12th October 2004GP lecture Series1 Primary and Secondary Prevention of Ischaemic Stroke David Hargroves, SpR in Stroke Medicine, SW Thames.

12th October 2004 GP lecture Series 1

Primary and Secondary Prevention of Ischaemic Stroke

David Hargroves,

SpR in Stroke Medicine,

SW Thames.


Incidence & Mortality

Developing64%

Developed12%

Transition24%

Third commonest cause of death

3% of world’s disability

Each year in England & Wales 110,000 suffer their first stroke.


Incidence

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


Primary Prevention

• Modifying Vascular risks *–Hypertension

–Hyperlipidaemia

–Hyperglycaemia

–Smoking

–Alcohol

*Warlow, C., C. Sudlow, et al. (2003). "Stroke." Lancet 362(9391): 1211-24.

Exercise

Weight reduction

Lower salt intake


Primary Prevention

• Identify those most at risk and treat aggressively* .–Diabetic patients.

–Previous vascular disease.

–Continued smokers.

*Weih, M., J. Muller-Nordhorn, et al. (2004). "[Risk factors in ischemic stroke. Review of evidence in primary prevention]." Nervenarzt 75(4): 324.


Deciding exactly what an individuals risk is

The estimated 10 yr. risk of CAD in a hypothetical 55yr old man and women according to levels of various risk factors. Lipids in units of mg/dl.

Wilson,P.W. (1994) Am. J. Hypertension; 7:75.


Hypertension

Arterovascular benefit from treating mild to moderate hypertension from 17 controlled studies. CAD reduced by 16% and Stroke by 40%. Absolute benefit slightly less ( numbers above graphs). Treatment for approximately 4-5 yrs prevented a CAD event or stroke in 2% of patients; preventing death in 0.8% patients.

Herbert, P.R. et al (1993), Arch Intern Med; 153:576.


Cumulative incidence of cardiovascular events over time in 6859 men and women who were initially free of hypertension and cardiovascular disease. High/ normal BP compared to optimal BP was associated with an adjusted hazard ratio for cardiovascular disease of 1.6 in men and 2.5 in women.Vasan, R.S. et al (2001), N Engl J Med; 345:1291.

Framingham Heart Study results:

High/normal <139/89

Normal <129/84

Optimal < 120/80


Primary Prevention

• Persistently elevated BP> 160/100 if no other risks.

• Persistently elevated BP>140/90 if raised cardiovascular risk.

NICE guidelines 18, Newcastle group (2004)

Hypertension


Primary Prevention

NICE guidelines on Hyperlipidaemia and cardiovascular risk 2004 still pending

Hyperlipidaemia

A practice decision based upon a cost/ risk local analysis.


Primary Prevention

• HbA1c < 7.5% if at risk of microvascular disease and < 6.5% if at risk of vascular disease *

*NICE guidelines (Excellence, N. I. f. C. (2004). Diabetes.)

Hyperglycaemia


Diabetic Patients


Secondary Prevention

• Antiplatelet agents

• Anticoagulation

• Carotid Surgery

• Modification of vascular risk factors


Antiplatelet therapy

• Start 300 mg aspirin daily for 7-10 days

• Ideally after brain imaging

• Reduce 75mg thereafter

• Avoids death or disabling stroke in 1 in 100 pts

RCP guidelines (I. S. W. Party (2004). national clinical guidelines for Stroke - 2nd edition, Royal College of Physicians.)


Antiplatelet Trialists’ Collaboration

Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106

Priorstroke/TIA

Acute MI

Pat

ient

s w

ith s

troke

, MI,

orva

scul

ar d

eath

(%)

25

20

Antiplatelet therapyControl

15

10

5

0Prior MI Other

high riskAll

high risk

22% odds reduction

29% oddsreduction

25% oddsreduction

32% oddsreduction

27% oddsreduction


Dipyridamole Plus Aspirin vs. Aspirin in Patients with Vascular Disease (15 trials)

Nonfatal MI

Nonfatal Stroke

Vascular Death

All Vascular Events

Nonvascular Death

Total Deaths

215

465

545

1188

214

750

% OddsReduction

-4

23

-3

10

-14

-6

No. of Events

0.50 0.75 1.00 1.25 1.50

Aspirin Alone Better

Dipyridamole Plus Aspirin Better

Odds Ratio and 99%Confidence Interval


CAPRIE StudyCAPRIE Study

Efficacy of Clopidogrel Bisulfate in Primary AnalysisEfficacy of Clopidogrel Bisulfate in Primary AnalysisMI,MI, IschemicIschemic Stroke, or Vascular DeathStroke, or Vascular Death

Months of FollowMonths of Follow--UpUp

Cum

ulat

ive

Eve

nt R

ate,

%C

umul

ativ

e E

vent

Rat

e, %

00

44

88

1212

1616

00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636

5.83%5.83%

ClopidogrelClopidogrel

AspirinAspirin

5.33%5.33%

Overall Overall RiskRisk

ReductionReduction

8.78.7%%**

Event Rate per YearEvent Rate per Year

P P = 0.045= 0.045

Although the statistical significance favoring PLAVIX (clopidogrAlthough the statistical significance favoring PLAVIX (clopidogrel bisulfate) over aspirin was marginal (el bisulfate) over aspirin was marginal (PP = 0.045),= 0.045),and represents the result of a single trial that has not been reand represents the result of a single trial that has not been replicated, theplicated, the comparatorcomparator drug, aspirin, is itself effectivedrug, aspirin, is itself effective((vsvs placebo) in reducing cardiovascular events in patients with recplacebo) in reducing cardiovascular events in patients with recent MI or stroke. Thus, the difference betweenent MI or stroke. Thus, the difference betweenPLAVIX and placebo, although not measured directly, is substantiPLAVIX and placebo, although not measured directly, is substantial.al.*ITT analysis.*ITT analysis.Plavix Package Insert.Plavix Package Insert.


Clopidogrel vs. Aspirin ?

• ‘Match’ study compared Aspirin with Aspirin and Clopidogrel in patients who had had a TIA or minor Stroke and were already taking Clopidogrel.

• No significant benefit achieved and increase in bleeding in Clop. + ASA grp.

Diener, H. C., J. Bogousslavsky, et al. (2004). "Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial." Lancet 364(9431): 331-7.


Choice of Antiplatelet

• Aspirin first line post TIA / CVA

• Aspirin plus Dipyridamole second line.

• Clopidogrel third line or in those intolerant to Aspirin.



Anticoagulation for AF• Anticoagulation should be started in every patient in

atrial fibrillation unless contraindicated

• Should be considered for patients with ischaemic stroke associated with mitral valve disease, prosthetic heart disease or within 3 months of myocardial infarction

• Anticoagulation should be not be started until brain imaging has excluded haemorrhage and until 14 days have passed from onset of ischaemic stroke


Symptomatic Carotid Stenosis

70-99% -surgery

50-69% -?

<50% -no surgery

NNT to prevent one stroke =22


Access to Neurovascular (NV)Clinics

• Study of delay from initial event to clinic assessment in three different localities; offering daily, weekly and fortnightly NV clinics.

• 377 enrolled.

• No. of patients seen within 14 day recommended window was 91%, 49%, 20% respectively.

Giles, M. F., Flossman, E., Rotherwell, P.M. (2004). How frequent must TIA and Stroke clinics be to satisfy guidelines on urgency of assessment ? British Geriatric Society, Harrogate.


Percutaneous Transluminal Angioplasty

Useful:

- Contraindications to CEA

- Stenosis at inaccessible sites

- Restenosis after CEA


National Clinical Guidelines

• Any patient with carotid territory area stroke and with minor or absent residual disability should be considered for CEA

• Carotid ultrasound should be performed on all patients being considered for CEA

• CEA should only be undertaken by a specialist surgeon with a proven low complication rate, and only if the stenosis is measured at greater than 70%


Modifying vascular profile as secondary prevention.

• Hypertension

• Hyperlipidaemia


Hypertension

• Common –80%

• Multifactorial

• Hypertension associated poor outcome


Stroke and usual BP among 2435 individuals with a Stroke and usual BP among 2435 individuals with a history of TIA or minor stroke.history of TIA or minor stroke.

Rodgers A, MacMahon S, et al. BMJ. 1996:313:147Rodgers A, MacMahon S, et al. BMJ. 1996:313:147

4.004.00

2.002.00

1.001.00

0.500.50

0.250.25

7575 8080 8585 9090 9595

Usual Diastolic BP (mmHg)Usual Diastolic BP (mmHg)

RelativeRelativerisk ofrisk ofsecondarysecondarystrokestroke

4.004.00

2.002.00

1.001.00

0.500.50

0.250.25

Usual Systolic BP (mmHg)Usual Systolic BP (mmHg)

120120 130130 140140 150150 160160 170170


There is a Continuous Epidemiological Relationship Between BloodThere is a Continuous Epidemiological Relationship Between BloodPressure Levels and Recurrent Stroke RiskPressure Levels and Recurrent Stroke Risk

Stroke and usual BP among 2435 individuals with a Stroke and usual BP among 2435 individuals with a history of TIA or minor stroke.history of TIA or minor stroke.

Rodgers A, MacMahon S, et al. BMJ. 1996:313:147Rodgers A, MacMahon S, et al. BMJ. 1996:313:147

4.004.00

2.002.00

1.001.00

0.500.50

0.250.25

7575 8080 8585 9090 9595

Usual Diastolic BP (mmHg)Usual Diastolic BP (mmHg)


4.004.00

2.002.00

1.001.00

0.500.50

0.250.25

Usual Systolic BP (mmHg)Usual Systolic BP (mmHg)

120120 130130 140140 150150 160160 170170


There is a Continuous Epidemiological Relationship Between BloodThere is a Continuous Epidemiological Relationship Between BloodPressure Levels and Recurrent Stroke RiskPressure Levels and Recurrent Stroke Risk


PROGRESS ObjectivePROGRESS Objective

Randomized placebo controlled trial designed to determine the effects of a blood pressure-lowering regimen on the risks of stroke and other major vascular events in hypertensive and non-hypertensive patients with a history of stroke or TIA

PROGRESS Collaborative Group. Lancet 2001; 358: 1033-41

PROGRESS ObjectivePROGRESS Objective

Randomized placebo controlled trial designed to determine the effects of a blood pressure-lowering regimen on the risks of stroke and other major vascular events in hypertensive and non-hypertensive patients with a history of stroke or TIA



Pro

port

ion

with

eve

nt

95% CI 17 - 38%

P<0.0001Placebo

Active

0.20

0.15

0.10

0.05

0.000 1 2 3 4 (Years)

28% risk reduction

Stroke Risk ReductionStroke Risk ReductionAll participantsAll participants


Pro

port

ion

with

eve

nt

95% CI 17 - 38%

P<0.0001Placebo

Active

0.20

0.15

0.10

0.05

0.000 1 2 3 4 (Years)

28% risk reduction

Stroke Risk ReductionStroke Risk ReductionAll participantsAll participants



Hypertensive 163/1464 235/1452

Non hypertensive 144/1587 185/1602

Total stroke 307/3051 420/3054

Major vascular events



Total events 458/3051 604/3054

Events/patientsActive Placebo

Favorsactive

Favorsplacebo

Risk reduction(95%CI)

Stroke

Risk Reduction forRisk Reduction for HypertensiveHypertensivevs Normotensivevs Normotensive PatientsPatients

32% (17 to 44)

27% (8 to 42)

28% (17 to 38)

29% (16 to 40)

24% (9 to 37)

26% (16 to 34)

0.5 2.0Hazard ratio

1.0




Total stroke 307/3051 420/3054

Major vascular events



Total events 458/3051 604/3054

Events/patientsActive Placebo

Favorsactive

Favorsplacebo

Risk reduction(95%CI)

Stroke

Risk Reduction forRisk Reduction for HypertensiveHypertensivevs Normotensivevs Normotensive PatientsPatients

32% (17 to 44)

27% (8 to 42)

28% (17 to 38)

29% (16 to 40)

24% (9 to 37)

26% (16 to 34)

0.5 2.0Hazard ratio

1.0




• Targets are systolic BP < 140 and diastolic < 85 mmHg– < 130/ 80 for patients with diabetes.

• Reduction should be considered using a combination of long acting ACE inhibitor (eg Perindopril or Ramipril) and a thiazide diuretic (eg Indapamide)

Hypertension Targets




• If total cholesterol is > 3.5 then a high dose statin is required.

• e.g. Simvastatin 40mg or Atorvastatin 20mg.

Hyperlipidaemia



ELIGIBILITY: MRC/BHF Heart Protection Study

• Increased risk of CHD death due to prior disease:

Myocardial infarction or other coronary heart disease;

Occlusive disease of non-coronary arteries; or

Diabetes mellitus or treated hypertension

• Age 40-80 years

• Total cholesterol 3.5 mmol/l (135mg/dl)

• Statin or vitamins not considered clearly indicated or contraindicated by patient’s own doctors


SIMVASTATIN: MAJOR VASCULAR EVENTS

(10269) (10267)

SIMVASTATIN PLACEBO Rate ratio & 95% CI

STATIN better PLACEBO better

Vascularevent

898 1212Major coronary

444 585Any stroke

939 1205Revascularisation

(19.8%) (25.2%)24% SE 3reduction

2033 2585

(2P<0.00001)

ANY OF ABOVE

0.4 0.6 0.8 1.0 1.2 1.4


SIMVASTATIN: MAJOR VASCULAR EVENTby PRIOR DISEASE

(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI

STATIN better PLACEBO better

999 1250(23.5%) (29.4%)Previous MI

460 591(18.9%) (24.2%)Other CHD (not MI)

No prior CHD

172 212(18.7%) (23.6%)CVD

327 420(24.7%) (30.5%)PVD

276 367(13.8%) (18.6%)Diabetes

24% SE 3reduction(2P<0.00001)

2033 2585(19.8%) (25.2%)ALL PATIENTS

0.4 0.6 0.8 1.0 1.2 1.4


SIMVASTATIN: MAJOR VASCULAR EVENTby LDL & TOTAL CHOLESTEROL

(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI

STATIN better PLACEBO betterLipid levelsat entry

LDL cholesterol (mmol/l)

598 756(17.6%) (22.2%)< 3.0 (116 mg/dl)

484 646(19.0%) (25.7%)3.0 < 3.5

951 1183(22.0%) (27.2%) 3.5 (135 mg/dl)

Total cholesterol (mmol/l)

360 472(17.7%) (23.1%)< 5.0 (193 mg/dl)

744 964(18.9%) (24.5%)5.0 < 6.0

929 1149(21.6%) (26.8%)> 6.0 (323 mg/dl)

24% SE 3reduction(2P<0.00001)

2033 2585(19.8%) (25.2%)ALL PATIENTS

0.4 0.6 0.8 1.0 1.2 1.4


Conclusions

• Clear evidence from good quality research

• Challenge now is to implement change

• Therapeutic nihilism no longer justified


Thank You

David Hargroves, SpR Stroke Medicine.

12th October 2004GP lecture Series1 Primary and Secondary Prevention of Ischaemic Stroke David Hargroves, SpR in Stroke Medicine, SW Thames.

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