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.

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.

Competing Interests: We declare no competing interests.

(© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)