Applying clinical trial evidence on antihypertensive therapy to older adults in the community
Authors: James P Sheppard
Journal: The Lancet Healthy Longevity (2021)

Management of high blood pressure (hypertension) is important for the prevention of cardiovascular disease, but this can be challenging in older patients, a population at greater risk of adverse events, for whom the benefits of treatment need to be weighed against potential harms. To examine this problem, recent clinical trials of antihypertensive therapy have focused specifically on older patients and have shown treatment to be beneficial in the prevention of cardiovascular disease outcomes.1Beckett NS Peters R Fletcher AE et al.Treatment of hypertension in patients 80 years of age or older.N Engl J Med. 2008; 358: 1887-1898Crossref PubMed Scopus (2330) Google Scholar, 2Williamson JD Supiano MA Applegate WB et al.Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial.JAMA. 2016; 315: 2673-2682Crossref PubMed Scopus (671) Google Scholar These trials form the basis for guideline recommendations around the world that encourage antihypertensive treatment prescription, even in the very old (aged ≥80 years).3Whelton PK Carey RM Aronow WS et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines.J Am Coll Cardiol. 2017; 71: 2199-2269PubMed Google Scholar, 4Williams B Mancia G Spiering W et al.2018 ESC/ESH Guidelines for the management of arterial hypertension.Eur Heart J. 2018; 39: 3021-3104Crossref PubMed Scopus (3210) Google Scholar, 5National Guideline CentreNational Institute for Health and Care Excellence. Hypertension in adults: diagnosis and management [NICE guideline 136]. Royal College of Physicians, London2019Google Scholar However, some researchers have questioned the extent to which these trials are representative of older people living in the community.6Sheppard JP Lown M Burt J et al.Generalizability of blood pressure lowering trials to older patients: cross-sectional analysis.J Am Geriatr Soc. 2020; 68: 2508-2515Crossref PubMed Scopus (11) Google Scholar In The Lancet Healthy Longevity, Peter Hanlon and colleagues7Hanlon P Corcoran N Rughani G et al.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.Lancet Healthy Longev. 2021; (https://doi.org/XXXXXXXX published online June 10.)Summary Full Text Full Text PDF Google Scholar present an elegant analysis comparing rates of serious adverse events reported in 110 trials of renin-angiotensin-aldosterone system (RAAS) drugs with community rates of hospitalisations or deaths derived from the electronic health records of more than 56 000 adults treated for hypertension in routine clinical practice. In particular, the authors stratified their analysis by age, comparing trials of RAAS drugs examined in patients of any age (ie, standard trials) with trials that focused specifically on older patients aged 65 years or older. By calculating the standardised ratio of event rates between participants in trials and patients in the community, the authors show the rate of serious adverse events to be four times higher for patients in the community compared with those recruited to trials, suggesting that these trials might therefore not be representative of all patients in the general population. A potential limitation of this analysis was the short length of follow-up in the trials included, with a median of just 63 days (IQR 56–98) in standard trials and 98 days (56–252) in older-people trials. By comparison, follow-up in the community cohort was 3 years. Although sensitivity analyses limiting follow-up in the community cohort to 90 days showed similar results, lower event rates seen in the trials might still be partly explained by this short period of follow-up, particularly if such rates vary over time. Most likely, as suggested by the authors, these two populations are fundamentally different in their characteristics. This is perhaps not surprising, given the design, setting, method of recruitment, and strict inclusion criteria applied to many trials.8Rothwell PM External validity of randomised controlled trials: “to whom do the results of this trial apply?”.Lancet. 2005; 365: 82-93Summary Full Text Full Text PDF PubMed Scopus (1601) Google Scholar A key rationale for conducting trials in older patients is to examine the benefits and harms of treatment in individuals who are at greater risk of adverse events. While serious adverse events rates were higher in the older-people trials than in standard trials (adjusted incident rate ratio 1·76, 95% CI 1·01–3·03), they remained four times lower than would be expected for equivalent patients living in the community (standardised ratio 4·76, 95% CI 2·89–7·86). This suggests that using age-based inclusion criteria alone to examine the benefits and harms of treatment in higher-risk populations might not be sufficient. Future studies should aim to actively target under-represented groups, perhaps by recruiting directly from primary care settings in the community or by including specific inclusion criteria relating to under-represented characteristics such as frailty; the development of simple tools for identifying frailty using data held within electronic health records could make this straightforward.9Clegg A Bates C Young J et al.Development and validation of an electronic frailty index using routine primary care electronic health record data.Age Ageing. 2016; 45: 353-360Crossref PubMed Scopus (419) Google Scholar Hanlon and colleagues7Hanlon P Corcoran N Rughani G et al.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.Lancet Healthy Longev. 2021; (https://doi.org/XXXXXXXX published online June 10.)Summary Full Text Full Text PDF Google Scholar suggest that physicians and guideline developers should be cautious when applying trial data to patients living in the community. From the data presented, it is not immediately clear (without cross referencing all of the trial registration numbers) whether the studies from the published literature included in this analysis reflect those used to inform clinical guidelines. In particular, two important trials in the context of hypertension management in older people were not included in Hanlon and colleagues' analysis. Findings from both the Systolic Blood Pressure Intervention Trial2Williamson JD Supiano MA Applegate WB et al.Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial.JAMA. 2016; 315: 2673-2682Crossref PubMed Scopus (671) Google Scholar and Hypertension in the Very Elderly Trial1Beckett NS Peters R Fletcher AE et al.Treatment of hypertension in patients 80 years of age or older.N Engl J Med. 2008; 358: 1887-1898Crossref PubMed Scopus (2330) Google Scholar are widely cited in clinical guidelines to justify the use of blood pressure-lowering treatment in older people.3Whelton PK Carey RM Aronow WS et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines.J Am Coll Cardiol. 2017; 71: 2199-2269PubMed Google Scholar, 4Williams B Mancia G Spiering W et al.2018 ESC/ESH Guidelines for the management of arterial hypertension.Eur Heart J. 2018; 39: 3021-3104Crossref PubMed Scopus (3210) Google Scholar An analysis of event rates from these trials, in comparison to rates in the community, would be useful for future guideline developers. In recognising that many trials are not representative, some guidelines encourage physicians to use clinical judgment when prescribing blood pressure-lowering therapy in patients with frailty and multimorbidity.4Williams B Mancia G Spiering W et al.2018 ESC/ESH Guidelines for the management of arterial hypertension.Eur Heart J. 2018; 39: 3021-3104Crossref PubMed Scopus (3210) Google Scholar, 5National Guideline CentreNational Institute for Health and Care Excellence. Hypertension in adults: diagnosis and management [NICE guideline 136]. Royal College of Physicians, London2019Google Scholar Although there is no reason to expect treatment to be less effective at preventing cardiovascular disease in these patients, one might expect the balance of benefit to harm to be different, as trials conducted in healthier populations might underestimate these harms. The difficulty for physicians is knowing whether the patient in front of them is represented in these trials or whether they are more like individuals living in the community with a higher risk of serious adverse events. One possible solution is to use routine clinical data to develop prediction models to identify those most at risk of serious adverse events, for whom treatment initiation or prescription continuation might not be appropriate. Prediction models have been successfully developed for determining bleeding risk in patients with atrial fibrillation taking anticoagulation therapy;10Pisters R Lane DA Nieuwlaat R de Vos CB Crijns HJ Lip GY A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.Chest. 2010; 138: 1093-1100Summary Full Text Full Text PDF PubMed Scopus (2960) Google Scholar however, for therapies used to treat hypertension, such tools are still unavailable. In their absence, physicians must continue to exercise their clinical judgment when prescribing antihypertensive therapy to older patients, taking into account each individual's clinical needs and long-term health priorities. I receive funding from the Wellcome Trust/Royal Society via a Sir Henry Dale Fellowship ( 211182/Z/18/Z ), as well as funding from the National Institute for Health Research (NIHR) School for Primary Care Research, NIHR Oxford Biomedical Research Centre, British Heart Foundation, and Stroke Association. 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 peopleTrials 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. Full-Text PDF Open Access