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

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 reninangiotensin-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. FindingsWe included 110 trials, of which 11 (10%) were older-people trials and 99 (90%) were standard trials. Olderpeople 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 olderpeople 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.

Multimorbidity

“…Indeed, one systematic review of 50 studies of trial inclusion and exclusion criteria encompassing 305 trials and 31 physical conditions found that more than half of the trials excluded more than half of patients with the conditions studied 241 . Even patient cohorts in trials that are specifically conducted in older people are likely to significantly differ from the clinical population 242 owing to explicit and implicit exclusion criteria or biases in trial recruitment (such as exclusion of house-bound individuals and those in care homes) 243 . These issues suggest that while treatment benefits observed in trials may be generally applicable to those with multimorbidity, the precise benefit in populations excluded from clinical trials may differ owing to varying baseline risk 244 or increased treatment harms 245 .…”

Assessing trial representativeness using serious adverse events: an observational analysis using aggregate and individual-level data from clinical trials and routine healthcare data

“…Another study found higher rates of SAEs in a UK psoriasis registry than in IPD from two psoriasis trials, even after re-weighting the register data to more closely resemble the trial populations [19]. Our own previous study also compared SAE rates in trial participants and patients in routine care finding higher rates in the routine care population after age-sex standardisation, but did so solely for trials of agents acting on the renin-angiotensin-aldosterone system in order to treat hypertension [9]. The current study adds to this somewhat sparse literature by examining the trial age-sex standardised observed/expected SAE ratio across a wide range of index conditions.…”

“…SAE rates may therefore be utilised to help assess trial representativeness. In trials for hypertension, we tested this hypothesis, finding that the SAE rates were consistently lower than predicted based on hospitalisation and death rates among people with hypertension in routine care [9]. We also found that although SAE rates were higher in hypertension trials which aimed to be representative of older people, the rates were still lower than in routine care.…”

Antihypertensive Deprescribing in Older Adults: a Practical Guide

“…Even trials of antihypertensive therapy in older people tend to be targeted at healthier populations, less likely to have frailty, multi-morbidity and polypharmacy, excluding those with limited life expectancy [ 16 ]. Indeed, a recent analysis comparing participants in trials of antihypertensive therapy to similar patients residing in the community, found much lower rates of serious adverse events reported in trials, suggesting that these patients were fitter and healthier than the general population [ 17 ]. As a result, physicians have very little information about the benefits and harms of treatment in older people with multi-morbidity and frailty.…”