Histamine-2 Antagonists Linked to Cognitive Impairment in Older African Americans

August 13, 2007 — New research suggests that long-term use of histamine-2 receptor antagonists (H2A) is associated with an increased risk for cognitive impairment among older African Americans.
Investigators at the Indiana University School of Medicine and the Regenstrief Institute in Indianapolis, Indiana, conducted a 5-year, prospective, observational study and found people who used H2As for 2 years or more had a 2.5 times greater risk for cognitive impairment.
"Taking these medications continuously appears to put older African-Americans at greater risk for the development of cognitive impairment. We need to study this further to determine how acid blockers might be causing or creating this effect and if it occurs only in African Americans," the study's principal investigator, Malza Boustani, MD, MPH, said in a statement.
The study is published in the August issue of the Journal of the American Geriatrics Society.
Dramatic Rise
According to the investigators, there has been a "dramatic rise" in the US prevalence of cognitive impairment, comorbid chronic disease, and exposure to multiple medications. In 2000, it was estimated that there were 7 million cases of dementia in the United States, a number that is expected to rise to 18.5 million by 2050.
The average number of medications among older adults attending primary care clinics is 5 to 6. Prescribed for the treatment of gastrointestinal disorders including acid reflux and ulcers, H2As are sold under brand names such as Axid, Pepcid, Tagamet, and Zantac and are among the most prescribed medications in the United States.
"Using pharmacy billing data, it is estimated that, over a 1-year period, 1.3% of US patients took at least one H2A and 1.6% took at least one PPI for more than 3 months. Excluding over-the-counter use, ranitidine and famotidine are among the top medications prescribed in the United States, with more than 16 million prescriptions dispensed in 2005," the authors write.
Findings from previous studies looking into the use of H2As and cognitive function in older adults have been inconsistent, with some reporting a possible beneficial effect, whereas others report contrary outcomes.
These inconsistencies, the authors note, are likely because of methodological biases such as outcome measurement or exposure and adjustment for potential confounders.
Underrepresented Population
To evaluate the link between exposure to H2As and incident cognitive impairment, the investigators used a community-based sample of African Americans, a population that they note has traditionally been underrepresented in such research.
The study included 1558 community-dwelling African Americans aged 65 and older with no baseline cognitive impairment. The primary endpoint was incident cognitive impairment, defined as incident dementia, cognitive impairment without dementia, or poor cognitive performance, as determined with combined cognitive assessments.
The investigators assessed the study subjects using the Community Screening Interview for Dementia (CSI-D) at baseline and again at 2 and 5 years. In-home inspections by trained interviewers at the 3 different study time points also determined prescription and over-the-counter use of H2As.
Of the 1558 study participants who completed the study follow-up period, 203 were using at least 1 H2A during one of the 3 data collection time points and 1355 had never used any H2As.
Participants were considered continuous users if they used H2As at every study time point. Intermittent users were defined as those who used an H2A during at least 1, but not all 3, data collection periods.
B12 Deficiency?
After adjusting for potential confounders including education, age, baseline CSI-D score, the use of drugs with definite central anticholinergic activities, as well as a history of diabetes and a history of depression, the investigators found that continuous use of H2As was linked to a significant increased risk for incident cognitive impairment compared with nonusers or intermittent users.
Because proton pump inhibitors (PPIs) are used as an alternative to H2As for the treatment of gastrointestinal disorders in older adults, the researchers also evaluated their association with incident cognitive impairment. However, adjusted analysis revealed no association between use of PPIs and incident cognitive impairment.
Although the mechanism responsible for the adverse cognitive effects associated with H2As is not clear, the authors speculate that it could be because of a potential anticholinergic effect of some H2As such as ranitidine and cimetidine, which can lead to the development of delirium and other cognitive deficits. They hypothesize that it may also the result of vitamin B12 deficiency associated with long-term use of H2As.
"Stomach acidity is necessary for the removal of vitamin B12 from dietary protein sources before it can be absorbed, so it might be that H2A prevents the absorption of vitamin B12. Because the body contains enough vitamin B12 stores for 2 to 5 years, a full dose of an H2A for more than 2 years might lead to vitamin B12 deficiency. In the current study, the incidence of cognitive impairment was significant only in those who used H2As continuously," the authors write.
The National Institute on Aging funded the study. Dr. Boustani has received support from the Paul B. Beeson K23 Career Development Award.
J Am Geriatr Soc. 2007;55:1248-1253.