Secondary Stroke Prevention

Dr Mehool Patel

Consultant Physician in Stroke & Elderly Medicine

Lewisham Healthcare NHS Trust

Lewisham, LONDON SE13 6LH

mehool.patel@nhs.net

Lewisham Healthcare NHS TrustLewisham LONDON SE13 6LH

OBJECTIVES Risk Factors for stroke

Secondary Stroke Prevention:

- TIA assessment

- Anti-platelet therapy after stroke

- Hypertension after stroke

- Cholesterol after stroke

- Warfarin & newer kids on the block!

STROKE 50 years ago !!!

HISTORY Stroke EXAMINATION Stroke

MANAGEMENT Prayers Will

STROKE 17 years ago !!!

HISTORY Stroke EXAMINATION Stroke

MANAGEMENT Prayers Will

Stroke care is a national priority!! 1999 National Clinical Guidelines for Stroke

National Sentinel Audit - RCP

2001 NSF for older people (5)

2005 National Audit Office report

2007 National Stroke StrategyMending hearts & brains - Roger Boyle

2008 HfL Stroke project

Stroke is a medical emergency!

‘Brain attack’ ‘Time is brain’

Faster Assessment & Investigations

Acute medical treatment

Immediate secondary prevention

Recognition & management of complications

Risk Factors Inherited

Behavioural

Physiological

Risk Factors-InheritedFactor

Age 55-64 vs 75+

Male

Family history

Black

RR

5

1.3

2.3

2.2

Stroke and age

Age specific rates per 1,000 population

0

5

10

15

20

25

<45 45-54 55-64 65-74 75-84 >84

Age group

rate

per

1,0

00

Erlangen 1.48London 1.14 P<0.001Dijon 0.93

Stroke & Ethnicity

Risk Factors- Behavioural

Factor

RR AR

Obesity 1.3

Physical inactivity 2.5

Hypercholesterolaemia 2.9

Acute Alcohol 5

Smoking 1.5 0.37

Risk Factors - Pathological

Factor

RR AR

Hypertension 7 0.8

Cardiac disease 3 0.1

AF 3 – 7 0.24

TIA 5-13 0.15

Diabetes Mellitus M 4.1 0.18

F 5.8 0.22

Homocysteinaemia 1.3 – 2.8

Stroke

Smoking

Excess alcoho

l

High blood

pressure

Diabetes

Family histor

y

High cholester

ol

Coronary artery

disease

Previous stroke/TIA (5-

13x)

Atrial fibrillatio

nAge

Secondary Stroke Prevention

Future risk can be predicted using lifestyle and clinical markers:

Any combination of these risk factors raises risk of further cardiovascular events considerably

Existing diseaseDiabetes

CKDStroke/TIA

PAD

Non-modifiable AgeGenderEthnicityFamily history

Modifiable Smoking

ObesityHypertension

LipidsGlycaemic control

Stress

Joint British Societies Guidelines on prevention of cardiovascular disease in clinical practice. Heart. 2005; 91 (Suppl V)

Managing the multivascular patient

MANAGING RISK FACTORS

TIA

Oxvasc Study

BMJ. 2004;328(7435):326.

High risk TIA: ABCD2 ruleABCD risk stratification to identify stroke risk

Age > 601

Bpressure >140/90 1

Clinical weakness 2speech 1

Duration > 60 min 210-59 min 1

<10 min0

Diabetes1

Risk stratification: ABCD2

Score % risk of stroke within 2 weeks

1 02 0

3 04 1

512% 6-7

31%

>3 admit Higher risk do present early after TIA Admit TIA on anticoagulants

MANAGING RISK FACTORS

Anti-platelet agents

Platelet Inhibition Pathways

ADP Pathway

TXA2 PathwayTXA2

TXA2 Receptor

ADP

ADP Receptor PLATELETPLATELET

Clopidogrel:Inhibits ADP platelet aggregation pathway

Clopidogrel:Inhibits ADP platelet aggregation pathway

CC

COXAspirin:

Inhibits thromboxaneA2 platelet

aggregation pathway

Aspirin:Inhibits thromboxane

A2 platelet aggregation pathway cAMP Pathway

PhosphodiesterasePhosphodiesterase

Dipyridamole: Inhibits

phosphodiesterase induced cAMP

release

Dipyridamole: Inhibits

phosphodiesterase induced cAMP

release

Trials of all antiplatelet agents

*Vascular events = myocardial infarction, stroke or vascular death1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86

Category % odds reduction

Acute myocardial infarction

Acute stroke

Prior myocardial infarction

Prior stroke/transient ischemic attack

CAD (e.g. unstable angina, heart failure)

PAD (e.g. intermittent claudication)

Risk of embolism (e.g. atrial fibrillation)

Other (e.g. diabetes)

All trials

1.00.50.0 1.5 2.0

Control betterAntiplatelet better

Aspirin (ASA) 75-150mg is effective in preventing cardiovascular events

Mechanisms for Aspirin ‘failures’

Non-atheromatous causes: embolism / arteritis

Reduced bioavailability of aspirin: - non-compliance

- concurrent NSAID preventing access to CXO site

Alternative pathways of platelet activation: - AdP, epinephrine, thrombin receptors, collagen

stimulation - increased platelet sensitivity to collagen and AdP

turnover of platelets: bone marrow production in response to stress e.g. CABG and introducing new platelets

Genetic polymorphisms: platelet glycoprotein receptor (Ia/IIa, Ib/V/IX and IIb/IIIa), vWf receptor, CXO-I, CXO-2, tXA synthase

CAPRIELancet 1996; 348: 1329–1339

19185 Stroke/MI/PVD MC,R: Aspirin (325) vs Clopidogrel (75) Composite: stroke/MI/vascular death 9.8% vs 10.7 % (RR 0.92, 95% CI: 0.85-1.00) Subgroup analyses: only PVD significant GI haemorrhages lower

ESPS-2J Neurol Sci 1996;143:1-13

MC, R: 6602 TIA or stroke in preceding 3 mths

Aspirin (50) vs Dipyridamole (400) vs A+D vs placebo

3 primary outcomes: Stroke, death, stroke + death

Aspirin more effective than placebo (18.1% reduction in stroke)

No difference between aspirin vs Persantin alone Incidence of stroke in favour of A+D

9.5% vs 12.5% (RR 0.76; 0.63-0.93)

ESPRITLancet 2006;367:1665-73

Aspirin vs Aspirin + Dipyridamole 2739 patients with TIA/Stroke Outcome: composite of first occurrence of:

- vascular deaths - non-fatal stroke

- non-fatal MI- major bleeding

complication

173 (13%) [A+D] vs 216 (16%) [A] (hazard ratio 0.80; ARR 1.0%/ year).

Considerations of ESPRIT and ESPS2

ESPRIT1

For 50% of patients in the ESPRIT study aspirin dose was 50mg or below

Dropout rates in the combination arm were high at 34%, primarily due to adverse events particularly headache. The dropout rate in the aspirin only group was 13%

ESPS22 Aspirin dose in the ESPS2 study of dipyridamole and

aspirin in the secondary prevention of stroke does not reflect UK practice: a 25mg bd dose of ASA monotherapy was used, which is below recommended UK guidelines3,4

References:1. ESPRIT Study Group. Lancet 2006;367:1665–16732. Diener HC et al. European Stroke Prevention Study 2. J Neurol Sci 1996;143:1-133. Royal College Physicians. National clinical guidelines for stroke. 2nd edition, 20044. NICE TA 90. May 2005

Sudlow, C. BMJ 2007;334:901

Meta-analysis of randomised trials of aspirin plus dipyridamole versus aspirin alone in patients with a prior ischaemic stroke or transient ischaemic attack (outcome: stroke, myocardial infarction, or vascular death) (adapted from the ESPRIT Study Group5)

Review on A + DSudlow, C. BMJ 2007;334:901

Pooled analyses shows benefit post-stroke

Adding D to A prevents 1 death in 100 pts /yr

Discuss with patient regarding:- above advantage

- adverse effects esp headaches and GI effects - inconvenience of pills

ANTITHROMBOTICS

Aspirin 300mg od for 2 weeks IST &

CAST

Followed by:

Clopidogrel 75 mg od Or

Aspirin 75 mg od + Dipyridamole Retard 200mg bd (for 2 years) ESPS2 + ESPRIT 2 (NICE recommendation)

Patients intolerant of Aspirin or ‘Aspirin’ failures: Clopidogrel 75mg od

MANAGING RISK FACTORS

Hypertension after stroke

British Museum: History of Medicine

Adapted from National Statistics Health Survey for England 2006; 1 (3): 1-25

0

10

20

30

40

50

60

70

16-24 25-34 35-44 45-54 55-64 65-74 >75

Age Group (Years)

Pre

va

len

ce

(%

) Men

Women

Prevalence of Hypertension (Health Survey of England, 2006)

Base: Aged 16 and over with three valid BP measurements

Individuals aged 40-70 years, starting at BP 115/75 mmHg

Adapted from Lewington S et al. Lancet 2002; 360: 1903-1913

CVmortality

risk

SBP/DBP (mmHg)

0

1

2

3

4

5

6

7

8

115/75 135/85 155/95 175/105

1

2

4

8

Hypertension increases CV mortality risk

Doubles with each 20/10 mmHg BP increment

RULE OF HALVES - 1

Only ½ of all hypertensives are aware of their condition

RULE OF HALVES - 2

Of those aware of hypertension, only ½ are on treatment

RULE OF HALVES - 3

Of those on treatment, only ½ are adequately controlled

Hypertension & Stroke Common AR 0.8

IST 82%: SBP > 140CAST 75%

40% Already on Rx

Hypertension associated with poor outcome

No agreed consensus

Hypertension after Acute Stroke : Reasons for no intervention

Natural history: reduction over 4-10 days

Dynamic cerebrovascular auto-regulation impaired

Consequences on ischaemic penumbral viability

Impaired Autonomic nervous system - impaired physiological response to systemic BP changes

Impairment of baroreceptor reflexAge & Ageing 2004;33:6-12

Hypertension after Acute Stroke: Reasons for intervention

Sustained BP increases haemorrhagic transformation

IST: SBP>150 10mm:4.2% early recurrence

Acute Stroke: Observational studies

Both high & low BP poor short-term prognosis

Others: No relationship

IST U-shaped relationship between BP & short-term mortality / long-term

outcomes 150

Acute Rx: Interventional studies

ACE inhibitors: Captopril & perindropril: No effect PROGRESS (med 8 mths: interquartile 2-21 mths) HOPE ? 3 months; no clear definition of no.

B BlockersNo diff. at 6 mths with propranolol ? some effect with labetalol

Ca cha. block.47 trials! No benefitINWEST - nimodipine: deleterious

Nitrates clinical use not established

Recent trials

CHHIPS : Control of Hypertension & Hypotension Immediately post-

stroke

ENOS:Efficacy of NO in Stroke

COSSACS:Continue Or Stop post-Stroke Antihypertensives Collaborative Study

Managing Hypertension after stroke

Is there HOPE for PROGRESS after LIFE?

HOPE- Heart Outcome Prevention Evaluation Study

9267 patients were randomised to Ramipril vs. placebo; >55 with one vascular disease or diabetes + one CV risk factor

32% stroke over 4 yrs

N Engl J Med. 2000 Jan 20;342(3):145-53.

PROGRESS

Perindopril protection against recurrent stroke study

• Perindopril + indapamide

• 43% recurrent stroke

• 40% major vascular events

• No significant benefit of agent given alone

• Overall stroke risk reduction due to BP

Lancet. 2001 Sep 29;358(9287):1033-41

LIFE

Losartan Intervention for Endpoint Reduction in hypertension study

• 9193 hypertensives with LVH

• Atenolol vs. Losartan : 4 years.

• No difference in BP

• 25% stroke risk with Losartan

How low is low enough? Which one do you use?Lancet 2002 Mar 23;359:995–1003

Practical prescribing

Hypertension after acute stroke

Anti-hypertensive therapy continued

New anti-hypertensive therapy after 10-14 days

Treat very high BP e.g. 220/120 urgently

A B C D

A C D

MANAGING RISK FACTORS

Statins

Cholesterol and Stroke

LIPID Pathophysiology LIPIDS: cholesterol, triglycerides, cholesterol esters

Cholesterol uses: Steroids, Vitamin D, phospholipid layer: cell m.

LIPOPROTEINS: vascular lipids

Chylomicrons Lipoprotein lipase deficiencyVLDL Familial hypertriglyceridaemiaIDL HypobetalipoproteinemiaLDL Familial hypercholesterolemia

Combined hyperlipidemiaHDL

(good)

Copyright ©2005 American College of Cardiology Foundation. Restrictions may apply.

Ray, K. K. et al. J Am Coll Cardiol 2005;46:1425-1433

LIPIDS & STATINS: Molecular pathway

Statins: CVD prevention Ameliorate endothelial dysfunction

Suppress inflammatory response shown by reduction of inflammatory cells in atherosclerotic plaque

Stabilise plaques; inhibit cholesterol accumulation on macrophages & inhibit smooth muscle cell proliferation

Reduce platelet aggregation and thereby reduce thrombus formation

Limit recurrent MI, thereby prevent LV dysfunction, minimising cardioembolic stroke.

Statins after Stroke - SSSS

- WOSCOPS- CARE- LIPID

Chol >5.0 and IHD

- MRC BHP studyNormal cholesterol

Statins & Stroke Heart Protection Study

DBPC RCT: 20, 536 CHD/Stroke/PVD ‘Strokes without CHD’

Statins + anti-oxidant vitamins

3286 Strokes CHD (1820 without CHD) 25 % reduction in ischaemic strokes

No difference in haemorrhagic strokes

Simvastatin prevents vascular events independent of pretreatment cholesterol, TG, age, sex, smoking or treatment of hypertension

CAUTION - STATINS Caution in our clinical practice?

• Side effects of Statins

• Costs

• High risk patients vs population Rx

• J shaped relationship with stroke• Relative risk reduction

STATIN ‘failures’

RR with Statins about 30%

50% of CVD pts have normal cholesterol - LDL C

HDL would thus have a role in CVD prevention

MANAGING RISK FACTORS

Warfarin in Atrial Fibrillation

Implications of AF in stroke

Incidence of stroke attributed to AF:• 1.5% at 50-59 yrs• 23.5% at 80-89 yrs

Stroke patients AF associated with:• Increased length of inpatient stay• Lower rate of discharge home

CHADS 2 score Congestive cardiac failure (any Hx) 1 Hypertension (prior Hx) 1 Age > 75 1 Diabetes mellitus 1 Secondary prevention: previous stroke/ TIA

(or systemic emboli) 2

• Low risk = 0

• Intermediate risk = 1-2

• High risk = 3 or more

BALANCE RISK vs BENEFIT

Warfarin after Stroke No overall benefit in acute stroke (heparin)

- Increase risk of haemorrhagic transformation!

Consider WARFARIN if AF after two weeks:confusion

falls bleeding

conditions practical feasibility

Discussion / Documentation of risk/benefit

Newer anticoagulants on the block!

Warfarin: - narrow therapeutic index

- variable pharmacodynamics & pharmacokinetics - dose monitoring

- drug and food interactions (lifestyle implications)

Dabigatran (licensed) 150 / 100 mg bd

Apixaban and Rivaroxaban

Investigations – secondary prevention

Blood testsFBC, ESR

U&E, Blood glucose, LFT, Lipid profile? Clotting screen & Thrombophilia screen

? Autoantibodies: anticardiolipin? Lupus anticoagulant & Sickle cell

? Homocysteine

ECG and ? CXR Brain imaging (CT or MRI + MRA) Carotid artery imaging (U/S or Angiography)

Echocardiography (TTE / ?TOE) 24 hour tape

What have you learnt? Risk Factors for stroke

Early TIA assessment

Anti-platelet therapy after Stroke

Hypertension after stroke

Cholesterol after stroke

Warfarin and new kids on the block!

“it is the duty of the physician to explain to the patient, or to his friends, that the condition is past relief, that medicines and electricity will do no good, and that there is no possible hope of cure”

William Osler