Strokes, Falls, Forgetfulness and Frailty Managing the Very Elderly Hypertensive

Strokes, Falls, Forgetfulness and Frailty Managing the Very Elderly Hypertensive John Potter Professor Ageing and Stroke Medicine University of East Anglia Oh God who knowest us to be set midst great dangers, that by reason of frailty we cannot always stand upright Book of Common Prayer

Leading Causes of Death in the Very Old UK 2016 Dementia/ALZ IHD Pneumonia/Flu Stroke Lower Resp Disease Dementia/ALZ IHD Stroke Pneumonia/Flu Lower Resp Disease Men and Women aged 80+ years 0 5.0 10.0 15.0 20.0 25.0 % % for 2013 Male Female ONS Feb 2017

Rodgers BMJ 1996 Risk of Stroke by Usual BP and Systolic Variability Mean BP levels (UK TIA Trial) DBP -5 mmhg 34±7% Stroke Reduction SBP -10 mmhg 28±8% Stroke Reduction n=2,435 TIA or recent stroke BP measured 4 monthly subsequently Lowest Risk group 130/80 mmhg SBP Variability Decile of SD SBP 7 measurements over 2 years, Results independent of mean SBP HR for Stroke Mean SBP of 10 readings 1.4 (0.6-0.3.6) Variability in SBP from 10 readings 13.0 (1.7-102.6) Rothwell Lancet 2010

Effects of BP Reduction for Secondary Stroke Prevention - Placebo Controlled Trials Study BP Status Age Mean HSCSG HT 63 Deserpidine+Th v Pl Drug Stroke Type Active v Placebo (n) Follow up (yrs) BP AvP mmhg TIA, CI, CH 233/219 2.8 25/12 Marti HT? CCB v Nil TIA, CI 170/94 1? Dutch TIA HT, N 69 BB v Pl TIA, mild CI 732,741 2.6 6/3 TEST HT 70 BB v Pl? 372/348 2.5 4/3 PATS HT, N 60 Non-Th v Pl TIA, CI 2841, 2824 2.8 6/3 HOPE HT, N 66 ACEI v Pl TIA, Stroke(?) 500, 513 5? PROGRESS HT, N 65 ACEI± Non-Th v Pl BPLPRS HT, N? ACEI± Non-Th v Pl TIA, CI, CH 3051, 3054 4 9/4 TIA, CI, CH 762, 758 4 14/6 PRoFESS HT, N 66 ARB v Pl CI 10146, 10186 2.5 4/2

Effects of BP Reduction for Secondary Stroke Prevention - Placebo Controlled Trials Outcome Odds Ratio (95% CI) All AHTs Odds Ratio (95% CI) Beta-Blockers Odds Ratio (95% CI) Diuretic Odds Ratio (95% CI) ACEI/ARB Odds Ratio (95% CI) Diuretic+ACEI Recurrent Stroke 0.71 (0.59-0.86) 0.93 (0.75-1.2) 0.68 (0.5-0.92) 0.93 (0.75-1.14) 0.55 (0.44-0.68) Ischaemic Stroke 0.87 (0.7-1.07) ICH 0.65 (0.41-1.05) Disabling/Fatal Stroke 0.71 (0.59-0.85) 2018 Spring CV Events 0.69 (0.57-0.85) 1.01 (0.81-1.3) 0.75 (0.63-0.90) 0.83 (0.61-1.13) 0.57 (0.48-0.68) MI 0.86 (0.73-1.01) 0.94 (0.6-1.5) 1.06 (0.6-1.78) 0.74 (0.56-0.98) 0.55 (0.38-0.79) CV Deaths 0.85 (0.75-0.96) All Deaths (0.83-1.07)BGS 0.95

The PROGRESS Trial Effects of Anti-hypertensive treatment Post-Stroke Baseline SBP Combo Therapy >160 140-159 120-139 <120 Mono Therapy >160 140-159 120-139 <120 Dual Therapy >160 140-159 120-139 <120 n=6105 Stroke/TIA Baseline SBP and Stroke Risk Achieved SBP and Stroke Risk Ischaemic Stroke Haemorrhagic Stroke P for trend 0.0005 P for trend 0.0001 Stroke Rate/year by Achieved SBP SBP Difference on Treatment 134 v 143 mmhg Normotensives (BP<160/90 mmhg) + Hypertensives (48%) - Entry BP 147/86 mmhg, Age 26-91 years Stroke or TIA in past 5 years Stroke Recurrence Reduced by 28% for a 9/4 mmhg difference (ICH by 50%) but effect decreased with Age Cognitive decline with stroke recurrence significantly reduced with Treatment (19%) Guidelines recommend Target BP<130/80 or <140/90 mmhg Arima J Hypertension 2006

3.0 2.0 1.0 0.5 Optimal BP Levels following recent Lacunar Stroke SPS3 trial (Secondary Prevention of Small Subcortical Strokes) Randomised, open label trial of MRI proven lacunar stroke patients between 2 weeks and 6 months post event Exclusions Disabling Stroke, previous ICH, Cortical Ischaemic stroke, Cognitive Impairment Normotensive or Hypertensive (including already treated) n= 3,020 Treatment Open Label, BP target SBP <130 or 130-149 mmhg, Mean F/U 3.7 years Primary End-Point Reduction in all Stroke SBP 11mmHg Achieved SBP & All Stroke 115 125 135 145 Mean SBP Outcome Higher Target Rate %per Pt Year Lower Target Rate %per Pt Year HR p value All Stroke 2.77 2.25 0.81 (0.64-1.03) 0.08 Ischaemic 2.40 2.00 0.84 (0.66-1.09) 0.19 ICH 0.29 0.11 0.37 (0.31-0.95) 0.03 Disabling/Fatal Stroke 0.89 0.72 0.81 (0.53-1.23) 0.32 MI 0.70 0.62 0.88 (0.56-1.39) 0.59 Major Vascular Event 3.46 2.91 0.84 (0.68-1.04) 0.10 Death 1.74 1.80 1.03 (0.79-1.35) 0.82 Lowest Stroke Risk @ 124/67 mmhg No benefit on Cognition No difference in Serious Adverse Events SPS3 Lancet 2013

BP levels and Bleeding Events during Anti-thrombotic Therapy (BAT Study) Multivariate-adjusted HR of SBP Parameters for development of ICH (per 10 mmhg increase). Time Course of BP in relation to Outcome n = 4009 (mean age 69 years) on Antithrombotic agents (Antiplatelets and/or Warfarin [44%]), BP at Baseline and last visit before ICH F/U 19 months In Warfarin users - Median INR 2.06 during F/U in all 3 groups Annual incidence of ICH by BP levels at Entry, Follow up and Last Visit Optimal BP for prevention of ICH <130/80 mmhg (ROC) Toyoda Stroke 2010

On-going BP trials in Secondary Stroke Prevention How to treat Hypertension Post Stroke Is as Low as you can Go best? How to treat Lipids Post Stroke Start Statin and Forget or Treat to Target? Does strict BP control reduce Cognitive impairment? ESH-CHL Stroke Optimal Treatment Trial Aim - 3 2 factorial design comparing: 3 SBP targets - <125 mmhg; <125-135; <135-145 and 2 LDL-C targets (< 1.8 v 1.8-2.8 mmol/l). Prospective multinational, randomized trial n=7500 aged 65+ years (Europe & China) with hypertension and a stroke/tia 1-6 months before randomization. F/U 4 years, start 2013 - end 2018. Primary Outcome Recurrent Stroke (fatal and non-fatal). Secondary Outcomes MACE, All Deaths, All CHD events, Ischaemic and Haemorrhagic stroke Cognitive Impairment (MOCA), Dementia

Secondary Stroke Prevention by Blood Pressure Reduction POST-STROKE: % 12 8 4 0 All Stroke <130mmHg, 130-140mmHg, CV Deaths >140mmHg levels on Treatment % Outcomes by Achieved SBP levels following Stroke/TIA Mean BP levels and BP variability are associated with increased Stroke recurrence and CV Risk AHT in the Non-Acute Stroke situation reduces Stroke Recurrence + CV events and?cognitive decline Benefits reduced with increasing age, Stroke Type and Frailty effects on Outcomes unclear?benefit for Normotensive as well as Hypertensive patients, greater effect with larger BP reduction? No evidence any antihypertensive class best (most evidence for Thiazide-like Diuretics ± ACEI) Optimal/Target BP levels post-stroke unclear?<130/80 mmhg in most cases (?Carotid Stenosis) Strict BP control may reduce ICH risk in patients treated with Antiplatelets or Anticoagulants

What is frailty?

What is frailty? OED Condition of being weak or delicate, being easily damaged Fried et al Frailty is a clinically recognizable state of increased vulnerability resulting from ageing-associated decline in reserve and function in multiple physiologic systems resulting in inability to cope with everyday or acute stressors 3 of 5 phenotypic factors unintentional wt loss (>5% of body weight), weakness (hand grip), exhaustion (questionnaire), slow walking speed (over 4.6m), low physical activity. Rockwood et al - Canadian Study of Healthy Ageing 9 point Frailty Scale - 1 Very Fit, completely independent - 9 completely dependent. Frailty - a clinical phenotype with a number of deficits accumulated over time (termed frailty index (FI) ) including physical, mental, social and environmental deficits. Electronic Frailty Index (efi) Comprises 36 deficits (2000 Read codes) including - Stroke, Syncope/Hypotension/Falls/Dizziness, Hypertension, IHD, PVD, CCF, CKD, Diabetes, Polypharmacy, Memory/Cognitive Impairment. No uniform definition

Hypertension and Cognition a Paradox with Frailty? Health, Ageing and Body Composition Study 1997-2007 3MSE Score (0-100) 3MMSE DSST Score Digital Symbol Substitution Test n=1657 Community dwelling, Fit, Treated Hypertensives aged 70-79 years, Observational study F/U 10 years Seated BPs x2 and Cognition Tests at Baseline 1, 3, 5, 8 and 10 year assessments At Baseline - 55% SBP> 150 mmhg, at 10 years 22%. DSST, but not MMSE, better in <120 v >150mmHg group Cognition fell in all BP groups over time Greatest decrease over 10 years in those with SBP >150 mmhg (DBP no effect) Racial differences in these changes evident Age, Educational level and Baseline score strongly influenced rate of decline BP Guideline Criteria SPRINT JNC-7 JNC-8 Reference Statistical significance tested by multivariate mixed models adjusted for co-variates including Baseline Cognition Hajjar JAMA Neuro 2017

Models Adjusted for Age, Sex, AF, ADLs SBP Hypertension and Cognition a Paradox with Frailty? MMSE 0-10 MMSE 11-17 * Sig compared to SBP 126-139 mmhg MMSE 18-23 MMSE 24-30 * * n = 1115 Aged 85-95 years Community dwelling in Finland 30% in each MMSE group on AHTs BP supine at home x2 Cognition by MMSE F/U 2 years Outcome Mortality by BP and MMSE adjusted for by other risk factors MMSE <21 increased Mortality Both High and Low BP in lowest MMSE Group predicted Survival Low BP in all Groups related to increased Mortality Weidung J Hypertension 2016

BP levels and 10 Year Mortality Risk Effects of Frailty 10 Yr Mortality HR (adjusted) ADL & Cognition Both Impaired Either Impaired Preserved SBP HR for Mortality per 10 mmhg INCREASE in SBP Milan Geriatrics 75+ Cohort Study DBP HR for Mortality per 10 mmhg INCREASE in DBP n=1587 aged 75+ (mean 82) Outpatients 64% Hypertensive 10 year F/U 66% Mortality Lowest Mortality at 165/85 mmhg Each SBP 10mmHg in those with impaired ADL + Cognition Reduced Mortality 11% @ 10 years Ogliari Age Ageing 2015

Quick-Step test in Elderly Hypertensives predicts those at Risk! n=2340, mean age 77 years (65-90) in National Health and Nutrition Examination Survey Walking Speed timed over 6 metres (Faster group >0.8m/sec, 56% of study population) Follow-Up 7 years Results adjusted for age, sex, race, lifestyle and use of antihypertensives. High BP >140/90 mmhg (50% population) Faster group younger, male, and higher education and less comorbidities and less AHT use. Follow-Up (years) Fast Walkers - Mortality 35% higher with high SBP Slow walkers no effect of BP on Mortality Those unable to do, High BP associated with Decreased Mortality (HR 0.38, 0.23-0.62) Odden Arch Int Med 2012

Risk Factor What Predicts Falls Risk in the Elderly Hypertensive? Prevalence % Falls <2 in 6 months v Non- Fallers Adjusted OR Falls >2 in 6 months v Non- Fallers Adjusted OR Age >80 years 47 1.4 (NS) 1.6 (NS) Female 84 2.2 1.9 (NS) Stroke 11 1.8 (NS) 3.4 OH >20/10mmHg 21 1.4 (NS) 2.0 Postural Dizziness/Syncope 22 2.3 2.3 Impaired ADLs 39 2.9 4.3 Fall in last year 33 2.7 3.5 Use of Walking Aid 21 2.7 3.2 Slow 6m Walk Test 32 2.8 4.1 MMSE <24/30 19 1.7 (NS) 3.2 Uncontrolled HT 42 2.8 3.1 Odds Ratio Controlled HT 58 1.4 (NS) 1.6 (NS) Population - Hypertensives attending Secondary Care aged 75+ 7 6 5 4 3 2 1 0 Postural SBP change & Frequent Falls Risk > +10 1 +10 2-0 -1 -<-10 3-11-20 4-21-30 5 >-30 6 Postural Change in SBP mmhg @ 1 min 55% of OH group reported NO postural dizziness 23% of No OH group reported postural dizziness

Does Antihypertensive use explain the increased Falls/Syncope Risk? AHT use and Serious Falls/Syncope Antihypertensive Use by Intensity None Adjusted HR (95% CI) for Serious Fall/Syncope 1 (Reference) Moderate 1.22 (0.8-1.71) High 1.24 (0.83-1.84) Antihypertensive Class RAS Blocker 1.06 (0.8-1.39) B-Blocker 0.89 (0.66-1.2) CCB 1.01 (0.83-1.45) Diuretic 0.94 (0.7-1.26) n=4961 aged 70+ community dwelling with Hypertension 16% untreated F/U 3 years - 9% had a Serious Fall BGS Spring 2018 Tinetti JAMA Int Med 2014 So what does predict Falls in Elderly Hypertensives? n=5236 aged 65+ years treated hypertensives Fit, Community dwelling Adjusted HR, linear and quadratic trends tested F/U 6.4 years 15% Serious Fall Bromfield Hypertension 2017

Do Antihypertensives Help or Hinder the Frail Very Elderly? The Trial Evidence

n = 3845 80 years (mean 83.6 years), 90% HT HYVET Trial Sitting SBP 160-199mmHg DBP <110mmHg; Standing SBP 140mmHg (OH - 7.9% Treatment v 8.8% Control) Follow-up Short, median 1.8 years excluded: Life expectancy <1 year, Dementia / Recent ICH / CCF / NH Resident Baseline BP 173/91 mmhg, Target BP (<150/80 mmhg) - Active 48% v Placebo 14% Results: For BP difference 15/6 mmhg @ 2years Outcome Active Treatment v Placebo Stroke Mortality Reduced by 39% (p<0.05) Heart Failure Reduced by 64% (p<0.001) All Cause Mortality Reduced by 21% (p<0.02) Fatal/Non-Fatal Stroke Reduced by 30% (NS) Myocardial Infarction Reduced by 28% (NS) CV Mortality Reduced by 23% (NS) SAEs 18.5% v 23.4% (p<0.001) Most benefits (apart from Stroke Mortality) not seen till after at least 1 year Effects of Antihypertensive Treatment on Cognitive Status Cognitive Decline 0.92 (0.82-1.05) Alzheimer s 0.85 (0.63-1.15) Vascular Dementia 0.87 (0.57-1.34) All Dementia 0.86 (0.67-1.09) Baseline MMSE 26 (range 15-30) Antihypertensive Treatment and Incident Dementia - Old Old Combined HR 0.87 (0.76-1.00, p=0.045)

Frailty Index calculated on minimum 30, maximum 60 potential deficits at Baseline for 2656 (69%) of all HYVET subjects Median Baseline FI 0.16 HYVET Trial Effects of Frailty Estimated log HR for Treatment effect by Frailty Index Fatal/Non-Fatal Stroke Fatal/Non-Fatal CV Events 36% 41% 0.2.4.6 0.2.4.6 Frailty Index Total Mortality 17% Log Hazard Ratio Analysis adjusted for age and sex Treated group Median FI 0.16 v Placebo FI 0.17, F/U 23 months Increasing FI at Baseline associated with increasing risk of Death, CV events and Stroke No significant interaction between Treatment benefit and Baseline FI Potential confounders Most only mildly Frail, 1/3 rd subjects excluded, short F/U etc

Intensive BP Reduction, CV Outcomes & Frailty in those aged 75+ - SPRINT Trail All Major CV Events by Frailty (Kaplan-Meier Curves for Primary Outcome) Frailty Index (FI 0.21) Frailty Index (FI >0.21) Years n=2636 Hypertensives mean age 80 years Frailty Index 37 item scale 31% Frail at Baseline Timed 4m walk Baseline and Annually Baseline BP 142/72 mmhg (v HYVET) F/U mean 3.1 years Intensive Target - SBP <120mmHg Standard Target SBP <140mmHg F/U 123/62 v 135/67 mmhg Primary Outcome - Major CV events reduced by 34% (p=0.001, at 3 years NNT 27) Same degree of Benefit in Frail Group No significant differences in OH, Falls or Syncope rate No difference in Gait Speed or other markers of mobility (Frailty) between Intensive and Standard BP Targets Williamson JAMA 2016

Antihypertensive Treatment and Cognition in those without Cerebrovascular Overall Cognition All Cause Dementia Disease (RCTs & Observational Studies, a Network Meta-analysis) Overall Benefit of Treatment, except for language - Time dependent effect RCTs and Observational Overall Benefit of Treatment, 9% reduction in Dementia Incidence 4 RCTs only No benefit Comparison of different AHT drug classes on Cognition Treatment Type Placebo CCB ACEI B- Blockers Diuretics ARB 0.60* 0.57* 0.47* 0.67* 0.54* CCB 0.03 - -0.11 0.10-0.03 ACEI 0.13-0.21 0.07 B-Blockers -0.07 - -0.13 Diuretics 0.06-17 RCTs, N = 13,734 patients, Mean Age 64 years, F/U median 6 months *p<0.05 for difference between drug types, -ve sign indicates adverse effect All AHTs reduced Cognitive Decline from Baseline except B-Blockers Effect Independent of Size of BP Reduction Effect may be Time Dependent Subjects mostly not very elderly or frail Marpillat J Hyperts 2013

Conclusions For the Very Elderly Those aged 80+ years with no/mild Cognitive Impairment (MCI) or mild Frailty, AHT reduces CV risk but benefits seen only after 1-2 years therapy Consider Treatment if SBP consistently >160mmHg (?lower), target unclear but <150mmHg or lower? SBP levels of <130mmHg in those with MCI or Dementia may impair Cognitive Function further Stopping AHT in those with Moderate/Severe Cognitive Impairment may not improve function Lack of randomised data on HT management of the really Frail or very elderly (>90 years) All Frail Hypertensives need a comprehensive assessment before Starting/Continuing AHT including: Postural BP, Cognitive function, Mobility and Frailty assessment, concomitant diseases and therapies Review regularly for adverse effects, especially in first 1-2 months, consider treatment withdrawal in those well controlled? Individualised therapy decisions based on co-morbidities, life expectancy and patient preferences There is more to Life than just living with a normal BP

Any Questions?

Does stopping Antihypertensive Treatment help Cognition? The Dante Leiden Study 385 Community based 75+ olds with Mild Cognitive Impairment (MMSE 21-27) All treated Hypertensives Randomised to Continue or Stop AHT for 16 weeks Battery of Psychological Tests at Baseline and F/U Overall NO effect of stopping on Cognitive function Specific Domains Executive, Memory Function, Psychomotor speed - NO Effect Cognitive Tests MMSE, Immediate and delayed Recall - NO Effect Limitations No blinding, relatively small numbers, short duration F/U, unable to assess AHT drug class effects Moonen JAMA Int Med 2015

Effects of Antihypertensive Treatment in Older Cognitively Impaired Patients All Subjects Baseline Daytime SBP All Subjects Baseline Office SBP Dementia Sub-group Daytime SBP MCI Sub-group Daytime SBP N = 172 Patients with MCI or Dementia, 70% on AHT, seen in Memory Clinic ABPM and Clinic BP Mean Age 79 Years Mean MMSE 22 Median F/U 9 months Observational study Lower SBP on Treatment associated with more marked Cognitive Decline Mossello JAMA Int Med 2015