Optimising Prescription of Treatment In older patients with Mild hypertension at Increased risk of Serious adverse Events (OPTIMISE2): a non-inferiority trial

Research question

What is the effect of antihypertensive deprescribing on emergency hospital admissions and death in older adults at higher risk of adverse events? Background

More than one in three adults aged 75+ years are prescribed =5 medications, a situation known as polypharmacy. Polypharmacy is associated with multi-morbidity, reduced independence and an increased risk of hospital admission due to adverse drug reactions. One approach to managing polypharmacy is to withdraw (deprescribe) medications where the risk of adverse events outweighs the likelihood of benefit.

Antihypertensives are the most frequently prescribed medication in patients with polypharmacy and although trials have shown that they reduce the risk of stroke and cardiovascular disease (CVD), including in older people, very few include participants with frailty and multi-morbidity. Indeed, antihypertensives can sometimes be harmful, increasing the risk of syncope, falls and acute kidney injury.

Some clinical guidelines suggest that doctors consider deprescribing antihypertensives, where the harms outweigh the benefits, without clear evidence on how harms can be assessed.

We recently completed the OPTiMISE trial, showing that antihypertensive deprescribing could be achieved without affecting systolic blood pressure (SBP) control (<150 mmHg for aged =80), and no differences in serious adverse events or health-related quality of life. However, the trial was limited to 12 weeks follow-up, so the longer-term effects deprescribing remain unknown. Modelling suggests that deprescribing is only likely to be cost effective in the longer-term in those at increased risk of adverse events. Aims

1. To determine whether deprescribing antihypertensives is safe and beneficial in older adults at risk of adverse events. 2. To determine whether deprescribing antihypertensives is cost-effective. Methods

This study will be a primary care based, randomised controlled trial, enrolling 3,014 participants aged 75+ years, receiving 2 or more antihypertensive medications with controlled SBP and moderate to severe frailty and/or high risk of adverse events. The trial will compare step-down antihypertensive medication reduction with usual care. The primary outcome will be a non-inferior difference (margin of 5%) in all-cause emergency hospital admissions and death at 1-year.

Secondary outcomes will include differences in stroke, CVD, death, all-cause hospitalisation, side effects, health-related quality of life, cognition, physical function and cost-effectiveness. If non-inferiority is demonstrated at 1-year, differences in outcomes will be further examined at 3-years.

Outcomes will be determined by intention to treat, using generalised logistic mixed effects models, adjusted for baseline age and region of England. An economic evaluation will measure and value the cost-effectiveness of deprescribing, through a within-trial evaluation and a decision-analytic model extending over a lifetime horizon.

Timelines for delivery

The trial will run for 4.75-years, with 27 months for recruitment, including a 6-month internal pilot. All participants will be followed for at least 12 months before primary data analysis in the final 10 months. If non-inferiority is demonstrated, the study will continue in passive follow-up for a further 8 months (providing an average of 3-years of following across the trial population).

Anticipated impact and dissemination

Findings will support treatment plans for hypertension in older individuals, and inform NICE hypertension and multi-morbidity guidelines. Results will be communicated through scientific journals, patient summaries and presentations at scientific meetings/community engagement events.