Hypertension and CVA

Dr PS Deb MD, DM

Director Neurology Guwahati Neurological Research Center, Assam

Hypertension

CVA

Hypertension

Hypertension and Stroke (WHO 2013)

Hypertension and Stroke (WHO 2013)

Diastolic BP as Risk Factor of Stroke (< 1990)

Diastolic BP as Risk Factor of Stroke (< 1990)

5 mm

Hg

7.5 m

mHg

10 m

mHg

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Stroke Prevention MacMohan

Stroke Prevention

Systolic BP as Risk factor for Stroke (>1990)

Systolic BP was more strongly correlated with 12-year risk of stroke mortality than diastolic BP in Framingham Heart Study

Prospective population based Copenhagen City Heart study also reported systolic BP is a better predictor of stroke than diastolic

Asia Pacific Cohort Studies Collaboration analyzing 37 cohort studies reported a continuous, log-linear association between systolic BP and risk of stroke down at least 115 mmHg.

After a 10 mmHg decrease in systolic BP was associated with a 41% lower risk of stroke in Asia and a 30% in Australia

Age and Stroke with Hypertension

Elevated BP and risk of stroke is weaker in older age compared to middle age

The Asia Pacific Cohort Studies Collaboration (APCSC)

Treating BP is still important due to increased incidence of stroke with aging.

Below 60

60-6

9

Above

700

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Stroke after 10mmHg Decrease of Systolic BP

Stroke Prevention

Pathogenesis of Stroke due to Hypertension

1. Large vessel Atherosclerosis

2. Medium vessel Arteriosclerosis

3. Small Vessel Lipohyalanosis

4. Cardioembolic stroke

Cerebral Ischemic Stroke

Normal flow, normal function

Synaptic transmission failure

Membrane pump failure

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50

10

0Time in hours

CB

F (

ml/1

00g

brai

n)

Low flow, raised O2 extraction, normal function

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Cerebral Autoregulation

Dys-autoregulation after Ischemic Stroke

Dys-autoregulation after Ischemic Stroke

Blood Pressure in Acute Ischemic Stroke

Systolic blood pressure on arrival at Emergency

• >139 mm Hg in 77%• >184 mm Hg in 15%.

The blood pressure is often higher in acute stroke patients with a history of hypertension

Blood pressure decreases spontaneously within 90 minutes after onset

BP control in Acute Ischemic Stroke

Is lowering of BP harmful?

Yes Is raising BP beneficial?

Yes

No

No What class of drug?

CC Blocker

AB Blocker

Vasodilators

Is lowering BP is harmful? Yes

Autoregulation is defective in acute ischemia but it is time dependent.

Oxygen extraction compensate to a point

BP control hamper perfusion of penumbra region

Lowering BP below >10-15% is potentially harmful

Hypertensive patient shows more significant decrease in MBP after induced hypotension than hypertension

Oral Nimodipine in acute ischemic stroke

A placebo-controlled randomized trial tested oral Nimodipine starting within 48 hours after ischemic stroke onset in 350 patients.

The systolic and diastolic blood pressures were both significantly lower in the Nimodipine group.

Functional outcome at 3 months was similar in the 2 treatment groups, but mortality was significantly higher in the Nimodipine group

Intravenous Nimodipine West European Stroke Trial (INWEST)

Nimodipine as cytoprotective therapy within 24 hours after ischemic stroke onset and found complications related to blood pressure lowering

Decrease in blood pressure was associated with intravenous Nimodipine therapy and worse clinical outcome at 21 days.

A decrease in diastolic blood pressure >10 mm Hg, but not in the systolic pressure, was significantly associated with worse outcome

Candesartan in Acute Stroke

An efficacy trial (n=2004) of candesartan showed a mean blood pressure reduction of 7/5 mm Hg at day 7

Favorable outcomes at 6 months, were less likely with candesartan than with placebo.

The Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS)

Patients were enrolled within 48 hours of stroke onset and the last dose of antihypertensive medication and were maintained in the 2 treatment arms for 2 weeks.

The study was terminated prematurely; however, continuation of antihypertensive medications did not reduce 2-week mortality or morbidity and was not associated with 6-month mortality or cardiovascular event rates.

Is lowering BP in AIS harmful? No

Defective autoregulation may not be present in all patients

Ischemic penumbra may not be present in all patients

Clinical experience indicates that many patients tolerates gentle treatment of high BP

Natural history studies demonstrate no deleterious effects of lowering BP

High BP at onset has poor prognosis

Hypertension during acute ischemic stroke

Extreme hypertension -> Encephalopathy, Cardiac complication, renal insufficiency

Moderate arterial hypertension during acute ischemic stroke might be advantageous by improving cerebral perfusion of the ischemic tissue

It might be detrimental by exacerbating edema and hemorrhagic transformation of the ischemic tissue

Candesartan in Acute Stroke

Starting an average of 30 hours after ischemic stroke onset in 342 patients with elevated blood pressure.

Blood pressure and the Barthel index score at 3 months were similar in the 2 study groups,

Patients who received the active drug had significantly lower mortality and fewer vascular events at 12 months.

Is Raising Blood Pressure in Acute Ischemic Stroke Beneficial? Yes

Is Raising Blood Pressure in Acute Ischemic Stroke Beneficial? Yes

Is Raising Blood Pressure in Acute Ischemic Stroke Beneficial? No

Is Raising Blood Pressure in Acute Ischemic Stroke Beneficial? No

Other problem of raising BP

Increase risk of ICH after lytic therapy

May increase amount and formation of cerebral edema

A 12% increase in terms of size of infarction.

May adversely affect cardiac function

Optimal BP during acute ischemic stroke

Extreme arterial hypotension is clearly detrimental, because it decreases perfusion to multiple organs, especially the ischemic brain, exacerbating the ischemic injury.

An ideal blood pressure range has not yet been scientifically determined for individual patient.

An ideal blood pressure range during acute ischemic stroke will depend on the stroke subtype and other patient specific co-morbidities.

Recommendation (AHA 2013)

1. Not for thrombolysis > 220/120 mmHg,

2. For Thrombolysis >185/100 mmHg

3. Severe cardiac failure, Aortic dissection, Hypertensive encephalopathy

4. Cautious blood pressure lowering when (IV Labetalol, IV Enalepril, Nitrendepine) avoid venodilators

When to Temporary discontinuation of AHT?

Because swallowing is often impaired, and responses to the medications may be less predictable during the acute stress.

When to Re-start Antihypertensive Therapy

After the initial 24 hours from stroke onset in most patients.

Individualize such therapy based on relevant co-morbidities, ability to swallow.

Hemorrhagic Strokes

Hypertension

ICH

Hypertension

Early hemorrhage growth in patients with intra-cerebral hemorrhage.

Time in Hours

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Hematoma Expansion

0-3 hr03-6 hr16-12 hr212-24 hr24-48 hr

Time

Num

ber

Elevated Systolic Blood Pressure May Predispose to Hematoma Enlargement

BP >200 BP <2000

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.Hematoma Enlargement

Hematoma volume and outcome

Type ICH Vol. mL Coma Prognosis

I < 30 - Good

II 30-60 - Fair

III 30-60 + Poor

>60 +

(Joseph P. Broderick et al Stroke 1993;24:987-993)

Is there Risk of treating Acute Hypertension?

How to treat Hypertension in ICH?

When should we treat Hypertension

What is the target mean arterial pressure for patients with intracerebral hemorrhage (ICH)?

Do we want to be aggressive or conservative?

What should first-line therapy be: beta blockers or calcium-channel blockers?

What should the duration of intravenous (IV) therapy be: 24 hours or 72 hours?

Primary aim

Primary aim

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Protocol schema: from INTERACT1 (Lancet Neurol 2008) and (Int J Stroke 2010)

Acute spontaneous ICH confirmed by CT/MRI

Definite time of onset within 6 hours

Systolic BP 150 to 220 mmHg

No indication/contraindication to treatment

In-hospital vital signs, NIHSS, GCS and BP over 7 days

Intensive BP lowering SBP <140 mmHg

Standard BP management Guidelines SBP <180 mmHg)

R

34

Acute spontaneous ICH confirmed by CT/MRI

Definite time of onset within 6 hours

Systolic BP 150 to 220 mmHg

No indication/contraindication to treatment

N=2800 gives 90% power for 7% absolute (14% relative) decrease (50% standard vs 43% intensive) in outcome

Patient Flow – 2839 patients recruited October 2008 to August 2012

1382 (98.5%) for primary outcome

1412 (98.3%) for primary outcome

2839 Randomised

28,829 Total estimated screened

3 no consent 1 missing baseline data 2 lost to follow-up 3 withdrew consent12 alive without mRS data

Reasons for exclusion (n=3572) 39% Outside time window 16% Judged unlikely to benefit 11% BP outside criteria 8% Planned early surgery 5% Refused 21% Other reasons

6411 Screening logs completed

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1403 Intensive BP lowering

1436 Standard BP lowering

5 no consent1 missing baseline data5 lost to follow-up4 withdrew consent9 alive without mRS data

Systolic BP time trends1 hour - Δ14 mmHg (P<0.0001)6 hour - Δ14 mmHg (P<0.0001)

Systolic BP controlMedian (iqr) time to treatment, hr - intensive 4 (3-5), standard 5 (3-7)

Intensive group to target (<140mmHg)462 (33%) at 1 hour731 (53%) at 6 hours

Mea

n S

ysto

lic B

loo

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g)

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R 15 30 45 60 6 12 18 24 2 3 4 5 6 7

StandardIntensive

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Minutes Hours Days / Time

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139

am pm am pm am pm am pm am pm am pm

P<0.0001beyond 15mins

Target level

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safe - no increase in death or harms

• secondary analyses - improved recovery of physical functioning and health-related quality of life in survivors

effective – borderline significant effect on the primary endpoint

Early intensive BP lowering treatment is

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Treatment effect smaller (4%) than expected 7% absolute, but:

• active-comparison study on background therapies, some with BP lowering properties (i.e. mannitol)• equates to NNT 25 (greater than aspirin and near late use of rtPA in ischaemic stroke)

No clear time-dependent relationship of treatment

• potential mechanisms beyond haematoma growth• benefits of BP control may take several hours to manifest• effects on haematoma growth and other results outlined in Symposium this afternoon

INTERACT2 - issues

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INTERACT2 resolves longstanding uncertainty over the management of elevated BP in acute ICH

Provides evidence regarding safety and efficacy in a broad range of patients with ICH

Defines for the first time a medical therapy for the management of acute ICH

As BP lowering treatment is low cost, simple to implement, and widely applicable, the treatment should become standard of care to patients with ICH in hospitals all over the world

Conclusions

39

Baseline

24 hrs

SBP<180 mm Hg

SBP<140 mm Hg

3 m

Recommendation AHA 2010

Hypertension is common during early states of ICH -> Expansion, Peri-hematoma edema and re-bleeding

A 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.

Association of low BP and deterioration is not consistent like ischemic stroke.

In patients presenting with a systolic BP of 150 to 220 mm Hg, acute lowering of systolic BP to 140 mm Hg is probably safe

• Class IIa; Level of Evidence: B

When to initiate oral antihypertensive medication?

After first 24-48 hours

Subarachnoid Hemorrhage

Subarachnoid Hemorrhage

Hypertensive Encephalopathy

When high perfusion pressure overwhelms cerebral autoregulation.

Can lead to blindness, seizures, coma, gradually worsening headache.

Pathologically-cerebral edema, petechial hemorrhg, microinfarcts.

Immediate Neuroimagng - to rule out ischemic stroke/hemorrhage

Hallmark is improvement in 12-24 hrs of BP redn.

HTN ENCEPH… DIFFN POINTS

Focal neurological deficit is unusual without cerebral bleed

Papilledema is almost always assoc with Htn enceph

Mental staus improves by 24-48hrs-delayed in CNS bleed

Brain dysfunction develops by 12-24 hrs in Htn but more acutely with ischemic stroke/bleed.

Posterior Reversible Encephalopathy Syndrome (PRES)

HTN ENCEPH…Treatment

short acting parenteral agents used.

MAP should decrease by 15-20% over 2-3 hrs. .

Prevention of Stroke - Trials

Diuretics CCBs ACE-I ARBs

ALLHAT (JAMA 2002)

ALLHAT (JAMA 2002)

HOPE ( ACCESS (Stroke 2003)

ASCOT (Lancet 2005)

PROGRESS (Lancet 2002)

MOSES (Stroke 2006)

Long term control of Hypertension following stroke

reduces recurrence of stroke

BP Control as Primary Prevention of Stroke

Both lifestyle modification and pharmacological therapy, are recommended (Class I; Level of Evidence A)

Systolic BP should be treated to a goal of <140 mm Hg and diastolic BP to <90 mm Hg because these levels are associated with a lower risk of stroke and cardiovascular events (Class I; Level of Evidence A).

In patients with hypertension with diabetes or renal disease, the BP goal is <130/ 80 mm Hg (also see section on diabetes) (Class I; Level of Evidence A).

Cerebral Small Vessel Disease (SVCD)

Incidence: 20-25% of Small vessel Infarcts (SVI) lacunar infarcts Short term better prognosis but not long term

Cerebral Microbleeds (CMBs)

MRI – 4.7% - 24.4% in community Ischemic stroke 19.4% Hemorrhagic stroke: 68.5% Lobar distribution in Amyloid Angiopathy Basal and Infratentorial in Hypertensive Vasculopathy Hypertension, Diabetes and Low serum Cholesterol as predisposition

A gradient-recalled echo and B susceptibility weighted imaging maps. Susceptibility-weighted imaging is more sensitive than gradient-recalled echo to venous structures.

THANKS