YΠΕΡΤΑΣΗ 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 1 out of 6 patients with non-fatal stroke has a recurrence in 5 years

256 128 64 32 16 8 4 2 1 0

Stroke Mortality vs Usual BP by Age

Age at risk: Systolic Blood Pressure Diastolic Blood Pressure 80-89 ys 70-79 ys 60-69 ys 50-59 ys 256 128 64 32 16 8 4 Age at risk: 80-89 ys 70-79 ys 60-69 ys 50-59 ys 2 1 0 120 140 160 180 Usual Systolic BP (mm Hg) 70 80 90 100 110 Usual Diastolic BP (mm Hg)

Prospective Studies Collaboration. Lancet. 2002;360:1903-1913

Hypertension and Stroke: Agenda

1.

Primary prevention of stroke 2.

Secondary prevention of stroke 3.

Blood pressure in acute stroke

Effects of BP Reduction on CV Events

1200 1000 800 600 400 200 Reduction in odds (%) Number of SD: 2p value 0 835 C 525 T 140 234 934 T 1104 C 470 560 768 T 964 C Stroke 38% SD 4 8.7

< 0.00001

CHD 16% SD 4 158 170 T C Remaining vascular deaths All vascular deaths 3.8

= 0.0001

4.8

< 0.00001

667 670 T C All other deaths

Meta-analysis of 5 randomized, placebo controlled studies in elderly hypertensives 600 500 400 300 288 T 438 C 346 T 208 438 C 279 383 T 494 C T = treatment C = control = fatal events 362 T 344 C 200 100 78 120 0 Stroke CHD Vascular Deaths All Other Deaths % (SD) reduction in odds 34% (6) 2P < 0.0001

19% (7) 2P < 0.05

The studies assessed the effects of BP reduction on stroke, coronary heart disease, vascular death, and nonvascular death in a total of 12,483 patients over age 60 (SBP difference of 12-14 mmHg, DBP difference of 5-6 mmHg), follow-up 5 years 23% (6) 2P < 0.001

-7% (8) 2P < 0.5

From MacMahon Clin Exp Hypertens 1993; 15: 967

Trial Benefit of Antihypertensive Drug Treatment in Older Patients with Isolated Systolic Hypertension Number of end-points Treat : Control Odds ratios and confidence limits Treatment better Reduction Treatment worse and SD SHEP SYST-EUR SYST-CHINA All Heterogeneity: P = 0.94

All CV endpoints 199 : 289 137 : 186 74 : 94 410 : 569 32% SD 5 2P < 0.0001

SHEP SYST-EUR SYST-CHINA All Heterogeneity: P = 0.83

Fatal and non-fatal stroke 103 : 159 47 : 77 45 : 59 195 : 295 37% SD 6 2P < 0.0001

SHEP SYST-EUR SYST-CHINA All Heterogeneity: P = 0.96

Fatal and non-fatal MI (including sudden death) 103 : 141 58 : 72 20 : 23 182 : 236 25% SD 8 2P = 0.004

0.5

1.0

1.5

Staessen JA Eur Heart J 1999; (Suppl P): 3-8

Is it Possible to Improve Stroke Protection ?

More aggressive blood pressure reduction New antihypertensive agents (ancillary properties) Global risk approach

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 CHD -23% * -15% Major CV events -15% * CHF -6% CV death -7% Total death -4% * Statistically significant

From Lancet 2003; 362: 1527

Meta-Analysis of Antihypertensive Treatment Trials: Effects on Stroke

Trials BP difference Relative risk Placebo-controlled studies ACEI vs placebo CA vs placebo More vs less 5 4 4 Active vs active regimen studies ACEI vs D/BB 5 CA vs D/BB 9 ACEI vs CA 5 -5 / -2 -8 / -4 -4 / -3 0.72 (0.64-0.81) 0.62 (0.47-0.82) 0.77 (0.63-0.95) +2 / 0 +1 / 0 +1 / +1 1.09 (1.00-1.18) 0.93 (0.86-1.00) 1.12 (1.01-1.25) 0.5

1.0

Relative risk Favours 1st listed 2.0

Favours 2nd listed

Lancet 2003; 362: 1527

Primary end points among all subjects enrolled in the Second Australian National Blood Pressure Study Group End Point Hazard Ratio (95% CI) P value 0.2

ACEi superior Diuretic superior 1.0 5.0

All CV events or death from any cause 0.89 (0.79-1.00) 0.02

All Coronary events 0.68 (0.47-0.98) Myocardial infarction 0.90 (0.75-1.09) 0.16

0.04

Stroke 1.02 (0.78-1.33) 0.91

Wing LMH et al, NEJM 2003

ALLHAT: Relative Risks and 95% Confidence Intervals (CIs) for Lisinopril/Chlorthalidone Comparisons in Prespecified Subgroups Stroke Relative Risk (95% CI) Favors Lisinopril Favors Chlorthalidone Relative Risk Total Age <65 y Age



65 y Men Women Black Nonblack Diabetic Nondiabetic Scales are shown in natural logarithm 1.15 (1.02-1.30) 1.21 (0.97-1.52) 1.13 (0.98-1.30) 1.10 (0.94-1.29) 1.22 (1.01-1.46) 1.40 (1.17-1.68) 1.00 (0.85-1.17) 1.07 (0.90-1.28) 1.23 (1.05-1.44) 0.5

1 2.0

JAMA 2002; Vol.288, No.23

HOPE Study: Primary Endpoints

20 16 12 8 P<0.001

17.7

14.1

P<0.001

8.1

6.1

P<0.001

12.2

9.9

ACE I Placebo P<0.001

4.9

3.4

P=0.001

12.2

10.4

4 0 Composite Endpoint Death from CV causes Myocardial infarction Stroke Death any cause

Hope Study Group N Engl J Med 342: 2000

Proportion of patients with first event, % 8 7 6 5 4 3 2 1 0 0 6

LIFE: Fatal / Nonfatal Stroke

Intention-to-Treat Atenolol 12 18 Adjusted Risk Reduction Unadjusted Risk Reduction 24 30 36 Study Month 42 48 Losartan 54 24.9%, p=0.001

25.8%, p=0.0006

60 66

Dahlöf B et al., Lancet 2002; 359: 995-1003

Summary of Reduction in Risk of Stroke

Total Patient Population 1 ISH Subgroup 2 Diabetes Mellitus Subgroup 3 AF Subgroup 4 No Evident Vascular Disease Subgroup 5 NNT Percent reduction in risk of stroke p-value 59 25% 0.001

28 40% 0.020

51 21% 0.204

11 49% 0.018

54 34% <0.001

1.

Dahlöf B et al. Lancet 2002;359:995-1003.

2.

Kjeldsen SE et al. JAMA 2002;288:1491-1498.

3.

4.

Lindholm LH. et al., Lancet 2002;359:1004-1010.

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.

Major CV events CV deaths Non-fatal MI Non-fatal stroke All MI Fatal MI All stroke Fatal stroke Total mortality

SCOPE

Candesartan n = 2477 n rate n Control n = 2460 rate Favours Candesartan 242 145 54 68 70 18 89 24 259 26.2

15.2

5.9

7.4

7.6

1.9

9.7

2.6

27.5

268 152 47 93 63 18 115 26 266 29.8

16.3

5.2

10.3

6.9

2.0

12.7

2.8

28.8

0.5

Favours Control 1.0

Relative Risk 2.0

The VALUE Trial: Secondary Endpoints and All-Cause Death All myocardial infarction No. at risk Valsartan Amlodipine % 7 6 5 4 3 2 1 0 0 % 6 5 7649 7596 Valsartan-based regimen Amlodipine-based regimen 12 7458 7458 24 7177 7205 HR = 1.19 95% CI 1.02-1.38 p = 0.02

36 6853 6905 48 6504 6562 60 3864 3840 72 1520 1532 All stroke No. at risk Valsartan Amlodipine 4 3 2 1 0 0 7649 7596 12 7448 7455 24 36 HR = 1.15 95% CI 0.98-1.35

p = 0.08

48 Time (months) 60 72 7170 7195 6877 6918 6515 6587 3859 3846 1516 1532 All heart failure No. at risk Valsartan Amlodipine All -cause death % % 16 14 12 7649 7596 10 8 6 4 2 0 0 4 3 2 9 8 7 6 5 1 0 0 No. at risk Valsartan Amlodipine 7649 7596 12 7444 7444 12 7496 7484 24 7169 7176 HR = 0.89 95% CI 0.77-1.03

p = 0.12

36 48 60 72 6852 6874 6498 6534 6072 6100 1513 1511 24 Time (months) 7267 7276 36 HR = 1.04 95% CI 0.94-1.14

p = 0.45

6994 7025 48 6682 6729 60 3981 3961 72 1563 1582

From Julius. Lancet June 14 2004

Study Dihydropyridine CCBs ABCD ALLHAT: CCB vs Diuretic CCB vs ACEI ELSA FACET INSIGHT MIDAS NICS SHELL STOP2: CONVINCE INVEST NORDIL VHAS



2 p = 0.804

CCB vs Conv.

CCB vs ACEI Heterogeneity: Heterogeneity: = 0.06; df = 1

 

2 2 = 9.32; df = 10 p = 0.502

Non-dihydropyridine CCBs = 4.64; df = 3 p = 0.201

Heterogeneity between subgroups: All CCBs Heterogeneity:



2 = 14.02; df = 14 p = 0.448

Fixed effect Random effect Fixed effect Random effect Fixed effect Random effect

0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6

Favours CCB Favours other drugs Odds Ratio (95% CI) 2p value 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) 0.006

0.006

0.184

0.390

0.002

0.002

Calcium-Channel Blockade and Stroke Prevention in Hypertension

From Angeli, Am J Hypertens 2004

Agenda

1.

Primary prevention of stroke 2. Secondary prevention of stroke 3.

Blood pressure in acute stroke

Survival with first and recurrent strokes

Proportion surviving 0.95

0.85

0.75

0.65

0.55

0.45

0.35

0.25

0 100 200 Survival first stroke P < 0.001

Survival recurrent stroke 300 400 Days since stroke 500 0 600 700

Adapted from Samsa G et al., Stroke 1999; 30: 338-349

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?

Association between usual levels of diastolic and systolic blood pressure and the risk of stroke among 2435 subjects with a history of ischaemic attack or minor stroke 4.00

2.00

1.00

0.50

4.00

2.00

1.00

0.50

0.25

75 80 85 90 95 Usual Diastolic Blood Pressure (mmHg) 0.25

120 130 140 150 160 170 Usual Systolic Blood Pressure (mmHg)

J Hypertension 1996, Vol 14 (suppl 2)

(with or without hypertension) Trial Carter HSCSG TEST Dutch TIA Total N 97 452 720 1473 2742 % Events Study 20.4% 18.5% 19.9% 7.1% 12.9% Control 43.8% 23.7% 19.8% 8.4% 15.0% 0.0

Overall treatment effect 2P = 0.07 x 2 test for heterogeneity 5.5, 3 df; p = 0.1

Odds Ratio & 95% CI 0.5

Treatment better 1.0

1.5

Treatment worse 2.0

Redn + SD 66% + 27 27% + 20 0% + 19 16% + 8 19% + 10

Secondary Stroke Prevention in a Population of 5665 Normotensive and Hypertensive Subjects: PATS Events BP (mmHg) Active (n = 2841) Placebo (n = 2824) 159 144 / 87 217 149 / 89 RR 0.72

p < 0.001

Chin Med J 1995; 108: 710-717

Incidence of fatal and non-fatal stroke in the randomized PATS Study

% 20 15 10 5 0 12.1

All patients Placebo n = 2824 8.2

Indapamide n = 2841 % 20 15 10 5 0 8.7

Normotensives Placebo n = 480 4.9

Indapamide n = 463

From Liu et al., 1998

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: Hypertensive patients: Normotensive patients: Baseline BP 147/86 mmHg; - 9.0/4.0 mmHg Baseline BP 159/94 mmHg; - 9.5/3.9 mmHg 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

0.20

Proportion with event 0.15

Stroke Risk Reduction

Placebo Active* 0.10

0.05

0.00

0 1

* Active: Perindopril 4 mg ± Indapamide

2 28% risk reduction 95% CI 17 - 38%

P

<0.0001

3 4

Lancet 2001; 358: 1033-41

Stroke Combination Single drug

Total stroke

Monotherapy vs Combination Therapy

Active Placebo Favours active Favours placebo Relative risk reduction (95% CI) 150/1770 157/1281

307/3051

255/1774 165/1280

420/3054

43% (30 to 54) 5% (-19 to 23)

28% (17 to 38)

Major vascular events Combination Single drug

Total events

231/1770 227/1281

458/3051

367/1774 237/1280

604/3054

40% (29 to 49) 4% (-15 to 20)

26% (16 to 34)

0.5

1.0

Hazard ratio 2.0

SBP ≥ 160 SBP 140-159 SBP < 140 DBP ≥ 95 DBP 85-94 DBP < 85

Total

Combination Therapy Stroke by baseline BP

Events active placebo Favours active Favours placebo 57 54 39 106 87 62 27 65 58

150

68 99 88

255

0.4

1.0

Hazard ratio 2.0

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%)

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)?

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) 180 170 160 150 140 130 120 110 100 90 80 70 Day 1 2 ICH MHT HTI STM EMB TIA Control 5 10 ICH MHT HTI Control EMB TIA Blood pressure (mmHg) 190 180 170 160 150 140 130 120 110 100 90 80 70 Day 1 2 5 10 HT, previous therapy HT, no previous therapy No HT Control HT, previous therapy HT, no previous therapy Control No HT

From Wallace, JAMA 1981; 246: 2173

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

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

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): - Britton (1990): 30-day stroke recurremce 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

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

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

Incidence of Ischemic Stroke Recurrency by SBP The International Stroke Trial 4 Recurrent ischaemic stroke within 14 days (%) 3 2 1 0 < 120 120-139 140-159 160-179 Baseline SBP (mmHg) 180-199 200+

From Leonardi-Bee, Stroke 2002; 33: 1315

Baseline BP and Prognosis in Patients with Acute Stroke % 90 80 70 60 50 40 30 20 10 0 % 90 80 70 60 50 40 30 20 10 0 Neurological deterioration < 120 121 140 141 160 161 180 181 200 SBP on admission (mmHg) > 200 < 70 71 80 81 90 91 100 101 110 DBP on admission (mmHg) > 110 % 90 80 70 60 50 40 30 20 10 0 % 90 80 70 60 50 40 30 20 10 0 Poor neurological outcome < 120 121 140 141 160 161 180 181 200 SBP on admission (mmHg) > 200 < 70 71 80 81 90 91 100 101 110 DBP on admission (mmHg) > 110 Mortality % 90 80 70 60 50 40 30 20 10 0 % 90 80 70 60 50 40 30 20 10 0 < 120 121 141 161 181 SBP on admission (mmHg) > 200 < 70 71 80 81 90 91 100 101 110 DBP on admission (mmHg) > 110

From Castillo, Stroke 2004; 35: 520

24-Hour ABPM and CV Prognosis in Acute Stroke

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

24-h Systolic Blood Pressure in Acute Stroke Patients With and Without Brain Edema at CT Scan Control after 5 Days SBP (mmHg) 180 160 140 120 100 3h With brain edema Without brain edema 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

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

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.

Antihypertensive Therapy for Acute Stroke American Heart Association / American Academy of Neurology Ischemic stroke: mmHg) is appropriate Statement of ISH: Comment 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 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 Based on pathophysiological consideration or individual case-report. No systematic review or large intervention trials on blood pressure manipulation in acute stroke.

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

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

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

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

ACCESS Study: Time Course of Blood Pressure

250 mmHg 200 150 100 50 0 Candesartan SBP Placebo SBP Candesartan DBP Placebo DBP

Stroke 2003; 34: 1699-1703

ACCESS Study: Cumulative Mortality at 12 Months and CV Events

0.3

0.2

RR 0.47

(CI 0.25-0.86) p = 0.026

0.1

0.00

100 200 300 Days under observation 400 Placebo Placebo-censored Candesartan Candesartan-censored

Stroke 2003; 34: 1699-1703

ACCESS Study: Conclusions

Although the mechanisms by which angiotensin type 1 (AT beneficial effects in cerebral and in myocardial ischemia.

1 ) receptor blockade affects cardiovascular morbidity and mortality are still unresolved, the present study shows that early neurohumoral inhibition has similar 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