1、Clinical Trials of Anti-Hypertensive Medication for MCI and dementia,Ingmar Skoog, M.D., Ph.D. Institute of Neuroscience and Physiology Unit of Neuropsychiatric Epidemiology Sahlgrenska Academy at Gteborg University Gteborg, Sweden,DISCLOSURES,Consultant: AstraZeneca for the SCOPE trial Speakers Bur
2、eau: Esai, JansenCilag, AstraZeneca, Shire, Pfizer, Novartis,Background,Prevalence of hypertension increases with age More than 50% of elderly populations have hypertension with current criteria (140/90) An emerging problem in the developing world,End-organ damage,The arterial tree Heart Kidney Brai
3、n Eyes,Systolic Blood Pressure,140,Cardiovascular Risk,HYPERTENSION IN RELATION TO COGNITION,HypertensionStroke White Matter LesionsCognitive impairment,A Brjesson Hanson 2001,Hypertension and the brain,Cerebral autoregulation Blood brain barrier dysfunction Decreased cerebral blood floow Stroke (he
4、morrhagic, ischemic) White matter lesions Dementia and Alzheimers disease,RISK OF DEMENTIA IN RELATION TO STROKE 70+ Gteborg,Lindn, Skoog et al Neuroepidemiology 2004,Cognitive impairment in non-demented stroke patients 70+ Gteborg,Lindn, Skoog et al Neuroepidemiology 2004,SILENT INFARCTS,The freque
5、ncy of silent infarcts on MRI increases with age (Vermeer et al, Stroke 2003)Increases the incidence of dementia (HR 2.3 (95-% CI 1.1-4.7) during 3.6 years follow-up Related to worse performance on psychometric testing at baseline Increases risk of clinical stroke on follow-up(Vermeer et al. N Engl
6、J Med 2003),RISK OF DEMENTIA IN RELATION TO INFARCTS ON CT AND HISTORY OF STROKE AT AGE 85 H-70 STUDY, GTEBORG, SWEDEN,Liebetrau & Skoog. Stroke 2004,Hypertension and the brain,Cerebral autoregulation Blood brain barrier dysfunction Decreased cerebral blood floow Stroke (hemorrhagic, ischemic) White
7、 matter lesions Dementia and Alzheimers disease,WHITE MATTER LESIONS IN RELATION TO DEMENTIA IN 85-YEAR-OLDS,% No dementia 34 Alzheimers disease 64* Vascular dementia 70* Other dementias 80*,Skoog et al J Geriatr Psychiatry Neurol 1994,Cognitive function in non-demented 85-year-olds in relation to w
8、hite matter lesions,Skoog et al. Acta Neurol Scand 1996,Hypertension and the brain,Cerebral autoregulation Blood brain barrier dysfunction Decreased cerebral blood floow Stroke (hemorrhagic, ischemic) White matter lesions Alzheimers disease,LONGITUDINAL STUDIES ON BLOOD PRESSURE AND ALZHEIMERS DISEA
9、SE,Previous high blood pressure5-15 yearsAlzheimers disease in late life,The H70-study in Gothenburg Skoog et al. Lancet 1996The Honolulu-Asia Aging Study Launer et al. Neurobiol Aging 2000The Rotterdam StudyRuitenberg et al. Dissertation 2000 Kaiser Permanente, USAWhitmer et al. Neurology 2005,Kuop
10、io, Finland Kivipelto et al. BMJ 2001 Kungsholmen StudyQiu et al Arch Neurol 2003 Chinese StudyWu et al Life Science 2003,Relation to AD pathology,HONOLULU-ASIA AGING STUDY,High midlife systolic blood pressureNeuritic plaque in old age,Petrovitch et al. Neurobiology of Aging 2000,Possible pathogenet
11、ic mechanisms,Ischemia increases production of beta-amyloid Blood-brain barrier dysfunction Renin-angiotensin system,A 15-year follow-up of blood pressure and dementia,Skoog et al. Lancet 1996,BLOOD PRESSURE IN ALZHEIMERS DISEASE,Increased before onsetLower just before or after onset,Hypertension an
12、d risk of MCI,Reitz et al. Arch Neurol. 2007;64:1734-40,Blood pressure and cognitive function,Midlife:High blood pressure related to lower cognitive functionOld age:Low blood pressure related to lower cognitive function,Treatment of hypertension and MCI/dementia/ Alzheimer disease,ANTIHYPERTENSIVE D
13、RUGS,Angiotensin Converting Enzyme Inhibitors or Angiotensin II type 1 (AT1) receptor blocker Beta-blockers Calcium-channel blockers Diuretics,Treatment targets in relation to dementia/MCI,Dementia,ADL Social abiliy,Mild Cognitive Impairment,Normal,Observational studies,BLOOD PRESSURE AND DEMENTIA,I
14、S IT DANGEROUS TO TREAT HYPERTENSION IN THE ELDERLY?,A 15-year follow-up of blood pressure and Alzheimers disease,Skoog et al. Lancet 1996,BLOOD PRESSURE IN RELATION TO DEMENTIA IN 85-YEAR-OLDS,Blood pressure mmHg mmHg mmHgSystolic 162 148* 151* Diastolic 79 78 76*,No Alzheimers Vascular Dementia di
15、sease dementia,Skoog et al. Hypertension 1998,LOW BLOOD PRESSURE AND ALZHEIMERS DISEASE,A risk factor for Alzheimers disease? A consequence of Alzheimers disease,Blood pressure decreases during the course of Alzheimers diseaseLower blood pressure is related to brain atrophy and number of neurons in
16、certain areas of the brain,HONOLULU-ASIA AGING STUDY,High midlife blood pressure in men not treated for hypertensionAlzheimers disease in old age Vascular dementia in old age,Launer et al. Neurobiology of Aging 2000,Prospective Population Study of Women in Gothenburg,High midlife blood pressure in w
17、omen not treated for hypertensionDementia in old age,Skoog et al 2008,ANTIHYPERTENSIVE DRUGS AND RISK OF DEMENTIA,Indianapolis (prevalence) OR Dementia 0.67 Alzheimers Disease 0.59 (Richards et al. J Am Geriatr Soc 2000;48:1035-41Kungsholmen (incidence) RR (95%-CI) Dementia 0.7 (0.6-1.0) (Guo et al.
18、 Arch Neurol 1999;56:991-996Rotterdam (incidence) RR (95%-CI) Dementia 0.76 (0.52-1.12) Vascular dementia 0.30 (0.11-0.99) (Int Veld et al. Neurobiol Aging, 2001; 22:407-412 Cashe County Study (incidence) RR (95%-CI) Alzheimers disease 0.64 (0.41-0.98) (Khachaturian et al . Arch Neurol 2006;63:686-9
19、2),Honolulu Asia Study,For each additional year of antihypertensive treatment there was a reduction in the risk of incident dementia (hazard ratio HR=0.94, 95% CI, 0.89 to 0.99) Same result for incident Alzheimers disease Thus, the longer time on treatment, the lower risk of dementia,Peila et al. St
20、roke 2006,RISK FACTORS DEMENTIA (SBU) Strong/moderate evidence,Age* ApoE e4 Family aggregation Midlife blood pressure Diabetes mellitus Antihypertensive drugs (protective)* Low education Leisure activity (protective),Fratiglioni et al,PREVIOUS DATA ARE BASED ON OBSERVATIONAL STUDIES RANDOMISED CONTR
21、OLLED TRIALS MORE RELIABLE THAN OBSERVATIONAL STUDIES,WHAT HAVE WE LEARNED FROM RANDOMISED CONTROLLED PREVENTION TRIALS?,LARGE HYPERTENSION TRIALS,Systolic Hypertension in the Elderly Program (SHEP) (N=4736): Chlorthalidon (D) Medical Research Councils (MRC) Treatment Trial of hypertension (N=4396):
22、 Atenolol (B), Hydrochlorthiazide (D) The Systolic Hypertension in Europe Study (Syst-Eur) (N=2418): Nitrendipine (C) The Study on Cognition and Prognosis in the Elderly (SCOPE) (N=4937): Candersatan (A) Perindopril Protection against Recurrent Stroke Study (PROGRESS) (N=6105): Perindopril (A) The H
23、ypertension in the Very Elderly Trial (HYVET) (N=3336): Indapamide (D) + perindopril (A),LARGE HYPERTENSION TRIALS,Systolic Hypertension in the Elderly Program (SHEP) (N=4736): Chlorthalidon Medical Research Councils (MRC) Treatment Trial of hypertension (N=4396): Atenolol, Hydrochlorthiazide The Sy
24、stolic Hypertension in Europe Study (Syst-Eur) (N=2418): Nitrendipine The Study on Cognition and Prognosis in the Elderly (SCOPE) (N=4937): Candersatan Perindopril Protection against Recurrent Stroke Study (PROGRESS) (N=6105): Perindopril The Hypertension in the Very Elderly Trial (HYVET) (N=3336):
25、Indapamide + perindopril (N Engl J Med 2008, Lancet Neurol 2008),SAMPLES,SHEP 160-219/90 MRC 160-209/115 Syst-Eur 160-219/95 No dementia,PROGRESS Prior stroke or TIA Mean age 64 SCOPE 160-179/90-99 MMSE 24-30 No dementia HYVET SBP above 160 Age above 80,COGNITIVE END-POINTS,Dementia (SHEP, Syst-Eur,
26、 SCOPE, PROGRESS, HYVET) Significant Cognitive Decline (PROGRESS, SCOPE),COGNITIVE END-POINTS,Mean change in cognitive function Syst-Eur, Progress, SCOPEMini Mental State Examination (MMSE) MRC:Paired associate learning, Trail Making Test,MAIN RESULTS Cardiovascular end points,Antihypertensive treat
27、ment reduced risk of most cardiovascular end points incl strokeAlso in HYVET, which only included persons above age 80 (N Engl J Med 2008),MAIN RESULTS DEMENTIA,Decreased incidence of dementia (Syst-Eur) No difference (SHEP, SCOPE, Progress, HYVET) No hypertension trial show increased risk for demen
28、tia or cognitive decline,MAIN RESULTS MEAN COGNITIVE CHANGE,No difference: MRC, SHEP, SCOPE, Syst-Eur, Less decline in active treatment group: PROGRESS,WHY SO NEGATIVE RESULTS?,Methodological issues,Age Healthy volunteer effect Selective attrition / missing data Time of follow-up Time in relation to
29、 dementia Diagnosis and detection of dementia TestingCeiling effectLearning effectSensitivity to change Subgroups? Risk groups? Type of drug Effect other than blood pressure,SAMPLES,SHEP Above age 60 MRC Age 65-74 Syst-Eur Above age 60 (mean 70) No dementia HYVET Age above 80,PROGRESS Prior stroke o
30、r TIA Mean age 64 SCOPE Age 70-89 (mean 76) MMSE 24-30 No dementia,Methodological issues,Age Healthy volunteer effect Selective attrition / missing data Time of follow-up Time in relation to dementia Diagnosis and detection of dementia TestingCeiling effectLearning effectSensitivity to change Subgro
31、ups? Risk groups? Type of drug Effect other than blood pressure,Mean test score at baseline,SYST-EUR: 28.5 (max 30) in MMSE SCOPE: 28.5 in MMSE,Methodological issues,Age Healthy volunteer effect Selective attrition / missing data Time of follow-up Time in relation to dementia Diagnosis and detection
32、 of dementia TestingCeiling effectLearning effectSensitivity to change Subgroups? Risk groups? Type of drug Effect other than blood pressure,Effect of differential drop-out in SHEP,Placebo group had more missed assessments CaVa events predicted missed assessments 20-30% of missed assessments were as
33、sumed to be cognitively impaired Then active treatment reduced the risk of cognitive impairment,DiBari et al. Am J Epidemiol 2001,Methodological issues,Age Healthy volunteer effect Selective attrition / missing data Time of follow-up Time in relation to dementia Diagnosis and detection of dementia T
34、estingCeiling effectLearning effectSensitivity to change Subgroups? Risk groups? Type of drug Effect other than blood pressure,Time of follow-up,SHEP 5 years MRC 4.5 years Syst-Eur Median 2.0 years PROGRESS Mean 3.9 years SCOPE Mean 3.7 years HYVET Mean 2.2 years,LONGITUDINAL STUDIES ON BLOOD PRESSU
35、RE AND ALZHEIMERS DISEASE,Previous high blood pressure5-15 yearsAlzheimers disease in late life,The H70-study in Gothenburg Skoog et al. Lancet 1996The Honolulu-Asia Aging Study Launer et al. Neurobiol Aging 2000The Rotterdam StudyRuitenberg et al. Dissertation 2000,Kuopio, Finland Kivipelto et al.
36、BMJ 2001 Kungsholmen Study Qiu et al Arch Neurol 2003 Chinese Study Wu et al Life Science 2003 USA Whittmer et al. Neurology 2005,Too short follow-up to evaluate an effect on dementia,Declining blood pressure before dementia onset,A 15-year follow-up of blood pressure and dementia,Skoog et al. Lance
37、t 1996,SAMPLES,SHEP 160-219/90 MRC 160-209/115 Syst-Eur 160-219/95 No dementia,PROGRESS Prior stroke or TIA Mean age 64 SCOPE 160-179/90-99 MMSE 24-30 No dementia HYVET SBP 160,If lowered blood pressure is a marker of preclinical dementia, those included in hypertension trials may be at low short-te
38、rm risk for dementia,Methodological issues,Healthy volunteer effect Selective attrition / missing data Time of follow-up Diagnosis and detection of dementia TestingCeiling effectLearning effectSensitivity to change Subgroups? Risk groups? Type of drug Effect other than blood pressure,CHANGE IN MMSE
39、SCORE,Ceiling effect in those with 29-30 Learning effect (test every 6 months) Less possibility for increase in those with 29-30,MMSE 30,MMSE 30,CHANGE IN COGNITIVE FUNCTION,MMSE 24,CHANGE IN MMSE SCORE,Ceiling effect in those with 29-30 Learning effect (test every 6 months) Less possibility for inc
40、rease in those with 29-30,Increase in test scores,MRC trial in hypertension Syst-Eur SCOPE,CHANGE IN MMSE SCORE,Ceiling effect in those with 29-30 Learning effect (test every 6 months) Less possibility for increase in those with 29-30,CHANGE IN MMSE SCORE FROM BASELINE (SCOPE),Methodological issues,
41、Healthy volunteer effect Selective attrition / missing data Time of follow-up Diagnosis and detection of dementia Testing Ceiling effect Learning effect Sensitivity to change Subgroups? Risk groups? Type of drug Effect other than blood pressure,SCOPE. Newcastle substudy Change in test scores,Saxby e
42、t al. Neurology 2008;70:1858-66,Treatment of hypertension in mild cognitive impairment (MCI),Treatment targets in relation to dementia,Dementia,ADL Social abiliy,Mild Cognitive Impairment,Normal,MMSE 24-28 AT BASELINE (SCOPE),More previous stroke (5.2% vs 3.0%) More diabetes mellitus (14% vs 10%) Le
43、ss myocardial infarction (4.3 vs 4.7%) Older (77.3 vs 75.8),Skoog et al Am J Hypertension 2005,Major Cardiovascular events in SCOPE (per 1000 person-years),Cardiovascular mortality, stroke, myocardial infarction,Skoog et al Am J Hypertension 2005,Non-fatal stroke (per 1000 person-years) in SCOPE,Sko
44、og et al Am J Hypertension 2005,Dementia (cumulative incidence) in SCOPE,Skoog et al Am J Hypertension 2005,Change in MMSE Score, ITT,-0.8,-0.7,-0.6,-0.5,-0.4,-0.3,-0.2,-0.1,0,Change in MMSE Score (adjusted),Cand n=1419,Cont n=1399,Baseline MMSE 29-30,Cand n=998,Cont n=1010,Baseline MMSE 24-28,p0.20
45、,p=0.04,Cand n=2417,Cont n=2409,All patients,p=0.20,Skoog et al Am J Hypertension 2005,Treatment of hypertension in demented,Treatment targets in relation to dementia,Dementia,ADL Social abiliy,Mild Cognitive Impairment,Normal,Not many studies on antihypertensive treatment in demented individuals an
46、d no RCT,Prevalence of hypertension (=blood pressure above 160/90) in 85-year-olds,Hypertension accelerates cognitive decline in Alzheimers disease,Hypertension at baseline was associated with steeper cognitive decline in Alzheimer patients below the age of 65. No effect of antihypertensive treatmen
47、t (Bellew et al 2004) Systolic hypertension at baseline was related to steeper cognitive decline in Alzheimer patients from the Cashe County Study. Mainly among the elderly. Antihypertensive treatment was related to a slower decline (Mielke et al 2007),Acetylcholinesterase inhibitors in Alzheimer pa
48、tients with hypertension,Better long-term effect of Rivastigmine in Alzheimer patients with hypertension (Erkinjuntti et al 2003) Better effect of Donepezil in Alzheimer patients with hypertension (Fukui et al 2005),Antihypertensive treatment slows progression of Alzheimer disease?,Treated hypertens
49、ives with Alzheimer disease, vascular dementia, mild cognitive impairment had better cognitive function (Hajjar et al 2005, Hanon et al 2006) In Alzheimer patients on acetylcholinesterase inhibitors, those on antihypertensive treatment performed better on MMSE after 40 weeks of treatment (Rozzini et al 2005),Treatment of hypertension may have an effect on cerebrovascular disease in individuals with cognitive impairment,PROGRESS MRI Substudy,
