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Curriculum Vitae• Nama : Prof DR Dr Hasan Sjahrir SpS(K),

• Jabatan/Pangkat : Guru besar Neurologi FK USU Medan/IV E• Tempat lahir: Kediri, 30-9-1947• Menikah, 2 anakJabatan/Posisi saat ini

1. Anggota Dewan Penasehat Pengurus Pusat Asosiasi Profesor Indonesia

2. Ketua II Pengurus Pusat Perdossi & Koordinator Nasional Kelompok Studi

3. Ketua Komisi Subspesialis Kolegium Neurologi Indonesia

4. Penasehat Kelompok Studi Nyeri Kepala Perdossi

5. Anggota International Headache Society

6. Ketua AAzI Wilayah Sumut

7. Ketua Pokdi Neurotraumatologi Perdossi Cabang Medan

8. Anggota Honorary Editorial Advisory Board Asia MIMS Indonesia

9. Anggota Editorial Board Medical Progress Journal Asia

10. Anggota Medical Advisory Board PT ASKES1

The Role of ARB’s in The Management of

Hypertensive Stroke Patients: Recent Updates

Hasan Sjahrir

Department of Neurology

Sumatera Utara University

Medan

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Key word: hypertension, ARB, stroke therapy

http://neurologi.usu.ac.id

HYPERTENSION

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Hypertension (HT)

• HT affects over 60 million Americans and 1 billion

people worldwide predicted to rise 60% by 2025 to

1.56 billion, with only 50% of patients being

adequately controlled.

• each increment in systolic BP of 20 mmHg or

diastolic BP of 10 mmHg doubles the risk of stroke

• There were significant reductions (P<0.0001) in the

rate of hospitalization and death from stroke

associated with the increases in antihypertensive

prescriptions

2/28/2011 4

Poulter N. Br J Cardiol 2010

Robinson JD. The Annals of Pharmacotherapy. 2009

Campbell NR. Hypertension. 2009

The INTERSTROKE study : 2010

• Case control study : 3000 pts acute stroke from 22 countries

• studies have failed to show a consistent relationship between total cholesterol and stroke risk

• 10 modifiable risk factors explain 90% of stroke risk

1. hypertension, current smoking, abdominal obesity, diet, and physical activity (80% of the risk of ischemic stroke and 90% of the risk of hemorrhagic strokes)

2. diabetes mellitus, alcohol intake, psychosocial factors, the ratio of apolipoprotein B to A1, and cardiac causes (atrial fibrillation or flutter, previous MI, and valve disease)

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O'Donnell MJ, Xavier D, Liu L, et al. Lancet 2010

The INTERSTROKE study : 2010

1. history of hypertension or blood pressure >160/90 (51.8%)

2. low regular physical activity (28.5%)

3. elevated waist-to-hip ratio (26.5%)

4. blood lipid level (ratio of ApoB to ApoA) (24.9%)

5. current smoking (18.9%)

6. poor diet (18.8%)

7. cardiac causes (arrhythmia, MI or valvular disease) 6.7%

8. depression (5.2%)

9. diabetes mellitus (5.0%)

10. psychosocial stress (4.6%)

11. alcohol intake >30 drinks per month (3.8%)

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O'Donnell MJ, Xavier D, Liu L, et al. Lancet 2010

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Metabolic Syndrome criteria

• At least when 3 following features are present

1. increased waist circumference (≥102 cm in men; ≥88 cm in women),

2. elevated triglyceride levels (≥150 mg/dL),

3. reduced high-density lipoprotein cholesterol (<40 mg/dL in women; <50 mg/dL in men),

4. elevated blood pressure (systolic ≥130 mm Hg, or diastolic ≥ 85 mm Hg), and

5. elevated fasting glucose (≥100 mg/dL).

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AHA/ASA CRITERIA 2010

JNC 7Classification SBP,

mm Hg DBP, mm Hg

No Compelling Indication With Compelling Indication*

Normal < 120 < 80 No antihypertensive drug No anti HT drug

Prehypertension 120–139 or

80–89 No antihypertensive drug Drugs for compelling indication

Stage 1 hypertension

140–159 or

90–99 Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination

Drugs for compelling indication. Otherdrugs (diuretics, ACEI, ARB, BB, CCB) as needed

Stage 2 hypertension

160 or

> 100 Two-drug combination for most†(usually thiazide-type diuretic and ACEI or ARB or BB or CCB)

Drugs for compelling indication. Otherdrugs (diuretics, ACEI, ARB, BB, CCB) as needed

Compelling indications are (1) CHF (2) MI (3) DM (4) Chronic Renal Failure (5) prior stroke2/28/2011 8

HYPERTENSION (HT)

JNC7 2004

• uncomplicated HT: Thiazide-t-diuretics : alone or combined

• high-risk conditionsthe initial use of other anti-HT drug (ACEi, ARBs, β-blockers, CCB).

• Pts HT will require ≥ 2 anti HTto achieve goal BP<140/90 mmHg, or <130/80 mmHg for pts with DM or chr kidney dis.

• If BP >20/10 mmHg above goal BP initiating therapy with 2 agents, one of which usually should be a thiazide-diuretic.

British Hypertension Society (BHS)and National Institute for Health and Clinical Excellence (NICE) 2006

• Pts aged 55 years and over, or black patients of any age, the

initial therapy should be either

– CCB or a diuretic (thiazide or thiazide-type diuretic e.g. indapamide, chlorthalidone)

• Pts younger than 55 years,

first-choice therapy should be

– ACEi or an ARBs if an ACEi is not tolerated

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Poulter N. Br J Cardiol 2010

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Beta blockers

• beta blockers have negative effects on both glucose/impaired glycemic control and lipid metabolism/ cause dyslipidemia favor weight gain

• β-blockers may have a reduced ability to protect against stroke (particularly atenelol was unable to prevent stroke in HT patients)

• although beta blockers reduce brachial blood pressure effectively, they do not lower central systolic blood pressure as much as ACEi, diuretics, or calcium antagonists,

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Lindholm LH, et al. a new meta-analysis Lancet 2005

Sierra A. Current Drug Therapy, 2006, 1, 9-16

Venkatesh Aiyagari and Philip B. Gorelick. Stroke 2009

CCB & ACEi controversy

• rates of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) in older hypertensive patients were similar in CCB- and ACE-inhibitor–treated patients

• CCBs significantly increased the risk of heart failure

• ACE inhibitors increased the risk of stroke, angina, peripheral artery disease (PAD), gastrointestinal (GI) bleeding, and angioedema. (p>0.0001)(Six-year event rateper 100 persons) CCBs are safer and better tolerated.

2/28/2011 11Leenen F. Hypertension 2006.

Beta blockers & Stroke :The metaanalysis of 13 such trials, a total of 105,951 pts.

• Beta blockers are not as effective as other

antihypertensive drugs in reducing stroke

• Beta Blockers showed

a 16% increased risk in strokecompared with other antihypertensive

drugs and a 3% increase in all-cause mortality.

Outcome (comparing

with other anti HT)

RR with beta

blockers

95% CI

Stroke 1.16 1.04-1.30

MI 1.02 0.93-1.12

All-cause mortality 1.03 0.99-1.08

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Lindholm LH, et al. a new meta-analysis Lancet 2005

Outcome RR with beta blockers

(+diuretic)

95% CI

Stroke 1.09 0.98-1.21

MI 1.00 0.81-1.22

All-cause

mortality

0.97 0.89-1.05

Outcome (comparing

with placebo)

RR with beta

blockers

95% CI

Stroke 0.81 0.71-0.93

MI 0.93 0.83-1.05

All-cause mortality 0.95 0.86-1.04

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Beta blockers

• beta blockers have negative effects on both glucose/impaired glycemic control and lipid metabolism/ cause dyslipidemia favor weight gain

• β-blockers may have a reduced ability to protect against stroke (particularly atenelol was unable to prevent stroke in HT patients)

• although beta blockers reduce brachial blood pressure effectively, they do not lower central systolic blood pressure as much as ACEi, diuretics, or calcium antagonists,

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Lindholm LH, et al. a new meta-analysis Lancet 2005

Sierra A. Current Drug Therapy, 2006, 1, 9-16

Venkatesh Aiyagari and Philip B. Gorelick. Stroke 2009

CCB & ACEi controversy

• rates of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) in older hypertensive patients were similar in CCB- and ACE-inhibitor–treated patients

• CCBs significantly increased the risk of heart failure

• ACE inhibitors increased the risk of stroke, angina, peripheral artery disease (PAD), gastrointestinal (GI) bleeding, and angioedema. (p>0.0001)(Six-year event rateper 100 persons) CCBs are safer and better tolerated.

2/28/2011 14Leenen F. Hypertension 2006.

ANGIOTENSIN RECEPTOR BLOCKERs (ARBs)

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LIVER

KIDNEY

PULMO &

KIDNEY

Arteriole, sympathic

Adrenal, pituitary

AT2 activation upregulation of

the AT2 receptors blood pressure-

lowering, cardiovascular remodelling ,stroke prevention

recruiting cerebral collateral

vessels enhancing neuronal resistance to anoxia, attenuating

prothrombosis, inflammation,

endothelial dysfunction that

mediate atherosclerosis.

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List of ARBs in US

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Trade Name Chemical Name

1. Cozaar (Merck)

2. Hyzaar (Merck)

3. Avapro (Bristol-Myers Squibb)

4. Avalide (Bristol-Myers Squibb)

5. Diovan (Novartis)

6. Diovan HCT (Novartis)

7. Atacand (AstraZeneca)

8. Atacand HCT (AstraZeneca)

9. Teveten (Solvay Pharma Inc)

10. Teveten HCT (Solvay Pharma In

11. Micardis (Boehringer Ingelheim)

12. Micardis HCT (Boehringer Ingelh

13. Benicar (Sankyo Pharma, Inc)

losartan

losartan/hydrochlorothiazide

irbesartan

irbesartan/hydrochlorothiazide

valsartan

valsartan/hydrochlorothiazide

candesartan cilexetil

candesartancilexetil/hydrochlorothiazide

Eprosartan

eprosartan/hydrochlorothiazide

Telmisartan

telmisartan/hydrochlorothiazide

olmesartan

Positive effect of ARB

1. blood glucose control by increasing insulin sensitivityreduced new onset diabetes

2. platelet anti-aggregating effects,

3. hypouricemic effects,

4. atrial antifibrillatory effects.

5. reduces the development of oxidative stress,

6. diminishing activation of inflammatory cells, including monocyte migration and adhesion to endothelial cells

8. may have protective effects for stroke that are independent of blood pressure reduction,

9. antiproliferative,

10. contribute to protect atherosclerosis and atherothrombosis

11. both ACEi and ARBs have been shown to alter factors that promote fibrinolysis and reduce thrombosis

12. encourage plaque rupture by enhancing MMP-1 activity

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Fitchett d.Vascular Health and Risk Management 2007

Townsend RR.Clin J Am Soc Nephrol 2008

Hankey GJ Stroke 2009

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Role & safety of ARB

• patients with HTN with comorbidities, such as HF, MI, DM, chronic kidney disease, and stroke, ACEi and ARBs appear to

provide added benefit beyond solely lowering blood pressure.

• ACEi and ARBs may be beneficial in the prevention of DM, AF, and recurrent stroke.

• A combination of an ARB and an ACE inhibitor may be more effective than either agent alone.

• A meta-analysis of the combination of ACE inhibitors and ARBs vs ACE inhibitors alone found that combination reduced ambulatory blood pressure by 4.7/3.0 mm Hg overall compared with 3.8/2.9 mm Hg for ACE inhibitor monotherapy.

2/28/2011 19(Miller AE et al. Formulary. 2006;41:274–284.)

ARBs and Cerebrovascular Protection

STUDY N TIME/YRS

DRUG STROKE REDUCTION %

LIFE 2002 9193 4.8 losartan/atenolol 26

SCOPE 2002 4964 3.7 Candesartan/placebo 28

MOSES 2005 1405 2.5 eprosartan/nitrendipine 25

PRoFESS 2007 20.332 2.5 Telmisartan/placebo 5

Ontarget 2004 25.620 5 Telmisartan/ramipril 32

VALUE 2004 15 245 4.2 Valsartan/amlodipine -15

ACCESS 2003 500 1 Candesartan/placebo 52

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•Losartan Intervention For Endpoint reduction in hypertension (LIFE) study

•SCOPE:Study on Cognition and Prognosis in the Elderly

•The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study

•Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS)

•Blood Pressure Lowering Treatment Trialists (BPLTC)

•Ongoing Telmisartan Alone and inCombination with Ramipril Global Endpoint Trial (ONTARGET)

•Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary

prevention(MOSES)

The Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC)

• A meta- analysis of 26 trials

• ACE inh reduction in the risk for stroke by 19% , for each 5-mm Hg reduction in BPARBs was 26%.

• There were no significant differences between ARB- and ACE inhibitor- based regimens for blood pressure-dependent effects on stroke.

• there were no significant differences in the effects of ARBs or ACE I on stroke.

2/28/2011 21Lancet 2003; 362: 1527–1535.

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Angiotensin Receptor Blocker

CANDESARTAN

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Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with

isolated systolic hypertension.

• 4964 pts : age 70 to 89 years.

– 1158 patients : systolic BP > 160 mm Hg and diastolic BP was no less than 90 mm Hg. The drug was given to 754 patients and the remainder served as controls.

• The results of the study are interesting. Despite the fact that there was no significant change in blood pressure in the treated group, there was a 42% reduction in stroke.

2/28/2011 23Papademetriou V, et al. J Am Coll Cardiol. 2004;44:1175-1180.

The ACCESS Study

Evaluation of Acute Candesartan Cilexetil Therapy in Stroke SurvivorsJoachim Schrader, MD et al (Stroke. 2003;34:1699-1703.)

• Background and Purpose-to assess the safety of modest blood pressure reduction by candesartan cilexetil in the early treatment of stroke.

• Methods—Five hundred patients were recruited in a prospective, double-blind, placebo-controlled, randomized, multicenter phase II study.

• Conclusions—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. candesartan cilexetil is a safe for early therapeutic option.

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The Candesartan Atenolol Carotid Haemodynamics Endpoint Trial (CACHET) Ariff et al Stroke 2006

• candesartan (8 to 16 mg per day) and atenolol (50 to 100 mg per day) reduced intima-media thickness (IMT) and intima-media area (IMA) and increased distensibility to similar extents after 52 weeks of treat.

• despite similar reductions in BP, treatment with atenolol resulted in a lesser reduction in left ventricular mass index, a decrease in lumen diameter and a reduction in carotid blood flow compared with candesartan. candesartan demonstrated BP-independent effects on ventricular and carotid arterial structure.

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Candesartan Augments Ischemia-Induced Proangiogenic State and Results in Sustained Improvement After Stroke

Anna Kozak, MS et al. (Stroke. 2009; 40:1870-1876.)

Background - acute treatment with candesartan in an experimental

model of stroke resulted in vascular protection and improved outcomes at 24 hours poststroke, (the mechanisms are unknown. )

Conclusion—Candesartan after reperfusion augments ischemia-

induced angiogenic state and provides long-term benefits. The beneficial effects may involve vascular protection and enhancement

of early angiogenic remodeling. (Matrix metalloproteinase-2 activity

and vascular endothelial growth factor expression were higher and cerebrospinal fluid was significantly more proangiogenic)

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SCAST TRIALThe Scandinavian Candersartan Acute Stroke

Sandset EC et al. International Journal of Stroke Oct 2010

• International randomised, placebo controlled, double blind trial

• 2500 pts within 30 hours of stroke SBP > 140 mmHg

• Randomly assigned to candesartan or placebo for 7 days (doses increasing from 4 to 16 mg once daily)

• Follow up period is 6 months

– Study outcomes:

• Functional : mRS

• Vascular death ( MI or stroke)

• Barthel Index

• EuroQol

• MMSE

• Health economy cost

Sandset EC, Bath PMW, Boysen G, et al. Lancet Februari 2011

• trial found no benefit and a hint of possible harm associated with antihypertensive treatment with candesartan in the acute phase of stroke

• the results of 10 previous trials of BP lowering in acute stroke, increase the reliability of the evidence and suggest that pharmacologically lowering blood pressure does not have a beneficial effect.

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STROKEManagement of

Hypertensive Stroke Patients: Recent Updates

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Guidelines for the Prevention of Stroke in Patients With

Stroke or Transient Ischemic AttackA Guideline for Healthcare Professionals From the American Heart

Association/American Stroke Association

Karen L. Furie, MD, MPH, FAHA, Chair et al (Stroke. 2011;42:00-00.)

1. DEFINITION:TIA (old): a

sudden neurological

deficit of presumed

vascular origin lasting

less than 24 hours

2. TIA(new): a transient

episode of neurological

dysfunction caused by

focal brain, spinal cord,

or retinal ischemia,

without acute infarction

Stroke Ischemic have been

defined as1. large-artery atherosclerotic

infarction, (extra/intracranial )

2. embolism from a cardiac

source;

3. small-vessel disease;

4. other determined cause such

as dissection, hypercoagulable

states, or sickle cell disease;

5. Infarcts of undetermined

cause.2/28/2011 30

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• 37 trials involving 9008 pts

• Large fall and increase blood pressures during the acute phase of stroke are associated with a poor outcome

• outcomes were not significantly reduced at any level of change in BP

• Both acute ischemic stroke and primary intracerebral hemorrhage are associated with high blood pressure (BP) in 75% of patients

• Additional BP lowering treatment might be more efficiently started very soon after the stroke (eg, within 6 to 12 hours of onset). Unfortunately there were insufficient data to analyze treatment effects in the hyperacute phase (6 hours). 2/28/2011 31

Relationship Between Therapeutic Changes in Blood

Pressure and Outcomes in Acute Stroke: A MetaregressionChamila M. Geeganage, Philip M.W. Bath (Hypertension. 2009;54:775-781.)

blood pressure changes in acute ischemic stroke

• High blood pressure during acute stroke Autoregulation is lost in the ischemic regionaggravates cerebral edemaprogressive reduction in perfusion pressure, strangulation of the salvageable penumbra, and progressive infarction

– SBP >180 mm Hg doubled the risk of poor outcomes

– SBP < 136 mm Hg increased the risk of poor outcomes by 30%.

– In patients over age > 80 years, a BP reduction > 28 mm Hg gave a 21.7-fold increase in the risk of poor outcomes

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Spence JD. Hypertension 2009

AHA/ASA Guidelines 2011 for Treatable Vascular Risk Factors : Hypertension

PRIMARY PREVENTION( Goldstein LB)

1. the JNC 7 report, including both lifestyle modification and pharmacological therapy, are recommended (Class I; Level A)

2. SBP should be a goal of <140 mm Hg and diastolic BP to <90 mm Hg are associated with a lower risk of stroke and cardiovascular events (Class I; Level A). DM or renal disease, the BP goal is <130/80 mm Hg (Class I; Level A).

SECONDARY PREVENTION(Furie KL)

1. BP reduction is recomm for both prevention of recurrent stroke and other vascular events in persons who are beyond the first 24 hours(Class I; Level A)

2. The optimal drugs are recommended is uncertain. The available data that diuretics or the combination of diuretics and an ACEI are useful (Class I; Level A)

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CLASS I

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AHA/ASA Guidelines 2011 for Treatable Vascular Risk Factors: Hypertension & Diabetes

PRIMARY PREVENTION(Goldstein LB 2011)

• Treatment of hypertension in adults with diabetes with an ACEI or an ARB is useful (Class I; Level of Evidence A).

SECONDARY PREVENTION

(Furie KL 2010)

• Use of existing guidelines for glycemic control and BP targets in patients with diabetes is recommended for patients who have had a stroke or TIA (Class I; Level of Evidence B).

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CLASS I

Guidelines for Treatable Vascular Risk Factors : HypertensionSECONDARY STROKE PREVENTION RECOMMENDATION AHA/ASA 2011

1. Because this benefit extends to persons with and without a documented history of Hypertension, this recommendation is reasonable for all patients with ischemic stroke or TIA who are considered appropriate for BP reduction (Class IIa; Level B)

2. An absolute target BP level and reduction are uncertain and should be

individualized, but benefit has been associated with an average reduction of approximately 10/5 mm Hg, and normal BP levels have been defined as 120/80 mm Hg by JNC 7 (Class IIa; Level B)

3. Several lifestyle modifications have been associated with BP reduction and are a reasonable part of a comprehensive antihypertensive

therapy These modifications include salt restriction; weight loss; consumption of a diet rich in fruits, vegetables, and low-fat dairy products; regular aerobic physical activity; and limited alcohol consumption.(Class IIa; Level of Evidence C)2/28/2011 35

CLASS II

• A meta-analysis of RCTs showed that antihypertensive medications BP lowering is associated with a 30% to 40% reduction in risk of stroke, recurrent stroke or TIA.

• There are excellent clinical outcome trial data proving that lowering BP with several classes of drugs, will reduce the complications of HT

– angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (BBs), Calcium channel

blockers (CCBs), thiazide-type diuretics,

• The choice of specific drugs and targets should be individualized and consideration of specific patient characteristics for which specific agents are probablyindicated (Class IIa; Level of Evidence B).2/28/2011 36

Furie KL et al. AHA/ASA Guidelines for the Prevention of Stroke /TIA .Stroke 2011

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JNC7Suresh,Lip YH. Expert Rev Cardiovasc Ther. 2008

1 HT ALONE ACEi, ARB,BBs,CCBs, Thiazide

2 HT + STROKE ACEIs + thiazide diuretic

3 HT+ DIABETES MELLITUS Thiazide diuretics, BBs, ACEIs, ARBs, and CCBs

4 HT+ RENAL DISEASE ACEIs and ARBs

5 HT+ AF ACEI, ARB

6 HEART FAILURE ACEIs, BBs, ARBs and aldosterone blockers

7 HT+STABLE ANGINA PECTORIS BB, alternative long-acting CCBs

8 HT+ ACUTE CORONARY SYNDR (UNSTABLE ANGINA, MI)

BBs and ACEIs

9 HT+ POST MYOCARD INFARC ACEIs, BBs, and aldosteroneantagonists

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THE BEST CHOICE OF RECOMMENDATION

• IV thrombolytic tx: BP should be lowered if > 185 mm Hg systolic or >110 mm Hg diastolic. After thrombolytic tx, SBP should be kept <180 mm Hg and DBP < 105 mm Hg.

• Anti HT agents should be give : the DBP is > 120 mm Hg or the SBP is > 220 mm Hg and limiting the drop in BP during the first 24 hours by approximately 15%. BP-lowering therapy as soon as 24 hours after acute ischemic stroke

• all major classes of BP-lowering agents may diminish recurrent stroke risk. Although some studies have suggested ACEi and ARBs may be more effective in recurrent stroke prevention than other anti HT drug

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Management of Blood Pressure for Acute and Recurrent

Stroke (Venkatesh Aiyagari and Philip B. Gorelick. Stroke 2009;40;2251-2256)

ARBs Should Be Regarded as First-Line Drugs for Stroke Prevention in Both Primary and Secondary Prevention Settings : No

Martin H. Strauss and Alistair Hall Stroke 2009;40;3161-3162

• In a meta-analysis of ARB versus any active comparator or placebo by these authors (n=53 318, 11 trials), ARB did not reduce stroke (OR, 0.92; 95% CI, 0.79 to 1.08)

• 2 large metaregression analyses (n=45 212, 9 trials; n=39 487, 8 trials), found no blood pressure-“independent” effects of ARB on stroke.

• In 2 major trials this year, ARB compared with placebo had absolutely failed to reduce stroke.

• ARB is not the choice of first-line therapy for prevention of stroke

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ARBs Should Be Regarded as First-Line Drugs for Stroke Prevention in Both Primary and Secondary Prevention Settings : No

Martin H. Strauss and Alistair Hall Stroke 2009;40;3161-3162

• It has been suggested that antihypertensive agents that increase Ang II levels (eg, ARB, dihydropyridine calcium channel blocker, diuretics) are more effective at preventing stroke than those that reduce Ang II levels (eg, angiotensin converting enzyme inhibitor and –β blockers)

• Extensive clinical trials confirm that ARBs have no unique role in the prevention of stroke. If one considers the unique cardiovascular protective benefits of ACEIs, however, the choice of first-line therapy for prevention of stroke is perhaps not a choice at all!

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Hypertension: in Over-50s

• Just Focus on Systolic Pressure

• systolic pressure rises with age, diastolic pressure increases until around age 50 and falls thereafter

• In persons older than 50 years, systolic blood pressure greater than 140 mmHg is a much more important cardiovascular disease (CVD) risk factor than diastolic blood pressure

• international guidelines advocate a target for systolic pressure treatment of below 140 mm Hg, and below 130 mm Hg for patients with diabetes

2/28/2011 41JNC 7

Williams B et al. Lancet 2008;

High dietary salt intake seen to worsen risk of ischemic strokes

• Northern Manhattan Study, "people who consumed more than 4000 mg per day of sodium had more than double the risk of stroke compared with those who consumed less than 1500 mg(AHA)hazard ratio 2.29 (95% CI 1.07-4.92).

• 2657 people from the cohort study (9.7 years)

• US dietary guidelines allow for a greater intake but still recommend that it fall below 2300 mg/day, or about a teaspoon of salt per day.

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Gardener H, Rundek T, Wright C, et al. Dietary sodium intake is a risk factor for incident ischemic

stroke: The Northern Manhattan Study (NOMAS). International Stroke Conference 2011; February

9, 2011

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Government Salt-Reduction Policy

• small reductions (10%) in sodium intake would result in decreases in blood pressure with two approach scenario models

1. the government working with food manufacturers to voluntarily cut sodium in processed foods.

2. scenario would be to create a "sodium tax" on food

– reducing the number of heart attacks and strokeswould save $32 billion in medical costs

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Smith-Spangler CM et al. Annals of Internal Medicine 2010

Frieden TR and Briss PA. Annals of Internal Medicine 2010

Guidelines for the Management of

Spontaneous

Intracerebral HemorrhageA Guideline for Healthcare Professionals From the American Heart

Association/American Stroke Association

The American Academy of Neurology affirms the value of this guideline as an

educational tool for neurologists.

The American Association of Neurological Surgeons and the Congress of

Neurological Surgeons have reviewed this document and affirm its educational

content.

Lewis B. Morgenstern, MD, FAHA, FAAN, Chair et al

(Stroke. 2010;41:2108-2129.)

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AHA/ASA Guidelines for the Management of Spontaneous ICH in Adults

Stroke. 2007;38:2001-2023

• HT may increase the risk ofongoing bleeding fromruptured small arteries andarterioles during the 1st hours.

• High BP is correlated withincreased ICP and volume ofhemorrhage

• overaggressive treatment of BPmay decrease cerebralperfusion pressure (CPP) andtheoretically worsen braininjury

Stroke. 2010;41:2108-2129

• HT could contribute to hydrostatic expansion of the hematoma, peri-hematoma edema, and rebleeding.

• High BP during acute stroke aggravates cerebral edema.

• a systolic BP of 150 to 220 mm Hg, acute lowering of systolic BP to 140 mm Hg is probably safe

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AHA/ASA Guidelines for Treating BP in Spontaneous ICH (class C)-2010

SBP and MAP mmHg TREATMENT 2007/2010

SBP > 200 mm Hg orMAP >150 mm Hg,

consider agressive reduction of BP with continuous IV infusion with frequent BP

monitor every 5 min

SBP > 180 mm Hg orMAP >130 mm Hg

there is the possibility of elevated ICP

Consider monitoring ICP and reducing BP using intermittent or continuous IV

medications is keep CPP >60-80 mmHg

SBP > 180 mm Hg or MAP is 130 mm Hg

there is not evidence of elevated ICP

Consider a modest reduction of BP (eq MAP of 110 mmHg or target BP of 160/90

mmHg) using intermittent or continuous IV medications to control BP, and clinically

reexamine the patient every 15 min2/28/2011 46

IV Anti HT :labetalol, hydralazine,

esmolol, nicardipine, enalapril,

(nitroglycerin, and nitroprusside)

lowering of BP by no more that 20% in

the first 24 hours

AHA/ASA Guidelines for the Management of Spontaneous ICH in Adults

Stroke. 2007

• The recommendation was tomaintain a systolic BP 180 mmHg and/or mean arterialpressure 130 mm Hg. Isolatedsystolic BP 210 mmHg is notclearly related to hemorrhagicexpansion or to neurologicalworsening.

• Reduction in mean arterialpressure by 15% (mean 142 to119 mm Hg) does not result inCBF reduction in humans

Stroke 2010

• systolic BP above 140 to 150 mm Hg within 12 hours of ICH is associated with more than double the risk of subsequent death or dependency

• the goal target of less than 140/90 or less than 130/80 mm Hg for diabetes or kidney disease is "reasonable.“ the BP pressure target, duration of therapy, and whether such treatment improves clinical outcomes remain unclear.2/28/2011 47

Control of elevated blood pressure in acute intracerebral hemorrhage

• The EuropeanStroke Initiative Guidelines recommend a target mean arterial pressure (MAP) of 125 mmHg in patients with a history of hypertension and 110 mmHg in those without a history of hypertension

• The Intensive Blood Pressure Reduction in AcuteCerebral Haemorrhage Trial (INTERACT) : early intensive blood pressure reduction is clinically feasible, well tolerated, and may reduce hematoma expansion in ICH, The relative risk of hematoma expansion was 36% lower (95% confidence interval 0-59%, P = 0.05)

2/28/2011 48Adeoye O. Medicine Reports 2010

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17

2/28/2011 49

Smoking, Hypertension Have Synergistic Effect on Hemorrhagic Stroke Risk

• for every 10-mm Hg rise in SBP, smokershad an additional 15% increase in risk ofhaemorrhagic stroke.

• Nonoptimal blood pressure levels andsmoking are the 2 most common causesof death in the world

2/28/2011 50Nakamura K. Stroke 2008

Hematoma expansion in ICH

• 14-38% of ICHs expand within 24 hrs

• Hypertension may predispose to ICH enlargement

2/28/2011 51

SBP(mmHg) hematome enlargment %

>200 21.5

176-200 14.3

150-175 13.6

<150 8.4

Fuyii et al, Stroke 1998,

Venkatesh Aiyagari and Philip B. Gorelick. Stroke 2009

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18

Hematoma enlargment

2/28/2011 52

AHA/ASA Guidelines for Spontaneous ICH-2010

• In terms of clot removal, that for most patients with ICH, the

usefulness of surgery is "uncertain."

• Pts with cerebellar hemorrhage who are deteriorating

neurologically or brainstem compression and/or hydrocephalussurgical removal of the hemorrhage as soon as possible.(CLASS 1)

• Initial th/ of pts with ventricular drainage alone rather than surgical removal is not recommended (CLASS III)

• For patients presenting with lobar clots of more than 30 mL and within 1 cm of the surface, evacuation of supratentorial ICH by

standard craniotomy might be considered (CLASS IIb)

2/28/2011 53Morgenstern LB et al.Stroke 2010;

Stroke haemorrhage

2/28/2011 54

3 dec 07

21 dec 07

16 jan 08

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19

2/28/2011 55

Brain stem Bleeding

2/28/2011 5611 Juli 200812 agustus 2008

THE END

2/28/2011 57

• Hasan Sjahrir

• Department of Neurology

• Sumatera Utara University

• Medan

• http://neurologi.usu.ac.id