PHARMACOTHERAPY OF VASCULAR DEMENTIA : a clinical point of view

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PHARMACOTHERAPY OF VASCULAR DEMENTIA a
clinical point of view

• Pr. Hervé ALLAIN
• University of Rennes, France
• and D. Bentué-Ferrer, S. Belliard,
• M. Djemaï-Zagloche

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VASCULAR DEMENTIA EPIDEMIOLOGY

• VaD 10 - 20 AD 50 - 60
• In Asia equivalence
• If ? 85 years VaD 46.9 AD 4 3.5
• Prevalence in Europe 3 - 9 (oldest group)
• Incidence 1 in the elderly

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DIAGNOSTIC ISSUES AND CLINICAL TRIALS

• DSM IV versus 1CD-10
• HACHINSKI Ischemia score
• ADDTC criteria (1)
• NINDS-AIREN (2)
• NEUROIMAGING (3)
• (1) Chui et al Neurology 1992 42
  473-480
• (2) Amar and Wilcock BMJ 1996 312
  227-231
• (3) Pullicino et al Neurology 1995 45
  1424-1425

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RISK FACTORS

• STROKE 13.6 are demented at 3 months
• 24.6 if supra-tentorial lesions
• risks for stroke ? risks for VaD
• GENETIC Cadasil
• Apolipoprotein (?4 allele)
• ATHEROGENIC FACTORS HTA, smoking, cholesterol
• PVWLs Periventricular white matter lesions
  (malignant or benign)
• paucity of epidemiologic study.
• prevention ?

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STROKE LESIONS ASSOCIATED WITH VASCULAR DEMENTIA
SYNDROMES

• MULTI-INFARCTS
• STRATEGIC - SINGLE INFARCTS
• SMALL-VESSEL DISEASE
• HYPOPERFUSION
• HEMORRHAGE
• OTHERS

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VaD BEHAVIORAL CHARACTERISTICSAharon-Peretz J.
et al Dement Geriatr. Cogn. Disord 2000 11
294-298

• AD VaD
• AGRESSION/AGITATION 1.2 (2.1) 3.5 (5.1)
• DEPRESSION 2.2 (3) 4.9 (4.2)
• ANXIETY 1.6 (2.8) 3.8 (4.8)
• APATHY 2.7 (4) 5.7 (4.4)
• Correlations with the severity of dementia

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COMPREHENSION OF EMOTIONSShimokawa A. et al
Dement Geriatr Cogn Disord 2000 11 268-274

• EMOTION RECOGNITION TASK (? score)
• CORRELATION WITH MMS IN VaD
• INDIFFERENCE TO INTERPERSONAL RELATIONSHIPS
• Consequence Psychotropics ? Rehabilitation ?

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PROGNOSISBrodaty et al. Arch Neurol 1993 50
643

• VaD AD
• FIVE YEAR MORTALITY RATE 63.6 31.8
• NURSING HOME ADMISSION RATE 31.8 20.6
•  Justification for treatment 

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Free - Radicals
OH hydroxyl
O2 Superoxyde
H2O2 H peroxyde
Fe2
O2
1 O2 Singulet oxygen
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Antioxidants and dementia (RCT)

• Vit E
• Selegiline
• EGb761
• Exifone
• N-acétylcysteine

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CASCADING GLIA REACTIONS

• PATHOLOGY

TNF-?
ACTIVATED MICROGLIA
IL-6
IL1?
NO
1) Activation of astrocyte 2) Damage 3) VaD AD
ONOO
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Alzheimer s Disease
Vascular Dementia
?
?-Amyloid
Amyloid Angiopathy
Brain Ischemia
INFLAMMATION/IMMUNE RESPONSE
Microglia Activation
Mature Astrocytes
Astrocyte Activation
?
?
NGF
O2, TNF-?, IL-1
?
Ca Overload
Neuronal Death
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PATHOGENIC MECHANISMS POSSIBLY INVOLVED IN
SUBCORTICAL VASCULAR DEMENTIA
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DRUGS AND TYPE OF DEMENTIA (I)Gambassi G et al,
Pharmacotherapy 1999 19 430
Hervé ALLAIN  Mémoire  ANVERS, Septembre 2000
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DRUGS AND TYPE OF DEMENTIA (II)Gambassi G et al,
Pharmacotherapy 1999 19 430

• VaD
• - older, less severe
• - more comorbidity
• - greater number of total drugs
• Type of drugs
• cardio-vascular, pulmonary
• anti-Parkinson, nutritional agents

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THE BASIS OF PHARMACOTHERAPY

• 1. P R I M A R Y P R E V E N T I O N
• Stroke ? HTA ? Cardiovascular risk
• 2. PREVENTION OF RECURRENCE
• Control of risk factors
• HTA, blood fluidity, lipids
• 3. SYMPTOMATIC TREATMENT
• Vasodilatators
• Metabolic approach
• Drugs for Alzheimer s Disease
• 4. FUTURE DIRECTIONS
• Drugs for cell death
• Trophic factors

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PRIMARY PREVENTION OF VASCULAR DEMENTIA (I)

• 1. TREAT HTA OPTIMALLY
• 2. TREAT DIABETES
• 3. CONTROL HYPERLIPIDAEMIA
• 4. TOBACCO ALCOOL
• 5. ANTICOAGULANTS FOR ATRIAL FIBRILLATION

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PRIMARY PREVENTION OF VASCULAR DEMENTIA (II)

• 6. ANTIPLATELET THERAPY
• 7. CAROTID ENDARTERECTOMY FOR SEVERE (? 70 )
  STENOSIS
• 8. DIETARY CONTROL
• 9. LIFESTYLE (stress, weight)
• 10. STROKE TIA NMDA, Ca, antioxidants
• 11. REHABILITATION

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TREATMENT OF ESTABLISHED VaD

• Aspirine 325 mg
• Oral anticoagulants ?
• Hydergine (metaanalysis)
• Nicergoline 30 mg bid
• Propentofylline 400 mg tid
• Nimodipine 90 mg
• Posatirelin (TRH analogue)
• Egb 761 (ginkgo)
• Memantine 20 mg

• Meyer et al. 1989
• SPIRIT 1997
• Schneider et Olin 1994
• Hermann et al 1997
• Marcusson et al 1997
• Pantoni et al 1996
• Parneti et al 1996
• Le Bars et al 1997
• Pearsons et al 1999

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CAVEATS IN CLINICAL RESEARCHSubcortical VaD

• DIAGNOSIS NO AGREEMENT, NO VALIDATED CRITERIA
• CRITERIA AND CUT-OFFS TO SEPARATE DEMENTIA FROM
  NON-DEMENTIA (MMS!) ARE NON SENSITIVE
• OUTCOME MEASURES (COGNITION) combination of
  multiple tests
• OUTCOME MEASURES (FUNCTIONAL) IADLgtADL
• FOLLOW-UP Clinical course
  variable progression slow
• plateau periods
• predictors unknown

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PREVENTIVE TREATMENTS

• SYST-EUR TRIAL
• Forette Lancet 1998 Nitrendipine
• SHEP TRIAL
• Shep Group Jama 1991 Beta-blocker Diuretic
  
• NUN STUDY
• Snowdon Jama 1997 small vessel anti HTA
• MULTI-INFARCTS
• Meyer Jags 1989 Aspirine 325 mg/d
• The question Symptomatic effect of drugs on
  cognition ? Nicardipine, Ginkgo,
  Biloba...

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EFFECTS OF NICARDIPINE AND CLONIDINE ON COGNITIVE
FUNCTIONS AND EEG IN ELDERLY HYPERTENSIVE
PATIENTS

• Denolle Th. et al. (in press) Patat et al. BJCP
  2000
• AIM short term effect, comparative of
  nicardipine on cognition and EEG
• POPULATION 15 elderly hypertensive patients.
• RESULTS ? BP, EEG (? alpha) No deleterious
  effect on cognition
• CONCLUSION
• - Alerting effect of nicardipine
• - Predictive value of such bridging studies
  (compare Phase II and Phase III)

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Clinical Trials (I) Calcium Channel Blockers

• Nimodipine (30 mg tid)
• Post-hoc subgroup analysis of the scandinavian
  Multi- Infarct Dementia Trial
• 6 months, Subgroup I subcortical VaD n 92,
  Subgroup II multi infarct dementia n
  167
• Functional rating scales neuropsychological
  tests CGI
• Subgroup I better performance, but results did
  not reach statistical significance
• subgroup II no trend to amelioration
• Pantoni et al. Neurol Sci 2000 175 124-134
  

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Clinical Trials (II) Calcium Channel Blockers

• Nicardipine (20 mg tid)
• randomized, double-blind, placebo-controlled
• 1 year, 156 patients (ITT)
• VaD
• functional disability, MMSE, Pfeiffer score
• no effect in the total group but decline delayed
  in females, in patients without previous
  treatments and those with anti platelet treatment
  Spanish group of nicardipine
  study in vascular dementia
• Rev Neurol 1999 9 835-845

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Clinical Trials (III) Calcium Channel Blockers

• Fasudil hydrochloride (intracellular calcium
  antagonist)
• 31 P - magnetic resonance spectroscopy Xe -
  computed tomography
• 8 weeks, 2 patients, 30 - 60 mg / day
• wandering symptoms disappeared, memory was mildly
  improved effects related to a direct action on
  intracellular energy metabolism and not on
  regional cerebral blood flow
• Kameis et al. Clin Neuro pharmacol 1996
  5 428-438

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Clinical Trials (IV)

• Nicergoline (30 mg bid)
• multicenter, randomized, double-blind, placebo
  controlled
• 6 months 3 weeks (simple blind), 136 patients
  (ITT)
• multi infarct dementia (DSM IV)
• SCAG, MMSE, CGI, 3 subtests of WAIS
• efficacy p lt 0.01 SCAG and MMSE Scores
• Hermann et al. Dement Geriatr Cogn Disord 1997
  8 9-17
• multicenter, randomised, double-blind, placebo
  controlled
• 24 months, 72 patients
• elderly hypertensive patients with leucoaraiosis
  (non-demented)
• nine neuropsychological tests (memory,
  concentration, verbal and motor performances)
• significant improvement or less deterioration in
  nicerpoline group. Bès et al. Eur J Neurol 1999
  3 313-322

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Clinical Trials (V)Neurotrophic factors

• Posatirelin (10 mg once a day)
• multicentre, parallel groups, double-blind versus
  placebo
• 12 weeks IM
• vascular dementia, NINDS-AIREN criteria
• GBS Rating Scale for dementia, Randt memory test,
  Toulouse -Pieron Attention test
• significant improvement in intellectual
  performance, orientation, motivation and memory
  compared to controls, maintained after drug
  withdrawal
• Parnetti L. et al. Acta Neurol Scand 1996
  456-463

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Clinicals Trials (VI)Neuroprotective (glia-cell
modulator)

• Propentofylline (300 mg)
• multinational, parallel-group, randomized,
  double-blind
• 12 months, 260 patients
• ADVaD
• global function, cognitive function, activities
  of daily living
• VaD GBS Total score (p 0.006), CGI item I (p
  0.004), CGI item II (p 0.044), SKT (p
  0.028) in favour of propentofylline
• Marcusson J. et al Dement Geriatr Cogn Disord
  1997 5320-328

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Clinicals Trials (VII)Neuroprotective

• Propentofylline (300 mg tid)
• review of phase III trials (4 double-blind,
  placebo-controlled, randomized)
• 6 months to 56 weeks AD n 901 VaD n 359
• GBS, CGI, MMSE, SKT, activities of daily living
• consistent improvements over placebo slowing
  the progression of the disease itself
• Rother M et al Dement Geriatr Cogn Disord 1998
  9 suppl 36-43

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Clinicals Trials (VIII)Neuroprotective

• Denbufylline (25,50 or 100 mg twice a day)
• multicenter, double-blind, randomized, controlled
  study
• 16 weeks, DAT n 226, VaD n 110
• MMSE, DSST, WAIS
• improvements for patients under denbufylline, not
  statistically significant
• Treves TA and Korczyn AD Dement Geriatr Cogn
  Disord 1999 10505-510

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Clinicals Trials (IX)

• Ginkgo biloba (extract Egb 761)
• placebo-controlled, randomised, double-blind
• 4 days/week, 4 weeks IV, 40 patients
• AD or mixte
• NAB, CGI, KAI
• significant improvement of psychopathology and
  cognitive performance
• Haase J et al 2 Gerontol Geriatr 1996 302 - 309

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An example of the Research Strategy EGb 761
f
Results - Placebo group - DCT
No of items recalled correctly (mean /-SD)
From Allain et al Clin. Ther. 1993
From Le Bars et al JAMA 1997 PHASE III
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Pharmacologic rationale for memantineMöbius HJ
Alzheimer Dis Assoc Disord 1999 13 suppl 3 s172
- s178
M
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Cochrane Review

• Nimodipine (1992) not recommended, no
  convincing evidence that nimodipine is a useful
  treatment for the symptoms of dementia (all
  subtypes)
• Piracetam (1998) not recommended - Effects
  found only on global impression of change (all
  subtypes of dementia)
• Lecithin (1999) results from randomized trials
  does not support the use of lecithin (all
  subtypes of dementia)
• Aspirin (1999) limited evidence that aspirin
  change cognitive outcome of VaD.

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CONCLUSIONS in 2000

• NO FIRM DEMONSTRATION OF EFFICACY
• NO EVIDENCE TO INDICATE ANY DEFINITIVE TREATMENT
• FOCUS ON FUNCTIONAL THAN COGNITIVE OUTCOME
  MEASURES
• WHAT ABOUT COMBINATION THERAPIES ?
• CLARIFY CLINICAL CHARACTERISTICS BEFORE
  CLINICAL TRIALS