Here we go again…another serious complication linked to acid-suppressing drugs known as proton pump inhibitors (PPIs). This time the adverse reaction appears to be an increased risk of heart attacks. It is only the latest in a surprisingly long list of serious side effects.

PPIs and MIs (Myocardial Infarctions, aka Heart Attacks)

The latest bad news for PPIs comes from investigators at Stanford University (PLoS One, June 10, 2015). They searched “over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population.” The conclusion:

“Our results demonstrate that PPIs appear to be associated with elevated risk of MI in the general population; and H2 blockers show no such association.”

In other words, powerful acid-suppressing drugs in the proton pump inhibitor category, such as esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix) and rabeprazole (Aciphex), were linked to an increased risk of heart attacks. That is in contrast to a different class of milder acid-suppressors (H2 antagonists) like cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid) or ranitidine (Zantac), which did not appear to be associated with a cardiovascular risk.

How Big a Risk of Heart Attacks?

Before we dig into the details of this study, let’s make one thing really clear. This was an epidemiological study. That means it was not a randomized controlled trial (RCT) in which one group of subjects received PPIs and another took placebo and were then followed for many years. That is the gold standard for determining benefit and risk.

On the other hand, this was a very large data-mining project. Almost 3 million people were analyzed. If there were something unique about heartburn patients that made them more vulnerable to heart attacks in general, those taking drugs like cimetidine or ranitidine should have also experienced a higher rate of heart attack. They didn’t.

The researchers discovered that people taking proton pump inhibitors were 16 to 21 percent more likely to experience a heart attack than those not on such acid-suppressing medications. That may not seem like a big risk until you take into account how many people are currently swallowing PPIs. The authors point out:

“Each year, it is estimated that over 113 million PPI prescriptions are filled globally. This, together with over-the-counter use, accounts for over $13 billion sales worldwide. In the US alone, about 21 million people used one or more prescription PPIs in 2009, making it the third highest seller in the country. The availability of PPIs over-the-counter is particularly more worrisome due to the absence of medical supervision.”

Given that so many people are now taking these medications, even a small risk could potentially translate into thousands or even tens of thousands of drug-related heart attacks annually.

We Told You So!

It is not nice to say “told you so,” but we warned visitors to this website back on October 3, 2013, that there might be a vascular problem linked to PPIs. To be specific, we stated:

“The latest concern is the discovery that acid-suppressing drugs may be linked to heart problems (Circulation, online, July 3, 2013). Researchers have found that PPIs lower levels of a natural compound called nitric oxide, which relaxes blood vessels and makes them more flexible. If drugs like Nexium lead to stiffer arteries, that could cause cardiovascular complications, especially for people with existing heart disease.”

We do our best to alert People’s Pharmacy subscribers to risks long before they reach the popular media. If you find this information helpful, please encourage friends and family to subscribe to our newsletter so they too can be alerted to the latest important health information.

Heart Attacks are NOT the Only PPI Problem!

Proton pump inhibitors have been linked to a number of other serious health problems. What shocks us is that many prescribers don’t seem concerned about these serious side effects. The FDA seems oblivious. After all, the agency deems PPIs so safe that the most popular brands (Prevacid, Nexium and Prilosec) are now available over the counter without any medical supervision.

Weakened Bones & Hip Fractures

Researchers have suspected for almost a decade that PPIs might contribute to fractures (JAMA, Dec. 27, 2006). An article in the Annals of Epidemiology (April, 2014) concluded: “Our study suggests that PPI use and hip fractures are associated, with risk increasing with longer duration and more recent use.” Since then, other studies have seemingly confirmed the relationship between powerful acid-suppressing drugs and fracture risk.

Pneumonia

A review of 26 studies (in PLoS One, June 4, 2015) reveals that:

“Outpatient PPI use is associated with a 1.5-fold increased risk of CAP [community-acquired pneumonia], with the highest risk within the first 30 days after initiation of therapy. Providers should be aware of this risk when considering PPI use, especially in cases where alternative regimens may be available or the benefits of PPI use are uncertain.”

That means that there may be a 50% increased risk of developing pneumonia in PPI takers compared to people not taking proton pump inhibitors. The authors go on to point out that:

“Given the widespread usage of PPI therapy, often without an appropriate indication, the excess risk of CAP among PPI users could translate into a substantial burden on the healthcare system. Moreover, the increased risk of hospitalization for CAP underscores the potential clinical and financial impact of this adverse effect. Careful consideration of the risks, benefits and alternative treatment options should occur with all PPI prescriptions. Our observation that CAP risk was increased with PPI therapy, regardless of PPI dose or participant age, implies that alternate therapies, when appropriate, may be a strategy for reducing CAP risk.”

C Diff (Clostridium difficile) Infections

C Diff infections can cause uncontrollable diarrhea. This condition is not only distressing; it can be life threatening. An article in the American Journal of Gastroenterology (July, 2012) makes the seriousness of the situation crystal clear:

“Clostridium difficile-associated diarrhea (CDAD) is a major cause of morbidity and increasing health-care costs among hospitalized patients…We have conducted a meta-analysis to summarize the association between PPIs and CDAD among hospitalized patients.”

The results of this analysis were:

“There is sufficient evidence to suggest that PPIs increase the incidence of CDAD. Our meta-analysis shows a 65% increase in the incidence of CDAD among PPI users. We recommend that the routine use of PPIs for gastric ulcer prophylaxis should be more prudent. Establishing a guideline for the use of PPI may help in the future with the judicious use of PPIs.”

Low Magnesium Levels (Hypomagnesemia)

One mineral that does not get adequate respect is magnesium. It is crucial for the normal functioning of every cell in the body. Magnesium is especially critical for the heart. When magnesium levels get too low, irregular heart rhythms (arrhythmias) can occur. An analysis of nine studies (PLoS One, Nov. 2014) revealed that “PPI use may increase the risk of hypomagnesemia.”

Low Iron Levels

Another mineral that may be affected by PPIs is iron. Here is a case report in the journal Internal Medicine, (online, Oct. 15, 2014).

“A 59-year-old man was orally administered rabeprazole, a proton pump inhibitor (PPI), for gastroesophageal reflux disease, after which he gradually developed iron-deficiency anemia. The anemia did not improve following the administration of ferrous fumarate, and endoscopic screening of the entire gastrointestinal tract, including the small intestine, did not reveal any findings indicating the cause of the anemia. The patient was then switched from rabeprazole to famotidine and the anemia was cured within three months. There is much debate as to whether the long-term use of PPIs causes iron-deficiency. However, this case strongly suggests that PPIs can induce iron-deficiency anemia.”

Japanese researchers (Circulation Journal, online, Nov. 12, 2015) evaluated a number of patients and concluded, “The frequency of anemia was significantly higher in patients receiving PPI than in those receiving no PPI..”

Low Vitamin B12 Levels And Other Deficiency Disorders

Questions have been raised about absorption of calcium as well as vitamin C in people taking proton pump inhibitors. Of even greater concern to us are vitamin B12 levels. Absorption of this essential nutrient appears to be reduced in the low-acidity environment created by PPIs. A study in JAMA (Dec. 11, 2013) concluded that “Previous and current gastric acid inhibitor use was significantly associated with the presence of vitamin B12 deficiency. These findings should be considered when balancing the risks and benefits of using these medications [acid suppressing drugs like PPIs].”

Bringing it all Back Home

By now we think you have the picture. Proton Pump Inhibitors appear to bring a lot of undesired baggage. The side effects mentioned above do not cover all possibilities. For example, an article in the journal Expert Review of Clinical Pharmacology notes that:

“The US FDA has recently issued a warning regarding fractures and the impaired magnesium absorption associated with the use of PPI. Thrombocytopenia [a serious blood disorder], iron deficiency, vitamin B12 deficiency, rhabdomyolysis and acute interstitial nephritis have also been reported with the use of PPIs. There is mounting evidence that PPIs are associated with serious adverse effects. Practitioners should be vigilant and counsel patients accordingly.”

The Fly in the Ointment

People who decide (after careful consultation with a physician) that PPIs carry too much risk for treating heartburn may consider stopping such medicines. DON’T! Sudden discontinuation of a proton pump inhibitor can lead to rebound hyperacidity. That means really awful discomfort. Heartburn symptoms can last for days, weeks or even months. The pain can be almost unbearable.

Getting off PPIs requires patience and persistence. Here is a link to give you some idea of what can happen and some hints about easing withdrawal symptoms.

You may also find our Guide to Digestive Disorders of value, since it has additional tips for nondrug approaches to coping with heartburn and discontinuing PPIs. And if you want to know why we worry about a link between PPIs and cancer, you will want to visit this link. We have been sounding this alarm since 2006 in the chapter on heartburn in our book, Best Choices from The People’s Pharmacy.

Please share your own PPI story, below and vote on this article at the top of this page.

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  1. Queen Frostine
    Reply

    I have a hiatal hernia & resulting GERD. The onset was rapid & severe, and medications barely help at all. My doctor recommended a Nissen fundoplication surgery to correct the hernia. He said medication was pointless since it’s really not helping the situation. I’ve been too scared to have the surgery and now don’t have health insurance, so for now it’s more PPI’s & H2’s. (And avoidance of practically every food & drink I once loved–spicy stuff, acidic stuff, caffeine & more). Oh, and I’m only in my early 30s. Joy.

    I take agmatine sulfate to (hopefully) offset some of the nitric oxide depletion caused by PPI’s. I also take B12 + L-methylfolate, Caltrate (calcium) & magnesium supplements. I’m hoping these supplements help balance out the damage to my bones, cardiovascular system & other organs caused by PPI’s, but I’m not too hopeful. I’m trying to limit my use of Prilosec currently, and the “rebound” acid effect is real :\

  2. CRC
    San Diego
    Reply

    I took PPIs for over 20 years. I tried to quit several times with the horrible rebound everyone else talks about. It wasn’t until I got old, had to do colonoscopies that I noticed how much better I felt when I had to be on clear liquid diet only. Then when evidence built against PPIs for awful side effects, and I researched it, I found that there is a strong possibility my irregular heart rhythm was caused by PPIs. I quit PPIs cold. I take two H2 Blockers per day, 15 to 60 minutes before eating my 2 main meals, and Gaviscon liquid one hour after eating and before bed. I also chew Tums sometimes.

    But I also totally simplified my diet and experimented adding food back in to eliminate my triggers. I find eating small quantities is crucial for me as I have a hiatal hernia and have silent reflux too. No coffee! It is my biggest foe. I have a whole list of things to avoid. My actions are SUCCESSFUL! Of course H2 blockers say “do not take more than two weeks”. . . wonder what they know?

  3. Dave S
    Reply

    Pepcid AC Heart Attack and AV Block Nerve problems:

    I took Pepcid AC for 3 days and suffered a heart attack, and now I have AV Block and constant nerve tingling down my legs. I was a healthy 30 year old male. Forget Pepcid AC and Zantac.

    Avoid these at all costs. Permanent AV Block? No Thank You, Pepcid.

  4. Dave S
    SF
    Reply

    Pepcid AC Heart Attack and AV Block Nerve problems

    I took Pepcid AC for 3 days and suffered a heart attack and now I have AV Block and constant nerve tingling down my legs. I was a healthy 30 year old male.

  5. Rose Armstrong
    Reply

    What do you do if you have a hiatal hernia and Barrett’s esophagus?

  6. Jackie
    OH Ohio
    Reply

    I have been taking omeprazole for 9 years for Barretts esophagus, how can I get off of it? Is there any other medicine that I can take?

  7. dale
    Reply

    I have severe heartburn, reflux and nausea. I have been taking 60 mg. 2 x day of Dexilant for years. I even have to take Zantac in the middle of the day.

    My doctor is no help. I don’t know what to do. Very concerned.

  8. Connie rogers
    McMinnville oregon
    Reply

    Very nice to get your input.

  9. Dee
    Nyc
    Reply

    Since many of us use PPIs what can we take as a supplement for the loss of nitric oxide? Would Arginie by it self b sufficient or does something else need to b added. There r other nutrients we loose due to PPIs. How does one find the best combination of supplements to take together to combat this loss . I have developed osteoporosis due to long term use of PPIs and I desperately try not to use PPIs.

    • Queen Frostine
      Las Vegas
      Reply

      A supplement called agmatine sulfate is thought to increase nitric oxide levels. It also has other purported benefits. I take it once a week to (hopefully) offset the damage done by PPI’s.

  10. Martha
    PA
    Reply

    The article in the Washington Post recently also mentioned that PPIs interact with blood thinners, like Plavix, but did not elaborate. Since I’m on a similar blood thinner, Effient, and taking Protonix, I’d like to know what the side effects are!

  11. B
    Charleston
    Reply

    I’ll try to post for the third time. Check out the Voice Institute of NY, Dr Kaufman. The site is geared towards silent refluxers; others will benefit, I’m sure. Run the checklist, read te articles and her professional papers, watch the Dr. Oz clip, and most importantly, buy the cook book because, besides great recipes, there is a lot of other important information about food. Hope this helps.

  12. Pat
    michigan
    Reply

    This is how I got off my PPI and how I helped my husband get off. Before doing this, I had asked my gastro doc about it and I hate to say it, but “duh” was pretty much what he said. A pharmacist told me to take a pill every other day, then extend the time. None of this would have worked for me. I’ve felt rebound and really having 4 kids was easier.
    I had a script for Prilosec. Once a week I would remove one of the little beads from the cap by pulling it apart. I used this amount for a week and then the next week removed 2 beads . There were 17 little beads in my pills and if I had discomfort one week, I would continue on the same amount until after several months, I’m totally off and so is my husband. Once in awhile as with most people we get the indigestion and just use one of the People’s Pharmacy’s home remedies. No more PPI’s in my life. My husband and I are 68- 2 old dogs still learning new tricks!

  13. Jeanne
    Connecticut
    Reply

    Thank you Peoples Pharmacy and Stanford University for researching this over used drug. I have been on Protonix for years and I have been worried recently about taking it anymore. My doctor just refills the script. I have had no intervention since I started taking it. Two years ago I had pnuemonia for the first time in my life and bronchitis the following year. I am tired all the time even with exercise and eating right due to osteoporsis. Weakened bones and hip fractures was especially news to me regarding this drug. The FDA is alseep at the wheel and have been for years. Big Pharma does not care about you or our children they just get richer and richer. Again, Thank you!!

  14. Pat
    Nevada
    Reply

    As usual over the counter meds are vilified by shills of big pharma while pharma’s killers of thousands/millions like viox and antidepressants maim with lifelong crippling side effects if not death go unchecked for decades. Big pharma sits on medical boards, hospital boards and universities and especially in the FDA. Do your research before you swallow anything.

    • Queen Frostine
      Reply

      This may shock you, but “Big Pharma” also manufactures over-the-counter meds & (gasp!) herbal supplements. They’re profiting either way. Every business is “for profit” so pharma is no different/worse in that regard.

  15. KDelphi
    Ohio
    Reply

    so what do we do, if we cannot stop taking them?

  16. Dave
    Reidsville NC
    Reply

    Is the suggested association of PPI’s with heart attack increase due to the medication or might it only be that reflux patients are sort of preselected patients who already can HAVE severe tissue inflammation that might then be associated with an increase in heart attacks?

    • Queen Frostine
      Reply

      If the 2nd scenario were true, you’d expect to see similar rates of heart problems in users of other acid meds like H2 blockers (Tagamet, Zantac, etc). But they don’t have abnormal heart attack incidence, so it’s definitely the PPI’s causing it.

  17. Jim
    seattle, WA
    Reply

    That’s all well and good, but if you try to get off PPI’s it’s almost unbearable! There are all these”natural” methods available, like using DGL, etc., but believe me, it’s not that easy! What they need to do is develop another medication that will allow you to get off of the PPI without the rebound effect. Believe me the rebound effect will rip your stomach right out! I’m worried that each time I try to get off of PPI’s I am doing more damage than i should.

  18. Linda
    valencia, ca
    Reply

    I was on PPIs for several years. Then 5 years ago I went in for an endoscopy and was told that my stomach was full of fundic polyps, which are common in PPI users. That distressed me, and I was motivated to get off the PPIs, but my doctor’s recommendation to start by using them every other day resulted in rebound heartburn. A friend who had successfully gotten off them told me to start by cutting the pills in half, then into quarters. I know the instructions on the drugs say not to do this, but she insisted that it had worked for her. I tried it and indeed it worked. After two or three weeks, I was completely off.

    I did use deglycyrrhizinated licorice (a supplement available at health food stores) to aid in the transition. I also gave up my long-time love affair with diet soda, which I found was a major trigger for me. In addition, I generally avoid fried foods and have to be careful with dark chocolate, tomato sauce, and citrus.

    I now find that I have to take magnesium, calcium, and B-12 supplements or I suffer from palpitations, leg cramps, and brittle nails, none of which were a problem before the PPI use.

  19. M C
    Greensboro
    Reply

    My doctor has prescribed Prilosec for silent reflux. I expressed my concerns so I will take it 2 months then taper off. Since I have had reflux for years I am not sure which path to take, drugs, no drugs, or homeopathic.

  20. Adarondax
    NY
    Reply

    That’s like saying size 3X underwear boosts risk of heart attacks.

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