By: Lauren Kaveski, Pharm.D. Candidate c/o 2013

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We see proton pump inhibitors (PPIs) used in many medication regimens, but it is unknown whether the majority of patients receive these medications for appropriate durations or indications.  For all labeled indications, other than Zollinger-Ellison Syndrome (a rare condition characterized by damaging gastrin hypersecretion and subsequent hydrochloric acid eviction from gastric parietal cells), the length of prescription PPI use should not exceed eight successive weeks.¹  This class of medications is readily accessible over the counter (OTC) with a projected usage of 14 days.¹  Extended PPI consumption is indicated for patients taking certain medications that augment the risk of a gastrointestinal bleed, such as long-term oral steroids, non-steroidal anti-inflammatory drugs (NSAIDs), and clopidrogel (Plavix^®).¹

Using PPIs for prophylaxis against ulceration of the gastrointestinal track remains an off-labeled indication, and it is unknown whether there is a better class of medications for this indication.  The PPIs available in the United States are rabeprazole (Aciphex^®), dexlansoprazole (Dexilant^®), esomeprazole (Nexium^®), lansoprazole (Prevacid^®), omeprazole (Prilosec^®), pantoprazole (Protonix^®), esomeprazole / naproxen (Vimovo^®), and omeprazole / sodium bicarbonate (Zegerid^®).  Omeprazole, omeprazole / sodium bicarbonate, lansoprazole, and pantoprazole are now available as generics, and each of these, except pantoprazole, are available as OTCs.^1,2

Reports from MedWatch^© motivated a number of investigators to conduct epidemiological studies, including but not limited to prospective and retrospective cohorts, case-control trials, medical chart reviews, and statistical data analyses on larger studies such as the Women’s Health Initiative.  There was conflicting evidence regarding the magnitude and existence of these associations.²  Although these studies were individually weak (as they could not evaluate causality; hence, only associations), their quantity has demanded clinical attention.²

Enclosed within the eighth edition of DiPiro’s, there is a chilling collection of adverse drug events  associated with PPIs.³  Data reveals that PPIs diminish the absorption of certain nutrients, such as iron, calcium, and cyanocobalamin (vitamin B12), and thus amplify osteoporotic pathogenesis and fracture risk.³  This class of medications may also cause an overgrowth of bacteria, increasing the risk of enteric infections and community-acquired pneumonia.³  Moreover, Clostridium difficile (C. diff.) infections may increase due to the more alkaline gastrointestinal milieu.³  Regardless of these issues, the message currently conveyed to readers is that long-term PPI use is “relatively safe.”³

Furthermore, in the subject area of bone fracture risk, studies are in disagreement.  The proposed pathophysiology of enhanced fracture risk is a hindrance in the proton/potassium ATPasein osteoclasts and/or thwarting in calcium absorption.³  However, calcium absorption is profoundly reliant on other variables, such as the presence of vitamin D, the calcium salt ingested, and the particular individual.³  Fracture risk is a more recent concern, as there is apparent association between hip, wrist, forearm, and spinal fractures and PPI use.⁴  Alas, the data is diverse and at odds.

One sizeable epidemiological study unearthed that PPI ingestion correlated with a 25% increase in total fracture risk and a 47% increase in spinal fracture risk in post-menopausal women.⁴  We need to remain mindful that these are not absolute risks; instead, they are odds-ratios that estimate relative risk.  Relative risk conveys more reliability than the odds-ratio measurement, particularly if the incidence of the event is more than 10%.  This particular study did not provide data to calculate the incidences of spine, wrist, or overall fractures; thus, it was not possible to computer the absolute risk.⁴  The discrepancy existing between the absolute risk of PPI users and nonusers was not quantifiable; so, it is not feasible to relay the clinical significance of this finding to the public.  For some reason, we have an incidence of hip fracture, but the null hypothesis remains true for this variable: there was no statistical difference between the two groups.⁴  Moreover, a noteworthy amount of confounding variables existed within the study (e.g. dissimilar baseline characteristics among groups), which may explain the elevated risk that was obtained.⁴

Despite the lack of strength of epidemiological and observational studies, the FDA is proactive.  It added the risk of increased hip, wrist, forearm, and spinal fractures to the prescription PPI labeling.  OTC PPIs do not have this warning, as they are for short-term use.  Since there is only an association between PPIs and fractures with long-term PPI use, the FDA declared that short-term PPI use probably does not increase the risk of fractures.⁴

Fracture risk is greatest in postmenopausal women over 50 years of age who have not already had a fracture.⁴  Data also yields an association between PPI use and fractures in elder males; but the data on this area remains conflicting and inconsistent at best.  Moreover, there is no firm correlation between bone mineral density and PPI use.⁴  Thus, patients should not stop taking their indicated PPIs, and should maintain regular evaluation from their physician every few months to govern whether the PPI is still required.  As with any medication, patients should receive the lowest effective doses and durations.

Cases of hypomagnesemia emerged in patients taking PPIs after three months of use.³  However, the vast majority of those who suffered this side effect took PPIs for at least a year.³  Hypomagnesemia may occur due to shrunken gastrointestinal absorption of magnesium, secondary to a less acidic atmosphere.³  If a patient takes medications that deplete magnesium, such as thiazide diuretics, he or she has an augmented risk.³  It is crucial to ensure that this side effect does not happen in digoxin users, as digoxin toxicity interconnects inversely to serum magnesium levels.³  Because the myocardium needs magnesium to effectively contract, altered levels prompt life-threatening arrhythmias, in addition to palpitations, tremor, seizures, and muscle cramps and spasms.³

Physicians should acquire baseline magnesium levels and periodically monitor levels in patients who may be candidates for extensive PPIs use or who take other medications that call for magnesium level examining.  If hypomagnesemia occurs, it may be irreversible, even with magnesium supplementation.³  Magnesium levels typically normalize in patients within a week of discontinuation of the causative PPI.³  Upon removal of the PPI, the patient can receive a histamine-2-receptor-antagonist (H2RA) to manage the rebound hypergastrinemia, as well as to replace the PPI if needed and if effective for the particular patient.³  Quick administration of intravenous magnesium to correct the situation is appropriate if hypomagnesemia becomes symptomatic or serum magnesium dwindles to less than one milliequivalent per liter.³  The FDA found no increased risk of occurrence of gastric / colon cancers or unwanted cardiovascular events, especially with omeprazole and esomeprazole, which was a public concern in the past.³

PPIs also increase the risk of infections.  This holds true for both short and long-term use.  This phenomenon is likely due to the PPIs’ ability to diminish the body’s natural acidic secretions that normally act as a barrier of defense against a plethora of microorganisms.  In other words, PPIs, as well as histamine-2 receptor antagonists (H2-blockers) to a slighter degree, make the gastrointestinal system, a more hospitable and welcoming place for microorganisms; this allows a change in flora to occur.  PPI users are at increased risk for succumbing to gram-negative induced nosocomial pneumonia.  Those at highest risk have undergone intubation and used PPIs.³

Upon evaluation of 25 of the references used in the article “New warnings that PPIs (e.g. omeprazole) might increase the risk of Clostridium difficile-associated diarrhea” that appeared in Pharmacist’s letter in March 2012, 17 epidemiological studies and one meta-analysis discovered a positive association or correlation – they found PPI use to be a risk factor for C. diff. infection.²  Three observational studies discovered no statistical difference in the risk for C. diff. for the variable of PPI or acid suppression therapy use.²  Three studies did not mention PPI use as a risk factor for acquisition of this gram positive, anaerobic, spore-forming bacillus.²

Risk factors commonly associated with C. diff. infection include²

• recent antibiotic use (especially greater than three used concomitantly) or the use of antibiotics other than oral vancomycin or metronidazole (e.g. fluoroquinolones, cephalosporins, clindamycin, intravenous vancomycin, macrolides, and intravenous beta-lactam/beta-lactamase inhibitors)
• use of acid suppressive medications such as PPIs and H2-blockers
• female gender
• increasing age
• recent hospitalization
• hypoalbuminemia
• intubation
• malignant disease
• history or renal failure
• inflammatory bowel disease
• irritable bowel syndrome
• methicillin-resistant Staphylococcus aureus infection
• use of medications that decrease gastrointestinal motility and NSAID use

It is important to note that these risk factors were from observational studies that can only point out an association and that their data is conflicting.  C. diff. is part of the gastrointestinal flora in healthy human beings.  In the institutional setting, those who receive PPIs are generally critically ill and in the intensive care unit for the treatment of some sort of infection which may require intubation.  This patient population is generally elderly and is administered multiple antibiotics.  C. diff. may invade effortlessly in a more alkaline environment caused by PPI use; however, this infection appears to be more dependent on prior antibiotic use.  Clinically, this is applicable to the patient if he or she was recently hospitalized; used a PPI; and had clear diarrhea, abdominal pain, and fever that do not subside after a few days.  In addition, a patient is at increased risk of C. diff. infection if he or she used a PPI in addition to possessing other risk factors.^2,3

SOURCES:

1. Lexi-Comp Online.  Website.  Available online at: http://www.crlonline.com/crlsql/servlet/crlonline.  Last Accessed March 10, 2012.
2. PL Detail-Document, Proton Pump Inhibitors (PPIs) and C. difficile.  Pharmacist’s Letter/Prescriber’s Letter.  March 2012.
3. Williams DB, Schade RR.  Chapter 39.  Gastroesophageal Reflux Disease.  AND Berardi RR, Fugit RV.  Chapter 40.  Peptic Ulcer Disease.  In: Talbert RL, DiPiro JT, Matzke GR, et al.  Pharmacotherapy: A Pathophysiologic Approach.  8th ed.  New York: McGraw-Hill; 2011.
4. Gray SL, LaCroix AZ, Larson J, et.  al.  Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women’s Health Initiative.  Arch Intern Med.  2010 May 10;170(9):765-71.

Published by Rho Chi Post