Yanofsky’s STROKE STUDIES Compendium:
Below is a brief
survey of Stroke Relevant Studies, that I consider to
be so important I carry them around in my Palm®. This is often updated and can
be found at our www.susqneuro.com website.
I welcome suggestions for possible additions.
Carotid Endarterectomy:Evidence Based
Review Neurology 2005;65:794-801
Therapeutic assessment
committee of the
n
Symptomatic if >70% stenosis, level A
n
Symptomatic if 50-69% stenosis, level B
n
Not indicated if <50% stenosis, level A
n
If Assymptomatic
>60% iff stroke/death rate <3% level A
n
ASA 51-325 mg before and after endarterectomy recommended
Level A evidence
Comparison of Warfarin
and Aspirin for Symptomatic Intracranial Arterial Stenosis:
Part of WASID trial group 569 patients with 50-99%
stenosis of major intracranial artery randomly
assigned to ASA 1300 mg v. Coumadin INR 2-3. F/u avg
1.8 yrs. Hazard ratio for death
=.46, major hmg =.39, MI or sudden death .40, Concl:
Warfarin ass’d with signif more hazardous events and provided no advantage over
aspirin for intracranial stenoisis.NEJM 352:1305-1316
March 31, 2005
MATCH TRIAL:
Management of Atherothrombosis with Clopidigrel versus Aspirin in Patinets
at Risk of Ischemic Events. 7599 High risk patients on Clopidigrel
randomized to treatment of added ASA 75 mg. or placebo. 21%: Hx TIA and 79% prior Ischemic Stroke. Most had other risk
factors for stroke. Double blind treatment lasted 18 Mos. Outcome:15.7% on both drugs had another ischemic event vs. 16.7% on
Clopidigrel alone (non-significant). 2.6% on ASA had
significant life-threatening bleeding as opposed to 1.3% without ASA. Concl: Adding ASA to Clopidigrel
only doubles the risk of significant bleeding but adds no significant
therapeutic benefit.
Ximelagatran for Stroke
Prevention in Patients with Atrial Fibrillation –
SPORTIF: Ximelagatran
36 mg. bid an oral direct thrombin inhibitor. Outcome: 1.62% vs 1.65% per year primary events in X gp
vs. Coumadin group (non-significant). Ximelagatran is ass’d with a
31.7% rate of major and minor bleeding as opposed to Coumadin
at 38.7%. Ximelagatran had a higher incidence of
transitory transaminase elevation. Ximelagatran gp had 16% RRR over Warfarin
(p=.63). Conclusion: Ximelagatran is as effective as Warfarin with less potential for drug interaction and
bleeding with predictable pharmacokinetics, low potential for food, drug and
alcohol interactions.
MRC Assymptomatic carotid surgery trial. LANCET 2004
1662 AsSympt
Pts 60% or more randomized to surgery v. med foll'd avg 2.7 yrs,
periop
stroke/death=2.3%
5 yr ipsi
stroke risk=5.1% surgery v 11.0 med..
PRoFESS will compare ASA plus DP with ASA plus Clopidigrel for secondary stroke prevention in 15,500
patients. Two other arms will have telmisartan (Micardis) added to the regimen to determine whether this
ARB adds benefit to decrease the risk of a second stroke.
SPARCL: 5 yr Prevention with
Aggressive Reduction of Cholesterol Levels will compare Atorvastatin
(Lipitor) with placebo in patient with recent TIA or
ischemic stroke.
CURE STUDY: NEJM 345:494-502 (
CAPRIE STUDY: Clopidigrel vs aspirin in patients at risk for ischemic events. 325 mg ASA vs clopidigrel in secondary stroke prevention. 19,185 patients, primary endpoints were ischemic strokes, MI’s, vascular death. Sec end points were ICH, leg amputation, nonfatal outcome events. RRR for stroke, vascular death, MI = 8.79% clop vs ASA p-.043. 5 fewer strokes , MI’s or vascular deaths per 1000 pts vs ASA
ESPS-2: European Stroke Prevention Study: ASA vs DPA vs. DPA+ASA vs placebo in secondary stroke prevention. 6602 pts or 1600 per group with TIA or ischemic stroke within 3 months. End points stroke, death, and or stroke death at 2 years. Sec end points are TIA or other vascular events in 2 years or MI. Outcome: Stroke37% ASA+DPA vs. placebo (p<.0001)23.1% DPA +ASA vs ASA (P=0.006). Stroke or death:12.9%DPA+ASA vs ASA (p<0.056). 56 fewer stroke per 1000 treated with DPA+ASA vs placebo. 30 fewer strokes per 1000 combo vs ASA. 56/1000 fewer strokes or deaths combo vs placebo; 27fewer strokes or death per 1000 combo vs ASA
HOPE: Heart Outcomes prevention evaluation: Ramipril 10 mg/day vs placebo in pts at risk for cardiovascular events.. 9297 pts with vasc disease, DM without known heart failure with prior stroke. Endpoints: MI, stroke, death from cardiovascular disease. Sec end points, Death from any cause, cardiac arrest, revascularization procedures, heart failure, Diabetic complications. Outcome: MI, stroke, death 21% Ramipril vs placebo (p<0.001)Stroke 32% (p<0.001), MI 20% (p<0.001),CV death 26% (p<0.001). 38 fewer MI, Stroke, death per 1000 treated with Ramipril, 21 fewer CV deaths per 1000, 24 fewere MI’s , 15 fewer strokes per 1000. NEJM 2000,342:145
PROGRESS: perindopril protection against recurrent stroke study. Perindopril was used with or without indapamide vs placebo for secondary stroke prevention. 6105 patients with history of prior stroke or TIA. Endpoints fatal and nonfatal stroke, fatal or disabling stroke, vascular events, dementia. Result: stroke 43% in combination group (p<0.0001), 5%for single agent (p=NS)28% event reduction overall (p<0.0001)26% less major vascular events. , 44 fewer fatal and nonfatal strokes per 1000, 56 fewer major vascular events per 1000 patients treated. Lancet 2001,358:1033
LIFE trial: 55-80 year olds w/HTN &LVH on EKG. Outcome: Decrease stroke risk with Losartan vs. Atenolol. Lancet 2002,359:995
ALLHAT: Pts 55 w/HTN and at least one other risk other CAD, RF. Outcome: No difference in overall CVD rates among Chlorthalidone, amlodipine, lisinopril.
For stroke prevention amlodipine>chlorthalidone>lisinopril. For Heart failure prevention chlorthalidone>lisinopril>amlodipine JAMA, 2002, 288:2981
WARSS: Warfarin aspirin recurrent stroke study: 2206 patients who had ischemic stroke within 30 days and no cardioembolic source or high grade stenosis. Endpoints ischemic stroke or death from any cause at two years. Found no significant difference in the prevention of recurrent stroke or death or in the occurrence of serious adverse events over 2 years.
IST: International Stroke Trial: ASA 300/Day vs placebo vs SQ heparin5000 units/ bid vs 12,500 ,for 14 days vs placebo. 19,435 patients with ischemic stroke over last 48 hours. . primary endpoints death at 14 days, death and dependency at 6 months, recurrent ischemic stroke, recurrent hem’c stroke, death or non-fatal stroke, transfused or fatal extracranial bleeds. Death at 14 days, heparin9% vs no heparin- 9.3% vs no ASA 9.4%. Death or dependency at 6 months heparin 63% vs no ASA 63.5 %. No benefit was derived from Heparin use, 11 fewer deaths or nonfatal strokes per 1000 patients treated with ASA14 fewer deaths or dependence within 6 months
CAST:Chinese acute Stroke Trial:ASA 160 mg/d vs placebo for 4 weeks following stroke, 21,106 patients, within 48 hours of acute stroke. RRR or death of any cause =14% ASA vs placebo, death or dependency 30.5%, death and nonfatal stroke, RRR=12%, 5.4% fewer deaths from ETOH.
HAEST: Heparin in Acute embolic stroke trial: LMWH(dalteparin) 100 units per kg sq. 449 Afib patients. No signif difference in 2 weeks, 3 months
French PFO/Aneurysm strudy. 581 new ischemic stroke study. Stroke rish was increased in PFO and atrial septal aneuroysm patints compared to control gropus (25.3% vs 4.2 %) No significant difference in occurrence of ischemic stroke. Combination of PFO + aneurysm was assd with an increased risk of ischemic stroke. ASA alone is inadequate treatment. Stroke risk was increased in the PFO/aneurysm group 15.2% vs. 4.2%. Annual stroke risk was 3.9% in PFO/atrial septal aneurysm 1.1%.
PROACT II: Prolyse in acute cerebral thromboembolism II: 6 hours, 180 patients with angiographically proven MCA occlusion. Slight or no disability=40% in treatment gp vs 25% in no prourokinase group. MCA recanalization=66% vs 18% (p<0.001)Symptomatic ICH =10% vs. 2%. Number needed to treat for slight to no disability -7. No difference in mortality at 90 days.
STAT: Stroke treatment with Ancrod trial. 3 hours, 500 ischemic stroke patients. “favorable” outcome ancrod=42.2% ancrod vs 34.4% placebo.Mortality 25.4 vs 23%.
Severe disability 11.8% vs 19.8%. Sympt ICH 5.2% vs. 2%. NNT for additional favorable outcome=13.NNT to prevent 1 severe disability=13. ICH 1 in 31
NINDS: 3 hour.291 part I, 333 part 2. Part I 4 point impr in NIHSS within 24 hours, part 2clinical outcome in 3 months. Minimal to no disability at 3 months=50% vs 38% placebo. Sympt ICH=6.4% vs. 0.6%. 3 month mortality=17% vs21% for placebo. NNT for minimal to no disability =8. 1 add’l sympt ICH per 17 treated patients.
Homocysteine: Non-fasting total homocysteine is an independent risk factor for stroke.
in men and women aged 60
years or older. Levels above 14 µmol/L are associated with an 80% increased
risk of total stroke.
AG Bostom et al. Nonfasting
plasma total homocysteine levels and stroke incidence
in elderly persons: The Framingham Study. Annals of Internal Medicine 1999 131:
352-355. Study:1,158 women
and 789 men from the Framingham Study (who had not had stroke) who were
examined between 1979 and 1982 and re-examined in 1992. Non-fasting total homocysteine levels were measured and demographic
information and medical histories taken. Average age was 70 years (range 59 to
91 years); systolic blood pressure 141 mm Hg (range 86 to 225 mm Hg); and total
homocysteine level 12.65 µmol/L (range 4.13 to 219.84
µmol/L).
Total homocysteine
levels were divided into quartiles: quartile one, 4.13 to 9.25 µmol/L; quartile
two, 9.26 to 11.43 µmol/L; quartile three, 11.44 to 14.23 µmol/L; and quartile
four, 14.24 to 219.84 µmol/L. Levels below 14 µmol/L are considered 'normal'.
Followed for a median of
9.9 years during which time 165 total strokes occurred, 153 of which were
non-hemorrhagic strokes and 100 were atherothrombotic
brain infarctions.
Total homocysteine levels were higher in men than in women (12.35 compared with 11.32 µmol/L), in patients with a history of atrial fibrillation than in those without (13.17 compared with 11.66 µmol/L) and in patients with a history of coronary heart disease than in those without (12.49 compared with 11.57 µmol/L). Levels did not differ between patients with or without diabetes or between cigarette smokers and non-smokers.
VISP: Vitamin Intervention in Stroke Prevention. 3680 pts post cerebral infarction best med therapy + high dose vits (25 mg pyridoxine, 0.4 mg cobalamine, 2.5 mg folic acid) in 1853 pts. Result: 2 micromol reduction in homocysteine in high dose vs. low dose vitamins. Unadjusted risk ratio for any stroke, CHD event, or death was 1.0 within 2 years. Risk of stroke was 9.2% in high dose vs. 8.8% in low dose group. Concl.: Moderate reduction in total homocysteine levels after nondisabling cerebral infarction had no effect on vascular outcomes during first 2 years of follow up. JAMA 291 (5):565-75,2004
Homocysteine and Risk of Ischemic Heart Disease and Stroke, a
meta-analysis: MEDLINE search 1/96-1/99.Stronger associations observed
in retrospective studies after the onset of disease than in
prospective studies. A 25% lower usual homocysteine
level (about 3 µmol/L) was associated with an 11% lower IHD risk and
19% lower stroke risk. JAMA. 2002;288:2015-2022.
The Swiss Heart Study: Double-blind placebo-controlled
trial. 553 patients enrolled after successful angioplasty of at least
1 significant coronary stenosis (
50%).
Randomly assigned to receive a combination of folic acid (1
mg/d), vitamin B12 (cyanocobalamin, 400
µg/d), and vitamin B6 (pyridoxine hydrochloride, 10 mg/d)
(n = 272) or placebo (n = 281) for 6 months. After a mean (SD)
follow-up of 11 (3) months, the composite end point was
significantly lower at 1 year in patients treated with homocysteine lowering therapy (15.4% vs
22.8%; relative risk [RR], 0.68) primarily due to a reduced rate of
target lesion revascularization (9.9% vs
16.0%; RR, 0.62) A nonsignificant trend was seen
toward fewer deaths (1.5% vs 2.8%; RR,
0.54) and nonfatal myocardial infarctions (2.6% vs
4.3%; RR, 0.60) JAMA. 2002;288:973-979.
Stroke Prevention: Antihypertensive Therapy—JNC VII: For Pts >50 SBP>140 more impt than DBP. Risk of CVD increases X2 q20/10 increase starting at 115/75. Pts at 55 have a 90%lifetime risk of HTN. Pts with SBP120-139 or DBP 80-89 are “prehypertensive” Use thiazide diuretic for mots pts alone or combined. If BP>20/10 iver giakm start with thiazide + another drug. Most pts require 2 or more drugs. Goal <140/90 or 130/80 if DM, renal disease, vasc disease. JAMA 2003,289:2560
Pravastatin and Simvastatin decrease risk of stroke-MI-Vascular death. Starting dose = 40 mg. Goal is LDL<100 or 75 if there is severe atherosclerosis.
Age, systolic blood
pressure, smoking, diabetes, history of atrial
fibrillation and coronary heart disease were risk factors for total stroke (see
Table 1).
Risk Factors:
Age, Per one year increase 1.06 (1.04-1.09)
Syst Blood Pressure, per 20 mm Hg 1.16(1.01-1.34)
Smoking 1.52 (1.03-2.24)
Diabetes 1.90 (1.25-2.89)
Atrial Fibrillation 2.29 (1.29-4.04)
|
Variable |
Relative risk (95% confidence
interval) |
|
Age,
per one-year increase |
1.06 (1.04 - 1.09) |
|
Systolic
blood pressure, per 20 mmHg increase |
1.16 (1.01 - 1.34) |
|
Smoking |
1.52 (1.03 - 2.24) |
|
Diabetes |
1.90 (1.25 - 2.89) |
|
Atrial fibrillation |
2.29 (1.29 - 4.04) |
|
Coronary
heart disease |
1.49 (1.04 - 2.16) |
|
Total homocysteine level (quartile 4 compared with quartile 1) |
1.82 (1.14 - 2.91) |
Compared with total homocysteine levels in quartile one, levels in quartile
four were associated with an 82% increased risk of total stroke (relative risk
1.82, 95% confidence interval 1.14 to 2.91); a 79% increased risk of
non-hemorrhagic stroke (relative risk 1.79, 95% confidence interval 1.11 to
2.89) and a 90% increased risk of atherothrombotic
brain infarction (relative risk 1.90, 95% confidence interval 1.02 to 3.51).
These results were adjusted for age, gender, smoking, diabetes, systolic blood
pressure and history of coronary heart disease or atrial
fibrillation.
Fish omega 3 Fatty Acids
Several, but not all, studies have shown that fish consumption protects
against stroke. This study takes the research a step further and examines the relationship
between fish and omega-3 polyunsaturated fatty acid intake and risk of stroke subtypes.This study was unable to further our
understanding of the association between intake of fish, omega-3
polyunsaturated fatty acids and stroke risk. Nevertheless, omega-3 fatty acids
(found in cold water fish such as mackerel, herring, halibut and salmon) have
many vital roles, for example they are essential for normal nerve impulse
transmission and brain function. The advice to eat one portion of these fish a week
is important for other reasons, like heart
attack survivability.Reference:H Iso et al. Intake of
fish and omega-3 fatty acids and risk of stroke in women. Journal of the American
Medical Association 2001 285: 304-312.Participants were 79,839 women, aged 34
to 59 years, from the US Nurses' Health Study, with no previous diagnosis of
cardiovascular disease, cancer, diabetes or hypercholesterolemia. In 1980
questionnaires assessed their lifestyle and medical history (which was updated
every two years) and their diet (which was re-examined in 1984, 1986 and 1990).
The women were followed for 14 years. Intakes of fish and long chain omega-3
fatty acids were calculated and the latter divided into quintiles. Strokes were
confirmed by medical records according to the criteria of the National Survey
of Stroke.
A total of 574 cases of
stroke were reported: 119 subarachnoid hemorrhages,
62 intraparenchymal hemorrhages, 303 ischaemic strokes (264 thrombotic
and 39 embolic) and 90 strokes of undetermined type. Of the thrombotic
infarctions, 90 were large-artery occlusive infarctions and 142 were lacunar infarctions.
There was no association
between fish intake and total stroke. Of the stroke subtypes, eating fish two
or more times a week was associated with a reduced risk of lacunar
infarction (relative risk 0.28, 95% confidence interval 0.12 to 0.67) compared
with eating fish less than once a month (based on 14 cases). These results were
adjusted for age, smoking, other cardiovascular risk factors (e.g. body mass
index, exercise) and dietary variables (e.g. saturated fat intake).
Women in the highest
quintile of omega-3 fatty acid intake had a reduced risk of total stroke
compared with women in the lowest quintile (relative risk 0.72, 95% confidence
interval 0.53 to 0.99). Of the stroke subtypes, the highest quintile of omega-3
fatty acids was associated with a reduced risk of lacunar
infarction (relative risk 0.37, confidence interval 0.19 to 0.73) compared with
the lowest quintile (based on 19 cases).
The few associations that
were found in this study were based on a small number of stroke cases and there
was no consistency among the associations observed. For example, an association
was found between the highest intake of omega-3 fatty acids and risk of total
stroke, but only one association was found among the seven subtypes of stroke.
Based on
these results the association between fish and omega-3 polyunsaturated fatty
acid intake and stroke risk is still open to question. The effect looks small,
but a larger number of stroke cases are needed to provide a more definitive
answer.
Fruit and Veggies Prevent Stroke
in Men
From the Framingham
study, a cohort study of 832 middle aged men has examined the effects of eating
fruit and vegetables on the risk of stroke. They were free of cardiac disease
at the start of the study, which had a 20-year follow-up.
Design:
The diet
of each subject was assessed at baseline from a single 24-hour recall. The
estimated number of servings of fruits and vegetables was used to differentiate
the men into five groups (quintiles) of increasing vegetable intake. The intake
of the lowest group was 0-2 servings a day, that of the middle group was 5
servings a day, while that of the group with the highest intake was 8-19
servings a day (mean 10 ).
A serving was defined, roughly, as 120 mL (half a
cup) for fruits and vegetables, 60 mL for tomato
sauce, 120 mL for peas, beans and corns, 28g or
potato chips (crisps), or a single potato.
During a follow-up period of 18-22 years all cardiovascular events, including
stroke, were reviewed by a panel of three physicians who used a set of
established criteria. For stroke outcomes the panel included at least two
experienced neurologists. Minimal criteria for stroke included abrupt onset of
a localised neurological deficit. Stroke was further characterised into ischaemic, or haemorrhagic stroke. Transient ischaemic
attacks (TIA) were recorded separately
Results:
Despite
the large differences in diets, there were few differences between the men in
the five groups (mean age 56 years at baseline) for systolic blood pressure,
serum cholesterol, ethanol intake or physical activity index. Men with the
largest fruit and vegetable index tended to have a slightly higher body mass
index and they smoked fewer cigarettes and had a higher energy intake.
As the
number of servings of fruit and vegetables increased, the number of stroke
events decreased. In men eating the lowest amount of fruit and vegetables, 19
of 100 had a stroke compared with only 8 of 100 among men eating the highest
amount. Similarly the number of completed strokes fell by nearly two thirds
from nearly 15 of 100 to 6 of 100 from low to high fruit and vegetable intake.
Take Home
Message:
Eating
quite moderate amounts of fruit and vegetables can substantially reduce the
risk of a stroke.
Reference:
MW Gillman, LA Cupples, D Gagnon et al. Protective effect of fruits and vegetables on
development of stroke in men. Journal of the American Medical Association 1995
273: 1113-7.
•
ASA reduces odds of composite stroke, MI, Vasc death by 25%
•
ASA reduces the odds of stroke by 30% but in pts entering
for stroke/TIA reduces the composite by only about 16%
•
Ticlid reduces combination by 30% in
post stroke patients
•
Clopidigrel less effective for stroke
Dipyridamole + ASA
•
Reduces composite outcome by 28% v. placebo
•
Post stroke/TIA RR reduction for stroke=37% ESPS I and II
•
Most probably no benefit in reducing MI
NNT Endarterectomy:
NASCET 70-99%
8
ECST
70-99% 8
NASCET 50-69%
20
NASCET
<50% 67
Assymt
VA >=50% 48
ACAS >=60 83
Number of
strokes that could be prevented in US by treating various factors assuming
730,000
Hypertension: 360,000
Cholesterol: 146,000
Smoking: 90,000
Atrial
Fibrillation: 69,000
ETOH: 34,000
Gorelick
Arch. Neurol. 1995;52:347-55
IV t-PA and Ischemic Stroke
studies:
Group: N %Mortality % Hemorrh MRS 0-1 (%)
NINDS
t-PA 312 17
6.4 46
NINDS
placebo 312 21 0.6 27
STARS
(US) 389 13 3.3 35
OSF
Peoria 57 9 5 47
*MRS
mostly 3 mo data. ECASS I and II Percentages were 40 and 42
**
MRS=Modified
Rankin. 0 or 1 little or no disability. 1 no disability with signs
Above
comparison is from David Gordon, MD U
Carotid Stent:
Global Survey of Interventionalists: 5210 Stented vessels:
stroke-death rate 5.1%, major stroke rate=1.5%. In Symptomatic pts stroke-death
= 5.8% In assymptomatics s-d rate = 3.4% Compared
with gold “do no harm” standard in assmptomatics -3%.
Also this is by operator’s self report and may be optimistic. Cathet. Cardiovasc Interv 2000;50:160-167
CAVITAS: Carotid and Vertebral Transluminal Angioplasty Study: 504 prox
cartotid randomly assigned to angio
v. CE. Stents used in 28% only. 96% of pts were
symptomatic. Mean stenosis 86.5%. Postproc
s-d rate = 9.9% in both groups. Major s-d =6.4% angiop
v. 5.9 CE.
CREST Trial: Carotid Revasc
Endarterect v. Stenting
Trial: Underway
Poss
Complications of Angioplasty and stenting: 1. Distal
Emboli, 2.In-Stent thrombosis/occlusion, 3. Hemodynamic
instability (37%?), 4.Hyperperfusion syndr, 5.Stent
deformation, 6.Restenosis
Possible
Indications for Stent: 1. Severe stenosis
with medical comorbidity 2. Severe intracranial Stenosis failing medical therapy 3. Radiation Arteriopathy 4. Symptomatic recurrent severe carotid stenosis post-endarterectomy
See Chaturvedi & Fessler:
Angioplasty and Stenting For Stroke Prevention.
Neurology
2002;59:664-668
Above is
meant to be a brief Survey of Relevant Studies. Pls
e-mail with other candidate studies for inclusion at yanofsky@pneuro.com and note that a
review of anti-platelet studies is available at the www.pneuro.com website as well
..\www.pneuro.com\publications\powerpoint\antiplatelet
agents for stroke\antiplatelets.htm