Benzodiazepine and Z-drug use and risk of pneumonia in patients with chronic kidney disease: A population-based nested case-control study.

Meng-Ting Wang,Hsin-An Chang,Yu-Juei Hsu,Chen Wei Lin,Cheng-Chin Kuo,Yun-Han Wang,Chen-Liang Tsai,Ya-Sung Yang,Ping-Hsun Wu

doi:10.1371/journal.pone.0179472

Abstract

BackgroundConcerns were raised about pneumonia development from benzodiazepines (BZDs) and Z-drugs, but direct evidence is limited, conflicting and without examining the highly susceptible patients with chronic kidney disease (CKD) nor specifying the risk for different drug utilizations. This study aimed to investigate whether use of BZDs and Z-drugs was each associated with an increased risk of pneumonia in a CKD population.MethodsWe performed a nested case-control study of 36,880 CKD patients analyzing the Taiwan National Health Insurance Database between 01/1/2000 and 12/31/2011. Among the study cohort, we identified 4,533 cases of pneumonia based on validated disease codes, chest x-ray examination, and prescriptions of respiratory antibiotics, and randomly selected 16,388 controls from risk sets, matched by sex, age, and number of CKD-related hospitalizations. All prescription filling records of BZDs and Z-drugs in the year before the event/index date were analyzed for cases and controls. Conditional logistic regressions were performed to estimate the odds ratios (ORs).ResultsCurrent use of BZDs was associated with a 1.31-fold (95% CI, 1.18–1.26) increased risk of pneumonia compared to nonuse, but not for recent and past use. The risk from current BZD use was confined to new initiation (adjusted OR, 2.47; 95% CI, 2.02–3.03) or use for ≤ 30 days, and elevated to 2.88-fold (95% CI, 1.87–4.42) with parenteral administration. New initiation and current short-term use of Z-drugs was associated with a 2.94-fold (95% CI, 1.65–5.26) and 1.75-fold (95% CI, 1.13–2.72) increased risk of pneumonia, respectively. The findings were robust to adoption of a case-crossover study that analyzed cases only.ConclusionsUse of BZRAs is associated with an increased risk of pneumonia in CKD patients, especially for patients newly initiating BZDs or Z-drugs or those injected with BZDs. Physicians should exercise cautions for signs of pneumonia when prescribing BZDs or Z-drugs to CKD patients.

Highlights

Benzodiazepine receptor agonists (BZRAs), including benzodiazepines (BZDs) and Z-drugs, are the mainstay treatments for insomnia and anxiety [1] and the most commonly prescribed psychotropic medications in many countries [2]
Current use of BZDs was associated with a 1.31-fold increased risk of pneumonia compared to nonuse, but not for recent and past use
The risk from current BZD use was confined to new initiation or use for 30 days, and elevated to 2.88-fold with parenteral administration

Summary

Introduction

Benzodiazepine receptor agonists (BZRAs), including benzodiazepines (BZDs) and Z-drugs, are the mainstay treatments for insomnia and anxiety [1] and the most commonly prescribed psychotropic medications in many countries [2]. In the United States, the annual number of BZRA prescriptions for insomnia continues to rise, exceeding 18 million outpatient prescriptions in 2009 [3]. Animal studies have shown that BZRAs could be a risk factor for pneumonia probably through direct suppression of innate immunity [7]. Concerns were raised about pneumonia development from benzodiazepines (BZDs) and Zdrugs, but direct evidence is limited, conflicting and without examining the highly susceptible patients with chronic kidney disease (CKD) nor specifying the risk for different drug utilizations. This study aimed to investigate whether use of BZDs and Z-drugs was each associated with an increased risk of pneumonia in a CKD population

Objectives

Methods

Results

Conclusion