Cholesterol goals and stroke

A high level of LDL cholesterol (160 mg/dL and above) reflects an increased risk of heart disease. Patients with a diagnosis of heart disease should aim for a target LDL cholesterol of less than 100 mg/dL. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) issued an evidence-based set of guidelines on cholesterol management in 2001 (Grundy, 2004) Since the publication of the ATP III, five major clinical trials of statin therapy with clinical endpoints have been published: HPS: Heart Protection Study (Collins, 2004) o Simvastatin significantly reduced the first event rate of stroke versus placebo (444 versus 585, P<0.0001) o There was no significant difference in strokes attributed to hemorrhage (51 versus 53, P=0.8) o Simvastatin also reduced the number of patients having TIAs alone compared with placebo (2.0% versus 2.4%, P=0.02) or requiring CEA or angioplasty (0.4% versus 0.8%, P=0.0003) PROSPER: Prospective Study of Pravastatin in the Elderly (Shepherd, 2002) o Statistically significant reduction in major vascular events in patients using pravastatin versus placebo (408 versus 473, P=0.014) o Death from CHD and nonfatal MI was significantly reduced by 24% (P=0.043) and CHD events were reduced by 19% in patients receiving active therapy (P=0.006) o Stroke risk was unaffected by pravastatin (P=0.8) and TIAs were decreased by 25% (P=0.51) ALLHAT: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial—Lipid Lowering Trial (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002) o Patients treated with chlorthalidone had a 15% lower risk for stroke (P=0.02) and a 10% lower risk of combined CVD (P=0.001) ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes—Lipid Lowering Arm (Sever, 2003) o The trial was stopped early because atorvastatin had resulted in a statistically significant reduction in CVD events: stroke (89 versus 121, P=0.024); total CV events (389 versus 486, P=0.0005); total coronary events compared with placebo (178 versus 247, P=0.0005) PROVE IT-TIMI 22: Pravastatin or Atorvastatin Evaluation and Infection—Thrombolysis in Myocardial Infarction 22 (Rouleau, 2005) o Standard treatment (statin) with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductants receiving active therapy (P=0.006) o Stroke risk was unaffected by pravastatin (P=0.8) and TIAs were decreased by 25% (P=0.51) ALLHAT: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial—Lipid Lowering Trial (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002) o Patients treated with chlorthalidone had a 15% lower risk for stroke (P=0.02) and a 10% lower risk of combined CVD (P=0.001) ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes—Lipid Lowering Arm (Sever, 2003) o The trial was stopped early because atorvastatin had resulted in a statistically significant reduction in CVD events: stroke (89 versus 121, P=0.024); total CV events (389 versus 486, P=0.0005); total coronary events compared with placebo (178 versus 247, P=0.0005) PROVE IT-TIMI 22: Pravastatin or Atorvastatin Evaluation and Infection—Thrombolysis in Myocardial Infarction 22 (Rouleau, 2005) o Standard treatment (statin) with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (pravastatin 40 mg/d) resulted in a 22% reduction in LDL cholesterol levels at 30 days compared with a 51% reduction with intensive therapy (atorvastatin 80 mg/d) o At two years, a relative risk reduction of 16% (95% CI, 5%-26%; P = 0.005) in the primary endpoint rate (death, MI, documented unstable angina requiring hospitalization, coronary revascularization, or stroke) was seen in patients receiving intensive statin treatment compared with standard statin therapy These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The trials confirmed the benefit of cholesterol-lowering therapy in high-risk patients and support the following: ATP III treatment goal of LDL cholesterol <100 mg/dL Inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL cholesterol lowering therapy in these patients Inclusion of older persons benefiting from therapeutic lowering of LDL cholesterol More recently, tn) with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (pravastatin 40 mg/d) resulted in a 22% reduction in LDL cholesterol levels at 30 days compared with a 51% reduction with intensive therapy (atorvastatin 80 mg/d) o At two years, a relative risk reduction of 16% (95% CI, 5%-26%; P = 0.005) in the primary endpoint rate (death, MI, documented unstable angina requiring hospitalization, coronary revascularization, or stroke) was seen in patients receiving intensive statin treatment compared with standard statin therapy These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The trials confirmed the benefit of cholesterol-lowering therapy in high-risk patients and support the following: ATP III treatment goal of LDL cholesterol <100 mg/dL Inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL cholesterol lowering therapy in these patients Inclusion of older persons benefiting from therapeutic lowering of LDL cholesterol More recently, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial demonstrated that when compared with placebo, atorvastatin 80 mg/d significantly reduced the risk of recurrent stroke in patients with recent stroke or TIA and no history of CHD, while substantially decreasing the risk of major coronary and CHD events and revascularization procedures (Welch, 2006). Table 7 provides the updated ATP III guidelines for cholesterol management (Grundy, 2004). Therapeutic lifestyle changes remain an essential modality in clinical management. Lifestyle changes, which include a healthy diet and exercise, must be an integral part of risk reduction therapy. When an LDL-cholesterol-lowering drug is employed in a person at high risk or moderately high risk, a reduction in LDL cholesterol levels of at least 30% to 40% beyond dietary therapy should be achieved, if feasible. Very high risk patients consider LDL <> If HDL is low consider niacin or gemfibrozil

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Hypertension recommendations after stroke

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) provided several new guidelines for hypertension prevention and management (Chobanian, 2004; Table 6). Some of the updates included:

• Thiazide-type diuretics should be used to treat most patients with uncomplicated hypertension, either alone or combined with drugs from other classes. Certain high-risk conditions are compelling indications for the initial use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers)
• Most patients with hypertension will require two or more antihypertensive medications to achieve goal blood pressure (<140/90 mm Hg or <130/80 mm Hg for patients with diabetes or chronic kidney disease)
• If blood pressure is more than 20/10 mm Hg above goal, consideration should be given to initiating therapy with two agents, one of which usually should be a thiazide-type diuretic
• even in normotensive patients, further reduction of blood pressure should be contemplated unless they have a high grade arterial stenosis.

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Modifiable risk factors for stroke

In 2001, the Stroke Council of the American Heart Association (AHA) issued a scientific statement on the primary prevention of ischemic stroke (Goldstein, 2001). The statement was based on the findings of an ad hoc writing group formed by the AHA council to review pertinent literature, published guidelines, and expert opinions regarding risk factors for ischemic stroke. 

According to the AHA council, each recommendation was based on five different levels of evidence. Further classification within the AHA scientific statement included the potential for modification (nonmodifiable, modifiable, or potentially modifiable) of the identified risk factor and the strength of evidence (well documented or less well documented).

Nonmodifiable risk factors included age, sex, race/ethnicity, and family history of stroke or TIA. Well-documented modifiable risk factors (all level I [data from randomized trials with low false-positive and low false-negative errors], grade A [supported by level I evidence]) included hypertension, smoking, diabetes/hyperinsulinemia/insulin resistance, asymptomatic carotid stenosis, atrial fibrillation, other cardiac disease (eg, valvular heart disease, intracardiac congenital defects), sickle cell disease, and hyperlipidemia. Less well-documented or potentially modifiable risk factors included hyperhomocysteinemia, obesity, physical inactivity, alcohol and drug abuse, hypercoagulability, hormone replacement therapy, oral contraceptive use, and inflammatory processes.

Hypertension was considered a major risk factor for stroke, as it remains underdiagnosed and inadequately treated. The relationship between stroke and systolic and diastolic blood pressures is direct, continuous, and apparently independent. More than 30 years of evidence reveals that adequately controlled hypertension is a factor in preventing stroke, as are beta-blocker and high-dose diuretic therapy. Particularly in elderly persons, isolated systolic hypertension is considered an important risk factor for stroke (systolic blood pressure of more than 160 mm Hg and diastolic blood pressure of less than 90 mm Hg). One trial involving 4,695 elderly patients with isolated systolic hypertension was terminated when a stroke reduction rate of 42% was reached in the patients who were actively treated with antihypertensive therapies (a long-acting dihydropyridine calcium antagonist as initial therapy and other drugs as part of step-two drug titration) compared with those taking placebo (Staessen, 1997).  The AHA recommends that adult patients undergo routine screening for hypertension at least once every two years. 

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MATCH trial

the Management of Atherothrombosis with Clopidogrel in High-Risk Patients With Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial, 7,599 high-risk patients with a recent history of TIA or ischemic stroke were randomized to receive either clopidogrel 75 mg plus aspirin 75 mg once daily or clopidogrel 75 mg plus placebo once daily.  Eligible patients had experienced a TIA or ischemic stroke within the last three months and had evidence of at least one additional risk factor within the last three years (prior ischemic stroke, MI, stable or unstable angina pectoris, diabetes, or symptomatic PAD). The primary endpoint was the composite of ischemic stroke, MI, vascular death, and rehospitalization for an acute ischemic event. The duration of treatment and follow-up was 18 months for each patient (Diener, 2004a; Diener, 2004b).

In the intent-to-treat analysis, 596 (15.7%) patients achieved the primary endpoint in the group receiving aspirin plus clopidogrel compared with 636 (16.7%) in the clopidogrel plus placebo group (relative risk reduction 6.4%, [95% CI, -4.6 to 16.3]; absolute risk reduction 1% [-0.6 to 2.7]). Life-threatening bleeding (defined as any fatal bleeding event, a drop in hemoglobin of  ≥50her clopidogrel 75 mg plus aspirin 75 mg once daily or clopidogrel 75 mg plus placebo once daily.  Eligible patients had experienced a TIA or ischemic stroke within the last three months and had evidence of at least one additional risk factor within the last three years (prior ischemic stroke, MI, stable or unstable angina pectoris, diabetes, or symptomatic PAD). The primary endpoint was the composite of ischemic stroke, MI, vascular death, and rehospitalization for an acute ischemic event. The duration of treatment and follow-up was 18 months for each patient (Diener, 2004a; Diener, 2004b).

In the intent-to-treat analysis, 596 (15.7%) patients achieved the primary endpoint in the group receiving aspirin plus clopidogrel compared with 636 (16.7%) in the clopidogrel plus placebo group (relative risk reduction 6.4%, [95% CI, -4.6 to 16.3]; absolute risk reduction 1% [-0.6 to 2.7]). Life-threatening bleeding (defined as any fatal bleeding event, a drop in hemoglobin of  ≥50 g/L, significant hypotension with need for inotropes [hemorrhagic shock], symptomatic intracranial hemorrhage, or transfusion of at least four units of red blood cells or equivalent amount of whole blood) was higher in the group receiving aspirin plus clopidogrel versus the group receiving clopidogrel plus placebo (96 [2.6%] versus 49 [1.3%]; absolute risk increase 1.3% [95% CI, 0.6-1.9]). Major bleeding (defined as significantly disabling [with persistent sequelae], intraocular bleeding leading to significant loss of vision, or transfusion of at least three units of red blood cells or equivalent amount of whole blood) was also increased in the group receiving aspirin and clopidogrel versus clopidogrel alone, but no difference was recorded in mortality (Table 3).

Adding aspirin to clopidogrel resulted in significantly more bleeding complications (almost double) than in the placebo and clopidogrel arm. Thng (defined as any fatal bleeding event, a drop in hemoglobin of  ≥50 g/L, significant hypotension with need for inotropes [hemorrhagic shock], symptomatic intracranial hemorrhage, or transfusion of at least four units of red blood cells or equivalent amount of whole blood) was higher in the group receiving aspirin plus clopidogrel versus the group receiving clopidogrel plus placebo (96 [2.6%] versus 49 [1.3%]; absolute risk increase 1.3% [95% CI, 0.6-1.9]). Major bleeding (defined as significantly disabling [with persistent sequelae], intraocular bleeding leading to significant loss of vision, or transfusion of at least three units of red blood cells or equivalent amount of whole blood) was also increased in the group receiving aspirin and clopidogrel versus clopidogrel alone, but no difference was recorded in mortality (Table 3).

Adding aspirin to clopidogrel resulted in significantly more bleeding complications (almost double) than in the placebo and clopidogrel arm. The MATCH trial demonstrated that monotherapy with clopidogrel is as effective as combination therapy with clopidogrel plus aspirin in specific high-risk cerebrovascular patients, and that the risk of life-threatening or major bleeding was clinically and statistically significantly increased by the addition of aspirin to clopidogrel.

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study was designed to evaluate the efficacy and safety of clopidogrel plus aspirin versus placebo plus aspirin in patients with established CAD, PAD, or cerebrovascular disease, or in patients with multiple risk factors for atherothrombosis who have not yet sustained an ischemic event (ie, primary stroke prevention)(Bhatt, 2006a).  This randomized, international, multicenter, double-blinded, placebo-controlled study enrolled a total of 15,603 patients worldwide. The rate of the primary efficacy endpoint (a composite of MI, stroke, or death from cardiovascular causes) was 6.8% with clopidogrel plus aspirin and 7.3% with placebo plus aspirin (relative risk, 0.93; 95% CI, 0.83-1.05; P=0.22). Overall, the combination of clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of the primary endpoint; however, statistically significant decreases were shown for individual secondary endpoints, including hospitalizations for ischemic events and nonfatal stroke.

In a pre-specified subgroup analysis, the rate of the primary endpoint among asymptomatic patients with multiple risk factors was 6.6% with clopidogrel plus aspirin and 5.5% with placebo plus aspirin (relative risk, 1.2; 95% CI, 0.91-1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with combination treatment with clopidogrel plus aspirin (3.9% versus 2.2%, P=0.01). In the subgroup with clinically evident atherothrombosis (ie, symptomatic), the rate was 6.9% with clopidogrel plus aspirin and 7.9% with placebo plus aspirin (relative risk, 0.88; 95% CI, 0.77 -0.998; P=0.046).

The rate of the primary safety endpoint (severe bleeding according to the Global Utilization of Strategies To Open Occluded Arteries [GUSTO] definition) was 1.7% in the clopidogrel plus aspirin group and 1.3% in the placebo plus aspirin group (relative risk, 1.25; 95% CI, 0.97-1.61; P=0.09).The rate of moderate bleeding was 2.1% in the clopidogrel plus aspirin group, as compared with 1.3% in the placebo plus aspirin group (relative risk, 1.62; 95% CI, 1.27-2.10; P<0.001). The rate of intracranial hemorrhage was similar in the two treatment groups. Hence, in CHARISMA, the rate of severe bleeding was not significantly greater with clopidogrel than with placebo, but clopidogrel was associated with a significant increase in the rate of moderate bleeding.

Overall, CHARISMA suggested some benefit may be observed with combination clopidogrel and aspirin treatment in patients with symptomatic atherothrombosis, but that the risks of bleeding may outweigh these benefits especially in patients with multiple risk factors.

Conversely, the combination of clopidogrel plus aspirin has been demonstrated to be superior to treatment with aspirin alone for patients with acute coronary syndromes and after coronary stenting (Ault,1999; Mehta, 2003; Steinbuhl, 2003; Mehta, 2001; Steinhubl, 2002; Peters, 2003). Whether dual antiplatelet therapy is superior to aspirin monotherapy for high-risk secondary prevention (ie, after TIA/stroke) requires further investigation.

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Mechanisms of antiplatelet drugs

Aspirin inhibits the cyclooxygenase enzyme, preventing the production of prostaglandin and thromboxane A2 (TXA2) from arachidonic acid. TXA2 activates the GP IIb/IIIa binding site on the platelet, allowing fibrinogen to bind (Physician's Desk Reference, 2004)(Aggrenox^® PI). Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibits the generation of TXA2, a powerful inducer of platelet aggregation and vasoconstriction. Paradoxically, aspirin blocks synthesis of prostacyclin by endothelial cells, resulting in an effect that promotes platelet aggregation.

Aspirin is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 20 minutes. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10 to 20 g), the plasma half-life may be increased to more than 20 hours (Physician's Desk Reference, 2004; Aggrenox^® PI). 

Clopidogrel is a potent, noncompetitive inhibitor of ADP-induced platelet aggregation (Plavix^® PI). Clopidogrel inhibits the binding of ADP to platelet membrane receptors. The effect of clopidogrel on ADP binding is irreversible and lasts for the duration of platelet life, about seven to ten days. The inhibition is specific and does not significantly affect cyclooxygenase or arachidonic acid metabolism.

The mechanism of action of clopidogrel is different from that of aspirin. Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, which has no effect on platelet aggregation. It represents about 85% of the circulating drug-related compounds in plasma. The elimination half-life of the main circulating metabolite was eight hours after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days.

Both low- and high-affinity ADP receptors are present on platelets, and the active metabolite of clopidogrel binds to the low-affinity receptors. ADP binding to this site is necessary for activation of the GP IIb/IIIa receptor, which is the binding site for fibrinogen. Fibrinogen links different platelets together to form the platelet aggregate. Clopidogrel thus ultimately inhibits the activation of the GP IIb/IIIa receptor and its binding with fibrinogen (Figure 2).
 
Dipyridamole has been suggested to act as an antiplatelet drug by several possible mechanisms (Aggrenox^® PI).  It directly stimulates prostacyclin synthesis, potentiates the platelet inhibitory actions of prostacyclin, and inhibits phosphodiesterase to raise platelet cyclic AMP levels. However, these effects may not occur at therapeutic levels of the drug; hence, the mechanism of action of dipyridamole remains to be elucidated. Dipyridamole is metabolized in the liver, primarily by conjugation with glucuronic acid, of which monoglucuronide (which has low pharmacodynamic activity) is the primary metabolite. In plasma, about 80% of the total amount is present as parent compound and 20% as monoglucuronide. Most of the glucuronide metabolite (about 95%) is excreted via bile into the feces, with some evidence of enterohepatic circulation. Due to the extended absorption phase of the dipyridamole component, only the terminal phase is apparent from oral treatment with aspirin/extended-release dipyridamole, which is 13.6 hours.

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FDA approved indications for aspirin

The US Food and Drug Administration (FDA) has approved the use of aspirin to reduce the risk of heart attack and stroke in adult men and women who have had a previous heart attack or ischemic stroke, or who are at high risk for these events (Physician's Desk Reference, 2004). The high-risk patient may have any of the following comorbid conditions:
 

• Previous TIA
• Chest pain (stable angina)
• History of certain heart procedures, such as angioplasty or bypass

Aspirin therapy may be considered as a secondary prevention strategy in men with diabetes and women who have evidence of large vessel disease. This includes men with diabetes and women with a history of MI, vascular bypass procedure, stroke or TIA, peripheral vascular disease, claudication, and/or angina (American Diabetes Association, 2002).

In addition to being used in secondary prevention, aspirin therapy may be considered as a primary prevention strategy in men and women with type 1 or type 2 diabetes who are at high risk for CV. This recommendation includes diabetic patients with one or more of the following risk factors (American Diabetes Association, 2002):

• A family history of CHD
• Cigarette smoking
• Hypertension
• Obesity (body mass index [BMI]>27.3 kg/m2 in women, >27.8 kg/m² in men)
• Albuminuria (micro or macro)
• Lipids:
  – Total cholesterol >200 mg/dL
  – LDL cholesterol >100 mg/dL
  – High density lipoprotein (HDL) cholesterol <45 mg/dL for men or <55 mg/dL for women
  – Triglycerides >200 mg/dL
• Age >30 years (the use of aspirin has not been studied in diabetic individuals under 30 years of age)

An aspirin regimen is not appropriate for everyone, nor is it sufficient for patients with PAD alone. A randomized, controlled trial evaluated the effect of aspirin (75 mg/d),  clopidogrel (75 mg/d), and then both drugs on several platelet function indices in patients with PAD (n=20). There was a significant (P=0.0001) decrease in adenosine diphosphate (ADP)-induced aggregation after clopidogrel but not after taking aspirin. In PAD, clopidogrel is a more potent inhibitor of ADP-induced platelet activation than aspirin; combination therapy is more effective than clopidogrel or aspirin monotherapy (Jagroop, 2004).

In the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial, clopidogrel was shown to be superior to aspirin in reducing cardiovascular and cerebrovascular ischemic events in patients with PAD (Figure 1) (CAPRIE Steering Committee, 1996).  Trials of dipyridamole monotherapy have not shown antithrombotic efficacy in PAD, and results from trials of dipyridamole and aspirin have been inconsistent (Hiatt, 2002).

Aspirin is contraindicated in patients with aspirin allergy, bleeding tendency, anticoagulant therapy, recent gastrointestinal bleeding, and clinically active hepatic disease (Physician's Desk Reference, 2004).

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Risk of stroke from symptomatic carotid stenosis

According to the American Heart Association scientific statement on the primary prevention of ischemic stroke, this patient has an estimated annual risk of stroke of 1% to 2% (Goldstein, 2001). The Toronto Asymptomatic Cervical Bruit Study prospectively followed a cohort of 500 asymptomatic patients with cervical bruits for a mean of 23 months (Chambers, 1986). The overall incidence of stroke at one year was 1.7% (1% in patients without previous TIAs); however, the incidence was 5.5% in patients with severe carotid artery stenosis (>75%). Cerebral ischemic events (TIA or stroke) occurred most frequently in men (P <0.025) and in patients of either sex with a history of severe carotid artery stenosis (P <0.0001), progressing carotid artery stenosis (P <0.0005), or heart disease (P <0.0005).
 
Additional observational studies such as the NASCET study suggest that the overall rate of underreported stroke ipsilateral to a hemodynamically significant extracranial carotid artery stenosis is 1% to 2% annually. 

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timing of carotid endarterectomy after stroke

Extracranial internal carotid artery stenosis accounts for 15% to 20% of ischemic strokes. Carotid endarterectomy (CEA) is the most common treatment for large internal carotid artery stenosis (Table 2). Early studies showed that CEA carried a high risk if performed within a few days after a large ischemic stroke (Bruteman, 1963; Blaisdell, 1969; Rob, 1969); therefore, many surgeons delayed performing CEA for four to six weeks after any stroke. 

To determine the effect of delaying CEA on oper with a trend toward benefit at two years, but not associated with a clear long-term benefit. Patients who underwent surgery within two weeks of their last TIA or mild stroke derive greater benefit from CEA. Symptomatic and asymptomatic patients undergoing CEA should be given aspirin (81 or 325 mg/d) prior to surgery and for at least three months following surgery to reduce the risk of stroke, MI, and death. Although data are not available, it is recommended that aspirin (81 or 325 mg/d) be continued indefinitely provided that contraindications are absent. At this time, the available data are insufficient to declare either CEA before or simultaneous with CABG as superior in patients with concomitant carotid and coronary artery occlusive disease. For patients with severe stenosis and a recent TIA or nondisabling stroke, CEA should be performed without delay, preferably within two weeks of the patient's last symptomatic event. There is insufficient evidence to support or refute the performance of CEA within four to six weeks of a recent moderate-to-severe stroke.


Extracranial internal carotid artery stenosis accounts for 15% to 20% of ischemic strokes. Carotid endarterectomy (CEA) is the most common treatment for large internal carotid artery stenosis (Table 2). Early studies showed that CEA carried a high risk if performed within a few days after a large ischemic stroke (Bruteman, 1963; Blaisdell, 1969; Rob, 1969); therefore, many surgeons delayed performing CEA for four to six weeks after any stroke. 

To determine the effect of delaying CEA on operative risk and benefit, data were pooled from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (Bond, 2003). A previous analysis of data from NASCET suggested that operative risk was not increased in patients who underwent surgery within 30 days of a nondisabling stroke (Gasecki, 1994). The retrospective subgroup analysis involved 100 surgical patients with severe (70% to 99%), angiographically defined carotid artery stenosis in whom a nondisabling hemispheric stroke was diagnosed at entry into the trial (Bond, 2003). A total of 42 CEAs were performed within 30 days (early group, ranging three to 30 days), and 58 were performed beyond 30 days (delayed group, range 33 to 117 days) after stroke. The risk of subsequent stroke after CEA was compared between the two groups. The postoperative (30 days after CEA) stroke rate was 4.8% in the early group and 5.2% in the delayed group, yielding a relative rate of 0.92 (95% CI, 0.16-5.27; P = 1.00). At the end of 18 months, the rates of any stroke or death were 11.9% and 10.3% for the early and delayed groups, respectively, resulting in a relative rate of 1.15 (95% CI, 0.38-3.52; P = 1.00). However, in the delayed group, more lesions were identified ipsilateral to the symptomatic side on the preoperative computed tomography (CT) scans.

The NASCET analysis revealed that CEA can be performed safely within two weeks of nondisabling ischemic stroke. Delaying the procedure by 30 days for patients with symptomatic high-grade stenosis exposes them to a risk of recurrent stroke, which may be avoidable by earlier surgery. The results also showed that benefit from CEA declines rapidly with increasing delay. This dx weeks after any stroke. 

To determine the effect of delaying CEA on operative risk and benefit, data were pooled from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (Bond, 2003). A previous analysis of data from NASCET suggested that operative risk was not increased in patients who underwent surgery within 30 days of a nondisabling stroke (Gasecki, 1994). The retrospective subgroup analysis involved 100 surgical patients with severe (70% to 99%), angiographically defined carotid artery stenosis in whom a nondisabling hemispheric stroke was diagnosed at entry into the trial (Bond, 2003). A total of 42 CEAs were performed within 30 days (early group, ranging three to 30 days), and 58 were performed beyond 30 days (delayed group, range 33 to 117 days) after stroke. The risk of subsequent stroke after CEA was compared between the two groups. The postoperative (30 days after CEA) stroke rate was 4.8% in the early group and 5.2% in the delayed group, yielding a relative rate of 0.92 (95% CI, 0.16-5.27; P = 1.00). At the end of 18 months, the rates of any stroke or death were 11.9% and 10.3% for the early and delayed groups, respectively, resulting in a relative rate of 1.15 (95% CI, 0.38-3.52; P = 1.00). However, in the delayed group, more lesions were identified ipsilateral to the symptomatic side on the preoperative computed tomography (CT) scans.

The NASCET analysis revealed that CEA can be performed safely within two weeks of nondisabling ischemic stroke. Delaying the procedure by 30 days for patients with symptomatic high-grade stenosis exposes them to a risk of recurrent stroke, which may be avoidable by earlier surgery. The results also showed that benefit from CEA declines rapidly with increasing delay. This decline in benefit over time was later shown to be more pronounced in women than men (P<0.001)(Rothwell, 2004). Benefit in women was confined to those randomized to less than two weeks after their last event, irrespective of severity of stenosis.

With the number of CEA procedures increasing, appropriate qualifying schemes (ie, preoperative condition assessment), as well as optimal methods for monitoring patients peri- and postoperatively are needed. A recent, evidence-based review reported by the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology provided the following recommendations (Chaturvedi, 2005):

• CEA is established as effective for recently symptomatic (within the previous six months) patients with 70% to 99% internal carotid artery angiographic stenosis. CEA should not be considered for symptomatic patients with <50% stenosis. CEA may be considered for patients with 50% to 69% symptomatic stenosis, but the clinician should consider additional clinical and angiographic variables. It is recommended that the patient have at least a five-year life expectancy and that the perioperative stroke/death rate should be <6% for symptomatic patients. Medical management is preferred to CEA for symptomatic patients with <50% stenosis.
• It is reasonable to consider CEA for patients between the ages of 40 and 75 years with asymptomatic stenosis of 60% to 99% if the patient has an expected five-year life expectancy and if the surgical stroke or death frequency can be reliably documented at <3%.
• No recommendation can be provided regarding the value of emergent CEA in patients with a progressing neurologic deficit.
• Clinicians should consider patient variables in CEA decision-making. Women with 50% to 69% symptomatic stenosis did not show clear benefit in previous trials. In addition, patients with hemispheric TIA/stroke had greater benefit from CEA than patients with retinal ischemic events. Clinicians should also evaluate several radiologic factors when considering CEA (eg, contralateral occlusion erases the small benefit of CEA in asymptomatic patients whereas in symptomatic patients, it is associated with increased operative risk but persistent benefit). CEA for symptomatic patients with angiographic near-occlusion is associated with a trend toward benefit at two years, but not associated with a clear long-term benefit. Patients who underwent surgery within two weeks of their last TIA or mild stroke derive greater benefit from CEA.
• Symptomatic and asymptomatic patients undergoing CEA should be given aspirin (81 or 325 mg/d) prior to surgery and for at least three months following surgery to reduce the risk of stroke, MI, and death. Although data are not available, it is recommended that aspirin (81 or 325 mg/d) be continued indefinitely provided that contraindications are absent.
• At this time, the available data are insufficient to declare either CEA before or simultaneous with CABG as superior in patients with concomitant carotid and coronary artery occlusive disease.
• For patients with severe stenosis and a recent TIA or nondisabling stroke, CEA should be performed without delay, preferably within two weeks of the patient's last symptomatic event. There is insufficient evidence to support or refute the performance of CEA within four to six weeks of a recent moderate-to-severe stroke.
   

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long term risk of survival after stroke or tia

Physicians have long been interested in the long-term determinants of survival and of risk of vascular events after minor ischemic stroke or TIA. In a prospective cohort of 2,473 participants from the Dutch TIA Trial (recruitment from 1986 to 1989), van Wijk and colleagues re-evaluated the ten-year risk of vascular events after TIA or minor ischemic stroke. After a mean follow-up of 10.1 years, 1,489 (60%) patients had died and 1,336 (54%) had had at least one additional vascular event. The ten-year risk of death and vascular event was 42.7% (95% CI, 40.8%-44.7%) and 44.1% (42.0%-46.1%), respectively. The risk for any vascular event including stroke was highest immediately after the ischemic event, but then began a decline that reached its lowest point about three years after the stroke. In the Dutch TIA study, predictors of death and the occurrence of a vascular event included age, diabetes, and evidence of vascular disease (van Wijk, 2005).

A recent meta-analysis to evaluate the risk of MI and vascular death after TIA and ischemic stroke included 39 studies and a total of 65,996 patients with mean follow-up of 3.5 years (Touzé, 2005). The annual risks were 2.1% (CI 95%, 1.9%-2.4%) for nonstroke vascular death, 2.2% (1.7%-2.7%) for total MI, 0.9% (0.7%-1.2%) for nonfatal MI, and 1.1% (0.8%-1.5%) for fatal MI. The time course of the risk of each outcome was also linear.

Because risks can change over time, patients with TIA and minor ischemic stroke should continue to be reassessed and treated to prevent cerebrovascular and cardiovascular events for the long term.

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risk of coronary disease with stroke

Patients with disease in one vascular site often have overlapping diseases on other vascular beds. The results of one study (n=1,886) showed significant overlap between three thrombotic conditions: coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral arterial disease (PAD)(Aronow, 1994).The following results were demonstrated:
 

• 25% of patients had at least two manifestations of their thrombotic disease in different locations
• In patients with CAD, stroke was present in 32% and PAD was present in 33%
• In patients with stroke, CAD was present in 53% and PAD was present in 33%
• In patients with PAD, CAD was present in 58% and stroke was present in 34%

The Reduction of Atherothrombosis for Continued Health (REACH) Registry collects data on atherosclerosis risk factors and treatment (Bhatt, 2006b; Steg, 2006). The goal of the registry is to provide long-term, comprehensive, clinical practice data on the many manifestations of atherothrombosis in a population large enough to represent the entire spectrum of those at risk.

A total of 67,888 patients aged 45 years and older from 44 countries had either (Bhatt, 2006b):

• CAD (n=40,258);
• CVD (n=18,843);
• PAD (n=8273); or
• Asymptomatic disease but three or more risk factors for atherothrombosis (n=12,389): treated diabetes mellitus; diabetic nephropathy; ankle-brachial index <0.9; asymptomatic carotid stenosis ≥70%; carotid intima media thickness of two times or more adjacent sites; systolic blood pressure ≥150 mm Hg despite therapy for at least three months; hypercholesterolemia treated with medication; current smoking of at least 15 cigarettes per day; men aged 65 years or older; or women aged 70 years or older

One-year data from REACH also demonstrate high CV and ischemic event rates across all cerebrovascular disease populations, similar to those seen in the total population with established atherosclerotic disease (Rother, 2006). Patients with previous stroke and TIA experience had the highest event rates (including hospitalization), followed by TIA-only and stroke-only subgroups (19.61% versus 14.86% versus 12.31%, respectively (P<0.001).

The prevalence of CAD has been assessed in cross-sectional studies of patients known to have concurrent coronary heart disease (CHD)(Rothwell, 2000). Nearly 50% of the patients have either clinical or imaging evidence of vascular disease in one or more other territory (Rothwell, 2000).

In conclusion, the risk of major secondary ischemic events, including CV death, is highest in individuals with previous stroke and TIA. Improved ischemic risk reduction in TIA patients, in particular, has the potential to prevent both morbid events and associated hospitalizations. Evaluation for the presence of CAD is often appropriate.

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Risk of stroke after a TIA

The risk of recurrent stroke is highest in the first few weeks after a first transient ischemic attack (TIA) or stroke. Knowledge of which stroke subtypes have the highest risk for early recurrence allows for a better prioritization of necessary investigations and treatments to prevent a second TIA or stroke.

Lovett and associates performed a meta-analysis on the risk of recurrent stroke assessed by etiologic subtype. The data were derived from two population-based studies, the Oxford Vascular Study and the Oxfordshire Community Stroke Project, and from two other published studies reporting equivalent data. Patients (n=1,709) were classified according to the four following etiologic subtypes of ischemic stroke: large artery atherosclerosis, small vessel stroke, cardioembolic, and undetermined.  Only 14% of the primary strokes evaluated were associated with large vessel atherosclerotic stroke; however, this subtype accounted for 37% of recurrences within seven days of the first event.
 
Compared with other subtypes, patients with stroke due to large vessel atherosclerosis had the highest odds of recurrence at seven days (odds ratio [OR] = 3.3, 95% confidence interval (CI), 1.5-7.0), 30 days (OR = 2.9, 95% CI, 1.7- 4.9), and three months (OR = 2.9, 95% CI, 1.9- 4.5).

At 30 days, patients with small vessel strokes had the lowest risk of recurrence (OR=0.2, 95% CI, 0.1- 0.6), followed by patients with cardioembolic (OR=1.0, 95% CI, 0.6-1.7) or undetermined (OR=1.0, 95% CI, 0.6-1.6) stroke (Table 1; Lovett, 2004).

The recurrence rate for the first year after a lacunar stroke and for the following two years is approximately 10% (Hier, 1991; Sacco, 1991). Only a minority of recurrent strokes are of lacunar etiology, which emphasizes the need for thorough evaluation of patients with lacunar strokes.

Cryptogenic stroke has been clearly associated with a heart defect known as patent foramen ovale (PFO) in patients younger than 55 years (Overell, 2000). There are few reports available concerning stroke recurrence in patients with PFO, and the published event rates vary considerably. In one study by Mas and colleagues, none of the patients with isolated PFO who had a cryptogenic stroke or TIA experienced a recurrent event during a two-year follow-up (Mas, 1995).  In a second study on cases of brain infarction (84% of which were cryptogenic) and PFO, the average annual rates of recurrence were 1.9% for stroke and 3.8% for stroke or TIA (Bogousslavsky, 1996).

Cervical artery dissection accounts for up to one fifth of ischemic strokes occurring before 45 years; however, recurrence is uncommon and usually represents a benign condition (Leys, 1997; Bassetti, 1996).

Stroke survivors are also at increased risk of mortality following the first stroke compared with the general population of the same age and sex. Although the mortality risk is greatest during the first 30 days following a stroke, the risk persists for several years. The increased risk of mortality has been attributed to vascular disease, specifically recurrent stroke and other cardiovascular (CV) conditions. In fact, stroke survivors are more likely to die from recurrent stroke and CV events (including MI) as they are from incident stroke (Kannel, 1994; Wilterdink, 1992; Sacco, 1994; Coull, 2004).

• Of the 209 stroke patients who died in the Oxfordshire Community Stroke Project between 31 days and five years after the first stroke, 19% died of the incident stroke, 17% died of a recurrent stroke, and 34% died of other CV events (Dennis, 1993)
• Among 231 patients in the Northern Manhattan Stroke Study (NOMASS) who died between 31 days and five years after the incident stroke, 8% died of the incident stroke, 7% died of a recurrent stroke, and 29% died of other CV events (Hartman, 2001)
• Among 362 patients in the Perth Community Stroke Study who died between 31 days and five years after the incident stroke, 19% died of the incident stroke, 8% died of a recurrent stroke, and 31% died of other CV events (Hankey, 2000)

In summary, the risk of early recurrent stroke is highest in patients with large vessel atherosclerotic stroke, which supports the need for carotid imaging and secondary prevention tactics. Long-term survival after stroke may be improved by appropriate, early, and sustained interventions aimed at preventing subsequent strokes and CV events.

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MERCI trial

Smith et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke. Stroke 2005; 36: 1432-1440.

Used device to open occluded intracranial large vessels within 8 hours. All patients were ineligible for iv tpa. Primary outcome measures were recanalization and safety. Secondary outcome measure was outcome at 90 days in recanalized v nonrecanalized patients. 46 % recanalized on an ITT. 7.1 % had significant complications. SICH occurred in 7.8 %. Good outcomes were more likely in patients who were recanalized.

Part I 55 patients Part !! 96 patients total 151. Criteria: NIHSS >8,. goal was TIMI 2. Mean NIH was 20. Mean time to treat was 4.3 hours. Vessel: ICA 19; ICA terminal bifurcation 14, MCA 57, VA 1 BA 9.

Six cases perf three embolized distal vessels, 3 more SAH 3 had significant groin hemorrhages. 7.8 % had SICH, 11 devices fractured ?due to over torquing device.

BY VESSEL: posterior 50 % favorable by NIHSS, 29-33 at MCA and ICA respectively. The 50 % recanalization of the MCA is less than that seen in PROACT 2 (66%).

Bridging Study

IMS Study Investigators. Combined Intravenous and IntraArterial recanalization for acute ischemic stroke: the interventionsal management of stroke study. Stroke 2004; 35:904-911.

80 subjects received iv tpa .6 mg/kg, 60 mg maximum over 30 minutes within 3 hours, then additional via microcatheter compared to literature placebo and NINDS patients. 80 subjects had mean NIHSS 18, median onset to iv needle of 140 minutes. 3 month mortality 16 % numerically lower but n/s; sich was 6.3 %; 3 month outcome was better.

Notes recanalization of ICA's in studies is around 10 %. MCA's is around 25 %. In NINDS patients with NIHSS> 20, only 10 % had minor or no disability at 3 months v 2 % of placebo. OUtcomes looked at: MRS score 0-2 at 3 months; NIHSS score at 24 hours; rate of recanalization (TIMI 2 or 3) and a few others. 1477 patients were screened to produce 80 patients.

30 % of patients had mrs of 0-1 at 90 days, 28 % had NIHSS <1>95. 43 % had MRS <2> 10 was a slightly tougher group than NINDS. THERE WERE THREE VESSEL PERFS THOUGHT TO BE SECONDARY TO BLIND NAVIGATION IN MCA DUE TO CLOT PRESENT. All 3 were AICH. There were 4 recurrent strokes, 2 ICH. 4 patients underwent hemicraniectomy due to massive cerebral edema.

56 % of group that got ia tpa (62=n) 28 had maor occlusions or severe stenosis, 11 % total recanalization (TIMI 3) and 56 % partly recanalize. Of 34 patients who recanalized 34 % had a favorable outcome compared to 12 % who only got TIMI 0 or 1. Of those who got ia tpa in 3 hours, 43 % had MRS 0-1 v. 13 % who got it within 3-4 hours, 27 % who got it 4-6 hours.

Followup article Broderick Stroke 2007 evaluated 81 patients who had better results with bridging than with iv tpa alone, nonstatistically different hemorrhage rates with more results on way.

PROACT II Study: A randomized controlled trial

Furlan A et al. Intra-arterial prourokinase for acute ischemic stroke JAMA 1999 282:21 2003-2011 "Prolyse in Cerebral thromboembolism 2" 180 patients with CVA< 6 hours with angiographically proven MCA occlusion without hemorrhage or early infarct signs at 54 sites. They were randomized to 9 mg IA pro UK plus heparin or just heparin. Main outcome measure was number with no disability ie modified Rankin of 2 or less at 90 days. Secondary outcomes were MCA recanalization, frequency of ICH, and mortality. 40 % of pro UK patients and 25 % controls had modified Rankin of 2 or less ( p=0.04). Mortality was 25 and 27 % respectively. Recanalization rate was 66 % and 18 % respeectively (p<0.001). SICH within 24 hours was 10 % and 2 % respectively. Conclusion- treatment improves outcome, main outcome measure.

Notes: angiographic inclusion criteria were TIMI grade 0 or 1 (no or minimal contrast perfusion). Randomization was 2:1, stratified into NIHSS 4-10, 11-20, and 21-30. ITT analysis was used. 12,323 patients were screened, 4 % (474) received angiography, of whom 180 were eligible and were randomized. Median NIHSS score was 18. The median time to initiation of treatment was 5.3 hours. 35 % v. 13 % suffered ICH (38/108' 7/54) although most were asymptomatic. SICH occurred in 10 % (11/108) v. 2 % (1/54) for a NTT to harm = 12. Compared to PROACT 1 which used smaller dose of pro-UK (6 v. 9) recanalization increased by 26 % but SICH increased by 4 %. The total ICH rates were similar to those reported in cases of embolic stroke. Higher rate of hemorrhage compared to iv tPA in NINDS (6.4%) ATLANTIS (7.2%) and ECASS II (8.8%) reflects baseline greater stroke severity and time to treatment in PROACT 2. Median NIHSS score was 17 in PROACT 2, 11 in ECASS 2 and AtTLANTIS, and 14 in NINDS. Recanalization rate of large vessel occlusion with iv tPA is 30 % (TIATTS study). Tomsick-- hyperdense MCA sign or NIHSS score > 10 predicts poor response to iv therapy. In this study only 1 patient was treated within 3 hours.

Perioperative Stroke

review article Selim M. NEJM 2007; 356:706-713.
Tidbits and quick facts cited from the literature
1. After bypass most strokes are ischemic and embolic, not hemorrhagic

2. 45 % occur in first day, 55% in second or subsequent days

3. Delayed stroke is due to post operative atrial fibrillation, that occurs in 30-50% of patients; coagulopathy with decreased fibrinolysis and activation of the hemostatic system; dehydration; stasis, and perioperative withholding of antiplatelet agents or anticoagulants. Rare causes are air, fat or paradoxical embolus or arterial dissection due to neck manipulation in surgery.

4. Most post CABG strokes, contrary to myth, are not related to hypoperfusion

5. Risk stratification method called "bootstrapping" was developed by the Northern New England Cardiovascular Study Group. Risk factors are numerous but the model weights most highly advanced age, urgent surgery, creatinine > 2.0 and a specific history of stroke or TIA within six months, especially with a symptomatic carotid artery (see separate post)

6. Risk of stroke from asymptomatic carotid lesions is higher than those without but still low and in most cases does not warrant two procedures.

7. Preop eval for risk factors might include MRI/ MRA/TCD / pre op ECHO

8. Predictors of postop atrial fibrillation are: advanced age, perioperative CHF or low EF; perioperative withdrawal of ACE inhibitors or B blockers; prior inferior wall MI; combined CABG/valve replacement and high post op magnesium

9. The discontinuation of warfarin or aspirin leads to increased perioperative risk especially in patients with coexisting CAD. The rate was 0.6 % with discontinuation without perioperative heparin and 0.0 % with heparin. The rate of major bleeding if the patient was on anticoagulation was 0.2 % for dental procedures, 0 % for arthrocentesis, cataract surgery, and upper or lower endoscopy without biopsy. One study (Larson et al., Chest, 2005) showed that moderate dose warfarin therapy (INR around 2.0) was safe and effective during knee or hip replacement.

10. Hyperglycemia intra or postoperatively is associated with higher rates of atrial fibrillation, stroke and death.

11. Treatment of electrolyte abnormalities and infections post operatively reduces stroke

12. The use of aspirin after CEA or CABG reduces stroke without increasing bleeding complications.

13. Whereas i-v t PA is contraindicated, arterial t PA or clot disruption is feasible postoperatively. In one study, 80 % of patients (n=36) who received arterial t PA within 6 hours after a perioperative stroke had partial or complete recanalization, 38 % had minimal or no residual disability at discharge, and the mortality rate was similar to non perioperative patients undergoing the procedure. 17 % had bleeding at the operative site, but most was minor.

14. Future directions include possible use of perioperative neuroprotective drugs; statins or beta blockers, or aprotinin are mentioned as possible worthy drugs to use in the setting.

Perioperative Stroke

review article Selim M. NEJM 2007; 356:706-713.
Tidbits and quick facts cited from the literature
1. After bypass most strokes are ischemic and embolic, not hemorrhagic

2. 45 % occur in first day, 55% in second or subsequent days

3. Delayed stroke is due to post operative atrial fibrillation, that occurs in 30-50% of patients; coagulopathy with decreased fibrinolysis and activation of the hemostatic system; dehydration; stasis, and perioperative withholding of antiplatelet agents or anticoagulants. Rare causes are air, fat or paradoxical embolus or arterial dissection due to neck manipulation in surgery.

4. Most post CABG strokes, contrary to myth, are not related to hypoperfusion

5. Risk stratification method called "bootstrapping" was developed by the Northern New England Cardiovascular Study Group. Risk factors are numerous but the model weights most highly advanced age, urgent surgery, creatinine > 2.0 and a specific history of stroke or TIA within six months, especially with a symptomatic carotid artery (see separate post)

6. Risk of stroke from asymptomatic carotid lesions is higher than those without but still low and in most cases does not warrant two procedures.

7. Preop eval for risk factors might include MRI/ MRA/TCD / pre op ECHO

8. Predictors of postop atrial fibrillation are: advanced age, perioperative CHF or low EF; perioperative withdrawal of ACE inhibitors or B blockers; prior if=nferior wall MI; combined CABG/valve replacement and high post op magnesium

9. The discontinuation of warfarin or aspirin leads to increased perioperative risk especially in patients with coexisting CAD. The rate was 0.6 % with discontinuation without perioperative heparin and 0.0 % with heparin. The rate of major bleeding if the patient was on anticoagulation was 0.2 % for dental procedures, 0 % for arthrocentesis, cataract surgery, and upper or lower endoscopy without biopsy. One study (Larson et al., Chest, 2005) showed that moderate dose warfarin therapy (INR around 2.0) was safe and effective during knee or hip replacement.

10. Hyperglycemia intra or postoperatively is associated with higher rates of atrial fibrillation, stroke and death.

11. Treatment of electrolyte abnormalities and infections post operatively reduces stroke

12. The use of aspirin after CEA or CABG reduces stroke without increasing bleeding complications.

13. Whereas i-v t PA is contraindicated, arterial t PA or clot disruption is feasible postoperatively. In one study, 80 % of patients (n=36) who received arterial t PA within 6 hours after a perioperative stroke had partial or complete recanalization, 38 % had minimal or no residual disability at discharge, and the mortality rate was similar to non perioperative patients undergoing the procedure. 17 % had bleeding at the operative site, but most was minor.

14. Future directions include possible use of perioperative neuroprotective drugs; statins or beta blockers, or aprotinin are mentioned as possible worthy drugs to use in the setting.

Spinal cord ischemia

Clinical imaging patterns, pathogenesis and outcomes in27 patients. Novy J et al. Arch Neurol 2006; Bogousslavsky types spinal cord infarcts based on clinical findings and vascular anatomy. 27 patients were studied. Two had TIA's (one repetitive TIAs while gardening-- mechanical stress). There were 6 syndromes 1) anterior spinal artery (10) produced a bilateral motor deficit with spinothalamic sensory deficit 2) anterior unilateral infarct occurred hemiparesis with contralateral ST deficit(4) 3 posterior unilateral infarct caused HP with ipsilateral meniscal sensory loss4 4) central cord infarct caused bilateral STT deficit without motor infarct3 5) posterior spinal artery infarct-- bilateral motor deficit with lemniscal sensory loss2 6) transverse infarct bilateral motor and complete sensory infarct.2 20 were idiopathic, three were associated with prolonged arterial hypotension just before infarction, and 3 had associated mechanical causes especially disc rupture. Of type 1, the most common type, 7 had chronic spinal disease and 6 had a sudden triggering movement. Anterior unilateral and posterior spinal artery had underlying spinal disease and triggering movements also. By contrast, central and transverse infarcts were more likely to be associated with hypotension. With mechanical stress, the most common lesion was of the radicular arteries. Initial pain was expected, with one patient developing C8 radiculopathy. Vertebral body infarcts occassionally occurred. Another syndrome reported in JNNP (1996) was fibrocartilaginous emboli after spine movement that presented with pain only, then progressive irreversible evolution and is always lethal. The prognosis was good in most patients.

Argabotran tPA Stroke study

study design and results in the first treated cohort. Arch Neurol 2006; 63:1057-1062. Argatroban is a direct thrombin inhibitor, commonly used for HIT that augments t PA in animal models. 15 patients with MCA occlusions with mean NIHSS score of 14 were given t-PA then argotroban. They received a 100 ug/kg bolus followed by a 1 ug/kg for 48 hours adjusted to a target PTT of 1.75 times control. 2 patients had SICH, 1 had asymptomatic bleeding, one died. 6 had complete recanalization, 4 had partial recanalization, and three ultimately reoccluded within 2 hours of t PA administration. Comment-- ARGIS 1 showed argatroban was safe but ineffective. Intravenous tPAdoes not benefit 57-58 % of patients who receive it. Only 20-30 % completely recanalize on TCD. Argatroban began before t PA finished. Argatroban was chosen because of its short half life and the ease of monitoring by APTT. The small group showed greater recanalization in combined treated group than in historical controls with just t PA.

CEA in practice

Feasby TE and Barnett HJM. Improving the appropriateness of carotid endarterectomy (editorial). Neurology 2007;68:172-173. Based on 2 articles within

Cutting to the chase, the article reminds us that the NTT (number to treat) to prevent a stroke for symptomatic stenotic carotid arteries is 7.6 over two years, v. 67 for asymptomatic carotid stenoses. The risk reduction correspondingly is 13.1 % and 1.5 % respectively.

The articles suggest that due to the publication of data, that inappropriate CEA is reduced, but one in 10 is still inappropriate, due to patients being too sick, too recent strokes, or only minor carotid stenosis. However, the major reason is that more CEA's are being done for asymptomatic carotid stenosis. Almost 3/4 of patients were asymptomatic. The national complication rate is between 3.5 and 4.5 percent of RECORDED complications. The trend is concerning.

Separately, my old friend Rich Dubinsky found that combined stroke/death rates among patients undergoing combined CEA/CABG was 38 %, leading to concern about the combined procedure for carotid artery stenosis that is asymptomatic..

Ataxic hemiparesis due to midbrain infarction

Kim et al. Neurology 2005;64:1227-1232

40 patients with midbrain infarction were divided into 4 types. 1) Anteromedial/paramedian group with lesions near the red nucleus (n=18) (IIIn palsy, INO, ataxia, perioral/ restricted hand numbness without weakness) 2) anterolateral group involving the crus cerebri and pyramidal tract and the substantia nigra (n=11) Symptoms were hemi-ataxia +/- hemiparesis 3) combined anterior group (n=6) and 4) lateral group involving the medial lemniscus and ascending trigeminal tract (n=2). These patients had sensory disturbance only. 5) 3 had bilateral/atypical lesions.

Symptoms in descending order were: gait ataxia (68%), dysarthria (55%), limb ataxia (50%), sensory symptoms (43%), IIIn palsy (25 %), limb weakness (23 %) and INO (13 %). Two syndromes were pure sensory stroke (group 4) and ataxic hemiparesis (usually thought to be either pontine or capsular).

Etiology were large vessel disease (60%) of BA or VA; small vessel disease in 25 %; cardioembolism in 3 %; unknown in 13 %. Of the large vessel disease patients , 71 % had atheromatous branch artery occlusion, 17 % had artery to artery embolus,and the rest were unknown.

top of the basilar syndrome

Emboli to the rostral portion of the basilar artery can produce this syndrome, with a wide variety of possible symptoms. Caplan (1980, Stroke) described 61 patients in a series, including 47 with an acute confusional state. 92 % had neuro-opthalmological abnormalities, especially affecting vertical eye movements. These include selective upgaze or downgaze syndrome or both, one and a half syndrome, Parinaud syndrome, skew deviation, and third and fourth nerve palsies. Nystagmus and light-near dissociation, homonymous field defects, internuclear opthalmoplegia, poorly reactive pupils, visual agnosias, memory deficits, hypersomnolence, all occur.

t-PA miscellany

1) In the NIHSS trial, those with score >20 had 17 % chance of bleeding compared to 3 % with a score less than ten 2) 0.6 mg/kg is considered an acceptable bridging dose 3)MERCI study (Stroek 2005:36:1432-1440) looked at patients up to 8 hours. The device is FDA approved the criteria are not. 46 % recanalized in the ITT analysis. Procedural complications occurred in 7 % and SICH in 7.1 %, Modified Rankin < 2 at 90 days was more common in those recanalized than those not recanlized (46 v. 10 %). 4) Brott 1992 t-pa risk but not efficacy increases with higher doses of t-pa. 5)

Carotid dissection

The most common clinical manifestation of ICA dissection is pain which refers to the head, eye, jaw, face or neck. Scalp tenderness may mimic GCA. Postganglionic Horner's syndrome occurs in 58 % and is often the presenting sign. 30 % experience episodes of transient monocular blindness, probably flow related rather than embolic, because of reversal of flow through the opthalmic artery. Episodes of visual loss may be precipitated by postural changes and associated with positive phenomena including sparkles and scintillations. Permanent vision loss is rare but stroke is common, even after a month or more, occurring in the retina or cerebrum, although the risk decreases markely over time. 10-15 percent develop cranial neuropathies especially of the lower cranial nerves, causing tongue weakness, dysarthria, dysphagia, and an unpleasant metallic taste. Ocular motor palsies and opthalmopareses are rare, occurring in 1-3 %, sometimes due to orbtial ischemia. Most cranial neuropathies heal within three months with the vessel. The annual stroke rate is 1.4 % overall.

Treatment of Cardiac problems in stroke

from table I NEJM 353:22:2361-72 "PFO in Young adults with unexplained stroke atrial myxoma-- sporadic or familial (Carney complex), most common primary cardiac tumor, 2:1 female predominance, less than 2 % of patients with cryptogenic stroke, rare but one third of cases present with systemic embolism. Treatment is surgical resection. No data regarding antiplatelet drugs or anticoagulation. Form papillary or pedicle may have gelatinous fragile extensions. papillary fibroelastoma (giant Lambl's excrescence)- hamartoma or reparative lesion of valves, usually left sided, aortic > mitral valve, much rarer cause of cryptogenic stroke, stroke risk is proportional to size and mobility, treatment is surgical if lesion > 1 cm, is mobile, otherwise best treatment not known. Valvular strands (Lambl's excrescence) filiform projections <> 2mm in systole, leads to MR; associations include CTD (Marfan's, EDS, others) 2.8 % of patients with cryptogenic stroke; rr stroke or TIA is 1.7 (age<> 50) with risk due to leaflet thickness, severity of MR, with strokes due to incident AF and mitral valve surgery. Treatment is antiplatelet therapy with anticoagulation not shown better; valve repair/replacement Intrapulmonary shunt-- very low occurrence with treatment is coil embolization aortic arch thrombosis-- thrombus attached to atheroma; very low occurrence; treatment is anticoagulation or surgery

Patent foramen ovales: quick facts

NEJM article2005:353:22:2361-2372 Etiologic role in stroke questioned due to a) prevalence of PFO b) gradient for right to left shunting must exist (normally exists only in early systole, with prolonged Vasalva, or pulmonary hypertension c) usual lack of evidence of peripheral venous embolic source d) evidence that the yearly risk of stroke in patients with PFO may be as low as 0.1 %. How to pick the bad PFO's from the beningn ones? Factors include a large separation of > 4 mm between the primum and secondum septa; increased right to left shunting; shunting at rest; increased septal mobility; and presence of ASA. Also risk factors for venous thromboembolism are important including trauma, recent surgery, oral contraceptive use and hypercoagulable states. Atrial septal aneurysm (ASA) prevalence at autopsy is about 1 %. 50-90 % have associated PFO (association does not work in reverse, only about 7 % of patients with PFO have ASA). Detection of thrombus in situ is helpful but rarely found. ASA is associated with prominent Eustachian valves or Chiari networks, membranes that facilitate right to left shunts, by directing flow from the IVC to fossa ovalis, and presence of tachyarrythmias predisposing to thromboembolism. Diagnosis TTE v. TEE-- TTE diagnoses about 25 % of PFO's but less than 10 % of ones without signs or symptoms. Contrast TEE diagnoses 57 % of patients with cryptogenic stroke. Treatment-- ASA v. anticoagulation-- risk of recurrence is low among patients <>10-155 mm. PFO + ASA has increased stroke recurrence (3.8 v. 1 %). Officially, use anticoagulation as its beneficial if there is recurrent stroke, systemic thrombosis or (blogger thought-- elevated d-dimer). Role of ASA (risk) is not certain if PFO not also present.

Suspect PFO if one sees an M shaped notch on inferior leads on EKG.

GESICA study of nat history of intracranial stenosis

M et al. Prospective study of Symptomatic Intracranial atherothrombotic intracranial stenoses: The Gesica study This is a natural history study of patients with intracranial stenosis of one or more vessel of more than 50 percent. 27 percent had clinical hemodynamic symptoms, After about two years, 14 percent had stroke and 24 percent TIA, but sixty percent had recurrent stroke when hemodynamic symptoms were present. This may be a subset of stroke patients for consideration for more aggressive treatments. Angioplasty was done in patients with antecedent tia (62 %) or stroke (37 %) with mean time to performance of 1.5 months. Periprocedure complication rate was 14 %. In this study of 102 patients with disease in all intracranial arteries, symptomatic ICAS failing medical therapy had a stroke rate up to 55 % within 36 days

Aspiration with lateral medullary strokes

Kim et al. Aspiration subsequent to a pure medullary infarction. Lesion sites, clinical variables and outcome. Arch Neurol 2000; 57:478-483. Relates to paramedian lesions in lower or middle medulla due to effects on tongue movement but only if severe enough. Aspiration is almost assured in intermediate (ie midpons) dorsolateral. Recovery typically occurs within several months.

Caudal paramedian midbrain syndrome

Mossuto-Agatiello L. Caudal paramedian midbrain syndrome. Neurology 2006; 66:1668-1671. Reviewed seminal cases of same by L'Hermitte (1941) and Garcin et al. (1971). Also reviewed five patients with evidence of paramedian midbrain infarction for clinical signs and symptoms. The authors suggest a unilateral lesion can produce bilateral symptoms. These include bilateral cerebellar ataxia, truncal ataxia, dysarthria, +/- eye movement disorders and palatal myoclonus. INO's, IIIn paresis/palsies can occur. MRI showed increased signal of the inferior olive. Rubral tremor may occur.

Sudden hearing loss can be ischemic

Mort DJ, Bronstein AM. Sudden deafness; editorial review. Current Opinion in Neurology 19:1:February 2006 pp.1-3(My summary)The two major causes of sudden deafness are postviral and ischemic. If accompanied by vertigo, sudden hearing loss may be the first sign of AICA stroke-- others appear later. If you are lucky, you will see MRI changes in the AICA part of the cerebellum or the pons, but not if the ischemia is purely cochlear. The cochlear supply usually lacks collaterals. Lee and Baloh found that ten percent of patients with vertebrobasilar stroke had unilateral hearing loss, almost always with vertigo. Treatment with steroids has class I evidence for being a beneficial treatment--even if the cause turns out to be vascular. Usually tapering oral steroids are given, sometimes with pentoxifylline, and occassionally acyclovir or valacyclovir. LDL apheresis also has been tried but lacks convincing evidence.

Symptoms of Giant cell arteritis

Gonzalez-Gay MA et al. Arteritis: Disease patterns of clinical presentation in a series of 240 patients. Medicine 2005;84:269-276. Purpose: to characterize the clinical presentation in biopsy proven cases in a stable and homogenous population. Study in Lugo, Spain. Headaches were present in 86 %. Scalp tenderness was significantly more common in patients presenting with headache, as was abnormal temporal artery examination, 79.8 v. 35.1 %. 54 % of biopsy proven patients had severe ischemic complications within one month of diagnosis. An abnormal TA exam was the best predictor of severe ischemic manifestations, with an odds ratio of 2.25. Anemia was associated with a lower risk of ischemic complications.

Other
ESR>50 in 89 percent
CRP more specific not elevated randomly

Motor stroke sparing the leg

Motor strokes sparing the leg.Different lesions and causes. Fretias et al. (Bogousslavsky) Arch Neurol 2000; 57:513-518. 895 infarcts were examined, and compared with 1644 cases involving the leg. Typically, leg involvement meant more likely small arteriolar disease, whereas absence of leg involvement meant superfical cortical disease in either of the branches of the MCA due to large artery emboli or atherosclerosis without stenosis

Livedo reticularis and neurologic disease

Kraemer M et al. Differential diagnosis in Neurological Patients with livedo reticularis and livedo racemosa. J Neurol 2005;252:1155-1166

review article. LRET is physiological and reversible with warming. LRAC is always pathological. LRET is induced by cold and certain drugs including amantadine, quinine and quinidine. LRAC has a slightly different morphology with irregular and broken segments, sometimes in a "starburst" pattern, whereas LRET is regular. Semantically, LRAC is identical to "symptomatic" LRET. LRAC is caused by obstructive disorders of the veins or viscosity changes in the blood. It is essentially "watershed ischemia" due to stagnation of flow in border zones between adjacent arterioles. LRAC occurs in Sneddon's syndrome and may precede ischemic strokes and be associated with apl antibodies. Diagnosis is by skin biopsy that shows proliferative non-vaculitic occlusion of the small arterioles (which is also seen in brain tissue in Sneddon's syndrome).

LRAC is most common in lupus and PAN, and following cholesterol embolization (CE) which is usually a complication of angiography, and which also can cause stroke. In CE, LRAC only occurs when the patient is standing. LRAC also is seen in essential thrombocythemia, DIC, and atrial myxoma.