clinical trials of anti-hypertensive medication for mci ...课件

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 lConsultant: AstraZeneca for the SCOPE trial lSpeakers Bureau: Esai, JansenCilag, AstraZeneca, Shire, Pfizer, Novartis Background lPrevalence of hypertension increases with age lMore than 50% of elderly populations have hypertension with current criteria (140/90) lAn emerging problem in the developing world End-organ damage lThe arterial tree lHeart lKidney lBrain lEyes SystolicSystolic BloodBlood PressurePressure 140140 CardiovascularCardiovascular Risk Risk HYPERTENSION IN RELATION TO COGNITION Hypertension Stroke White Matter Lesions Cognitive impairment A Brjesson Hanson 2001A Brjesson Hanson 2001 Hypertension and the brain lCerebral autoregulation lBlood brain barrier dysfunction lDecreased cerebral blood floow lStroke (hemorrhagic, ischemic) lWhite matter lesions lDementia and Alzheimers disease RISK OF DEMENTIA IN RELATION TO STROKE 70+ Gteborg AgeStroke patients Age-matched controls %OR95%-CI 70-801836.7(2.6-17.6) 80+34104.8(2.8-8.3) All2874.7(3.0-7.4) Lindn, Skoog et al Lindn, Skoog et al NeuroepidemiologyNeuroepidemiology 2004 2004 Cognitive impairment in non-demented stroke patients 70+ Gteborg StrokeControls Cognitive Disturbance %OR Memory 6 2 2.6* Language16 113.8* Praxis3621 2.1* Gnosia20 5 4.8* Abstraction17 9 2.0* Any6131 3.5* Lindn, Skoog et al Lindn, Skoog et al NeuroepidemiologyNeuroepidemiology 2004 2004 SILENT INFARCTS lThe frequency of silent infarcts on MRI increases with age (Vermeer et al, Stroke 2003) lIncreases the incidence of dementia (HR 2.3 (95-% CI 1.1-4.7) during 3.6 years follow-up lRelated to worse performance on psychometric testing at baseline lIncreases 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 history1.0 Infarcts/No history (”silent infarcts”) 2.5* No infarcts/History 4.4* Infarcts + History5.2* LiebetrauLiebetrau 64:1734-40 Blood pressure and cognitive function lMidlife:High blood pressure related to lower cognitive function lOld age:Low blood pressure related to lower cognitive function Treatment of hypertension and MCI/dementia/ Alzheimer disease ANTIHYPERTENSIVE DRUGS lAngiotensin Converting Enzyme Inhibitors or Angiotensin II type 1 (AT1) receptor blocker lBeta-blockers lCalcium-channel blockers lDiuretics TreatmentTreatment targetstargets in relation to in relation to dementiadementia/MCI/MCI DementiaDementia ADLADL Social Social abiliyabiliy Mild Mild CognitiveCognitive ImpairmentImpairment NormalNormal 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. Skoog et al. LancetLancet 1996 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 No Alzheimers Vascular Dementia disease dementiaDementia disease dementia Skoog et al. Hypertension 1998 LOW BLOOD PRESSURE AND ALZHEIMERS DISEASE lA 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 (Indianapolis (prevalenceprevalence) )OROR DementiaDementia 0.670.67 AlzheimersAlzheimers DiseaseDisease 0.590.59 (Richards et al. J Am (Richards et al. J Am GeriatrGeriatr SocSoc 2000;48:1035-41 2000;48:1035-41 Kungsholmen (Kungsholmen (incidenceincidence) )RR (95%-CIRR (95%-CI ) ) DementiaDementia 0.7 (0.6-1.0)0.7 (0.6-1.0) (Guo et al. (Guo et al. ArchArch NeurolNeurol 1999;56:991-996 1999;56:991-996 Rotterdam (Rotterdam (incidenceincidence) ) RR (95%-CI RR (95%-CI) ) DementiaDementia 0.76 (0.52-1.12)0.76 (0.52-1.12) VascularVascular dementiadementia 0.30 (0.11-0.99)0.30 (0.11-0.99) ( (IntInt VeldVeld et al. et al. NeurobiolNeurobiol AgingAging, 2001; , 2001; 22:407-41222:407-412 CasheCashe County County StudyStudy ( (incidenceincidence) ) RR (95%-CI RR (95%-CI) ) AlzheimersAlzheimers diseasedisease 0.64 ( 0.64 (0.41-0.98)0.41-0.98) (Khachaturian(Khachaturian et al . et al . Arch Arch NeurolNeurol 2006;63:686-92) 2006;63:686-92) Honolulu Asia Study lFor 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) lSame result for incident Alzheimers disease lThus, the longer time on treatment, the lower risk of dementia PeilaPeila et al. Stroke 2006 et al. Stroke 2006 RISK FACTORS DEMENTIA (SBU) Strong/moderate evidence lAge* lApoE e4 lFamily aggregation lMidlife blood pressure lDiabetes mellitus lAntihypertensive drugs (protective)* lLow education lLeisure activity (protective) FratiglioniFratiglioni et al 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 lSystolic Hypertension in the Elderly Program (SHEP) (N=4736): Chlorthalidon (D) lMedical Research Councils (MRC) Treatment Trial of hypertension (N=4396): Atenolol (B), Hydrochlorthiazide (D) lThe Systolic Hypertension in Europe Study (Syst-Eur) (N=2418): Nitrendipine (C) lThe Study on Cognition and Prognosis in the Elderly (SCOPE) (N=4937): Candersatan (A) lPerindopril Protection against Recurrent Stroke Study (PROGRESS) (N=6105): Perindopril (A) lThe Hypertension in the Very Elderly Trial (HYVET) (N=3336): Indapamide (D) + perindopril (A) LARGE HYPERTENSION TRIALS lSystolic Hypertension in the Elderly Program (SHEP) (N=4736): Chlorthalidon lMedical Research Councils (MRC) Treatment Trial of hypertension (N=4396): Atenolol, Hydrochlorthiazide lThe Systolic Hypertension in Europe Study (Syst-Eur) (N=2418): Nitrendipine lThe Study on Cognition and Prognosis in the Elderly (SCOPE) (N=4937): Candersatan lPerindopril Protection against Recurrent Stroke Study (PROGRESS) (N=6105): Perindopril lThe Hypertension in the Very Elderly Trial (HYVET) (N=3336): Indapamide + perindopril (N Engl J Med 2008, Lancet Neurol 2008) SAMPLES lSHEP 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 lHealthy volunteer effect lSelective attrition / missing data lTime of follow-up lDiagnosis and detection of dementia lTesting Ceiling effect Learning effect Sensitivity to change lSubgroups? Risk groups? lType of drug lEffect other than blood pressure CHANGE IN MMSE SCORE lCeiling effect in those with 29-30 lLearning effect (test every 6 months) lLess possibility for increase in those with 29-30 MMSE 30MMSE 30 MMSE 30MMSE 30 CHANGE IN COGNITIVE FUNCTIONCHANGE IN COGNITIVE FUNCTION MMSE 24MMSE 24 CHANGE IN MMSE SCORE lCeiling effect in those with 29-30 lLearning effect (test every 6 months) lLess possibility for increase in those with 29-30 Increase in test scores lMRC trial in hypertension lSyst-Eur lSCOPE CHANGE IN MMSE SCORE lCeiling effect in those with 29-30 lLearning effect (test every 6 months) lLess possibility for increase in those with 29-30 CHANGE IN MMSE SCORE FROM BASELINE (SCOPE) MMSE score at baseline Increase %Decrease % 30 (N=1653)044 29 (N=1214)3637 28 (N=929)4334 27 (N=528)4937 26 (N=354)4937 25 (N=177)5433 24 (N=81)3645 Methodological issues lHealthy volunteer effect lSelective attrition / missing data lTime of follow-up lDiagnosis and detection of dementia lTesting Ceiling effect Learning effect Sensitivity to change lSubgroups? Risk groups? lType of drug lEffect other than blood pressure SCOPE. Newcastle substudy Change in test scores CandesartanPlacebop 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. Saxby et al. NeurologyNeurology 2008;70:1858-66 2008;70:1858-66 Treatment of hypertension in mild cognitive impairment (MCI) TreatmentTreatment targetstargets in relation to in relation to dementiadementia DementiaDementia ADLADL Social Social abiliyabiliy Mild Mild CognitiveCognitive ImpairmentImpairment NormalNormal MMSE 24-28 AT BASELINE (SCOPE) lMore previous stroke (5.2% vs 3.0%) lMore diabetes mellitus (14% vs 10%) lLess myocardial infarction (4.3 vs 4.7%) lOlder (77.3 vs 75.8) Skoog et al Am J Hypertension 2005Skoog et al Am J Hypertension 2005 Major Cardiovascular events in SCOPE (per 1000 person-years) MMSE 24-2833.6 29-3024.7 * Cardiovascular mortality, stroke, myocardial infarction Skoog et al Am J Hypertension 2005Skoog et al Am J Hypertension 2005 Non-fatal stroke (per 1000 person-years) in SCOPE MMSE 24-2810.6 29-307.6 * Skoog et al Am J Hypertension 2005Skoog et al Am J Hypertension 2005 Dementia (cumulative incidence) in SCOPE MMSE % 24-284.4 29-301.0 * Skoog et al Am J Hypertension 2005Skoog 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 p0.20p=0.04 Cand n=2417 Cont n=2409 All patients p=0.20 Skoog et al Am J Hypertension 2005Skoog et al Am J Hypertension 2005 Treatment of hypertension in demented TreatmentTreatment targetstargets in relation to in relation to dementiadementia DementiaDementia ADLADL Social Social abiliyabiliy Mild Mild CognitiveCognitive ImpairmentImpairment NormalNormal 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 lHypertension 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) lSystolic 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 lBetter long-term effect of Rivastigmine in Alzheimer patients with hypertension (Erkinjuntti et al 2003) lBetter effect of Donepezil in Alzheimer patients with hypertension (Fukui et al 2005) Antihypertensive treatment slows progression of Alzheimer disease? lTreated hypertensives with Alzheimer disease, vascular dementia, mild cognitive impairment had better cognitive function (Hajjar et al 2005, Hanon et al 2006) lIn 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 lWhite matter hyperintensities (WMH) rated at baseline and after a mean of 36 months (n=192) l24 individuals developed new WMH lActive treatment reduced new WMH with 43% (p=0.17) lMean total volume of WMH was significantly more reduced in the active treatment group (p=0.012) lMost reduced in patients with severe WMH at baseline (p0.0001) Dufouil et al. Circulation 2005 SUBANALYSES lPROGRESS Dementia wit