Benzodiazepine use and risk of stroke: A retrospective population-based cohort study

Benzodiazepine use and risk of stroke: A

retrospective

population-based cohort study

Wei-Shih Huang,

,

Chih-Hsin Muo,

,

Shih-Ni Chang,

,

Yen-Jung Chang,

,

Chon-Haw Tsai,

and Chia-Hung Kao,

*

S

adults.2 Identification of potential risk factors is one

of the most important methods for preventing the recurrence of stroke.

For the general population, benzodiazepines (BZD) are one of the most frequently prescribed classes of drugs. Among older adults, BZD use ranges from 10% to 42% worldwide.3–6 Cheng et al.7 found

that the rate of BZD use among Taiwanese older adults was even higher: the 1-year-period prevalence was approximately 43%. The relation between BZD use and subsequent risk of stroke remains controversial. Some studies have indicated that BZD use may

improve acute stroke outcomes through GABAergic stimulation,8,9 whereas other studies have indicated

that there are greater risks of stroke in BZD users because of possible GABAA-mediated neurochemical

mechanisms.10–13 Because BZD are so commonly prescribed,

even a small risk accompanying their use

could have important clinical implications and also spark the interest of the public. A large populationbased

study has the potential to clarify the relation between BZD and stroke. We therefore used the

National Health Insurance (NHI) database of Taiwan to investigate the relation between exposure to

BZD and the occurrence of stroke in the Taiwanese population.

METHODS

Data sources

This study was based on reimbursement data from the Taiwanese NHI system, which contained all medical claims from the system. The NHI system has provided affordable health care for all of the island’s residents since 1996. From its inception, the NHI system has covered health care for more than 96% of the total Taiwanese population and maintains contractual relations with more than 97% of all clinics

and hospitals in Taiwan. As of 2007, more than 99% of the population was enrolled in the insurance program. For research and administrative purposes, the National Health Research Institute (NHRI) from the Department of Health built several randomly selected claim databases representative of the entire population (generally referred to as NHIRD).

The data we used were a sub-data set from the NHIRD containing a record of all reimbursement claims from 1996 to 2009 for 1 000 000 randomly selected patients representative of the population (approximately 5% of all insurants). Details on this population-based cohort database have previously been published.14 Diagnoses were coded according to

the ICD-9-CM.

We confirm that all data were de-identified and analyzed anonymously. In addition, this study was also approved by the Ethics Review Board at China Medical University (CMU-REC-101-012).

Study patients

Patients who newly underwent treatment for at least 2 months between the years 2000 and 2003 were defined as the study group (BZD group). We excluded patients with histories of stroke before the index date, as well as those younger than 20 years. ‘Index date’ in this study refers to the first date of BZD prescription.

A total of 38 671 patients were extracted from the database to form the BZD group.

For each BZD group patient identified, approximately one insurant with no record of BZD treatment

and no history of stroke was randomly selected from the same index month and year. They were then frequency-matched to each BZD case according to age (5-year intervals), sex and baseline comorbidity, including coronary artery disease (CAD), diabetes, hypertension and hyperlipidemia. These insurants were designated the non-BZD comparison cohort (non-BZD group).

Based on the ICD-9-CM classification, we searched for baseline comorbid conditions in study patients, including CAD (ICD-9-CM: 410–414), hypertension (ICD-9-CM: 401–405), diabetes mellitus (ICD-9-CM: 250), and hyperlipidemia (ICD-9-CM: 272). We also considered the ischemic stroke prevention medication, including aspirin, clopidogrel and warfarin.

Those medications were used before the beginning of the study.

Each patient’s case was followed until the following outcomes: a new diagnosis of stroke (ICD-9-CM 430–438; ischemic stroke, ICD-9-CM 433–438; hemorrhagic stroke, ICD-9-CM 430–432); censorship for loss to follow-up, death, or latest withdrawal from the NHI system; or until the end of the

follow-up period on 31 December 2009 (whichever came first).

Annual duration and dosage levels for BZD in the exposure cohort were stratified by 25th percentile: <0.3, 0.3–0.9, 1.0–3.9 and ≥ 4.0 g for annual dosage and <15, 15–29, 30–94 and ≥ 95 days for annual duration.

Statistical analysis

The χ2-test was used to compare distributions of sex,

age, and comorbidities between BZD and non-BZD groups. The incidence densities of stroke were calculated

for each cohort. The BZD-to-non-BZD hazard ratios (HR) of stroke with 95% confidence interval (CI) for each variable (including overall risk of stroke and stroke-subtype-specific risk) were estimated using univariate and multivariate Cox proportional hazards regression models. For future projections, we estimated the incidences and HR of stroke according to

comorbidity. The association between annual dosage/ duration for BZD use and stroke was also assessed. All analyses were performed using SAS 9.1 (SAS Institute, Cary, NC, USA). A significance level of 0.05 was considered statistically significant. In stratified analyses,

the significance level was set at 0.0045 for avoiding the type I error.

RESULTS

A total of 77 334 patients ≧20 years of age, including 38 663 patients with no BZD exposure and 38 671 patients with BZD exposure were included in our analysis (Table 1). Female patients accounted for the majority of the BZD group (55.4%). More than half of the BZD group (55.3%) was between 20 and 49 years of age. The BZD group had the proportionally highest

percentages of hypertension (29.5%), and then hyperlipidemia (15.1%), CAD (12.6%), and diabetes mellitus

(9.54%). Compared with the non-BZD group, the BZD group likely received aspirin (8.19% vs 7.26%, P < 0.0001) (Table 1).

Table 2 shows overall and age-specific incidence densities and HR for stroke according to sex and BZD-use status. Overall, the incidence of stroke was not statistically lower in the non-BZD group (5.44 per 1000 person-years) than in the BZD group (5.60 per 1000 person-years) with a crude HR of 1.01 (95%CI = 0.94–1.09) and adjusted HR of 0.97 (95%CI = 0.90– 1.05) after adjusting for aspirin use. Furthermore, stratified analysis by age showed that the risk of stroke increased significantly for BZD patients aged 20–39 years (adjusted HR = 1.99, 95%CI =1.32– 3.01), but decreased for BZD patients aged 60–69

years (adjusted HR = 0.74, 95%CI =0.64–0.85) (Table 2). HR stratified by sex showed the same trend in both men and women. In particular, for men aged 60–69 years, the BZD group had a significantly decreased risk of stroke compared with the non-BZD group (HR = 0.70, 95%CI =0.59–0.84).

Table 3 shows the association of BZD use with risks of different stroke subtypes according to age. The HR of hemorrhagic stroke was lower in the BZD group when compared with the non-BZD group (HR = 0.77, 95%CI = 0.64–0.92). For patients aged 20–39 years, the HR of developing ischemic stroke was 2.53-fold higher for the BZD group (95%CI = 1.48–4.35).

Conversely, for patients in the BZD group aged 40 years or older, the hemorrhagic stroke (HR = 0.70,

95%CI =0.64–0.92) was lower than in the non-BZD group (Table 3).

Young people without comorbidities in the BZD group in particular had a 2.80-fold higher risk of stroke than those in the non-BZD group (95%CI =

1.67–4.71). Overall, BZD patients with CAD or hypertension had lower risks of stroke than patients in the

non-BZD group, and these trends carried through to older adult patients (Table 4).

The association between the annual dosage/ duration levels for BZD and stroke is presented in Table 5. Compared to the non-BZD group, subjects who annually received under the median dosage (<1 g) or duration (<30 days) had a significantly lower risk of stroke. Conversely, those who received over the first quartile dosage or duration had a significantly higher risk. There was the same trend in those aged 40 years or older.

DISCUSSION

Compared to the non-BZD group, patients with BZD use in our study had a lower risk of hemorrhagic stroke, especially in subjects older than 40 years (P < 0.005, Table 3). Conversely, there was a higher

risk of ischemic stroke in patients aged 20–39 years who used BZD as compared with the non-BZD group (P < 0.005, Table 3). Patients with a lower annual dosage (<1 g) or duration (<30 days) of BZD use had a significantly lower risk of stroke in the elder group and patients with a higher annual dosage (≥4 g) or duration (≥95 days) of BZD use had a significantly higher risk of stroke in all age groups (P < 0.0001, Table 5).

To our knowledge, this study was the first population-based investigation of this group of 38 671 Taiwanese patients who use BZD. For the

comparison group, we randomly frequency-matched each patient with BZD use to a person from the cohort

without BZD use according to age, sex, and index calendar year.

Two points should be mentioned before further discussion. First, BZD, a class of psychoactive drugs for medical problems, such as anxiety, insomnia, and convulsion, are recognized as one of the most widely prescribed medications worldwide.15 Second, physicians

in Taiwan prescribe BZD for anxiety and insomnia,

which is similar to global practice. Our subjects were retrieved from a random sample of 187 413

people enrolled in Taiwan’s NHI program.16

BZD enhance the effects of the neurotransmitter gamma-aminobutyric acid (GABA), which results in sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnesic functions. GABA is the main inhibitory neurotransmitter in the central nervous system and acts by reducing depolarization-induced and ischemia-induced glutamate release.17,18 GABA

can trigger hyperpolarization of neurons through

anion channels (GABAA) and presynaptic G-proteincoupled

receptors (GABAB).19 This hyperpolarization

counteracts the depolarization, which is the initiating event in the biochemical ischemic cascade.20 Enhancing

neuroprotective in acute stroke and result in a significantly better outcome21 because of its inhibiting

effects on presynaptic glutamate release, the activities of N-methyl-D–aspartate (NMDA) and non-NMDA receptors, voltage-gated ion channels, and perhaps peri-infarct depolarizations.22,23 GABA-ergic activation

reduces the metabolic respiratory rate, preserving glucose and reducing acidosis, and facilitates local cerebral blood flow.24 GABA receptor agonists

can induce hypothermia, which is also regarded as a neuroprotective condition for acute stroke.25,26 To test

these theories, a multicenter, randomized, stratified, double-blind, placebo-controlled clinical human trial was conducted. This 2006 trial reported that diazepam treatment in acute stroke resulted in lower early recurrence rates of stroke in infarct patients, but the results were not statistically significant.9 Our

study showed a lower risk of hemorrhagic stroke in any aged patients with BZD use (P < 0.001), especially in patients older than 40 years (P < 0.0001,

Table 3). We also found that patients who annually received lower dosage (<1 g) or duration (<30 days) BZD had a significantly lower risk of stroke in the elder group (P < 0.0001, Table 5). These results support the above theories.

Conversely, some studies have indicated that BZD use may possibly increase the risk of stroke. Animal studies revealed that both blood flow and glucose use decreased following administration of the GABA agonist in the conscious rats10 and blockade of GABAA

receptors in rats led to a significant increase in regional cerebral blood flow (rCBF) in the focal ischemic

area.11 An experimental challenge trial with the sedative

midazolam, a non-selective BZD that potentiates the activity of GABA at the GABAA receptor, has shown

temporary re-emergence of many elements of a clinical syndrome that had been precipitated in the acute state after a focal brain infarct but had undergone

considerable remission in the days to years after.12

Kozma et al. found that their BZD control group had significantly greater odds of stroke-related events when compared with patients using risperidone (odds ratio of 1.96; P = 0.001) and patients using all atypical antipsychotics (odds ratio of 2.05, P < 0.001).13 In

another placebo-controlled study of risperidone, the rate of stroke was twice as common in the risperidonetreated

group (4%) as in the placebo group (2%).27

Similarly, in placebo-controlled trials of olanzapine, the rate of stroke was 1.3% in the olanzapine-treated group and 0.4% in the placebo group.28 Patients recovering

from stroke who use drugs from the BZD class

have been reported to have a poorer recovery of sensorimotor29

and upper-extremity30 functions. Goldstein31

documented the risks accompanying the use of diazepam and certain other medications by people who have had a stroke and suggests that BZD should generally be avoided in certain stroke patients.32 Some

patients who recovered from neurological deficits demonstrated a transient reemergence of syndromes after administration of anesthesia.33–35 Our study

showed that BZD use would significantly increase risk of ischemic stroke in younger patients aged 20–39 years and patients who annually received higher dosage (≥4 g) or duration (≥95 days) BZD had a significantly higher risk of stroke in all age groups (P < 0.0001, Table 5). These results support the above theories.

Because of the population-based design of this

study, we were able to achieve a high level of inherent representativeness in this study. Furthermore, the data on BZD use and stroke diagnoses used in this study

were extremely reliable. However, this study has limitations. First, detailed information, such as smoking

habits, alcohol consumption, body mass index, socioeconomic status, and family history, were not available

risk factors for stroke and could plausibly be associated with BZD prescription. However, because the

NHIRD covers nearly the entire population of Taiwan with a universal reimbursement policy, it is unlikely

that these variables influenced the decisions of physicians to prescribe BZD. Second, evidence derived from

a cohort study is generally of lower quality than that derived from randomized control trials. The cohort

study design is subject to many biases related to confounding adjustment. Despite our meticulous study

design with adequate controls over confounding factors, bias may have existed in unmeasured or unknown confounders. Third, diagnoses from the NHIRD claims were made primarily for administrative billing purposes and were not verified scientifically. We were unable to contact patients directly on their BZD use because entries were anonymous and identified only by number. Finally, our data did not include prescriptions for BZD that occurred prior to 1996. Therefore, cumulative dosage of BZD may have been underestimated, weakening observed associations.

Conclusions

Compared to the non-BZD group, this retrospective population-based cohort study showed a significantly lower risk of hemorrhagic stroke in all age

patients, especially in subjects older than 40 years (P < 0.0001) and a significantly higher risk of ischemic stroke in patients aged 20–39 years (P < 0.0001) with BZD use. There was also a BZD-dose–response phenomenon. Compared to the non-BZD group,

patients with a lower annual dosage (<1 g) or duration (<30 days) of BZD use had a significantly lower

risk of stroke in the elder group and patients with a higher annual dosage (≥ 4 g) or duration (≥ 95 days) of BZD use had a significantly higher risk of stroke in all age groups. This may suggest neuroprotection under lower-dosage BZD use and neurotoxicity under

higher-dosage BZD use. The mechanisms of these effects, whether due to neuroendocrine responses, stress hormone levels or sympathetic tone, remain a question for further research.