Does complete remission from GORD symptoms lie in an increased treatment course?

Gastro-oesophageal reflux disease (GORD) is an increasingly prevalent disease in the western world.1Associate Professor Peter Katelaris, senior staff specialist at the Department of Gastroenterology, Concord Hospital, said, "Along with the UK and US, Australia has one of the highest incidence rates of GORD."

GORD can be treated quite effectively with proton-pump inhibitors (PPIs). PPIs reduce the physical symptoms of GORD such as heartburn and regurgitation as well as the endoscopic evidence in a patient such as oesophageal ulcers present in erosive GORD.²

The problem however is that the physical symptoms do not always correlate with the erosion that is evident through endoscopy. This presents issues with treatment if only the one symptom is measured. Patients that feel no physical symptoms may still have mucosa damage and patients who are completely clear of erosion may still experience acid reflux. If assessment of treatment outcome with PPIs is only measured with one of the two scales then a patient can appear to be in remission when in fact the GORD is not completely cleared. Serious complications can results when GORD is not properly treated, such as further erosion and ulceration, narrowing of the oesophageal tube and Barrett’s oesphogus.² Commonly patients with GORD are only assessed by the one scale; microscopy or symptom relief.³

Bardhan et al (2007) conducted a large scale clinical trial comparing two known effective proton-pump inhibitors (PPIs) for GORD patients; esomeprazole (Nexium) and pantoprazole (Somac). The predominant aim of the trial was to use the comparison and analysis of the PPI pharmacodynamic actions in patients to assess how long treatment should be continued for and whether this can be assessed effectively with the traditional measures of GORD symptom analysis.³

Bardhan et al (2007) hypothesised that both of these traditional assessment measures are necessary to assess the effectiveness of PPIs, as neither alone are sufficient to correctly define the endpoint of treatment.³

The study aimed to determine the optimal course for PPI treatment. Participants were assessed for complete remission which is defined as the point where both physical signs and symptoms experienced are healed and relieved.³

The results indicated that use of endoscopic or symptom relief alone do not reliably determine the endpoint of GORD and hence the 4 to 8 week treatment with PPIs may not be enough to treat the disease. A 12 week treatment course was found to be necessary for some patients to achieve complete remission.³

Gastro-oesophageal reflux disease is a long-term and relapsing disorder which needs to be treated efficiently in order to prevent relapse and other oesophageal complications.¹ PPIs are a very efficacious and safe treatment option for GORD, however, some patients may continue to show signs or symptoms of the disease after they have been treated. Often it is attributed to poor medication compliance by the patient or to incorrect timing of the dosage.²

In this trial, it was therefore necessary to assess the course of treatment in order to determine whether the patient’s incomplete treatment response was in fact due to an overestimation of the efficacy of PPIs in the usual 4 to 8 week treatment regimes.³

The traditional measures generally used to assess the success of PPI treatment are endoscopic evidence showing no sign of oesophageal erosion or symptom relief expressed by the patient. The method used depends on physician and patient preference.

The study was a randomised double-blind drug study that included 418 patients (after exclusions) across 46 countries. 204 patients received pantoprazole and 214 received esomeprazole, both 40mg once-daily doses. The study was conducted over 12 weeks which was the pre-determined "end-point". The patients were to continue for up to 12 weeks until they achieved complete remission. If patients still had not reached complete remission by 12 weeks the treatment was deemed as not effective.³

There were 5 required assessment visits; an initial session before the drug was taken, one on initial administration of the drug and three follow up sessions during the treatment period. A baseline endoscopy was carried out at the initial session and the GORD was rated on a four point scale for severity (LA classification). H. pylori levels were also tested at this time. Endoscopy was carried up on the three follow up sessions.³

The participants were required to complete a validated scale, the ReQuest^TM questionnaire, each day of the twelve week treatment demonstrating symptoms experienced. There were two separate ReQuest^TM subscales; one scale for any complaints directly regarding the GI tract including acid reflux, digestion, and nausea; and the other scale for general well-being including complaints not directly related to GORD symptoms.

A/Prof Katelaris said, "The ReQuest^TM scale is very thorough and detailed, naturally more symptoms will be identified if patients take time everyday to answer several questions about their condition as a pose to one visit to a GP."

Minor gastro-disturbances were not included as the symptom relief scale was set at a background threshold that correlates to a healthy person’s minor symptoms.³

Complete remission was assessed on the three follow up sessions and compared to baseline testing. The two measures that formed the complete remission assessment were analysed separately. This was organised as follows:³

1. 4-8 week complete remission
2. 4, 8, 12 week endoscopically confirmed healing
3. 4, 8, 12 week symptom relief
4. 4, 8, 12 week complete remission, symptom relief, endoscopic healing for H. pylori positive and negative patients

In terms of drug efficacy there were no significant differences between esomeprazole or pantoprazole. There were also no significant differences in the safety between the medications or in the rate of achieving complete remission.³

In terms of drug efficacy analysis, the major results from the trial were as follows:³

• Most of the patients who experienced complete remission by 12 weeks had done so by 4 weeks; approximately 60% of patients in each drug group.
• At 4 weeks approximately 75% of patients had achieved endoscopically confirmed healing. This rose over the next two follow up sessions; at 12 weeks over 95% of patients had healed.
• The symptom relief was very similar in terms of improvement rate as endoscopically confirmed healing. At 12 weeks over 90% of patients had achieved complete symptom relief.
• H. pylori positive and negative patients did not show significantly different improvements from each other in either drug condition.

In terms of proportion of patients, complete remission was achieved later than symptom relief or endoscopic healing alone at all three follow-up sessions.³

Seventy-three patients experienced adverse events during the study time-course and discontinued treatment. None of the adverse events experienced by participants in the study were considered to be related to the study medication. Only 3 participants in the esomeprazole group were classed as non-responders and discontinued the study, no pantoprazole participants were non-responders.³

The results from this trial suggest that the traditional endpoints of treatment assessment may not be adequate to determine the efficacy of the drug in a proportion of patients.³

Initial treatment regimes for PPIs are usually set for four to eight weeks. However this study has shown that at this stage only two out of three patients have complete remissions from the physical symptoms and signs. At this same stage if signs and symptoms were measured separately approximately three quaters of patients would show improvements, indicating an overestimate of drug efficacy at 4 weeks of treatment.³

By maintaining PPI administration for 12 weeks, clinicians will see improvement in the proportion of patients that are complete responders of treatment. Commonly, non-responders are put on another course of PPI treatment with twice daily dosing and intra-oesophageal pH monitoring.² This may not be necessary if an initial 12 week course is adhered to. This study confirms the safety of increasing the use of both esomeprazole and pantoprazole.³

Dr Robert Heading, consultant at the Department of Gastroenterology, Glasgow Royal Infirmary, helped to develop the ReQuest^TM questionnaire. He said, "The first and most important message for clinical practice is that doctors should talk to patients carefully! Just asking about their heartburn after a period of treatment it is likely to be much better but if the patient is also asked about any continuing limitation of food intake, sleep disturbances, bloating and abdominal discomfort it may become evident that there is still some persistence of the problem with associated quality of life impairment."

References

1. Delaney BC. Review article: Prevalence and epidemiology of gastro-oesophageal reflux disease. Alimentary Pharmacology & Therapeutics. 2004; 20(8): 2-4.
2. Freston JW. Therapeutic choices in reflux disease: Defining the criteria for selecting a proton-pump inhibitor. American Journal of Medicine. 2004; 117(5): 14-22.
3. Bardhan KD, Achim A, Riddermann T, Pfaffenberger B. A clinical trial comparing pantoprazole and esomeprazole to explore the concept of achieving "complete remission" in gastro-oesophageal reflux disease. Alimentary Pharmacology & Therapeutics. 2007; 25: 1461-9.