Observed and expected serious adverse event rates in randomised clinical trials for hypertension: an observational study comparing trials that do and do not focus on older people

Hanlon, P. , Corcoran, N. , Rughani, G., Shah, A. S.V., Mair, F. S. , Guthrie, B., Renton, J. P. and McAllister, D. A. (2021) Observed and expected serious adverse event rates in randomised clinical trials for hypertension: an observational study comparing trials that do and do not focus on older people. Lancet Healthy Longevity, 2(7), e398-e406. (doi: 10.1016/S2666-7568(21)00092-1) (PMID:34240062) (PMCID:PMC8245327)

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Abstract

Background: Representativeness of antihypertensive drug trials is uncertain, as many trials recruit few or no older people. Some trials specifically recruit older participants to address this. Here, we assess the representativeness of trials focusing on older people by comparing the rates of serious adverse events in these trials with the rates in trials of a general adult population (ie, standard trials), and comparing these findings to the rate of hospitalisations and deaths in people with hypertension starting a similar treatment in routine clinical practice. Methods: For this observational study, we identified randomised controlled trials (phase 2/3, 3, or 4) of renin-angiotensin-aldosterone system (RAAS) drugs for hypertension registered from 1999 onwards with ClinicalTrials.gov. Serious adverse events are routinely included in trial reports and are predominantly accounted for by all-cause hospitalisations and deaths. We compared serious adverse event rates in older-people trials (minimum inclusion age ≥60 years) and standard trials (minimum inclusion age <60 years) using Poisson regression models adjusted for trial characteristics (drug type, comparison type, phase, and outcome type). We identified a community cohort of 56 036 adults with hypertension commencing similar drugs to obtain an expected rate of emergency or urgent hospitalisations or deaths, and compared this rate to observed serious adverse event rates in each trial, adjusted for age and sex. For standard trials and for older-people trials, we calculated the standardised ratio of the expected to the observed rate of serious adverse events using Poisson regression models. Findings: We included 110 trials, of which 11 (10%) were older-people trials and 99 (90%) were standard trials. Older-people trials had a higher rate of serious adverse events than did standard trials (median events per person per year 0·18 [IQR 0·12–0·29] vs 0·11 [0·08–0·18]; adjusted incidence rate ratio 1·76 [95% CI 1·01–3·03]). The hospitalisation and death rate in the community for those taking RAAS antihypertensives was much greater than the rate of serious adverse events reported in standard trials (standardised ratio [SR] 4·23, 95% CI 3·51–5·09) and older-people trials (4·76, 2·89–7·86), adjusting for age and sex. The magnitude of risk increase for serious adverse events in community patients taking RAAS did not differ when comparing older-people and standard trials (ratio of SRs 1·13, 95% CI 0·66–1·92). Interpretation: Trials report substantially fewer serious adverse events than expected from rates of hospitalisations and deaths among similar-aged people receiving equivalent treatments in the community. Serious adverse event rates might be a useful metric to assess trial representativeness. Clinicians should be cautious when applying trial recommendations to older people, even when trials focus on older participants. Funding: Wellcome Trust, Medical Research Council.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McAllister, Professor David and Renton, Dr Joanne and Hanlon, Dr Peter and Rughani, Dr Guy and Mair, Professor Frances and Corcoran, Dr Neave
Authors: Hanlon, P., Corcoran, N., Rughani, G., Shah, A. S.V., Mair, F. S., Guthrie, B., Renton, J. P., and McAllister, D. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > General Practice and Primary Care
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Public Health
Journal Name:Lancet Healthy Longevity
Publisher:Elsevier
ISSN:2666-7568
ISSN (Online):2666-7568
Published Online:10 June 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Lancet Healthy Longevity 2(7): e398-e406
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
305232Understanding prevalence and impact of frailty in chronic illness and implications for clinical managementFrances MairMedical Research Council (MRC)MR/S021949/1HW - General Practice and Primary Care
173492Combining efficacy estimates from clinical trials with the natural history obtained from large routine healthcare databases to determine net overall treatment benefitsDavid McAllisterWellcome Trust (WELLCOTR)201492/Z/16/ZInstitute of Health & Wellbeing