The People's Perspective on Medicine

Add Strokes to the Scary List of PPI Side Effects

The list of serious PPI side effects keeps expanding. Add strokes and heart attacks to several other complications like infections, fractures and dementia.

Proton pump inhibitors like esomeprazole, lansoprazole or omeprazole are the most popular treatments for heartburn and reflux disease. It is estimated that 15 million Americans spend $10 billion on such drugs annually. The FDA considers these medications so safe that it has approved drugs like Nexium, Prevacid and Prilosec for over-the-counter sale. But new PPI side effects are still being discovered.

PPIs and Strokes:

Danish researchers analyzed medical records of more than 244,000 adults. They found that those taking PPIs were 21 percent more likely to experience a stroke over the following six years. The higher the dose, the greater the risk.

Why Pharmacologists Love Dose Response Curves:

Pharmacologists like to use the term “dose response curve” to mean that the more you take of something the greater the likelihood there will be an effect. A baby aspirin (81 mg) does not cause a lot of stomach upset for most people. Two aspirin pills, however, increase the likelihood of heartburn. Someone who takes six aspirin tablets four times a day will be at even greater risk for complications. That’s a dose response curve. Another way to think of it is alcohol. One glass of wine won’t make many people drunk. Three glasses might get you close to the legal limit. Five glasses over two hours could get your arrested for driving under the influence.

Here is what the researchers found with PPIs. It was reported at the meetings of the American Heart Association Meetings in New Orleans (Nov. 2016). A high dose (over 80 mg) of pantoprozole (Protonix) produced a 94 percent increased risk of a clotting stroke compared with people not taking an acid-suppressing drug. Patients who took 40 mg of omeprazole experienced a 40 percent increased risk.

When side effects go up as the dose is raised, that’s pretty convincing evidence. It is not, however, proof positive. This was an epidemiological study so cause and effect have not been established. The investigators suggest a follow-up clinical trial to confirm the results. In the meantime, patients are urged to take PPIs only for serious digestive disorders for as short a period of time as possible.

How Plausible Is This New Complication?

Stroke is not the only cardiovascular complication of PPIs. A prior study published in the journal PLoS One (June 10, 2015) reported a linkage between these heartburn drugs and heart attacks. There is even a proposed mechanism.

The Law of Unintended Consequences:

PPIs block an ATPase enzyme (a proton pump) that prevent the stomach lining from making hydrochloric acid. Gastroenterologists like to think that is a good thing. But it turns out PPIs are not so selective.

That is not the only enzyme the drugs affect. They also interfere with another enzyme (DDAH). This enzyme is important for cardiovascular health. When it is inhibited, wheels are set into motion that lead to a cascade of events that may have unexpectedly harmful vascular effects (Circulation, Aug 20, 2013). Another critical enzyme, nitric oxide synthase is indirectly affected. This enzyme is essential for making…you guessed it…nitric oxide. This compound is essential for dilating blood vessels and keeping them flexible. Without enough nitric oxide on board you end up with what doctors call “endothelial dysfunction.”

We call this the law of unintended consequences. Push on the balloon in one place and it just may bulge somewhere else. If nitric oxide levels drop there could be an increased risk for both heart attacks and strokes.

Other Scary PPI Side Effects

In recent years there have been a surprising number of serious adverse reactions linked to proton pump inhibitors. Here is a partial list:

  • Infections (pneumonia, Clostridium difficile, aka C. diff)
  • Kidney damage (chronic kidney disease)
  • Heart attacks and vascular calcification
  • Dementia, Alzheimer’s disease
  • Malabsorption of nutrients (calcium, magnesium, zinc, vitamin B12)
  • Weakened bones, osteopenia, osteoporosis, fractures
  • Blood disorder (thrombocytopenia, anemia, iron deficiency)

Popular Proton Pump Inhibitors

  • Dexlansoprazole (Dexilant)
  • Esomeprazole (Nexium)
  • Esomeprazole plus naproxen (Vimovo)
  • Lansoprazole (Prevacid)
  • Omeprazole (Prilosec)
  • Omeprazole plus sodium bicarb (Zegerid)
  • Pantoprazole (Protonix)
  • Rabeprazole (Aciphex)

The People’s Pharmacy Bottom Line:

PPIs are not the super safe drugs we once imagined. If an herb or a dietary supplement were found to have half the side effects of PPIs, the FDA and most health professionals would be demanding its removal from the market.

Although such drugs can be beneficial for many patients, we suspect that they are over prescribed. We also think that the FDA’s decision to make them available without medical supervision was short sighted. We think that over-the-counter sale of PPIs should be reconsidered.

No one should ever stop a PPI suddenly or without medical supervision. Rebound hyperacidity can cause unbearable heartburn symptoms.

People who would like to learn more about other ways to deal with indigestion may find our Guide to Digestive Disorders of interest.



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About the Author
Joe Graedon is a pharmacologist who has dedicated his career to making drug information understandable to consumers. His best-selling book, The People’s Pharmacy, was published in 1976 and led to a syndicated newspaper column, syndicated public radio show and web site. In 2006, Long Island University awarded him an honorary doctorate as “one of the country's leading drug experts for the consumer.” .
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How long does the patient have to be on the PPI medication on the study before it can lead to stroke? Protonix?

After 20 years of taking pepcid and Tums for heartburn, I started experiencing vomiting and other severe acid attacks as a result of stress, resulting in an esoaphogitis (sp.) grade 4. I am now on a PPI (30mg prescribed, 15mg purchased OTC taken daily) with no side effects at this time. Since I am 81 years old, I am not very concerned about long-range effects. lol.

**My main question is, when 21% increase of stroke is noted in a study, what is the percentage of stroke in total? Percentages can be so misleading in these articles.

Why do they put so many infants and young children on these terrible drugs??? My granddaughter who is disabled and now 16 months old was placed on Previcid for this silent heartburn nonsense that so many doctors say that babies have! Well now she is on a feeding tube and still taking Previcid! I told my daughter-in-law about the side effects, and she said that it only applied to grown ups!

Well, I was on these medications for years and years and glad I weaned myself off. Now I am truly concerned about my granddaughter and other infants and toddlers being prescribed these drugs long term!

I was on Protonix for over 10 yrs. I asked my Gastro Doc if I could wean off. He said yes, so I did so, very slowly over several months. I’m glad I did. I use lifestyle changes to manage my GERD/Acid Reflux and thankfully rarely have issues.

Finally got off of Nexium. It was a slow process over a 6 month period decreasing dosages gradually. After off of the PPI’s. two months later had more serious problems due to GERD. They put me back on Nexium and now wanting again to reduce the dosage and see how I do.

It is a difficult battle doing things in moderation to keep our bodies functioning correctly. Wish I knew the magic formula. Talk to the doctors and they swear I need to be on Nexium. Read about the damage these PPI’s can do and want to get off of them. In the meantime trying find the right balance. Most difficult part is finding proven factual information that medical doctors will discuss and help you with.

I don’t believe putting a person on 40 mg of nexium twice a day is complete answer. Many doctors handle the GERD problem this way. Education about the side affects and how to cut back should be a part of the program. Even literature talking about this would be helpful. Complete avoidance of the education part I believe is detrimental to a persons health.

I had taken Prevacid for well over 10 years to counter the effects of a few months of Fosamax which, ultimately, I could not tolerate. Knowing PPI’s shouldn’t be taken long-term I’d tried several times to stop the drug only to have nearly debilitating heartburn/reflux.

When a regular gastroscopy revealed uncountable stomach polyps (another side effect of long-term use of PPI’s) I made a serious effort to stop the Prevacid. This was successfully accomplished in large part through the information I got from The People’s Pharmacy. A follow-up gastroscopy 2 years later showed only 3 or 4 polyps!

The occasional heartburn I now have is quickly relieved with a little Bragg’s apple cider vinegar in a little water. It sounds counter-intuitive but it really does work.

What about other OTC drugs, like Pepcid, Tagamet, Zantac or even Pepto-Bismol, Maalox or Rolaids? Do these pose the same sorts of dangers?

They do not. The research specifically looked at drugs like Tagamet and Pepcid. No association.

I was advised to take Prilosec about 10 years ago for GERD. But at the same time was told to minimize its use because of known adverse bone effects and maximize the use of antacids like Zantac.

I experimented and found that I could take one Prilosec and then Zantac 150 twic a day thereafter for up to 10 days before GERD sysmptoms reappeared. As a result, I settled on taking Prilosec once per week and Zantac 150 2X the rest of the week. That works for me almost all of the time and when it doesn’t Tums/Rolaids is adequate to control the problem.

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