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Reflux oesophagitis
Oesophageal damage
Prevalence
Systematic review
Short-term healing
Long-term maintenance
A review of all proton pump inhibitors compared with all histamine antagonists is published elsewhere on these Bandolier Internet pages (http://www.ebandolier.com/bandopubs/gordf/gord.html). It was supported by an educational grant from the Astra Foundation. Editorial control was solely that of the authors. Data from direct comparisons of omeprazole and ranitidine only have been used here as an example of deriving NNTs from different types of output.

Gastro-oesophageal reflux is the process of reflux of stomach contents into the oesophagus. The consequence is a chemical insult from acid and enzymes. Reflux happens commonly but infrequently in many people, and it does not cause major harm because the natural peristalsis of the oesophagus clears the refluxate back into the stomach. In others where acid reflux from the stomach is persistent, the result is damage to the oesophagus causing symptoms or macroscopic oesophageal damage, and here gastro-oesophageal reflux disease (GORD) can be said to be present.

GORD produces a characteristic set of symptoms, though significant oesophagitis can be present without symptoms. Heartburn is most common; it is often described as gnawing or burning pain behind the sternum, and it may be severe enough to radiate to the arm or jaw. Usually occurring within an hour or so of a meal it can be made worse by lying down. Heartburn can wake the patient at night, and is most frequent in those with the most severe disease. Heartburn occurs occasionally in many people after a fatty or spicy meal, but in GORD the symptoms occur frequently after any sort of meal. Alcohol and coffee also induce symptoms. Antacids relieve symptoms.

Oesophageal damage

The lining of the oesophagus is ill-equipped to resist stomach acids. The stomach has cells which produce a bicarbonate-mucus barrier which protects them from stomach acid: oesophagus does not have this protective barrier. The result of refluxed stomach acid is to damage the lining of the oesophagus. This damage can be microscopic, but is often macroscopic and seen on endoscopy.

Endoscopic oesophageal damage is graded on a scale of 1-4 with increasing severity of damage.
  • Grade 0 is given to normal oesophagus with no macroscopic damage.
  • Grade 1 describes an oesophagus with a few areas of erythema, mucosal friability and contact bleeding. These are minor changes regarded as normal by some gastroenterologists.
  • Grade 2 oesophagitis has small superficial linear erosions. These tend to lie on the crests or tops of the mucosal folds and may have some surface exudate.
  • Grade 3 describes the condition when these erosions coalesce and join around the circumference of the oesophagus. A cobblestone appearance is created by islands of oedematous tissue between the erosions.
  • Grade 4 is characterised by extensive mucosal damage with deep ulcers. Strictures may develop, and where this happens there may be less damage above the stricture because the stricture forms a barrier to stomach acids.


The correlation between endoscopic grading and symptoms is not good. Severe symptoms can occur with low grade oesophagitis, and conversely severe oesophageal damage can sometimes occur with few symptoms.

Prevalence

Surveys in the USA have indicated that 44% of the adult population has heartburn at least once a month. Six out of ten of these never consult a GP about it. About 13% of the adult population take some type of indigestion aid at least twice a week. There seem to be few reliable figures on the numbers of patients who present to GPs with reflux symptoms, but a health authority with an adult population of 470,000 will have an estimated 7,500 patients seeing GPs with dyspepsia and almost 3,000 having an endoscopy, over half for oesophageal or gastrointestinal problems, including suspected ulcer.

Treatment options

These include lifestyle change and use of antacid or alginates; none of these is particularly effective. Mucoprotective agents and motility stimulants may be used, but suppression of acid secretion with H2A or PPI is the most common form of treatment. Antireflux surgery is said to be useful in some patients, and to be effective.

Systematic review

Reports were sought of comparisons between any proton pump inhibitor (PPI) and any histamine-2 antagonist (H2A) in reflux oesophageal disease with endoscopic healing as the outcome measure. Both short-term healing and long-term maintenance were included. Papers were included in the systematic review of effectiveness if they fulfilled the criteria:-
  • Full journal publication
  • Randomised trial
  • Compared PPI with H2A, or
  • Compared either PPI or H2A with placebo
  • Examined gastro-oesophageal reflux disease (GORD), erosive oesophagitis or gastritis, or reflux oesophagitis
  • Had endoscopic healing as an outcome or
  • Had adverse event outcomes
  • Had short-term outcomes at 4 and/or 8 weeks, or
  • Had long-term maintenance outcomes at 6 or 12 months

Short-term healing

Twenty-three reports with 5,118 patients fulfilled the inclusion criteria. One report had no endoscopic healing data, but did have adverse event information. Of the reports with endoscopic healing, ten (1393 patients) compared omeprazole with ranitidine, two reports (339 patients) omeprazole with cimetidine and three reports (525 patients) lanzoprazole with ranitidine. Quality scores were high using a validated scale from 1 to 5 [1]. Four studies had a score of 2, three of 3, eleven of 4 and five of 5. The median score was 4. Bandolier 33 showed how it is important to use studies of high quality (scores above 2) to avoid over-estimating treatment effects.

Information from randomised controlled trials which compared ranitidine and omeprazole with endoscopic healing of erosive oesophagitis after eight weeks is shown in the Table below. The overall NNT for omeprazole compared with ranitidine was 3.3. This mean that for every three patients with erosive reflux oesophagitis treated with omeprazole, one will be healed who would not have been healed if they had been treated with ranitidine.

Odds ratios, relative risk and NNTs have been calculated, and the rate of healing in the omeprazole and ranitidine groups is shown in the Table for each trial.

L'Abbé plot

This shows that all the studies are well to the upper left of the line of equality meaning that in all trials omeprazole was more effective than ranitidine. The L'Abbé plot also provides extra information that the NNT does not. While the NNT gives us the treatment-specific benefit of omeprazole over ranitidine, the L'Abbé plot shows us the overall effect of treatment. So we can see that about 80% of patients are healed with omeprazole while only about 45% are healed with ranitidine.
Summary data from randomised controlled trials comparing omeprazole and ranitidine for endoscopic healing of erosive oesophagitis after eight weeks. EER is 8-week endoscopic healing rate with omeprazole and CER the 8-week endoscopic healing rate with ranitidine.
This can be a useful source of information for patients, since it also conveys information the patient most wants - how likely am I to get better (or be harmed) with this treatment. For an individual patient this is an absolute which includes both treatment-specific and non-specific effects of treatment. Here the non-specific effect is contained within the results for ranitidine, but if we had been examining a treatment compared with placebo, the L'Abbé plot will give us that also.

NNT from ARR

For the overall results, the proportion getting benefit with omeprazole was 78%, or 0.78, and for ranitidine it was 44% or 0.44. So the NNT calculation becomes:

NNT = 1/ARR = 1/(0.78-0.44) = 1/0.34 = 3

which is close to the 3.33 calculated from raw data in the review.

NNT from OR

Looking at the table of odds ratios and NNTs in the previous story , if we go to the column with the odds ratio nearest the overall of 3.7, and track along the control event rate nearest that in our review for ranitidine of 0.4, we obtain an NNT of 3. Again close to the overall NNT of 3 calculated from raw data in the review.

NNT from RRR

The relative risk increase from the table is (78-44)/44 = 77%. The PEER is 44%, and our NNT from the nomogram is 3.

Long-term maintenance

Seven reports with 1,635 patients fulfilled the inclusion criteria. Four reports (1094 patients) compared omeprazole with ranitidine, one omeprazole with placebo, one lanzoprazole with placebo and one omeprazole and ranitidine alone and in combination with cisapride. The most commonly used doses were omeprazole 20 mg and ranitidine 300 mg daily. Two studies had a quality score of 3, four of 4 and one of 5.

Information from randomised controlled trials which compared ranitidine and omeprazole with endoscopic healing of erosive oesophagitis after eight weeks is shown in the Table.
The overall NNT for omeprazole compared with ranitidine was 2.8. This mean that for every three patients with healed erosive reflux oesophagitis treated with omeprazole, one more will still be healed after one year who would not have been if they had been treated with ranitidine.

L'Abbé plot
Summary data from randomised controlled trials comparing omeprazole and ranitidine for maintenance of endoscopic healed erosive oesophagitis after time point nearest to one year. EER is one-year still-healed rate (on endoscopy) with omeprazole and CER the one-year still-healed rate (on endoscopy) with ranitidine.
This shows that all the trials are above the line of equality, but with much wider spread. The one-year remission rates with ranitidine vary from 9% to 49%, and for omeprazole between 50% and 89%. The difference - the treatment-specific effect, is much the same, though, giving consistent NNTs.

NNT from ARR

For the overall results, the proportion getting benefit with omeprazole was 70%, or 0.70, and for ranitidine it was 30% or 0.30. So the NNT calculation becomes:

NNT = 1/ARR = 1/(0.70-0.30) = 1/0.40 = 2.5

which is close to the 2.8 calculated from raw data in the review.

NNT from OR

Looking at the Table of odds ratios and NNTs in the previous story, if we go to the column with the odds ratio nearest the overall of 4.2, and track along the control event rate nearest that in our review for ranitidine of 0.3, we obtain an NNT of 3. Again close to the overall NNT of 2.8 calculated from raw data in the review.

Reference

  1. AR Jadad, RA Moore, D Carroll, C Jenkinson, DJM Reynolds, DJ Gavaghan, HJ McQuay. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 1996 17: 1-12.



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