Benzodiazepines Increase Stroke Risk in Alzheimer’s

As stroke is often detrimental for individuals with AD, these results warrant caution in BZDR use in this vulnerable population.

Benzodiazepine use is associated with a 20% increased risk for stroke among older adults with Alzheimer’s disease (AD), according to a new study published in International Clinical Psychopharmacology.

A group of Finnish researchers, headed by Heidi Tiapale from the Kuopio Research Centre of Geriatric Care at the University of Eastern Finland, investigated the risk for any stroke and for ischemic and hemorrhagic stroke associated with incident benzodiazepine (BZD) and related drug (BZDR) use among 45 050 community-dwelling individuals with newly diagnosed AD (mean age, 80 years). Participants were identified from the Medication Use and Alzheimer’s Disease (MEDALZ) cohort, consisting of 70,718 Finnish individuals who received a clinically verified AD diagnosis between 2005 and 2011. To be considered “incident” use, a 12-month washout period was required in subjects who had previously used benzodiazepines.

BZDRs included BZDs (diazepam, nitrazepam, chlordiazepoxide, clobazam, oxazepam, alprazolam, lorazepam, and temazepam) and “Z-drugs,” which included zopiclone and zolpidem. Patients were allowed to change from one BZDR drug to another if there was no break in drug availability. Diagnoses of stroke were based on data recorded in the Hospital Discharge and Causes of Death registers.

During the follow-up period (median, 2.3 years), 21.9% (n=9879) of individuals started taking BZDRs. Of these, 2397 (5.3%) experienced stroke. The crude rate of strokes per 100 person years was 1.97 (95% CI, 1.96-1.97).

The majority of strokes were ischemic (76%), followed by hemorrhagic (22%), and the remainder were unspecified. The age-adjusted rate of strokes was 2.24 events (95% CI, 1.95-2.52) per 100 person-years during BZDR use vs 1.84 (95% CI, 1.77-1.91) strokes per 100 person-years during nonuse.

Compared with nonuse, BZDR use was associated with an increased risk for any stroke (adjusted hazard ratio [aHR], 1.21; 95% CI, 1.04-1.40) and ischemic stroke (aHR, 1.21; 95% CI, 1.02-1.44). There was a nonsignificant association between BZDR use and hemorrhagic stroke (aHR, 1.26; 95% CI, 0.91-1.74). Stroke risk associated with Z-drug use was similar to that of BZD use, suggesting “that neither drug group is a safer alternative for older individuals in terms of the risk of stroke,” the researchers wrote.

They also assessed available information on comorbidities and related drug use for each condition, including cardiovascular disease and diabetes, and did not find increased use of these drugs among BZDR users compared with nonusers, implying that “the association between BZDR use and stroke is not because of more common or severe cardiovascular conditions.”

According to the researchers, no previous study had examined the stroke-associated risk in older individuals receiving BZDR treatment. The “major strength” of their study, they stated, is that it used a nationwide cohort of community-dwelling individuals with clinically verified diagnosis of AD. However, they noted, it is possible that stroke was underdiagnosed in old and frail individuals with multiple comorbidities in addition to AD, as previous research has suggested that individuals with dementia are less likely to be admitted to a stroke unit or to receive thrombolysis.

The authors acknowledge limitations of the study related to the use of register-based data, which may lead to “possible residual confounding by indication, as register-based data lacked information on indication of drug use as well as severity of AD.”

Despite this limitation, the researchers point to an important clinical implication of their research. “As stroke is often detrimental for individuals with AD, our results warrant caution in BZDR use in this vulnerable population.”

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Taipale H, Koponen M, Tanskanen A, et al. Use of benzodiazepines and related drugs is associated with a risk of stroke among persons with Alzheimer’s disease [published online January 7, 2017]. Int Clin Psychopharmacol. doi: 10.1097/YIC.0000000000000161