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Secondary Stroke Prevention
Dr Mehool Patel
Consultant Physician in Stroke & Elderly Medicine
Lewisham Healthcare NHS Trust
Lewisham, LONDON SE13 6LH
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