Title: Optimising Prescription of Treatment In older patients with Mild hypertension at Increased risk of Serious adverse Events (OPTIMISE2): a non-inferiority trial
Funder: Department of Health and Social Care

Abstract: Background_x000D_ More than one in three adults aged 75+ years are prescribed five or more drugs to treat their long-term conditions. People who take lots of drugs are more likely to end up with reduced independence and quality of life as they get older. They are also more likely to end up in hospital due to drug side effects. One solution is to stop or ‘deprescribe’ drugs which no longer provide benefit, or could be potentially harmful._x000D_ _x000D_ The most commonly prescribed drugs in older people are those used to lower blood pressure. These drugs reduce the risk of a stroke and heart attack. However, in some frail older people, they might also be harmful, causing kidney problems and fainting (leading to serious falls). This could cancel out any potential benefits of treatment. This uncertainty makes blood pressure lowering drugs an ideal target for deprescribing. However, very little research has been done in this area._x000D_ _x000D_ We have completed the largest trial of blood pressure drug deprescribing to date, and whilst successful, the study only included 12 weeks of follow-up. Currently, we do not know if deprescribing is safe or effective in the longer term (a year or more)._x000D_ _x000D_ Aims_x000D_ This trial will establish whether deprescribing common drugs that lower blood pressure is safe in older people. We will answer:_x000D_ 1. What is the effect of deprescribing blood pressure lowering drugs on hospital admissions and death?_x000D_ 2. Does deprescribing improve quality of life and/or save money for the NHS?_x000D_ _x000D_ Methods_x000D_ Building on our previous trial of 569 people, we will carry out a larger trial enrolling 3,014 participants. We will actively follow them up for one year. Participants will be aged 75 years or older and taking blood pressure lowering drugs, but not have raised blood pressure readings. We will focus on those who are frail and/or with a higher risk of serious drug related side-effects. The trial will examine whether deprescribing is safe in this group, by measuring how many people are admitted to hospital or die in the year after having blood pressure lowering drugs withdrawn. This number will be compared to the number of people who are admitted or die among those who have not had their medications withdrawn. If the numbers are similar, then deprescribing will be viewed as safe. If safe, we will continue the trial and passively follow-up participants using their electronic health records for an average of three years to see whether deprescribing reduces hospital admissions over that longer time period. We will also check if deprescribing affects quality of life and/or costs for the NHS._x000D_ _x000D_ Dissemination_x000D_ Results from this work will be communicated to key audiences through scientific journals, patient summaries and presentations at scientific meetings and community engagement events.

Lay abstract: Research question_x000D_ What is the effect of antihypertensive deprescribing on emergency hospital admissions and death in older adults at higher risk of adverse events?_x000D_ _x000D_ Background_x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ Aims_x000D_ 1. To determine whether deprescribing antihypertensives is safe and beneficial in older adults at risk of adverse events._x000D_ 2. To determine whether deprescribing antihypertensives is cost-effective._x000D_ _x000D_ Methods_x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ Timelines for delivery_x000D_ 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)._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ 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.

Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: GENERIC HEALTH RELEVANCE