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GMA Position Statement On the Use of Proton Pump Inhibitors

Proton Pump Inhibitors (PPIs) belong to a class of antacid medications used in the treatment of acid peptic disorders, including Gastroesophageal Reflux Disease (GERD) and Peptic Ulcer Disease, and to reduce the risk of gastrointestinal bleeding in critically ill patients and individuals treated with anticoagulation therapy.  The PPIs have demonstrated outstanding efficacy and remarkable safety over a period of three decades of use.  They have been used by tens of millions of individuals worldwide, frequently for prolonged periods, and sometimes lifelong, due to the chronic nature of the conditions being treated.   PPIs have been prescribed confidently by physicians, and have demonstrated such safety that they can now be obtained over the counter, without a prescription, and they can be used without professional supervision.  No medications are without side effects, however.  Could there be a downside to prolonged use of a PPI, or are the PPIs safe for long term use?

Recently, there have been a series of observational studies published in the medical literature, and reviewed and discussed in the media, suggesting an association between prolonged PPI use and myocardial infarction (heart attacks), chronic kidney disease, and dementia.  Over the past 10 years, studies have been published linking long-term and high dose PPI use to an increased bone fracture risk. All of these studies were retrospective in design, meaning that the researchers reviewed events occurring in the past.  They compared groups of individuals using PPIs to similar groups of individuals not taking PPIs, and looked for differences in the incidence of any illnesses or side effects between the different groups.  In the case of myocardial infarctions, a data mining technique was used to review tens of millions of medical record entries from millions of individuals to detect associations.  In the case of dementia, only cohorts of elderly individuals (average age = 84) were reviewed. What the researchers uncovered were weak associations linking the use of PPIs to the above conditions.

It is important to understand first of all that these studies were retrospective, and no conclusion regarding causation can be made based on retrospective observational data.  Only prospective controlled clinical trials can detect a cause and effect relationship between PPIs and alleged side effects, and these prospective trials have not been performed. That is, the published studies cannot be used as evidence that PPIs cause heart attacks, chronic kidney disease, dementia, or an increased bone fracture risk.  The associations detected may only be a correlation of two events tending to occur together but without causation.

A good example of correlation without causation is provided to us by the George Mason University Statistics Department, and can be found at www.stats.org/causation-vs-correlation.  “Girls who watch soap operas are more likely to have eating disorders.”  Does this mean that watching soap operas causes eating disorders, or that avoiding watching soap operas will reduce the risk of having an eating disorder?  Of course not!  Similarly, elderly individuals who take PPIs are slightly more likely to have dementia.  Does this mean that the PPIs are causing dementia?  No!  There may be many other factors involved, and causation cannot be determined.

The second important concept to understand is that the demonstrated associations between PPIs and various illnesses are only weak, modest associations.  For example, there is a 30% increased risk, of dementia in the patient cohort taking a PPI compared to the patient cohort not taking a PPI.  This means that if the incidence of dementia is 3 out of 300 individuals not using a PPI, we can expect an incidence of dementia in 4 out of 300 individuals using a PPI.  This is not a very compelling association.  There may be a 90% increased risk of kidney failure in chronic PPI users.  This does not mean that 90% of PPI users will get kidney failure!  It means that if the incidence of kidney failure is 1 out of 100 individuals not using a PPI, we can expect an incidence of kidney failure in roughly 2 out of 100 individuals using a PPI.  This was the strongest association detected, also not compelling, and causation not proved.

As of 2015, there were 34 observational studies with nearly 2 million participants reporting an association between PPI use and increased fracture risk.  The magnitude of the association is weak, and most likely due to confounding factors (the individuals taking PPIs have more illnesses in general than the individuals not taking PPIs).  There is no clear dose-response relationship and there is no association between PPI therapy and fracture risk in those at highest risk.  Finally, there is no clear mechanism through which PPI therapy increases the risk of fracture, as recent randomized trials show no impact of PPI therapy on calcium absorption and there is no association between PPI therapy and the risk of osteoporosis.

Based on our review of the medical literature, and in agreement with our professional societies (The American Gastroenterological Association and The American College of Gastroenterology), we strongly believe that the PPIs are safe for long term, including lifelong use, and there is insufficient evidence to change PPI use based on the perceived risk of myocardial infarction, chronic kidney disease, dementia, and bone fractures.  PPIs should only be used for approved indications, and where the benefit clearly outweighs the risk, such as the long-term management of Gastroesophageal Reflux Disease.  PPIs are often used for unapproved indications, such as the treatment of functional dyspepsia (bloating and distension).  If you are unsure whether to continue a PPI, please arrange an office visit to review your case and formulate a plan of care.  PPIs should be taken at the lowest dose that controls troublesome symptoms and/or tissue injury.  If you have any question regarding the dose you are taking, please arrange an office visit to review your case.   Even though PPIs are available without a prescription, we believe that they should not be taken without medical supervision.  If you are taking a PPI long term, you should be evaluated at least every 2 years.  Routine lab testing to include a Comprehensive Metabolic Panel and a Magnesium level should be performed annually; this can be provided by your primary care physician.  We do not recommend bone mineral density evaluations for individuals taking PPI therapy other than what would be normally indicated.  There is no evidence to support prescription of calcium and/or vitamin D to an individual simply because he or she is taking a PPI.

Finally, there are individuals who for whatever reason do not want to use PPIs, or who have reactions or side effects attributed to PPIs, or who have an incomplete response to PPIs.  Fortunately, there are safe and effective alternatives to PPI use.  The Stretta procedure is an endoscopic treatment for reflux disorder, approved by the FDA and introduced in 2000, then upgraded and reapproved in 2011.  At the time of endoscopy, radiofrequency energy is applied directly to the lower esophageal sphincter (LES).  Stretta therapy remodels the musculature of the LES without surgery.  Clinical studies have demonstrated both safety and efficacy, with a significant reduction in symptom scores and a significant improvement in health related quality of life.  Reduction or elimination of PPI use has also been demonstrated.   Another alternative treatment is fundoplication surgery.  At the time of surgery, the top portion of the stomach is wrapped around the lower esophagus to replace the function of the LES.  This surgical procedure can be done “open” or by laparoscopy.  Long term studies have demonstrated that fundoplication is as effective as, if not slightly better than medical therapy in controlling reflux over the long term, but of course there are surgical risks involved.  If you are interested in Stretta or surgery, or if you think you might be a candidate for either of these procedures, please arrange an office visit to discuss these alternatives.  Thank you for your time and patience.