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Proton Pump Inhibitor news items

I know many on here take PPI's or H2 blockers for GERD. I've taken both for close to 10 years, and have always suspected that their propensity to wreak havoc with gut flora may be responsible for my current condition. Here are a few news items on these drugs which users may find enlightening, if not troubling.

Proton Pump Inhibitor Use Linked to Clostridium Difficile Infection

Arch Intern Med. 2010;170:747-748, 772-778, 784-790.

Use of proton pump inhibitors (PPIs) is linked to Clostridium difficile infection, according to the results of 2 studies reported in the May 10 issue of the Archives of Internal Medicine. The articles describing this prospective analysis are part of a series about PPIs in the Archives of Internal Medicine entitled "Less Is More."

First Study: Howell and Colleagues

"The incidence and severity of Clostridium difficile infections are increasing," write Michael D. Howell, MD, MPH, and colleagues from Beth Israel Deaconess Medical Center in Boston, Massachusetts. "Acid-suppressive therapy has been suggested as a risk factor for C difficile, but this remains controversial."

In this pharmacoepidemiologic cohort study, the investigators conducted a secondary analysis of prospectively collected data from 101,796 patients who were discharged from a tertiary care medical center during a 5-year period. Acid suppression treatment was the primary exposure of interest, classified by intensity (no acid suppression, histamine2-receptor antagonist [H2RA] treatment, daily PPI use, and PPI use more often than daily).

The risk for nosocomial C difficile infection increased with increasing level of acid suppression. This risk was 0.3% (95% confidence interval [CI], 0.21% - 0.31%) in patients not receiving acid suppressive treatment, 0.6% (95% CI, 0.49% - 0.79%) in those receiving H2RA treatment, 0.9% (95% CI, 0.80% - 0.98%) in those using PPIs daily, and 1.4% (95% CI, 1.15% - 1.71%) in patients using PPIs more often than daily.

The association persisted after adjustment for comorbid conditions, age, antibiotics, and propensity score–based likelihood of receiving no acid suppression treatment. The odds ratio was 1 for no acid suppression (reference), 1.53 for H2RA treatment (95% CI, 1.12 - 2.10), 1.74 for daily PPI use (95% CI, 1.39 - 2.18), and 2.36 for more frequent PPI use (95% CI, 1.79 - 3.11). A matched cohort analysis and nested case-control techniques resulted in similar estimates.

"Increasing levels of pharmacologic acid suppression are associated with increased risks of nosocomial C difficile infection," the study authors write. "This evidence of a dose-response effect provides further support for the potentially causal nature of iatrogenic acid suppression in the development of nosocomial C difficile infection."

Limitations of this study include observational design, possible residual confounding or selection bias, and lack of data about use of acid suppressive medications or antibiotics before admission.

Second Study: Linsky and Colleagues

The second study, by Amy Linsky, MD, from Boston Medical Center in Massachusetts, and colleagues, was a retrospective cohort study using administrative databases of the New England Veterans Healthcare System. From October 1, 2003, through September 30, 2008, there were 1166 inpatients and outpatients treated with metronidazole or vancomycin hydrochloride for incident C difficile infection.

Of these patients, 527 (45.2%) were given oral PPIs within 14 days of diagnosis, and 639 (54.8%) were not. The investigators measured the hazard ratio (HR) for recurrent C difficile infection, which was defined as a positive toxin result in the 15- to 90-day period after incident C difficile infection.

Compared with patients not using PPIs, those using them were more likely to have recurrent C difficile infection (25.2% vs 18.5%), with an adjusted HR of recurrent C difficile infection of 1.42 (95% CI, 1.11 - 1.82), based on Cox proportional survival methods.

Among patients exposed to PPIs, risks for recurrent C difficile infection were highest among those older than 80 years (HR, 1.86; 95% CI, 1.15 - 3.01) and among those given antibiotics not targeting C difficile during follow-up (HR, 1.71; 95% CI, 1.11 - 1.64).

"...PPI use during incident CDI [C difficile infection] treatment was associated with a 42% increased risk of recurrence," the study authors write. "Our findings warrant further studies to examine this association and careful consideration of the indications for prescribing PPIs during treatment of CDI."

Limitations of this study include use of observational databases, possible misclassification of exposure, and potential misclassifications of a positive test result for C difficile toxin alone as a clinically relevant recurrence.

Editorial: Risk Increase Not Modest

In an accompanying editorial, Mitchell H. Katz, MD, from the San Francisco Department of Public Health, San Francisco, California, describes these studies as well as the others described in the series, "Less Is More."

"The increases in the risk of Clostridium difficile infection with PPIs are not at all modest, reflecting the likely importance of gastric acid in protecting against infection from this pathogen," Dr. Katz writes.

"A pharmacoepidemiologic study of more than 1,000,000 hospital discharges in this issue of the Archives demonstrates a dose-response curve between level of acid suppression and C difficile infection.... Another article in this issue extends this association by demonstrating that the use of PPIs during treatment for C difficile infection was associated with a 42% increase in the rate of C difficile recurrence."

The authors of the study by Howell and colleagues have disclosed no relevant financial relationships. The study by Linsky and colleagues was supported by the resources of the Veterans Affairs Cooperative Studies Program and using the facilities of the Veterans Affairs Boston Healthcare System. The authors of the study by Linsky and colleagues have disclosed no relevant financial relationships.
 
Proton-Pump Inhibitor Withdrawal May Cause Rebound Acid Hypersecretion

Gastroenterology. 2009;137:20-39, 80-87.

July 2, 2009 — Proton-pump inhibitor (PPI) therapy for 8 weeks induces acid-related symptoms in healthy volunteers after withdrawal, according to the results of a randomized, double-blind, placebo-controlled trial reported in the July issue of Gastroenterology.

"Rebound acid hypersecretion (RAHS) has been demonstrated after 8 weeks of treatment with a proton-pump inhibitor (PPI)," write Christina Reimer, from Køge University Hospital, Copenhagen University in Copenhagen, Denmark, and colleagues. "If RAHS induces acid-related symptoms, this might lead to PPI dependency and thus have important implications."

PPIs Induce Acid-Related Symptoms

In this study, 120 healthy volunteers were randomized to receive placebo for 12 weeks or esomeprazole 40 mg/day for 8 weeks followed by 4 weeks of placebo. Clinically relevant acid-related symptoms were defined as a score of 2 or higher on one of the questions regarding heartburn, acid regurgitation, or dyspepsia on the Gastrointestinal Symptom Rating Scale (GSRS), which was completed weekly.

At baseline, GSRS scores were statistically similar in both groups. Compared with the placebo group, the PPI group had significantly higher GSRS scores for acid-related symptoms at week 10 (1.4 ± 1.4 vs 1.2 ± 0.9; P = .023), week 11 (1.4 ± 1.4 vs 1.2 ± 0.9; P = .009), and week 12 (1.3 ± 1.2 vs 1.0 ± 0.3; P = .001).

Of volunteers receiving PPI, 44% (26/59) reported at least 1 relevant, acid-related symptom in weeks 9 to 12, as did 15% (9/59; P < .001) in the placebo group. In the PPI group, the proportion reporting dyspepsia, heartburn, or acid regurgitation was 13 (22%) of 59 at week 10, 13 (22%) of 59 at week 11, and 12 (21%) of 58 at week 12 vs 7% (P = .034), 5%, and 2% (P = .001), respectively.

"PPI therapy for 8 weeks induces acid-related symptoms in healthy volunteers after withdrawal," the study authors write. "This study indicates unrecognized aspects of PPI withdrawal and supports the hypothesis that RAHS has clinical implications."

Limitations of this study include the use of healthy volunteers, which prevents determining whether symptoms develop as a consequence of RAHS to the same degree in patients with dyspeptic symptoms. In addition, the randomly skewed assignment of most subjects infected with Helicobacter pylori to the placebo group prevented determining whether the acid rebound phenomenon is clinically significant in infected subjects.

"We find it highly likely that the symptoms observed in this trial are caused by RAHS and that this phenomenon is equally relevant in patients treated long term with PPIs," the study authors conclude. "These results justify the speculation that PPI dependency could be 1 of the explanations for the rapidly and continuously increasing use of PPIs."

Inform Patients of Potential Risks

In an accompanying editorial, Kenneth E. L. McColl, MD, and Derek Gillen, MD, from the University of Glasgow Gardiner Institute, Glasgow, United Kingdom, note that findings from this study challenge current liberal PPI prescribing patterns and suggest changes in prescribing habits that should be considered.

"More effort should be made to identify contributory lifestyle factors and to utilize milder medications such as antacids or alginates," Drs. McColl and Gillen write. "Patients often ask about the safety and likelihood of side effects from [PPI] therapy. Now that rebound acid secretion has been demonstrated to induce symptoms, we are probably obliged to inform them about rebound acid hypersecretion and its potential effects."

The Danish Medical Research Council, Københavns Amts Research Foundation, and Region Sjællands Research Foundation supported this study. AstraZeneca provided the medication and placebo. Two of the study authors have disclosed relevant financial relationships with AstraZeneca, Nycomed, Eisai, and/or Wyeth. Drs. Mccoll and Gillen have disclosed no relevant financial relationships.
 
Small Intestinal Bacterial Overgrowth Common Among Long-Term PPI Users

Clin Gastroenterol Hepatol 2010.

In patients with gastroesophageal reflux disease (GERD), long-term use of proton pump inhibitors (PPI) contributes to bacterial overgrowth in the small intestine, new research from Italy shows.

Small intestinal bacterial overgrowth, in which the small bowel is colonized by large numbers of bacteria ordinarily found in the colon, produces bloating, diarrhea and other symptoms, the researchers explain.

Led by Dr. Lucio Lombardo, of the Mauriziano U.I. Hospital in Torino, the investigators used glucose hydrogen breath tests to look for small intestinal bacterial overgrowth in 450 consecutive patients enrolled in three groups:

-- 200 GERD patients treated with PPIs for a median of 36 months;

-- 200 patients with irritable bowel syndrome (IBS) who had not used PPIs for at least 3 years; and

-- 50 healthy controls who had not used PPIs for at least 10 years.

"The rationale for using IBS as 'pathologic' control stands on the large prevalence of small intestinal bacterial overgrowth in IBS patients and the overlapping of symptoms between the two clinical conditions," the authors said.

According to their article published online in Clinical Gastroenterology and Hepatology, they found small intestinal bacterial overgrowth in 50% of the PPI users with GERD, 24.5% of the IBS patients, and 6% of the healthy controls. There were significant differences in prevalence between GERD/PPI patients and the IBS patients (odds ratio = 3.14; p < 0.001), between GERD/PPI patients and controls (OR = 16.0; p < 0.001), and between IBS patients and controls (OR = 6.12; p < 0.005).

All subjects with small intestinal bacterial overgrowth were given high-dose rifaximin for 2 weeks. Treatment was successful in 87% of cases in the PPI group and in 91% of cases in the IBS group.

The authors suggest that PPI-related small intestinal bacterial overgrowth may be under-diagnosed because the symptoms overlap with those of other gastrointestinal disorders.

They point out that while the glucose hydrogen breath test only indirectly detects the condition, it's noninvasive and reproducible, whereas the current standard -- aspiration of duodenal-jejunal content for culture -- is not.

However, they add, the "gold standard for the diagnosis of small intestinal bacterial overgrowth is yet to be defined."
 
Proton-Pump Inhibitor Use Linked to Increased Risk for Hospital-Acquired Pneumonia

JAMA. 2009;301:2120-2128.

Proton-pump inhibitor use is linked to increased risk for hospital-acquired pneumonia, according to the results of a large, hospital-based pharmacoepidemiologic cohort study reported in the May 27 issue of the Journal of the American Medical Association.

"The use of acid-suppressive medication has been steadily increasing, particularly in the inpatient setting, despite lack of an accepted indication in the majority of these patients," write Shoshana J. Herzig, MD, from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and colleagues. "Recent data in the outpatient setting suggest an increased risk for community-acquired pneumonia in current users of acid-suppressive medication (both proton-pump inhibitors and histamine2 receptor antagonists)."

The goal of this prospective study was to evaluate the association between acid-suppressive medication and hospital-acquired pneumonia. The study cohort consisted of all patients who were admitted to a large, urban academic medical center in Boston, Massachusetts, from January 2004 through December 2007, who were 18 years or older and hospitalized for 3 or more days without being admitted to the intensive care unit.

Any order for a proton-pump inhibitor or histamine2 receptor antagonist was considered as use of acid-suppressive medication. Potentially confounding factors were controlled through traditional and propensity-matched multivariable logistic regression. The primary endpoint of the study was the incidence of hospital-acquired pneumonia, defined with codes from the International Classification of Diseases, Ninth Revision, Clinical Modification, in patients using vs not using acid-suppressive medication.

Of 63,878 admissions in the final cohort, hospital-acquired pneumonia developed in 2219 admissions (3.5%). In more than half of admissions (52%), acid-suppressive medication was ordered (27,236 received proton-pump inhibitors and 7548 received histamine2 receptor antagonists). Most of these medications (89%) were ordered within 48 hours of admission.

Compared with patients not exposed to acid-suppressive medications, those who were exposed had a higher unadjusted incidence of hospital-acquired pneumonia (4.9% vs 2.0%; odds ratio, 2.6; 95% confidence interval [CI], 2.3 - 2.8).

In the group exposed to acid-suppressive medication, the adjusted odds ratio of hospital-acquired pneumonia was 1.3 (95% CI, 1.1 - 1.4), based on multivariable logistic regression. Findings were identical with use of matched propensity-score analyses. Although the association was significant for proton-pump inhibitors (odds ratio, 1.3; 95% CI, 1.1 - 1.4), it was not significant for histamine2 receptor antagonists (odds ratio, 1.2; 95% CI, 0.98 - 1.4).

"In this large, hospital-based pharmacoepidemiologic cohort, acid-suppressive medication use was associated with 30% increased odds of hospital-acquired pneumonia," the study authors write. "In subset analyses, statistically significant risk was demonstrated only for proton-pump inhibitor use."

Limitations of this study include inability to determine the potential benefits of acid-suppressive medication in preventing gastrointestinal tract bleeding, concerns regarding the validity of International Classification of Diseases, Ninth Revision, Clinical Modification, coding, and lack of information on the temporal association between use of acid-suppressive medication and diagnosis of hospital-acquired pneumonia. Other limitations include possible unmeasured confounders and insufficient power to exclude a small but increased risk associated with histamine2 receptor antagonists.

"These results occur in the context of an increasing body of literature suggesting an association between acid-suppressive medication and pneumonia," the study authors conclude. "Further scrutiny is warranted regarding inpatient prescribing practices of these medications."

The study authors have disclosed no relevant financial relationships. Dr. Herzig was funded by the Health Resources and Services Administration of the Department of Health and Human Services to support the Harvard Medical School Fellowship in General Medicine and Primary Care. The study contents are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Health and Human Services.
 
If that is not enough information concerning this class of drugs, here is the latest information from the FDA.

Safety Announcement

[05-25-2010] The U.S. Food and Drug Administration (FDA) is revising the prescription and over-the-counter (OTC) labels for a class of drugs called proton pump inhibitors to include new safety information about a possible increased risk of fractures of the hip, wrist, and spine with the use of these medications.

Proton pump inhibitors work by reducing the amount of acid in the stomach. Nexium, Dexilant, Prilosec, Zegerid, Prevacid, Protonix, Aciphex, and Vimovo are available by prescription to treat conditions such as gastroesophageal reflux disease (GERD), stomach and small intestine ulcers, and inflammation of the esophagus. Prilosec OTC, Zegerid OTC, and Prevacid 24HR are sold over-the-counter (OTC) for the treatment of frequent heartburn.

The new safety information is based on FDA's review of several epidemiological studies that reported an increased risk of fractures of the hip, wrist, and spine with proton pump inhibitor use. Some studies found that those at greatest risk for these fractures received high doses of proton pump inhibitors or used them for one year or more (see Data Summary section).The majority of the studies evaluated individuals 50 years of age or older and the increased risk of fracture primarily was observed in this age group.

Full article below.

http://www.fda.gov/Drugs/DrugSafety...ormationforPatientsandProviders/ucm213206.htm

Dan
 
If that is not enough information concerning this class of drugs, here is the latest information from the FDA.

Safety Announcement

[05-25-2010] The U.S. Food and Drug Administration (FDA) is revising the prescription and over-the-counter (OTC) labels for a class of drugs called proton pump inhibitors to include new safety information about a possible increased risk of fractures of the hip, wrist, and spine with the use of these medications.
Thanks Dan, yeah the concern about screwed up calcium absorption has been around for awhile, I'm glad the FDA is finally saying something about it. The problem of course is that these drugs are HUGELY profitable for the corporations that make them, and with the level of corruption we have in all of our regulatory processes, money comes 1st. I love the way the OTC packaging always says something to the effect "Not to be taken for more than 2 weeks", when they know damned well people are on them for years.

About a year before my gut finally went nuts, and maybe 7 years into my acid blocker odyssey, I went to my 1st GI appointment, and told the gastroenterologist I thought permanently causing such a massive change in digestive chemistry was an obviously bad idea. I asked his opinion of a number of procedures for tightening up the LES. Doctors, being human, prefer the easy way out, so he poo-poo'd my concerns, told me none of the procedures was foolproof (no doubt true), and suggested I stick with the PPI's. I would give anything to get off these bloody things (now taking H2 blockers, because the omeprazole began suddenly to give me vertigo, but the affect is the same). I know this sounds silly, but I have often wondered what the effect would be of routinely drinking a huge quantity of water, then hanging upside down from a bar. No kidding. Perhaps if you did this periodically for some time (say, 2-3 times/day for 10 minutes, over the period of a month or so) the pressure of the water against the LES over time would increase its tone to the point where it would again begin to function. Again, I know that sounds nuts, but it also seems possible. There MUST be some way to deal with this other than drugs, or questionable surgical procedures.
 
I was originally given these acid blockers prior to my diagnosis. The problem was not Crohn's directly, but an H-Pylori infection from using antacids due to my stricture.

So basically I allowed H-Pylori to move into my Stomach, because of using too many Rolaids. I got rid of it, and that was a huge relief, but the stricture was still there. I have not used a antacid for over three years. I was eating them at over a roll a day prior to that.

I do not remember the particulars about your problem, but H-Pylori is often the cause of reflux, burning Stomach, etc. Actually all of these acid blockers are pretty much rebranded old school Ulcer treatments. Once H-Pylori was found to cause Ulcers, these should have went by the wayside. But, it seems that Ulcers and other H-Pylori related problems were rebranded as acid reflux also.

Dan
 
Dan - I haven't been tested for H. Pylori, but I did do a course of amoxicillin/clarithromycin, to no affect. H. Pylori tends to be more associated with peptic ulcers than GERD anyway, and I don't have the former. In fact, some evidence suggests H. Pylori may actually prevent GERD. In my case, I think it's an incompetent lower esophageal sphincter that is the culprit.

I really do think that water thing could work. If I can come up with an easy/comfortable way to hang upside. Maybe an old swing set... laugh.gif
 
Your symptoms are similar to what mine were, prior to my surgery for removal of my stricture. I really hope they are not misdiagnosing your condition.

The burning Stomach lining was from H-Pylori, so that part is not the same as your condition.

I know of two people that have had your condition, and both had surgery to fix the flap or whatever the technical name for it is, and they are doing pretty well now.

Has anyone presented a surgical option to fix the problem?

One thing you can try, and it will either work or fail miserably, is to take a teaspoon of Apple Cider Vinegar before a meal, and see if the problem is reduced. I have also heard of GERD being caused by insufficient Stomach Acid. There are some that claim that this is more often the problem related to GERD than too much acidity. Of course, if there is an actual physical problem with the flap, or a stricture, this will only make it worse.

Something to try, if you want to try narrow down the problem.

The water thing might work. I have had much stranger things that have worked better than any conventional treatment. I would try it, since you are not really out anything if it does not work.

Dan
 
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Proton Pump inhibitors and IBD

This is also a theory of mine.

I had never had a problem with diarrhoea until I started taking PPI'S, yes they cured the acid reflux but a month after starting taking them I have had bad diarrhoea.
And a year and a half later I am told I have crohn's.

There is a theory that the reduction in stomach acid allows the nasty bacteria gain a foot hold and to infect the bowel leading to IBD.

I was already on the PPI'S but I get the impression that people get put on them anyway after being diagnosed with IBD in which case the baddies are going to thrive.

Anyone care to comment on this theory?
 
Just saw this bumped. Thought I'd post that I go through severe antacid withdrawal when I go more than a day without them. The reflux is 10x worse. Then I take a double dose(sometimes triple if it's really bad). I have always known that this can't be good for me.
so now my question is, I take an H2 blocker, not a PPI. Are the risks the same?

curlywatts, I can tell you that in my first appointment with my new GI, I was instantly put on antacids. I never had reflux before that, can you believe it? But took his advice and took them just because he deemed them necessary and now I have awful reflux, and can't live without antacids.:ybatty:
 

ekay03

My dog has hands!
my first appointment with my new GI, I was instantly put on antacids. I never had reflux before that, can you believe it? But took his advice and took them just because he deemed them necessary and now I have awful reflux, and can't live without antacids.:ybatty:
This is the way I ended up on Nexium!
 
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