Download G. Secondary Prevention of Stroke Educational Supplement

G. Secondary Prevention of Stroke Educational Supplement
Manuel Murie-Fernandez MD, Andrew McClure, Katherine Salter, Robert Teasell MD
FRCPC
G1.
G1.1
Transient Ischemic Attack……………………………………………………………………… 2
Case Study: TIA…………………………………………………………………………………. 3
G2.
G2.1
G2.2
Hypertension…………………………………………………………………………………….. 6
Case Study: Hypertension………………………………………………………………………8
Case Study: Intracerebral Hemmorrhage and Hypertension……………………………... 12
G3.
G3.1
Hyperlipidemia and Hypercholesterolemia…………………………………………………..20
Case Study: Hyperlipidemia…………………………………………………………………. 21
G4.
G4.1
Diabetes………………………………………………………………………………………… 28
Case Study: Diabetes………………………………………………………………………… 30
G5.
G5.1
Lifestyle Modification…………………………………………………………………………...38
Case Study: Lifestyle Modification…………………………………………………………...39
G6.
G6.1
Homocysteine and Stroke....…………………………………………………………………..51
Case Study: Homocysteine………………………………………………………………….. 52
G7.
G7.1
Antiplatelet Agents…………………………………………………………………………….. 55
Case Study: Antiplatelet Agents…………………………………………………………….. 56
G8.
G8.1
Atrial Fibrillation and Coumadin....…………………………………………………………… 69
Case Study: Atrial Fibrillation and Anticoagulation………………………………………... 70
G9.
G9.1
Patent Foramen Ovale…………………………………………………………………………82
Case Study: PFO………………………………………………………………………………83
G10.
G10.1
G10.2
G10.3
G10.4
Carotid Artery Stenosis………………………………………………………………………...87
Case Study: Carotid Endarterectomy (CEA)………………………………………………..88
Case Study: Symptomatic Stenosis (>50%)……………………………………………….. 91
Case Study: Non-symptomatic Stenosis…………………………………………………… 83
Case Study: Recurrent Carotid Stenosis…………………………………………………… 94
109 pages
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G1. Transient Ischemic Attack
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G1. Transient Ischemic Attack
G1.1 Case Study: TIA
Case Study
A 32 year old female patient presents to the Emergency Room and tells you that
something strange happened one hour ago: She couldn’t see out of her left eye for 50
minutes. Although she can see fine now, she and her family want to know what might have
caused this temporary blindness.
Q1. What do you think happened and what it is your recommendation?
Answers
1. TIA
2. Immediate workup (preferably by neurologist) for stroke risk.
Discussion
TIA is a syndrome defined as the sudden onset of focal neurological loss of presumed vascular
origin lasting less than 24 hours with full recovery commonly occurring within 2 hours. One of
the possible symptoms of a TIA is retinal ischemia (transient monocular blindness). The
following definition of TIA has recently been proposed: a "brief episode of neurological
dysfunction caused by a focal disturbance of brain or retinal ischemia, with clinical symptoms
typically lasting less than 1 hour, and without evidence of infarction" (Albers et al. 2002).
The patient should receive a medical examination (by a neurologist if possible) as soon as
possible and undergo a full risk evaluation for stroke because TIA is a risk factor for stroke.
Q2. The patient and her family want to know more about the role of TIA as a possible risk
factor for Stroke. What information can you give them?
Answer
1. TIA is a significant risk factor for stroke
Discussion
A TIA is considered a very significant risk factor for a stroke. Two population based studies and
two randomised controlled trials (Rothwell and Warlow 2005) reported that 23% of individuals
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presenting with stroke had a history of TIA and in 43% of these patients the TIA event preceded
the stroke event by less than 7 days. Johnston et al. (2000), Lisabeth et al. (2004), and
Gladstone et al (2004) all concluded that approximately one half of strokes following TIA will
take place within the first 48 hours. Van Wijk et al. (2005) reported the 10-year risk for vascular
events following TIA to be 35.8%.
With this knowledge, the National Stroke Association (2006) emphasized the importance of
urgent assessment and intervention following TIA because intervention can reduce the 90 day
risk for stroke.
Q3. Which clinical features are predictive of greater stroke risk with a TIA?
Answers:
1. Age (older)
2. High blood pressure
3. Unilateral weakness
4. Speech impairment
5. Length of symptoms
6. Diabetes
Discussion
Johnston et al. (2007) validated the use the unified ABCD2 score for the prediction of 2 day risk
of stroke after a TIA.
Score for the Prediction of 2-day Risk of Stroke (Johnston et al. 2007)
Risk Factor
Points
Age ≥ 60 years
1
Raised blood pressure (Systolic ≥ 140 mmHg and/or diastolic ≥ 90 mmHg)
1
Clinical features
2
 Unilateral weakness
1
 Speech impairment without weakness
Duration of symptoms in minutes
2
 ≥ 60
1
 10 – 59
Diabetes
1
The 2 day risk for stroke following TIA was reported to be 1% for those with a score of 0-3 (low
risk), 4.1% for those with a score of 4-5 (moderate risk), and 8.1% for those with a score of 6-7
(high risk) (Johnson et al. 2007). This score was also able to predict the risk of stroke from 7 to
90 days following the TIA event.
The risk of stroke following TIA is also influenced by the vascular territory in which the initial
event occurred. Vertebrobasilar territory risk for subsequent stroke is higher than the carotid
territory (OR= 1.70, 95% CI 1.3 - 2.2) (Flossman and Rothwell 2003).
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References
Albers GW, Caplan LR, Easton JD, Fayad PB, Mohr JP, Saver JL, Sherman DG, for the TIA Working
Group. Transient ischemic attack: proposal for a new definition. N Engl J Med. 2002; 347:1713–1716.
Flossmann E, Rothwell PM. Prognosis of vertebrobasilar transient ischaemic attack and minor stroke.
Brain 2003;126:1940-1954.
Gladstone DJ, Kapral MK, Fang J, Laupacis A, Tu JV. Management and outcomes of transient ischemic
attacks in Ontario. CMAJ 2004;170:1099-1104.
Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department
diagnosis of TIA. JAMA 2000;284:2901-2906.
Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very
early stroke risk after transient ischaemic attack. Lancet 2007;369:283-292.
Lisabeth LD, Ireland JK, Risser JMH, et al. Stroke Risk After Transient Ischaemic Attack in a PopulationBased Setting. Stroke 2004;35:1842-1846.
Rothwell PM, Warlow CP. Timing of TIAs preceding stroke: time window for prevention is very short.
Neurology 2005;64:817-820.
Van Wijk I, Kappelle LJ, van Gijn J, et al. Longterm survival and vascular event risk after transient
ischaemic attack or minor ischaemic stroke: a cohort study. Lancet 2005;365:2098-2104.
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G2. Hypertension
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G2. Hypertension
Canadian Best Practice Recommendations (2008): Recommendation 2.2 - Management of
High Blood Pressure
Hypertension is the single most important modifiable risk factor for stroke. Blood pressure
should be monitored in all persons at risk for stroke.
2.2a. Blood pressure assessment
i. All persons at risk of stroke should have their blood pressure measured at each health care
encounter, but no less than once annually [Evidence Level C] (CHEP, NICE, RCP).
ii. Proper standardized techniques, as described by the Canadian Hypertension Education
Program, should be followed for blood pressure measurement (CHEP).
iii. Patients found to have elevated blood pressure should undergo thorough assessment for the
diagnosis of hypertension following the current guidelines of the Canadian Hypertension
Education Program [Evidence Level A] (ASA, CHEP, RCP).
iv. Patients with hypertension or at risk for hypertension should be advised on lifestyle
modifications. [Evidence Level C]. Refer to recommendation 2.1, "Lifestyle and risk factor
management," for details on lifestyle modifications.
2.2b. Blood pressure management
i. The Canadian Stroke Strategy recommends target blood pressure levels as defined by the
Canadian Hypertension Education Program (CHEP) guidelines for prevention of first stroke,
recurrent stroke, and other vascular events.
CHEP 2008 Recommendations for Management of Blood Pressure (excerpts used with
permission; see www.hypertension.ca/chep for detailed information (Khan et al. 2008):
• For the prevention of first stroke in the general population the systolic blood pressure treatment
goal is a pressure level of less than 140 mm Hg [Evidence Level C]. The diastolic blood pressure
treatment goal is a pressure level of less than 90mm Hg [Evidence Level A].
• Blood pressure lowering treatment is recommended for patients who have had a stroke or
transient ischemic attack to a target of less than 140/90 mm Hg [Evidence Level C].
• In patients who have had a stroke, treatment with an angiotensin-converting enzyme (ACE)
inhibitor or diuretic is preferred [Evidence LevelB].
• Blood pressure lowering treatment is recommended for the prevention of first or recurrent
stroke in patients with diabetes to attain systolic blood pressures of less than 130 mm Hg
[Evidence Level C] and diastolic blood pressures of less than 80 mm Hg [Evidence Level A].
• Blood pressure lowering treatment is recommended for the prevention of first or recurrent
stroke in patients with nondiabetic chronic kidney disease to attain a blood pressure of less than
130/80 mm Hg [Evidence Level C].
ii. Randomized controlled trials have not defined the optimal time to initiate blood pressure
lowering therapy after stroke or transient ischemic attack. It is recommended that blood pressure
lowering treatment be initiated (or modified) prior to discharge from hospital. For patients with
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nondisabling stroke or transient ischemic attack not requiring hospitalization, it is recommended
that blood pressure lowering treatment be initiated (or modified) at the time of the first medical
assessment [Evidence Level B] (EXPRESS, PROGRESS).
iii. For recommendations on specific agents and sequence of agents, please refer to the current
Canadian Hypertension Education Program guidelines (Khan et al. 2008).
G2.1 Case Study: Hypertension
Case Study
A 55 year old woman is admitted to the impatient rehabilitation unit with a lacunar infarct
in the right thalamic/subcortical area. Her past medical records state that she has a
history of hypertension which is not well controlled. The nurse notes that the patient’s
blood pressure (BP) is 145/90 mmHg and that she is not currently taking any
antihypertensive medication.
Q1. What are the risk factors for this patient having a new stroke?
Answers
1. Stroke
2. Hypertension
Discussion
Stroke: Having had a stroke is a significant risk for the development of further strokes.
Goldberg and Berger (1988) reported that one in four hospital admissions for stroke are due to
recurrence and patients who have had a stroke are five times as likely to experience a
reoccurrence when compared to those who have not had a stroke. Coull and Rothwell (2004)
suggested that recurrent events account for up to 30% of the strokes reported in populationbased studies and are more likely to be fatal or disabling than first strokes. Cardioembolic
strokes had the greatest risk for recurrence while lacunar stroke had the lowest risk (Kaplan et
al 2005).
Hypertension: Hypertension is the most significant risk factor for stroke. However, despite its
high prevalence and modifiable nature, as few as 1 in 4 stroke patients receive adequate blood
pressure control (Amar et al 2004). Hypertension is a risk factor for both the first stroke and the
recurrence (the hazard ratio for recurrent stroke was 1.42 per standard deviation of systolic
blood pressure and 1.39 per standard deviation of diastolic pressure, this would translate into a
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reduction in relative risk of 13% for each 9 mmHg drop in systolic BP and 11% for a 4 mmHg
drop in diastolic BP).
Q2. What BP level is considered normal?
Answer
1. Less than 120/80 mmHg
Discussion
Normal BP levels have been defined as <120/80 mm Hg by the Seventh Report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (Chobanian et al. 2003).
Q3. The patient tells you that her current BP (145/90 mmHg) is normal for her and that
she questions whether it needs to be treated because she doesn’t want to have to take
any “pills”. What can you tell her?
Answer
1. Her BP is considered to be elevated.
2. Hypertension is a modifiable risk factor for stroke.
3. Treatment of hypertension will reduce her risk of stroke.
4. Medications are often needed as nonpharmacological methods are often unsuccessful.
Discussion
It is important to inform the patient that high BP is a modifiable risk factor for having a new
stroke; in other words, her chances of having a second stroke will decrease if her hypertension
is treated.
Based on The Ontario Heart and Stroke Foundation’s (2003) recommendations, this patient’s
BP should be less than 140/90. The British Hypertension Society guidelines state that for nondiabetic patients with hypertension the optimal blood pressure treatment goals are systolic blood
pressure <140 mmHg and diastolic blood pressure <85 mmHg.
A combination of antihypertensive medication and lifestyle modifications will help this patient
lower her BP and, consequently, her risk of stroke. Lifestyle modifications are associated with
BP reductions and should be included as part of a comprehensive antihypertensive therapy.
Q4. After the patient agrees to be treated, the resident asks what pharmacological
treatments are available for hypertension and which treatment would be most
appropriate for this patient. What would be your initial treatment?
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Answer
1. Diuretic alone or in combination with an ACE inhibitor
Discussion
Therapy with a diuretic, alone or in combination with ACE inhibitor, could be recommended
based on available data (Hilleman and Lucas 2004). However, individual cases may not
respond equally to the same treatment and reduction and control of BP may require the use of
multiple antihypertensive agents (Spence 2003). The use of combination treatment has been
found to effectively reduce stroke, myocardial infarction, and all vascular events outcomes by
40-45% (Rashid et al. 2003). An example of the benefit of combined therapy over single
therapy is the PROGRESS trial (2001) which was a randomized controlled trial in which 6105
individuals were randomized to receive either active treatment or placebo. Active treatment
consisted of either perindopril 4mg/day + indapamide at the physician’s discretion (n=1,770) or
perindopril alone (n=1,281). Placebo groups were similarly divided into those receiving double
(n=1,774) vs. single placebo (n=1,280) to match treatment conditions. Primary outcome in all
conditions was total stroke. Combination therapy with perindopril & indapamide produced larger
risk reductions for total stroke than treatment with perindapril alone. Hypertensive and nonhypertensive patients with history of ischaemic stroke or TIA both benefited from combined
therapy.
Many agents have been assessed for use as antihypertensive treatments in the reduction of BP
in the primary and secondary prevention of stroke. The research studies supporting or not
supporting different pharmacological options are presented in the table below.
Summary of Pharmacological Treatment of Hypertension and Reduction of Risk of
Stroke:
Study
Agent(s) Assessed
Effect on Stroke Risk
ACE-Inhibitors
UKPDS
Captopril vs. Atenolol
Increased risk (Captopril)
CAPPP
Captopril vs. -blocker +
Increased risk (Captopril)
diuretic
HOPE
Ramipril vs. placebo
Reduced risk
PROGRESS
Perindopril + diuretic vs.
Reduced risk
placebo
Australian BP Study
Similar risk for nonfatal stroke,
Various ACE-inhibitors vs.
increased for fatal (ACEvarious diuretics
inhibitor)
ALLHAT
Lisinopril vs. diuretic
Increased risk (Lisinopril)
-blockers/-RA
SHEP
Atenolol + diuretic vs. placebo Reduced risk
Note: The results of UKPDS, CAPPP, LIFE and ASCOT-BPLA also consider the use of -blockers.
Ca-channel blockers/Ca antagonists
NORDIL*
Diltiazam + regimen vs.
regimen alone
Syst-Eur 1*
Nitrendipene vs. placebo
Syst-Eur 2*
Nitrendipene vs. placebo
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Reduced risk
Reduced risk
Reduced risk
HOT*
ALLHAT (2002)
ASCOT-BPLA*
Felodipene + regimen vs.
Felodipene + regimen + ASA
Amlodipine vs. diuretic
Amlodipine-based vs.
Atenolol-based
-adrenergic blockers
ALLHAT (2000)
Doxazosin vs. diuretic
Angiotensin Receptor blockers (ARBs)
LIFE*
Losartan-based regimen vs.
Atenolol-based regimen
ACCESS
Candesartan Cilextil at day
one post-stroke vs. control of
HTN commencing on day 7
VALUE
Valsartan-based regimen vs.
Amlodipine-based regimen
SCOPE
MOSES*
ONTARGET
Candesartan-based regimen
vs. regimen not including ARB
or ACE inhibitors
Eprosartan vs. Nitrendipine
Ramipril vs. Telmisartan vs.
Ramipril + Telmisartan
Reduced risk with reduced
BP. ASA no added effect.
No significant difference
between treatments.
Reduced risk (Amlodipine)
Increased risk (Doxazosin)
Reduced risk (Losartan)
Reduced risk with immediate
treatment
No significant difference in
risk reduction -- trend
favouring Amlodipine.
Reduced risk
Reduced rate of events
(Eprosartan)
No significant between group
differences in stroke risk.
* therapy administered included the possible additions of ACE-inhibitors (or -blockers or -blockers),
and/or diuretics as part of a treatment regimen designed to reduce BP to meet target.
Q5. List the reasons why it is important to treat hypertension in stroke survivors?
Answers:
1. Most important treatable risk factor
2. High prevelance
3. Easily modifiable
4. Proportional risk
5. Reduction associated with decreased risk.
Discussion
 Hypertension is the most powerful treatable risk factor.
 It has a high prevalence and is easily modifiable.
 Declining stroke incidence and mortality over the last 4 decades has been attributed to
better management of hypertension.
 Risk of stroke rises proportionally with increasing systolic and diastolic blood pressure.
 Kaplan et al. (2006) reported a 9 mmHg drop in systolic blood pressure reduced the relative
risk of recurrent stroke by 13% while a 4mmHg drop in diastolic blood pressure results in an
11% drop in relative risk.
 Treatment of systolic hypertension in the elderly decreases the risk of stroke by 36%.
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
There is strong evidence that a reduction in blood pressure is associated with a decreased
risk of stroke.
Q6. Two important studies looking at the treatment of hypertension post-stroke were the
PROGRESS and HOPE trials. Describe both of theses trials.
Answers:
1. The PROGRESS trial randomized 6105 patients (both HBP and non-HBP) with a history of
ischemic stroke or TIA to either perindopril 4mg/day + indapamide versus perindopril alone
versus placebo. The researchers found a 28% reduction in relative risk was associated with
the combined treatment of perindopril + indapamide, as compared to perindopril alone.
2. The HOPE trial randomized 3577 diabetic patients (age 55+ and history of cardiovascular
disease) to 10 mg Ramipril/day versus placebo. Ramipril lowered the risk of myocardial
infarction by 22%, stroke by 33%, cardiovascular disease by 37%, and total mortality by
24%.
G2.2 Case Study: Intracerebral Hemorrhage and Hypertension
Case Study
34 year old obese male presented to hospital emergency room with aphasia, right
hemiparesis and decreased level of consciousness. CT scan showed a large left
intracerebral hemorrhage. BP was 236/124. Patient was admitted to the ICU.
Past medical history was a 2 year history of malignant hypertension complicated by two
hypertensive crisis in the month before his stroke for which he was treated but he failed
to follow through with his prescriptions. At the time of admission and in the ICU his BP
proved extremely difficult to control and he was discharged from the ICU with a BP of
170/95.
Q7. What treatment options are available?
Answers
1. Thiazide diuretic (i.e. hydrochlorthiazide)
2. ACE inhibitor (i.e. Ramipril – HOPE trial; Perindopril – PROGRESS; Captopril not to be
used)
3. ARB (angiotensin receptor blocker) (i.e. Losartan – LIFE trial; Candesartan; Eprosartan –
MOSES trial)
4. Calcium channel blocker (i.e. Diltiazem – NORDIL; Amlodipine)
5. Beta-blocker
6. Salt restrictions
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* These medications can be used in combination for resistant hypertension
Case Study (continued)
He was admitted to rehabilitation and during his rehabilitation stay his blood pressure was
generally running between 120-140 systolic and 70-90 diastolic with occasional BPs of 150160 systolic and 90-100 diastolic.
Medication s for HBP while on the rehabilitation unit included Amlodipine 7.5 mg q12h,
Metoprolol 150 mg q12h, Perindopril 2 mg OD, Prazosin 6 mg q6h with the suggestion of
adding an additional 12.5 mg of Hydrochlorthiazide to further regulate the patient’s blood
pressure.
Discussion (from the SREBR 11th Edition; Teasell et al. 2008)
“Many different types of pharmacological therapies have been assessed both on their own and
in combination with each other. Most have clearly demonstrated a relationship between the
reduction of blood pressure and reduced risk of stroke.
In a systematic review and meta-analysis of 7 clinical trials that examined the effects of lowering
blood pressure in patients with previous stroke, Rashid et al. (2003) found that results varied
with the drug classes used in the trials selected for their analysis. Alone, alpha-receptor
agonists appeared to have little or no effect on stroke rates, while diuretics reduced stroke by
32%. Though ACE-inhibitors alone were not shown to be as effective in this analysis, the most
powerful treatment effect was found in the combination of an ACE-inhibitor and a diuretic. The
use of this combination effectively reduced stroke, myocardial infarction and all vascular event
outcomes by 40 – 45% (Rashid et al. 2003).
Turnbull et al. (2003) conducted several meta-analyses using data from 29 placebo-controlled
randomized trials examining the effectiveness of various blood-pressure lowering regimens.
The authors concluded that all commonly used anti-hypertensive therapies were effective in
reducing risk for cardiovascular events, including stroke; however, larger reductions in blood
pressure were associated with larger reductions in risk (Turnbull et al. 2003). Rashid et al.
(2003) demonstrated that, overall, antihypertensive therapy (beta-blockers, diuretics, ACEinhibitors) was associated with a reduction in stroke events of up to 25% (OR=0.76) and that
this reduction in risk for stroke events was related primarily to the magnitude of blood pressure
reduction rather than the agent used. Further meta-analysis has supported this finding and has
identified a dose-response relationship between blood pressure reduction and the reduction of
stroke risk such that a 10-mmHg reduction in systolic pressure is associated with a 31%
reduction in stroke risk (Lawes et al. 2004). In addition, it has been suggested that the benefits
of blood pressure lowering may not be confined to hypertensive patients, but may also extend to
patients who are normotensive and at risk for stroke (Lawes et al. 2004; Mancia 2004). In the
past, caution has been urged with regard to the use of antihypertensive therapy among
normotensive or hypotensive patients in light of a possible J-shaped relationship between blood
pressure and risk for stroke (Lawes et al. 2004; Mason et al. 2004; Mancia, 2004). However, a
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study of data from the ongoing WACS trial demonstrated a linear relationship between systolic
blood pressure and the risk of cardiovascular disease in a population of women with a history of
CVD or ≥3 cardiovascular risk factors (Mason et al. 2004).”
References
Amar J, Cambou JP, Touze E, et al. Comparison of Hypertension Management After Stroke and
Myocardial Infarction: Results From ECLAT1--A French Nationwide Study. Stroke 2004; 35:1579-1583.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ,
Oparil S, Wright JT Jr, Roccella EJ, for the National Heart, Lung, and Blood Institute Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High
Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7
Report. JAMA 2003; 289:2560–71.
Coull A, Rothwell PM. Underestimation of the early risk of recurrent stroke. Evidence of the need for a
standard definition. Stroke 2004; 35:1925-1929.
Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results
of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study
Investigators. Lancet 2000;355:253-259.
Goldberg G, Berger GG. Secondary Prevention in Stroke: A Primary Rehabilitation Concern. Arch Phys
Med Rehabil 1988; 69:32-40.
Heart and Stroke Foundation of Ontario. Best practice guidelines for stroke care: A resource for
implementing optimal stroke care, 2003.
Hegele RA. Angiotensin-converting enzyme (ACE) inhibition in the secondary prevention of vascular
disease: the Heart Outcomes Prevention Evaluation (HOPE) Trial and its substudies. Current
Atherosclerosis Reports 2000; 2(5):361-62.
Hilleman DE, Lucas BD Jr. Angiotensin-converting inzyme inhibitors and stroke risk: Benefit beyond blood
pressure reduction? Pharmacotherapy 2004; 24:1064-76.
Kaplan RC, Tirschwell DL, Longstreth WT, Jr., et al. Vascular events, mortality, and preventive therapy
following ischemic stroke in the elderly. Neurology 2005; 65:835-842.
Khan NA, Hemmelgarn B, Herman RJ, et al. Canadian Hypertension Education Program. The 2008
Canadian Hypertension Education Program recommendations for the management of hypertension: part
2 — therapy. Can J Cardiol 2008; 24:465-475.
PROGRESS Collaborative Group. Randomized trial of perindopril-based blood pressure-lowering
regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;
358(9287):1033-41.
Rashid P, Leonardi-Bee J, Bath P. Blood pressure reduction and secondary prevention of stroke and
other vascular events: A systematic review. Stroke 2003; 34:2741-49.
Spence JD. Treatment of renovascular and adrenocortical hypertension in the elderly. Drugs and Aging
2003; 6:63-65.
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Teasell RW, Foley NC, Salter K, Bhogal SK, Jutai J, Speechley MR. Evidence-Based Review of Stroke
Rehabilitation (11th edition). Canadian Stroke Network; 2008.
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Key Study: Hypertension
Chapman N, Huxley R, Anderson C, et al. Effects of a perindopril-based blood pressurelowering regimen on the risk of recurrent stroke according to stroke subtype and medical
history: the PROGRESS Trial. Stroke 2004;35:116-121.
Perindopril Protection Against Recurrent Stroke Study (PROGRESS) Collaborative
Group. Effects of a Perindopril-based blood pressure-lowering regimen on disability and
dependency in 6105 patients with cerebrovascular disease. Stroke 2003;34:2333-2338.
PROGRESS Collaborative Group. Randomized trial of perindopril-based blood pressurelowering regimen among 6,105 individuals with previous stroke or transient ischaemic
attack. Lancet 2001; 358(9287):1033-41.
Methods
Outcomes
Population studied
were hypertensive and
non-hypertensive
patients with a history
of stroke or transient
ischaemic attack. A
total of 6105 patients
were studied. 3501
received active
treatment flexible
regimen based on ACE
inhibitor perindopril
(4mg daily) with
addition of diuretic
indapamide at
discretion of the
treating physicians
while 3054 received a
placebo.
During a mean 3.9 yrs of follow-up – active treatment
reduced BP by 9/4 mm Hg. 10% of active treatment patients
suffered stroke compared to 14% of placebo (28% risk
reduction, p<.0001). Active treatment also reduced risk of
total major vascular events.
With treatment, relative risk reduction for ischaemic stroke
was 24% and 50% for intracerebral haemorrhage. Relative
risk of any stroke was reduced by 26% in patients with a
baseline history of ischaemic stroke and 49% in patients
whose history included an intracerebral haemhorrage.
Treatment effects were not modified by antiplatelet or
antihypertensive therapy or by AF, residual neurological
signs or time since historical cerebrovascular event.
Additional analysis revealed that BP reduction benefits were
seen across all age groups for both men and women and for
Asian and Western subjects, although blood pressure
differences were greater among Asian subjects than among
Western subjects. Reductions in stroke risk were greater in
participants < age 65 – each decade of age increase was
associated with ¼ less relative risk reduction.
Percentage Ischemic Stroke (IS) was
reduced for a Group taking Perindopril
and Indapamide vs. a Placebo Group
Percentage IS was
reduced after 3.9 yrs (%)
Author, Year
Country,
Pedro Score
PROGRESS
Collaborative
Group
2001, 2003,
2004
International
8 (RCT)
40
36
35
p=.02
30
25
20
15
6
10
5
0
Combination Therapy
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Single-drug Therapy
Percentage of Recurring Stroke Types
seen in original IS and TIA Patients vs.
ICH Patients
IS or TIA
ICH
70
IS= Ischem ic
Stroke
TIA= transient
ischemic attack
ICH=
intracerebral
hem orrhage
60
Type (%)
Percentage of Recurrent Stroke
80
50
40
30
20
10
0
Ischemic Stroke
H emorrhagic
Qualifying Event
Percentage of Patients Disabled or Dependent
for the Active treatment (angiotension) Group vs.
Placebo Group
Dependent
Disabled
0
5
10
15
20
Percentage of Patients at 4 yrs follow-up (%)
Active Treatment
25
Placebo
Relative Risk Reductions in Stroke, Major Vascular Events
and Mortality Associated with a Perindopril-Based BloodPressure-Lowering Regimen
4%
Outcome
Total Deaths
9 5 % C I ( - 12 t o 18 ) *
9 5% C I (16 t o 34 )
Total Vascular Events
Total Stroke
26%
9 5 % C I ( 17 to 3 8 )
0%
5%
10%
15%
20%
28%
25%
30%
Risk Reduction Associated with Active Treatment (%)
*Non-significant risk reduction.
Importance: The PROGRESS trial studied the use of a long-acting ACE inhibitor (perindopril)
in conjunction with a thiazide diurection (inda pamide). This combination, used in the prevention
of hypertension, led to a relative risk reduction of 48% for recurrent stroke. The number needed
to treat to prevent the development of another stroke was 45. Even non-hypertensive stroke
- 17 -
patients demonstrated a significant decline in stroke risk. The PROGRESS trial demonstrated
that lowering blood pressure not only reduced risk of stroke but also, not unexpectedly reduced
the risk of functional disability and dependency.
Relevant SREBR Conclusions: Reduction of blood pressure via antihypertensive therapy is
associated with a reduction in stroke events. Control of hypertension post-stroke is associated
with a decreased risk of functional disability and dependency.
- 18 -
Key Study: Hypertension
Effects of ramipril on cardiovascular and microvascular outcomes in people with
diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart
Outcomes Prevention Evaluation Study Investigators. Lancet 2000;355:253-259.
Author, Year
Country,
Pedro Score
HOPE Study
Investigators
2000
International
8 (RCT)
Methods
Outcomes
Population studied was
diabetic stroke patients.
1,808 patients received 10
mg Ramipril and 400 IU
vitamin E while 1769
received a placebo daily.
The study stopped 6 months early because of consistent
benefit of Ramipril compared to placebo. Ramipril
lowered risk of combined primary outcome by 25%
(p=.0004), myocardial infarction by 22%, stroke by 33%,
cardiovascular death by 37%, total mortality by 24%,
revascularization by 17%, overt nephropathy by 24%.
25
p=.057
p=.0004
20
p=.036
p=.031
15
p=.004
p=.01
p=.019
NS
NS
p=.0001
p=.027
10
p=.0074
p=.04
NS
5
NS
Primary Outcome
Secondary Outcomes
MI =Myocardial Infraction; ON =Overt nephropathy;
TIA =transient ischemic attacks; LT =laser therapy
ON, LT, Dialysis
Dialysis
LT
Worsening
angina
TIA
Any heart failure
ON
Revascularisation
Heart failure
Unstable angina
Total mortality
Cardiovascular
death
Stroke
MI
0
Combined
Percentage of Patients (%)
The Relationship between Ramipril and Placebo Treatment for
Clinical Outcomes
Other outcome
Ramipril
Placebo
Importance: This study looked at diabetic stroke patients, some of whom were hypertensive
and others who were not. Ramipril reduced the risk of recurrent stroke in both hypertensive and
non-hypertensive diabetic stroke patients.
Relevant SREBR Conclusion: There is strong evidence that the addition of a Ca-antagonist to
a regimen that may include ACE-inhibitors or beta-blockers and a diuretic decrease the risk of
stroke evients in both diabetic and non-diabetic stroke patients.
- 19 -
G3. Hyperlipidemia and Hypercholesterolemia
- 20 -
G3. Hyperlipidemia and Hypercholesterolemia
Canadian Best Practice Recommendations (2008): Recommendation 2.3 - Lipid
Management
Lipid levels should be monitored in all persons at risk for stroke.
2.3a. Lipid assessment
i. Fasting lipid levels (total cholesterol, total glycerides, low-density-lipoprotein [LDL] cholesterol,
high-density-lipoprotein [HDL] cholesterol) should be measured every 1 to 3 years for all men 40
years or older and for women who are postmenopausal and/or 50 years or older [Evidence
Level C] (McPherson et al., VA/DoD). More frequent testing should be performed for patients
with abnormal values or if treatment is initiated.
ii. Adults at any age should have their blood lipid levels measured if they have a history of
diabetes, smoking, hypertension, obesity, ischemic heart disease, renal vascular disease,
peripheral vascular disease, ischemic stroke, transient ischemic attack or asymptomatic carotid
stenosis [Evidence Level C] (McPherson et al.).
2.3b. Lipid management
i. Ischemic stroke patients with LDL cholesterol of >2.0mmol/L should be managed with lifestyle
modification and dietary guidelines [Evidence Level A] (AU, CSQCS, McPherson et al., VA/DoD)
ii. Statin agents should be prescribed for most patients who have had an ischemic stroke or
transient ischemic attack to achieve current recommended lipid levels [Evidence Level A] (AU,
CSQCS, McPherson et al., VA/DoD).
G3.1 Case Study: Hyperlipidemia
Case Study
A 68 year old man was admitted into the stroke rehabilitation program with an ischemic
stroke on the left ACM territory. He has a history of hyperlipidemia and the cholesterol
related results from a recent blood test are as follows:
 Total cholesterol 4.1 mmol/L
 Triglycerides 0.74 mmol/L
 LDL 2.83 mmol/L
 HDL cholesterol 0.94 mmol/L
 Total cholesterol to HDL ratio 4.4
- 21 -
Q1. When the patient asks about the cause of his stroke, the resident tells him that high
cholesterol is a major risk factor and that it is the likely cause of his stroke. Do you
agree with the resident and why?
Answer
1. No
2. It is not possible at this point to say it is the most likely cause of his stroke.
Discussion
Although it is known that a relationship exits between cholesterol plasma levels and
cardiovascular risk, the exact nature of this relationship has not yet been established (Gorelick
2002, Amarenco et al. 2004). After adjusting for multiple risk factors, there is a weak
association between cholesterol level and risk of ischemic stroke (Shahar et al. 2003).
However, it has been demonstrated that the treatment of hypercholesterolemia with HMG-CoA
reductasa inhibitors (statins) reduces the risk of cardiovascular events, including stroke
(Lewington et al. 2007).
Q2. After your explanation, the resident asks “if hyperlipidemia is not a major risk factor,
do you still have to treat it”?
Answer
1. Yes
2. Reducing hyperlipidemia or hypercholesterolemia does reduce stroke incidence.
Discussion
Hyperlipidemia should be treated. Meta-analyses of clinical trials examining lipid-lowering
therapies have reported significant reductions in overall stroke incidence (both fatal and nonfatal), although research has failed to demonstrate any significant reduction in haemorrhagic
stroke (Law et al. 2003, Corvol et al. 2003).
Q3. How would you treat the hyperlipidemia?
Answers
1. Reduce dietary intake of saturated fats and cholesterol.
2. Weight reduction
3. Increase physical activity
4. Use of statins.
- 22 -
Discussion
A review of recent prevention guidelines concerning cholesterol lowering by statin use in stroke
prevention (Pearson et al. 2002, Smith et al. 2001) suggests that the National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High
Cholesterol in Adults (Adult Treatment Panel III 2001) is one of the most comprehensive guide
for management of lipids in persons who have or are at risk for cerebrovascular disease.
NCEP emphasizes LDL-C lowering and recommends 2 major modalities for LDL-C lowering:
 Therapeutic lifestyle change: Therapeutic lifestyle change stresses a reduction in
saturated fats and cholesterol intake, weight reduction, and an increase in physical
activity.
 Drug-specific therapy: Drug therapy options and management of metabolic syndrome
and other dyslipidemias are addressed in the NCEP guideline (Adult Treatment Panel III
2001, www.nhlbi.nih.gov/guidelines/cholesterol/index.htm). Among treatments, statins
are the gold standard treatment. There is strong evidence that statins are effective
treatment interventions for lowering cholesterol and reducing the risk of stroke and TIA
(CARE and LIPIDS studies, Byington et al. 2001). Atrovastatin will reduce the risk of
recurrent stroke in individuals with previous stroke (SPARCL study, Amarenco et al
2003, 2006). The most common adverse effects associated with statin therapy are
gastrointestinal upset, muscle aches, and hepatitis or hepatotoxicity (gorelick, 2002).
Q4. What are the target values for treating hyperlipidemia following stroke?
Answer
1. Stroke patients are considered high risk patients
2. For high risk patients aim for values of LDL < 2.5 mmol/L and Total cholesterol to HDL ratio
< 4.0.
Discussion
The treatment is individualized for each patient and depends on both the risk factors and the
Cholesterol results. Although you can use different tables, we include here the Canadian
guidelines for target Serum lipid levels per risk category, and the ATP III Guidelines.
Canadian Guidelines for Target Serum Lipid Levels per Risk Category
High Risk
Moderate Risk
Low Risk






LDL < 2.5 mmol/L AND
Total cholesterol to HDL ratio < 4.0
LDL < 3.5 mmol/L AND
Total cholesterol to HDL ratio < 5.0
LDL < 4.5 mmol/L AND
Total cholesterol to HDL ratio < 6.0.
- 23 -
ATP III LDL-C Goals and Cutpoints for TLC and Drug Therapy in Different Risk Categories and
Proposed Modifications BZased on Recent Clinical Trial Evidence (Grundy et al. 2004)
Risk Category
Consider Drug Therapy9
LDL-C Goal
Initiate TLC
<100 mg/dL
(optional goal
6
<70 mg/dL)
≥ 100 mg/dL
≥ 100 mg/dL10 (<100 mg/dL:
consider drug options)9
Moderately high risk: 2 + risk
3
4
factors (10 yr risk 10% - 20%)
3
Moderate risk: 2 + risk factors
4
(10 yr risk <10%)
<130 mg/dL7
≥130 mg/dL8
≥ 130 mg/dL (100-129 mg/dL:
11
consider drug options)
<130 mg/dL
≥130 mg/dL
≥160 mg/dL
Lower risk: 0-1 risk factors5
<160 mg/dL
≥ 160 mg/dL
≥ 190 mg/dL (160-189 mg/dL: LDLlowering drug optional)
1
High risk: CHD or CHD risk
equivalents2 (10 yr risk >20%)
8
1
CHD includes history of myocardial infarction, unstable angina, stable angina, coronary artery procedures
(angioplasity or bypass surgery), or evidence of clinically significant myocardial
ischemic.
2
CHD risk equivalents include clinical manifestations of noncoronary forms of atherosclerotic disease (peripheral
arterial disease abdominal aortic aneurysm, and arotid artery disease (transient ischemic attacks or stroke of carotid
origin or >50% obstruction of a carotid artery), diabetes, and 2 + risk factors with 10 year risk for hard CHD >20%.
3
Risk factors include cigarette smoking, hypertension (BP ≥140/90 mmHg or an antihypertensive medicine), low HDL
cholesterol (<40 mm/dL), family history of premature CHD (CHD in male first-degree relative <55 years of age; CHD
in female first-degree relative < 65 years of age), and age (men ≥45 years; women ≥55years).
4
Electronic 10 year risk calculators are available at www.nhlbi.nih.gov/guidelines/cholesterol.
5
Almost all people with zero or 1 risk factor have a 10 year risk < 10% and 10 year risk assessment in people with
zero or 1 risk factor is thus not necessary.
6
Very high risk favors the optional LDL-C goal of <70 mg/dL, and in patients with high triglycerides, non-HDL-C <100
mg/dL.
7
Optional LDL-C goal <100 mg/dL.
8
Any person at high risk or moderately high risk who has lifestyle-related risk factors (e.g., obesity, physical inactivity,
elevated triglyceride, low HDL-C, or metabolic syndrome) is a candidate for therapeutic lifestyle changes to modify
these risk factors regardless of LDL-C level.
9
When LDL-lowering drug therapy is employed, it is advised that intensity of therapy be sufficient to achieve at least a
30% to 40% reduction in LDL-C levels.
10
If baseline LDL-C is <100 mg/dL, institution of an LDL-lowering drug is a therapeutic option on the basis of available
clinical trial results. If a high-risk person has high triglycerides or low HDL-C, combining a fibrate or nicotinic acid with
LDL-lowering drug can be considered.
11
For moderately high-risk persons, when LDL-C level is 100 to 129 mg/dL, at baseline or on lifestyle therapy,
initiation of an LDL-lowering drug to achieve an LDL-C level <100 mg/dL is a therapeutic option on the basis of
available clinical trial results.
- 24 -
Lipids Monitoring
Patient has known
hyperlipidemia and on a statin
Patient has no history of
hyperlipidemia
Baseline fasting lipid profile
(preferably in acute care)
Lipids at or below targets
Lipids above targets
No dose change, recommend
to repeat in 6 – 12 months
Baseline fasting lipid profile
Lipids at or below targets
Start on statin and repeat
fasting lipid profile in 2-4 wks
Lipids above targets
Lipids at or below targets
Start on statin and repeat
fasting lipid profile in 2-4 wks
Q5. Why is it important to distinguish between LDLs, HDLs and total cholesterol in high
risk patients?
Answers
1. Canadian Guidelines note that LDL-C should be < 2.5 mmol/L
2. Total cholesterol to HDL ratio < 4.0.
3. Total cholesterol < 4-5 mmol/L
Discussion
 LDL is the bad cholesterol; LDL should be less than 2.5 mmol/L and there is linear
correlation between total cholesterol/LDL and stroke mortality.
 HDL is the good cholesterol and total cholesterol to HDL ratio should be <4.0.
 Too much cholesterol is not good - Total cholesterol > 5.50 increases relative risk of stroke
by 1.3.
- 25 -
Q6. Describe the pharmacological treatment of hypercholesterolemia.
Answer
1. Statins, HMG-CoA reductase inhibitors, are considered the first-line treatment for
hypercholesterolemia.
Discussion
 Statins are now considered first line treatment.
 Statins are HMG-CoA reductase inhibitors.
 Regulate LDL receptor activity and reduce the entry of LDL cholesterol into circulation.
 Most common adverse effects are GI upset, muscle aches and hepatitis/hepatotoxicity
(<1%); rare complication is severe myopathy +/- rhabdomyolysis.
 Statins used post-MI resulted in a 24-34% risk reduction for stroke.
Q7. Describe your treatment for each of the following cases.
Patient Description
Lipid Profile
Case A: Post Stroke
– High Risk
Total cholesterol 4.75
LDL 2.4 mmol/L
HDL 1.2 momol/L
Case B: Post Stroke
– High Risk
Total cholesterol 5.8
LDL 3.3 mmol/L
HDL 1.4 mmol/L
Total cholesterol 4.72
LDL cholesterol 3.0 mmol/L
HDL 1.04 mmol/L
Total cholesterol 5.2
LDL cholesterol 2.6 mmol/L
HDL cholesterol 1.2 mmol/L
Case C: Post Stroke
– High Risk
Case D: Post Stroke
– High Risk
Proposed Treatment and
Rationale
No treatment needed. All
cholesterol numbers are at target
levels and total cholesterol to HDL
<4.0.
Treatment with statin and diet. Total
cholesterol and LDL-C is high and
total cholesterol to HDL > 4.0.
Treatment with statin and diet. LDLC is high and total cholesterol to
HDL > 4.0.
Treatment with statin and diet. Total
cholesterol to HDL > 4.0, LDL > 2.5.
References
Adult Treatment Panel III. Executive Summary of the Third Report of The National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults. JAMA 2001; 285:2486-97.
Amarenco P, Bogousslavsky J, Callahan AS, et al. Design and baseline characteristics of the stroke
prevention by aggressive reduction in cholesterol levels (SPARCL) study. Cerebrovasc Dis 2003; 16:38995.
- 26 -
Amarenco P, Bogousslavsky J, Callahan A, III, et al. High-dose atorvastatin after stroke or transient
ischemic attack. N Engl J Med 2006; 355:549-59.
Amarenco P, Tonkin AM. Statins for stroke prevention: disappointment and hope. Circulation 2004; 109
(suppl 1): III-44-49.
Byington RP, Davis BR, Plehn JF, et al. Reduction of stroke events with Pravastatin. The Prospective
Pravastatin Pooling (PPP) Project. Circulation 2001; 103:387-92.
Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P, Lechat P. Differential effects of lipid-lowering
therapies on stroke prevention: A meta-analysis of randomized trials. Archives of Internal Medicine 2003;
163:669-76.
Gorelick PB. Stroke prevention therapy beyond antithrombotics: Unifying mechanisms in ischaemic stroke
pathogenesis and implications for therapy: An invited review. Stroke 2002; 33:862-75.
Grundy SM, Cleeman JI, Bairey Merz CN, Brewer HB Jr., Clark LT, Hunninghake DB, Pasternak RC,
Sidney C. Smith SC Jr., Stone NJ. Implications of Recent Clinical Trials for the National Cholesterol
Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110(2):227-39.
Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol,
ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003; 326:1423-30.
Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, et al. Blood cholesterol and vascular
mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies
with 55,000 vascular deaths. Lancet. 2007; 370(9602):1829-39.
McPherson R, Frohlich J, Fodor G, et al. Guidelines for the diagnosis and treatment of dyslipidemia and
prevention of cardiovascular disease: recommendations for the diagnosis and treatment of dyslipidemia
and prevention of cardiovascular disease. Can J Cardiol 2006; 22:913-927.
Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM, Fortmann SP, Franklin BA, Goldstein LB,
Greenland P, Grundy SM, Hong Y, Miller NH, Lauer RM, Ockene IS, Sacco RL, Sallis JF Jr, Smith SC Jr,
Stone NJ, Taubert KA. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002
update: Consensus Panel guide to comprehensive risk reduction for adult patients without coronary or
other atherosclerotic vascular diseases: American Heart Association Science Advisory and Coordinating
Committee. Circulation 2002; 106:388-91.
Shahar E, Chambless LE, Rosamond WD, et al. Plasma lipid profile and incident ischaemic stroke. The
atherosclerosis risk in communities (ARIC) study. Stroke 2003; 34:623-31.
Smith SC Jr, Blair SN, Bonow RO, Brass LM, Cerqueira MD, Dracup K, Fuster V, Gotto A, Grundy SM,
Miller NH, Jacobs A, Jones D, Krauss RM, Mosca L, Ockene I, Pasternak RC, Pearson T, Pfeffer MA,
Starke RD, Taubert KA. AHA/ACC scientific statement: AHA/ACC guidelines for preventing heart attack
and death in patients with atherosclerotic cardiovascular disease: 2001 update: a statement for
healthcare professionals from the American Heart Association and the American College of Cardiology.
Circulation 2001; 104:1577-79.
- 27 -
G4. Diabetes
- 28 -
G4. Diabetes
Canadian Best Practice Recommendations (2008): Recommendation 2.4 - Diabetes
Management
2.4a. Diabetes Assessment
i. All individuals in the general population should be evaluated annually for type 2 diabetes risk
on the basis of demographic and clinical criteria [Evidence Level C] (CDA).
ii. A fasting plasma glucose should be performed every 3years in individuals > 40 years of age
to screen for diabetes [Evidence Level C] (CDA). More frequent and/or earlier testing with either
a fasting plasma glucose or plasma glucose sample drawn 2 hours after a 75-g oral glucose
load should be considered in people with additional risk factors for diabetes [Evidence Level C]
(CDA). Some of these risk factors include family history, high-risk population, vascular disease,
history of gestational diabetes, hypertension, dyslipidemia, overweight, abdominal obesity,
polycystic ovary syndrome.
iii. In adults, fasting lipid levels (total cholesterol, HDL cholesterol, total glycerides and calculated
LDL cholesterol) should be measured at the time of diagnosis of diabetes and then every 1 to 3
years as clinically indicated. More frequent testing should be performed if treatment for
dyslipidemia is initiated [Evidence Level C] (CDA).
iv. Blood pressure should be measured at every diabetes visit [Evidence Level C] (CDA).
2.4b. Diabetes Management
i. Glycemic targets must be individualized; however, therapy in most patients with type 1 or type
2 diabetes should be targeted to achieve a glycated hemoglobin (HbA1c) level 7.0% in order to
reduce the risk of microvascular complications [Evidence Level A] (CDA) and, for individuals
with type 1 diabetes, macrovascular complications. [Evidence Level C] (CDA).
ii. To achieve an HbA1c 7.0%, patients with type 1 or type 2 diabetes should aim for a fasting
plasma glucose or preprandial plasma glucose targets of 4.0 to 7.0 mmol/L [Evidence Level B]
(CDA).
iii. The 2-hour postprandial plasma glucose target is 5.0–10.0 mmol/L [Evidence Level B]. If
HbA1c targets cannot be achieved with a postprandial target of 5.0–10.0 mmol/L, further
postprandial blood glucose lowering, to 5.0–8.0 mmol/L, can be considered [Evidence Level C]
(CDA).
iv. Adults at high risk of a vascular event should be treated with a statin to achieve an LDL
cholesterol 2.0mmol/L [Evidence Level A] (CDA).
v. Unless contraindicated, low dose acetylsalicylic acid (ASA) therapy (80 to 325 mg/day) is
recommended in all patients with diabetes with evidence of cardiovascular disease, as well as
for those individuals with atherosclerotic risk factors that increase their likelihood of
cardiovascular events [Evidence Level A] (CDA).
- 29 -
G4.1 Case Study: Diabetes
Case Study
A 55 year old man was admitted into the rehabilitation unit with a right MCA ischemic
stroke and he has no known history of medical problems or complications.
Q1. The nurse tells you that he has a fasting plasma glucose level of 127 mg/dL or 7.0
mmol/L. Is he diabetic?
Answer
1. Yes. Diagnosis of diabetes according to 2008 CDA Guidelines: Fasting plasma glucose 7.0
mmol/L (fasting = no caloric intake for at least 8 hours) or casual plasma glucose 11.1
mmol/L + symptoms of diabetes.
Discussion
Normal fasting glucose levels are defined as glucose <100 mg/dL (5.6 mmol/L), whereas
impaired fasting glucose has been defined at levels between 100 and126 mg/dL (5.6 and 6.9
mmol/L). A fasting plasma glucose level >126 mg/dL (7.0 mmol/L) or a casual plasma glucose
>200 mg/dL (11.1 mmol/L) meets the threshold for the diagnosis of diabetes (American
Diabetes Association 2004 and 2008 CDA Guidelines). Casual = any time of the day, without
regard to the interval since the last meal. Classic symptoms of diabetes = polyuria, polydipsia
and unexplained weight loss or 2 hour plasma glucose with a 75 gm oral glucose tolerance test
(11.1 mmol/L).
Q2. His Hemoglobin A1C level is 8.2%. What is its significance?
Answer
Hemoglobin A1c level >7% is defined as inadequate control of hyperglycemia.
Discussion
Glycosylated (or glycated) hemoglobin (hemoglobin A1c, Hb1c , HbA1c, or A1C; sometimes
also HgA1c) is a form of hemoglobin used primarily to identify the average plasma glucose
concentration over prolonged periods of time. It is formed in a non-enzymatic pathway by
hemoglobin's normal exposure to high plasma levels of glucose. Glycosylation of hemoglobin
- 30 -
has been implicated in nephropathy and retinopathy in diabetes mellitus. Monitoring the HbA1c in
type-1 diabetic patients may improve treatment (Larson et al. 1990).
Q3. Provide a classification for diabetes.
Answer
1. Prediabetes
2. Type 1 diabetes
3. Type 2 diabetes
4. Gestational diabetes
5. Other specific types – eg LADA (latent autoimmune diabetes in adults), prednisone-induced
hyperglycemia
Discussion
Diabetes is estimated to affect 8% of the adult population.
1. Prediabetes is a practical and convenient term for impaired fasting glucose and impaired
glucose tolerance, conditions that place individuals at risk of developing diabetes and its
complications.
2. Type 1 diabetes is an early onset failure of the pancreas to produce sufficient insulin.
3. Type 2 diabetes, on the other hand is characterized by insulin resistance and progressive
beta-cell failure.
Q4. How is diabetes related to stroke?
Answers
1. Diabetics have increased susceptibility to atherosclerosis, hypertension, obesity and
hyperlipidemia
2. Diabetics, in particular, have elevated levels of triglycerides, reduced levels of HDL
cholesterol and increased LDLs when compared to a non-diabetic sample.
3. Glucose intolerance has been shown to double the risk of a stroke
4. Diabetes has an independent effect on stroke risk after controlling for other risk factors with
relative risks ranging from 1.5-3.0.
5. Diabetes is present in 15% to 33% of patients with ischemic stroke and its treatment
reduces the stroke risk.
Discussion (from SREBR 11th edition; Teasell et al. 2008)
Diabetics have an increased susceptibility to atherosclerosis, hypertension, obesity and
hyperlipidemia. Elevated levels of triglycerides, reduced levels of HDL cholesterol and
increased small, dense LDL particles have been found in individuals with diabetes when
compared to a non-diabetic sample (Krauss 2004). The presence of glucose intolerance has
been shown to double the risk of a stroke (Sacco 2001). Sacco (2001) notes “Diabetes is a
determinant of atherosclerosis and microangiopathy of the coronary, peripheral and cerebral
- 31 -
arteries. Death from cerebrovascular disease is greatly increased among subjects with elevated
blood glucose values (Balkan et al. 1998). Cohort studies have demonstrated an independent
effect of diabetes on stroke risk after controlling for other risk factors with relative risks ranging
from 1.5 to 3.0 (Sacco et al. 1997, Wolf et al. 1991, Barrett-Connor et al. 1988, Kuller et al.
1985).” A recent study based on data from the FINNSTROKE study (Kaarisalo et al. 2005)
found that the presence of diabetes mellitus was associated with a higher risk for death and
disability by day 28 following stroke (OR = 1.20 and 1.51 respectively). Diabetes is frequently
encountered in stroke care, being present in 15% to 33% of patients with ischemic stroke and its
treatment reduces the stroke risk (American Diabetes Association 2004, Karapanayiotides et al.
2004, Woo et al. 1999).
As noted in reviews undertaken by Stern (1998) and Sacco (2001), conflicting information exists
regarding the relative risk of stroke in diabetic women (i.e. vs. non-diabetic women) when
compared to the relative risk for men with diabetes. Stern (1998) cited a summary of 16 studies
on the mortality and diabetes in which only half reported an increased risk for cardiovascular
disease in women as opposed to men. A recent analysis of data pooled from 9 large
epidemiological studies (n=27,269) conducted in the United States, revealed that diabetic
women had a 3.37-fold increased risk of fatal stroke (Women’s Pooling Project; Ho et al. 2003).
After adjustment for additional factors such as total cholesterol, BMI, systolic and diastolic blood
pressure, blood pressure medication use, smoking, educational status, age and race, diabetic
women had a similar risk for fatal stroke as non-diabetic women who had suffered a previous
stroke (hazard ratio = 3.07 vs. 4.67; p=0.43). Subjects with both diabetes and a history of
stroke were found to be 7.95 times more likely to experience a fatal stroke than women with no
history of diabetes or stroke. Ho et al. (2003) recommend that, given their analysis, women with
diabetes should be considered a high-risk group for fatal stroke and, therefore, be treated as
aggressively as patients with a history of previous stroke.
Q5. Is glycemic control associated with secondary stroke prevention?
Answer
1. The evidence that glycemic control reduces the risk of a second stroke has been slow to
come.
2. Glycemic control is often associated more with prevention of microvascular complications
(retinopathy, nephropathy, peripheral neuropathy) than macrovascular complications
(stroke, myocardial infarction, peripheral vascular disease)
3. Recent data suggests that glycemic control may help prevent strokes in patients with type 2
diabetes (particularly if they are obese) but not in type 1 diabetics
Discussion (from the SREBR 11th edition; Teasell et al. 2008)
A report from the UK Prospective Diabetes Study (UKPDS 33) demonstrated that the use of
intensive blood glucose measures (sulphonylurea or insulin) was associated with a significant
(p=0.29), 12% reduction of risk for any diabetes-related endpoint when compared to
conventional treatment (UKPDS Study Group, 1998). Most of this effect could be attributed to a
significant reduction in microvascular events. Examination of risk for stroke, in particular,
revealed no significant risk reduction associated with intensive glycemic control (RR = 1.11 95%
CI 0.81, 1.51). However, a secondary analysis of 342 obese patients treated with metformin
- 32 -
(UKPDS 34) revealed significant decreases in diabetes-related endpoints (p=0.0034), mortality
(p=0.021) and stroke (p=0.032) when compared to conventional intensive interventions for
blood glucose control including chlorpropamide, glibenclamide and insulin (UKPDS Study
Group, 1998).
In a recent systematic review and meta-analysis, Stettler et al. (2006) examined the reported
findings of 8 randomized controlled trials assessing the effects of improved glycemic control in
individuals with Type 1 and Type 2 diabetes mellitus (DM). Treatments included sulfonylurea,
metformin, insulin, multiple insulin injection therapy, continuous subcutaneous insulin infusion
(Type I only) and intensive self-monitoring of blood glucose. The authors determined that
improved glycemic control was associated with reduced risk for macrovascular complications
(IRR = 0.38 for Type 1 and 0.81 for Type 2 DM). For individuals with Type 1 DM, benefits were
most evident in the reduction of cardiac and peripheral vascular events, while in Type 2 DM,
reductions were observed in peripheral vascular disease and stroke. In addition, improved
glycemic control was most beneficial in younger patients who had DM of shorter duration.
Overall, in a 10-year period, the number of patients one would need to treat with enhanced
glycemic control measures in order to prevent a single macrovascular event were reported to be
16 for Type 1, 14 for low-risk Type 2 and 7 for high-risk Type 2 DM (Stettler et al. 2006).
The majority of studies examining the impact of glycemic control have not been specific to the
secondary prevention of macrovascular events. The PROactive study (Charbonnel et al. 2004,
Dormandy et al. 2005) examined the impact of treatment with pioglitazone (a peroxisome
proliferator activator gamma agonist) for glycemic control on the secondary prevention of
macrovascular events in patients with Type 2 DM. In this patient sample, the addition of
pioglitazone was associated with reduced risk for the recurrence of stroke.
Q6. List three different groups of treatments recommended for glycemic control.
Answer
1. Diet and exercise.
2. Oral hypoglycemic drugs.
3. Insulin.
Case Study (continued)
The 55 year old man who was admitted into the rehabilitation unit with a right MCA
ischemic stroke with no known history of medical problems or complications has now been
diagnosed with type 2 diabetes. His fasting blood sugar is 7.0 mmol/L and his hemoglobin
A1c is 8.2%. He has no other complications apart from the stroke.
Q7. Describe a glycemic control protocol for his new found Type 2 diabetes.
- 33 -
Answer
1. Lifestyle intervention is important (initiation of nutrition therapy and physical activity).
Discussion
Lifestyle Intervention
1. Nutritional therapy can reduce glycated haemoglobin by 1.0-2.0% and, when used with
other components of diabetes care, can further improve clinical and metabolic outcomes.
Consistency in carbohydrate intake, and spacing and regularity in meal consumption may
help control blood glucose and weight. Replacing high-glycemic index carbohydrates with
low-glycemic index carbohydrates in mixed meals has a clinically significant effect on
glycemic control in people with type 1 or type 2 diabetes.
2. Structured physical activity counselling by a physician or skilled healthcare personnel or
case managers has been very effective in increasing physical activity, improving glycemic
control, reducing the need for antihyperglycemic agents and insulin, and producing modest
but sustained weight loss. Before beginning a program of physical activity more vigorous
than walking, people with diabetes should be assessed for conditions that might be certain
contraindications to certain types of exercise, predispose to injury or be associated with
increased likelihood of cardiovascular disease.
Case Study (continued)
Despite nutritional interventions and a structured physical activity program his
Hemoglobin A1C still comes back at 8.3%.
Q8. What treatment is indicated now?
Answer
1. Because the HA1c remains elevated but <9.0% the treatment of choice is Metformin, an oral
hypoglycaemic agent.
Discussion
Metformin, an oral hypoglycaemic is considered the first-line treatment for type 2 diabetes.
Q9. How important is BP control important in this diabetic patient post stroke?
Answer
1. It is even more important than in non-diabetic patients.
- 34 -
Discussion (from the SREBR 11th edition; Teasell et al. 2008)
There is recent evidence that stroke patients with diabetes are at significantly increased risk of
disability and mortality (Otiniano et al. 2003; Ho et al. 2003). Despite the lack of conclusive
evidence proving a causal link between tight glycemic control and stroke risk reduction, there is
evidence that aggressive treatment of blood pressure (<150/85 mm Hg) among patients with
type II diabetes significantly reduces the risk of stroke by 44% (UK Prospective Diabetes Study
Group 1998). The Syst-Eur Investigators (1999) and HOPE Study investigators (2000) reported
substantial reductions in stroke risk with anti-hypertensive therapies (73% and 33%
respectively). There is strong evidence supporting the effectiveness of blood pressure control in
dramatically reducing the risk for both fatal and nonfatal stroke in individuals with diabetes.
Agents assessed for use with diabetic populations include ACE-inhibitors (captopril and
ramipril), β-blockers (atenolol) and calcium channel blockers (nitrendipine). Given the relative
effectiveness of the agents tested, and the reported benefits of a tightly controlled blood
pressure (UKDPS 1998), it has been suggested that the choice of medication may be less
important than reaching and maintaining an optimal targeted blood pressure (Vinik & Flemmer
2002).
A meta-analysis of twenty-seven trials examined the effectiveness of blood pressure reduction
on major cardiovascular events in adults with diabetes (Turnbull et al. 2005). The authors found
that for the outcome of stroke, there was no difference in the effects of treatment regimens
based on the use of ACE-inhibitors, calcium antagonists, angiotensin receptor blockers, betablockers and diuretics between individuals with and without diabetes. All regimens appeared
comparable in their ability to reduce the short to medium-term risks of macrovascular
complications. Lower target blood pressures resulted in fewer major cardiovascular events and
cardiovascular deaths in patients with diabetes compared to those without diabetes (p=0.03 and
0.02, respectively).
Conclusions from SREBR Regarding Diabetes and the Treatment of Hypertension
There is strong (Level 1a) evidence that treatment of hypertension in diabetic patients
reduces the risk of stroke. There is moderate evidence (Level 1b) evidence that neither
calcium channel blockers nor ACE inhibitors are superior to a diuretic in the initial
treatment of hypertension in individuals with diabetes mellitus, impaired fasting glucose
levels or normoglycemia.
AHA/ASA Treatment Recommendations for Diabetes




More rigorous control of blood pressure and lipids should be considered in patients with
diabetes
Although all major classes of antihypertensives are suitable for the control of BP, most
patients will require more than one agent. ACE inhibitors and ARBs are more effective
in reducing the progression of renal disease and are recommended as first-choice
medications for patients with diabetes mellitus.
Glucose control is recommended to near normoglycemic levels among diabetics with
ischemic stroke or TIA to reduce microvascular complications
The goal for Hb A1c should be 7%
- 35 -
Diabetic Monitoring
(Canadian Diabetes Association Clinical Practice Guidelines 2003)
Patient has no history of
diabetes
Patient is a known diabetic
Fasting blood glucose in
acute care to screen for
diabetes
Hb A1C (preferably in acute
care) to assesses diabetic
control
> 6.9 mmol/L
Repeat fasting blood
glucose in rehab (twice if
not done in acute care)
<5.7 mmol/L
Normal, no
further action
BG testing ac meals, pc
meals, and hs prn
5.7 – 6.9 mmol/L
(may indicate IFG/IGT)
>11 mmol/L
(diabetes)
2hPG in Oral Glucose
Tolerance test
(75-g OGTT)
6.1 – 6.9 (IGF)
Recommend to repeat
HbA1C after discharge
every 3-6 months
7.8 – 11.1 mmol/L (IGT)
Dietary and/or medication
interventions for IGT
IFG – impaired fasting glucose
IGT – impaired glucose tolerance
2hPG – 2 hour plasma glucose
References
American Diabetes Association. ADA clinical practice recommendations. Diabetes Care. 2004; 27:S1–
S143.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes
Association 2003 clinical practice guidelines for the prevention and management of diabetes in Canada.
Can J Diabetes 2003: 27(Suppl 2):S1-152.
Charbonnel B. Dormandy J. Erdmann E. Massi-Benedetti M. Skene A. PROactive Study Group. The
prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce
cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients. Diabetes
Care 2004; 27(7):1647-53.
- 36 -
Karapanayiotides T, Piechowski-Jozwiak B, van Melle G, Bogousslavsky J, Devuyst G. Stroke patterns,
etiology, and prognosis in patients with diabetes mellitus. Neurology 2004; 62:1558-62.
Larsen ML, Hørder M, Mogensen EF. Effect of long-term monitoring of glycosylated hemoglobin levels in
insulin-dependent diabetes mellitus. N. Engl. J. Med. 1990; 323(15):1021–25.
The DCCT Research Group. Adverse events and their association with treatment regimens in the
Diabetes Control and Complications Trial. Diabetes Care 1995; 18:1415-1427.
The DCCT Research Group. The effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;
329:977-986.
Stettler C, Allemann S, Juni P, et al. Glycemic control and macrovascular disease in types 1 and 2
diabetes mellitus: Meta-analysis of randomized trials. Am Heart J 2006; 152:27-38.
Teasell RW, Foley NC, Salter K, Bhogal SK, Jutai J, Speechley MR. Evidence-Based Review of Stroke
Rehabilitation (11th edition). Canadian Stroke Network; 2008.
Watkins P. The UKPDS. A model for gathering the evidence for the management of chronic diseases. UK
Prospective Diabetes Study Group. Journal of the Royal College of Physicians of London 1998;
32(6):510-1.
Woo D, Gebel J, Miller R, Kothari R, Brott T, Khoury J, Salisbury S, Shukla R, Pancioli A, Jauch E,
Broderick J. Incidence rates of first-ever ischemic stroke subtypes among blacks: a population-based
study. Stroke 1999; 30:2517–22.
- 37 -
G5. Lifestyle Modification
- 38 -
G5. Lifestyle Modification
Canadian Best Practice Recommendations (2008): Recommendation 2.1 – Lifestyle and
risk factor management
Persons at risk of stroke and patients who have had a stroke should be assessed for vascular
disease risk factors and lifestyle management issues (diet, sodium intake, exercise, weight,
smoking and alcohol intake). They should receive information and counselling about possible
strategies to modify their lifestyle and risk factors [Evidence Level B] (AU, NZ, RCP, VA/DoD).
Lifestyle and risk factor interventions should include:
i. Healthy balanced diet: High in fresh fruits, vegetables, low-fat dairy products, dietary and
soluble fibre, whole grains and protein from plant sources and low in saturated fat, cholesterol
and sodium, in accordance with Canada's Food Guide to Healthy Eating [Evidence Level B]
(ASA, CHEP, RCP).
ii. Sodium: The recommended daily sodium intake from all sources is the Adequate Intake by
age. For persons 9– 50 years, the Adequate Intake is 1500 mg. Adequate Intake decreases to
1300 mg for persons 50–70 years and to 1200 mg for persons > 70 years. A daily upper
consumption limit of 2300 mg should not be exceeded by any age group [Evidence Level B].
See www.sodium101.ca for sodium intake guidelines.
iii. Exercise: Moderate exercise (an accumulation of 30 to 60 minutes) of walking (ideally brisk
walking), jogging, cycling, swimming or other dynamic exercise 4 to 7days each week in addition
to routine activities of daily living [Evidence Level A]. Medically supervised exercise programs
are recommended for high-risk patients (e.g., those with cardiac disease) (ASA, CHEP, EBRSR,
NZ).
iv. Weight: Maintain goal of a body mass index (BMI) of 18.5 to 24.9 kg/m2 and a waist
circumference of <88cm for women and < 102 cm for men [Evidence Level B] (ASA, CHEP,
OCCPG).
v. Smoking: Smoking cessation and a smoke-free environment; nicotine replacement therapy
and behavioural therapy [Evidence Level B] (ASA, CHEP, CSQCS, RCP). For nicotine
replacement therapy, nortriptyline therapy, nicotine receptor partial agonist therapy and/or
behavioural therapy should be considered [Evidence Level A] (ASA, AU).
vi. Alcohol consumption: Two or fewer standard drinks per day; and fewer than 14 drinks per
week for men; and fewer than 9 drinks per week for women [Evidence Level C] (ASA, AU,
CHEP).
G5.1 Case Study: Lifestyle Modification
Case Study
- 39 -
A 54 year old male patient is admitted to the rehabilitation unit. He has been a lifelong
smoker and has a history of alcoholism. As well, he is overweight (with a BMI of 36kg/m2)
and acknowledges that he rarely engages in physical activity.
Q1. What known modifiable risk factors does he have?
Answer
 Smoking
 Alcohol
 Obesity
 Physical activity
Q2. How can physical activity affect the risk of stroke?
Answer
1. Physical activity reduces the risk of stroke through lowering BP, decreasing weight,
improving vasodilatation, improving glucose control and improving cardiovascular health.
Discussion
In a meta-analysis, Lee et al. (2003) demonstrated that highly active individuals were reported
as having a 27% lower risk of stroke than individuals who were less active. Moderately active
individuals also had a significantly reduced risk of stroke when compared with low active
individuals (RR=0.8, p<0.001). These benefits were reported for both ischaemic and
haemorrhagic strokes. A plausible explanation for these observed reductions is that physical
activity tends to lower BP and weight (Thompson et al. 2003, Kokkinos et al. 1995), enhance
vasodilation (Endres et al. 2003), improve glucose tolerance (Kohrt et al. 1993, Dylewicz et al.
1999), and promote cardiovascular health (Williams et al. 2002). Through lifestyle modification,
exercise can minimize the need for more intensive medical and pharmacological interventions
or enhance treatment end points.
For those at risk for recurrent stroke and TIA, sedentary behaviours complicate the recovery
process and affect recurrent risk status. Because disability after stroke is substantial and
because neurological deficits predispose to activity intolerance and physical deconditioning, the
challenge for clinicians is to establish a safe therapeutic exercise regimen that allows the patient
to regain pre-stroke levels of activity and then to attain sufficient physical activity and exercise to
reduce stroke recurrence (Sacco et al. 2006).
Recommendations from the Heart and Stroke Association (Sacco et al. 2006) include:
 Promote physical activity.
 Moderate intensity exercise for 30 minutes on most days of the week.
- 40 -
Q3. Is the patient obese?
Answer
Yes. Obesity is defined as a body mass index (BMI) of >30 kg/m2.
Discussion
Obesity, (defined as a body mass index (BMI) of >30 kg/m2) is strongly related to several major
risk factors, including hypertension, diabetes, dyslipidemia (Mann 1974, Turcato et al. 2000),
and poor diet. Clinically, abdominal obesity is defined by a waist circumference >102 cm (40 in)
in men and 88 cm (35 in) in women.
Q4. What can you tell the patient regarding obesity and diet in the secondary prevention
of stroke?
Answer
1. Abdominal obesity, more than general obesity, is related to stroke risk.
2. Diet is important in treatment of hypertension and hyperlipidemia.
Discussion
Obesity: Several studies have suggested that abdominal obesity, rather than general obesity,
is more related to stroke risk (Suk et al. 2003, Dey et al. 2002). For stroke, a significant and
independent association between abdominal obesity and ischemic stroke was found in all
racial/ethnic groups in the Northern Manhattan Study (Suk et al. 2003). Comparing the first
quartile of waist-to-hip ratio with the third and fourth quartiles gave ORs of 2.4 (95% CI, 1.5 to
3.9) and 3.0 (95% CI, 1.8 to 4.8), respectively, after adjustment for other risk factors and BMI.
Diet: Diet may be of significance in the modification of several risk factors for stroke including
hypertension and dyslipidemia. Dietary patterns, more than any single nutrient or food, may
have cumulative effects on the risk of stroke (Hu 2002).
Recommendations:
 Increased consumption of fruits, legumes, and vegetables.
 Low-fat, low cholesterol, and low sodium diet.
 Diet rich in omega-3 fatty acids, whole grains, and nuts.
In summary, weight reduction should be considered for all overweight ischemic stroke and TIA
patients to maintain the goal of a BMI of between 18.5 and 24.9 kg/m2 and a waist
circumference of <35 inches for women and <40 inches for men (Sacco et al. 2006).
- 41 -
Q5. The patient does not want to stop smoking. What can you tell him regarding smoke
cessation in the secondary prevention of stroke?
Answer
1. Smoking generally doubles the risk of stroke.
2. There is a dose-responsive risk.
3. The risk of stroke is reduced by quitting smoking.
Discussion
Smoking increases the risk of both ischemic and haemorrhagic stroke in a positive doseresponse manner at all ages, in both sexes, and among different racial/ethnic groups. Exposure
to environmental smoke is also associated with an increased risk of stroke. This means that
quitting smoking will act as a secondary preventative measure for him and a primary
preventative measure for his family.
Because ethical issues preclude conducting RCTs for smoking after stroke, RCTs of quitting
after stroke are not available. However, from observational studies, we know that risk of stroke
decreases after quitting and that the elevated risk disappears after 5 years. In addition,
smoking cessation is associated with a reduction in stroke-related hospitalizations (Lightwood et
al. 1997, Naidoo et al. 2000) and therefore supports secondary prevention efforts.
Q6. The patient tells you that he is going to need help in order to avoid cigarette
consumption. What can you suggest to help him?
Answer
1. Counseling, nicotine products, and oral smoking cessation medications have all been found
to be effective in helping smokers to quit.
Q7. What can you tell the patient regarding alcohol consumption as a risk factor for
stroke?
Answer
1. Light alcohol consumption reduces the risk of ischemic stroke.
2. Heavy drinking increases the risk of stroke.
Discussion
There is limited evidence that light (1-2 drinks per day) alcohol consumption reduces risk for
ischemic stroke while heavy drinking (more than 5 drinks per day) increases it. Given this
patient is an alcoholic, and in light of their obesity, recommendation of a significant reduction in
alcohol consumption would be appropriate.
- 42 -
Recommendations for Modifiable Behavioural Risk Factors (Sacco et al. 2006)
Class/Level of
Risk Factor Recommendation
Evidence
All ischemic stroke or TIA patients who have smoked in
Class I, Level C
the past year should be strongly encouraged not to
smoke.
Smoking
Avoid environmental smoke.
Class IIa, Level C
Counseling, nicotine products, and oral smoking
Class IIa, Level B
cessation medications have been found to be effective for
smokers.
Patients with prior ischemic stroke or TIA who are heavy
Class I, Level A
drinkers should eliminate or reduce their consumption of
alcohol.
Alcohol
Light to moderate levels of 2 drinks per day for men and
Class IIb, Level C
1 drink per day for nonpregnant women may be
considered.
Weight reduction may be considered for all overweight
Class IIb, Level C
ischemic stroke or TIA patients to maintain the goal of a
BMI of 18.5 to 24.9 kg/m2 and a waist circumference of
Obesity
<35 in for women and <40 in for men. Clinicians should
encourage weight management through an appropriate
balance of caloric intake, physical activity, and behavioral
counseling.
For those with ischemic stroke or TIA who are capable of Class IIb, Level C
engaging in physical activity, at least 30 minutes of
moderate-intensity physical exercise most days may be
Physical
considered to reduce risk factors and comorbid
Activity
conditions that increase the likelihood of recurrence of
stroke. For those with disability after ischemic stroke, a
supervised therapeutic exercise regimen is
recommended.
Class 1: Conditions for which there is evidence for and/or general agreement that the procedure or
treatment is useful and effective.
Class 2: Conditions for which there is conflicting evidence and/or a divergence of opinion about the
usefulness/efficacy of a procedure or treatment
 Class 2a – Weight of evidence or opinion is in favor of the procedure or treatment
 Class 2b – Usefulness/efficacy is less well estabilished by evidence or opinion).
Class 3: Conditions for which there is evidence and/or general agreement that the procedure or
treatment is not useful/effective and in some cases may be harmful.
Level of Evidence A: Data derived from multiple randomized clinical trials
Level of Evidence B: Data derived from a single randomized trial or nonrandomized studies
Level of Evidence C: Expert opinion or case studies
References
Dey DK, Rothenberg E, Sundh V, Bosaeus I, Steen B. Waist circumference, body mass index, and risk
for stroke in older people: a 15 year longitudinal population study of 70- year-olds. J Am Geriatr Soc
2002; 50:1510-18.
- 43 -
Dylewicz P, Przywarska I, Szczesniak L, Rychlewski T, Bienkowska S, Dlugiewicz I, Wilk M. The
influence of short-term endurance training on the insulin blood level, binding, and degradation of 125Iinsulin by erythrocyte receptors in patients after myocardial infarction. J Cardiopulm Rehabil 1999; 19: 98105.
Endres M, Gertz K, Lindauer U, Katchanov J, Schultze J, Schrock H, Nickenig G, Kuschinsky W, Dirnagl
U, Laufs U. Mechanisms of stroke protection by physical activity. Ann Neurol 2003; 54:582-90.
Hu FB. Dietary pattern analysis: a new direction in nutritional epidemiology. Curr Opin Lipidol 2002; 13:39.
Kohrt WM, Kirwan JP, Staten MA, Bourey RE, King DS, Holloszy JO. Insulin resistance in aging is related
to abdominal obesity. Diabetes 1993; 42:273-81.
Kokkinos PF, Narayan P, Colleran JA, Pittaras A, Notargiacomo A, Reda D, Papademetriou V. Effects of
regular exercise on blood pressure and left ventricular hypertrophy in African-American men with severe
hypertension. N Engl J Med 1995; 333:1462-67.
Lee CD, Folsom AR, Blair SN. Physical activity and stroke risk. Stroke 2003; 34:2475-82.
Lightwood JM, Glantz SA. Short-term economic and health benefits of smoking cessation: myocardial
infarction and stroke. Circulation 1997; 96:1089-96.
Mann GV. The influence of obesity on health (second of two parts). N Engl J Med 1974; 291:226-32.
Naidoo B, Stevens W, McPherson K. Modelling the short term consequences of smoking cessation in
England on the hospitalisation rates for acute myocardial infarction and stroke. Tobacco Control 2000;
9:397400.
Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke
or transient ischemic attack: a statement for healthcare professionals from the American Heart
Association/American Stroke Association Council on Stroke: co-sponsored by the Council on
Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this
guideline. Stroke 2006; 37:577-617.
Suk SH, Sacco RL, Boden-Albala B, Cheun JF, Pittman JG, Elkind MS, Paik MC, for the Northern
Manhattan Stroke Study. Abdominal obesity and risk of ischemic stroke: the Northern Manhattan Stroke
Study. Stroke 2003; 34:1586-92.
Thompson PD, Buchner D, Pina IL, Balady GJ, Williams MA, Marcus BH, Berra K, Blair SN, Costa F,
Franklin B, Fletcher GF, Gordon NF, Pate RR, Rodriguez BL, Yancey AK, Wenger NK, for the American
Heart Association Council on Clinical Cardiology Subcommittee on Exercise, Rehabilitation, and
Prevention; and American Heart Association Council on Nutrition, Physical Activity, and Metabolism
Subcommittee on Physical Activity. Exercise and physical activity in the prevention and treatment of
atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology
(Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical
Activity, and Metabolism (Subcommittee on Physical Activity). Circulation 2003; 107:3109-16.
Turcato E, Bosello O, Di Francesco V, Harris TB, Zoico E, Bissoli L, Fracassi E, Zamboni M. Waist
circumference and abdominal sagittal diameter as surrogates of body fat distribution in the elderly: their
relation with cardiovascular risk factors. Int J Obes Relat Metab Disord 2000; 24:1005-10.
Williams MA, Fleg JL, Ades PA, Chaitman BR, Miller NH, Mohiuddin SM, Ockene IS, Taylor CB, Wenger
NK, for the American Heart Association Council on Clinical Cardiology Subcommittee on Exercise,
Cardiac Rehabilitation, and Prevention. Secondary prevention of coronary heart disease in the elderly
- 44 -
(with emphasis on patients 75 years of age): an American Heart Association scientific statement from
the Council on Clinical Cardiology Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention.
Circulation 2002; 105:1735-43.
- 45 -
Key Study: Alcohol Consumption
Reynolds K, Lewis B, Nolen JD, Kinney GL, Sathya B, He J. Alcohol consumption and
risk of stroke: a meta-analysis. JAMA 2003;289(5):579-588.
Author, Year,
Country,
Pedro Score
Reynolds et al.
2003
ns
Methods
Outcomes
Meta-analysis
Included 35 observational
studies examining the effects of
alcohol consumption on stroke
risk.
Relative Risk (RR)
2.5
A significant (p=0.01), J-shaped relationship was
found between the amount of alcohol consumed
per day and the risk for ischaemic stroke.
Individuals who consumed 1-2 drinks per day had
the least risk for ischaemic stroke (RR=0.72),
while those having more than 5 drinks per day had
the most risk (RR=1.69) when compared to a
group of abstainers. Results also showed a linear,
dose-dependent effect, with heavy drinking (> 5
drinks per day) associated with a relative risk of
haemorrhagic stroke of 2.18
Relative Risk of Stroke Associated with Varying Levels of
Alcohol Consumption
*
9*
64 1.6
.
1
2
*
18
2.
1.5
1
*
83 .8*
0.
0
*
72
0.
Stroke
Types
Overall
Ischemic
0.5
Hemmorrhagic
0
<12
12 to 24
24 to 60
>60
Alcohol Consumption (grams/day)
* Significant risk reductions/increases (95% CI excludes 1.00)
Importance: This meta-analysis confirmed that heavy alcohol consumption (> 5 drinks per day)
increases risk for stroke and that this relationship is dose-dependent. However, this study also
showed that light-to-moderate alcohol consumption (1-2 drinks per day) may be a protective
factor.
Relevant SREBR Conclusion: Heavy alcohol consumption increases the risk of stroke. Light
to moderate alcohol consumption may be beneficial.
- 46 -
Key Study: Smoking
Bonita R, Duncan J, Truelsen T, Jackson RT, Beaglehole R. Passive smoking as well as
active smoking increases the risk of acute stroke. Tob Control 1999;8:156-160.
Author, Year,
Country,
Pedro Score
Bonita et al.
1999
New Zealand
ns
Methods
Outcomes
ODDS RATIO
Cohort Study
521 patients with first-ever acute stroke
and 1851 community controls were
included in this population-based study.
Controls were obtained from a crosssectional survey of major cardiovascular
risk factors measured in the same
population. Questionaires were
administered by trained nurse
interviewers.
8
7
6
5
4
3
2
1
0
Environmental tobacco smoke exposure
was associated with a significantly
increased risk of stroke among both nonsmokers and long-term ex-smokers (odds
ratio (OR) = 1.82; 95% confidence
interval (95% CI) = 1.34 to 2.49).
Additionally, active smokers had a
fourfold risk of stroke compared with to
those who had never smoked (OR = 4.14;
95% CI = 3.04 to 5.63).
Adjusted Odds Ratios showing Risk of First ever Stroke
Associated with Smoking Status: Men & Women, 35-74
7.06
6.63
R ef erenc e G ro up
3.89
3.45
1.82
1.89
1.00
N o nE xpo se d
to E T S *
E xpo s ed
to E T S *
≥15 cig/ day
P a ssive S m o kers
All odds ratios are significant
(CI excludes 1.00 and p< .05)
6- 14
cig/ day
≤5 c ig/ da y
A c tive s m o kers
< 2 yea rs
2- 10 yea rs
E x-S m o kers
SMOKING STATUS
*Environmental To bacco Smoke
Importance: Bonita et al. (1999) demonstrated that increased risk of stroke is not confined to
active smokers. Exposure to environmental tobacco smoke is associated with an increased risk
of stroke among non-smokers and long- term (> 10 years) ex-smokers (OR = 1.82). The
authors also reported that active smoking is associated with a four-fold increase in the risk of
stroke when active smokers are compared to all non-smokers and a six-fold increase when they
are compared to non-smokers who are not exposed to environmental smoke.
Relevant SREBR Conclusion: Smoking increases the risk of stroke while smoking cessation
reduces the risk.
- 47 -
Key Study: Physical Activity
Lee CD, Folsom AR, Blair SN. Physical activity and stroke risk. Stroke 2003;34:2475-2482.
Author, Year
Country,
Pedro Score
Lee et al.
2003
ns
Methods
Outcomes
Meta-analysis
Included 23 studies (18 cohort
studies and 5 case control)
published between 1983 and
2002 that examined the
association between physical
activity and stroke incidence or
mortality.
Highly active individuals were reported as having a
27% lower risk of stroke than individuals who were
designated as “low active”. Individuals who were
designated as moderately active also had a
significantly reduced risk of stroke when compared
to low active individuals (RR=0.80, p<0.001).
Relative Risk of Stroke Incidence and Mortality for Highly
Active Individuals Across Different Study Types
Relative Risk (RR)
1
0.8
0.6
0.75
0.73
95% CI (.69 to .82)
95% CI (.67 to .79)
0.36
0.4
0.2
95% CI (.25 to .52)
0
Cohort
Case-Control
Both
Type of Study
Note: All risk reductions significant (p<.05).
Importance: This meta-analysis demonstrated the benefits activity and that both high and
moderate levels of activity decrease the risk of ischaemic and haemorrhagic strokes.
Relevant SREBR Conclusion: There is limited (Level 2) evidence that increasing physical
activity is associated in a graded manner with reduction in risk of stroke (both ischaemic and
haemorrhagic). Even moderate levels of physical activity are associated with a significant stroke
risk reduction (20%).
- 48 -
Key Study: Behavioural Intervention
Fagerberg B, Wikstrand J, Berglund G, Ola Samuelsson O, Agewall S, for the Risk Factor
Intervention Study Group. Mortality rates in treated hypertensive men with additional risk
factors are high but can be reduced. A randomized intervention study. Am J Hypertens
1998;11:14-22.
Author, Year
Country
Pedro Score
Risk Factor
Intervention Study
(RIS)
Fagerberg et al.
1998
(Sweden)
7 (RCT)
Methods
Outcomes
High-risk male patients, aged 50 – 72
with treated hypertension, were
randomized to receive a multifactoral,
behavioural intervention (n=253) or
usual care (n=255). The behavioural
intervention consisted of a program
designed to change eating habits and a
smoking cessation program. Patients
were followed for a mean of 6.6 years.
Overall risk for cardiovascular events
(both fatal and nonfatal) was 29% lower
in the intervention group (p=0.41). Risk
of stroke was lower in the intervention
group (RR=0.53). Relative to the usual
care group, the intervention group
demonstrated lowered serum
cholesterol (p<0.0001) and higher
adjusted smoking quit rates (p=0.12)
after 3 years of follow-up.
Reduction of Mortality Rates in Treated Hypertensive Men with Additional Risk Factors:
Fagerberg et al. 1998.
70
RR*=0.62
60
Intervention
Number of Events
50
Usual Care
RR*=0.56
40
30
RR**=0.53
20
10
Treated hypertensive men with at least one
additional risk factor (defined as elevated
cholesterol, diabetes mellitus or smoking) were
randomly allocated to receive usual care (n=255)
or a risk factor group intervention to encourage
dietary change and smoking cessation (n=253).
Mean follow-up time was 6.6 years. Outcomes
included fatal and nonfatal cardiovascular events.
Relative to usual care, the risk of fatal and
nonfatal cardiovascular events was 29% lower in
the behavioural intervention group.
0
All
Deaths
C.V.
Death
Fatal
stroke
Non-fatal
stroke
*RR=Relative Risk; ** Relative Risk for cumulative
stroke events.
- 49 -
Percentage of Both Nonsmoker and Alive Patients for
Multifactorial Risk Factor
Invention vs. Usual Care
Mortality for Smokers
vs. Non-smokers
30.4
30
28
30
p=.000
25
16.7
20
15
10
5
Non-smoker and Alive (%)
Mortality of Patients (%)
35
p=0.01
2
25
20
11
15
10
5
0
0
Smokers
Multifactorial Risk
Factor
Intervention
Non-smokers
Usual Care
Importance: Fagerberg et al. (1998) demonstrated that behavioural interventions can reduce
overall risk for both fatal and nonfatal cardiovascular events. Results showed that, relative to
the usual care group, the intervention group had lowered serum cholesterol (p<0.0001) and
higher adjusted smoking quit rates (p=0.12) after 3 years of follow-up.
Relevant SREBR Conclusion: Behavioural intervention can be an effective means to reduce
stroke risk.
- 50 -
G6. Homocysteine and Stroke
- 51 -
G6. Homocysteine and Stroke
G6.1 Case Study: Homocysteine
Case Study
A 45 year old male presented with a right subcortical stroke. The neurologist feels that it
was probably due to a high homocystine levels in his blood.
Q1. What is homocysteine and what are considered normal serum levels?
Answer
1. Homocysteine is a sulphur-containing amino acid.
2. Normal serum plasma homocysteine level is 5-15 umol/L.
Discussion
Homocysteine is a sulphur-containing amino acid that has been linked to cardiovascular disease
and stroke. A normal serum level of plasma homocysteine is from 5 to15 µmol/L. Mid to
moderate elevations are from 16 to100 µmol/L. Levels greater than 100mm/L are considered to
be severe hyperhomocysteinemia.
Q2. Is hyperhomocystinemia associated with secondary cardiovascular events?
Answer
1. Yes
Discussion
Bos et al. (2005) demonstrated that an elevated risk for secondary cardiovascular events
including stroke and TIA was associated with high plasma homocysteine levels (>=13.7 µmol/L
vs <= 10.7 µmol/L) among stroke patients 45 years or younger (HR=1.6; 95% IC 1 to 2.5).
Q3. What is the relationship between folic acid, vitamin B6, and Vitamin B12 levels and
plasma homocysteine levels?
Answer
- 52 -
1. Folic acid, vitamin B6 and vitamin B12 levels are inversely related to plasma homocysteine
levels.
Discussion
While it is true that levels of folic acid, vitamin B6 and Vitamin B12 are inversely related to
plasma homocysteine levels, treatment with folic acid and/or B6 and B12 has not been shown to
reduce the risk of stroke (Toole et al. 2004).
For patients with ischemic stroke or TIA and hyperhomocysteinemia, daily standard multivitamin
preparations with adequate B6 (1.7 mg/d), B12 (2.4 µg/d), and folate (400 µg/d) are reasonable
measures to reduce homocysteine levels, given their safety and low cost. However, there is no
evidence that reducing homocysteine levels will lead to a reduction in stroke recurrence.
Reference
Bos MJ, van Goor ML, Koudstaal PJ, Dippel DW. Plasma homocysteine is a risk factor for recurrent
vascular events in young patients with an ischaemic stroke or TIA. J Neurol 2005; 252:332-37.
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischaemic stroke to
prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention
(VISP) randomized controlled trial. JAMA 2004; 291:565-575.
- 53 -
Key Study: Homocysteine and Stroke
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with
ischaemic stroke to prevent recurrent stroke, myocardial infarction, and death: the
Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA
2004;291:565-575.
Author, Year
Country,
Pedro Score
VISP Trial
Toole et al.
2004
USA/Canada/
Scotland
8 (RCT)
Methods
Outcomes
N=3680 subjects with nondisabling
cerebral infarction. All patients received
best medical & surgical care and, in
addition, were randomly assigned to
receive either daily high-dose
supplementation of folic acid (2.5 mg.),
vitamin B6 (25 mg) and vitamin B12 (0.4
mg) or daily low-dose supplementation
of the same vitamins (200g, 6g and
20g respectively. Outcomes included
recurrent cerebral infarction (primary),
coronary heart disease (secondary) and
death (secondary). Follow-up=2 years.
There was no treatment effect on any
endpoint. RR for any of the outcomes
(unadjusted) was 1.0. Chances of an
outcome event within the 2-year follow-up
period were 18% in high dose and 18.6% in
the low dose group. There was, however,
an association between baseline
homocysteine levels and outcomes such
that a 3mol/L lower level was associated
with a 10% risk reduction for stroke (p=0.05)
in the low-dosage group and a nonsignificant trend to lowered risk (2%) in the
high-dosage group.
Importance: A meta-analysis (Bouchy et al. 1995) suggested that high levels of homocysteine
area ssociated with increased risk of therosclerotic vascular disease and that a prolonged
reduction of plasma homocysteine of 5 umol/L would reduce risk by approximately 33%. While
an association was demonstrated between baseline homocysteine levels and stroke risk,
treatment with folic acid, vitamin B6 and vitamin B12 supplementation did not result in the
expected risk reductions. Study limitations that may have affected the results include a small
sample population with only mildly elevated homocysteine levels, very modest reductions in
homocysteine levels and a limited follow-up period. A recent post hoc analysis of VISP data
identified a subgroup of participants most likely to benefit from VISP supplementation (Spence
et al. 2005).
Relevant SREBR Conclusion: Treatment with folic acid and/or vitamins B6 & B12 does not
reduce stroke risk.
- 54 -
G7. Antiplatelet Agents
- 55 -
G7. Antiplatelet Agents
Canadian Stroke Guidelines (2008): Recommendation 2.5 – Antiplatelet therapy
All patients with ischemic stroke or transient ischemic attack should be prescribed antiplatelet
therapy for secondary prevention of recurrent stroke unless there is an indication for
anticoagulation [Evidence Level A] (ASA, AU, CSQCS, ESO, NZ, RCP, VA/DoD).
i. ASA, combined ASA (25 mg) and extended-release dipyridamole (200 mg), or clopidogrel may
be used depending on the clinical circumstances [Evidence Level A].
ii. For adult patients on ASA, the usual maintenance dosage is 80 to 325 mg per day [Evidence
Level A] (CSQCS, VA/DoD), and in children with stroke the usual maintenance dosage of ASA is
3 to 5 mg/kg per day for the prevention of recurrent stroke [Evidence Level C] (AHA-P).
iii. Long-term combinations of ASA and clopidogrel are not recommended for secondary stroke
prevention [Evidence Level B] (CHARISMA, MATCH).
G7.1 Case Study: Antiplatelet Agents
Case Study
A 68 year old man with a right MCA is admitted into the rehabilitation unit. He has had a
carotid ultrasound that shows a cholesterol plaque occluding 40% of the lumen of the right
internal carotid vessel.
Q1. Assuming that he has had an atherotrombotic stroke, what treatment would you
recommend to avoid a stroke recurrence?
Answer
1. Antiplatelet agents.
Discussion
Platelets and fibrin aggregate on diseased or damaged arteries and promote the formation of
thrombi which can occlude the artery at the site of formation or embolize to a different location.
As such, platelets and the mechanisms of adhesion, activation, and aggregation play an
important role in thrombus development and progression of atherothrombosis (Serebruany et al.
2004, Goldszmidt and Caplan 2003, Easton 2001).
- 56 -
Q2. What is the major adverse side-effect of antiplatelet therapy?
Answer
1. Increased risk of bleeding.
Discussion
Antiplatelet agents increase the risk of bleeding (OR=1.2) (Antithrombotic Trialists´Collaboration
2002).
Q3. Knowing there may be an increased risk of bleeding, would this influence your
decision to use antiplatelet treatment and why?
Answer
1. No. Risk-benefit ratio is low with advantages for stroke prevention.
Discussion
In high risk individuals with a history of previous stroke or TIA, antiplatalet therapy is associated
with a decrease in risk of ischemic stroke (OR=.75). This means that a 25% reduction in risk of
stroke carries with it the risk of approximately 1-2 additional major extracranial bleeds per 1000
patients per year (Antithrombotic Trialists´Collaboration 2002).
Q4. Describe the different types of antiplatelet therapy?
Answer
 ASA
 Thienopyridines – Clopidogrel and Ticlopidine
 Dipyridamole
Q5. If antiplatelet therapy is the treatment of choice, which drug would be the initial
choice?
Answer
1. Monotherapy with low-dose ASA (81 mg/day) would be the initial choice.
- 57 -
Discussion
Aspirin is the least expensive, most widely studied, and most commonly used antiplatelet agent
(Goldsmitz and Caplan 2003). Treatment with aspirin reduces the risk of a vascular event in
high risk patients (including recurrent stroke) by 23% (Antithrombotic Trialists´Collaboration
2002).
In a meta-analysis, Algra and Van Gijn (1999) evaluated the benefit of ASA monotherapy in
patients with prior stroke or TIA and found that aspirin reduced the odds of stroke, myocardial
infarction or vascular death by 16% and the relative risk reduction when compared to placebo
was 13%.
Q6. The patient’s family believe the patient should get at least 325 mg of Aspirin per day.
How do you respond?
Answer
1. ASA 81 mg/day is just as effective as 325 mg/day with less potential side effects.
Discussion
Low doses of ASA may be effective in interfering with platelet aggregation (blocking
thromboxane A2 formation) while not substantially inhibiting the production of prostacyclin (an
antiaggregation prostaglandin produced in the endothelial cells which can be inhibited with
higher doses of ASA) (Easton 2001).
Doses of 75-150 mg/day of ASA appear to have the greatest effect, reducing the risk of stroke
by 32% (Antithrombotic Trialists´Collaboration 2002). Risk for major bleeding associated with
ASA therapy has not been found to be dose-dependent and is similar with all levels of daily
dosages under 325 mg (Diener and Ringleb 2002, Antithrombotic Trialists´ Collaboration 2002).
However, Serebuny et al. (2004) reported in a metanalysis that low dose ASA (<100mg/day) is
associated with a lower risk (3.6%) for hemorrhagic events (including both major and minor
events), while doses in excess of 100 mg/day were associated with a relatively high risk (9.1%).
Higher doses of aspirin have also been shown to be associated with a greater risk of
gastrointestinal hemorrhage (Hansson et al. 1998, Antithrombotic Trialists’ Collaboration 2002).
Q7. When should antiplatelet treatment be initiated and when should it be terminated?
Answer
Antiplatelet treatment should be initiated in the acute phase and is usually continued for the rest
of the patient’s life.
Discussion
- 58 -
Antiplatelet therapy in acute stroke patients results in 9 fewer recurrent strokes for every 1000
patients treated. With prolonged therapy (mean 29 months) this number increases to 36 per
1000 treated (Antithrombotic Trialists’ Collaboration 2002).
Case Study (continued)
You tell the nurse that the patient is going to begin taking 81mg of aspirin/day but the
nurse tells you that the patient is allergic to ASA.
Q8. Which other treatment options are available?
Answer
1. Clopidogrel.
Discussion
Clopidogrel, a thienopyridine, is an accepted alternative for patients in whom ASA therapy is
contraindicated. Thienopyridines inhibit platelet activation and aggregation (Easton 2001,
MacWalter and Shirley 2002, Goldszmidt and Caplan 2003).
Q9. The nurse questions you about the difference between ASA and Clopidogrel in
terms of effectiveness.
Answer
1. ASA and Clopidogrel have comparable effectiveness.
Discussion
Among patients with previous TIAs or stroke, Clopidogrel therapy has been found to reduce the
risk of vascular events and further stroke events slightly more than aspirin therapy (OR= 0.9 and
OR=0.86, respectively). This is equivalent to an absolute reduction in stroke events of 16 per
1000 patients (Hankey et al. 2004).
Clopidogrel is also indicated in patients who have an ischemic stroke while taking aspirin. There
is no evidence that increasing the dose of aspirin provides additional benefit (Saco et al. 2006).
Q10. The nurse asks you why Clopidogrel is not used more often as the first line
treatment.
- 59 -
Answer
1. Clopidogrel has more side-effects for the same efficacy.
Discussion
Although thienopyridines and ASA do not have a significant difference in terms of the risk of
intracranial or extracranial haemorrhage, treatment with thienopyridines is associated with a
reduced risk for gastrointestinal haemorrhage (OR=0.71), indigestion/nausea/vomiting
(OR=0.84), an increased risk for diarrhea (OR=1.34 to 2.27), and skin rashes (OR=1.32 to 2.23)
(Hankey et al 2004). Thienopyridines are more expensive and not available in a generic
preparation. Treatment with ticlopidine requires frequent and ongoing blood testing and is no
longer used.
Q11. Clopidogrel and Ticlopidine are both thienopyridines. Describe the differences
between these two medications.
Answer
1. Ticlopidine has unacceptable side-effect profile, being associated with neutropenia and
thrombotic thrombocytopenia purpura.
Discussion
Ticlopidine: Ticlopidine is associated with a higher rate of adverse effects than ASA (62.3%
versus 53,2%). It is also associated with neutropenia more often than ASA (OR=2.7; Hankey et
al. 2004) and has been linked to thrombotic thrombocytopenic purpura (Macwalter and Shirley
2002, Diener and Ringleb 2002). Furthermore, blood tests are required at 2 week intervals for
the first 3 months of therapy and screening must be continued indefinitely (Easton 2001,
Macwalter and Shirley 2002, Diener and Ringleb 2002). Given the above, ticlopidine is not
considered an effective or acceptable alternative to aspirin in the secondary prevention of stroke
(Sacco 2003).
Clopidogrel: The benefits of clopidogrel are similar to those of ticlopidine, while its side effects
are similar to those seen with ASA therapy (Easton 2001, Macwalter and Shirley 2002, Diener
and Ringleb 2002). Clopidogrel was compared with ASA in the CAPRIE study (1996). The
primary end point, a composite outcome of ischemic stroke, MI, or vascular death, occurred in
8.7% fewer patients treated with clopidogrel compared with aspirin (P=0.043). However, in a
subgroup analysis of those patients with prior stroke, the risk reduction with clopidogrel was
slightly smaller and nonsignificant. Clopidogrel is an appropriate substitute for those patients
who are intolerant of ASA or sho have a strokewhile on ASA (ASA-failures).
Q12. The resident asks about using combination therapy of different antiplatelet
therapies.
- 60 -
Answers
1. The addition of aspirin to clopidogrel had little added benefit and the small demonstrated
benefit when compared to Clopidogrel alone was outweighed by a higher rate of bleeding
events associated with combined therapy (i.e. MATCH trial).
2. The addition of dipyridamole to ASA has a small benefit over ASA alone with a higher rate of
side effects (largely headaches).
3. There does not appear to be a significant benefit to combination over single antiplatelet
therapy.
Discussion
Because antiplatelet drugs work through different mechanisms, in theory the effects of different
drugs may be cumulative. The only way to prove this is with comparative studies of different
treatment strategies.
Clopidogrel Plus ASA versus Clopidogrel Alone. The MATCH study: compared treatment
with clopidogrel plus ASA to clopidogrel monotheraphy in high risk patients with recent
ischaemic stroke or TIA. 7,559 patients with previous ischemic stroke and at least one
additional vascular factor were assigned at random to receive either ASA (75 mg/day; n=3797)
or matching placebo (n=3802). All patients received 75 mg clopidogrel once per day.
Treatment continued for 18 months. Primary outcome was the composite of ischaemic stroke,
myocardial infarction, vascular death and rehospitalization for an acute ischaemic event.
A small non-significant trend favouring the combination of clopidogrel and ASA vs clopidorgrel
alone (relative risk reduction=6.4%; p=0.244) was noted. In the combined group there were
significantly more incidents of life-threatening bleeding as well as more incidents of major
bleeding and minor bleeding (Diener et al. 2004).
Clopidogrel Plus ASA verses ASA Alone. The CHARISMA study compared the
effectiveness of clopidogrel plus ASA to ASA alone in patients with either cardiovascular
disease or multiple risk factors. There was no significant benefit associated with combination
therapy when compared to ASA monotherapy. Combined therapy was associated with
increased episodes of moderate to severe bleeding.
Summary: Clopidogrel Plus ASA Combination Therapy. Although both studies suggest that
the combination of clopidogrel and ASA is ineffective, this could be due to the study limitations.
Nevertheless, there is little convincing evidence that the addition of clopidogrel to aspirin
improves outcome in high-risk individuals with previous TIA or stroke (Norris and Barnett 2006).
Dipyridamole Plus ASA. The ESPS study compared high doses of ASA plus dipyridamole to
placebo in patients with a previous stroke or TIA. Both fatal and nonfatal strokes were reported
to be reduced by 38.1% when compared to placebo. The ESPS-II compared ASA plus
Dipyridamole to ASA monotherapy or dipyradole monotherapy in patients with a previous stroke
or TIA. 6,602 participants with a recent history of TIA or complete ischaemic stroke were
randomly allocated to one of 4 groups: (1) Dipyrimadole 200 mg twice/day, (2) ASA 25 mg
twice/day (3) ASA 25 mg and Dipyrimadole 200 mg each twice per day or (4) matched placebo.
Primary outcomes used to examine the efficacy of dipyridamole & ASA were stroke (fatal &
nonfatal); death (from all other causes) and stroke and/or death (combined outcome). Mean
- 61 -
length of follow-up was 2 years. The risk of stroke or death was reduced by 18% with ASA
alone, 16% with dypiridamole alone and 24% with the combination.
The ESPRIT study: compared ASA plus dypiridamole versus ASA monotheraphy in patients
with previous stroke or TIA. A reduction in ischemic events was noted but was not quite
significant. More patients withdrew from the combination therapy group than the ASA group,
mostly due to headache-related side effects.
Recommendations for Antiplatelet Drug Use (Heart and Stroke Foundation 2003)
(modified)
Use antiplatelet agents in secondary prevention of stroke when the origin is not
cardioembolic.
Current choices include ASA, Plavix and Aggrenox (strong evidence).
Ticlid (ticlopidine) is no longer recommended for stroke prevention due to its side effect
profile
Dose of 81-325 mg ASA/day should be initiated within 48 hours after the first stroke.
Aggrenox and Plavix are indicated in Canada only if there is an ASA failure, i.e.
TIA/stroke on ASA.
ASA use results in an 18% risk reduction of stroke vs. placebo.
High doses of ASA are not required to achieve therapeutic effect, i.e. 81-325 mg daily is
effective.
Plavix is at least as effective as ASA and may be slightly more effective.
Combo ASA and dipyridamole results in up to a 37% risk reduction of stroke vs. placebo
and is up to 23% more effective than either alone.
Combination of Plavix/ASA is no better than ASA alone.










AHA/ASA Recommendations for Antithrombotic Therapy for Noncardioembolic Stroke or
TIA (Sacco et al. 2006).
For patients with noncardioembolic ischemic stroke or TIA, antiplatelet agents rather than oral
anticoagulation are recommended to reduce the risk of recurrent stroke and other
cardiovascular events.





Aspirin (50 mg – 325 mg/day), the combination of aspirin and extended-release
dipyridamole, and clopidogrel are all acceptable options for initial therapy.
Clopidogrel may be considered over aspirin alone on the basis of direct-comparison
trials. Insufficient data are available to make evidence-based recommendations with
regard to choices between antiplatelet options other than aspirin. Selection of an
antiplatelet agent should be individualized based on patient risk factor profiles, tolerance
and other clinical characteristics.
Addition of aspirin to clopidogrel increases the risk of haemorrhage and is not routinely
recommended for ischemic stroke or TIA patients.
For patients allergic to aspirin, clopidogrel is reasonable.
For patients who have an ischemic cerebrovascular event while taking aspirin, there is
no evidence that increasing the dose of aspirin provides additional benefit. Although
- 62 -
alternative antiplatelet agents are often considered for noncardioembolic patients, no
single agent or combination has been well studied in patients who have had an event
while receiving aspirin.
References
Algra A, van Gijn J. Cumulative meta-analysis of aspirin efficacy after cerebral ischaemia of arterial origin.
Journal of Neurology, Neurosurgery and Psychiatry 1999; 66:255.
Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet
therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. BMJ 2002; 324:7186.
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk
of ischaemic events (CAPRIE). Lancet 1996; 348(9038):1329-39.
Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone
after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised,
double-bline, placebo-controlled trial. Lancet 2004; 364:331-37.
Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2.
Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143:1-13.
Diener HC, Ringleb P. Antithrombotic secondary prevention after stroke. Current Treatment Options in
Cardiovascular Medicine 2002; 4:429-40.
Easton JD. Future perspectives for optimizing oral antiplatelet therapy. Cerebrovasc Dis 2001; 11(Suppl
2):23-28.
Goldszmidt AJ, Caplan LR. Stroke Essentials. Royal Oak, Michigan: Physicians' Press, 2003.
Hankey G, Sudlow CLM, Dunbabin DW. Thienopyridines or aspirin to prevent stroke and other serious
vascular events in patietns at high risk of vascular disease? A systematic review of the evidence from
randomized trials. Stroke 2004; 31:1779-84.
Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H,
Westerling S. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with
hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial: HOT Study
Group. Lancet 1998; 351:1755–62.
MacWalter RS, Shirley CP. A benefit-risk assessment of agents used in the secondary prevention of
stroke. Drug Safety 2002; 25:943-63.
Norris JW, Barnett HJ. CHARISMA: the antiplatelet saga continues. Stroke 2006; 37:2428-29.
Sacco RL. Preventing stroke among black patients: the challenges continue. JAMA 2003; 289:3005-07.
Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke
or transient ischemic attack: a statement for healthcare professionals from the American Heart
Association/American Stroke Association Council on Stroke: co-sponsored by the Council on
Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this
guideline. Stroke 2006; 37:577-617.
- 63 -
Serebruany VL, Malinin AI, Eisert RM, Sane DC. Risk of bleeding complications with antiplatelet agents:
Meta-analysis of 338.191 patients enrolled in 50 randomized controlled trials. American Journal of
Hematology 2004; 75:40-47.
- 64 -
Key Study: Antiplatelet Agents
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in
patients at risk of ischaemic events (CAPRIE). Lancet. 1996 Nov 16;348(9038):1329-39.
Author, Year
Country,
Pedro Score
CAPRIE
Steering
Committee
Gent et al. 1996
Canada/
International
8 (RCT)
Methods
Outcomes
Patients with a history of recent
cardiovascular events were
randomized to receive 75 mg
clopidogrel + aspirin placebo
(n=9553) or 325 mg aspirin +
clopidogrel placebo (n=9546) for
1-3 years.
Patients treated with clopidogrel had a 5.32%
annual risk of ischaemic stroke, MI or vascular
death compared with 5.83% with aspirin. The
difference in rates was statistically significant
and reflects a relative risk reduction of 8.7% in
favour of clopidogrel. There were no differences
in terms of safety.
Outcome Event Groups for Clopidogrel vs. Aspirin Treatment
Percentage of Patients (%)
100
90
p=.043
p=.076
p=.081
p=.29
80
p=.71
70
60
50
40
30
20
10
IS, MI or vascular
death
IS, MI, amputation
or vascular death
Vascular death
IS =ischemic stroke; MI = myocardial infraction; * includes
primary intracerebral hemorrhage
Aspirin
Clopidogrel
Aspirin
Clopidogrel
Aspirin
Clopidogrel
Aspirin
Clopidogrel
Aspirin
Clopidogrel
0
Any* stroke, MI, Death of any cause
death of any cause
Non-fatal
Fatal
Importance: The CAPRIE trial demonstrated that Clopidogrel was a suitable substitute for
ASA, although not significantly better.
Relevant SREBR Conclusion: There is moderate (Level 1b) evidence that Clopidogrel is
similar to aspirin with regard to safety, but as effective as ticlopidine in reducing the risk of
recurrent stroke.
- 65 -
Key Study: Antiplatelet Agents
Diener HC, Bogousslavsky J, Brass LM, et al. 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 2004;
364:331-337.
Author, Year
Country,
Pedro Score
MATCH
Investigators
Diener et al.
2004
International
8 (RCT)
Methods
Outcomes
7599 patients who had an
ischaemic stroke or TIA within 3
months. Patients also had at
least one of previous ischaemic
stroke, previous myocardial
infarction, angina pectoris,
diabetes mellitus or symptomatic
peripheral artery disease (PAD).
Participants were randomly
assigned to the ASA treatment
group (clopidogrel 75 mg/day plus
aspirin 75 mg/day; n=3797) or the
placebo condition (75 mg/day
clopidogrel plus matching
placebo). Treatment continued
for 18 months. Follow-up
occurred at 1,3,6,12 and 18
months after randomization.
With regard to the primary outcome (composite of
ischaemic stroke, myocardial infarction, vascular
death or re-hospitalization for any acute ischaemic
event), there was a small, nonsignificant trend
favouring the combination of clopidogrel and ASA
vs. clopidogrel alone (relative risk reduction =
6.4%; p=0.244). With regard to the secondary
endpoint of ischaemic stroke, either fatal or nonfatal, there was a relative risk reduction of 7.1%
in favour of combined therapy. However, this
trend was not significant (p=0.353). In the
combined therapy group, there were significantly
more incidents of life-threatening bleeding
(p<0.0001) as well as more incidents of major
bleeding (p<0.0001) and minor bleeding
(p<0.0001). Gastrointestinal bleeding was the
most common cause of both life-threatening and
major bleeding events in the clopidogrel plus
aspirin treatment group.
Percentage of
Patients (%)
Percentage of Patients with Bleeding Events for Patients Recieving
Both Aspirin and Clopidogrel vs Clopidogrel
3
2.5
2
1.5
1
0.5
0
*
*
*
Life-threatening
Bleeding
Aspirin and Clopidogrel
Major Bleeding
Clopidogrel
Minor Bleeding
*p<.0001
Importance: This study showed that the combination of Clopidogrel and ASA was no more
effective than the two of them together and only served to increase the incidence of bleeding
events.
Relevant SREBR Conclusion: The combination of clopidogrel and ASA is not more effective
than either Clopidogrel or ASA alone and is associated with an increased incidence of bleeding
events.
- 66 -
Key Study: Antiplatelelt Agents
Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke
Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of
stroke. J Neurol Sci 1996;143:1-13.
Author, Year
Country,
Pedro Score
ESPS-2
Diener et al.
1996
Belgium
8 (RCT)
Methods
Outcomes
6602 patients with prior TIA or
stroke were randomized to
receive 50 mg ASA daily,
dipyridamole, the 2 agents in
combination or placebo.
The primary end points were
stroke death or the combined
stroke/death.
After 24 months of follow-up, the risk of stroke or
death was reduced by 18% with ASA alone;16%
with dipyridamole alone and 24% with
combination therapy when compared to placebo.
In the group receiving combination therapy, the
risk for stroke was reduced by 36% vs. placebo.
There was no statistically significant effect on the
overall death rate.
Secondary End Points for Various Drug Treatments
p< .001
Ischemic events
p< .01
Other vascular events
Myocardial Infraction
NS
0
2
4
6
8
10
12
14
Percentage of Patients (%)
ASA =aspirin; DP =dipyridamole;
DP-ASA =combination of DP and ASA
Placebo
- 67 -
ASA
16
18
DP
DP-ASA
20
p=
0.
07
3
p=
0.
05
6
15
p=
0.
03
9
p=
0.
01
5
20
p=
.0
16
RRR
25
p=
.0
13
30
.0
06
p<
0.
00
1
35
p=
0
40
p=
0.
00
2
p<
0
.0
01
Relative Risk Reductions (RRR) for Several Treatment
Group Comparisons
10
5
0
ASA vs. Pl
DP vs. Pl
DP-ASA vs. Pl
ASA =aspirin; DP =dipyridamole; DPASA =combination of DP and ASA;
Pl =placebo; v s.
DP-ASA vs.
ASA
Stroke
DP-ASA vs. DP
Stroke or Death
Percentage of Patients Reporting Adverse Events for Various Drug
Treatments
Dizziness
NS
Bleeding any site
p<0.001
Headache
p<0.001
p<0.001
Diarrhea
Gastric pain
NS
Vomiting
p=0.046
NS
Dyspepsia
Nausea
NS
Gastrointestinal event
p=0.042
p<0.001
Any Adverse Effect
0
10
20
30
40
Percentage of Patients (%)
ASA =aspirin; DP =dipyridamole;
DP-ASA =combination of DP and ASA
Placebo
50
ASA
60
DP
70
DP-ASA
Importance: This study showed an ASA-dipyridamole combination was more effective than
ASA alone in preventing recurrent strokes.
Relevant SREBR Conclusion: ASA in combination with dipyridamole is more effective than
ASA alone in reducing the risk for recurrent stroke.
- 68 -
G8. Atrial Fibrillation and Coumadin
- 69 -
G8. Atrial Fibrillation and Coumadin
Canadian Stroke Guidelines (2008): Recommendation 2.6 – Antithrombotic Therapy in
Atrial Fibrillation
Patients with stroke and atrial fibrillation should be treated with warfarin at a target international
normalized ratio of 2.5, range 2.0 to 3.0 (target international normalized ratio of 3.0 for
mechanical cardiac valves, range 2.5 to 3.5) [Evidence Level A], if they are likely to be compliant
with the required monitoring and are not at high risk for bleeding complications (ASA, AU,
CSQCS, ESO, SIGN, VA/DoD).
G8.1 Atrial Fibrillation and Anticoagulation
Case Study
A 76 year old man is admitted to your rehabilitation unit with a left MCA stroke. In the
emergency department atrial fibrillation was diagnosed and was thought to be the cause of
the stroke.
Q1. What is the relationship between atrial fibrillation and the development of stroke?
Answer
1. AF is a powerful, independent risk factor for ischemic stroke.
2. Leads to embolic stroke, with emboli formed within the fibrillating left atrium.
Discussion
Atrial fibrillation (AF) has been identified as a powerful, independent risk factor for ischemic
stroke (SPAF III writing committee 1998) increasing the risk of stroke by as much as 5-fold for
individuals over the age of 70. 16% of all ischemic strokes within this age group are associated
with non-valvular AF (Hart and Halperin 2001, Devuyst and Bogousslavsky 2001). The
formation of left atrial thrombi in AF patient is linked to stasis within the fibrillating atrium,
although contributing factors have not been well defined (Hart and Halperin 2001, Khairy and
Nattel 2002).
Q2. What are some other cardiac disorders that could lead to an embolic stroke?
- 70 -
Answer
Cardiac risk factors can be divided into atrial fibrillation, myocardial disease and cardiac valve
factors.
Discussion
Cardiac Risk Factors for Ischaemic Stroke
Definite Risk Factor
Atrial Fibrillation
Myocardial Disease
Coronary artery disease
Cardiac failure
Left ventricular failure
Intracardiac thrombus
Cardiac Valve Abnormalities
Mitral stenosis
Mitral valvular calcifications
Prosthetic valves
Endocarditis
Possible Risk Factor
Patent foramen ovale
Atrial septic aneurysm
Spontaneous echo contrast
Valve strands
Q3. Once a patient with AF has had a stroke, what is the risk for recurrence of stroke?
Answers
1. Within the first 2 weeks following a stroke event, the risk of recurrence has been estimated
to be 0.1%-1.3% per day. Conversely, the risk for AF patients with a history of prior stroke
or TIA has been estimated to be 12% per annum (Devuyst and Bogousslavsky 2001).
2. The presence of AF in individuals following their first ischemic stroke has been shown to be
associated with higher rates of stroke recurrence (6.9% vs 4.7%, p=0.04) (Marini et al.
2005).
Q4. Describe some contraindications for anticoagulant therapy?
Absolute Contraindications
 Subarachnoid or cerebral haemorrhage
 Malignant hypertension
 Serious active bleeding
 Recent brain, eye and spinal cord surgery
 Lack of patient compliance ie. monitoring the PT, PTT.
Relative Contraindications
 Severe hypertension
 Major recent surgical operation
- 71 -






Recent major trauma
Active GI bleeding
Bacterial endocarditis
Severe renal failure
Severe hepatic failure
Haemorrhagic diathesis
Q5. Which drug would you use for anticoagulant therapy in this patient?
Answer
Warfarin (a vitamin K antagonist).
Discussion
The activity of warfarin is monitored by the measurement of INR. Because of the prolonged
onset action of Warfarin, the results of dosage adjustments may not be seen until 3 to 5 days
later. Warfarin is highly bound to plasma proteins and medications may increase its effect. Also
other medications may decrease the effect of warfarin by inducing hepatic microsomal
enzymes.
Q6. The patient’s daughter asks you if treatment with warfarin is effective and also wants
to know the optimal range of INR.
Answers
1. Warfarin has been shown to reduce the risk of recurrent stroke in appropriate patients by
almost two-thirds.
2. INR should range between 2.0 and 2.5 or 3.0.
Discussion
Anticoagulation therapy has been found to reduce the rate of stroke in patients with previous
TIA by 56% (p=0.09) and by 63% (p<0.001) in patients with history of stroke (Hart et al. 2004).
The most effective range of INR (International Normalized Ratio) has been identified as being
between 2.0 and 2.5 (Albers et al. 2001, Khairy and Nattel 2002, Hart and Halperin 2001, Oden
et al. 2006).
Summary of Anticoagulation with Adjusted-dose Warfarin in Atrial Fibrillation
Study
AFASAK 1
BAATAF
SPAF 1
CAFA
INR Range
2.8 – 4.2
1.5 – 2.7
2.0 – 4.5
2.0 – 3.0
- 72 -
Reduced Stroke Risk
+
+
+
+ (ns)
VA-Stroke Prevention
EAFT
SPAFII
SPAFIII
Second Copenhagen Study AF
1.5 – 2.7
2.5 – 4.0
2.0 – 4.5
2.0 – 3.0
2.0 – 3.0
2.2 – 3.5 vs.
Japanese AF study
1.5 – 2.1
ns = reduction in stroke risk was non-significant
+
+
+
+
+
+
(both groups)
Q7. The patient’s daughter asks you when treatment should be initiated.
Answer
1. Warfarin should be initiated as soon as possible.
2. A delay in initiating warfarin is appropriate for patients with large infarcts or uncontrolled
hypertension.
Discussion
Hart el al. (2002) suggest that ASA followed by early initiation of adjusted dose warfarin therapy
is reasonable for AF patients following a primary stroke. The authors also suggested that
anticoagulation could be undertaken as soon as the patient is both medically and neurologically
stable.
The AHA/ASA Guidelines recommend initiation of oral anticoagulation within 2 weeks of an
ischemic stroke or TIA; however, for patients with large infarcts or uncontrolled hypertension,
further delays may be appropriate.
Q8. The nurse asks you to explain to the patient any negative side effects associated
with warfarin.
Answer
1. Main side effect is an increased risk of bleeding.
Discussion
Anticoagulant therapy is associated with the increased risk of both major and minor
haemorrhagic events. The risk for bleeding is related to a number of factors including intensity
of treatment, patient age, and fluctuation of INR (Devuyst and Bogousslavsky 2001, MacWalter
and Shirley 2002). Hart and Halperin (2001) reported that the rate of intracerebral haemorrhage
while on an appropriately adjusted dose to be 0.5% per year.
Q9. The resident asks why not use ASA alone as treatment for atrial fibrillation.
- 73 -
Answer
1. ASA therapy (300-325 mg/day) is associated with a reduction in the risk of stroke with AF.
2. Meta-analyses clearly show Coumadin to be more effective than ASA.
Discussion
ASA therapy (300-325mg/day) is associated with a reduction in the risk of stroke in individuals
with AF, as compared to no treatment. However, doses of 150-200 mg/day do not appear to be
either safe or effective. Conversely, results of the EAFT trial as well as several meta analyses
(Segal et al. 2000, Albers et al. 2001, Hart et al. 1999, Perrret-Guillaume and Whal 2004) clearly
suggest that anticoagulant therapy (dose adjusted warfarin) is more effective in preventing
strokes among individuals with atrial fibrillation than antiplatelet therapy (ASA).
For patients unable to take oral anticoagulants, aspirin (325 mg/d) is recommended.
References
Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE. Antithrombotic therapy in atrial
fibrillation. Chest 2001; 119:194S-206S.
Devuyst G, Bogousslavsky J. Cardiac Anomalies. In:Norris JW, Hachinski V, eds. Stroke Prevention. New
York: Oxford University Press, 2001:161-75.
Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with
atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131:492-501.
Hart RG, Halperin JL. Atrial fibrillation and stroke: Concepts and controversies. Stroke 2001; 32:803-808.
Hart RG, Palacio S, Pearce LA. Atrial fibrillation, stroke, and acute antithrombotic therapy: Analysis of
randomized clinical trials. Stroke 2002; 33:2722-27.
Hart RG, Pearce LA, Koudstaal PJ. Transient ischaemic attacks in patients with atrial fibrillation.
implications for secondary prevention: The European Atrial Fibrillation Trial and Stroke Prevention in
Atrial Fibrillation III Trial. Stroke 2004; 01.
Khairy P, Nattel S. New insights into the mechanisms and management of atrial fibrillation. CMAJ 2002;
167:1012-20.
MacWalter RS, Shirley CP. A benefit-risk assessment of agents used in the secondary prevention of
stroke. Drug Safety 2002; 25:943-63.
Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of
ischemic stroke: results from a population-based study. Stroke 2005; 36:1115-19.
Oden A, Fahlen M, Hart RG. Optimal INR for prevention of stroke and death in atrial fibrillation: a critical
appraisal. Thromb Res 2006; 117:493-99.
Perret-Guillaume C, Wahl DG. Low-dose warfarin in atrial fibrillation leads to more thromboembolic
events without reducing major bleeding when compared to adjusted-dose. Thromb Haemost 2004;
91:394-02.
- 74 -
Segal JB, McNamara RL, Miller MR, et al. Prevention of thromboembolism in atrial fibrillation. A metaanalysis of trials of anticoagulatns and antiplatelet drugs. Journal of General Internal Medicine 2000;
15:56-67.
SPAF III writing committee for the Stroke Prevention in Atrial Fibrillation Investigators. Patients with
nonvalvular atrial fibrillation at low risk of stroke during treatment with aspirin: Stroke Prevention in Atrial
Fibrillation III Study. JAMA 1998; 279:1273-77.
- 75 -
Key Study: Atrial Fibrillation and Coumadin
Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE. Antithrombotic
therapy in atrial fibrillation. Chest 2001;119:194S-206S.
Author, Year
Country,
Pedro Score
Albers et al. 2001
ns
Methods
Outcomes
Reviewed literature that examined
the efficacy and safety of different
anticoagulation therapies for the
prevention of stroke in patients with
non-rheumatic atrial fibrillation.
Found that adjusted dose warfarin therapy
is substantially more effective than ASA in
reducing risk of cardioembolic stroke in
individuals with atrial fibrillation. The most
effective INR was found to be 2.5, with a
range from 2.0 and 3.0.
Importance: Albers et al. (2001) found that, for patients with atrial fibrillation who are at high
risk of stroke, adjusted dose warfarin therapy is more effective than aspirin.
Relevant SREBR Conclusion: Atrial fibrillation increases the risk of cardioembolic stroke;
stroke patients with AF are at high risk for recurrent stroke and should receive anticoagulation
therapy.
- 76 -
Key Study: Atrial Fibrillation and Coumadin
Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke
in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131:492-501.
Author, Year
Country,
Pedro Score
Hart et al.
1999
ns
Methods
Outcomes
Meta-analysis
Identified 16 randomized trials that
tested the efficacy and safety of
antithrombotic agents used to prevent
stroke in patients with atrial fibrillation.
Treatment with adjusted-dose warfarin was
found to reduce stroke by 62% with absolute
risk reductions of 2.7% per year for primary
prevention and 8.4% per year for secondary
prevention. In comparison, treatment with
aspirin was found to reduce stroke by 22%.
Overall, adjusted-dose warfarin was found to
be more efficacious than aspirin.
Importance: Hart et al. (1999) demonstrated that while adjusted-dose warfarin and aspirin are
both effective in reducing the risk of stroke in patentis with atrial fibrillation, warfarin is
substantially more efficacious than aspirin.
Relevant SREBR Conclusion: There is strong (Level 1a) evidence that the use of
anticoagulation therapy, particularly with adjusted dose warfarin, substantially reduces the risk
of primary and secondary stroke in individuals with atrial fibrillation.
- 77 -
Key Study: Atrial Fibrillation and Coumadin
Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack
or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet
1993;342:1255-1262.
Author, Year
Country,
Pedro Score
EAFT
European Atrial Fibrillation
Study Group 1993
Netherlands
7 (RCT)
Methods
Outcomes
1,007 non-rheumatic atrial
fibrillation patients with a recent TIA
or minor ischaemic stroke were
grouped by eligibility to receive anticoagulation therapy. Anticoagulation eligible patients (group
1) were randomized to receive
adjusted dose anticoagulation (INR
2.5 – 4.0), aspirin (300 mg/day) or
placebo. Those not eligible for anticoagulation therapy (group 2) were
randomized to receive either ASA
or placebo. Mean duration of
follow-up was 2.3 years.
Among group 1 patients, risk of
stroke was reduced from 12% per
year to 4% per year when anticoagulation therapy was compared
to placebo (HR = 0.34). Among all
patients receiving ASA, the rate of
events was 15% compared to 19%
for those patients receiving placebo
(HR=0.83). Anticoagulation therapy
was significantly more effective in
preventing stroke than ASA
(HR=0.60). The rate of major
bleeding events while on anticoagulation therapy was 2.8% and
0.9% while taking ASA.
Effect of Oral Anticoagulation and Aspirin on Risk of Vascular
Events in Patients with Non-Rheumatic Atrial Fibrillation (NRAF)
after a Transient Ischemic Heart Attack (TIA): ~2 year Follow-up
Hazard Ratio (HR)
1.00
0.82
0.83
p=.37
p=.12
0.86
0.80
0.60
0.40
0.20
0.53
p=.001
p=.31
0.91
p=.48
0.34
p<.001
0.00
Anticoagulant vs. Placebo (Group 1* Only)
* P atients eligible for anticoagulatio n.
**P atients ineligible for antico agulation.
Aspirin vs. Placebo (Groups 1and 2* combined)
Comparison
Primary Outcome
All Strokes
All Deaths
Importance: This study showed that Coumadin was significantly more effective than ASA in
reducing the risk of stroke in patients with non-rheumatic atrial fibrillation following a TIA or
minor ischemic event.
Relevant SREBR Conclusion: There is strong (Level 1a) evidence that the use of
anticoagulation therapy, particularly with adjusted dose warfarin, substantially reduces the risk
of primary and secondary stroke in individuals with atrial fibrillation.
- 78 -
Key Study: Atrial Fibrillation and Coumadin
European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in
patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med
1995;333:5-10.
Author, Year
Country,
Pedro Score
EAFT (European Atrial
Fibrillation Study Group) 1995
Netherlands
ns
Methods
Outcomes
Using a subset of 214 patients
with non-rheumatic atrial
fibrillation from the EAFT, the
authors calculated INR-specific
incidence rates of stroke.
The ideal intensity of
anticoagulation was found to be
between an INR of 2.0 and 3.9.
INRs below 2.0 were not found to
have any treatment effect, while
INRs above 5.0 were found to
increase the occurrence of
bleeding complications.
Incidence of Ischemic and Bleeding Events According to
INR* Range (Intensity of Anticoagulation Therapy)
INR* Range
≥5.0
4.0-4.9
Major Bleeding
3.0-3.9
Ischemic Event
2.0-2.9
Either Event
<2.0
0
10
20
30
40
50
60
70
Number of Events per 100 person years
*International Normalized Ratios
Importance: This trial demonstrated that the ideal intensity of anticoagulation for patients with
atrial fibrillation and a recent minor cerebral ischemia is between an INR of 2.0 and 3.9. Based
on their findings, the authors recommended that INRs below 2.0 and above 5.0 should be
avoided.
Relevant SREBR Conclusion: There is strong (Level 1a) evidence that treatment with ASA
300 – 325 mg/day is associated with reduced risk of stroke when compared to no treatment in
individuals with atrial fibrillation. However, anticoagulant therapy (dose-adjusted warfarin) is
more effective in preventing strokes among individuals with atrial fibrillation than antiplatelet
therapy (ASA).
- 79 -
Key Study: Atrial Fibrillation and Coumadin
Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke
associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in
Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med 1992;327:1406-1412.
Methods
Outcomes
571 men with chronic
non-rheumatic atrial
fibrillation were randomly
allocated to a treatment
condition receiving
adjusted dose, low
intensity warfarin (INR 1.5
– 2.7) or to a matching
placebo condition. Mean
follow-up was 1.7 years.
Among patients with no history of stroke, the reduction
in risk for stroke associated with warfarin therapy was
0.79 (p=0.001). The annual event rate in patients
over age 70 was 4.8%/annum in the placebo group
and 0.9%/annum in the warfarin therapy group.
Stroke was more common among patients with a
history of previous cerebral infarction (9.3%/annum in
the placebo group vs. 6.1%/annum in the warfarin
group). Major haemorrhages occurred at the rate of
1.3% per annum with warfarin therapy.
The Relationship between Primary and Secondary End
Points in Patients with no History of Cerebral Infraction for
Warfarin vs. Placebo Treatment
p=.003
10
Percentage of Patients
per year (%/yr)
Author, Year
Country,
Pedro Score
Veterans Affairs
Stroke Prevention
in Nonrheumatic
Atrial Fibrillation
Investigators
Ezekowitz et al.
1992
USA
8 (RCT)
8
6
NS
p=.001
4
2
0
Cerebral Infraction
Death
Placebo
- 80 -
Cerebral Infraction or
Death
Warfarin
Intercurrent Events for Patients with no
History of Cerebral Infraction for Warfarin
vs. Placebo Treatment
Percentage of Patients per year (%/yr)
14
12
p=.04
10
8
6
NS
4
NS
2
0
Vascular
Events
Major
Hemorrhage
Placebo
Minor
Hemorrhage
Warfarin
Importance: Coumadin reduces the risk of stroke in chronic atrial fibrillation when compared to
placebo.
Relevant SREBR Conclusion: There is strong (Level 1a) evidence that the use of
anticoagulation therapy, particularly with adjusted dose warfarin, substantially reduces the risk
of primary and secondary stroke in individuals with atrial fibrillation.
- 81 -
G9. Patent Foramen Ovale
- 82 -
G9. Patent Foramen Ovale
G9.1 Case Study: PFO
Case Study
You see a 45 year old woman in your outpatient clinic. She has had a TIA and her
echocardiogram shows a patent foramen ovale (PFO).
Q1. What it is a PFO?
Answer
1. Patent foramen ovale is a congenital defect in the interarterial septum.
2. Associated with a right-left shunt.
Discussion
Patent foramen ovale (PFO) is a persistence of an embryonic defect in the interatrial septum
and is present in up to 27% of the general population. Atrial septal aneurysms, defined as >10mm excursions of the interatrial septum, are less common and are present in approximately 2%
of the population. The prevalence of PFOs and atrial septal aneurysms does not appear to vary
by race/ethnicity (Rodriquez 2003).
- 83 -
Q2. Is PFO a stroke risk factor?
Answer
1. Studies have found an association between PFO and strokes of unknown etiology.
Discussion
The prevalence of PFO in patients <55 years with strokes of unknown etiology is 46%
(Bogousslavsky et al.1996, Homma et al. 2002, Lamy et al. 2002). Estimates for the rate of
annual stroke recurrence in patients with strokes of unknown etiology and PFO vary widely,
ranging from 1.5% to 12%, depending on the study population (Mas and Zuber 1995, Mas et al.
2001, De Castro et al. 2000, Bogousslavsky et al. 1996, Homma et al. 2002, Cujec et al. 1999).
Q3. How can PFO be treated?
Answer
1. Antiplatelet therapy unless there is some other indication for anticoagulation.
Discussion
For patients with an ischemic stroke or TIA and a PFO, antiplatelet therapy is reasonable to
prevent a recurrent event. Warfarin is appropriate for high-risk patients who have other
indications for oral anticoagulation, such as those with an underlying hypercoagulable state or
evidence of venous thrombosis (Sacco et al. 2006).
Q4. The resident asks you if it is necessary to close the PFO.
Answer
1. Operation is not recommended unless it is a recurrent stroke despite optimal medical
therapy.
Discussion
Insufficient data exists to make a recommendation about PFO closure in patients with a first
stroke and a PFO. PFO closure may be considered for patients with recurrent stroke of
unknown etiology despite optimal medical therapy. Can choose either an open surgical or a
transcatheter closure.
Open Surgical: In a study involving 32 young patients with stroke of unknown etiology or TIA
who underwent surgical closure of a PFO, there were no major complications or recurrent
vascular events at the 19 month follow-up (Ruchat et al. 1997, Devuyst et al. 1996). In a 2-year
- 84 -
follow-up of a cohort of 91 patients with stroke of unknown etiology or TIA who underwent
surgical closure, 7 TIAs but no major complications were reported (Dearani et al. 1999).
Transcatheter: A review of 10 non-randomized unblinded transcatheter closure studies for
secondary prevention reported a 1-year rate of recurrent neurological events of 0% to 4.9% in
patients undergoing transcatheter closure compared with 3.8% to 12.0% in medically treated
patients (Khairy et al. 2003).
References
Bogousslavsky J, Garazi S, Jeanrenaud X, Aebischer N, Van Melle G. Stroke recurrence in patients with
patent foramen ovale: the Lausanne Study: Lausanne Stroke With Paradoxical Embolism Study Group.
Neurology 1996; 46:1301-05.
Cujec B, Mainra R, Johnson DH. Prevention of recurrent cerebral ischemic events in patients with patent
foramen ovale and cryptogenic strokes or transient ischemic attacks. Can J Cardiol 1999; 15:57-64.
Dearani JA, Ugurlu BS, Danielson GK, Daly RC, McGregor CG, Mullany CJ, Puga FJ, Orszulak TA,
Anderson BJ, Brown RD Jr, Schaff HV. Surgical patent foramen ovale closure for prevention of
paradoxical embolism-related cerebrovascular ischemic events. Circulation 1999; 100(supp ll):171-75.
Devuyst G, Bogousslavsky J, Ruchat P, Jeanrenaud X, Despland PA, Regli F, Aebischer N, Karpuz HM,
Castillo V, Guffi M, Sadeghi H. Prognosis after stroke followed by surgical closure of patent foramen
ovale: a prospective follow-up study with brain MRI and simultaneous transesophageal and transcranial
Doppler ultrasound. Neurology 1996; 47:1162–66.
Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP, for the PFO in Cryptogenic Stroke Study
(PICSS) Investigators. Effect of medical treatment in stroke patients with patent foramen ovale: Patent
Foramen Ovale in Cryptogenic Stroke Study. Circulation 2002; 105:2625–31.
Lamy C, Giannesini C, Zuber M, Arquizan C, Meder JF, Trystram D, Coste J, Mas JL. Clinical and
imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA
Study: Atrial Septal Aneurysm. Stroke 2002; 33:706-11.
De Castro S, Cartoni D, Fiorelli M, Rasura M, Anzini A, Zanette EM, Beccia M, Colonnese C, Fedele F,
Fieschi C, Pandian NG. Morphological and functional characteristics of patent foramen ovale and their
embolic implications. Stroke 2000; 31:2407-13.
Khairy P, O’Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of patent foramen
ovale and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med 2003; 139:753-60.
Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G, Coste J, for the Patent Foramen
Ovale and Atrial Septal Aneurysm Study Group. Recurrent cerebrovascular events associated with patent
foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001; 345:1740-46.
Mas JL, Zuber M. Recurrent cerebrovascular events in patients with patent foramen ovale, atrial septal
aneurysm, or both and cryptogenic stroke or transient ischemic attack: French Study Group on Patent
Foramen Ovale and Atrial Septal Aneurysm. Am Heart J 1995; 130:1083-88.
Rodriguez CJ, Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP, for the PICSS Investigators.
Race-ethnic differences in patent foramen ovale, atrial septal aneurysm, and right atrial anatomy among
ischemic stroke patients. Stroke 2003; 34:2097-2102.
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Ruchat P, Bogousslavsky J, Hurni M, Fischer AP, Jeanrenaud X, von Segesser LK. Systematic surgical
closure of patent foramen ovale in selected patients with cerebrovascular events due to paradoxical
embolism: early results of a preliminary study. Eur J Cardiothorac Surg 1997; 11:824-27.
Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke
or transient ischemic attack: a statement for healthcare professionals from the American Heart
Association/American Stroke Association Council on Stroke: co-sponsored by the Council on
Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this
guideline. Stroke 2006; 37:577-617.
- 86 -
G10. Carotid Artery Stenosis
- 87 -
G10. Carotid Artery Stenosis
Canadian Stroke Guideline (2008): Recommendation 2.7 – Carotid Intervention
2.7a Symptomatic carotid stenosis
Patients with transient ischemic attack or nondisabling stroke and ipsilateral 70%–99% internal
carotid artery stenosis (measured on a catheter angiogram or by 2 concordant noninvasive
imaging modalities) should be offered carotid endarterectomy within 2 weeks of the incident
transient ischemic attack or stroke unless contraindicated [Evidence Level A] (ASA, AU,
CSQCS, ESO, NZ, SIGN 14).
i. Carotid endartarectomy is recommended for selected patients with moderate (50%–69%)
symptomatic stenosis, and these patients should be evaluated by a physician with expertise in
stroke management [Evidence Level A] (ASA, AU, CSQCS, NZ, SIGN 14).
ii. Carotid endarterectomy should be performed by a surgeon with a known perioperative
morbidity and mortality of < 6% [Evidence Level A] (ASA, CSQCS, ESO, NZ).
iii. Carotid stenting may be considered for patients who are not operative candidates for
technical, anatomic or medical reasons [Evidence Level C].
iv. Carotid endarterectomy is contraindicated for patients with mild (< 50%) stenosis [Evidence
Level A] (ASA, CSQCS, SIGN 14).
2.7b Asymptomatic carotid stenosis
Carotid endarterectomy may be considered for selected patients with asymptomatic 60%–99%
carotid stenosis.
i. Patients should be less than 75 years old with a surgical risk of < 3%, a life expectancy of > 5
years and be evaluated by a physician with expertise in stroke management [Evidence Level A]
(AAN, AHA, AU, CSQCS).
G10.1 Case Study: Carotid Endarterectomy (CEA)
Case Study
A 62 year old woman was admitted to your rehabilitation unit with a left MCA ischemic
stroke. 75% stenosis of the left internal carotid artery due to atherosclerotic plaque was
found on carotid ultrasound.
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Q1. What issues must be considered when deciding on therapeutic options?
Answers
1. Grade of occlusion (< 50%, 50-69%, >70%)
2. Cost-benefit of surgery (Risk of medical treatment, Benefit of surgery)
3. Surgical risk
Q2. In this case, what will be your recommendation and why?
Answers
1. Carotid endarterectomy
2. NASCET trial showed that >70% occlusion benefits from carotid endarterectomy.
Discussion
Carotid endarterectomy (CEA) has become the standard treatment for severe symptomatic
carotid artery stenosis following ECST and the NASCET trial publications. In both studies,
treatment was found to be effective and durable at the 8 year follow-up. The number needed to
treat in order to prevent one stroke at 2 years is 8 (Goldsmidt and Caplan 2003).
In order to examine the benefit of carotid endarterectomy (CEA), 659 patients with symptomatic,
high-grade (70 – 99%) carotid artery stenosis were randomized to receive either optimal
medical treatment (n=331) or surgical intervention (n=328). Rates of stroke and death were
reported at two years post CEA. 30-day rate of stroke and/or death was reported to be 5.8%.
At two years, CEA was associated with an absolute reduction in risk for ipsilateral stroke of
173.5% (p<0.001). (NASCET 1991, Bettman et al. 1998, Hill et al. 2004).
Q3. The medical student asks you why you think carotid endarterectomy (CEA) should
be used instead of carotid artery stenting (CAS).
Answer
1. CAS is a good as CAS over the short to medium term, but the risk of severe restenosis is
higher.
Discussion
The CAVATAS I investigation (2001) compared CEA and CAS. The researchers found no
difference between CEA and CAS in rates of disabling stroke and death or the rate of ipsilateral
stroke at both 30-day and 3 year follow-ups. However, one year following treatment, severe
restenosis was more frequent among patients who had received CAS treatment (p<0.001).
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CAS may fulfil a role in treating carotid artery stenosis in specific subgroups of patients:
(Connors et al. 2003, Cohen et al. 2003)
 Patients not eligible for CEA.
 Patients with contralateral occlusion.
 PostCEA restenosis.
 Radiation-induced stenosis.
 Surgically inaccessible lesions.
Case Study (continued)
The radiologist revises his report; the grade of stenosis was 60%, not 75%.
Q4. Does this change your treatment decision?
Answer
1. Results of NASCET were less impressive for the 50-69% stenosis group. One must
carefully calculate the risk of the intervention but CEA is still an option.
Discussion
While CEA has been found to result in significant benefits in patients with moderate stenosis
(50-69%), the results are less convincing than they are in patients with more severe stenosis
(Barnett and Meldrum 2001, Rothwell et al. 2003a, Rothwell et al. 2003b). In this case, the
number needed to treat to prevent one stroke at 2 years is 20 (Goldsmidt and Caplan 2003).
Thus, for patients with moderate stenosis, one must calculate the risk of the intervention. The
American Heart Association (Biller et al. 1998) recommended that the combined risk of
stroke/death resulting from the CEA should be no more than 3% for asymptomatic patients, 5%
for TIA patients, 7% for stroke patients and 10% for patients with recurrent stenosis. Rothwell et
al. (1999) proposed the following risk assessment model, which encompasses both medical and
surgical risk.
Proposed Risk Assessment Model (Rothwell et al. 1999)
Prognostic Variable
Risk Points
Medical Model:
Cerebral vs. ocular events
1
Plaque surface irregularity
1
Any events in past 2 months
1
Carotid Stenosis (pick one):
70-79%
0
80–89%
1
90-99%
2
Surgical Model:
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Female
1*
Peripheral Vascular disease
1*
Systolic blood pressure >180 mmHg
1*
* if stenosis = 70 – 99%, surgical risk points are subtracted and
the value of each is ½ .
CEA is only of significant benefit in patients with a score ≥ 4. In patients with prognostic scores
of less than 4, the procedure was of no significant benefit and may have been harmful to
patients with prognostic scores of one or less.
Based on data from the Ontario Carotid Endarterectomy Register History, there are some risk
factors that are significantly associated with higher rates of adverse outcomes (death or nonfatal
stroke) within 30 days following CEA.
 History of stroke or TIA (OR=1.75)
 Atrial Fibrillation (OR=1.89)
 Contralateral carotid occlusion (OR=1.72)
 Congestive heart failure (OR=1.8)
 Diabetes (OR=1.8)
In this model, one point is added for each risk factor that is present and total scores reflect
increasing levels of risk. A risk score of 4 in this model was found to be associated with a
15.8% increase in risk of death and/or stroke (Tu et al. 2003).
Q5. How long after the symptomatic event do you recommend performing the CEA?
Answer
1. The sooner the better.
Discussion
Both the NASCET and ECST trials demonstrated that the amount of time between the
symptomatic ischaemic event and CEA has no effect on the 30-day perioperative risk of stroke
and death and may result in decreasing benefits (Rothwell et al 2004).
Early CEA within 2 weeks of a symptomatic event (excluding progressive or major disabling
stroke) was not associated with increased operative or perioperative risk. However, the benefit
associated with CEA in terms of 5 year absolute risk reduction of ischaemic stroke, decreased
as the time between symptomatic event and CEA increased (p<0.001) (Rothwell et al. 2004,
Fairhead et al. 2005).
In patients with moderate stenosis, absolute benefit was observed only for those patients
randomized to CEA treatment within 2 weeks of the initial symptomatic event (Rothwell et al
2004).
G10.2 Case Study: Symptomatic Stenosis (<50%)
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Case Study
A 62 year old woman was admitted to your rehabilitation unit with a left MCA ischemic
stroke. A 40% stenosis due to atherosclerotic plaque was found on the carotid ultrasound.
Q6. What will be your recommendation in this case and why?
Answer
1. Medical treatment is the only option.
2. Not a surgical candidate.
Discussion
Medical treatment would be the recommended option. In symptomatic patients with less than
50% stenosis, there appears to be no benefit associated with surgical treatment (Barnett and
Meldrum 2001, Rothwell et al. 2003a, Rothwell et al. 2003b).
Recommendations for Carotid Endarterectomy in Symptomatic Cartid Artery
Stenosis (Barnett et al. 2002)
Patients with symptomatic stenosis  70% face greater risk when treated medically
than surgically. CEA is most beneficial in the following patients:
 healthy elderly  75 years of age
 hemispheric TIA
 tandem extracranial and intracranial lesions
 without angiographic evidence of collateral pathways
 widespread leukoaraiosis (higher perioperative risk)
 occlusion of contralateral carotid artery (higher perioperative risk)
 intraluminal thrombus (higher perioperative risk)
Patients with symptomatic stenosis of 50% - 69%. Only some patients in this
category benefit from intervention and benefits realized are much smaller. The
following patients may be harmed:
 patients with transient monocular blindness only, especially those with few risk
factors
 women with few risk factors
Patients with near occlusion of the symptomatic artery AND patients with lacunar
strokes and stenosis >50%:
 medical treatment carries a lower risk of stroke than for patients without these
conditions
 CEA is still indicated with no additional perioperative risk, “but the benefit is
- 92 -
muted”.
G10.3 Case Study: Non-symptomatic Stenosis
Case Study
You see a 55 year old man in your outpatient clinic. He has an asymptomatic 55% stenosis
in his right internal carotid artery.
Q7. What is the risk of stroke for this patient?
Answer
1. The one year risk of stroke in patient with ICA stenosis is 1-3%. The 10 and 15 year risk of
stroke if >50% stenosed is 9.3% and 16.6% respectively.
Discussion
The short term risk for stroke associated with internal carotid artery stenosis is 1-3% per year,
depending on the degree of stenosis (Norris et al 1991, European Carotid surgery trials
Collaborative 1995).
Over the long term, the 10 and 15 year risk for stroke has been reported to be 5.7% and 8.7%,
respectively, in individuals with less than 50% internal carotid artery stenosis, and 9.3% and
16.6% in individuals with 50% or greater stenosis (Nadareishvili et al. 2002).
However, at all degrees of stenosis, more than 40% of strokes in asymptomatic arteries have
been found to be attributable to origins other than large artery lesions suggesting that risk needs
to be calculated taking into account only those strokes that could be prevented by surgical
intervention (Barnett et al 2002).
Guidelines for the Use of Carotid Endarterectomy (Canadian Neurological
Society, Findlay et al. 1997)
CEA is clearly recommended for patients with ICA stenosis  70% if:
 stenosis is symptomatic
 there is no worse distal, ipsilateral, carotid distribution arterial disease
 patient is in stable medical condition
 rates of major surgical complications (stroke & death) among patients of the
treating surgeon are less than 6%
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Surgery is not recommended for asymptomatic stenoses of less than 60%.
 CEA should not be considered for asymptomatic stenoses unless the combined
rate of stroke and death among patients of the treating surgeon is less than 3%
Symptomatic stenoses of less than 70% and asymptomatic stenoses of less than
60% are uncertain indications.
Carotid Stenosis
Symptomatic?
Yes
No
Grade
Evaluated
Risk
> 70%
50 – 69%
< 50%
CEA
Possible?
Evaluated
Risk
Medical
Treatment
Yes
No
CEA
CAS
Medical Risk
Surgical Risk
Medical Risk
Surgical Risk
G10.4 Case Study: Recurrent Carotid Stenosis
Case Study
You see a 52 year old man in your outpatient clinic who was treated with CEA for his
symptomatic 70% stenosis of his left internal carotid artery. In his new ultrasound you
find a restenosis of 80% and he is complaining about recurrent numbness in his right side
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Q8. Which treatment do you recommend in this situation, carotid endarterectomy or
carotid artery stenting?
Answer
1. For recurrent carotid stenosis post carotid endarterectomy, carotid artery stenting results in
similar outcomes.
Discussion
In the treatment of early and late recurrent carotid stenosis post CEA, CAS has been found to
result in similar anatomic and neurologic outcomes when compared to repeat CEA (Bowser et
al. 2003).
References
Barnett HJM, Meldrum HE, Eliasziw M. The appropriate use of carotid endarterectomy. Canadian Medical
Association Journal 2002; 166:1169-79.
Barnett H.J.M., Meldrum HE. Surgical Measure to Prevent Stroke. In:Norris JW, Hachinski V, eds. Stroke
Prevention. New York: Oxford University Press, 2001.
Bettmann MA, Katzen BT, Whisnant J, et al. Carotid stenting and angioplasty : A statement for healthcare
professionals from the Councils on Cardiovascular Radiology, Stroke, Cardio-Thoracic and Vascular
Surgery, Epidemiology and Prevention, and Clinical Cardiology, American Heart Association. Circulation
1998; 97:121-23.
Biller J, Feinberg WM, Castaldo JE, et al. Guidelines for carotid endarterectomy. A statement for
healthcare professionals from a special writing group of the stroke council, American Heart Association.
Stroke 1998; 29:554-62.
Bowser AN, Bandyk DF, Evans A, et al. Outcome of carotid stent-assistend angioplasty versus open
surgical repair of recurrent carotid stenosis. J Vasc Surg 2003; 38:432-38.
CAVATAS investigators. Endovasular versus surgical treatment in patients with carotid stenosis in the
Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet
2001; 357(9270):1729-37.
Cohen JE, Lylyk P, Ferrario A, Gomori JM, Umansky F. Carotid stent angioplasty: The role of cerebral
protection devices. Neurol Res 2003; 25:162-68.
Connors JJ, Sacks D, Becker GJ, Barr JD. Carotid artery angioplasty and stent placement: Quality
improvement guidelines to ensure stroke risk reduction. J Vasc Interv Radiol 2003; 14:S317-S319.
European Carotid Surgery Trialists Collaborative Group. Risk of stroke in the distribution of an
asymptomatic carotid artery. Lancet 1995; 345:209-12.
Fairhead JF, Mehta Z, Rothwell PM. Population-based study of delays in carotid imaging and surgery and
the risk of recurrent stroke. Neurology 2005; 65:371-75.
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Findlay JM, Tucker WS, Ferguson GG, Holness RO, Wallace MC, Wong JH. Guidelines for the use of
carotid endarterectomy: current recommendations from the Canadian Neurosurgical Society. Can Med
Assoc J 1997; 157:653-9.
Goldszmidt AJ, Caplan LR. Stroke Essentials. Royal Oak, Michigan: Physicians' Press, 2003.
Hill MD, Foss MM, Tu JV, Feasby TE. Factors influencing the decision to perform carotid endarterectomy.
Neurology 2004; 62:802-05.
Nadareishvili ZG, Rothwell PM, Beletsky V, Pagniello A, Norris JW. Long-term Risk of Stroke and Other
Vascular Events in Patients With Asymptomatic Carotid Artery Stenosis. Arch Neurol 2002; 59:1162-66.
NASCET investigators. Clinical alert: benefit of carotid endarterectomy for patients with high-grade
stenosis of the internal carotid artery: National Institute of Neurological Disorders and Stroke, Stroke and
Trauma Division. Stroke 1991; 22:816-17.
Norris JW, Zhu CZ, Bornstein NM, Chambers BR. Vascular risks of asymptomatic carotid stenosis. Stroke
1991; 22:1485-90.
Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJ. Sex difference in the effect of time from
symptoms to surgery on benefit from carotid endarterectomy for transient ischaemic attack and
nondisabling stroke. Stroke 2004; 35:2855-61.
Rothwell PM, Gutnikov SA, Fox AJ, et al. Analysis of pooled data from the randomised controlled trials of
endarterectomy for symptomatic carotid stenosis. Lancet 2003; 361:107-16.
Rothwell PM, Gutnikov SA, Warlow CP. Reanalysis of the final results of the European Carotid Surgery
Trial. Stroke 2003; 34:514-23.
Rothwell PM, Warlow CP, et al. Prediction of benefit from carotid endarterectomy in individual patietns: a
risk-modelling study. Lancet 1999; 353:2105-10.
Tu JV, Wang H, Bowyer B, Green L, Fang J, Kucey D. Risk factors for death or stroke after carotid
endarterectomy. Observations from the Ontario Carotid Endarterectomy Registry. Stroke 2003; 34:356875.
- 96 -
Key Study: Carotid Artery Occlusion and Reperfusion Interventions
Alamowitch S, Eliasziw M, Barnett HJ. The risk and benefit of endarterectomy in women
with symptomatic internal carotid artery disease. Stroke 2005;36:27-31.
Author, Year
Country,
Pedro Score
Alamowitch et
al. 2005
ns
Methods
Outcomes
Using data from two large trials
(NASCET and ACE), the
efficacy of CE and medical
therapy was compared in
women and men with
symptomatic ICA stenosis.
Female sex was found to be associated with a
significantly higher 30-day risk of death and a nonsignificant, but increased, risk for the composite of
stroke and death following CEA. Similar long-term
benefits were found for men and women with > 70%
stenosis in terms of absolute risk reduction;
however, among patients with 50-69% stenosis,
CEA was of benefit among men only.
5-Year Absolute Risk Reductions (ARR) in Stroke Associated
wth Carotid Endarterectomy (CE) in Men and Women
p<.001
p=.007
20%
p=.02
15%
ARR (%) 10%
p=.94 (NS)
5%
Men
Women
0%
≥70%
59-69%
% of Symptomatic Internal Carotid Artery
(ICA) Stenosis
Importance: Carotid endarterectomy was shown to be efficacious for both men and women if >
70% stenosis but only men if stenosis was 59-69%.
Relevant SREBR Conclusion: There is strong evidence (Level 1a) that carotid endarterectomy
is an effective and durable means by which to reduce the risk of stroke in individuals with
symptomatic carotid artery stenosis of 70 – 99%.
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Key Study: Carotid Artery Occlusion and Reperfusion Interventions
Barnett HJM, Taylor DW, Eliasziw M et al., for the North American Symptomatic Carotic
Endarterectomy Trial Collaborators. Benefit of carotid endarterectomy in symptomatic
patients with moderate and severe stenosis. N Engl J Med 1998; 339: 1415-1425.
Author, Year
Country,
Pedro Score
NASCET Trial
Collaborators
Barnett et al.
1998
Canada/USA
8 (RCT)
Methods
Outcomes
Patients with moderate carotid
stenosis were stratified to degree
of stenosis and randomized to
receive medical treatment
(n=1118) or surgical intervention
(n=1108) and followed for an
average of 5 years.
Among patients with 50-69% stenosis treated
surgically, there was a significant reduction in the
failure rate (fatal or nonfatal ipsilateral stroke).
Among patients with less than 50% stenosis
treated surgically, there was not a statistically
significant reduction in the failure rate.
Events that Define Treatment Failure for Patients who
underwent Carotid Endarterectomy vs. Medical Care
Medical Therapy
Surgical Therapy
Event Defining Treatment Failure for
Stenosis 50-69%
Any disabling stroke or death from any
cause
p=.032
p=.005
Any stroke or death from any cause
NS
Any disabling stroke
p=.026
Any stroke
NS
Disabling ipsilateral stroke
p=.045
Any ipsilateral stroke
0
10
20
30
40
Failure Rates (%)
50
Importance: Patients with carotid artery stenosis of 50-69% benefit more from carotid
endarterectomy surgery when compared to medical therapy; < 50% carotid artery stenosis do
not benefit from the surgery when compared to medical therapy.
Relevant SREBR Conclusion: There is strong evidence (Level 1a) that carotid endarterectomy
is an effective and durable means by which to reduce the risk of stroke in individuals with
symptomatic carotid artery stenosis of 70 – 99%.
- 98 -
Key Study: Carotid Artery Occlusion and Reperfusion Interventions
Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade
carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial
Collaborators. N Engl J Med 1991;325:445-453.
Author, Year
Country,
Pedro Score
NASCET Trial Collaborators
Barnett et. al.
1991
Canada/USA
8 (RCT)
Methods
Outcomes
Patients in 2 predetermined strata based
on severity of carotid stenosis – 30-69% &
70-99% were randomized to receive
medical treatment or surgical intervention
(carotid endarterectomy). All patients
received optimal medical care, including
antiplatelet therapy. The results of 659
patients in the severe stenosis stratum
(70 to 99%) were reported.
The absolute risk reduction
of any ipsilateral stroke and
for a major or fatal
ipsilateral stroke at two
years was significantly
greater in the surgical
patients (n=328) than in the
medical patients (n=331).
Importance: This RCT showed that there is a benefit of carotid endarterectomy in preventing
ipsilateral strokes when there was > 70% stenosis.
Relevant SREBR Conclusion: There is strong evidence (Level 1a) that carotid endarterectomy
is an effective and durable means by which to reduce the risk of stroke in individuals with
symptomatic carotid artery stenosis of 70 – 99%.
- 99 -
Key Study: Carotid Artery Occlusion and Reperfusion Interventions
Coward LJ, Featherstone RL, Brown MM. Safety and efficacy of endovascular treatment
of carotid artery stenosis compared with carotid endarterectomy: a Cochrane systematic
review of the randomized evidence. Stroke 2005;36:905-911.
Author, Year
Country,
Pedro Score
Coward et al.
2005
ns
Methods
Outcomes
Meta-analysis
To evaluate the safety and efficacy
of endovascular techniques, a
literature search was conducted to
identify randomized trials
investigating carotic angioplasty
and/or stenting as compared to
surgery. Five trials involving 1269
patients were included.
No significant differences between the two
treatments were found regarding the odds of
treatment-related death or any type of stroke
at either the 30-day or 1 year follow-ups.
However, endovascular treatment was found
to significantly reduce the risk of cranial nerve
injury (OR, 0.13; CI, 0.06 to 0.25)
Importance: Although no significant differences were found regarding the major risks of
treatment, this study demonstrates that minor complication rates favor endovascular treatment
over stenting.
Relevant SREBR Conclusion: There is strong evidence (Level 1a) that carotid endarterectomy
is an effective and durable means by which to reduce the risk of stroke in individuals with
symptomatic carotid artery stenosis of 70 – 99%.
- 100 -
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