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Y ΠΕΡΤΑΣΗ ΚΑΙ ΑΓΓΕΙΑΚΟ ΕΓΚΕΦΑΛΙΚΟ ΕΠΕΙΣΟΔΙΟ

Y ΠΕΡΤΑΣΗ ΚΑΙ ΑΓΓΕΙΑΚΟ ΕΓΚΕΦΑΛΙΚΟ ΕΠΕΙΣΟΔΙΟ. ΑΝΔΡΕΑΣ ΠΙΤΤΑΡΑΣ MD. Stroke: the Medical Impact of the Problem. 5 millions of deaths/year: third cause of mortality 15 millions/year of non-fatal strokes: first cause of disability Second cause of dementia

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Y ΠΕΡΤΑΣΗ ΚΑΙ ΑΓΓΕΙΑΚΟ ΕΓΚΕΦΑΛΙΚΟ ΕΠΕΙΣΟΔΙΟ

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  1. YΠΕΡΤΑΣΗ ΚΑΙ ΑΓΓΕΙΑΚΟ ΕΓΚΕΦΑΛΙΚΟ ΕΠΕΙΣΟΔΙΟ ΑΝΔΡΕΑΣ ΠΙΤΤΑΡΑΣ MD

  2. Stroke: the Medical Impact of the Problem 5 millions of deaths/year: third cause of mortality 15 millions/year of non-fatal strokes: first cause of disability Second cause of dementia 1 out of 6 patients with non-fatal stroke has a recurrence in 5 years

  3. 256 256 128 128 64 64 32 32 16 16 8 8 4 4 2 2 1 1 120 140 160 180 0 0 Stroke Mortality vs Usual BP by Age Age at risk: Age at risk: Systolic Blood Pressure Diastolic Blood Pressure 80-89 ys 80-89 ys 70-79 ys 70-79 ys 60-69 ys 60-69 ys 50-59 ys 50-59 ys Stroke Mortality(Floating Absolute Risk and 95% CI) 70 80 90 100 110 Usual Systolic BP (mm Hg) Usual Diastolic BP (mm Hg) Prospective Studies Collaboration. Lancet. 2002;360:1903-1913

  4. Hypertension and Stroke: Agenda 1. Primary prevention of stroke 2. Secondary prevention of stroke 3. Blood pressure in acute stroke

  5. Effects of BP Reduction on CV Events C C T C T Total numbers of individuals affected C T T C T Stroke CHD Remaining vascular deaths All vascular deaths All other deaths Reduction in odds (%) Number of SD: 2p value 38% SD 4 8.7 < 0.00001 16% SD 4 3.8 = 0.0001 4.8 < 0.00001

  6. Total number of individuals affected

  7. Benefit of Antihypertensive Drug Treatment in Older Patients with Isolated Systolic Hypertension Trial SHEP SYST-EUR SYST-CHINA All Heterogeneity: P = 0.94 SHEP SYST-EUR SYST-CHINA All Heterogeneity: P = 0.83 SHEP SYST-EUR SYST-CHINA All Heterogeneity: P = 0.96 Number of end-points Treat : Control All CV endpoints 199 : 289 137 : 186 74 : 94 410 : 569 Fatal and non-fatal stroke 103 : 159 47 : 77 45 : 59 195 : 295 Fatal and non-fatal MI (including sudden death) 103 : 141 58 : 72 20 : 23 182 : 236 Odds ratios and confidence limits Reduction and SD Treatment better Treatment worse 32% SD 5 2P < 0.0001 37% SD 6 2P < 0.0001 25% SD 8 2P = 0.004 0.5 1.0 1.5 Staessen JA Eur Heart J 1999; (Suppl P): 3-8

  8. Is it Possible to Improve Stroke Protection ? More aggressive blood pressure reduction New antihypertensive agents (ancillary properties) Global risk approach

  9. BPLT Trialist Collaboration Group - Prospective Meta-Analysis Comparison of More and Less Intensive Blood Pressure Lowering ABCD-H, ABCD-N, HOT, UKPDS =  BP 4.2 / 3.5 mmHg More vs Less Stroke -23%* CHD -15% Major CV events -15%* CHF -6% CV death -7% Total death -4% * Statistically significant From Lancet 2003; 362: 1527

  10. Meta-Analysis of Antihypertensive Treatment Trials: Effects on Stroke Placebo-controlled studies ACEI vs placebo CA vs placebo More vs less Active vs active regimen studies ACEIvs D/BB CA vs D/BB ACEIvs CA Trials 5 4 4 5 9 5 BP difference -5 / -2 -8 / -4 -4 / -3 +2 / 0 +1 / 0 +1 / +1 Relative risk 0.72 (0.64-0.81) 0.62 (0.47-0.82) 0.77 (0.63-0.95) 1.09 (1.00-1.18) 0.93 (0.86-1.00) 1.12 (1.01-1.25) 0.5 1.0 2.0 Relative risk Favours 1st listed Favours 2nd listed Lancet 2003; 362: 1527

  11. Primary end points among all subjects enrolled in the Second Australian National Blood Pressure Study Group ACEi superior Diuretic superior 0.2 1.0 5.0 End Point Hazard Ratio (95% CI) P value All CV events or death 0.89 (0.79-1.00) 0.02 from any cause All Coronary events 0.68 (0.47-0.98) 0.16 Myocardial infarction 0.90 (0.75-1.09) 0.04 Stroke 1.02 (0.78-1.33) 0.91 Wing LMH et al, NEJM 2003

  12. ALLHAT: Relative Risks and 95% Confidence Intervals (CIs) for Lisinopril/Chlorthalidone Comparisons in Prespecified Subgroups Stroke Relative Risk(95% CI) FavorsLisinopril FavorsChlorthalidone Relative Risk Total 1.15 (1.02-1.30) Age <65 y 1.21 (0.97-1.52) Age 65 y 1.13 (0.98-1.30) Men 1.10 (0.94-1.29) Women 1.22 (1.01-1.46) Black 1.40 (1.17-1.68) Nonblack 1.00 (0.85-1.17) Diabetic 1.07 (0.90-1.28) Nondiabetic 1.23 (1.05-1.44) 0.5 1 2.0 Scales are shown in natural logarithm JAMA 2002; Vol.288, No.23

  13. HOPE Study: Primary Endpoints P<0.001 20 ACE I Placebo 17.7 16 P=0.001 P<0.001 14.1 12.2 12.2 P<0.001 12 10.4 9.9 Incidence (%) 8.1 8 P<0.001 6.1 4.9 3.4 4 0 Composite Endpoint Death from CV causes Myocardial infarction Stroke Death any cause Hope Study Group N Engl J Med 342: 2000

  14. 8 7 6 5 4 3 2 1 0 LIFE: Fatal / Nonfatal Stroke Intention-to-Treat Proportion of patients with first event, % Atenolol Losartan Adjusted Risk Reduction 24.9%, p=0.001 Unadjusted Risk Reduction 25.8%, p=0.0006 0 6 12 18 24 30 36 42 48 54 60 66 Study Month Dahlöf B et al., Lancet 2002; 359: 995-1003

  15. Summary of Reduction in Risk of Stroke Total ISH Diabetes AF No Evident Patient Subgroup Mellitus Subgroup Vascular 2 4 Population1 Subgroup Disease 3 Subgroup 5 NNT 59 28 51 11 54 Percent reduction 25% 40% 21% 49% 34% in risk of stroke 0.001 0.020 0.204 0.018 <0.001 p-value 1. Dahlöf B et al. Lancet 2002;359:995-1003. 2. Kjeldsen SE et al. JAMA 2002;288:1491-1498. 3. Lindholm LH. et al., Lancet 2002;359:1004-1010. 4. Dahlöf B et al. Presented at the European Society of Cardiology Congress; Berlin, Germany; August 31–September 4, 2002. Poster 2163. 5. Devereux RB et al. American Heart Association Scientific Sessions; Chicago, IL, USA; November 17–20, 2002. Oral presentation.

  16. SCOPE Candesartan n = 2477 Control n = 2460 Favours Candesartan Favours Control Major CV events CV deaths Non-fatal MI Non-fatal stroke All MI Fatal MI All stroke Fatal stroke Total mortality n 242 145 54 68 70 18 89 24 259 rate 26.2 15.2 5.9 7.4 7.6 1.9 9.7 2.6 27.5 n 268 152 47 93 63 18 115 26 266 rate 29.8 16.3 5.2 10.3 6.9 2.0 12.7 2.8 28.8 0.5 1.0 2.0 Relative Risk

  17. The VALUE Trial: Secondary Endpoints and All-Cause Death 7 9 % % Valsartan-based regimen Amlodipine-based regimen 8 6 7 5 6 All myocardial infarction All heart failure 4 5 4 3 3 2 HR = 1.19 95% CI 1.02-1.38 p = 0.02 2 HR = 0.89 95% CI 0.77-1.03 p = 0.12 1 1 0 0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 No. at risk Valsartan Amlodipine No. at risk Valsartan Amlodipine 7649 7596 7458 7458 7177 7205 6853 6905 6504 6562 3864 3840 1520 1532 7649 7596 7444 7444 7169 7176 6852 6874 6498 6534 6072 6100 1513 1511 16 6 % % 14 5 12 4 All stroke All -cause death 10 8 3 6 2 4 HR = 1.04 95% CI 0.94-1.14 p = 0.45 HR = 1.15 95% CI 0.98-1.35 p = 0.08 1 2 0 0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 Time (months) Time (months) No. at risk Valsartan Amlodipine No. at risk Valsartan Amlodipine 7649 7596 7448 7455 7170 7195 6877 6918 6515 6587 3859 3846 1516 1532 7649 7596 7496 7484 7267 7276 6994 7025 6682 6729 3981 3961 1563 1582 From Julius. Lancet June 14 2004

  18. Study Dihydropyridine CCBs ABCD ALLHAT: CCB vs Diuretic CCB vs ACEI ELSA FACET INSIGHT MIDAS NICS SHELL STOP2: CCB vs Conv. CCB vs ACEI Heterogeneity: 2 = 9.32; df = 10 p = 0.502 Non-dihydropyridine CCBs CONVINCE INVEST NORDIL VHAS Heterogeneity: 2 = 4.64; df = 3 p = 0.201 Heterogeneity between subgroups: 2 = 0.06; df = 1 p = 0.804 All CCBs Heterogeneity: 2 = 14.02; df = 14 p = 0.448 Fixed effect Random effect Fixed effect Random effect Fixed effect Random effect Odds Ratio (95% CI) 1.60 (0.61-4.20) 0.94 (0.83-1.07) 0.82 (0.71-0.94) 0.63 (0.27-1.46) 2.56 (0.79-8.29) 0.91 (0.65-1.26) 2.01 (0.50-8.08) 1.03 (0.38-2.80) 0.97 (0.61-1.54) 0.87 (0.71-1.06) 0.96 (0.79-1.18) 0.90 (0.84-0.97) 0.90 (0.84-0.97) 1.15 (0.89-1.47) 0.88 (0.72-1.08) 0.81 (0.66-1.01) 1.25 (0.33-4.68) 0.92 (0.82-1.04) 0.93 (0.78-1.10) 0.90 (0.85-0.97) 0.90 (0.85-0.97) 2p value 0.006 0.006 0.184 0.390 0.002 0.002 Calcium-Channel Blockade and Stroke Prevention in Hypertension 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 From Angeli, Am J Hypertens 2004 Favours CCB Favours other drugs

  19. Agenda 1. Primary prevention of stroke 2.Secondary prevention of stroke 3. Blood pressure in acute stroke

  20. Secondary Stroke Prevention 1. Is BP a risk factor for stroke recurrence? 2. Does BP reduction decrease the incidence of stroke recurrence? 3. Which antihypertensive drugs should be used?

  21. Relative risk of stroke

  22. Secondary Stroke Prevention in a Population of 5665 Normotensive and Hypertensive Subjects: PATS Active (n = 2841) Placebo (n = 2824) RR 0.72 p < 0.001 Events BP (mmHg) 159 144 / 87 217 149 / 89 Chin Med J 1995; 108: 710-717

  23. PROGRESS: Secondary Stroke Prevention 6.105 hypertensive and non-hypertensive patients with a history of stroke or TIA BP reduction with perindopril monotherapy or combined with indapamide vs placebo on top of standard treatment Total population: Baseline BP 147/86 mmHg; - 9.0/4.0 mmHg Hypertensive patients: Baseline BP 159/94 mmHg; - 9.5/3.9 mmHg Normotensive patients: Baseline BP 136/79 mmHg; - 8.8/4.2 mmHg Combined therapy: - 12.3/5.0 mmHg; monotherapy: - 4.9/2.8 mmHg Lancet 2001; 358: 1033

  24. Stroke Risk Reduction 0.20 0.15 0.10 0.05 0.00 Placebo Proportion with event Active* 28% risk reduction 95% CI 17 - 38% P<0.0001 0 1 2 3 4 Follow-up time (years) Lancet 2001; 358: 1033-41 * Active: Perindopril 4 mg ± Indapamide

  25. Monotherapy vs Combination Therapy Stroke Combination Single drug Total stroke Major vascular events Combination Single drug Total events Active 150/1770 157/1281 307/3051 231/1770 227/1281 458/3051 Placebo 255/1774 165/1280 420/3054 367/1774 237/1280 604/3054 Favours active Favours placebo Relative risk reduction (95% CI) 43% (30 to 54) 5% (-19 to 23) 28% (17 to 38) 40% (29 to 49) 4% (-15 to 20) 26% (16 to 34) 0.5 1.0 2.0 Hazard ratio

  26. Combination Therapy Stroke by baseline BP SBP ≥ 160 SBP 140-159 SBP < 140 DBP ≥ 95 DBP 85-94 DBP < 85 Total active 57 54 39 27 65 58 150 Events placebo 106 87 62 68 99 88 255 Favours active Favours placebo Risk reduction (95% CI) 47% (27 to 62%) 41% (16 to 58%) 39% ( 9 to 59%) 62% (41 to 76%) 36% (12 to 53%) 37% (12 to 55%) 43% (30 to 54%) 0.4 1.0 2.0 Hazard ratio

  27. Hypertension and Stroke Primary prevention: Reduced incidence of stroke Secondary prevention: Reduced incidence of recurrent stroke Acute phase of stroke: 80% have BP > 140/90 mmHg 50% have a history of hypertension Mortality 30 days: 7.6% ischemic strokes 37.5% hemorrhagic strokes To treat (Spencer, 1985) or not to treat (Yatsu, 1985)?

  28. Average SBP and DBP for First Ten Hospital for Each Stroke Diagnostic Class, and Relative to History of Hypertension and Hypertensive Treatment Blood pressure (mmHg) Blood pressure (mmHg) ICH HT, previous therapy MHT HTI STM HT, no previous therapy EMB TIA No HT Control Control HT, previous therapy ICH MHT STM HT, no previous therapy HTI Control Control EMB No HT TIA Day 1 2 5 10 Day 1 2 5 10 From Wallace, JAMA 1981; 246: 2173

  29. High Blood Pressure in Acute Phase of Stroke Initially, elevated blood pressure may be beneficial by increasing blood flow to ischemic penumbra (physiological compensatory mechanism) Sustained elevation in blood pressure may be harmful by increasing cerebral edema and the likelihood of the hemorrhagic transformation of ischemic infarct

  30. High Blood Pressure and Prognosis in Acute Stroke Observational Studies A) No prognostic impact - Miah (1983): 1 and 2 year mortality - Britton (1985): progression of neurological symptoms at discharge - Dollberg (1986): survival at discharge - Carlberg (1993): 30-day mortality - Fiorelli (1995): death or disability after 4 months

  31. High Blood Pressure and Prognosis in Acute Stroke Observational Studies B) Negative impact: high blood pressure = worse prognosis - Dunne (1987): severe disability or death, neurological symptoms - Tuhrim (1988): 30-day outcome - Sacco (1989): 30-day stroke recurremce - Britton (1990): in-hospital mortality - Davalos (1990): 3-month deterioration - Dandapani (1995):mortality and severe disability - Henon (1995): 3-month death or disability - Leonardi-Bee (2002):early stroke recurrency, late death or dependency

  32. High Blood Pressure and Prognosis in Acute Stroke Observational Studies C)Positive impact: high blood pressure = better prognosis - Allen (1984): 2-month dependence or death - Jorgensen (1996): early stroke progression - Semplicini (2003): 7-day neurological outcome

  33. High Blood Pressure and Prognosis in Acute Stroke Observational Studies Possible hypotheses for conflicting results - Only patients with cerebral hemorrhage (4 studies) - Patients of stroke unit (4 studies) - Patients investigated after one week or more (6 studies) - Patients continuing or starting antihypertensive therapy (4 studies) - Retrospective studies - Observer bias or interobserver errors

  34. Incidence of Ischemic Stroke Recurrency by SBP The International Stroke Trial Recurrent ischaemic stroke within 14 days (%) Baseline SBP (mmHg) From Leonardi-Bee, Stroke 2002; 33: 1315

  35. Baseline BP and Prognosis in Patients with Acute Stroke Neurological deterioration Poor neurological outcome Mortality % % % < 120 121 - 140 141 - 160 161 - 180 181 - 200 > 200 < 120 121 - 140 141 - 160 161 - 180 181 - 200 > 200 < 120 121 - 140 141 - 160 161 - 180 181 - 200 > 200 SBP on admission (mmHg) SBP on admission (mmHg) SBP on admission (mmHg) % % % < 70 71 - 80 81 - 90 91 - 100 101 - 110 > 110 < 70 71 - 80 81 - 90 91 - 100 101 - 110 > 110 < 70 71 - 80 81 - 90 91 - 100 101 - 110 > 110 DBP on admission (mmHg) DBP on admission (mmHg) DBP on admission (mmHg) From Castillo, Stroke 2004; 35: 520

  36. 24-Hour ABPM and CV Prognosis in Acute Stroke Correlation: Goulene (2003): worse: 146/ 71 better: 137/ 67 Sobrino (1999): dead: 167/ 81 alive: 134/ 78 Damasceno (1999): dead: 196/120 alive: 165/101 Robinson (1997): worse: 156/ 88 better: 140/ 80 No correlation: Lip (1997): no correlation between 24-hour ABPM and middle-term prognosis

  37. 24-h Systolic Blood Pressure in Acute Stroke Patients With and Without Brain Edema at CT Scan Control after 5 Days 180 SBP (mmHg) 160 140 120 With brain edema Without brain edema 100 3h 5h 7h 9h 11h 13h 15h 17h 19h 21h 23h 25h 27h Time from stroke onset * Statisticamente significativa From Vemmos, J Hypertens 2003; 21: 2162

  38. Independent Predictors of Early Complete Recovery Baseline Mathew score > 74 Lack of hypertension No brain edema on CT scan 20% to 30% drop in MAP, day 2 Odds Ratio 331.3 1.9 4.2 2.9 95% CI 45.2-2426.2 1.1-3.1 2.1-2.8 1.3-6.3 From Chamorrd Stroke 1998; 29: 1890

  39. Detrimental Effect of Blood Pressure Reduction in the First 24 Hours of Acute Stroke Onset J. Oliveira-Filho, S.C.S. Silva, C.C. Trabuco, B.B. Pedreira, E.U. Sousa, and A. Bacellar Neurology 2003; 61: 1047 Conclusion: Blood pressure reduction in the first 24 hours of stroke onset is independently associated with poor outcome after 3 months.

  40. Antihypertensive Therapy for Acute Stroke American Heart Association / American Academy of Neurology Ischemic stroke: systolic blood pressure > 220 mmHg or diastolic blood pressure > 120 mmHg Hemorrhagic stroke: systolic blood pressure > 180 mmHg or diastolic blood pressure > 105 mmHg JNC 7 Guidelines (2003): … in acute stroke control of blood pressure at intermediate levels (of approximately 160/100 mmHg) is appropriate Statement of ISH: Modest (5-10%) reductions in blood pressure produce minimal or no measurable changes in cerebral blood flow. By contrast, large (> 15%) reductions in blood pressure can reduce perfusion Comment Based on pathophysiological consideration or individual case-report. No systematic review or large intervention trials on blood pressure manipulation in acute stroke.

  41. The ACCESS Study Evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors Joachim Schrader, MD; Stephan Lüders, MD; Anke Kulschewski, MD; Jürgen Berger, PhD; Walter Zidek, MD; Johannes Treib, MD; Karl Einhäupl, MD; Hans Christoph Diener, MD; Peter Dominiak, MD; on behalf of the ACCESS Study Group Stroke 2003; 34: 1699-1703

  42. ACCESS Study: Design Candesartan Cerebral Ischaemia + Hypertension 500 PT, 55 centri Candesartan if hypertensive Placebo No treatment if normotensive > 72 hours from stroke Day 1 7 1 year 4-16 mg/d according to baseline BP; combination treatment allowed Stroke 2003; 34: 1699-1703

  43. ACCESS Study: Principal Inclusion and Exclusion Criteria Inclusion Motor deficit Negative TAC for hemorrhagic stroke Hypertension to be treated a) SBP > 200 mmHg and/or DBP > 110 mmHg within 6-12 hours b) SBP > 180 mmHg and/or DBP > 105 mmHg within 24-36 hours Exclusion Age > 85 years Patient not conscious Occlusion or stenosis > 70% of internal carotid artery Malignant hypertension III-IV NYHA cardiac failure Unstable angina Stroke 2003; 34: 1699-1703

  44. ACCESS Study: Endpoint of the Trial Primary endpoint Death and disability (at 3 months) Combined secondary endpoint Total mortality + Cerebrovascular events + Cardiac events Stroke 2003; 34: 1699-1703

  45. ACCESS Study: Time Course of Blood Pressure 250 Candesartan SBP Placebo SBP Candesartan DBP Placebo DBP mmHg 200 150 100 50 0 3 Mo 6 Mo Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 12 Mo Study start Recruitment Stroke 2003; 34: 1699-1703

  46. ACCESS Study: Cumulative Mortality at 12 Months and CV Events 0.3 RR 0.47 (CI 0.25-0.86) p = 0.026 0.2 Cumulative event rate Placebo Placebo-censored Candesartan Candesartan-censored 0.1 0.0 0 100 200 300 400 Days under observation Stroke 2003; 34: 1699-1703

  47. ACCESS Study: Conclusions Although the mechanisms by which angiotensin type 1 (AT1) receptor blockade affects cardiovascular morbidity and mortality are still unresolved, the present study shows that early neurohumoral inhibition has similar beneficial effects in cerebral and in myocardial ischemia. The fact that no cardiovascular or cerebrovascular event occurred as a result of hypotension is of significant clinical importance. When there is need for or no contraindication against early antihypertensive therapy, candesartan cilexetil is a safe therapeutic option according to the ACCESS results. Stroke 2003; 34: 1699-1703

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