Title: Antihypertensive interventions in older adults: estimating benefits and risks in clinical datasets
Funder: Department of Health and Social Care

Abstract: Background Antihypertensive guidelines for older adults are based on extrapolation from younger cohorts. There is insufficient evidence to guide clinical management of hypertension into old age, and no consideration of complex co-morbidity and multiple medications. Adults over 75 are under-represented in Randomised Controlled Trials(RCTs). As highlighted in Cochrane reviews of hypertension, there are limited data on adverse events related to antihypertensive prescribing. The Clinical Practice Research Datalink(CPRD) provides anonymised primary care clinical record data, which Professor Melzer's team has funding to access for this and related projects. Clinical record research is a useful adjunct to RCT evidence to develop valid guidelines, particularly for older people, as it provides real-world estimates of treatment effects and adverse events. Traditional analysis of observational data, eg.multivariable regression, only model for known, measured confounding. Quasi-experimental statistical approaches including propensity scoring have limitations in achieving matched comparisons. In addition to propensity scoring we will use a new statistical approach, the Prior Event Rate Ratio(PERR). PERR aims to account for unmeasured confounding factors and has reproduced results from RCTs using observational datasets from CPRD, with promising results. This method may be useful in exploring whether repeatable events in the elderly, like fracture or myocardial infarction, are more or less common with antihypertensive treatment. Aims My overall aim is to improve the benefits and safety of antihypertensive prescribing in older adults. Specifically, I aim to estimate real world' health benefits and possible adverse outcomes of antihypertensive prescribing in adults over 75. I aim to apply quasi-experimental statistical approaches to estimate overall outcomes plus outcomes for common subgroups of patients and common combinations of antihypertensive medications. Plan of Investigation Population: Sample of over 2 million people over 65 years old from CPRD. Inclusion criteria: Cases are all adults over 75 years old with hypertension as defined by Quality of Outcomes Framework rules or defined by NICE criteria and evident within blood pressure clinical file. Control cases with hypertension but without exposure will be matched to cases. Exclusion criteria: Data of insufficient quality for analysis, as defined by CPRD.Stage 1: Descriptive analysis The target population will be identified, and data will be cleaned and sorted. This will include identifying patients with hypertension from measured blood pressure records and diagnoses. I will order the drug and clinical files to enable identification of medication based exposure groups, extraction of potential variables and covariates and generation of outcome measures. Descriptive analysis will be performed, including: Incidence and prevalence of hypertension and antihypertensive prescribing by drug class, drug and dose Co-morbidity Co-prescribing Correlates of antihypertensive treatment eg. demographics Stage 2: Estimation of risk Within each exposure group I will estimate the risk of:Cardiovascular outcomes eg. myocardial infarction/angina, stroke/TIA, Adverse events outcomes eg. Falls, fractures, dizziness, incontinence, hospital admission, renal impairmentIn order to reduce the influence of unmeasured confounding I will use and compare the established quasi-experimental methods, including PERR. I will initially compare outcome estimates to trial results for patients similar to those randomised, to calibrate the analysis methods. I will then extend the analysis to groups who have not been studied in clinical trials. This will involve subgroup analysis according to exposure group. Stage 3: Risk stratification modellingThe calculated risk estimations will be used in risk stratification modelling to estimate benefits/risks of commonly co-prescribed antihypertensive medications. Potential Benefits This study will provide the first real-life estimate of risk versus benefit of antihypertensive prescribing in adults over 75 years. This study has potential to guide treatment protocols for the largest growing population group (adults over 75) for a very common condition (hypertension), and to make prescribing safer.

Lay abstract: This research will evaluate the safety and efficacy of blood pressure prescribing in adults over 75 using over 1 million anonymised clinical records from UK GP practices. Analysis will include descriptive analysis, analysis of risk using regression models and the prior event rate ratio (a novel statistical technique to reduce the influence of unmeasured confounding factors) and risk stratification modelling for commonly co-prescribed antihypertensives. Expected outcomes will include estimating risks and benefits of prescribing in this age group, which will benefit patients, clinicians and policy-makers and have an impact on safety of prescribing and guidelines for hypertension in older people.

Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR