75 No studies have demonstrated that heparin is useful in mitigating the

neurologic effects of a stroke.

Low-molecular-weight heparins (LMWHs) and heparinoids have been evaluated

in several studies for acute stroke. Two doses

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of nadroparin were compared with placebo in one randomized, double-blind,

placebo-controlled trial.

76 There were no differences in death rates or functional

ability at 3 months among the three treatment arms. However, at 6 months, patients

receiving high-dose nadroparin (i.e., 4,100 anti-Xa international units BID) had

improved function. A large randomized, placebo-controlled trial of dose-adjusted

danaparoid, a low-molecular-weight heparinoid, did not demonstrate improvement in

danaparoid-treated patients.

77

In addition, no improvements were observed in studies

of dalteparin and certoparin.

78

,

79 Similar to heparin, LMWHs and heparinoids are not

indicated in the acute treatment of stroke.

Deep vein thrombosis and pulmonary embolism are common complications in

patients following a stroke. Intermittent Compression Devices such as Venodynes,

which prevent pooling of blood in the lower extremities, should be applied within 24

hours of admission to the hospital unless contraindicated. The incidences of deep

vein thrombosis and pulmonary embolism were reduced in most studies in which

patients received heparin, LMWHs, or heparinoids.

80

Unfractionated heparin 5,000 units subcutaneously twice daily or three times daily

can be initiated in P.C. for deep venous thrombosis prophylaxis after 24 hours of

thrombolytic administration once a repeat head CT ruled out ICH. Heparin is

considered a cheap and effective option compared to LMWHs.

ANTIPLATELETS

Aspirin

One study evaluated early administration of aspirin in acute stroke. The Chinese

Acute Stroke Trial compared 160 mg/day of aspirin administered within 48 hours of

the onset of stroke symptoms with placebo.

81 Patients who received aspirin had

reduced early mortality rates, but there was no difference in the primary endpoint of

death or dependency at discharge from the hospital. Two other studies did not

demonstrate benefit with aspirin.

63

,

74 When data from these studies are combined, a

slight beneficial effect of aspirin is seen with regard to reducing the risk of early

stroke recurrence. Current recommendations are for aspirin 325 mg to be

administered within 24 to 48 hours of the onset of stroke symptoms, except when

alteplase is administered. When alteplase is given aspirin should be given 24 to 48

hours after alteplase administration but still within 48 to 72 hours of onset of stroke

symptoms.

53

In our patient, P.C., alteplase was used, aspirin should not be given until

24 to 48 hours after the end of the alteplase infusion and once a repeat 24 hour head

CT ruled ICH.

There has been limited published evidence available for the usage of other

antiplatelets such as clopidogrel or dipyridamole in the acute treatment of ischemic

stroke. Small pilot studies suggested some utility to these antiplatelets without

providing solid evidence of a clear benefit of the well-established aspirin in acute

ischemic stroke treatment. In the clopidogrel with aspirin in acute minor stroke or

TIA (CHANCE), the investigators randomized in a double-blind, placebo-controlled

study 5,170 patients within 24 hours after the onset of symptoms of a minor stroke or

TIA to an initial loading dose of 300 mg clopidogrel followed by 75 mg/day for 90

days with aspirin at a dose of 75 mg/day for the for the 21 days, or to placebo plus

aspirin 75 mg for 90 days. This study conducted in China found that the combination

was superior to aspirin in reducing the risk of stroke in the first 90 days. The

patients’ selection did not include major stroke or patients who received

thrombolytics.

82 Given that our patient received thrombolytic, aspirin is the preferred

option.

Glycoprotein IIb/IIIa Inhibitors

Platelet glycoprotein IIb/IIIa inhibitors have also been studied in acute stroke. A

placebo-controlled phase II trial of abciximab given within 24 hours of acute stroke

showed a trend toward improved functionality in abciximab-treated patients, but the

study was not powered to show the significance for this outcome.

83

In another placebo-controlled, phase II study of patients with acute stroke, the

direct thrombin inhibitor, argatroban, was associated with statistically significant

improvements in neurologic symptoms and daily living activities.

84 The number of

patients enrolled in this study was small, but the results show promise. Currently, the

use of these agents is limited to clinical trials.

ENDOVASCULAR INTERVENTIONS

CASE 61-2, QUESTION 6: What other non-pharmacological interventions might be also considered for the

acute treatment of stroke in P.C.?

A number of endovascular treatment options for ischemic stroke are available and

include intra-arterial fibrinolytics, mechanical thrombectomy with coil retrievers

such as the Mechanical Clot Retrieval System (Merci) or stent retrievers such as

Solitaire FR and Trevo, combination intra-arterial thrombolytics with mechanical

thrombectomy, mechanical clot aspiration with the Penumbra system, and acute

angioplasty and stenting.

53

Intra-arterial thrombolytics administration requires an experienced stroke center

and careful selection to identify patients who would benefit. As with intravenous

fibrinolytics, intra-arterial thrombolytics should be administered within 6 hours of

onset of symptoms, in patients with occlusions of the middle cerebral artery who are

not a candidates for intravenous alteplase. Urokinase is the only fibrinolytic with

randomized trials that has been shown to be effective in clot lysis, resulting in

recanalization and restoration of blood flow.

85

,

86 While intra-arterial thrombolytics

can be considered when intravenous fibrinolytics is predicted to fail (large vessel

occlusion) or is contraindicated, these therapies, if available to be administered by a

skillful interventional neuroradiologist, should be considered. Lack of identification

of optimal dose and evidence of effectiveness in occlusions outside of the middle

cerebral artery limit the widespread use of intra-arterial thrombolytics.

53 Mechanical

removal of the clot has been evaluated alone or in combination with pharmacological

fibrinolysis. Four devices are currently available: MERCI, Penumbra, Solitaire FR,

and Trevo. The most current guidelines recommend using the stent retrievers

(Solitaire or Trevo) over coil retrievers, such as Merci.

The most recent evidence with these devices is promising. In patients with stroke

secondary to occlusions in the proximal anterior intracranial circulation, patients

who underwent thrombectomy using a stent retriever device (Solitaire) after

receiving intravenous alteplase reduced significantly the 90 days disability without

increasing risk of ICH or mortality compared to intravenous alteplase monotherapy.

87

Similar results were also found in four other trials comparing endovascular therapy

with intravenous thrombolytics to standard therapy with intravenous thrombolytics

alone for documented large occlusions in the proximal anterior circulation. Intraarterial thrombectomy reduced disability and improved outcomes.

88–91 These trials

compared to earlier trials required angiographic confirmation by CT of an

intracranial occlusion for eligibility, while earlier trials that did not require such

confirmation or used older devices (Merci and Penumbra) did not find such

benefit.

92–95

Stroke Education

CASE 61-2, QUESTION 7: What information and instruction should be given to P.C. regarding future stroke

symptoms?

Early treatment of acute stroke with available or investigational drugs appears to

be the most important factor in determining optimal outcome. Nearly every clinical

trial demonstrating some

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benefit of pharmacotherapy for acute stroke has shown the greatest effect for

patients who are treated within a few hours of the onset of stroke symptoms.

Immediate detection of stroke symptoms and initiation of treatment are imperative.

The primary rate-limiting step in diagnosis and provision of medical care is

recognition by the patient of stroke symptoms. Every patient who is at increased risk

of stroke should be carefully instructed to seek emergent medical attention if they

experience any weakness or paralysis, speech impairment, numbness, blurred vision

or sudden loss of vision, or altered level of consciousness. These symptoms should

be handled with the same urgency as the symptoms of a myocardial infarction. The

pharmacist should ensure that P.C. and his caregivers know the symptoms of stroke

and understand what to do if they occur.

Complications

CASE 61-2, QUESTION 8: What complications associated with stroke might P.C. experience?

Agitation, delirium, stupor, coma, cerebral edema, and increased intracranial

pressure are other acute symptoms that can be associated with ischemic stroke. These

symptoms correlate with the specific blood vessels that are affected, and the

development of these complications in P.C. would depend on the progression of his

stroke.

Seizures may occur in up to 20% of stroke patients. Pneumonia, pulmonary edema,

cardiac arrest, deep vein thrombosis, and arrhythmias are commonly associated with

ischemic stroke and should be managed as they occur. In P.C., these may occur soon

after his stroke or be related to a rapidly developing neurologic event such as further

infarction, hemorrhage, or severe cerebral edema. Pneumonia or deep venous

thromboses are related primarily to inactivity, and the risk of these events will

increase the longer P.C. remains immobile.

Stroke patients frequently experience psychologic reactions. The most common

psychiatric complication is depression, occurring in 30% to 50% of patients.

96

The severity of depression varies from mild to major depressive episodes. If the

depression interferes with recovery and the rehabilitative process, it should be

managed with the use of a selective serotonin reuptake inhibitor or other appropriate

agent. Severe psychomotor depression may respond to CNS stimulants, such as

methylphenidate or dextroamphetamine. Because of P.C.’s hypertension, stimulants

should be used only with careful blood pressure monitoring.

Prognosis

CASE 61-2, QUESTION 9: After 4 days in the hospital, P.C.’s neurologic status is stabilized. Will further

neurologic improvements be realized?

Neurologic deficits in stroke patients are not considered stable or fixed until at

least 8 to 12 months have elapsed. During this time, neurologic function may return

but rarely to normal. The prognosis after ischemic stroke depends on a variety of

factors including age, hypertension, coma, cardiopulmonary complications, hypoxia,

and neurogenic hyperventilation. However, infarction of the middle cerebral artery is

associated with a poor chance for recovery. Recently, physical and occupational

therapy techniques involving restriction of activity in the unaffected limb or limbs

have proven to be effective in patients regaining lost function. Therefore, it is

possible that P.C. will experience further neurologic improvement.

SECONDARY PREVENTION AFTER ISCHEMIC

STROKE OR TIA

CASE 61-2, QUESTION 10: What antiplatelet or anticoagulation therapy would be recommended for

secondary stroke prevention for P.C.?

Antiplatelet Therapy for Secondary Prevention

Because platelets play a key role in the formation of atheromatous clots, various

antiplatelet drugs, such as aspirin, combination aspirin/dipyridamole, ticlopidine,

clopidogrel, and cilostazol, have been studied for secondary prevention. Cilostazol

is the only agent not approved by the Food and Drug Administration (FDA) for

secondary prevention of ischemic strokes and TIAs arising from non-cardioembolic

origin. These agents generally work by either preventing the formation of TXA2 or

increasing the concentration of prostacyclin. These actions seek to reestablish the

proper balance between these two substances, thus preventing the adhesion and

aggregation of platelets (Table 61-4). Around 22% relative risk reduction of stroke,

myocardial infarction, or death is noted with these agents compared to placebo in

patients with prior TIA or stroke.

97 Based on the current guidelines for noncardioembolic ischemic stroke and TIAs secondary prevention, aspirin, clopidogrel,

or combination aspirin/dypiridamole extended release are considered first-line

therapy.

5

ASPIRIN

The effectiveness of aspirin for secondary prevention of non-cardioembolic ischemic

stroke and TIA is supported by evidence of high quality. At least 15 randomized

trials, with 7 being placebo-controlled, have studied aspirin alone or in combination

with other antiplatelet drugs in the prevention of vascular events.

45

,

98–102

Patients were enrolled in these studies for as long as 5 years after experiencing a

vascular event (i.e., TIA, stroke, unstable angina, or myocardial infarction). Followup periods lasted from 1 to 6 years. The incidence of ischemic stroke or TIA ranged

from 7% to 23%: the aspirin-treated patients experienced an average 22% decrease

in relative risk of a stroke compared with those receiving placebo. In 10 trials that

considered only TIA or stroke patients, there was a 24% relative risk reduction in the

incidence of nonfatal stroke associated with the use of aspirin. The risk reduction

rate is equal for men and women.

98

,

103

Dosages of aspirin used in clinical trials have ranged from 30 to 1,500 mg/day. In

a meta-analysis of placebo-controlled studies comparing 900 to 1,500 mg/day of

aspirin with similar studies of 300 to 325 mg/day, there was a 23% reduction in the

risk of cerebrovascular events for patients receiving 900 to 1,500 mg/day and a 24%

reduction in risk for patients receiving 300 to 325 mg/day.

97 A prospective

comparison of aspirin doses in 3,131 patients showed a 14.7% frequency of nonfatal

stroke or nonfatal myocardial infarction in patients receiving 30 mg of aspirin a day

and a 15.2% frequency in patients receiving 283 mg of aspirin a day, a nonsignificant

difference between these two doses.

104 The Swedish Aspirin Low-Dose Trial

showed an 18% reduction in stroke in patients taking 75 mg of aspirin daily

compared with placebo.

105 Helgason et al. compared the effects of 325, 650, 975, and

1,300 mg of aspirin a day in stroke patients.

106 Platelet aggregation studies were

performed to determine the effects of aspirin. Eighty percent of patients had complete

suppression of aggregation at a daily dose of 325 mg, an additional 5% responded at

650 mg/day, only 1% more responded at 975 mg/day, and there was no further

response at 1,300 mg. As aspirin doses increase, so does the risk of gastrointestinal

(GI) bleeding.

107

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The recommended dose for aspirin is 50 to 325 mg/day. The goal is to use the

lowest effective aspirin dosage, thereby limiting the risk of GI adverse effects. In the

United States, a dose of 81 mg enteric-coated aspirin is usually started.

TICLOPIDINE

Ticlopidine is an antiplatelet agent approved only for the prevention of TIA and

stroke for patients with a prior cerebral thrombotic event. By inhibiting ADP-induced

platelet aggregation, its activity differs from that of aspirin. While effective in

reducing risk of stroke, its use is limited by serious hematological and GI adverse

effects.

108

,

109

CLOPIDOGREL

Clopidogrel is chemically related to ticlopidine and works by inhibiting platelet

aggregation induced by ADP. A randomized, double-blind, international trial

(Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events [CAPRIE])

compared clopidogrel 75 mg/day with aspirin 325 mg/day.

110 Patients enrolled in the

study had a history of atherosclerotic vascular disease manifested by recent ischemic

stroke, myocardial infarction, or symptomatic peripheral vascular disease. Using

intention-to-treat analysis, a 5.3% risk of an event in patients receiving clopidogrel

and a 5.83% risk in patients receiving aspirin were observed. This represents a

statistically significant relative risk reduction of 8.7%, favoring clopidogrel. Ontreatment analysis showed a relative risk reduction of 9.4%, again in favor of

clopidogrel. For patients whose primary condition for entry into CAPRIE was stroke,

the relative risk reduction was 7.3%; however, this difference was not statistically

significant. Patients receiving clopidogrel more frequently experienced rash and

diarrhea compared with those receiving aspirin. Patients receiving aspirin were

more frequently affected by upper GI distress, intracranial hemorrhage, and GI

hemorrhage. Significant reductions in neutrophils occurred in 0.10% of patients on

clopidogrel and in 0.17% of patients on aspirin. Some cases of thrombocytopenia

purpura are reported in the literature.

111

Clopidogrel is as effective and safe as aspirin. Clopidogrel is an alternative to

aspirin in secondary prevention of stroke.

5 Polymorphisms in the hepatic enzymes

involved in the metabolism and activation of clopidogrel (CYP 1A2, CYP3A4,

CYP2C19) or within the platelet P2Y12

receptor may affect clopidogrel’s antiplatelet

therapy. Similarly, drug interactions affecting the CYP2C19 P450 cytochrome can

lead to decreased effectiveness of clopidogrel. Commonly prescribed proton pump

inhibitors, such as omperazole, have been suggested to decrease efficacy of

clopidogrel. It is suggested to avoid the combination of omeprazole and clopidogrel

until more solid evidence is available.

5

ASPIRIN/DIPYRIDAMOLE

Dipyridamole inhibits phosphodiesterase and augments prostacyclin-related platelet

aggregation inhibition. Four large randomized clinical trials have evaluated the

secondary prevention effect of aspirin and dipyridamole combination among patients

with stroke or TIAs. Two European studies have shown benefit with a combination

of aspirin and dipyridamole. In the first study, a combination of aspirin 325 mg/day

and immediate release 75 mg dipyridamole three times/day was compared with

placebo.

112 Results from this study showed that the combination reduced the

combined risk of stroke and death by 33% and the risk of stroke by 38%. The Second

European Stroke Prevention Study enrolled patients who had experienced a previous

stroke or TIA and found that aspirin combined with dipyridamole was more effective

than placebo, dipyridamole alone, and aspirin alone.

113

A sustained-release formulation of dipyridamole was used for this study. A 37%

relative risk reduction was found for the combination treatment, and a 23% relative

risk reduction was found for aspirin alone. The dipyridamole dose for this study was

200 mg twice a day (BID), and the aspirin dose was 25 mg BID. Absolute risk

reduction was approximately 1.5% annually. Headache occurred more frequently in

patients receiving dipyridamole alone or in combination with aspirin. Bleeding

complications were less frequent in patients receiving dipyridamole compared with

aspirin alone. As a result of these findings, a combination product of aspirin and

dipyridamole is available. The combination of sustained-release dipyridamole and

aspirin is an acceptable alternative for secondary prevention of stroke when initial

secondary prevention has failed.

In the 2006 open label European/Australian Stroke Prevention in Reversible

Ischemia Trial (ESPRIT), with a mean follow-up of 3.5 years, the combination

aspirin/dipyridamole was associated with an absolute risk reduction of 1%/year for

the composite primary outcome of vascular mortality, nonfatal stroke, nonfatal MI, or

major bleeding (13% vs. 16%) Bleeding rates were similar between the two groups.

Combination aspirin/dipyridamole was discontinued secondary to headaches in 8.8%

of patients. Of note, the aspirin dose ranged from 30 to 325 mg, and 83% of the

patients took the extended release formulation of dipyridamole.

114

Clopidogrel was compared with the combination aspirin and extended release

dipyridamole in the non-inferiority Prevention Regimen for Effectively Avoiding

Second Strokes trial.

115 Among the patients with non-cardioembolic ischemic stroke

who were followed for a mean of 2.5 years, there was no difference in stroke rates

between the two intervention arms. The risk of gastrointestinal hemorrhage was

higher in the aspirin plus extended dipyridamole group compared to clopidogrel

(4.1% vs. 3.6%). Clopidogrel was better tolerated with less bleeding and less

headaches than the combination.

CILOSTAZOL

Cilostazol is a vasodilator and antiplatelet agent. It has action on intracellular cyclic

AMP and is a phosphodiesterase-3 inhibitor that is used mainly for intermittent

claudication in patients with peripheral artery disease.

116

In Asian studies, cilostazol

100 mg twice daily was found to equally reduce risk of vascular events compared to

aspirin in non-cardioembolic stroke. However, headache, diarrhea, palpitations,

dizziness, and tachycardia were more frequent with cilostazol than aspirin, leading to

more discontinuation in therapy (20% vs. 12%).

117

,

118 Given the ventricular

tachycardia risk associated with cilostazol, it is contraindicated in patients with heart

failure.

116

WARFARIN AND ORAL ANTICOAGULANTS

Large randomized trials have compared oral anticoagulants with aspirin in the

secondary prevention of stroke and TIA. In one study, aspirin 30 mg/day was

compared with oral anticoagulants in doses adjusted to maintain an INR between 3.0

and 4.5.

119 This study was terminated early when the mortality rate attributable to

major bleeding events in the anticoagulant group was double the rate in the aspirin

group. In this study, there was no difference between anticoagulants and aspirin in the

frequency of stroke. A second study compared warfarin, dosed to maintain the INR

between 1.4 and 2.8, and aspirin 325 mg/day.

120

Results from this study did not demonstrate a significant difference between

aspirin and warfarin with regard to the prevention of stroke or major hemorrhagic

events. However, minor hemorrhages were significantly more frequent among

patients receiving warfarin. A third study was terminated early because of safety

concerns in the warfarin arm of the

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study.

121 The target INR for this study was 2 to 3 in the warfarin arm compared

with aspirin. The study was stopped owing to significantly higher rates of adverse

events in individuals receiving warfarin and no difference in the risk of stroke.

Events including major hemorrhage, myocardial infarction, or sudden death, and

overall death were increased in those receiving warfarin. Warfarin is not generally

recommended for secondary prevention of non-cardioembolic stroke. In secondary

prevention of cardioembolic stroke originating from atrial fibrillation, warfarin or

the newer oral anticoagulants are preferred first-line therapy.

47

ASPIRIN COMBINED WITH CLOPIDOGREL

A major study has compared clopidogrel 75 mg/day with the combination of

clopidogrel 75 mg/day and aspirin 75 mg/day.

122 There was no difference in the risk

of recurrent stroke or other cardiovascular outcomes between the groups, but the

combination therapy group had a significant increase in life-threatening bleeding.

Some individuals may be resistant to aspirin’s effects on platelets.

123 Although poorly

understood and studied, aspirin resistance may be related to the presence of extra

platelet sources of TXA2 and an interaction with over-the-counter nonsteroidal antiinflammatory drugs or high levels of circulating 11-dehydro-thromboxane B2

.

Cyclooxygenase-2 expression is induced during human megakaryopoiesis and

characterizes newly formed platelets.

124–126 There are no data to suggest that

increasing the aspirin dose will overcome possible resistance to the antiplatelet

effects of aspirin, but it is clear that an increased dose of aspirin increases the risk of

major bleeding.

Surgical Interventions for Secondary Prevention

Carotid endarterectomy and carotid artery stenting are available to prevent ischemic

stroke or TIAs. These are designed to either remove the source for an embolism or

improve circulation to ischemic areas of the brain.

CAROTID ENDARTERECTOMY

Carotid endarterectomy (CEA) is a common surgical procedure for correcting

atheromatous lesions responsible for causing a TIA or ischemic stroke. In this

procedure, the carotid artery is surgically exposed, and the atheromatous plaque is

excised. CEA combined with pharmacotherapy is considered first-line option for

patients with a high-grade (>70% angiographic stenosis) atherosclerotic carotid

stenosis.

5 Other patients do not benefit as much from such procedure, and the benefit

does not outweigh the risk of such procedure. CEA is most effective for patients with

an ulcerated lesion or stenotic clot that occludes greater than 70% of blood flow in

the ipsilateral carotid artery and who experience symptoms of a TIA or stroke. Use

of CEA in these patients may result in a 60% reduction in stroke risk during the

subsequent 2 years.

127 Of six to eight patients treated with CEA, one stroke will be

prevented within 2 years.

128 The use of CEA in other patient groups must be balanced

with the risk of the procedure and life expectancy.

129 CEA is beneficial in patients

with 50% to 69% stenosis of the carotid artery.

5 Surgery should be done within 2

weeks of a TIA or stroke. Generally, CEA is not indicated in patients who have

permanent neurologic deficits or total occlusion of the carotid artery. CEA should be

done by a surgeon with less than 6% morbidity and mortality rates.

Aspirin also has been used for prevention of restenosis after CEA. During the first

year after CEA, 25% of patients will redevelop a stenotic lesion, with more than half

of these causing a greater than 50% reduction in carotid blood flow.

103

Stent placement is useful in preventing restenosis. Initial studies indicated that

combination therapy with aspirin 325 mg/day and dipyridamole 75 mg three times a

day would decrease the rate of restenosis. However, a subsequent randomized,

placebo-controlled study using this regimen in post-CEA patients did not substantiate

the earlier findings.

130 A combination of clopidogrel with aspirin has been shown to

reduce postoperative ischemic events.

131

Carotid Artery Angioplasty and Stenting

As an alternative to CEA, balloon angioplasty and placement of stents can also

improve blood flow through a stenosed artery. This is a less invasive procedure

associated with less patient discomfort and a shorter recovery time. During this

procedure, a catheter with a small, deflated balloon is placed in the stenosed artery,

and the atherosclerotic lesion is pressed into the arterial wall when the balloon is

inflated. A small, plastic tube stent is placed in the artery to prevent the vessel from

collapsing at the site of the lesion.

Carotid artery angioplasty and stenting (CAS) is another alternative. The initial

study of this procedure was halted because of poor outcomes.

132 Subsequently, two

studies have shown that CAS is not inferior to CEA, but further study is underway to

determine whether CAS is more beneficial than CEA.

133

,

134 CAS can be used in

patients who are not candidates for CEA.

SPONTANEOUS INTRACEREBRAL

HEMORRHAGE

Clinical Presentation and Treatment

CASE 61-3

QUESTION 1: S.P. is a 58-year-old man who is sitting at home watching television with his wife when he

develops confusion, nausea, severe headache, and right arm weakness. His wife immediately calls for an

ambulance and by the time paramedics arrive, S.P. is slumped in his chair and unresponsive. Significant past

medical history includes poorly controlled hypertension, atrial fibrillation, and osteoarthritis. He takes lisinopril 10

mg by mouth daily, warfarin 4 mg by mouth daily, and acetaminophen 1,000 mg by mouth three times daily for

these conditions. Upon presentation to the ED, his blood pressure is 184/114 mm Hg. A CT scan shows an

intracerebral hemorrhage. Key electrolyte concentrations, coagulation studies, and blood counts are within

normal limits except for an INR of 4.8 and a blood glucose level of 194 mg/dL.

S.P.’s neurologic symptoms and the appearance of blood on his CT scan are consistent with a diagnosis of

intracerebral hemorrhage (ICH).

What risk factors for spontaneous intracerebral hemorrhage does S.P. have?

S.P.’s uncontrolled hypertension and his use of warfarin has increased his risk of

ICH.

135 Specifically, use of warfarin increases the risk of ICH by two to five times

depending on the degree of anticoagulation.

136

,

137 Patients, such as S.P., who are

taking warfarin before ICH and present with an INR >3 are at greater risk for

developing larger hematomas, which are associated with worse outcomes, compared

to those taking warfarin and presenting with a lower INR.

138

,

139 Patients taking oral

anticoagulants are also at greater risk of death after ICH versus those not taking

anticoagulants.

136 Other drugs that may increase the risk of ICH include targetspecific oral anticoagulants, such as dabigatran, rivaroxaban, apixaban, and

edoxaban; heparin,

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LMWHs, fondaparinux, and other parenteral anticoagulants; aspirin and other

antiplatelet agents; selective serotonin reuptake inhibitors; and sympathomimetics,

such as amphetamines, phenylpropanolamine, cocaine, and caffeine-containing

medications.

140–144 Additional risk factors for non-traumatic ICH include advanced

age, history of stroke, diabetes, smoking, excessive alcohol consumption, African

American ethnicity, and low cholesterol levels, especially in the absence of HMGCoA reductase inhibitor use.

145

,

146 Genetic predisposition does not play a role in

most hemorrhagic strokes except for those caused by AVMs.

CASE 61-3, QUESTION 2: What are the key principles of therapy in patients presenting with spontaneous

intracerebral hemorrhage?

Initial management of spontaneous ICH involves (1) preventing hematoma

expansion and (2) preventing and managing elevated intracranial pressure.

To minimize hematoma expansion, anticoagulants should be reversed immediately

in patients such as S.P., who present with drug-induced coagulopathies, and blood

pressure should be carefully managed. Methods for preventing and managing

elevated ICP include avoiding hypotonic fluids as well as medical and surgical

methods. Ancillary therapies including treatment of fever and avoiding hypoglycemia

and hyperglycemia are also suggested.

CASE 61-3, QUESTION 3: What pharmacotherapy should be initiated to reverse S.P.’s anticoagulantinduced coagulopathy?

Up to 20% of patients with ICH present with a drug-induced coagulopathy, like

S.P.

147

,

148 Because hematoma growth within the first 24 hours of ICH is directly

associated with worse outcomes and reversal of warfarin-induced coagulopathies

within 4 hours of ICH has been shown to limit hematoma expansion, it is important to

reverse coagulopathies in a timely manner.

149

,

150 All anticoagulant and antiplatelet

medications should be immediately discontinued, and agents should be administered

to remove the anticoagulant medication from the body and reverse its effect.

151

Although S.P. was using warfarin for prevention of ischemic stroke in the setting of

atrial fibrillation, because of his acute ICH, the benefit of reversing the warfarin in

order to improve neurologic outcome greatly outweighs the short-term risk of

ischemic stroke resulting from anticoagulant reversal. If a patient has taken an oral

anticoagulant within the last two hours, activated charcoal may be considered to

prevent absorption; however, it is important to ensure the patient can tolerate enteral

administration. Historically, fresh frozen plasma (FFP) has been used to reverse

warfarin-induced coagulopathies in patients such as S.P.; however, prothrombin

complex concentrates (PCCs) have recently become the recommended agents to

rapidly reverse anticoagulation because of warfarin.

152 FFP contains all the clotting

factors depleted by warfarin but can take several hours to thaw and administer and

may be associated with pulmonary complications and edema because of the volume

required. In contrast, PCCs may reverse the INR within minutes because they can be

administered more rapidly. Additionally, PCCs are associated with a lower risk of

volume overload and pose a lower risk of infection than FFP. Use of PCCs in this

setting has been shown to more effectively limit hematoma expansion compared to

FFP, but improvement in clinical outcomes has not been demonstrated to date.

153

,

154

Three-factor PCCs contain factors II, IX, and X while 4-factor PCCs also includes

factor VII. PCC availability may be limited by institutional policies, in part, because

of the high cost of treatment relative to other therapeutic options.

155 Because the effect

of PCC and FFP is short-lived, patients with warfarin-induced coagulopathy should

concomitantly receive 10 mg of IV vitamin K (phytonadione) by slow infusion.

152

Newer oral anticoagulants indicated for non-valvular atrial fibrillation include

dabigatran, rivaroxaban, apixaban, and edoxaban.

156–158 Although data regarding

management of ICH patients receiving these agents are limited, some experts suggest

using a PCC product. Idarucizumab is a monoclonal antibody that can be used to

reverse dabigatran. Agents for reversal of other target-specific anticagulants are

under study. Importantly, dabigatran can be removed through hemodialysis. As with

warfarin-induced coagulopathies, reversal agents should be administered promptly

and activated charcoal should be considered.

Other drug-induced ICHs may occur in patients receiving heparin, LMWHs, the

parenteral factor Xa inhibitor fondaparinux, and antiplatelet agents such as aspirin

and clopidogrel. Protamine sulfate may be used for the reversal of heparin and

LMWH, while fondaparinux activity may be antagonized with PCCs. No intervention

has been shown to be clearly beneficial in patients experiencing ICH and taking

antiplatelet agents, although studies are ongoing.

151

To reverse his warfarin-induced coagulopathy, S.P. should receive a weight-based

dose of a PCC product and 10 mg IV vitamin K by slow IV infusion.

CASE 61-3, QUESTION 4: How should S.P.’s acute hypertension be managed?

Excessive hypertension may expose patients with ICH to elevated risk of

hematoma expansion, neurologic deterioration, and worse outcomes.

159

,

160 Lower

blood pressures have been suggested to potentially worsen prognosis; however, this

phenomenon is not as well documented as it is with ischemic stroke.

161

,

162 Several

studies have shown that rapid blood pressure reduction to a SBP of less than 140 mm

Hg is safe in patients with ICH presenting with hypertension.

163–166 Additionally,

studies suggest that aggressive acute blood pressure control can improve functional

outcomes and may be associated with a trend toward a reduction in death.

159

,

163

It is

important to note that patients presenting with SBPs above 220 mm Hg and those with

very severe ICHs have not been well represented in studies.

Based on these studies, current guidelines suggest that lowering SBP to less than

140 mm Hg in patients presenting with an SBP 150 to 220 mm Hg and no

contraindications to antihypertensive therapy is safe and may improve outcomes. In

patients presenting with an SBP >220 mm Hg, it is recommended to initiate

aggressive antihypertensive therapy with an IV infusion and to carefully monitor the

patient.

151 Nicardipine and labetalol are most commonly used antihypertensive agents

in patients with ICH, but hydralazine, nitroprusside, or nitroglycerin may be

considered depending on the clinical situation. If labetalol is used to control acute

blood pressure, it should be administered as IV boluses, potentially in combination

with an IV infusion. Nicardipine is only administered as an IV infusion.

S.P.’s blood pressure exceeds 150 mm Hg, so IV antihypertensive therapy is

indicated. It would be appropriate to initiate an IV nicardipine infusion at 5 mg/hour

and titrate every 5 minutes to achieve an SBP of less than 140 mm Hg in S.P.

CASE 61-3, QUESTION 5: Hours after admission, S.P.’s mental status worsens, likely because of severely

elevated ICPs. What therapy should S.P. receive for his elevated ICP?

Elevated ICP refers to excessive pressure inside the intracranial vault and may

occur in patients with severe hemorrhagic and ischemic strokes as well as in those

suffering from traumatic brain injury, brain tumors, hydrocephalus, and hepatic

encephalopathy. It can lead to brain hypoxemia and cause herniation. S.P.’s

worsened mental status may be consistent with elevated ICP. Other symptoms of

elevated ICP include headache, vomiting, cranial

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nerve palsies, and the combination of bradycardia, respiratory depression, and

hypertension.

In patients with neurologic emergencies, such as S.P., hypotonic fluids such as

dextrose 5% in water should be avoided in favor of isotonic fluids such as 0.9%

sodium chloride (normal saline) and Lactated Ringers because hypotonic fluids can

exacerbate cerebral edema and worsen ICP.

151 When considering fluids patients are

receiving, it is important to evaluate both maintenance fluids patients are getting and

the fluids in which IV medications are diluted. In patients with elevated ICPs, IV

medications should be diluted in 0.9% sodium chloride rather than dextrose 5% in

water or other hypotonic fluids whenever possible.

Treatment of elevated ICP involves patient care measures, pharmacotherapy, and

surgical interventions. First, the head of the bed should be elevated to at least 30

degrees once it is clear that S.P. is not hypovolemic in order to minimize blood and

fluid accumulation in the brain. Hyperventilation (increasing the patient’s respiratory

rate and/or the volume of air he breathes with each respiration) with a PaCO2 goal of

<30 mm Hg may be considered for a very short time in S.P. until other interventions

can be implemented. Hyperventilation should not be continued long-term because it

can compromise cerebral blood flow.

S.P. should receive aggressive analgesic medications, such as fentanyl and

morphine. Sedatives, such as propofol, should also be administered.

151 Hyperosmolar

agents, including intravenous mannitol, dosed at 0.25 to 1 g/kg every 4 to 6 hours, or

hypertonic sodium chloride may be considered to establish an osmotic gradient that

can facilitate the movement of fluid out of the brain, thus reducing ICP.

151

,

167

Clinicians may place an intracranial pressure monitor or utilize neurologic exams to

guide treatment with hyperosmolar agents. If an ICP monitor is used, hyperosmolar

therapy would be indicated to maintain an ICP of <20 mm Hg while if an ICP monitor

is not utilized, a worsening in neurologic exam consistent with elevated ICP would

warrant therapy. If S.P. continues to exhibit elevated ICPs after hyperosmolar and

aggressive analgesia and sedation, a continuous infusion of a neuromuscular blocking

agent should be administered. Last-line measures that may be considered include use

of a barbiturate coma.

In patients who develop hydrocephalus because of an ICH or another condition, a

ventriculostomy may be employed. A ventriculostomy is a surgically placed drain

that resides in the ventricle and is used to drain CSF. Finally, open craniotomy, or

removal of a portion of the skull, in the area of edema, may be considered in highly

selected situations; however, the efficacy of this approach is questionable in many

patients.

CASE 61-3, QUESTION 6: What other ancillary therapies may be appropriate for S.P.?

S.P. may benefit from (1) maintenance of normothermia with acetaminophen if he

develops a fever and (2) avoiding hypoglycemia or excessive hyperglycemia.

Although the clinical benefit of antipyretic therapy has not been clearly established

in ICH, fever is associated with a worse prognosis.

168

It is recommended that S.P.’s

body temperature should be monitored and acetaminophen may be administered to

achieve normothermia.

151 Studies evaluating mild hypothermia are ongoing.

Both hypoglycemia and hyperglycemia should be avoided in hemorrhagic stroke.

Hypoglycemia can directly lead to neurologic injury while hyperglycemia is

associated with worsened neurologic outcome after from stroke. Current guidelines

recommend avoiding both hypoglycemia and hyperglycemia but do not suggest a

specific blood glucose range.

151 Considering that his blood glucose is markedly

elevated, S.P. should be initiated on an insulin regimen in accordance with

institutional policies.

Seizures can complicate approximately 16% of all strokes and may be difficult to

observe because they are often non-convulsive.

151

,

169 However, because studies of

prophylactic antiepileptic therapy have failed to demonstrate consistent benefit and

have sometimes indicated harm,

170 current guidelines do not recommend routine

seizure prophylaxis.

151 Antiepileptic therapy should be initiated promptly if a patient

develops seizures during or after the development of an ICH.

CASE 61-3, QUESTION 7: What secondary prevention strategies should be recommended for S.P. after he

recovers from his ICH?

For S.P. and any patient who has suffered an ICH, key modifiable risk factors that

should be addressed upon stabilization include maintaining blood pressure at less

than 130/80 mm Hg, smoking cessation, treating sleep apnea, avoiding excessive

alcohol use, and abstaining from cocaine and other illicit drugs.

151

,

169

REHABILITATION

CASE 61-4

QUESTION 1: Patient J.A. has had a stroke and has received appropriate acute care. He is ready to be

discharged from the hospital but still has trouble walking, talking, and performing activities of daily living. For

patients who require rehabilitative care after hospital treatment of an ischemic or hemorrhagic stroke, what

interventions will aid their recovery?

Patients who have suffered ischemic and hemorrhagic strokes often require longterm rehabilitation after their acute treatment. Rehabilitation is directed at managing

daily functions, enhancing existing neurologic function, and attempting to regain lost

function. Considerations for daily functions include activities of daily living and

bowel and bladder management through balanced pharmacologic interventions.

Efforts should be made to allow patients to function independently with activities of

daily living and manage the psychologic effects of stroke. Enhancement of current

neurologic function and minimizing depression includes elimination of drugs that may

compromise patients’ memory and mental function. These include benzodiazepines,

major tranquilizers, and sedating antiepileptic drugs.

Localized spasticity is a common complication after strokes. Spasticity affecting a

single limb frequently responds to regional motor nerve blocks with botulinum toxin.

Aggressive physical therapy is also essential to the management of spasticity.

Systemic antispasticity agents such as diazepam, baclofen, or dantrolene sodium are

not used routinely because of the risk for toxicity. They are used only when spasticity

involves multiple parts of the body or is unresponsive to other therapies.

Other less common impediments to patients’ recovery after stroke include

decubitus ulcers, hypercalcemia, and heterotopic ossification (e.g., the laying down

and calcification of a bone matrix in muscle surrounding major joints). Prevention

through meticulous skin care is the key to the management of pressure ulcers.

Mobilizing patients as soon as possible after stroke can prevent hypercalcemia and

heterotopic ossification.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

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Key References

Easton JD et al. Definition and evaluation of transient ischemic attack. Stroke. 2009;40:2276–2293. (2).

Eikelboom J et al. Antiplatelet drugs. Antithrombotic therapy and prevention of thrombosis, 96th ed: American

College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2, Suppl): e89s–e119s.

(116).

Hacke W et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med.

2008;359:1317–1329. (66).

Jauch EC et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for

healthcare professionals from the American Heart Association/American Stroke Association. Stroke.

2013;44:870–947. (53).

Kernan WN et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a

guideline for healthcare professionals from the American Heart Association/American Stroke Association.

Stroke. 2014;45:2160–2236. (5).

Meschia JF et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the

American Heart Association/American Stroke Association. Stroke. 2014;45:3754–3832. (4).

Mozaffarian D et al. Heart disease and stroke statistics—2015 update: a report from the American Heart

Association. Circulation. 2015;131:e29–e322. (1).

Hemphill JC 3rd et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for

Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke.

2015;46(7):2032–2060. (151).

Key Websites

American Heart Association. http://www.americanheart.org/presenter.jhtml?identifier=4755.

American Stroke Association. http://www.strokeassociation.org/STROKEORG/.

Center for Disease Control and Prevention. http://www.cdc.gov/stroke/.

National Institute of Neurological Disorders and Stroke.

http://www.ninds.nih.gov/disorders/stroke/stroke.htm.

COMPLETE REFERENCES CHAPTER 61 ISCHEMIC AND

HEMORRHAGIC STOKE

Mozaffarian D et al. Heart disease and stroke statistics—2015 update: a report from the American Heart

Association. Circulation. 2015;131(4):e29–e322.

Easton JD et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare

professionals from the American Heart Association/American Stroke Association Stroke Council; Council on

Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on

Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. Stroke.

2009;40(6):2276–2293.

Howard G et al. Decline in US stroke mortality: an analysis of temporal patterns by sex, race, and geographic

region. Stroke. 2001;32(10):2213–2220.

Meschia JF et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from

the American Heart Association/American Stroke Association. Stroke. 2014;45(12):3754–3832.

Kernan WN et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a

guideline for healthcare professionals from the American Heart Association/American Stroke Association.

Stroke. 2014; 45(7):2160–2236.

Astrup J et al. Cortical evoked potential and extracellular K

+

and H

+

at critical levels of brain ischemia. Stroke.

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Biesbroek JM et al. Prognosis of acute subdural haematoma from intracranial aneurysm rupture. J Neurol

Neurosurg Psychiatry. 2013;84(3):254–257.

Schuss P et al. Aneurysm-related subarachnoid hemorrhage and acute subdural hematoma: single-center series

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