Long Term Acid Suppressant Medications (ppi’s): Concerns and Care

Maintenance antisecretory acid therapy (PPI’s) are used in many patients, particularly those with gastroesophageal reflux disease(GERD). With the long-term use of any medication, drug safety becomes an important issue. Acid (HCl) is normally secreted into the gastric lumen, where it serves to both digest dietary protein and maintain a sterile environment by removing ingested bacterias. Proton pump inhibitors (PPIs) are strong acid suppressants, and thus long term usage has raised several issues which shall be discussed in this article.

The three main concerns regarding the long-term usage of proton pump inhibitors (PPIs) include :

1. Risk of infectious complications – including Pneumonias, Cl difficile diarrhoeas

2. Malabsorption of Iron, Vitamin B12, Magnesium and Metabolic bone disease

3. Hypergastrinemia, Gastric carcinoids and Atrophic Gastritis

Other concerns include acute interstitial nephritis (kidney disease) and drug interactions particularly reducing the effect of Clopidogrel, which is used in coronary stented patients to reduce the risk of stent blockage.

InfectionsA concern with any form of gastric acid inhibition is an increased risk of enteric infections since gastric acid normally protects against these infections. In addition, a reduction in gastric acid secretion permits bacteria to more easily colonize the upper gastrointestinal tract, which may predispose to pneumonia.

Clostridium difficile and other enteric infectionsThe best documented association of PPI use with enteric infections has been with C. difficile diarrhea, even in patients not exposed to antibiotics(1-7). C. difficile is an anaerobic organism that sporulates; acid-resistant spores are presumed to be the major vector of disease transmission. Three meta-analyses of observational studies have demonstrated an increased risk of C. difficile infections in patients treated with PPIs(8-10). A 2012 meta-analysis of 42 observational studies that included 313,000 patients found that PPI use was significantly associated with an increased risk of both incident and recurrent C. difficile infection(9).

The US Food and Drug Administration (FDA) has issued a safety alert encouraging providers to consider a diagnosis of C. difficile-associated disease in PPI users with persistent diarrhea(11). Given the potential risk of C. difficile infection, the FDA has also recommended that providers prescribe the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Associations with other enteric infections, including Campylobacter and Salmonella, have also been reported(12-15), but the risk is uncertain(16).

PneumoniaThe risk of pneumonia in PPI users may be increased due to a reduction in gastric acid secretion, permitting bacteria to more easily colonize the upper gastrointestinal tract. The increased risk has been seen with both community-acquired pneumonia (CAP) and health care associated pneumonia (HCAP)(17-19). A meta-analysis of 31 studies found that patients taking PPIs or H2 receptor antagonists (H2RAs) were at increased risk for pneumonia(20).

MalabsorptionConcern has been expressed regarding the effects of long-term PPI use on iron and vitamin B12 absorption, though any effects are generally mild, clinically insignificant, and addressed by supplement therapy(21). On the other hand, magnesium and calcium malabsorption may be bigger problems, predisposing to hypomagnesia and metabolic bone disease.

Magnesium absorptionHypomagnesemia due to reduced intestinal absorption has been described with PPI use(22). In March 2011, the FDA issued a safety alert warning providers of the risk of hypomagnesemia in patients who have been on PPIs long-term (generally longer than one year)(23).

Hip fracture and calcium malabsorptionLong-term use of PPIs may influence bone metabolism. Hypochlorhydria could theoretically reduce calcium absorption(24) and inhibit osteoclastic activity(25,26), thereby decreasing bone density. A case-control trial suggested that long-term use of PPIs was associated with a slightly increased risk of hip fractures in those older than 50 years of age and that the magnitude of the risk increase was proportional to both PPI dose and duration of therapy(27). A meta-analysis that included 11 cohort and case-control studies examined the risk of fractures associated with PPI use(28). The 11 studies included 1,084,560 patients with 62,210 PPI users, 71,339 patients with hip fractures, 161,179 patients with any-site fractures, and 5728 patients with spine fractures. The risk of hip fracture was increased among PPI users compared with nonusers. There was also an increased risk of spine and any-site fracture. The FDA has mandated revised safety information on all PPIs about a possible increased risk of fractures of the hip, wrist, and spine with the use of these medications(29). The FDA also recommends that healthcare professionals who prescribe PPIs consider whether a lower dose or shorter duration of therapy would adequately treat the patient’s condition.

Vitamin B12 malabsorptionLong-term therapy with omeprazole has been associated with vitamin B12 malabsorption(30,31). Thus, it is reasonable to assess vitamin B12 levels periodically (eg, annually) in patients who are on long-term treatment with PPIs(32).

Iron malabsorptionGastric acid plays a role in the absorption of nonheme iron, and the use of PPIs has been associated with decreased iron absorption(21,33-35). However, in most cases the decreased absorption does not appear to be of clinical significance. One exception may be in patients who require oral iron supplementation(35,36).

HypergastrinemiaAn initial concern with omeprazole was the induction of hypergastrinemia and gastric carcinoid tumors in rats, changes also demonstrated with chronic ranitidine exposure(37). While patients treated with omeprazole for up to 11 years have shown some enterochromaffin cell hyperplasia, no dysplasia or neoplastic changes have been observed(38).

The clinical significance of other theoretical risks related to hypergastrinemia (such as colon cancer) has not been established. One study found no increased risk of colon cancer in long-term users of a PPI(39).

Atrophic gastritisPatients receiving maintenance therapy have a propensity to develop chronic atrophic gastritis. Although the risk of atrophic gastritis in this context remains unclear, it could theoretically lead to an increased incidence of gastric cancer. In one study, for example, atrophy developed in over 30 percent of patients after omeprazole therapy for a five-year period(40). However, since the omeprazole-treated patients developed atrophy only in the presence of a concomitant H. pylori infection, it was suggested that only the H. pylori infected group was at risk. We do not routinely test for H. pylori in patients who require long-term therapy with a proton pump inhibitor since the risk of atrophic gastritis is small and, in the uncommon patient who develops it, the clinical consequences are uncertain.

Acute interstitial nephritisPPIs have been associated with acute interstitial nephritis (AIN)(41-44). Drug-induced AIN is not dose-dependent, and recurrence or exacerbation can occur with a second exposure to the same or a related drug.

Drug interactionsClinically important drug interactions with PPIs are rare. However, some data suggest decreased activation of clopidogrel when used in conjunction with omeprazole on the basis of a shared hepatic metabolic pathway. Other mechanisms by which PPIs might negatively impact cardiovascular outcomes have also been proposed(45). In 2009, the US Food and Drug Administration (FDA) concluded that patients taking clopidogrel should consult with their clinician if they are taking or considering taking a PPI, including over-the-counter PPI preparations(46-47). PPIs, with the exception of pantoprazole, have been associated with reduced effectiveness of clopidogrel and a resulting 40% increased risk of coronary stent occlusions(48).

DISCONTINUING PROTON PUMP INHIBITORSMany patients with gastroesophageal reflux disease (GERD) and dyspepsia are maintained on proton pump inhibitors (PPIs), but some concerns have been expressed regarding the long-term safety of these medications, as well as potentially important drug interactions. As a result, some asymptomatic patients who do not have other indications for being on a PPI may be candidates for having their PPI discontinued, though many relapse once the medication is stopped. Previous studies have demonstrated rebound gastric acid hypersecretion following the discontinuation of PPIs in patients managed for prolonged periods of time with these agents. As discussed below, no specific method for discontinuing the use of PPIs has been proven effective, and no approach is universally accepted(49,50). Moreover, despite the definition of “prolonged therapy” being likewise unclear, patients treated for a period of six months might be considered candidates for dose tapering. The following are general guidelines that may be employed when stopping a PPI:

• Patients with GERD or dyspepsia are considered for a taper after being asymptomatic for a minimum of three months.

• Patients treated for acute duodenal and gastric ulcers or as part of a course of treatment for H. pylori for four to eight weeks do not require a taper.

  In summary, several health related hazards have been identified with a prolonged use of PPI’s, and the the key is to use PPIs only when clearly indicated, and to reassess continued use, so that long-term therapy is used judiciously(51).

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