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The association between antihypertensive treatment and serious adverse events by age and frailty: A cohort study.

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Koshiaris, Constantinos 
Lay-Flurrie, Sarah 


BACKGROUND: Antihypertensives are effective at reducing the risk of cardiovascular disease, but limited data exist quantifying their association with serious adverse events, particularly in older people with frailty. This study aimed to examine this association using nationally representative electronic health record data. METHODS AND FINDINGS: This was a retrospective cohort study utilising linked data from 1,256 general practices across England held within the Clinical Practice Research Datalink between 1998 and 2018. Included patients were aged 40+ years, with a systolic blood pressure reading between 130 and 179 mm Hg, and not previously prescribed antihypertensive treatment. The main exposure was defined as a first prescription of antihypertensive treatment. The primary outcome was hospitalisation or death within 10 years from falls. Secondary outcomes were hypotension, syncope, fractures, acute kidney injury, electrolyte abnormalities, and primary care attendance with gout. The association between treatment and these serious adverse events was examined by Cox regression adjusted for propensity score. This propensity score was generated from a multivariable logistic regression model with patient characteristics, medical history and medication prescriptions as covariates, and new antihypertensive treatment as the outcome. Subgroup analyses were undertaken by age and frailty. Of 3,834,056 patients followed for a median of 7.1 years, 484,187 (12.6%) were prescribed new antihypertensive treatment in the 12 months before the index date (baseline). Antihypertensives were associated with an increased risk of hospitalisation or death from falls (adjusted hazard ratio [aHR] 1.23, 95% confidence interval (CI) 1.21 to 1.26), hypotension (aHR 1.32, 95% CI 1.29 to 1.35), syncope (aHR 1.20, 95% CI 1.17 to 1.22), acute kidney injury (aHR 1.44, 95% CI 1.41 to 1.47), electrolyte abnormalities (aHR 1.45, 95% CI 1.43 to 1.48), and primary care attendance with gout (aHR 1.35, 95% CI 1.32 to 1.37). The absolute risk of serious adverse events with treatment was very low, with 6 fall events per 10,000 patients treated per year. In older patients (80 to 89 years) and those with severe frailty, this absolute risk was increased, with 61 and 84 fall events per 10,000 patients treated per year (respectively). Findings were consistent in sensitivity analyses using different approaches to address confounding and taking into account the competing risk of death. A strength of this analysis is that it provides evidence regarding the association between antihypertensive treatment and serious adverse events, in a population of patients more representative than those enrolled in previous randomised controlled trials. Although treatment effect estimates fell within the 95% CIs of those from such trials, these analyses were observational in nature and so bias from unmeasured confounding cannot be ruled out. CONCLUSIONS: Antihypertensive treatment was associated with serious adverse events. Overall, the absolute risk of this harm was low, with the exception of older patients and those with moderate to severe frailty, where the risks were similar to the likelihood of benefit from treatment. In these populations, physicians may want to consider alternative approaches to management of blood pressure and refrain from prescribing new treatment.


Acknowledgements: We thank Lucy Curtin for administrative support throughout the project. We thank Richard Riley and Margaret Ogden for their contributions as STRATIFY Investigators to the project. This work uses data provided by patients and collected by the NHS as part of their care and support. We are very grateful to all those patients who permit their anonymised routine NHS data to be used for this approved research. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Funder: National Institute for Health and Care Research Applied Research Collaboration Oxford and Thames Valley; funder-id:

Funder: National Institute for Health Research

Funder: British Medical Association

Funder: UK Research and Innovation; funder-id:

Funder: European Union

Funder: National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care Yorkshire and Humber; funder-id:

Funder: Health Data Research UK

Funder: NIHR Oxford Biomedical Research Centre; funder-id:


Humans, Aged, Antihypertensive Agents, Cohort Studies, Frailty, Retrospective Studies, Hypotension, Syncope, Electrolytes

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PLoS Med

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Public Library of Science (PLoS)
Wellcome Trust (211182/Z/18/Z)
NIHR School for Primary Care Research (418)
National Institute for Health Research (Senior Investigator Award)
National Heart, Lung, and Blood Institute (K01 HL140170)