Terje Johannessen

The Predictive Value of History in Dyspepsia

Symptomatic patients referred to an open-access upper gastrointestinal endoscopy completed a detailed, self-administered questionnaire aimed at assessing the predictive value of history in dyspepsia. Nine hundred and thirty patients were suitable for analysis. Of these, 29% were found to have organic dyspepsia. A substantial overlap of symptoms and demographic data was found among the various endoscopic diagnoses. Discriminating variables were identified by stepwise logistic regression analysis and included in predictive score models. Pain relieved by antacids, age above 40 years, previous peptic ulcer disease, male sex, symptoms provoked by berries, and night pain relieved by antacids and food were found to predict organic dyspepsia with a sensitivity and specificity of approximately 70%, when applied on the observed material. Similar probabilities were found for score models of peptic ulcer and esophagitis. In general, the low prevalence of organic diseases resulted in low positive and high negative predictive values. Accordingly, the main impact of the predictive models may be to reduce the number of negative endoscopies rather than to predict a precise diagnosis. Independent of disease category and age, 41% of the subjects expressed a fear of malignancy, emphasizing the value of reassurance from a negative endoscopy.

Relationship between Endoscopic Hiatus Hernia and Gastroesophageal Reflux Symptoms

Little is known about the relationship between hiatus hernia (HH) and gastroesophageal reflux symptoms (GERS). Nine hundred and thirty patients submitted to gastroscopy because of symptoms completed a self-administered questionnaire. Fourteen per cent showed esophagitis (ES) and 17% HH. Forty-nine per cent of the patients with HH had endoscopic ES, and 60% of those with ES had HH. The severity of ES was dependent (p less than 0.05) on both the presence and the size of HH. After exclusion of patients with peptic ulcer and malignancy, patients with and without HH and ES were compared with regard to the presence of single symptoms and a weighted GERS score based on symptoms proven to be typical for ES. Only borderline differences were found between patients with ES and HH and those with ES and no HH. The former group, however, presented with significantly (p less than 0.001) more GERS than the patients with HH only. Nevertheless, the patients with HH as the only pathologic finding had significantly (p less than 0.01) more GERS than the patients with no major endoscopic abnormality. This study indicates a close association between HH and gastroesophageal reflux disease and supports the clinical significance of an endoscopically detected HH.

Cimetidine Responders in Non-Ulcer Dyspepsia

The effect of cimetidine and placebo was examined in 123 patients with non-ulcer dyspepsia (NUD) by means of a 12-day multi-crossover model with 5 regular interchanges between cimetidine and placebo. The evaluation of effect in individual patients was based on the number of times cimetidine was associated with less symptoms than the preceding or following placebo period. If cimetidine had no effect, the probability of being defined as a cimetidine responder was 25%. In general, cimetidine was associated with less symptoms than placebo (p less than 0.0001). Forty patients were identified as cimetidine responders (R) and the remaining patients were termed non-responders (NR). Symptoms compatible with gastroesophageal reflux were significantly more frequent in R than in NR, whereas the opposite was true for symptoms of the irritable colon syndrome. The ability of symptoms selected by stepwise logistic regression to predict response to cimetidine showed at best a sensitivity of 75% and a specificity of about 65%. No differences were found between R and NR with regard to acid secretion, endoscopic and histologic findings, or the result of an acid perfusion test. The present study supports the existence of a subgroup of cimetidine responders among patients with NUD characterized by symptoms suggestive of gastroesophageal reflux disease in the absence of confirmatory objective evidence.

The effect of cimetidine in non-ulcer dyspepsia: experience with a multi-cross-over model

The symptomatic effect of cimetidine was examined in 27 patients with non-ulcer dyspepsia (NUD) by means of a multi-cross-over model (MCO model) for testing the symptomatic effect of drugs in individual patients. None of the patients showed an ulcer at the time, but 20 patients had evidence of previous peptic ulcer disease. The variant of the MCO model used included six treatment periods and three regular interchanges between cimetidine and placebo. Treatment periods lasted 2 or 4 days. The individual results were evaluated on the basis of the number of times (X score) cimetidine was associated with less symptoms than the preceding or following placebo. In general, cimetidine was associated with significantly (p less than 0.02) less symptoms than placebo. The X-score distribution was therefore skew in favour of high scores. Five patients showed the maximal X score of 5. The chance of getting an X score of 5 when cimetidine is not better than placebo is about 9%. Accordingly, the risk of being wrong when defining these five patients as cimetidine responders is 9%. The present study confirms that the MCO model may identify individual cimetidine responders among patients with NUD.

The intensity and variability of symptoms in dyspepsia

During the waiting time for upper gastrointestinal endoscopy 165 patients with dyspepsia completed a questionnaire and a diary for daily measurements of the symptoms pain, heartburn, and global complaints. 23 patients (14%) had peptic ulcer disease (PUD), 18 oesophagitis (11%), and the rest were labelled nonulcer dyspepsia (NUD). NUD was further subdivided into ulcer-like, reflux-like, dysmotility, and essential NUD by means of predefined symptom profiles. 39 (24%) patients were on H2 receptor antagonist treatment. In general, the intensity of the daily symptoms was rather low, and except for a higher rating of heartburn in oesophagitis, there were no significant differences between PUD, oesophagitis, and NUD--treated or untreated. NUD patients with reflux-like dyspepsia had significantly more heartburn than the group with essential NUD; otherwise there were no differences between the subgroups of NUD. The individual daily ratings for abdominal pain, heartburn, and global symptoms varied by an average standard deviation of 64%, 97% and 47% of the mean values, respectively, and were independent of treatment or diagnoses. There was an approximately 40% probability that two successive days had different levels of symptoms. Only 10% of the patients showed stable symptoms, and the patients were completely symptom-free for 20% of the observation period. Symptoms in dyspepsia patients disclosed low intensity and high variability in this study. Such factors may be important sources of bias in clinical trials.

Cimetidine On-Demand in Dyspepsia Experience with Randomized Controlled Single-Subject Trials

Double-blind randomized controlled trials in single subjects (N of 1 RCTs) have demonstrated a beneficial symptomatic effect of cimetidine in reflux- or ulcer-like non-ulcer dyspepsia (NUD). However, spontaneous fluctuations in symptoms reduce the validity of such trials when performed as continuous trials with fixed dosages. This study was carried out to identify individual responders to cimetidine in NUD, peptic ulcer disease, and oesophagitis and to confirm the beneficial average effect of cimetidine in these clinical entities. We evaluated N of 1 multi-crossover trial designs, which compare the effects of single doses of cimetidine and placebo taken on-demand for symptomatic relief. Each trial consisted of six cimetidine (400 mg or 800 mg) and six placebo tablets randomized in successive pairs. The symptomatic effect of each tablet was measured 1/2-6 h after the intake. Outcomes were assessed by individual p values and confidence intervals. A minimal clinically important difference was defined, to assess the clinical significance as demonstrated by the confidence intervals. Thirteen of 25 patients (52%) with reflux- and ulcer-like NUD obtained individual p values below 0.20. Similarly, 7 of 9 patients (78%) with oesophagitis and 6 of 12 patients (50%) with peptic ulcer obtained such p values. On the basis of the 80% confidence intervals the corresponding numbers of subjects with clinically significant effect were six (NUD), three, and three. The combined data showed a significantly better effect of cimetidine than of placebo (p less than 0.0001) in each of the three diagnostic groups studied. Cimetidine taken on-demand may have a rapid symptom-relieving effect in dyspepsia.(ABSTRACT TRUNCATED AT 250 WORDS)

The Natural Course of Peptic Ulcer Disease and its Predictors

BACKGROUND Little is known about todays natural course of peptic ulcer disease (PUD). METHODS A follow-up study based on a structured telephone interview was attempted in 728 patients with an endoscopic diagnosis of peptic ulcer in 1980-84. RESULTS Seven patients (1%) died because of PUD during the 8- to 10-year follow-up period. Of the 441 interviewed patients 15.2% had experienced no further clinical manifestations of PUD, 10.9% had had bleeding and 0.7% perforation, and 17.5% had been operated on. The operated patients reported fewer symptoms (p < 0.01) during the last 2 weeks before the interview than those not operated on. On an average the unoperated patients had had symptoms and had used histamine-2-receptor antagonists (H2RA) 12 and 10 weeks per year, respectively. Long-term treatment with H2RA was reported by 18%. More than one-third (36%) of the unoperated patients stated that the symptoms had had a significant negative impact on their lives. Age at onset of disease and index ulcer, family history, use of anti-inflammatory drugs and alcohol, bleeding, and another chronic disease were found to be significant predictors of the course. CONCLUSION In more than one-third of the patients with PUD the course is still burdened with many symptoms and complications.

The Symptomatic Effect of 1-Day Treatment Periods with Cimetidine in Dyspepsia Combined Results from Randomized, Controlled, Single-Subject Trials

Before endoscopy a double-blind, randomized, controlled, single-subject trial comparing the symptomatic effect of 1-day treatment periods with cimetidine and placebo was conducted in patients with dyspepsia. Results from 339 patients were analysed. The trial lasted 12 days and consisted of 6 treatment days with 400 mg cimetidine three times daily and 6 days with placebo three times daily. The order of the treatments was randomized within six pairs, and a randomization test based on daily measures of global symptoms provided individual p values. Aggregation of the measures from all subjects showed that cimetidine alleviated the symptoms significantly better than placebo in peptic ulcer disease (PUD) (p less than 0.0001), oesophagitis (p less than 0.001), and non-ulcer dyspepsia (NUD) (p less than 0.0001). Twenty-seven per cent of the patients with PUD, 26% of those with oesophagitis, and 12% of the patients with NUD obtained individual p values of less than 0.10 and were defined as responders. The best predictors of the response to cimetidine in NUD were age above 40 years, heartburn or acid regurgitations being the worst symptom, and night pains relieved by food, milk, or antacids. In conclusion, the applied single-subject trial confirmed the overall symptomatic effect of cimetidine in dyspepsia and identified individual responders among patients with NUD with a clinically reasonable profile. The low proportion of responders among patients with PUD or oesophagitis suggests that the model has a low sensitivity for identification of individual responders and that the single-subject trial design in dyspepsia needs further refinement.

On-demand therapy in gastroesophageal reflux disease: a comparison of the early effects of single doses of fast-dissolving famotidine wafers and ranitidine tablets

In this double-masked, double-dummy, randomized, single crossover study, we compared single doses of a fast-dissolving wafer formulation of famotidine with a conventional tablet formulation of ranitidine in patients with gastroesophageal reflux disease (GERD). Patient preference time until symptomatic relief, and predictive characteristics of early responders were assessed. Eligible patients had a clinical diagnosis of GERD and symptoms of GERD of sufficient severity to require relief. The study treatment was one dose of famotidine (20-mg wafer) and one dose of ranitidine (150-mg tablet), which were given in a randomized order and taken as needed. The patients were instructed to measure the symptomatic effects on a seven-point categorical scale (1 = worse to 7 = free of symptoms) at 15, 30, 45, 60, 120, and 180 minutes. After the clinical phase of the trial, the patients indicated their global assessment of efficacy and their preference for the wafer or the tablet. Of the 829 patients who completed the study, significantly more preferred the wafer to the tablet. While there was no significant difference in the global assessment of efficacy, the famotidine wafer provided significantly better relief than the ranitidine tablet during the first hour after dosing. However, at 120 and 180 minutes, the degree of relief was similar for the two drugs. The time until a clinically significant effect was also similar for the two drugs, and approximately one half of the patients experienced such improvement within 3 hours. Multivariate analyses disclosed no predictive characteristics of early symptomatic effect.

Combined Single Subject Trials

Randomized controlled single subject trials are designed as multiple crossovers between the treatments to be compared. Results from such independent trials may be combined and integrated for the purpose of extending the conclusions beyond the single subject. Unlike the conventional crossover group trial, the primary goal of the combined single subject study is not to demonstrate an overall clinical benefit of a drug, but to indicate the features typical for drug responders. The external validity of combined single subject trials depends on the same prerequisites as are employed in group trials: strict entry criteria, uniform treatment procedures, consensus targets for outcome measures, and acceptable statistical tests. In clinical research the main role of combined single subject trials should be to elucidate new insight and generate hypotheses that could optimize the design of subsequent group trials.