高血压英文ppt精品课件clinicaltrials of antihypertensive medication for mci and

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 l Consultant: AstraZeneca for the SCOPE trial l Speakers Bureau: Esai, JansenCilag, AstraZeneca, Shire, Pfizer, Novartis Background l Prevalence of hypertension increases with age l More than 50% of elderly populations have hypertension with current criteria (140/90) l An emerging problem in the developing world End-organ damage l The arterial tree l Heart l Kidney l Brain l Eyes Systolic Blood Pressure 140 Cardiovascular Risk HYPERTENSION IN RELATION TO COGNITION Hypertension Stroke White Matter Lesions Cognitive impairment A Brjesson Hanson 2001 Hypertension and the brain l Cerebral autoregulation l Blood brain barrier dysfunction l Decreased cerebral blood floow l Stroke (hemorrhagic, ischemic) l White matter lesions l Dementia and Alzheimers disease RISK OF DEMENTIA IN RELATION TO STROKE 70+ Gteborg Age Stroke patients Age-matched controls % % OR 95%-CI 70-80 18 3 6.7 (2.6-17.6) 80+ 34 10 4.8 (2.8-8.3) All 28 7 4.7 (3.0-7.4) Lindn, Skoog et al Neuroepidemiology 2004 Cognitive impairment in non-demented stroke patients 70+ Gteborg Stroke Controls Cognitive Disturbance % % OR Memory 6 2 2.6* Language 16 1 13.8* Praxis 36 21 2.1* Gnosia 20 5 4.8* Abstraction 17 9 2.0* Any 61 31 3.5* Lindn, Skoog et al Neuroepidemiology 2004 SILENT INFARCTS l The frequency of silent infarcts on MRI increases with age (Vermeer et al, Stroke 2003) l Increases the incidence of dementia (HR 2.3 (95-% CI 1.1-4.7) during 3.6 years follow-up l Related to worse performance on psychometric testing at baseline l Increases risk of clinical stroke on follow-up (Vermeer et al. N Engl J Med 2003) RISK OF DEMENTIA IN RELATION TO INFARCTS ON CT AND HISTORY OF STROKE AT AGE 85 H-70 STUDY, GTEBORG, SWEDEN OR No infarcts/No history 1.0 Infarcts/No history (”silent infarcts”) 2.5* No infarcts/History 4.4* Infarcts + History 5.2* Liebetrau 64:1734-40 Blood pressure and cognitive function l Midlife:High blood pressure related to lower cognitive function l Old age:Low blood pressure related to lower cognitive function Treatment of hypertension and MCI/dementia/ Alzheimer disease ANTIHYPERTENSIVE DRUGS l Angiotensin Converting Enzyme Inhibitors or Angiotensin II type 1 (AT1) receptor blocker l Beta-blockers l Calcium-channel blockers l Diuretics Treatment targets in relation to dementia/MCI Dementia ADL Social abiliy Mild Cognitive Impairment Normal Observational studies BLOOD PRESSURE AND DEMENTIA IS 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 mmHg Systolic 162 148* 151* Diastolic 79 78 76* No Alzheimers Vascular Dementia disease dementia Skoog et al. Hypertension 1998 LOW BLOOD PRESSURE AND ALZHEIMERS DISEASE l A risk factor for Alzheimers disease? lA consequence of Alzheimers disease Blood pressure decreases during the course of Alzheimers disease Lower blood pressure is related to brain atrophy and number of neurons in certain areas of the brain HONOLULU-ASIA AGING STUDY High midlife blood pressure in men not treated for hypertension Alzheimers 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 women not treated for hypertension Dementia 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;48:1035-41 Kungsholmen (incidence) RR (95%-CI) Dementia 0.7 (0.6-1.0) (Guo et al. Arch Neurol 1999;56:991-996 Rotterdam (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;63:686-92) Honolulu Asia Study l 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) l Same result for incident Alzheimers disease l Thus, the longer time on treatment, the lower risk of dementia Peila et al. Stroke 2006 RISK FACTORS DEMENTIA (SBU) Strong/moderate evidence l Age* l ApoE e4 l Family aggregation l Midlife blood pressure l Diabetes mellitus l Antihypertensive drugs (protective)* l Low education l Leisure activity (protective) Fratiglioni et al PREVIOUS DATA ARE BASED ON OBSERVATIONAL STUDIES RANDOMISED CONTROLLED TRIALS MORE RELIABLE THAN OBSERVATIONAL STUDIES WHAT HAVE WE LEARNED FROM RANDOMISED CONTROLLED PREVENTION TRIALS? LARGE HYPERTENSION TRIALS l Systolic Hypertension in the Elderly Program (SHEP) (N=4736): Chlorthalidon (D) l Medical Research Councils (MRC) Treatment Trial of hypertension (N=4396): Atenolol (B), Hydrochlorthiazide (D) l The Systolic Hypertension in Europe Study (Syst-Eur) (N=2418): Nitrendipine (C) l The Study on Cognition and Prognosis in the Elderly (SCOPE) (N=4937): Candersatan (A) l Perindopril Protection against Recurrent Stroke Study (PROGRESS) (N=6105): Perindopril (A) l The Hypertension in the Very Elderly Trial (HYVET) (N=3336): Indapamide (D) + perindopril (A) LARGE HYPERTENSION TRIALS l Systolic Hypertension in the Elderly Program (SHEP) (N=4736): Chlorthalidon l Medical Research Councils (MRC) Treatment Trial of hypertension (N=4396): Atenolol, Hydrochlorthiazide l The Systolic Hypertension in Europe Study (Syst-Eur) (N=2418): Nitrendipine l The Study on Cognition and Prognosis in the Elderly (SCOPE) (N=4937): Candersatan l Perindopril Protection against Recurrent Stroke Study (PROGRESS) (N=6105): Perindopril l The Hypertension in the Very Elderly Trial (HYVET) (N=3336): Indapamide + perindopril (N Engl J Med 2008, Lancet Neurol 2008) SAMPLES l SHEP 160-219/ 160 If lowered blood pressure is a marker of preclinical dementia, those included in hypertension trials may be at low short-term risk for dementia Methodological issues l Healthy volunteer effect l Selective attrition / missing data l Time of follow-up l Diagnosis and detection of dementia l Testing Ceiling effect Learning effect Sensitivity to change l Subgroups? Risk groups? l Type of drug l Effect other than blood pressure CHANGE IN MMSE SCORE l Ceiling effect in those with 29-30 l Learning effect (test every 6 months) l Less possibility for increase in those with 29-30 MMSE 30 MMSE 30 CHANGE IN COGNITIVE FUNCTION MMSE 24 CHANGE IN MMSE SCORE l Ceiling effect in those with 29-30 l Learning effect (test every 6 months) l Less possibility for increase in those with 29-30 Increase in test scores l MRC trial in hypertension l Syst-Eur l SCOPE CHANGE IN MMSE SCORE l Ceiling effect in those with 29-30 l Learning effect (test every 6 months) l Less possibility for increase in those with 29-30 CHANGE IN MMSE SCORE FROM BASELINE (SCOPE) MMSE score at baseline Increase % Decrease % 30 (N=1653) 0 44 29 (N=1214) 36 37 28 (N=929) 43 34 27 (N=528) 49 37 26 (N=354) 49 37 25 (N=177) 54 33 24 (N=81) 36 45 Methodological issues l Healthy volunteer effect l Selective attrition / missing data l Time of follow-up l Diagnosis and detection of dementia l Testing Ceiling effect Learning effect Sensitivity to change l Subgroups? Risk groups? l Type of drug l Effect other than blood pressure SCOPE. Newcastle substudy Change in test scores Candesartan Placebo p Attention 0.004 -0.036 0.04 Episodic memory 0.14 -0.22 0.04 Speed of cognition -2.3 -17.4 0.15 Working memory 0.0014 0.0010 0.90 Executive function -0.0031 -0.0023 0.95 Saxby et 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) l More previous stroke (5.2% vs 3.0%) l More diabetes mellitus (14% vs 10%) l Less myocardial infarction (4.3 vs 4.7%) l Older (77.3 vs 75.8) Skoog et al Am J Hypertension 2005 Major Cardiovascular events in SCOPE (per 1000 person-years) MMSE 24-28 33.6 29-30 24.7 * Cardiovascular mortality, stroke, myocardial infarction Skoog et al Am J Hypertension 2005 Non-fatal stroke (per 1000 person-years) in SCOPE MMSE 24-28 10.6 29-30 7.6 * Skoog et al Am J Hypertension 2005 Dementia (cumulative incidence) in SCOPE MMSE % 24-28 4.4 29-30 1.0 * 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 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 and no RCT Prevalence of hypertension (=blood pressure above 160/90) in 85-year-olds % Non-demented (N=346) 63.9 Demented (N=147) 46.3 * Alzheimer disease (N=64) 42.2 Vascular dementia (N=69) 53.6 Hypertension accelerates cognitive decline in Alzheimers disease l Hypertension at baseline was associated with steeper cognitive decline in Alzheimer patients below the age of 65. No effect of antihypertensive treatment (Bellew et al 2004) l 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 patients with hypertension l Better long-term effect of Rivastigmine in Alzheimer patients with hypertension (Erkinjuntti et al 2003) l Better effect of Donepezil in Alzheimer patients with hypertension (Fukui et al 2005) Antihypertensive treatment slows progression of Alzheimer disease? l Treated hypertensives with Alzheimer disease, vascular dementia, mild cognitive impairment had better cognitive function (Hajjar et al 2005, Hanon et al 2006) l 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 l White matter hyperintensities (WMH) rated at baseline and after a mean of 36 months (n=192) l 24 individuals developed new WMH l Active treatment reduced new WMH with 43% (p=0.17) l Mean total volume of WMH was significantly more reduced in the active treatment group (p=0.012) l Most reduced in patients with severe WMH at baseline (p0.0001) Dufouil et al. Circulation 2005 SUBANALYSES l PROGRESS Dementia with recurrent stroke reduced by 34% (p=0.03) CONCLUSIONS l Hypertension is very common in elderly popul