2010-04-09 20:18:05 UTC

Short-Term Empiric PPI Therapy Is Effective

April 9, 2010

Ann Ouyang, MD, AGAF

Ann Ouyang, MD, AGAF

Graham H. Jeffries Professor of Medicine, Division of Gastroenterology and Hepatology, Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, PA  


Up to 44 percent of the U.S. population reports symptoms of GERD, and up to 32 percent complains of dyspepsia. The approach to these patients has significant implications for health and health-care costs.

An argument favoring the empiric use of any medication in treating a condition needs to consider the rationale for the treatment, evidence that such an approach is beneficial to patients and the risks of adopting this treatment approach.

Rationale for use of PPIs in GERD/NERD

The proton pump (H+/K+ ATPase) is the final step in a cascade of signaling events leading to acid production. Proton pump inhibitors (PPIs) inhibit active pumps, binding irreversibly. Continued synthesis of new proton pumps accounts for the need for continuous treatment with PPIs.

GERD includes patients with heartburn and/or regurgitation, both with esophagitis and with intact esophageal mucosa (non-erosive reflux disease [NERD]). Community-based studies suggest that NERD accounts for 70 percent of patients with GERD. Symptom severity does not accurately predict the severity of esophagitis, and there is no validated symptom algorithm to predict the presence of erosive esophagitis. An empiric treatment approach implies treating both patients with erosive esophagitis and NERD. There is conflicting literature concerning the relationship between the amount of acid reflux and the severity of esophagitis. Despite this, considerable literature supports the superiority of PPIs in healing mucosal inflammation over other acid-suppressive therapy, such as histamine H2 receptor antagonists (H2RA) in erosive esophagitis.1 PPIs are generally accepted as initial treatment in erosive esophagitis. If one argues that empiric therapy should not be used in NERD, one would require endoscopy in all patients to exclude erosive esophagitis.

Evidence for efficacy of PPI for GERD/NERD

Patients with erosive esophagitis respond better to PPIs with greater and more rapid symptom relief than do patients with NERD.2 Seventy percent to 80 percent of patients with erosive esophagitis will have symptom resolution after PPI treatment for four weeks compared to 50 percent and 60 percent of patients with NERD.

Randomized controlled trials comparing empiric treatment of patients with symptomatic GERD showed that PPIs were more effective than placebo, H2RAs or prokinetics in controlling heartburn, and empiric treatment with PPIs is also more effective than placebo, H2RAs and prokinetics in patients with NERD. The benefit was greater in those treated empirically, presumably because some of the patients had erosive esophagitis.3


Recent reports indicate risks from long-term treatment with PPIs for calcium absorption and the theoretical risk of the effect of higher pH on the ability of ascorbic acid to remove nitrites from gastric juice; these are long-term use concerns. The effect of concomitant use of PPIs on the efficacy of clopidogrel is important and should be considered before starting patients on an empiric course of PPIs. However, this is likely to be relevant in a minority of patients.

The benefit to patients is the use of a medication that is likely to be effective in improving symptoms and quality of life in more than half of the patients; testing may not change the decision to use PPIs. If erosive esophagitis is found on endoscopy, most physicians would treat the patients with a PPI. If normal mucosa is found, what would be the next step? We know that the amount of acid reflux detected by a 24-hour pH probe study does not predict the likelihood of response to a PPI. A normal amount of acid reflux may be seen even in patients with erosive esophagitis, making it unlikely that one would withhold a PPI trial in a patient with GERD-like symptoms based on the 24-hour pH probe result.4

Which approach costs more: an initial empiric PPI treatment approach or diagnostic testing first, then treatment? This depends on the cost of medications and testing, and differs depending on the country. Generic PPIs have decreased the cost of empiric treatment significantly.

Several studies show that on-demand therapy with PPIs results in maintenance of improved health-related quality of life and degree of patient satisfaction, further reducing the cost of this approach.

Rationale for use of PPIs in FD

The Rome III criteria define non-ulcer (functional) dyspepsia (FD) as a chronic condition with one or more of the symptoms of epigastric pain, epigastric burning, early satiety and/or bothersome post-prandial fullness in the absence of structural disease to explain the symptoms. Making the diagnosis in the strict sense requires diagnostic testing.

Symptoms of FD may result from several patho-physiologic processes. These include impaired accommodation of the fundus, Helicobacter pylori (H. pylori) infection, gastroparesis or dysrhythmia, intestinal dysmotility, visceral hypersensitivity, and psycho-social disorders. What role does acid have in the patho-physiology of FD? Limited physiologic studies suggest that duodenal acid infusion results in greater nausea in dyspeptic patients than in controls, suggesting hypersensitivity of the duodenum to acid.5 In healthy participants, duodenal acid infusion increases fundic compliance and decreases fasting fundic tone. This is associated with a higher perception and symptom score in response to the same distending pressures.6 Whether this reflex is altered in patients with functional dyspepsia is unknown.

Evidence of efficacy of PPI as empiric treatment in FD

Despite the lack of evidence that acid secretion is altered in patients with FD, there are several studies examining the response to PPIs and other acid-suppressing medication. A review identified 73 random controlled trials comparing the efficacy of a variety of drugs in improving global dyspepsia symptom and quality-of-life scores. In general, PPIs, H2RA and prokinetics proved more effective than placebo.7 Other studies suggest that the strategy of empiric treatment with PPI followed by H. pylori testing or testing for H. pylori and eradication, if positive, resulted in similar symptom and quality-of-life outcome after one year to empiric treatment with PPI alone, but resulted in less endoscopies per patient.

In most published studies, FD was diagnosed after diagnostic studies. Should empiric PPIs be used in uninvestigated dyspepsia in patients who have no alarm symptoms? Random controlled studies comparing prompt endoscopy as an initial step compared to acid suppression with either a PPI or H2RA report conflicting results in costs and outcome. Four of five studies showed no difference in effect of these different strategies. A recent Dutch double-blind, placebo-controlled study compared a step-up approach to acid suppression to a step-down approach, starting with a PPI as initial treatment of uninvestigated individuals with new onset dyspepsia. With more than 600 subjects, the study showed a similar treatment success rate with either approach or a similar use of medical resources, with the only difference being the contribution of the cost of the prescribed medications. A 70 percent treatment success was noted at six months. With the PPIs becoming generic, the cost of medications is likely to decrease, impacting the cost-utility of an empiric treatment approach.8


Adopting empiric PPI use to treat uninvestigated non-ulcer dyspepsia raises concern about potentially missing another serious diagnosis. Appropriate stratification of patients by age and other risk factors would reduce this. A treatment-only approach without diagnostic testing may not be as efficacious in the U.S. as reported in the Netherlands, given the mindset of many patients that a diagnostic test is important to rule out life-threatening conditions, no matter how unlikely it is that these conditions are present.

The final word

There is excellent evidence that an approach of short-term empiric treatment with PPIs is effective in treating patients with GERD and NERD. Although the literature suggests that this approach is as effective as testing and treating in FD when selected to exclude patients with alarm features, the likelihood of these results being borne out in the U.S. is less clear because of the concern for missed diagnoses by patients.


  1. Khan M, Santana J, Donnellan C, Preston C, Myayyedi P. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev 2007 Apr 18;(1):CD003244.
  2. Orlando R, Monyak JT, Silbrg DG. Predictors of heartburn resolution and erosive esophagitis in patients with GERD. Curr Med Res Opin 2009;25: 2091-102 (Supported by Astra Zeneca).
  3. Van Pinxteren B, Numans, ME, Bonis PA, Lau J. Short-term treatment with proton pump inhibitors, H1-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Database Syst Rev 2006 Jul 19;3:CD002095. Review.
  4. Avidan B, Sonnenberg A, Schnell TG, Sontag SJ. Acid Reflux is a poor predictor for severity of erosive reflux esophagitis. Dig Dis Sci 2002;47:2565-2573.
  5. Samson M, Verhagen MA, vanBerghe Henegouwen GP, Smout AJ. Abnormal clearance of exogenous acid and increased acid sensitivity of the proximal duodenum in dyspeptic patients. Gastroenterology 1999;116:761-2.
  6. Lee KJ, Vos R, Janssens J, Tack J. Influence of duodenal acidification on the sensorimotor function of the proximal stomach in humans. Am J Physiol Gastrointest Live Physiol 2004: 286:G278-84.
  7. Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Sytem Rev 2006;Oct 18:CD001960.
  8. Van Marrewijk Cj, Mujakovic S, Fransen GAJ et al. Effect and cost-effectiveness of step-up versus step-down treatment with antacids, H2-receptor antagonists, and proton pump inhibitors in patients with new onset dyspepsia (DIAMOND study): A primary-care-based randomized controlled trial. Lancet 2009:373:215-225.

More on Dyspepsia / Non-Ulcer Dyspepsia

Choose from 30 breakout sessions at the 2018 AGA Postgraduate Course

March 21, 2018

Delve deeper into specific clinical topics that interest you and get concrete action items that can be immediately implemented into your practice.

Save the Date: 2018 AGA Postgraduate Course

Jan. 11, 2018

This year’s course will take place on June 2 and 3, 2018, in Washington, D.C.

Image Challenge: An Unusual Cause of Dysphagia in an Elderly Woman

Nov. 8, 2017

What caused a 66-year-old woman, with occurrence of hemoptysis several days before presenting, one month of dysphagia?