TRATAMIENTO DEL TRASTORNO COGNITIVO VASCULAR Y DEMENCIA VASCULAR

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Dirigido a neurólogos, geriatras y médicos internistas.

Bussiness Towers Hotel de San Borja

18 de octubre 2011

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  • Ischemic Stroke Subtypes: A Population-Based Study of Incidence Rates Among Blacks and Whites Background and Purpose: Blacks have an excess burden of stroke compared with whites; however, data comparing ischemic stroke subtypes among the 2 groups are limited and typically involve relative frequencies. The objective of this study is to compare the incidence rates of ischemic stroke subtypes between blacks and whites within a large, representative, biracial population. Methods: The Greater Cincinnati/Northern Kentucky Stroke Study is designed to measure incidence rates and trends of all strokes within a well-defined, large, biracial population. Hospitalized cases were ascertained by International Classification of Disease (9th revision; ICD-9) discharge codes. Out-of-hospital events were ascertained by prospective screening of emergency department admission logs, review of coroners’ cases, and monitoring all public health and hospital-based primary care clinics. A sampling scheme was used to ascertain events from nursing homes and all other primary care physician offices. All potential cases underwent detailed chart abstraction and confirmed by physician review. Based on all available clinical, laboratory, and radiographic information, ischemic stroke cases were subtyped into the following categories: cardioembolic, large-vessel, small-vessel, other, and stroke of undetermined cause. Race-specific incidence rates were calculated and compared after adjusting for age and gender, and standardizing to the 1990 US population. Results: Between July 1, 1993, and June 30, 1994, 1956 first-ever ischemic strokes occurred among blacks and whites in the study population. Small-vessel strokes and strokes of undetermined cause were nearly twice as common among blacks. Large-vessel strokes were 40% more common among blacks than whites, and there was a trend toward cardioembolic strokes being more common among blacks. Conclusions: The excess burden of ischemic strokes among blacks compared with whites is not uniformly spread across the different subtypes. Large-vessel strokes are more common and cardioembolic stroke are as common among blacks, traditionally thought to be more common among whites.
  • The Lifetime Risk of Stroke: Estimates From the Framingham Study Background and Purpose: The lifetime risk (LTR) of stroke has not been reported for the United States population; such data would assist public education and health planning. Methods: Framingham Original cohort participants (n=4897) who were stroke- and dementia-free at 55 years of age were followed biennially for up to 51 years (115 146 person years). We estimated the sex-specific 10-, 20-, and 30-year risks and LTR of developing a stroke by baseline age and blood pressure (BP) and compared it with the risk of developing Alzheimer disease (AD). Results: A total of 875 participants (522 women) developed a first-ever stroke; 749 (448 women) had an ischemic stroke. LTR of stroke was high and remained similar at ages 55, 65, and 75 years, approximating 1 in 5 for women and 1 in 6 for men. Participants with a normal BP (120/80 mm Hg) had approximately half the LTR of stroke compared with those with high BP (140/90 mm Hg). The LTR of AD at age 65 (292 participants; 211 women) approximated 1 in 5 for women and 1 in 10 for men. The LTR of developing either stroke or dementia approximated 1 in 3 in both sexes. Conclusion: The LTR of stroke in middle-aged adults is 1 in 6 or more, which is equal to or greater than the LTR of AD. Women had a higher risk because of longer life expectancy. BP is a significant determinant of the LTR of stroke, and promotion of normal BP levels in the community might be expected to substantially reduce this risk.
  • in't Veld BA, Ruitenberg A, Hofman A, Stricker BH, Breteler MM (2001) Antihypertensive drugs and incidence of dementia: the Rotterdam Study. Neurobiol Aging 22, 407-412.
  • PROGRESS: Perindopril Protection Against Recurrent Stroke Study 6105 sujetos con AIT o stroke previo recibieron un inhibidor de la enzima convertidora de angiotensina (IECA), perindopril con posible adicion de diuretico, indapamida vs placebo. Syst-Eur: Systolic Hypertension in Europe 2418 hipertensos sistolicos recibieron un bloqueador de canales de calcio (BCC), nitrendipino con adicion posible de un IECA (enalapril), diuretico (hidroclorotiazida), o ambos vs placebo. SHEP: Systolic Hypertension in the Elderly Program 4736 hipertensos sistolicos de edad promedio 72 anos recibieron un diuretico, clortalidona con posible adicion de beta-bloqueador (atenolol), o bloqueador del sistema nervioso simpatico (reserpina) vs placebo. HYVET: Hypertension in the Very Elderly Trial 3336 hipertensos (PAS: 160-200, PAD<110 mmHg) mayores de 80 anos de edad, recibieron un diuretico, indapamida con posible adicion de un IECA (perindopril) vs placebo.
  • The Study on Cognition and Prognosis in the Elderly (SCOPE), which included 4,964 hypertensive patients over 70 years old without dementia, assessed the effect of a stepwise treatment for hypertension angiotensin-receptor blockers (candesartan ± hydrochlorothiazide) compared to placebo on cognitive function or dementia after a follow-up period of 3.7 years.
  • Syst-Eur: Forette F, Seux ML, Staessen JA, Thijs L, Birkenhäger WH, Babarskiene MR, BabeanubS, Bossini A, Gil-Extremera B, Girerd X, Laks T, Lilov E, Moisseyev V, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Fagard R (1998) Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 35, 1347-1351. Cochrane: Lopez-Arrieta JM, Birks J (2002) Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev, CD000147, suggested a positive effect of nimodipine in AD patients to slow cognitive decline compared to placebo in short-term trials, but no data were available for studies with longer follow-ups. PROGRESS: Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, Chalmers J; PROGRESS Collaborative Group (2003) Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 163, 1069-1075. Ohrui T , Matsui T, Yamaya M, Arai H, Ebihara S, Maruyama M, Sasaki H (2004) Angiotensin-converting enzyme inhibitors and incidence of Alzheimer's disease in Japan. J Am Geriatr Soc 52,649-50. OSCAR: Hanon O, Berrou JP, Negre-Pages L, Goch JH, Nádházi Z, Petrella R, Sedefdjian A, Sévenier F, Shlyakhto EV, Pathak A (2008) Effects of hypertension therapy based on eprosartan on systolic arterial blood pressure and cognitive function: primary results of the Observational Study on Cognitive function And Systolic Blood Pressure Reduction open-label study. J Hypertens 26, 1642-1650. PRoFESS: Diener HC, Sacco RL, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlöf B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C, Voigt T, Weber M, Yoon BW; Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study group (2008) Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol 7, 875-884.
  • Proposed interaction between the renin–angiotensin system and APP metabolism The putative interaction between the ACE pathway and the APP metabolism pathway that leads to the formation of Aβ is illustrated. Under normal (ie, drug-free conditions) ACE can have the positive potential (green arrow) to degrade Aβ that is formed from APP processing. The amount of ACE available to do this is partly genetically linked such that some genotypes that are found to have increased prevalence in Alzheimer’s disease are also associated with lower levels of ACE. Under this model it is also clear that following the action of ACE on angiotensin 1 there may be a negative eff ect (blue arrows) on cognitive performance through angiotensin-2-mediated depression of acetylcholine (ACh) release and also negative eff ects with respect to increased probability of hypertension. With the introduction of an ACE inhibitor, which will negatively aff ect ACE activity, the positive benefi ts to Aβ degradation may be reduced or abolished, but equally the negative effects resulting from angiotensin 2 action on either ACh release or hypertension are reduced. With the introduction of an angiotensin-receptor blocker (ARB) the successful management of angiotensin-2-mediated hypertension and reduced ACh release are maintained while still allowing ACE activity to go unaltered and potentially act to positively reduce Aβ concentrations. The relation of ACE genotype with respect to eff ects of ACE inhibitors and ARBs is unclear.
  • Amyloid-β (Aβ) accumulation in the brain parenchyma leads to the formation of Aβ oligomers and amyloid plaques, which are toxic to neurons, whereas its accumulation in the perivascular region leads to cerebral amyloid angiopathy (CAA), which disrupts vessel function and is associated with cerebral haemorrhage. Aβ has a relatively short half-life (t1/2) in the brain: ~2– 4 h in mice and ~8 h in humans. Major Aβ clearance pathways include receptor-mediated clearance by cells in the brain parenchyma (neurons and glia), along the interstitial fluid (IsF) drainage pathway and through the blood–brain barrier (BBB), and proteolytic degradation by endopeptidases. The comparative effects of apolipoprotein E3 (APOE3) and APOE4 are indicated. In all major cellular Aβ clearance pathways, LDLR-related protein 1 (LRP1) is involved and is likely to clear Aβ either directly or when Aβ binds to its chaperones, which are also LRP1 ligands (for example, APOE and α2-macroglobulin). Low-density lipoprotein receptor (LDLR) function in Aβ clearance is likely to involve Aβ–APOE complexes. Very low density lipoprotein receptor also has a role in the clearance of Aβ–APOE complexes at the BBB. IDE, insulin-degrading enzyme.
  • O, cs: Observational, cross sectional
  • Because the major goal of the present study was to assess on the follow-up MRI examination the evolution of WMHs, a special procedure had to be implemented to ensure that image interpretation conditions were as similar as possible for both examinations in a given subject. The steps of this procedure were as follows: (1) The follow-up T2 volume was first aligned to the initial one with the automatic image registration algorithm.23 (2) Histogram equalization was then applied to the 2 T2 volumes, thereby ensuring comparable image characteristics in terms of signal intensity. (3) Finally, a PC-based, user-friendly graphic interface was developed to allow the radiologist to visualize side by side the slices of both the initial and follow-up MRI examinations.
  • The beneficial effect of this blood pressure–lowering regimen remained significant after adjustment for several variables, including age, gender, stroke type, baseline blood pressure, and severity of WMH at baseline. We also observed a 43% (95% CI 7% to 89%) risk reduction of the occurrence of new WMH in the active treatment group compared with the placebo group, although the difference did not reach statistical significance (8/89 [9.0%] versus 16/103 [15.5%], respectively; P=0.17). WMHs are strongly associated with hypertension, and the results of some large observational cohort studies suggest that patients whose hypertension is better controlled have a more limited progression of WMH. The present study, the first to have implemented an MRI-based assessment of WMH in a randomized trial, confirms that it is possible to limit WMH progression with a perindopril-based blood pressure– lowering regimen in patients with cerebrovascular disease. A post hoc analysis also indicates that the greatest beneficial effect of antihypertensive therapy on WMH progression was observed in the group of patients who had severe WMH at entry. This result is consistent with previous studies showing that over time, patients with greater lesion volume at baseline have a greater increase in the number or total volume of WMHs. The present findings must be considered in light of the limited power of the study. During the mean 3-year follow-up period, 24 of 192 patients developed new WMH, a ratio consistent with previous studies, but these relatively small numbers affect the power to detect the effect of treatment . They also do not allow us to give precise estimates of the treatment effect on the incidence of WMH or the volume of incident WMH by regimen (perindopril alone or perindopril plus indapamide) or by stroke type.With regard to volume of WMH, we decided per protocol to measure only the volume of new WMH. Another option would be to also study the growth of baseline WMH, because it could participate in the overall increase in volume of WMH. Although the question addressed would be slightly different, this option should be considered in future studies to increase their power to detect a treatment effect. In our estimation of the volume of new WMH, we carefully excluded scars caused by stroke that occurred during follow-up, because the treatment effect for stroke could mask its effect on WMH. Furthermore, of the 20 patients who had a stroke during follow-up, only 2 had new WMHs, and exclusion of these patients from the analysis did not modify the results with regard to meaning and statistical significance. Selection of patients is a potential limitation of the present study, because those who agreed to participate in the MRI substudy were healthier than those who refused. This selection bias, which is usual in MRI studies, had no effect on the balanced distribution of the variables between the placebo and the active treatment arm. Furthermore, because the strongest treatment effect was seen in patients with the most severe grades of WMH at baseline, that is, in patients more likely to refuse than agree to participate, the selection bias observed is probably conservative. We therefore believe that this selection had no bearing on the validity of the present results, although it could have affected the study power. Despite its limited power, our study has several strengths. Among the patients included in the selected centers, 87% (281/322) agreed to participate in the study, and among those who had their first MRI examination and who could participate, 93% (192/206) agreed to have a second MRI examination. Overall, despite deaths and patients who met exclusion criteria for MRI, the participation rate was 85% (192/225) between both examinations. The study is further strengthened by the methods used to estimate the volume of WMH. Limitations of visual scales to evaluate WMH severity, as well as WMH changes over time, have been discussed extensively. We used a semiautomated method to identify incident WMHs and to measure their volume. Special care was taken in standardizing the quality and reading conditions of the T2 scans acquired 3 years apart in the same patient. Finally, this substudy had the same favorable characteristics as the main PROGRESS study in terms of good adherence to treatment and maintained blood pressure difference throughout follow-up. The selection of patients mentioned above limits our ability to extend the results of this substudy to all patients enrolled in the PROGRESS trial. The present study showed, in a particular subset of patients, that it is possible to limit the progression of WMH. These results now need to be confirmed and extended in further clinical trials, such as in hypertensive patients free of cerebrovascular disease. Our results could help design such future studies in terms of number of patients, duration of follow-up, stratification on baseline severity of WMH, and methods used to estimate the volume of WMH.
  • Aspirin: Aspirin reduces the risk of recurrent stroke and other major vascular events by at least 13% (95% CI 6–19%) compared with control, when administered acutely and over the long term. Aspirin is affordable, widely available, and reasonably safe. Although aspirin increases the risk of major bleeding by about 70% (risk ratio [RR] 1·71 [95% CI 1·41–2·08]), the absolute annual increase is modest (0·13% [0·08–0·20%]), indicating that one additional major bleeding episode will occur each year for every 769 patients (95% CI 500–1250) treated with aspirin. The increased risk of bleeding is mainly due to an increase in major gastrointestinal bleeding (RR 2·07 [95% CI 1·61–2·66]; absolute annual increase 0·12% [0·07–0·19%]) and intracranial bleeding (RR 1·65 [1·06–5·99]; absolute annual increase 0·03% [0·01–0·08%]). Clopidogrel: Clopidogrel is significantly but marginally more effective than aspirin: it reduced the long-term risk of stroke and other major vascular events by 8·7% (95% CI 0·3–16·5%) compared with aspirin among 19 185 patients at high vascular risk, and by 7·3% (−5·7% to 18·7%) among a subgroup of 6431 patients with ischaemic stroke. Clopidogrel also causes less gastrointestinal bleeding than 325 mg aspirin daily (RR 0·69 [95% CI 0·48–1·00]; absolute annual decrease 0·12% [0·00–0·28%]), but does not reduce the risk of other types of bleeding. However, the cost of clopidogrel is substantially greater than that of aspirin. The long-term use (18 months) of aspirin plus clopidogrel is no more eff ective than clopidogrel alone in prevention of ischaemic stroke, myocardial infarction, vascular death, and rehospitalisation for acute ischaemia (RR 0·94 [95% CI 0·84–1·05]). Moreover, use of this combination for 18 months was associated with an increase in lifethreatening bleeding (2·6% on aspirin and clopidogrel vs 1·3% on aspirin; absolute risk increase 1·3% [0·6–1·9]). Aspirin plus extended-release dipyridamole The combination of aspirin and ER dipyridamole is significantly more effective than aspirin alone in reducing the risk of stroke and other major vascular events (hazard ratio [HR] 0·82 [95% CI 0·72–0·92]), without excessive bleeding or myocardial infarction in patients with previous TIA or ischaemic stroke. However, a direct comparison of 75 mg clopidogrel daily with the combination of 25 mg aspirin and 200 mg ER dipyridamole twice daily in 20 332 patients with ischaemic stroke showed no signifi cant diff erence between either regimen in the prevention of recurrent stroke (9·0% on aspirin plus ER dipyridamole vs 8·8% on clopidogrel; HR 1·01 [95% CI 0·92–1·11]), myocardial infarction (1·7% vs 1·9%; HR 0·90 [0·73–1·10]), and the composite of stroke, myocardial infarction, and death from vascular causes (13·1% vs 13·1%; HR 0·99 [0·92–1·07].
  • Horizontal MRI scan. T1-weighted image. The arrows point to cystic infarcts in the white matter. (b) Coronal whole-hemisphere section with the Loyez myelin stain. The asterisk indicates an area of cystic infarct. The arrows point to areas of leukoencephalopathy containing microinfarcts and gliosis. The black circle indicates the location, in the superior bank of the intraparietal sulcus, of the area shown in figure. cf calcarine fissure; ipl inferior parietal lobule; ips intraparietal sulcus; spl superior parietal lobule. (a) Superior bank of the intraparietal sulcus in a 55-year-old control specimen. The tissue is processed for AChE. The single arrows point to cholinergic fibers coming from the nucleus basalis. The double arrows point to AChE-rich neuronal cell bodies. These neurons are not cholinergic; they are cholinoceptive and respond to the acetylcholine released from cholinergic terminals. (b) Same region of the brain in the 36-year-old CADASIL patient. The single arrows point to cholinergic axons and the double arrows to cholinoceptive neurons. The density of cholinergic axons is very much diminished.
  • La modulacion alosterica de los receptores nicotinicos presinapticos se piensa causan un incremento en la liberacion de varios neurotransmisores, mientras que la modulacion alosterica de los receptores nicotinicos post-sinapticos potencia los efectos de la union a los receptores de Ach. (Samochocki M, Hoffl e A, Fehrenbacher A, Jostock R, Ludwig J, Christner C, Radina M, Zerlin M, Ullmer C, Pereira EF, Lubbert H, Albuquerque EX, Maelicke A: Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. J Pharmacol Exp Ther 2003; 305: 1024–1036)
  • TRATAMIENTO DEL TRASTORNO COGNITIVO VASCULAR Y DEMENCIA VASCULAR

    1. 1. Tratamiento del Trastorno Cognitivo Vascular y Demencia Vascular
    2. 2. <ul><li>Factores de Riesgo en TCV/DV </li></ul><ul><li>Prevención Primaria en TCV/DV </li></ul><ul><li>Prevención Secundaria en TCV/DV </li></ul><ul><li>Alivio Terciario en TCV/DV </li></ul><ul><li>Receptores nicotínicos en EA y TCV/DV </li></ul><ul><li>Evidencias clínicas de IChE en TCV/DV </li></ul>Trastorno Cognitivo Vascular
    3. 3. <ul><li>Factores de Riesgo en TCV/DV </li></ul><ul><li>Prevención Primaria en TCV/DV </li></ul><ul><li>Prevención Secundaria en TCV/DV </li></ul><ul><li>Alivio Terciario en TCV/DV </li></ul><ul><li>Receptores nicotínicos en EA y TCV/DV </li></ul><ul><li>Evidencias clínicas de IChE en TCV/DV </li></ul>Trastorno Cognitivo Vascular
    4. 4. Enfermedad vascular cerebral Lagunas “silentes” Injuria vascular cerebral Esclerosis Hipocampo Enfermedad de Alzheimer LSB Vol SGc Volumen hipocampo Las demencias son de origen vascular? MEMORIA EJECUTIVO GLOBAL
    5. 5. Patogénesis de TCV: Hipótesis Vascular Factor Riesgo Vascular Ateroesclerosis Infarto Cerebral Stroke Factor Riesgo Vascular Enfermedad Vascular Cerebral Injuria Vascular Cerebral Trastorno Cognitivo Vascular
    6. 6. Frecuencia de FRV por subtipo Stroke isquémico HTA, factor de riesgo mas común para stroke Schneider AT. Stroke 2004;35:1552-1556
    7. 7. Framinghan Study: Riesgo de Stroke por PA basal Schneider AT. Stroke 2006;37:345-350 PA Normal: PAS<120 y PAD<80 PreHTN: 120≤PAS<140 ó 80≤PAD<90 HTN 1: 140≤PAS<160 ó 90≤PAD<100 HTN 2: PAS≥160 ó PAD≥100
    8. 8. Hipertensión arterial y TCV Estudio Sujetos Clasificación PA End Point Follow-up Resultado Launer, 2000, HAAS 3,703 hombres J-A, 57% no tratados PAD PAS Severa Alta ≥95 ≥160 Alta 90-94 140-159 Normal 80-89 110-139 Demencia 27 años Riesgo de demencia: PAD severa alta: 3.8 (1.6-8.7) PAD alta: 4.3 (1.7-10.8) PAS severa alta: 4.8 (2.0-11.0) Kivipelto, 2001 1449 sujetos, 65 -79 años edad PAS alta ≥160 Demencia 21 años Riesgo de demencia: 2.3 (1.0-5.5) Kivipelto, 2002 1449 sujetos, 65 -79 años edad PAS alta ≥ 160 EA 21 años Riesgo para EA: 2.6 (1.1 – 6.6) Posner, 2002 1259 sujetos, ≥ 65 años edad ND EA, DV 7 años Riesgo EA: 0.9 (0.7-1.3) Riesgo DV: 1.8 (1.0 -3.2) Kivipelto, 2005 1449 sujetos, 65 -79 años edad PAS alta ≥ 140 Demencia, EA 21 años Riesgo demencia: 1.97 (1.03-3.77) Riesgo EA: 1.57 (0.78 -3.14) Luchsinge 2005 1138 sujetos Edad media: 76.2 ND EA 5.5 años Riesgo EA: 1.4 (0.9 -2.1) Li, 2007 2356 sujetos ≥ 65 años edad PAD PAS Límite/Alta 80-89 ≥160 Normal <80 <140 Demencia 8 años Riesgo de demencia: PAS alta: 1.60 (1.01-2.55) PAD limite alta: 1.59 (1.07-2.35)
    9. 9. Hipertensión y declinación cognitiva: Secuencia y otros factores PA normal PA sub-optima HTA leve HTA crónica TCV-sD DEMENCIA Obisesan TO. Clin Geriatr Med 2009;25:259-288 0 años 1-3 años 2-4 años 10-20 años 1-2 años 1-2 años
    10. 10. Incidencia acumulada de Demencia Comparación de casos de Stroke y Controles Ivan CS et al. Stroke 2004;35: 1264-1268 Casos Controles 11.0% 19.3% Tasa Riesgo: 2 (IC 95%, 1.5 – 3.1) Años Incidencia Acumulada Demencia
    11. 11. Probabilidad de diagnóstico de demencia en función de patología EA con y sin infarto Schneider JA. Neurology 2004;62: 1148-1155 Con Infarto Sin Infarto
    12. 12. <ul><li>Síntomas neurológicos focales </li></ul><ul><li>Signos neurológicos focales </li></ul><ul><li>Infarto estratégico/múltiple </li></ul><ul><li>LSB confluentes </li></ul><ul><li>Síndrome disejecutivo u otro síndrome cognitivo </li></ul><ul><li>Conservación pruebas de memoria? </li></ul>Injuria Cerebral Isquémica Factores de Riesgo Prevención Secundaria Alivio Terciario Tratamiento de TCV y DV Hipertensión Diabetes Colesterol LDL Cardiopatía DEMENCIA Prevención y Tratamiento Primario
    13. 13. <ul><li>Factores de Riesgo en TCV/DV </li></ul><ul><li>Prevención Primaria en TCV/DV </li></ul><ul><li>Prevención Secundaria en TCV/DV </li></ul><ul><li>Alivio Terciario en TCV/DV </li></ul><ul><li>Receptores nicotínicos en EA y TCV/DV </li></ul><ul><li>Evidencias clínicas de IChE en TCV/DV </li></ul>Trastorno Cognitivo Vascular
    14. 14. Prevencion y Tratamiento Primario de Factores de Riesgo Cognitivo <ul><li>Síntomas neurológicos focales </li></ul><ul><li>Signos neurológicos focales </li></ul><ul><li>Infarto estratégico/múltiple </li></ul><ul><li>LSB confluentes </li></ul><ul><li>Síndrome disejecutivo u otro síndrome cognitivo </li></ul><ul><li>Conservación pruebas de memoria? </li></ul>Injuria Cerebral Isquémica Factores de Riesgo Prevención Secundaria Alivio Terciario Hipertensión Diabetes Colesterol LDL Cardiopatía DEMENCIA Prevención y Tratamiento Primario
    15. 15. <ul><li>Rotterdam Study (n=7046). </li></ul><ul><li>n=2015 con antihipertensivos. </li></ul><ul><li>Tratamiento de PA: </li></ul><ul><ul><li>Riesgo disminuído de DV (RR=0.30 después 2.2 años). </li></ul></ul><ul><ul><li>Riesgo disminuído de stroke (RR=0.61 después 4.6 años). </li></ul></ul><ul><ul><li>Riesgo disminuído de LSB (RR=0.39 después 5 años). </li></ul></ul><ul><li>Tratar 46 pacientes hipertensos por 5 años puede prevenir un episodio de stroke. </li></ul>Antihipertensivos y demencia: Estudio observacional In’t Veld BA et al. Neurobiol Aging 2001;22:407-412
    16. 16. Antihipertensivos y declinacion cognitiva: Estudios longitudinales Nagai M et al. Am J Hypertens 2010;23:116-124 Autor n Seguimiento (años) Evaluación Resultados Tzourio, 1999 1,373 4 Declinación MMSE: Caída ≥ 4 puntos Declinación cognitiva menor en hipertensos tratados vs no tratados: RR (95% CI)=1.9 (0.8-4.4) vs 4.3 (2.1-8.8) Murray, 2002 1,617 5 Screening comunidad Riesgo reducido de compromiso cognitivo en 38%: OR (95% CI)=0.62 (0.45-0.84) Korf , 2004 543 30 IRM: Atrofia hipocampo Riesgo incrementado para atrofia hipocampo en pacientes nunca tratados con antihipertensivos: OR(95% CI)=1.7 (1.12-2.65) Hanon, 2008 25,745 1/2 MMSE Reducción PA asociado con incremento de 0.8 puntos en MMSE entre las visitas basal y final (p<0.001)
    17. 17. Antihipertensivos y demencia: Estudios longitudinales Nagai M et al. Am J Hypertens 2010;23:116-124 Autor n Seguimiento (años) Tipo demencia Medicación Asociación Guo, 1999 1810 3 Demencia Diurético (83%) Reducción RR (95% CI)=0.70 (0.6-1.0) Qiu , 2003 1270 6 EA AntiHTA Reducción RR (95% CI)=0.5 (0.5-0.9) Khatchaturian 2006 3308 3 EA AntiHTA Reducción RR (95% CI)=0.64 (0.41-0.98) Peila, 2006 1294 ≥ 12 Demencia EA AntiHTA HR para demencia HR (95% CI)=0.40 (0.22-0.75) HR para EA HR (95% CI)=0.35 (0.16-0.78) Lindsay , 2002 6434 5 EA AntiHTA No significativo RR (95% CI)=0.91 (0.64-1.30) Morris, 2002 634 4 EA Diuréticos y betabloqueadores No asociación Yasar, 2005 1092 11 EA BCC-DHP No significativo RR (95% CI)=0.30 (0.07-1.25) In’tveld 2001 7046 2.2 DV EA AntiHTA Reducción para DV RR (95% CI)=0.30 (0.11-0.99) No significativo para EA RR (95% CI)=0.83 (0.49-1.93)
    18. 18. Meta-análisis de antihipertensivos que evalúan demencia incidente PROGRESS, RR Syst-Eur, RR SHEP, RR HYVET, RR Combinado (Ramdom) Cochrane Q=2.409; p=0.491Test for overall effect; p=0.045 Activo, (N/n) Placebo, (N/n) Hazard ratio (95% CI) 3051 / 193 1238 / 11 2361/ 37 1687 / 126 3054 / 217 1180 / 21 2371 / 44 1649 / 137 0.89 (0.74 – 1.07) 0.50 (0.25 – 1.02) 0.84 (0.55 – 1.30) 0.90 (0.71 – 1.13) 0.87 (0.76 – 1.00) A favor del tratamiento A favor del control 0.2 0.5 1.0 2.0 Peters R. et al. Lancet Neurol 2008;7:683-689
    19. 19. Porcentaje de reducción de demencia en grupos tratados en RCT Nagai M et al. Am J Hypertens 2010;23:116-124 0 1 2 3 4 5 10 20 30 40 50 60 70 SEGUIMIENTO (años) % reducción de demencia SYST-EUR SCOPE SYST-EUR extensión abierta PROGRESS demencia con stroke PROGRESS terapia dual PROGRESS SHEP HYVET-COG Tratar 52 pacientes por 5 años podría evitar un caso de demencia Tratar 1000 pacientes por 5 años podría evitar 20 casos de demencia
    20. 20. Existe efecto de clase de anti-HTA sobre funcion cognitiva? Dickstein DL et al. Mt Sinai J Med 2010;77:82-102 Característica de soporte ACC IECA ARA Evidencia clínica Syst-Eur (1998) Cochrane (2002) PROGRESS (2003) Japon-Ohrui et al (2004) OSCAR (2008) PRoFESS (2008) Drogas eficaces Nitrendipino Nimodipino Perindopril Capto/Perin vs Enal /imida Eprosartan AAS+dipiridamol/clopidogrel/telmisartan Mecanismos propuestos <ul><li>Dismin. producción peroxido. </li></ul><ul><li>Dismin. Influjo IC masivo Ca. </li></ul><ul><li>Inhibe activacion citocinas . </li></ul><ul><li>AII inhibe liberacion de Ach. </li></ul><ul><li>Mejora el FSC. </li></ul><ul><li>Disminuye stress oxidativo. </li></ul><ul><li>Incrementa expresion EDI. </li></ul><ul><li>Activa depuracion de ß-A. </li></ul>
    21. 21. Rol de IECA y ARA sobre Angiotensina 2 cerebral: Mecanismos propuestos Kehoe PG, Wilcock GK. Lancet Neurol 2007;6:373-378
    22. 22. Tiempo de tratamiento anti-HTA y el riesgo de demencia
    23. 23. APOE y “depuración”de β -amiloide Bu G. Nature Rev Neurosci 2009;10:333-344
    24. 24. Uso de estatinas en EA y TCV/DV Luzzi S. et al. J Alz Dis 2010;19:1661-1673 Autor n Estudio Población Resultados Hajjar,2002 655 O, cs Edad: 78.7±0.3 Riesgo reducido para EA: OR (95% CI)=0.37 (0.19-0.74) Zamrini,2004 3397 O, cs Pacientes con EA Riesgo reducido para EA: OR (95% CI)=0.61(0.42-0.87) Rea, 2005 2798 O, p-l Edad ≥ 65 No asociación. Zandi, 2005 5092 O, p-l Edad ≥ 65 No asociación. Green, 2006 2378 O, cs Pacientes con EA Baja probabilidad de tener EA. Rosenberg, 2008 216 O, p-l EA incidente Baja tasa anual de incremento en CDR-sum. Arvanitakis, 2008 929 O, p-l Edad: 75±0.6 No asociación. Haag, 2009 6992 O, p-l Población general Riesgo reducido para EA: HR (95% CI)=0.57 (0.37-0.90) Collins, 2002 20536 RCT-simvas FRV (40-80 a) No beneficio. Sparks, 2006 98 RCT-atorvas EA leve-moderado Mejoría significativa en cognición y memoria tras 6 meses. Trompet, 2009 5804 RCT-pravas FRV (70-82 a) No diferencia en declinación cognitiva tras 42 meses.
    25. 25. <ul><li>Factores de Riesgo en TCV/DV </li></ul><ul><li>Prevención Primaria en TCV/DV </li></ul><ul><li>Prevención Secundaria en TCV/DV </li></ul><ul><li>Alivio Terciario en TCV/DV </li></ul><ul><li>Receptores nicotínicos en EA y TCV/DV </li></ul><ul><li>Evidencias clínicas de IChE en TCV/DV </li></ul>Trastorno Cognitivo Vascular
    26. 26. Hipertensión Diabetes Colesterol LDL Cardiopatía <ul><li>Síntomas neurológicos focales </li></ul><ul><li>Signos neurológicos focales </li></ul><ul><li>Infarto estratégico/múltiple </li></ul><ul><li>LSB confluentes </li></ul><ul><li>Síndrome disejecutivo u otro síndrome cognitivo </li></ul><ul><li>Conservación pruebas de memoria? </li></ul>Injuria Cerebral Isquémica Factores de Riesgo Prevención y Tratamiento Primario Prevención Secundaria Alivio Terciario Prevencion y Tratamiento Secundario de Trastorno Cognitivo Vascular DEMENCIA
    27. 27. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) Cohorte PROGRESS (N=6105) 3051 Activo 3054 Placebo Negativo para demencia 2240 Activo 2199 Placebo Positivo para demencia 768 Activo 812 Placebo DEMENCIA 193 Activo 217 Placebo NO DEMENCIA 562 Activo 580 Placebo Demencia con Stroke recurrente 43 Activo 65 Placebo Otros tipos de Demencia 150 Activo 152 Placebo Tzourio T. et al. Arch Int Med 2003;163:1069-1075
    28. 28. Efectos del tratamiento anti-HTA y el riesgo de demencia en PROGRESS Tzourio T. et al. Arch Int Med 2003;163:1069-1075 Demencia con Stroke recurrente Otras demencias Todas las demencias Activo, (n/N) Placebo, (n/N) Reduccion Riesgo(95% CI), % 43/ 3051 150/ 3051 193 / 3051 65/ 3054 152 / 3054 217 / 3054 34 (3 a 55) 1 (-24 a 22) 12 (-8 a 28) A favor del tratamiento A favor del control 0.5 1.0 2.0 Efectos en todos los participantes Terapia de combinación Terapia con droga única 106/ 1770 87/ 1281 136/ 1774 81 / 1280 23 (0 a 41) -8 (-48 a 21) Efectos en Sub-grupos Hipertensos basales No hipertensos basales 100/ 1464 93/ 1587 114/ 1452 103 / 1602 13 (-16 a 34) 12 (-18 a 34) No trastorno cognitivo basal Trastorno cognitivo basal 72/ 2574 121/ 477 104/ 2591 113 / 463 31 (6 a 50) -5 (-42 a 22)
    29. 29. Efectos del tratamiento anti-HTA y LSB según IRM en PROGRESS 281 voluntarios (140 Activo,141 Placebo) MUESTRA FINAL 225 Pacientes 254 Primera IRM SEGUIMIENTO IRM 192 Pacientes Dufouil C. et al. Circulation 2005;112:1644-1650 322 pacientes (10 centros) 41 rehusaron primera IRM 27 Excluidos: 18 IRM, 9 muertes 29 Excluidos: IRM baja calidad 14 rehusaron segunda IRM 33 Excluidos: 13 IRM, 6 muertes
    30. 30. Protocolo radiológico: IRM en T2 Dufouil C. et al. Circulation 2005;112:1644-1650
    31. 31. Presencia y volumen de LSB incidente por grupo de tratamiento en PROGRESS Dufouil C. et al. Circulation 2005;112:1644-1650 Modelo 1: Valor p generado po:r regresion logistica (ANCOVA) ajustado para edad, sexo y centro. Modelo 2: Valor p generado po:r regresion logistica (ANCOVA) ajustado para edad, sexo y centro, peso, tipo de stroke, niveles PA y tipo de tratamiento, intervalo (en meses) entre las 2 IRM y severidad basal de LSB (si fuera aplicable). Característica LSB Total (n=192) Placebo (n=103) Activo (n=89) Valor p Modelo 1 Valor p Modelo 2 LSB incidente, n (%) 24(13) 16(16) 8(9) 0.17 0.10 Volumen medio LSB incidente, mm 3 (DS) 1.8(0.5) 2.0(0.7) 0.4(0.8) 0.012 0.009 Volumen LSB incidente por grado inicial LSB, mm 3 (DS) No LSB 0.05(0.8) 0 0.09(0.8) 0.76 0.81 LSB Leve a Moderada 1.2(1.2) 1.3(1.0) 0.9(1.0) 0.58 0.71 LSB Severa 6.5 (2.0) 7.6 (1.0) 0 <0.0001 <0.0001
    32. 32. Tratamiento antiplaquetario y reducción de riesgo de stroke, IM o muerte vascular Aspirina vs control Meta-análisis, 11 RCTs,9469 pacientes Reducción riesgo relativo (%) -10 10 20 30 Hankey GJ. et al. Lancet Neurol 2010;9:273-284 0 40 50 Dipiridamol vs Aspirina Meta-análisis, 3 RCTs, 3386 pacientes Trifusal vs Aspirina Meta-análisis, 4 RCTs, 2918 pacientes Ticlopidina vs Aspirina 1 RCT, 3069 pacientes Clopidogrel vs Aspirina 1 RCT, 19 185 pacientes de alto riesgo Clopidogrel vs Aspirina 1 RCT, 6431 pacientes stroke isquémico Clopidogrel+Aspirina vs Aspirina 1 RCT, 15 602 pacientes de alto riesgo Clopidogrel+Aspirina vs Aspirina 1 RCT, 4320 pacientes stroke isquémico Dipiridamol+Aspirina vs Aspirina Meta-análisis, 6 RCTs, 7612 pacientes Clopidogrel+Aspirina vs Clopidogrel 1 RCT, 7599 pacientes Dipiridamol+Aspirina vs Clopidogrel 1 RCT, 20 332 pacientes
    33. 33. <ul><li>Factores de Riesgo en TCV/DV </li></ul><ul><li>Prevención Primaria en TCV/DV </li></ul><ul><li>Prevención Secundaria en TCV/DV </li></ul><ul><li>Alivio Terciario en TCV/DV </li></ul><ul><li>Receptores nicotínicos en EA y TCV/DV </li></ul><ul><li>Evidencias clínicas de IChE en TCV/DV </li></ul>Trastorno Cognitivo Vascular
    34. 34. Alivio Terciario de Demencia Vascular Hipertensión Diabetes Colesterol LDL Cardiopatía <ul><li>Síntomas neurológicos focales </li></ul><ul><li>Signos neurológicos focales </li></ul><ul><li>Infarto estratégico/múltiple </li></ul><ul><li>LSB confluentes </li></ul><ul><li>Síndrome disejecutivo u otro síndrome cognitivo </li></ul><ul><li>Conservación pruebas de memoria? </li></ul>Injuria Cerebral Isquémica Factores de Riesgo Prevención y Tratamiento Primario Prevención Secundaria Alivio Terciario DEMENCIA
    35. 35. Kavirajan H, Schneider LS . Lancet Neurol 2007;6:782–792 Inhibidores de Colinesterasas en DV y TCV RCT n Edad Puntajes Basales Cambio ADAScog HIS MMSE ADAScog Donepezil307 199 placebo 198 donepezil 5 206 donepezil 10 73.9 9.9 21.3 20.7 0.72 Donepezil308 193 placebo 208 donepezil 5 215 donepezil 10 75.0 9.5 22.3 20.1 -0.10 GAL-INT-6 196 placebo 396 Galantamin 75.1 20.5 22.8 0.0 GAL-INT-26 391 placebo 397 Galantamin 72.3 11.8 -0.3 VantagE 345 placebo 365 rivastigmine 72.9 19.2 23.3 0.4 MMM300 156 placebo 165 memantine 76.4 7.8 16.9 21.04 1.6 MMM500 284 placebo 295 memantine 77.4 >4 17.6 25.7 2.3
    36. 36. 2 -2 -4 0 Kavirajan H, Schneider LS . Lancet Neurol 2007;6:782–792 IChE y Memantina en DV y TCV: ADAScog Droga Placebo n Media (DS) n Media (DS) Donezepil 10 mg vs placebo 307 196 -0.96(5.49) 194 0.72(5.64) 308 199 -1.75(4.70) 180 -0.10(5.36) Donezepil 10 mg vs placebo 307 195 -1.52(5.74) 194 0.72(5.64) 308 194 -2.19(6.27) 180 -0.10(5.36) Galantamina 24 mg vs placebo GAL-INT-6 149 -2.00(6.10) 77 0.00(6.76) GAL-INT-26 367 -1.80(5.94) 373 -0.30(6.32) Rivastigmina 12 mg vs placebo VantagE 360 -0.70(7.21) 338 0.40(6.99) Memantina 20 mg vs placebo MMM300 147 -0.40(5.70) 141 1.60(6.10) MMM500 277 0.53(7.02) 261 2.28(7.77)
    37. 37. Eficacia y tolerabilidad de IChE en DV y TCV Demaerschalk BM, Wingerchuk DM . Neurologist 2007;13:37–41 Droga NNT, No.(95% CI) NNH, No.(95% CI) Donepezil, 5 mg/d 11 (5 - 400) 50 (NS) Galantamina 24 mg/d 7 (4 - 20) 7 (4 - 13) Rivastigmina Evidencia insuficiente Evidencia Insuficiente Memantina 20 mg/d 13 (NS) Seguro y bien tolerado
    38. 38. <ul><li>Factores de Riesgo en TCV/DV </li></ul><ul><li>Prevención Primaria en TCV/DV </li></ul><ul><li>Prevención Secundaria en TCV/DV </li></ul><ul><li>Alivio Terciario en TCV/DV </li></ul><ul><li>Receptores nicotínicos en EA y TCV/DV </li></ul><ul><li>Evidencias clínicas de IChE en TCV/DV </li></ul>Trastorno Cognitivo Vascular
    39. 39. Bases racionales para la eficacia de IChE en TCV/DV <ul><li>Estimular la transmision colinérgica mejora el aprendizaje y la retención en el envejecimiento normal ( Yesavage et al. Neurology 2002;59:123-125 ). </li></ul><ul><li>La mayor proporción de casos de TCV/DV tienen además EA con pérdida de neuronas colinérgicas en areas antero-basales. </li></ul><ul><li>La disrrupción de las vias colinérgicas de areas antero-basales hacia corteza frontal ( Selden et al. Brain 1998;121:2249-2257 ) por LSB o infartos. </li></ul>
    40. 40. Demencia Vascular Isquémica Subcortical Circuito Pre-Frontal-Subcortical
    41. 41. Interrupción de vías colinérgicas por lesiones de sustancia blanca o infartos Selden NR et al . Brain 1998;121:2249–2257 Ishii N. Neurology 1986;36: 340-345 B A C D E F
    42. 42. Denervación colinérgica en CADASIL Mesulam M et al. Neurology 2003;60:1183–1185 CONTROL CADASIL EXISTEN BASES BIOQUIMICAS PARA EL MANEJO DE AChE EN CADASIL O BINSWANGER
    43. 43. Mecanismo de acción común de IChE
    44. 44. Galantamina además produce modulación alostérica de receptores nicotínicos de ACh Yakada-Takatori Y et al . Biol Pharm Bull 2009;32(3):318–324
    45. 45. Acción dual de Galantamina y Neuroprotección Galantamina Modulador Alostérico RnACh RnACh alfa 7 Inducción de Bcl 2 Protección contra toxicidad amiloide Protección contra toxicidad glutamato Protección contra apoptosis Protección contra stress neuronal colinérgico IAChE Receptores Muscarinicos Disminución producción Amiloide NEUROPROTECCIÓN
    46. 46. Las tareas de atención y galantamina: Tiempo de Reacción Simple -200 -100 0 100 200 GAL-USA-24 (Todos los sujetos) 0 4 8 Semanas -200 -100 0 100 200 GAL-USA-24 (MMSE 12-18) 0 4 8 Semanas -400 -100 0 100 200 6 26 52 Semanas 300 -200 -300 13 -400 -100 0 100 200 6 26 52 Semanas 300 -200 -300 13 A C D B Galvin JE et al . Alzheimer Dis Assoc Disord 2008;22:30–38 Cambio Promedio en el Tiempo Reacción ± EE (ms) Cambio Promedio en el Tiempo Reacción ± EE (ms) Cambio Promedio en el Tiempo Reacción ± EE (ms) Cambio Promedio en el Tiempo Reacción ± EE (ms) GAL-GBR-2 (Todos los sujetos) GAL-GBR-2 (MMSE 12-18) Mejoría GAL DON Mejoría Mejoría Mejoría
    47. 47. Las tareas de atención y galantamina: Tiempo de Reacción de Elección -200 -100 0 100 200 0 4 8 Semanas -200 -100 0 100 200 0 4 8 Semanas -400 -100 0 100 200 6 26 52 Semanas 300 -200 -300 13 -400 -100 0 100 200 6 26 52 Semanas 300 -200 -300 13 A C D B * * GAL vs. DON; P =0.030 Galvin JE et al . Alzheimer Dis Assoc Disord 2008;22:30–38 Cambio Promedio en el Tiempo Reacción ± EE (ms) Cambio Promedio en el Tiempo Reacción ± EE (ms) Cambio Promedio en el Tiempo Reacción ± EE (ms) Cambio Promedio en el Tiempo Reacción ± EE (ms) GAL-USA-24 (Todos los sujetos) GAL-USA-24 (MMSE 12-18) GAL-GBR-2 (Todos los sujetos) GAL-GBR-2 (MMSE 12-18) GAL DON Mejoría Mejoría Mejoría Mejoría
    48. 48. Las tareas de atención y galantamina: Test de Vigilancia Digital y Fuerza de atención -800 -200 0 200 400 Todos los Sujetos 6 26 52 Semanas 600 -400 -600 13 A * * GAL vs. DON; P =0.0.027 -800 -200 0 200 400 Subgrupo moderado (MMSE 12-18) 6 26 52 Semanas 600 -400 -600 13 B -100 0 100 Subgrupo Moderado (MMSE 12-18) 6 26 52 Semanas 200 13 B -100 0 100 Todos los Sujetos 6 26 52 Semanas 200 13 A Galvin JE et al . Alzheimer Dis Assoc Disord 2008;22:30–38 Cambio Promedio en el Tiempo Reacción ± EE (ms) Cambio Promedio en el Tiempo Reacción ± EE (ms) Cambio Promedio en el Tiempo Reacción ± EE (ms) Cambio Promedio en el Tiempo Reacción ± EE (ms) GAL DON Mejoría Mejoría Mejoría Mejoría
    49. 49. <ul><li>Factores de Riesgo en TCV/DV </li></ul><ul><li>Prevención Primaria en TCV/DV </li></ul><ul><li>Prevención Secundaria en TCV/DV </li></ul><ul><li>Alivio Terciario en TCV/DV </li></ul><ul><li>Receptores nicotínicos en EA y TCV/DV </li></ul><ul><li>Evidencias clínicas de IChE en TCV/DV </li></ul>Trastorno Cognitivo Vascular
    50. 50. Galantamina en DV y EA con ECV Erkinjuntti T et al . Lancet 2002;359:1283–1290
    51. 51. Flujo de pacientes con DV y EA con ECV 750 pac. Elegibles 592 pac. randomizados <ul><li>158 Descontinuaron </li></ul><ul><li>126 No criterios de inclusi ón </li></ul><ul><li>14 Retiro consentimiento </li></ul><ul><li>18 Otras razones </li></ul>196 placebo 396 galantamina <ul><li>33 Descontinuaron </li></ul><ul><li>16 Eventos adversos </li></ul><ul><li>5 Muertes </li></ul><ul><li>1 Retiro consentimiento </li></ul><ul><li>1 No adaptado </li></ul><ul><li>10 Otras razones </li></ul>196 analizados ITT 163 completaron 6m <ul><li>102 Descontinuaron </li></ul><ul><li>78 Eventos adversos </li></ul><ul><li>4 Muertes </li></ul><ul><li>6 Retiro consentimiento </li></ul><ul><li>4 No adaptado </li></ul><ul><li>10 Otras razones </li></ul>396 analizados ITT 294 completaron 6m
    52. 52. Beneficio cognitivo con galantamina (n=388) (n=354) (n=319) (n=290)* (n=357)* (n=194) (n=183) (n=173) (n=162) (n=186) ADAS-cog/11 Casos Observados LOCF a 6 meses Placebo Galantamine Placebo Galantamine Mejoría Deterioro Erkinjuntti T et al . Lancet 2002;359:1283–1290 Cambio desde el Basal en el Puntaje Total
    53. 53. Beneficio funcional con galantamina (n=387) (n=311) (n=288)ᵻ (n=332) ᵻ (n=192) (n=165) (n=161) (n=171) Evaluación de Discapacidad en Demencia Erkinjuntti T et al . Lancet 2002;359:1283–1290 Mejoría Deterioro Cambio desde el Basal en el Puntaje Total Casos Observados LOCF a 6 meses Placebo Galantamine Placebo Galantamine
    54. 54. Beneficio conductual con galantamina (n=378) (n=300) (n=279)‡ (n=322)‡ (n=186) (n=162) (n=154) (n=165) Inventario Neuropsiquiátrico Basal Semana 6 Mes 3 Mes 6 Tiempo desde Randomización Erkinjuntti T et al . Lancet 2002;359:1283–1290 Mejoría Deterioro Casos Observados LOCF a 6 meses Placebo Galantamine Placebo Galantamine Cambio desde el Basal en el Puntaje Total
    55. 55. Galantamina en DV
    56. 56. Flujo de pacientes con DV 750 pac. Elegibles 592 pac. randomizados 196 placebo 396 galantamina <ul><li>59 (15%) Descontinuaron </li></ul><ul><li>27(7%) Eventos adversos </li></ul><ul><li>4(1%) Muertes </li></ul><ul><li>11(3%) Retiro consentimiento </li></ul><ul><li>8(2%) No adaptado </li></ul><ul><li>3(1%) Inelegible continuar </li></ul><ul><li>1(<1%)Respuestai nsuficiente </li></ul><ul><li>0 Perdida en seguimiento </li></ul><ul><li>5(1%) Otras razones </li></ul>390 recibieron TTO 379 analizados ITT <ul><li>93(23%) Descontinuaron </li></ul><ul><li>54(14%) Eventos adversos </li></ul><ul><li>1(<1%) Muertes </li></ul><ul><li>18(5%) Retiro consentimiento </li></ul><ul><li>10(3%) No adaptado </li></ul><ul><li>3(1%) Inelegible continuar </li></ul><ul><li>1(<1%)Respuesta insuficiente </li></ul><ul><li>2(1%)Perdida en seguimiento </li></ul><ul><li>4 (1%) Otras razones </li></ul>396 recibieron TTO 388 analizados ITT
    57. 57. Variaciones en ADAS-cog con galantamina * p = 0.007 vs placebo ᵻ p < 0.001 vs placebo 0 8 12 26 Tiempo (semanas) * ᵻ Auchus AP et al. Neurology 2007;69: 448-458 Cambio Promedio (± EE) en ADAS-Cog desde el Basal Placebo ( n = 372) Galantamina ( n = 364) Mejoría Deterioro
    58. 58. Variaciones en ADCS-ADL con galantamina 0 8 12 26 Tiempo (semanas) Auchus AP et al. Neurology 2007;69: 448-458 Cambio Promedio (± EE) desde el Basal Placebo ( n = 365) Galantamina ( n = 360) Mejoría Deterioro
    59. 59. ADAS-cog según sub-grupos Cambio Promedio (±EE) Auchus AP et al. Neurology 2007;69: 448-458 Placebo ( n = 365) Galantamina ( n = 360) N = 116 N = 113 N = 195 N = 183 N = 51 N = 48 N = 109 N = 118 Infartos Lacunares Múltiples p = 0.021 Enfermedad de Sustancia Blanca p < 0.001 Infartos Territoriales Múltiples p = 0.046 Infarto Estratégico Único p = 0.628 Mejoría Deterioro
    60. 60. Conclusiones <ul><li>La interrupción de las vias colinérgicas explican los síntomas cognitivos y conductuales de DV y EA con ECV. </li></ul><ul><li>El efecto modulador alostérico de los receptores nicotínicos parece tener efecto neuroprotector. </li></ul><ul><li>Galantamina tiene mejor efecto que donepezilo en las tareas de atención. </li></ul><ul><li>No se puede afirmar que galantamina rinde mejores resultados en DV y EA con ECV que los otros IChE. </li></ul>
    61. 61. Nilton Custodio [email_address] www.neuroconsultas.com twitter.com/neuroconsultas neuroconsultas.blogspot.com neuroconsultas slideshare.net/neuroconsultas

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