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.
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.
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