More Good News for PPIs: NO Increased Risk of Dementia

From ACG SmartBrief (thanks to Ben Gold for this):

A study published in The American Journal of Gastroenterology found no link between the use of proton-pump inhibitors and increased dementia risk. The study, led by Muhammad Ali Khan, MD, examined 11 studies with a combined 642,949 participants, and researchers said “PPI use among patients who have a valid indication for it, should not be curtailed because of concerns about dementia risk.”

The American Journal of Gastroenterology: January 2, 2020 – Volume Publish Ahead of Print – Issue – p doi: 10.14309/ajg.0000000000000500

Abstract

INTRODUCTION:

Long-term use of proton pump inhibitors (PPIs) has been associated with a wide variety of potentially serious adverse effects including a possible increased risk of dementia. Studies evaluating this association have reached divergent conclusions. We aimed to evaluate this proposed association further and to assess the quality of the evidence in its support.

METHODS:

We searched MEDLINE, EMBASE, ISI Web of Science, and Cochrane databases for studies examining a link between PPI use and dementia, up to February 2019. Studies reporting summary results as hazard ratio (HR) or odds ratio (OR) were pooled using the DerSimonian and Laird random-effects model for meta-analyses. Methodological quality of individual observational studies was assessed using the Newcastle-Ottawa scale and the overall quality of evidence rated as per the GRADE approach.

RESULTS:

We identified and included 11 observational studies comprising 642,949 subjects; 64% were women. Most studies were short-term ranging from 5 to 10 years. There were 158,954 PPI users and 483,995 nonusers. For studies summarizing data as adjusted HR, pooled HR for all causes of dementia was 1.10 (0.88–1.37); for Alzheimer dementia only, it was 1.06 (0.72–1.55). For studies summarizing data as adjusted OR, pooled OR for all causes of dementia was 1.03 (0.84–1.25) and for Alzheimer dementia only 0.96 (0.82–1.11). Per Newcastle-Ottawa scale assessment, 10 studies were of high quality and 1 was of moderate quality. By applying GRADE methodology, quality of evidence for both outcomes was very low.

DISCUSSION:

We found no evidence to support the proposed association between PPI use and an increased risk of dementia. PPI use among patients who have a valid indication for it, should not be curtailed because of concerns about dementia risk.

Related blog posts:

P’tit Train du Nord Linear Park

 

Risk of Vitamin B12 Deficiency with Persistent PPI Usage

From NY Times, nyti.ms/1kwQHPF :

People who use certain acid-suppressing drugs for two years or longer are at increased risk of vitamin B12 deficiency, which can lead to anemia, neurological problems or dementia, researchers reported on Tuesday.

The drugs in question are called proton-pump inhibitors, or P.P.I.’s, and histamine 2 receptor antagonists, and they are available by prescription and over the counter under brand names like Prevacid, Prilosec and Nexium. Nearly 157 million prescriptions were written for P.P.I.’s alone last year.

“People who are taking these medications are more likely than the average person to be vitamin B12 deficient, and it’s a potentially serious problem,” said Dr. Douglas A. Corley, senior author of the new study, published in The Journal of the American Medical Association. “This raises the question of whether people taking these medications for long periods should be screened for vitamin B12 deficiency.”

Dr. Corley has received funding from Pfizer, which makes a P.P.I. called Protonix.

He and his colleagues at Kaiser Permanente in Oakland, Calif., examined the medical records of 25,956 adults who received vitamin B12 deficiency diagnoses between 1997 and 2011, comparing them with 184,199 patients without B12 deficiency during that period.

Patients who took P.P.I’s for more than two years were 65 percent more likely to have a vitamin B12 deficiency, the researchers found. Higher doses of P.P.I’s were more strongly associated with the vitamin deficiency, as well.

Twelve percent of patients deficient in vitamin B12 had used P.P.I.’s for two years or more, compared with 7.2 percent of control patients. The risk of deficiency was less pronounced among patients using H2RA’s long term: 4.2 percent, compared with 3.2 percent of nonusers.

The new study is the largest to date to demonstrate a link between taking acid suppressants and vitamin B12 deficiency across age groups. Earlier small studies focused primarily on the elderly.

Robert J. Valuck, a professor of pharmacy at the University of Colorado in Aurora, was surprised that the association in the new report was strongest in adults younger than age 30. “It’s not safe to assume vitamin B12 deficiency is only an issue in the elderly,” he said.

Bottomline: patients (not just elderly) on chronic PPIs may need to be tested for vitamin B12 deficiency.

Related blog entries:

Are we missing Vitamin B12? | gutsandgrowth

A C difficile two-fer

Two recent review articles on Clostridium difficile are quite useful:

  • Mezoff EA, Cohen MB. J Pediatr 2013; 163: 627-30.
  • Dupont HL. Clin Gastroenterol Hepatol 2013; 11: 1216-23.

The first publication reviews acid suppression and the risk of C difficile infection (CDI).  It starts off with  a terrific piece of advice from Sir William Osler: “One of the first duties of the physician is to educate the masses not to take medicine.”  The authors note that pH above 4 has been shown to increase bacterial survival, including  C perfringe spores in a mouse model.  In addition, the article notes that there have been concerns as early as 1982 that acid suppression could be a risk factor for CDI.  Several recent studies were summarized, including the following:

  • A recent meta-analysis (Kwok CS et al. Am J Gastroenterol 2012; 107: 1011-9) with 42 studies (N= 313,000 patients) “found an association between PPI use and risk of CDI (OR1.74, 05%CI 1.47-2.85).”
  • A review of the literature (Deshpande A et. Clin Gastroenterol Hepatol 2012; 10: 225-33) between 1990-2010 found an overall increase in CDI risk with PPIs to be OR 2.15 (95% CI 1.81-2.55). No prospective studies were identified.
  • In pediatrics, a study (Turco et al. Alimentary Pharmacol Therapeut 2010; 31: 754-9) with 910 children admitted for abdominal pain and diarrhea identified 68 with CDI.  Compared with control patients, use of PPIs was significantly higher in CDI patients (OR 4.52, 95% CI 1.4-14.4).

The FDA has stated that PPIs may be associated with an increased risk of CDI.  In addition, the use of antibiotics “appear to act synergistically with PPIs.”  Thus, the authors recommend stopping PPIs in those who do not need them.  Periodic ‘holidays’ or dosing step-downs may help assess continued need for PPIs.

The second publication succinctly reviews the diagnosis and management of CDI.  The various diagnostic methods are compared in Table 1.  Therapeutic options for 1st time infection are reviewed in Table 2.  For adults with mild-to-moderate infections, metronidazole (500 mg TID for 10 days) is preferred.  Vancomycin or Fidaxomicin are recommended for more severe infections.

Table 3 lists treatment options for recurrent CDI.  Repeat course of any of the 1st round treatments can be considered depending on patient’s illness severity.  In addition, other potential treatments included the following:

  • vancomycin tapered dose (week 1: 125 mg 4 times/day, week 2: 125 mg 2 times/day, week 3: 125 mg once/day, week 4: 125 mg every other day, week 5 & 6: 125 mg every third day)
  • rifaximin (550 mg BID x 20 days)
  • high-dose vancomycin (250-500 mg 4 times/day for 10 days) followed by S boulardii (2 capsules BID for 28 d)
  • fecal microbiota transfer (FMT) –“although family member stool donors have been used, the current movement is toward volunteer donor pools.”  [I do not think ‘current movement’ was intended as a pun by the authors.]  Volunteer donors could lower the screening costs.
  • intravenous immunoglobulin (small clinical trials have failed to show efficacy)
  • monoclonal antibodies to toxins A/B

Related blog posts:

One for the PPI team

While this blog in previous posts has pointed out some shortcomings of proton pump inhibitors (PPIs), at the same time this class of medications remains a crucial part of pediatric gastroenterology practice.  In most patients, the benefits of these medications far outweigh the potential risks.

One of the risks has been a low rate of increased infections due to lowering gastric acid which provides some protection against enteric infections.  More information about PPIs show that these medications are not likely to increase the risk of small intestinal bacterial overgrowth (SIBO) (Am J Gastroenterol 2012; 107: 730-35 –thanks to Ben Gold for showing me this article).

In this retrospective study from 2004-2010, 1191 patients were included with 566 receiving PPI therapy.  Mean age: 63 years for PPI users and 59 years for nonusers. Glucose breath hydrogen testing (GBHT) for bacterial overgrowth did not differ significantly between PPI users and nonusers.  The authors acknowledge that there have been conflicting reports previously between the use of PPIs and the development of SIBO (see Table 5 of article); interestingly, SIBO with PPIs has occurred predominantly in studies from Europe.  The authors note that while achlorhydria leads to SIBO, the intermittent surges of acid production with PPIs should be sufficient to prevent SIBO.

Additional references/previous blog posts:

  • Proton pump inhibitors–infection risk with cirrhosis
  • The Medical Pendulum and Gastroesophageal Reflux
  • -Gastroenterol Hepatol 2011; 7: 10-2.  Risk of infections with PPIs.
  • -Gut 2007; 56: 802-8.  SIBO with IBS.
  • -NEJM 2010; 363: 2114. large Denmark study. 5082 fetuses with PPI exposure (out of 840,968 live births. Risk of birth defects NOT increased with exposure during 1st trimester. Possible slight increase with preconception use except with omeprazole.
  • -Gastroenterol 2010; 139: 1115. Review of safety of PPIs.
  • -Gastroenterol 2010; 139: 93. n=167,000. PPIs associated with hip fracture risk, OR 1.3, in patients with other risk factors.
  • -Gastroenterol 2010; 138: 896-904. 5 yrs of PPI -no increase risk in hip/spine fx.
  • -Arch Intern Med 2010; 170: 765-71, 747 (ed). PPI not related to hip fx (n=161,806) women 50-79. INCREASE risk of spine fx, hazard risk 1.47
  • -Arch Intern Med 2010; 170: 772-8. PPIs increase risk of CDT (hazard ratio 1.42 –42% increase in risk), n=1166.
  • -Arch Intern Med 2010; 170: 784-90. n=101,796.  Risk of nosocomial infection: OR 1.74 for daily PPI, OR 2.36 if BID Rx; thus ~70% increase risk of nosocomial infection.

Proton pump inhibitors–infection risk with cirrhosis

In a previous post (The Medical Pendulum and Gastroesophageal Reflux), I note that enthusiasm for proton pump inhibitors has started to wane.  In addition, a significant number of reported of potential side effects were referenced.  Another potential adverse effect is increasing the rate of spontaneous bacterial peritonitis (SBP) in patients with cirrhosis (Clin Gastroenterol Hepatol 2012; 10: 422-27).

This retrospective study examined 65 hospitalized cirrhotic patients with paracentesis-proven SBP between 2006-2009 and compared them to 65 contemporaneous hospitalized cirrhotic patients without SBP.   Patients with SBP had a higher incidence of use of PPI within previous 7 days: 71% versus 42%.  Of patients with SBP receiving PPI, the authors state that 68% did not have a documented indication for PPI use.

Additional references/previous posts:

  • Treating reflux does not help asthma
  • -Risk of Hypomagnesemmia -2011. http://www.fda.gov/drugs/drugsafety/ucm245011.htm
  • Gastroenterology 2010; 139: 1115.  Review of safety of PPIs.
  • Gastroenterology 2010; 139: 93. n=167,000. PPIs associated with hip fracture risk, OR 1.3, in patients with other risk factors.
  • Gastroenterology 2010; 138: 896-904. 5 yrs of PPI -no increase risk in hip/spine fx.
  • Arch Intern Med 2010; 170: 765-71, 747 (ed). PPI not related to hip fx (n=161,806) women 50-79. INCREASE risk of spine fx, hazard risk 1.47
  • Arch Intern Med 2010; 170: 772-8. PPIs increase risk of Clostridium difficile infection (hazard ratio 1.42 –42% increase in risk), n=1166.
  • Arch Intern Med 2010; 170: 784-90. n=101,796. OR 1.74 for daily PPI, OR 2.36 if BID Rx; thus ~70% increase risk of nosocomial infection.
  • Clin Gastro & Hep 2010; 8: 504. Increased bacterial overgrowth with PPI use.
  • -JAMA 2009; 301: 2120-2128. Use of PPIs associated with INCREASED hospital acquired pneumonia by ~30%. Could result in 180,000 HAP cases/yr with ~33,000 deaths. n+ 63,878 admissions, 52% on PPIs or H2RAs (83% PPIs, 17% H2RAs). H2RAs NOT associated with HAP cases.