Original Article
Altered mental status in older adults with histamine2-receptor antagonists: A population-based study

https://doi.org/10.1016/j.ejim.2014.06.021Get rights and content

Highlights

  • We compare risk of adverse events in older adults on standard vs. low H2RA dosing.

  • Urgent neuroimaging with hospitalization as proxy for altered mental status was used.

  • Standard dosing was linked to increased risk of neuroimaging with hospitalization.

  • Older adults were recommended to start on low H2RA doses for control of GERD symptoms.

Abstract

Background

Standard doses of histamine2-receptor antagonists (H2RAs) may induce altered mental status in older adults, especially in those with chronic kidney disease (CKD).

Methods

Population-based cohort study of older adults who started a new H2RA between 2002 and 2011 was conducted. Ninety percent received the current standard H2RA dose in routine care. There was no significant difference in 27 baseline patient characteristics. The primary outcome was hospitalization with an urgent head computed tomography (CT) scan (proxy for altered mental status), and the secondary outcome was all-cause mortality also within 30 days of a new H2RA prescription.

Results

Standard vs. low H2RA dose was associated with a higher risk of hospitalization with an urgent head CT scan (0.98% vs. 0.74%, absolute risk difference 0.24% [95% CI 0.11% to 0.36%], relative risk 1.33 [95% CI 1.12 to 1.58]). This risk was not modified by the presence of CKD (interaction P value = 0.71). Standard vs. low H2RA dose was associated with a higher risk of mortality (1.07% vs.0.74%; absolute risk difference 0.34% [95% CI 0.20% to 0.46%], relative risk 1.46 [95% CI 1.23 to 1.73]).

Interpretation

Compared to a lower dose, initiation of the current standard dose of H2RA in older adults is associated with a small absolute increase in the 30-day risk of altered mental status (using neuroimaging as a proxy), even in the absence of CKD. This risk may be avoided by initiating older adults on low doses of H2RAs for gastroesophogeal reflux disease, and increasing dosing as necessary for symptom control.

Introduction

Each year millions of patients in Canada are prescribed histamine2-receptor antagonists (H2RAs) for the treatment of gastroesophageal reflux disease [1]. Histamine2-receptor antagonists are also widely available without a prescription in many countries including Canada, implying that their use is even more widespread than prescription data suggests. A standard daily dose of a H2RA (ranitidine [Zantac] 300 mg/day or famotidine [Pepcid] 40 mg/day; usually divided into twice a day) is recommended in popular drug prescribing references for gastroesophageal reflux symptom control in patients of all ages when kidney function is preserved (Table 1) [2], [3], [4], [5].

However, older adults have age-related changes in pharmacokinetics and pharmacodynamics such as reduced first-pass liver metabolism, as well as increased fat content and decreased body water that reduces a drug's volume of distribution (important with hydrophilic drugs such as H2RAs) [6], [7]. Such changes can increase the risk of drug toxicities with standard dosing [6], [7]. Furthermore, H2RAs undergo renal excretion, and older adults often experience an age-related decrease in glomerular filtration rate, even in the absence of kidney disease [8]. The loss of kidney function has been attributed primarily to a loss of glomeruli, tubular atrophy, interstitial fibrosis and arteriosclerosis [8]. As such, the current standard dose of H2RA in older adults may lead to adverse drug events such as mental status changes (e.g., confusion, hallucination) or arrhythmias (e.g., tachycardia, atrioventricular block) [4], [5]. Older adults with bona fide chronic kidney disease may be the most vulnerable to H2RA toxicity from reduced renal elimination [9].

To date, hundreds of case reports from the United States Food and Drug Administration in addition to several literature reviews and prospective studies have noted the potential for H2RAs to induce an altered mental status — which often precipitates hospitalization and death among the elderly [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. For example, Slugg et al. conducted a small prospective convenience study of 41 inpatients to correlate ranitidine pharmacokinetics with the incidence of altered mental status and found 13 cases of ranitidine associated delirium (32%) primarily in the context of older age and kidney disease [13]. However, studies have generally been limited by the lack of data on outpatient H2RA use, relatively limited sample sizes, and a general lack of evidence to support the use of lower doses to reduce the incidence of altered mental status.

To inform this issue, we conducted a population-based cohort study to compare the 30-day risk of altered mental status and mortality in older adults initiated on an oral H2RA either at a standard dose or at a low dose in routine outpatient settings. We also investigated whether this association was modified by the presence of chronic kidney disease.

Section snippets

Setting and study design

Residents of the province of Ontario, Canada have universal access to hospital care and physician services. Those 65 years of age or older also have universal prescription drug coverage (approximately two million individuals in 2012) [19]. All health care encounters are recorded in databases held securely in a linked, de-identified form at the Institute for Clinical Evaluative Sciences (ICES) in Ontario, Canada. We conducted a population-based retrospective cohort study using these data sources.

Results

The study included 212,250 eligible older adults in routine outpatient care who were dispensed a new oral H2RA (Fig. 1). A total of 193,135 patients (91%) were initiated on a standard H2RA dose, and 19,115 patients (9%) initiated on a low dose. Dosing remained largely unchanged for subsequent prescriptions (Appendix C). Most prescriptions were written by a primary care physician. There was no significant difference in 27 of the 29 baseline characteristics measured in each of the standard and

Interpretation

We conducted this study to compare the 30-day risk of altered mental status using neuroimaging as a proxy in older adults initiated on either a standard dose or a low dose of oral H2RA in routine outpatient care. Compared to a lower H2RA dose, receipt of a standard dose was associated with an increased 30-day risk of hospitalization with urgent neuroimaging and all-cause mortality, possibly late and extreme outcomes in the spectrum of altered mental status.

The magnitude of the increase in the

Conflict of interests

The authors declare that they have no relevant financial interests. Dr. Garg received an investigator-initiated grant from Astellas and Roche to support a Canadian Institutes of Health Research study in living kidney donors, and his institution received unrestricted funding from Pfizer for research unrelated to the current project. The Institute for Clinical Evaluative Sciences (ICES) is a non-profit research corporation funded by an annual grant from the Ontario Ministry of Health and

Acknowledgements

We thank Brogan Inc., Ottawa, for use of its Drug Product and Therapeutic Class Database, Gamma Dynacare for use of the outpatient laboratory database and the team at London Health Sciences Centre, St. Joseph's Health Care, and the Thames Valley Hospitals for providing access to the Cerner laboratory database.

Support

Mr. Tawadrous was supported by a Medical Student Schulich Research Training Program award from the Schulich School of Medicine and Dentistry. Dr. Garg was supported by a Clinician

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