscopy approach at 12 months was significantly higher than a “test and treat” strategy (US$179.05 vs US$87.10, p<0.0001).
Conclusion: A H pylori “test and treat” strategy is more cost-effective but less satisfying than prompt endoscopy in the management of young Asian patients with uncomplicated dyspepsia.
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The initial management of Asian patients with dyspepsia remains controversial. Guidelines from the USA1 and Europe2 have recommended an empirical Helicobacter pylori “test and treat” strategy instead of an upper gastrointestinal endoscopy in adults without any features of malignancy. This approach is particularly advocated in populations with a high H pylori prevalence and has been suggested to be more cost-effective than empirical antisecretory treatment or prompt endoscopy.2 3 Although H pylori prevalence is known to be higher in Asia compared with the West,4 there is serious concern regarding the safety of a H pylori “test and treat” approach in Asians due to the higher incidence of gastro-oesophageal malignancy.
Recent endoscopy-based surveys of patients with dyspepsia in East Asia have revealed that adults <45 years of age without alarm symptoms could still harbour gastric malignancy.5–7 This finding has led many to conclude that a non-invasive approach alone in these populations would risk missing treatable gastric malignancy in a proportion of young adults. Furthermore, one of the studies from Shanghai, China, demonstrated that almost 30% of young adults with gastric cancer were H pylori negative, leading the authors to advocate “prompt endoscopy” for most of their patients.6 However, Asia remains a geographically vast and diverse region, and similar studies on dyspeptics from Southern China have shown that the mean age of patients with gastric cancer at presentation was 54 years.8
In the South East Asian region, it has been observed that the age of onset of gastro-oesophageal malignancy differs somewhat from that of the Far East. Endoscopy-based studies in our institution9 and from neighbouring countries10 have demonstrated that young patients with uninvestigated dyspepsia rarely have underlying malignancy and that most organic disease was strongly associated with H pylori. It has therefore been postulated that a H pylori “test and treat” strategy may be cost-effective in the South East Asian region, although this has never been proven.11 Furthermore, the Asian Pacific Working Party on dyspepsia previously reported that endoscopy-based management alone was considered expensive in the Asia Pacific region due to limited healthcare services.12 Although several proposals for management strategies have been suggested, clinical evidence on the efficacy of either endoscopy- or non-endoscopy-based approaches in Asian patients is lacking.
We present the results of a prospective randomised trial comparing a H pylori “test and treat” strategy with prompt endoscopy in young South East Asian adults with uninvestigated dyspepsia, examining cost-effectiveness, safety and satisfaction with the local population.
The study was approved by our local institutional ethics committee. All patients were recruited from the Primary Care Clinics of the University of Malaya, which provide a regular service to the local community. Patients aged ⩽45 years presenting with uninvestigated dyspepsia were invited to participate in the study. Dyspepsia was defined as predominant upper abdominal discomfort for >4 weeks, with any associated symptoms, including heartburn and regurgitation. Patients with the following features were excluded: age >45 years or <18 years; symptoms of weight loss, progressive dysphagia or those suggestive of anaemia; pregnancy; had had previous H pylori testing, any contraindication to endoscopy or sedation; those who failed to turn up for their initial test; and those on regular doses of non-steroidal anti-inflammatory drugs (NSAIDs). Intermittent or occasional NSAID use was not an indication for exclusion.
All patients were interviewed by a gastroenterologist (SM, KLG) or primary care doctor (AV, MM, YCC) to explain the details of the study prior to randomisation. Dyspepsia was confirmed and its severity assessed with a validated instrument, the Leeds Dyspepsia Questionnaire (LDQ).13 The LDQ is an 8-item symptom-based questionnaire assessing the severity of dyspepsia through the frequency and severity of various upper gastrointestinal symptoms. The total score ranges from 0 to 40, with lower values indicating less severe and higher values more severe dyspepsia.14 Patients were randomised to either non-invasive H pylori testing or prompt endoscopy by a trained research assistant, blinded to the severity of symptoms. Using a computer-generated random number table, patients with an odd number were assigned to undergo endoscopy, whilst those with an even number were allocated to undergo non-invasive testing. Data on baseline demography, duration of dyspepsia, family history of malignancy and underlying concern were obtained at the initial visit. The latter was assessed by structured questions: “Are you worried that (a) you may have an ulcer, (b) you may have stomach cancer, (c) you may have another disease (eg, gallstones) or are you not worried at all?”.
All patients were instructed to discontinue any antisecretory treatment for 2 weeks and to use antacids prior to the test if necessary. Patients who were randomised to upper endoscopy (oesophagogastroduodenoscopy (OGD)) were given appointments within 2–3 weeks. Upper endoscopy was performed with conscious sedation using midazolam in an open-access list at the teaching institution’s endoscopy unit. Two biopsies were taken, one each from the antrum and the body, for detection of H pylori using a local rapid urease test kit, shown to have a 96.6% sensitivity and 99.2% specificity for H pylori detection.15 Following recovery, endoscopic findings were explained to the patient by an endoscopist as per routine clinical practice. Patients with a positive urease test were given H pylori eradication treatment (see below), those with structural abnormalities were treated accordingly, and patients with normal findings were reassured or given empirical treatment based on their predominant symptom.
Patients randomised to empirical H pylori testing ([13C]urea breath test (UBT)) had the test done at the initial visit or 2 weeks later if they were taking antisecretory medication. H pylori testing was performed using a UBT (isotope-selective infrared spectroscopy method16) shown to have a sensitivity of 98.3% and a specificity of 98.6% in our local population.17 Those tested positive were given eradication treatment consisting of pantoprazole 40 mg, amoxycillin 1 g and clarithromycin 500 mg twice a day each, for 1 week. This regime had previously been found to have an eradication success rate of 90.7% locally.18 Adults who were allergic to penicillin were given metronidazole instead. Patients who were negative for H pylori were reassured or given empirical treatment based on their predominant symptom. A subsequent H pylori test was not performed in all those who received eradication treatment, in accordance with our routine practice, due to the additional cost involved.
Following the initial tests and treatments, subsequent medical care of trial patients was left to the discretion of their family doctors. Patients were invited back for visits at 1, 6 and 12 months to obtain information on healthcare utilisation. At the last visit, they were asked to rate their symptom change (same, better, worse), a repeat measurement of the LDQ was performed and their overall satisfaction with their initial test assessed using a 4-point Likert scale: 1 = very dissatisfied, 2 = dissatisfied, 3 = satisfied, 4 = very satisfied. Underlying reasons for their satisfaction scores were also obtained.
The primary outcome of the study was to assess the mean difference in LDQ score between OGD and UBT patients. The planned sample size of 410 patients had an 80% power to detect a mean change of 1.2 in the LDQ score between both groups at the 5% significance level. The SD of the change in LDQ score was estimated at 4.3.13 Secondary outcomes of the study included (1) determining the safety of the non-invasive H pylori “test and treat” strategy by monitoring for the development of sinister pathology, (2) examining cost differences between the management strategies at 12 months and (3) assessing satisfaction with either modality based on satisfaction scores at 1 year. Data for these outcomes were analysed on an intention-to-treat basis.
Costing data were based on the total dyspepsia-related resource use per patient at trial completion. The costs of primary and secondary care consultations, investigation procedures and hospital admissions were based on the Malaysian Medical Association 2002–4 procedural code book (table 1). The cost of drugs for dyspepsia were based on pharmaceutical retail prices as outlined in the Drug Index of Medical Specialities (Malaysia).19 Data on resource use were identified mainly from patient interview. As primary care in urban Malaysia is mostly privatised, patients were asked to produce receipts as evidence of visits to their family doctors and drug prescription purchase. Hospital records were cross-checked in cases where emergency room visits were made.
All continuous variables were expressed as means and compared between the two groups by using two-sample t tests or the Mann–Whitney U test, where appropriate. Categorical data were compared using χ2 test with Yates correction. All tests were two-tailed and analysed using a standard statistical software package, SPSS (Chicago, Illinois, USA) version 11.5.
A total of 471 Malaysian patients were found to be eligible for the study during the recruitment period from January 2004 to October 2005 (fig 1). Of these, 39 patients were excluded for the following reasons: declined to participate n = 34, became pregnant before test n = 3, emigrated from the country n = 1 and missing data n = 1. The remaining 432 were enrolled, with 222 randomised to H pylori “test and treat’ (UBT) and 210 to prompt endoscopy (OGD). Demographic details of patients who were enrolled are highlighted in table 2. The mean (SD) ages of patients (31 (8) vs 30 (8) years), sociodemograpics, ethnicity and duration of dyspepsia were similar in both groups. However, the mean LDQ score at presentation was higher in the OGD group (21.9 (6.4) vs 19.3 (6.4)) compared with the UBT group. No significant differences in basic demography were noted between the patients who were excluded and those who were enrolled.
The H. pylori prevalence in the UBT group was 35.3%, whilst that in the OGD group was 30%. Table 3 shows the endoscopic findings in patients randomised to the OGD group. A total of 131 (62.1%) patients had a normal finding (ie, functional dyspepsia), 21 (10%) had evidence of peptic ulcer disease and 33 (15.7%) had erosive gastro-oesophageal reflux disease, most of which were grade A or B (Los Angeles classification). All patients with H pylori infection in both the UBT and OGD groups were able to complete the eradication course successfully, although 14/141 (9.9%) patients described mild oral and/or gastrointestinal side effects of treatment.
At the end of the 12-month follow-up period, 194/222 (87.4%) UBT patients and 193/210 (91.9%) OGD patients were able to complete the study (fig 1). We were able to contact (by phone) 38/45 patients who failed to complete the 12-month follow-up. None of the patients in the OGD group had developed any complications or evidence of malignancy during the study period. In the UBT group, two patients developed serious disease subsequently. A male patient of Chinese ethnicity, aged 43 years and diagnosed positive with the UBT, developed peritonitis from a perforated duodenal ulcer on the seventh day of his eradication treatment. An urgent laparotomy with repair of the perforated ulcer was successfully performed and he required hospitalisation for 7 days. In another female patient of Malay ethnicity, aged 44 years, a diagnosis of pancreatic cancer was made 8 weeks after a positive UBT. When her case notes were reviewed, she clearly had dyspeptic symptoms without alarm features at presentation. Metastatic pancreatic cancer was diagnosed following an exploratory laparotomy, when she presented with obstruction of the small intestine. Palliative chemotherapy was initiated soon after, but she succumbed to her illness 6 months after diagnosis. A further two patients were diagnosed with concomitant biliary disease 6 months after their initial test, but dyspeptic symptoms persisted following cholecystectomy in both patients. The endoscopic diagnoses of 25 UBT patients who had the procedure during the subsequent 12 months were as follows: normal n = 14, oesophagitis n = 4, hiatus hernia n = 2, gastritis n = 3, duodenitis n = 1 and duodenal bulb scar (healed ulcer) n = 1.
Subjective assessment of symptom change at the end of 12 months revealed similar proportions of patients with no difference in symptoms (36 UBT vs 39 OGD), symptom improvement (182 UBT vs 169 OGD) and worsening of symptoms (4 UBT vs 3 OGD) (p = 0.83). Objectively, the mean change in LDQ score at the end of 12 months (in all evaluable patients) was not different between the OGD and the UBT group (15.9 (7.9) vs 15.1 (7.2), mean difference 0.89; 95% CI −2.4 to 0.6) (fig 2). The number of patients with complete resolution of dyspeptic symptoms—that is, LDQ = 0, was 95 (48.7%) and 60 (31.3%) in the UBT and OGDS group, respectively. When the LDQ score was analysed based on H pylori status, no significant differences were noted in the UBT group (15.3 (7.1) H. pylori positive vs 14.9 (7.3) H. pylori negative, mean difference 0.4) or in the OGD group (14.6 (7.6) H. pylori positive vs 16.3 (8.0) H. pylori negative, mean difference –1.7).
Health resource utilisation and cost
The total dyspepsia-related healthcare utilisation in both groups is summarised in table 4. No significant differences in consultation of either primary or secondary medical facilities were noted between the two groups of patients. Additional upper endoscopy was performed in more patients in the UBT group compared with the OGD group (25 vs 10, p = 0.03), and CT examinations were required in the two UBT patients who developed serious disease as mentioned above. Drug utilisation for dyspepsia was based on the total number of weeks that drugs were prescribed over the 12-month period. In the OGD group, there was a significantly higher rate of H2 receptor antagonist (5.3 (9.7) vs 3.9 (9.2) weeks, p = 0.017), proton pump inhibitor (3.6 (8.8) vs 2.0 (7.5), p<0.001) and prokinetic (1.4 (4.7) vs 0.4 (2.5), p<0.001) drug use compared with the UBT group over the 12-month period. At the end of 12 months, the cumulative median cost of managing patients in the OGD group was US$179.05 (range 114.50–1154.00), as compared with US$87.10 (range 38.70–2588.70) for patients in the UBT group (p<0.0001). If the cost of the initial diagnostic tests were excluded from analysis, the median cumulative cost of managing patients in the OGD group still remained higher than that of the UBT group (US$64.50 vs US$48.40, p = 0.007).
Compared with patients in the UBT group, significantly more patients in the OGD group were “very satisfied” with their initial treatment strategy (80 (40.0%) vs 48 (21.6%), p<0.0001); fig 3. In contrast, more patients in the UBT group were dissatisfied with their initial treatment strategy compared with patients in the OGD group (37 (16.7%) vs 23 (11.0%), p = 0.086). Potential factors to explain patients’ level of satisfaction with either treatment strategy were analysed (table 5). Amongst patients who were satisfied (ie, very satisfied and satisfied), 123 (68%) OGD patients reported that an invasive examination was the main reason for better satisfaction levels. In contrast, only 89 (48.5%) UBT patients felt that a simple, non-invasive approach was important for them. Amongst patients who were dissatisfied (ie, dissatisfied and very dissatisfied), family history of malignancy was noted to be higher in the UBT group (13.5% vs 0%, p = 0.06).
To our knowledge, this is the first study in the Asia Pacific region comparing prompt endoscopy with a non-invasive H pylori “test and treat” strategy in young multiracial Asians with uncomplicated dyspepsia. All patients were derived from a primary care setting, which is where the majority of patients with uncomplicated dyspepsia are managed. We accept, however, that a potential selection bias may have been introduced by individual family doctors who referred patients for the study. Nevertheless, the results of the study remain relevant for various reasons. Apart from the initial treatment of dyspeptics, subsequent management was left to individual family doctors or specialist physicians. The data on health resource utilisation are therefore reflective of true practice in this Asian region. A trained research assistant, rather than a medical practitioner, obtained data during the follow-up period to limit medical advice/reassurance to the patient during the study. Finally, we obtained prospective data on health resource utilisation as well, as opposed to retrospective examination of health records/databases.
This study has affirmed the absence of gastro-oesophageal malignancy in young South East Asians with uncomplicated dyspepsia. In the two UBT patients who developed serious complications, it is arguable that prompt endoscopy would not have prevented these complications. Medical treatment following an endoscopic diagnosis would not have had sufficient time to prevent the perforation of a duodenal ulcer from occurring. In the advanced pancreatic cancer case, again endoscopy of the upper gastrointestinal tract alone would not have made the diagnosis any earlier. Although it is recognised that pancreatic disease may present with symptoms of dyspepsia,20 it is not part of routine clinical practice to investigate for pancreatic disease with other modalities (such as CT or endoscopic ultrasound) in patients without any alarm features, especially in the primary care setting. During the 12-month follow-up period, none of the remaining patients was diagnosed with gastrointestinal malignancy. Amongst the UBT patients who subsequently had endoscopy, peptic ulcer disease was not evident apart from the single case with duodenal scarring, which was H pylori related. Similarly, almost all cases of peptic ulcers in the OGD group were H pylori related. Hence the H pylori “test and treat” approach in this population would be effective in treating dyspeptics with underlying peptic ulcer disease, provided they did not consume NSAIDs on a regular basis.
In terms of clinical effectiveness, objectively measured by the improvement of dyspepsia (LDQ) score at 12 months, a prompt endoscopy approach in our patients was no better compared with the H pylori “test and treat” strategy. The findings concur with other published Western studies comparing prompt endoscopy and H pylori “test and treat”.24–26 However, young South East Asian patients in this study were more satisfied with endoscopy compared with UBT despite apparent similar levels of anxiety regarding organic disease in both patient groups. “Invasive testing” was the main determinant of higher satisfaction levels in patients who had prompt endoscopy, and this may suggest that other factors that were not examined in this study, such as psychological disturbances, may have had a role. Similar observations of reassurance from endoscopy in White dyspeptics have also been described in previous studies,22 although the duration is thought to be short lived.23
Despite the higher satisfaction observed, we have demonstrated that prompt endoscopy in young Asian dyspeptics did not result in a reduction of healthcare resource utilisation. Fewer patients in the OGD group had repeat endoscopies compared with the UBT group (10 vs 25) during the 12-month follow-up, but no significant differences in medical consultation frequency were noted and there was a clear increase in drug consumption. Although the efficacy of antisecretory treatment alone in dyspepsia has not been proven,21 it appears that initial prescribing following endoscopy, done in an attempt to treat abnormal endoscopic findings (almost 40% in our series), had resulted in longer courses of antisecretory treatment in such patients. In contrast, prescribing in the UBT group was done on symptoms alone, and mostly by primary care doctors. The increased drug utilisation in the OGD group had an obvious impact on our economic evaluation. The cumulative cost of dyspepsia-related resources, either inclusive of the initial diagnostic tests or not, was significantly higher in the OGD compared with the UBT group (table 4).
To date, three studies examining H pylori “test and treat” versus prompt endoscopy have been published in full,24–26 and all three have been conducted in European patients. The studies by Lassen et al26 and McColl et al25 were conducted mostly in a secondary setting and their findings demonstrated no differences in clinical symptoms, quality of life, satisfaction levels and medical resources after 12 months between patients who had initial prompt endoscopy and those who had H pylori “test and treat”. In contrast, the more recent study by Arents et al24 and ours, which have been conducted predominantly in a primary care setting, indicate some differences in medical resource utilisation between both groups of patients. More PPIs were consumed by patients who had prompt endoscopy, whilst the “test and treat” group had higher medical consultation rates.24 Similarly, patients who had prompt endoscopy had higher drug consumption rates in our study, but no differences in medical consultation over the follow-up period. However, unlike the Western studies, the young Asian patients were more satisfied with prompt endoscopy. Nevertheless, our economic data clearly demonstrated cost savings with a H pylori “test and treat” approach.
We conclude that a H pylori “test and treat” strategy is as effective as prompt endoscopy for symptom improvement and cheaper in the management of young Asian patients with uncomplicated dyspepsia. However, it is less satisfying than prompt endoscopy for these patients. Our findings support a recently published individual patient data meta-analysis where Ford et al summarised that prompt endoscopy in Western dyspeptics conferred a small benefit in dyspepsia improvement, but was not more cost-effective than initial H pylori “test and treat”.27 Bearing in mind the limited health resources in the Asia Pacific region, as previously stated, we believe that it would be prudent to adopt a H pylori “test and treat” strategy as the initial management strategy for young South East Asian patients with uncomplicated dyspepsia. The long-term benefit of such an approach in young Asians remains uncertain, although a 6-year follow-up study of one of the original European cohorts has shown no clinical differences, but a continued increase in resource utilisation in the endoscopy group.28
This study was part funded by the following: a Vote F research grant from the Medical Faculty, University of Malaya; a Fundamental Research Vote from the Institute of Postgraduate Studies, University of Malaya, and a Research grant from the Malaysian Society of Gastroenterology and Hepatology. We are grateful to Abbot Laboratories Malaysia, for the kind sponsorship of H pylori eradication treatment kits (Klacid 7) for all patients in this study.
Competing interests: None.
Ethics approval: The study was approved by the local institutional ethics committee,
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