Ischemic Stroke Treatment Trials

05 November 2004

TYPES:

1. Hemorrhage 20%

2. Infarct 80%

a.                             Large artery atherothromboembolic disease

b.                             Cardioembolism

c.                             Small vessel thrombotic disease

d.                             Other known etiology (hypercoagulable, dissection, vasculitis)

e.                             Cryptogenic

Antiplatelet Agents

Aspirin

585 patients with threatened stroke followed in randomised trial for 26 mths taking either aspirin, sulfinpyrazone or in combination.

Aspirin reduced risk of continuing ischemic attacks, stroke or death by 19%.

Aspirin reduced risk of stroke or death by 31%.

The Canadian Cooperative Study Group: A randomised trial of aspirin and sulfinpyrazone in threatened stroke. New England Journal of Medicine 299: 53-59, 1978. 

19435 patients randomised to treatment with either aspirin 300 daily/ aspirin 300 + heparin 12500 bd / aspirin 300 + heparin 5000 bd / heparin 12500 bd / heparin 5000 bd / no aspirin & no heparin within 48 hrs of stroke onset.

At 14 days, heparin group had fewer recurrent ischemic strokes but offset by similar sized increase in hemorrhagic strokes.

Heparin 12500 bd associated with more bleeds & deaths.

At 6 mths, neither heparin regimen offered any clinical advantage at 6 mths.

Aspirin has a small but worthwhile improvement at 6 mths.

International Stroke trial Collaborative Group: The International Stroke Trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischemic stroke. Lancet 349:1569-81, 1997.

6602 patients with recent ischemic stroke randomised to either placebo, aspirin 50 mg daily, extended release dipyridamole 400mg, aspirin 50 & ER dipyridamole 400 mg.

1300 mg as effective as 50 mg aspirin (SALT study)

Relative risk reduction 16.3%  for stroke (p=0.039) with dipyridamole

Relative risk reduction  18.1% for stroke (p=0.013) with aspirin

Relative risk reduction  37% for stroke (p=0.039) with dipyridamole and aspirin.

?effects on mortality

The SALT Collaborative Group: Swedish Aspirin Low Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischemic events. Lancet 338: 1345-9, 1991.

Diener HC et al: European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in secondary prevention of stroke. J Neurol Sci 143:1-13, 1996.

Ticlopidine 

1072 patients in randomised double blind trial assessing effect of ticlopidine 250mg bd versus placebo in reducing rate of stroke, AMI or vascular death in patients who have had a recent atheroembolic or lacunar stroke (not cardioembolic) over 3 yrs.

Event rate of 15.3% in placebo compared to 10.8% in ticlopidine group

I.e. relative risk reduction of 30.2% (p=0.006)

1% reversible neutropenia (occurred within first 3 mths)

2% rash

2% diarrhea

Gent M et al: The Canadian American Ticlopidine Study (CATS) in Thromboemblic Stroke. Lancet 348:1329-39, 1989.

8814 patients with recent transient or mild persistent focal cerebral or retinal ischemia randomised to ticlopidine 250 mg bd or aspirin 1300 mg daily followed up for 3 years  concerning risk of stroke or death.

At 3 yrs, 10% stroke for ticlopidine compared to 13% for aspirin ie 21% risk reduction (p=0.024)

20% diarrhea

14% rash

<1% reversible neutropenia

Hass W et al: A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high risk patients. New England Journal of Medicine 321:501-7, 1989.

Clopidogrel

19185 patients with atherosclerotic disease (recent ischemic stroke, AMI or symptomatic peripheral vascular disease) in randomised, blinded trial taking either clopidogrel 75 mg daily or aspirin 325 mg daily.

Clopidogrel group had annual risk of 5.32% of ischemic stroke, vascular death or AMI compared to aspirin 5.83%

I.e. relative risk reduction of 8.7% (p=0.043) favoring clopidogrel.

CAPRIE  Steering Committee: A randomised blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE) Lancet 348:1329-1339, 1996.

Heparin

2750 patients (within 48 hrs of acute ischemic stroke) randomised to receive high dose nadroparin (4100 IU bd), nadroparin (4100 IU daily) or placebo for 10 days followed up for 6 mths.

At 6 mths,  45% in high dose group, 52% low dose group, 65% placebo group died or became dependent

I.e. an effect in favor high dose nadroparin.

No significant increase in hemorrhagic transformation.

Kay R et al: Low molecular weight heparin for treatment of acute ischemic stroke. . New England Journal of Medicine 333:1588-93, 1995.

1281 patients in randomised, double blind, placebo controlled trial of danaparoid in ischemic stroke of <24 hrs duration.

At 10 days,  RR4 of serious intracranial bleeding with treatment group (p=0.05)

At 3 months, no difference between groups.

Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators: Low molecular weight heparinoid ORG 10172 (Danaparoid) and outcome after acute ischemic stroke. JAMA 279: 1265-72, 1998.

19435 patients randomised to treatment with either aspirin 300 daily/ aspirin 300 + heparin 12500 bd / aspirin 300 + heparin 5000 bd / heparin 12500 bd / heparin 5000 bd / no aspirin & no heparin within 48 hrs of stroke onset.

At 14 days, heparin group had fewer recurrent ischemic strokes but offset by similar sized increase in hemorrhagic strokes.

Heparin 12500 bd associated with more bleeds & deaths.

At 6 mths, neither heparin regimen offered any clinical advantage at 6 mths.

Aspirin has a small but worthwhile improvement at 6 mths.

International Stroke trial Collaborative Group: The International Stroke Trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischemic stroke. Lancet 349:1569-81, 1997.

 Warfarin

420 patients with nonrheumatic Af randomised to either warfarin (INR 1.2-1.5) or placebo/aspirin with 2.2 yrs follow-up.

0.41% per year for stroke in warfarin group compared to control of 2.98% per year (p=0.002)

no increase risk of hemorrhage.

The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigations: The effect of low dose warfarin on risk of stroke in patients with nonrheumatic atrial fibrillation. . New England Journal of Medicine 323:1505-11, 1990.

892 patients in prospective cohort study with 2 years follow-up assessing risk stratification scheme for patients with nonvalvular Af. All patients took 325 mg aspirin daily.

Risk groups: recent CCF or FS<25%, previous thromboembolism, systolic hypertension>160, female >75yo.

Rate of events for all groups 2.2.% per year.

Rate of events for hypertension 3.6% per year.

Rate of events for no risk factors 1% per year.

Risk of major bleeding during aspirin treatment 0.5% per year.

Stroke Prevention in Atrial Fibrillation Study III: Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with aspirin. JAMA 279:1273-77, 1998.

For Af, no benefit of aspirin at 75 mg daily.

Aspirin at 325 mg daily provides for 28% risk reduction.

Stroke Prevention in Atrial Fibrillation Study Investigators: Preliminary report of  stroke prevention in atrial fibrillation study. New England Journal of Medicine 322: 863-8, 1990.

Petersen P et al: Placebo controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications  in chronic atrial fibrillation: the Copenhagen AFASAK study. Lancet 1:175-9, 1989.

Thrombolysis

624 patients with acute ischemic stroke (meeting specific criteria, see below) randomised to placebo or t-PA 0.9 mg/kg (max of 90mg, 10% delivered as bolus with remaining 90% over 1 hour) with no anticoagulants nor antiplatelet agents in ensuing 24 hrs.

At 24 hrs no difference between 2 groups.

At 3 months, 30%  for t-PA group more likely to have minimal or no disability.

At 3 months, mortality 17% t-PA group compared to 21% placebo group (p=0.30)

Symptomatic cerebral hemorrhage 6.4% in t-PA group compared to 0.6% for placebo (p<0.001)

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue Plasminogen Activator for Acute Ischemic Stroke. New England Journal of Medicine 333:1581-7, 1995.

620 patients randomised to treatment with either 1.1 mg/kg of rt-PA or placebo within 6 hrs of stroke meeting specific criteria.

At 90 days, neurologic recovery was better in treatment group.

However, significantly more hemorrhages.

Trial had major protocol violations.

The European Cooperative Acute Stroke Study (ECASS): Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA 274: 1017-25, 1995.

622 patients randomised to treatment within 6 hrs of onset of stroke of either 1.5 MU streptokinase /aspirin or aspirin alone.

At 10 days, odds ratio 2.7 (p<0.00001)fatality for treatment group.

At 6 months, no statistical difference in mortality or disability between streptokinase or control group.

Multicentre Acute Stroke Trial – Italy (MAST-I) Group: Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischemic stroke. Lancet 346:1509-14, 1995.

Streptokinase given at AMI dosages rather than lowered dosages such as t-PA trials.

Streptokinase causes excessive mortality & hemorrhages.

Donnan G et al: Australian Streptokinase Trial (ASK) In: del Zoppo G et al: Thrombolytic Therapy in Acute Ischemic Stroke. Berlin, Heidelberg: Springer-Verlag, 1993: 80-85.

Hommel M et al: Termination of trial of streptokinase in severe acute ischemic stroke (MAST-E). Lancet 345: 57, 1994.

Carotid Endarterectomy

EC-IC bypass is ineffective for preventing cerebral ischemia in patients atherosclerotic disease  in carotid and middle cerebral arteries.

The EC/IC Bypass Study Group: Failure of extracranial-intracranial  arterial bypass to reduce the risk of ischemic stroke. New England Journal of Medicine 313: 1191-1200, 1985.

669 patients with symptomatic carotid stenosis of 70-99% (hemispheric or retinal TIA or nondisabling stroke in preceding 120 days) in randomised trial comparing medical treatment (1300mg aspirin plus smoking cessation, antilipemic, diabetic & antihypertensive therapy as required) with carotid endarterectomy.

All patients underwent angiography.

Probability of ipsilateral stroke at 2 yrs 26% in medical group compared with 9% in surgical group

I.e. absolute risk reduction of 17% (P<0.001)

Probability of major or fatal ipsilateral stroke at 2 yrs 13.1% medical vs 2.5% surgical

Ie absolute risk reduction of 10.6% (p<0.001)

North American Symptomatic Carotid Endarterectomy in Symptomatic patients with High Grade Stenosis: Beneficial effect of carotid endarterectomy in symptomatic patients with high grade carotid stenosis. New England Journal of Medicine 325:445-53, 1991.

659 patients studied with ipsilateral  symptomatic severe carotid stenosis and contralateral carotid stenosis or occlusion.

Medically treated patients at 2 yrs, risk of ipsilateral stroke 69.4% (occluded contralateral), 29.3% (severe contralateral) & 26.2% (mild contralateral).

Surgically treated patients at 2 yrs, risk of ipsilateral stroke 22.1%(occluded contralateral), 9.3% (severe contralateral) & 8.3% (mild contralateral).

I.e. 68.2% relative risk reduction with surgery.

Perioperative risk of stroke and death 14.3%(occluded contralateral) vs 4.5%(contralateral stenosis)

Andrew P et al: Long term prognosis and effect of endarterectomy in patients with symptomatic severe carotid stenosis and contralateral stenosis or occlusion: results from NASCET. J. Neurosurgery 83:77882, 1995.

2295 patients evaluated for risk of stroke in 3 yrs of follow-up in asymptomatic carotid artery disease.

At 3 yrs, risk of stroke:

          0-29% Stenosis 1.8%

          30-60% Stenosis 2.1%

          70-99% Stenosis 5.7%

          80-89% Stenosis 9.8%

          90-99% Stenosis 14.4%

          occlusion            3.7%

The European Carotid Surgery Triallists Collaborative Group: Risk of stroke in distribution of an asymptomatic carotid artery. Lancet 345: 209-12, 1995.

4657 patients with asymptomatic carotid artery stenosis of  60% or greater randomised to either surgical or medical treatment followed up for 2.7 yrs.

Aggregate risk over 5 yrs for ipsilateral stroke or death estimated to be 5.1% for surgical group compared to 11% medical group.

I.e. aggregate risk reduction of 53% (p<0.05)

Provided perioperative mortality <3%.

Executive Committee for Asymptomatic Carotid Atherosclerosis Study: Endarterectomy for asymptomatic carotid artery stenosis. JAMA 273: 1421-8, 1995.

1599 patients with moderate (50-69%) stenosis randomised to surgical or medical treatment with 4.5 yrs follow-up.

No benefit would be gained in a period <5 yrs in patients undergoing carotid endarterectomy compared to medical treatment.

The European Carotid Surgery Triallists Collaborative Group: Endarterectomy for moderate symptomatic carotid stenosis: interim results from MRC European Carotid Surgery Trial. Lancet 347: 1591-3, 1996.