Use of Anti Platelet Agents for Prevention[1]

8/14/2019 Use of Anti Platelet Agents for Prevention[1]

1/31

Use of Antiplatelet Agents for Prevention

of Ischemic Stroke

R. Charles Callison, MD, Harold P. Adams, Jr, MD*

Division of Cerebrovascular Diseases Department of Neurology,

Carver College of Medicine University of Iowa, 200 Hawkins Drive,Iowa City, IA 52242, USA

Effective prevention may be the most cost-effective strategy for managing

patients who have ischemic cerebrovascular disease, because it helps elimi-

nate the costs of acute care and rehabilitation and the economic impact of

lost productivity from premature death or disability. In addition, prevention

avoids human suffering associated with ischemic stroke. Although no inter-

vention may entirely eliminate the risk for ischemic stroke, therapies areavailable that have been proven to lower the likelihood of a cerebrovascular

event.

Interventions are prescribed to a broad range of persons who have not

experienced ischemic neurologic symptoms (primary prevention) and to

those who have already experienced a stroke or the warning symptoms (sec-

ondary prevention) (Box 1) [1]. The division between primary and secondary

prevention is rather arbitrary, because patients who have symptomatic cor-

onary artery disease may undergo therapies to prevent myocardial infarc-

tion (secondary prevention) and ischemic stroke (primary prevention). Onthe other hand, besides secondary prevention of recurrent ischemic stroke,

management is also aimed at lessening the likelihood of myocardial infarc-

tion, symptomatic ischemia in other vascular territories, or vascular death

[2]. Most medical interventions to lower the risk for stroke are prescribed

similarly in either the setting of primary or secondary prevention.

Overall management to lower risk for ischemic stroke is multifaceted.

Management includes measures to treat risk factors for accelerated athero-

sclerosis and stroke, antithrombotic therapies to lower the risk for

Dr. Adams was a co-investigator in trials sponsored by Boerhinger-Ingelheim and Sanofi-

Aventis/Bristol-Myers Squibb.

* Corresponding author.

E-mail address: [email protected] (H.P. Adams).

0733-8619/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.ncl.2008.06.005 neurologic.theclinics.com

Neurol Clin 26 (2008) 10471077
mailto:[email protected]://www.neurologic.theclinics.com/http://www.neurologic.theclinics.com/mailto:[email protected]


2/31

thromboembolism, and surgery to treat a defined arterial or cardiac lesion

(Box 2). Treatment decisions are made on a case-by-case basis, with most

patients receiving some combination of medication and recommendations

for lifestyle modification. Some patients will also undergo surgical or endo-

vascular interventions. This article discusses antithrombotic treatment for

ischemic stroke prevention, placing major emphasis on the indications for

and administration of antiplatelet therapy.

Antithrombotic therapy: general considerations

Antithrombotic medications are the keystone of management to lower

risk for ischemic stroke, myocardial infarction, and vascular death among

patients who have ischemic cerebrovascular disease. Virtually all patients

who experience a stroke or the warning symptoms should be treated with

these medications (see Box 2). Choices include anticoagulants and antiplate-

let agents. These medications should be used in combination with treat-ments aimed at modifying cardiovascular and stroke risk factors, and

surgical procedures. These medications may be prescribed as a single agent

or in combinations.

Atithrombotic medication is selected based on several factors that must

be considered for each patient (Box 3). The presumed underlying cause of

the patients neurologic symptoms is especially important. Long-term

Box 1. Stroke risk factors

NonmodifiableAge

Male gender

Race

Low birth weight

Family history of stroke or other ischemic disease

Prior stroke, transient ischemic attack (TIA), ischemic heart

disease, peripheral (leg) artery disease

ModifiableCardiovascular disease

Hypertension

Diabetes mellitus

Hyperlipidemia

Cigarette smoking

Atrial fibrillation

Physical inactivity

Sickle cell disease

Postmenopausal use of estrogen-progesterone medications

1048 CALLISON & ADAMS


3/31

administration of oral anticoagulants is recommended for most patients

who have cerebral ischemia secondary to high-risk cardiac disorders, includ-

ing atrial fibrillation [2]. In general, the benefit of lowering the risk for stroke

is considerably greater when using adjusted doses of oral anticoagulants

compared with antiplatelet agents. However, antiplatelet agents may be pre-

scribed for patients who have a contraindication to oral anticoagulants [2].

Depending on the nature of the underlying coagulation disorder, either oral

anticoagulants or antiplatelet agents are prescribed. Data are limited on the

usefulness of antithrombotic medications in patients who have hypercoagu-lable disorders. In general, antiplatelet agents are preferred for treating

patients who have intracranial or extracranial arterial disease [2]. Antiplate-

let agents are usually administered to individuals who have stroke of unde-

termined origin. The presumed vascular territory (carotid versus

vertebrobasilar circulation) has less influence on the selection of antithrom-

botic medications.

Plans for surgical or endovascular interventions also affect management

with antithrombotic agents. Antiplatelet agents are usually prescribed in the

pre- and postoperative management of patients undergoing carotid endar-terectomy or other vascular operations. Combinations of antiplatelet agents

(eg, aspirin plus clopidogrel) usually are given to patients undergoing angio-

plasty and stenting.

Use of antithrombotic medications at the time of a new stroke also affects

decisions about subsequent treatment. A new stroke may be considered a fail-

ure of previous antithrombotic treatment, and a different medication is often

Box 2. Stroke prevention

Risk factor modificationLifestyle changes (weight loss, diet, exercise)

Smoking cessation

Antihypertensives

Oral and injectable hypoglycemics

Lipid-lowering agents

Antithrombotic agents

Aspirin

Clopidogrel or ticlopidineDipyridamole

Oral anticoagulants (most commonly warfarin)

Surgical procedures

Carotid endarterectomy

Endovascular surgery

Other cardiac procedures

1049USE OF ANTIPLATELET AGENTS


4/31

Box 3. Side effects and other concerns of commonly used

antithrombotic agentsAspirin

Bleeding and bruising

Epigastric distress

Gastrointestinal ulcer and hemorrhage

Intracranial hemorrhage

Allergic nasal polyposis and anaphylaxis

Teratogenicity in the first trimester of pregnancy

DipyridamoleHeadache

Epigastric distress

Bleeding and bruisinga

Intracranial hemorrhagea

Ticlopidine


Allergic urticaria


Thrombotic thrombocytopenia purpuraAgranulocytosis

Cholestatic hepatitis

Diarrhea

Clopidogrel


Allergic urticaria


Thrombotic thrombocytopenic purpurab

Agranulocytosisb

Warfarin



Gastrointestinal or urinary hemorrhage

Warfarin-associated skin necrosis

Hemorrhagic fatty necrosis

Frequent laboratory monitoring and dose adjustments

Interactions with medications and foodTeratogenicity

a Bleeding is a complication of dipyridamole when used in combination with aspi-

rin. This may be from the action of aspirin alone or the combination of the two agents.b The frequency of thrombotic thrombocytopenic purpura and agranulocytosis

with clopidogrel is substantially lower than with ticlopidine and does not require

laboratory monitoring.



5/31

prescribed. In addition, patients may have contraindications to a specific med-

ication. For example, patients may have a history of allergy or intolerance to

aspirin. Cognitively impaired patients, those considered at high risk for falls,and those who have problems with a complex treatment regimen also may not

be able to take some medications, such as oral anticoagulants. In addition, the

presence of concomitant diseases, including coronary or peripheral artery dis-

ease, may affect treatment decisions.

Although oral anticoagulants remain an important treatment option for

patients at high risk for stroke, use is restricted largely to those who have

cardioembolic events and some whose neurologic symptoms are caused by

an inherited or acquired coagulation disorder [2]. Oral anticoagulants

have not been effective in preventing stroke among patients in whom it oc-curs secondary to arterial diseases, such as extracranial or intracranial large

artery atherosclerosis, or among those who have symptoms despite treat-

ment with antiplatelet therapy [36]. Anticoagulants are currently not

a treatment option for most patients who experience stroke secondary to

arterial disease, and therefore this article focuses on the use of antiplatelet

agents. In some instances, antiplatelet agents are combined with oral antico-

agulants to treat persons at especially high risk for stroke.

Antiplatelet agents have been tested in a broad range of subjects who

have symptomatic or ischemic vascular disease, including those who recentlyexperienced TIA or ischemic stroke. These agents reduce the risk for nonfa-

tal myocardial infarction, nonfatal ischemic stroke, and vascular death by

approximately 25% [7]. They also lower the need for major vascular opera-

tions, including reconstructive surgery or endovascular procedures.

However, these medications have established efficacy as adjuncts for pre-

venting thromboembolic complications of these operations [8].

Responses to antiplatelet therapy are not influenced by the patients gen-

der or age. Patients who are hypertensive and nonhypertensive, and diabetic

and nondiabetic respond equally well [7]. Unfortunately, despite theirproven track record, antiplatelet agents are underused [8]. Given the low

cost of aspirin, financial considerations should not be the reason antiplatelet

agents are not prescribed in patients who have ischemic disease. The Joint

Commission now includes the initiation of antithrombotic therapy (most

commonly an antiplatelet agent) before discharge as a quality of care

marker for patients hospitalized with a TIA or ischemic stroke [9].

Aspirin

Aspirin (acetylsalicylic acid) was first developed in the 19th century for

treating inflammatory diseases and managing symptomatic pain. In the mid-

1950s, Craven [10] described the potential usefulness of aspirin for preventing

heart attack and stroke in a general practice setting. Aspirin was then found to

have a profound effect on inhibiting the actions of cyclo-oxygenase-1 on plate-

let function, and could therefore be used as an antithrombotic agent [11,12].



6/31

Aspirin is the most extensively studied medication for the primary or sec-

ondary prevention of ischemic vascular events [7]. It has been tested in

a broad spectrum of patients and has been found to be effective when givenin a broad range of doses. For many years, aspirin has been the standard

against which other medical or surgical interventions are compared. Aspirin

has several advantages: it is an inexpensive over-the-counter medication, it is

easy to administer, and no specific monitoring is required.

Pharmacology

Suppression of cyclo-oxygenase activity leads to decreased production of

prostaglandins and thromboxane A2, which in turn limits platelet aggrega-tion. The effects on platelets and megakaryocytes are irreversible, and there-

fore the antiplatelet aggregating actions of aspirin persist the 7 to 10 days of

the platelets life. These effects persist even if the blood levels of aspirin have

declined. Aspirin is readily absorbed from the gastrointestinal tract, with

a slower rate when using an enteric-coated preparation.

Platelet function inhibition may be detected within 1 hour of administra-

tion of a 325-mg nonenteric-coated aspirin tablet. Because starting treat-

ment at a lower dose (eg, 81 mg) will not suppress platelet function for

several days, a rationale exists for starting treatment with one 325-mg tabletof aspirin (loading dose) and maintaining therapy with an 81-mg dosage. If

immediate antiplatelet effects are strongly desired, aspirin could be given in

a rapid-release formulation, but the necessity of this approach is unclear

[13].

Larger doses of aspirin exceeding 600 mg also have an inhibitory but

reversible effect of the endothelial production of prostacyclin, which could

have a theoretic prothrombotic effect [14]. Other nonsteroidal anti-inflam-

matory agents, including ibuprofen, may interfere with the antiplatelet

effects of aspirin [15,16]. Using these medications may contribute to aspirinresistance or aspirin response variability. Although the clinical implications

of these interactions are unclear, it seems that these medications should not

be given within 8 hours of aspirin administration.

The anti-inflammatory actions of aspirin also may affect white blood cell

function and thus may help stabilize atherosclerotic plaques [17,18]. There-

fore, aspirin could lower the risk for ischemic events in ways other than pre-

venting platelet aggregation. Aspirin also may have some neuroprotective

effects, although this attribute has not been established with any certainty

[19].

Aspirin resistance or variability of response

Considerable interest has been shown in the concept of aspirin resistance,

which is now referred to by some experts as aspirin variability of response

(AVR) [2022]. The antiplatelet aggregating actions of aspirin may vary



7/31

among individuals; some may be relatively insensitive to the effects of aspi-

rin whereas others may develop resistance with prolonged use [23]. The

prevalence and importance of AVR are unknown [2426]. Chen and col-leagues [27] concluded that AVR may be associated with an increased risk

for ischemic events among persons who have coronary artery disease. In

general, aspirin resistance is defined as the retention of normal platelet func-

tion despite aspirin use.

Presumably, a relative resistance to aspirins pharmacologic actions could

explain some recurrent strokes among persons taking the medication. A

potential relationship may exist between the aspirin dose or use of an

enteric-coated preparation and the finding of AVR [28]. Based on the find-

ings that many other medications, including oral anticoagulants, have differ-ent therapeutic effects in different patients, a possible individual resistance to

aspirins actions or a dosage relationship makes sense.

Responses to aspirin may be affected by factors such as patient compli-

ance, smoking, hyperglycemia, hyperlipidemia, or concomitant medications

[25,29]. A potential genetic factor that directly or indirectly affects platelet

cyclo-oxygenase also may be present [30]. However, a leading explanation

may be lack of compliance with the treatment regimen rather than failure

of the medication to inhibit platelet function [20,31].

The diagnosis of AVR is currently based primarily on the findings ofa laboratory evaluation examining platelet function [20,3234]. However,

no agreement exists about the best test to screen for platelet function or

when the tests should be performed [25]. Currently, no standard method

to diagnose AVR is available [29]. Considerable confusion exists about

the importance of AVR in the development of recurrent ischemic events

among persons taking the medication [35]. Much additional research is

needed to determine if the syndrome of AVR is clinically important and

to establish the best response to this phenomenon. Therefore, according

to current evidence-based guidelines, routine point-of-care or other plateletfunction tests to monitor therapy with aspirin or other antiplatelet agents

are not recommended in general practice [36].

Safety

The safety profile of aspirin is very well-known. Although it has been

available for more than a century and is an over-the-counter medication

that many people have used, it is a potent medication and patients should

be warned about possible adverse reactions. Some people may experience al-lergic reactions, including rash or anaphylaxis. Those who have a history of

nasal polyps or asthma may be at higher risk. Epigastric pain, gastritis, and

upper gastrointestinal hemorrhage are the most common side effects and

may require discontinuance. Sze and colleagues [37] estimated that pro-

longed use of aspirin increases the risk for peptic ulcer disease by approxi-

mately 350%.



8/31

Because aspirin is a potent inhibitor of platelet function, bleeding is a po-

tential complication. The estimated risk for major bleeding is 3.5 per 100

patient-years [38]. Bleeding, including intracranial hemorrhage, may occurwith a broad range of daily doses. This relationship should not be unex-

pected, because aspirin has potent effects on platelet function, even at low

doses. Clinical trials testing aspirin treatment initiated within a few hours

after stroke onset show a modest association with the development of hem-

orrhagic transformation or other intracranial bleeding [39,40]. Trials of as-

pirin in the primary prevention of ischemic events have reported a slight

increase in risk for hemorrhagic stroke [41]. The risk for intracranial hemor-

rhage has been estimated to be 12 in 10,000 [42].

Aspirin may also aggravate surgery-associated bleeding, and surgeonsoften request that patients stop taking the medication before an elective

operation. No dosage relationship exists with bleeding other than for gastro-

intestinal hemorrhage, which is correlated with doses greater than 325 mg/d.

Using enteric-coated preparations may lower the risk for upper gastrointes-

tinal complications. In addition, patients may be prescribed antacids or gas-

troprotective medications to lower the gastric side effects of aspirin. Aspirin

may have teratogenic effects, but it can be administered after the first trimes-

ter of pregnancy [43].

Potential indications and efficacy

Aspirin is used for the primary prevention of myocardial infarction in

men and the primary prevention of ischemic stroke in women [41,44]. The

differences in responses to aspirin between men and women probably reflect

the natural history of atherosclerotic disease in the two genders. Because

men have a higher rate of early myocardial infarction, aspirins impact on

preventing these events would be more apparent than among women. The

best dosage for preventing myocardial infarction is 75 to 325 mg/d, andthe same dosage is probably equally effective for preventing ischemic stroke

[4547].

Based on a meta-analysis of trials enrolling several thousand subjects, the

Antiplatelet Trialists Group concluded that aspirin was equally effective in

reducing vascular events in men and women [7]. Although national guide-

lines do not recommend aspirin for primary prevention of stroke in men,

it remains an important therapy for preventing ischemia in high-risk asymp-

tomatic individuals, especially among men older than 50 years [1,4850].

Besides reducing the risk for ischemic stroke, aspirin may lower the likeli-hood of myocardial infarction or other causes of vascular death.

Additional research is underway to test the role of aspirin in primary pre-

vention of vascular events [51]. The Aspirin to Reduce the Risk of Initial

Vascular Events (ARRIVE) is a placebo-controlled primary prevention trial

studying the benefits of 100 mg of aspirin over 10 years among men and

women who have a 10% to 20% risk for cardiovascular events.



9/31

Many clinical trials have tested aspirins ability to prevent ischemic stroke

among persons who experienced a TIA or stroke, and most have tested the

medication in patients who have symptomatic large artery atherosclerosis orlacunar disease. The first clinical trials tested a dosage of 1300 mg/d [5254].

Lower daily dosages (30325 mg/d) were then tested and shown to be

equally effective [5557]. In addition, the lower doses were associated with

fewer gastrointestinal side effects. The Aspirin Carotid Endarterectomy

Trial found that lower dosages of aspirin (81325 mg/d) were superior to

larger doses (6501300 mg/d) in reducing cardiac and cerebrovascular events

[58]. In the Second European Stroke Prevention Study, aspirin in a dosage

of 50 mg/d was found to reduce the risk for stroke by approximately 16%

compared with placebo [59].The trials have consistently shown a benefit from aspirin in reducing the

risk for ischemic stroke among high-risk patients. Based on a meta-analysis,

Algra and van Gijn [60] estimated that aspirin reduces risk for major stroke

by approximately 16%.

In addition to lowering the likelihood of stroke, aspirin also has been

shown to reduce the chances of myocardial infarction or vascular death.

In addition, evidence suggests that low-dose aspirin is equal or superior to

larger doses in prophylaxis against stroke [2,61,62]. Based on these findings,

the guidelines do not recommend increasing the dose of aspirin in patientswho experience ischemic symptoms while taking low-dose aspirin.

Aspirin also has been shown to be superior in preventing non

cardioembolic stroke. The Warfarin-Aspirin Recurrent Stroke Study

showed no difference between aspirin and the oral anticoagulant. Although

a trend was seen toward a lower event rate and fewer bleeding complications

in the aspirin group, these differences were not statically significant [3].

Another head-to-head trial studying the prevention of recurrent stroke

among patients who had symptomatic intracranial atherosclerosis found

no difference between aspirin and warfarin in terms of primary event rate,but a significantly higher rate of major hemorrhage was seen in the warfarin

group [6,63,64]. In an international study, antiplatelet therapy was superior

to warfarin in preventing stroke among patients who had arterial disease [4].

Recent use of aspirin is not a contraindication for emergency treatment

of acute ischemic stroke with intravenous thrombolytic therapy. On the

other hand, national guidelines recommend that aspirin therapy not be

initiated within 24 hours of treatment with tissue plasminogen activator

(tPA) [9]. One clinical trial found that concomitant administration of aspirin

increased the risk for serious bleeding after treatment with streptokinase[65].

Several trials have administered aspirin within the first hours after onset

of stroke; in this setting, aspirin often was used as the control to which an

anticoagulant was compared [39,40,6669]. In these studies, aspirin seemed

to be equal to or more effective than the anticoagulant. A meta-analysis of

two large trials of aspirin showed that initiation of aspirin within 48 hours of



10/31

stroke was associated with a modest but statistically significant improve-

ment in outcomes [39,40]. Much of aspirins benefit may have been in pre-

venting early recurrent stroke. One study evaluating the efficacy of aspirinin halting progression of neurologic worsening noted no impact on out-

comes [70]. Current guidelines recommend that most patients receive aspirin

within 48 hours after the onset of stroke [9].

Although no large-scale clinical trials have tested aspirin among patients

who have moyamoya disease, arterial dissections, or other vasculopathies, it

is often prescribed. The potential for intracranial bleeding from collateral ves-

sels in patients who have moyamoya disease and the presumed lower risk for

hemorrhage with aspirin may favor its use over anticoagulants. Although

some physicians prescribe oral anticoagulants to patients who have arterialdissection, the relatively low risk for recurrent stroke among these patients

may also favor the use of aspirin. No data from randomized trials are available

to provide information about the possible use of either antiplatelet agents or

anticoagulants in treating patients who have arterial dissection.

Aspirin is not effective for preventing intraventricular thrombus among

patients who have experienced a recent myocardial infarction. It is also

not effective in preventing embolic events among patients who have mechan-

ical prosthetic cardiac valves, especially in the mitral position [71]. However,

aspirin seems to be the appropriate antithrombotic therapy for patients whohave aortic bioprosthetic valves [72], and although Brueck and colleagues

[73] concluded that it was not necessary among these patients, most physi-

cians prescribe it.

No difference has been shown between aspirin and oral anticoagulants in

preventing recurrent stroke among persons who have patent foramen ovale

(PFO) and neurologic symptoms [74]. A French trial administered aspirin to

several groups of young adults who had PFO and ischemic stroke [75]. The

rates of recurrent embolic events were similar among patients who had PFO

and those who did not experience the cardiac change. These results suggestthat aspirin may be useful in treating patients who have cardiac diseases that

have a relatively low risk for embolization.

Several trials have tested the efficacy of aspirin among persons who have

atrial fibrillation [7679]. At a daily dosage of 325 mg, aspirin reduces the

risk for ischemic stroke by approximately 20%. Still, aspirin is not as effec-

tive as oral anticoagulants [80,81], even among older persons who have

atrial fibrillation [82]. Currently, aspirin should be reserved for treating

patients who have atrial fibrillation and a high risk for complications

from oral anticoagulants. The currently recommended dosage of aspirin,which is the only one tested in trials of atrial fibrillation, is 325 mg/d [2].

Dipyridamole

Dipyridamole was the second antiplatelet agent extensively tested for pre-

venting stroke among high-risk patients. The medication was initially tested



11/31

as a monotherapy, given as a relatively short-acting formulation. Early trials

were generally negative and the enthusiasm for dipyridamole waned. How-

ever, ensuing trials tested either conventional or sustained-release formationof dipyridamole alone or in combination with aspirin, and results have pro-

vided the strongest evidence for the role of dipyridamole in secondary pre-

vention of stroke.

Pharmacology

A potent vasodilator, dipyridamole also has antiplatelet effects through

the inhibition of cyclic nucleotide phosphodiesterase. As a result, cyclic

adenosine monophosphate builds up within the platelet, preventing aggrega-tion [83]. It also blocks the uptake of adenosine within the platelet [11].

Dipyridamole also may prolong survival of platelets, affect the synthesis

of prostaglandins, and have vasoprotective properties.

Because of variable absorption of dipyridamole, systemic bioavailability

may be low. The use of a sustained-release preparation increases its bioavail-

ability. Dipyridamole is metabolized in the liver. Its effects on platelet func-

tion are reversible and the aggregation drops after the medication is

stopped. The half-life of dipyridamole is approximately 10 hours. Thus,

the medication must be given in a twice-daily regimen to maintain therapeu-tic effects on platelet function. A currently marketed preparation is 25 mg of

aspirin and 200 mg of sustained-released dipyridamole.

Safety

Bleeding is not a major complication of dipyridamole [84]; headache is the

most frequent and troublesome side effect. In some instances, the headache

can be sufficiently severe to indicate possible subarachnoid hemorrhage. Usu-

ally the headache develops within the first days of treatment. Patients whohave a history of migraine may not be able to tolerate the medication. In

some patients who have a history of headache, clinicians may initiate treat-

ment with one tablet of the combination of aspirin and dipyridamole given

daily [85] and later increase the dosage to the twice-daily regimen.

Dipyridamole may also cause epigastric distress in some patients.

Because of its vasodilatory effects on coronary arteries, concern exists that

dipyridamole may increase the likelihood of myocardial ischemia. However,

studies have not shown an increased risk for myocardial infarction with the

aspirin/dipyridamole combination [86,87].Because the daily dosage of aspirin in the combination is 50 mg, some

cardiologists have recommended supplementing it with an additional

81-mg tablet, either whole or half, to assure that the patient is receiving at

least 75 mg of aspirin per day. Although it has vasodilatory actions, dipyr-

idamole does not lower blood pressure with long-term administration [88].

No laboratory monitoring is required.



12/31


The results of the first trials did not show dipyridamole to be efficacious

[89,90]. Thereafter, a European trial found that the combination of aspirin

and dipyridamole was superior to placebo, but whether the effect was

related primarily to the aspirin was unclear [91]. In the Second European

Stroke Prevention Study, sustained-release dipyridamole, 200 mg, taken

twice daily resulted in an approximately 16% reduction in ischemic events

compared with placebo; the effectiveness was approximately the same as

with aspirin, 25 mg, administered twice daily [59].

The same trial found that the combination of aspirin and dipyridamole

was superior to either medication when given alone. Furthermore, an

approximate 23% relative risk reduction for stroke was seen, favoring

aspirin plus sustained-release dipyridamole over aspirin alone. Subse-

quently, an investigator-initiated international trial also showed the com-

bination of aspirin and dipyridamole to be superior to aspirin

monotherapy [92].

Although the combination has not been shown to reduce the risk for

myocardial infarction or vascular death, the studies were not statistically

powered to prove these reductions.

Recently, the results of the Prevention Regimen for Effectively Avoiding

Second Strokes (PRoFESS) trial [93] were presented at a large international

meeting. The trial compared aspirin plus sustained-release dipyridamole to

clopidogrel for preventing recurrent stroke events among patients who

had noncardioembolic ischemic stroke. Over a mean follow-up of approx-

imately 2.5 years, the rates of recurrent stroke were 9.0% among individuals

taking aspirin and dipyridamole and 8.8% for those prescribed clopidogrel.

No differences were noted in the composite end points of recurrent stroke,

myocardial infarction, or vascular death.

This trial showed a higher rate of major bleeding events, including intra-

cranial hemorrhages, among patients taking aspirin and dipyridamole

(4.1%) than those taking clopidogrel (3.6%). Approximately 6% of patients

taking the aspirin/dipyridamole combination had to discontinue the medica-

tion prematurely because of headaches. How the results of PRoFESS will

affect future plans for selecting antiplatelet agents for preventing recurrent

stroke is unclear. Clopidogrel and the combination of aspirin and dipyrida-

mole seem to be roughly equal in efficacy.

Ticlopidine

Ticlopidine was the first thienopyridine developed as an antiplatelet

aggregating agent. It was tested in two large trials of secondary prevention

of stroke among patients who experienced TIA or stroke [94,95]. Ticlopidine

also was evaluated as an adjunctive antiplatelet agent for treating patients

who had ischemic heart disease [96,97]. Subsequent concerns about the



13/31

safety of ticlopidine, particularly its association with the development of

thrombotic thrombocytopenia purpura (TTP), have reduced ticlopidines

role in clinical practice for preventing stroke.

Pharmacology

Ticlopidine blocks in vivo platelet responses to ADP-induced aggregation

and signal transduction [98100]. The medication affects binding of fibrino-

gen to the platelet glycoprotein IIb/IIIa receptor [99]. It irreversibly alters

platelet function and prolongs the bleeding time. Almost 90% of a single

250-mg dose of ticlopidine is absorbed rapidly and reaches a peak plasma

concentration within 1 to 3 hours [99]. The usual daily dose is 250 mg twice

daily, and it has a half-life of approximately 24 to 36 hours.The antiplatelet actions of ticlopidine gradually increase after starting

treatment, and inhibition of platelet aggregation is delayed by 24 to 48 hours

after starting treatment [100]. Maximal suppression of platelet function does

not occur until 1 to 2 weeks after starting treatment. Therefore, ticlopidine is

not an effective therapy for the acute treatment of patients who have ische-

mic vascular disease. The antiplatelet effects of ticlopidine disappear over

approximately 1 week after stopping treatment.

Safety

Because ticlopidine is a potent antiplatelet agent, hemorrhage is a poten-

tial complication. Bleeding may occur in any site, including inside the cra-

nial vault. Risk for gastrointestinal bleeding is less than with aspirin.

Although abdominal pain can accompany ingestion of ticlopidine, it does

not cause gastritis or peptic ulcer disease.

Unusual complications of ticlopidine include pulmonary disease, chole-

static hepatitis, and jaundice [101,102]. Skin eruptions, including urticaria,

most commonly develop within the first 2 weeks of starting ticlopidine.Potentially life-threatening hematologic complications may also occur,

most commonly within the first 3 to 4 months of treatment [103]. Neutrope-

nia, including agranulocytosis, may develop in 0.5% of cases. Because of the

risk for neutropenia and TTP, complete blood cell and platelet counts must

be monitored every 2 weeks during the initial 3 months of treatment.

Although some persons, especially African Americans, may have a benign

cyclical neutropenia, the development of neutropenia usually prompts stop-

ping of the medication. Patients who have severe ticlopidine-associated neu-

tropenia usually require hospitalization and often receive granulocytecolony-stimulating factor to reduce the risk for infectious complications

[104]. The use of ticlopidine is complicated by TTP at a frequency of

approximately 0.02% [105,106]. Seriously affected patients also may have

hemolytic uremic syndrome [107]. Most patients who have TTP require hospi-

talization, and early intervention may be lifesaving. Treatment is centered on

plasma exchange, although relapses of TTP may occur despite intervention.



14/31


Clinical trials have shown the efficacy of ticlopidine in treating patients

who have ischemic heart disease, peripheral artery disease, and diabetic ret-

inopathy in addition to those who have ischemic cerebrovascular disease

[96,97,108]. The medication has been tested as monotherapy (usually com-

pared with aspirin) or in combination with aspirin.

In a trial that enrolled patients who experienced recent ischemic stroke,

the Canadian-American Ticlopidine Study found that ticlopidine reduced

the risk for recurrent stroke by approximately 30% compared with placebo

[95]. In a trial comparing aspirin or ticlopidine in preventing stroke among

patients experiencing warning symptoms, ticlopidine was found to reduce

the risk for new ischemic events by approximately 14% [94]. Most benefit

was found within the first few months of starting treatment.

More recently, a large trial tested the efficacy of aspirin or ticlopidine

for preventing stroke among African Americans [109,110]. Recurrent

stroke, myocardial infarction, or vascular death was diagnosed in 14.7%

of subjects taking ticlopidine and 12.3% taking aspirin. Overall, the trial

showed that ticlopidine was not better than aspirin among these high-

risk patients.

Clopidogrel

Clopidogrel, another thienopyridine, is widely used for treating patients

who have ischemic vascular disease, including those at risk for stroke. It

was initially tested in a large trial that enrolled subjects who had symptom-

atic coronary artery, cerebrovascular, and peripheral vascular disease [111].

Since the approval of clopidogrel by regulatory bodies, it has been tested

alone or in combination with aspirin in several clinical settings.

Pharmacology

Clopidogrel has a chemical structure and pharmacologic actions similar

to ticlopidine. Clopidogrel is administered orally at a usual daily dose of

75 mg. The pharmacokinetic properties of clopidogrel differ slightly from

ticlopidine [99]. It is rapidly absorbed and metabolized. The antiplatelet

effects of clopidogrel can be detected within 2 hours of a loading dose of

300 to 400 mg [112,113].

An acutely ill or unstable patient may be treated with an initial dose of

300 to 600 mg of clopidogrel; thus, this therapy may be useful in emergencytreatment of ischemia [114,115]. For instance, Kennedy and colleagues [116]

administered a loading dose of clopidogrel in combination with aspirin for

the emergency treatment of patients who experienced recent TIA. Thereaf-

ter, a daily dose of 75 mg maintains the antiplatelet effects.

The effects on platelet aggregation disappear approximately 1 week after

clopidogrel is stopped. Using caffeine after administering a loading dose of



15/31

clopidogrel may further enhance platelet inhibition, probably through syn-

ergistic actions on cyclic AMP [117].

Atorvastatin, lovastatin, and simvastatin, which have effects on theCYP3A4 pathway, may lessen the antiplatelet effects of clopidogrel. How-

ever, Saw and colleagues [118] did not find any impact on the frequency

of either ischemic or bleeding events in patients receiving clopidogrel and

one of the statin agents. Other studies found that statin medications do

not affect the antiplatelet activity of loading or maintenance doses of clopi-

dogrel [119,120].

The antiplatelet aggregating effects of clopidogrel are not affected by the

angiotensin-converting enzyme inhibitors. Administering omeprazole as

a gastroprotective agent was found to lessen the actions of clopidogrel onplatelet function [121]. Conversely, cilostazol seems to increase the antipla-

telet effects of clopidogrel given in conjunction with aspirin [122].

Clopidogrel resistance

Cases of potential clopidogrel resistance have been reported

[28,30,123,124]. Similar to patients who have presumed aspirin resistance,

this diagnosis is based on the results of platelet aggregation testing. In

one study of 50 patients receiving clopidogrel as part of preprocedural treat-ment before stenting, 14 were found to be resistant to clopidogrel [125].

Among patients who had diabetes, a sizable percentage treated with the

combination of aspirin and clopidogrel retained platelet function [126

128]. A Hungarian study could not find a specific genetic polymorphism

that might explain the resistance of platelets to treatment with clopidogrel

[129]. Barnes and colleagues [26] could not find any evidence of resistance

to dual antiplatelet agents as a distinct clinical syndrome.

Safety

Bleeding, including intracranial hemorrhage, is a potential complication

of treatment with clopidogrel, particularly when the medication is given

with aspirin. A large trial found that clopidogrel was associated with a lower

risk for gastrointestinal hemorrhage than aspirin [111]. Vilahur and col-

leagues [130] tested the ability of platelet concentrates to reverse the antith-

rombotic effects of clopidogrel. They found that 10 and 12.5 platelet

concentrate units would respectively inhibit 300 or 600 mg loading doses

of clopidogrel-induced platelet disaggregation.Many complications associated with ticlopidine also can occur with

clopidogrel, although the frequency seems less. A Japanese study found that

clopidogrel was safer than ticlopidine [131]. Because the risk for neutropenia

is low, patients receiving clopidogrel do not require hematologic monitoring.

Cases of TTP have been reported, including those with complicating

hemolytic uremic syndrome [132134]. Overall, the risk for TTP is



16/31

considerably less than with ticlopidine. TTP usually develops within the first

2 weeks of starting treatment with clopidogrel. Plasma exchange is the usual

management for patients who have clopidogrel-associated TTP, withrepeated exchanges needed in some instances. Fatal aplastic anemia may

also occur [135].


An international trial showed that clopidogrel was more effective than

aspirin in preventing ischemic events (5.32% versus 5.83%) [111]. The primary

benefit was found among the subgroup of patients who had symptomatic

peripheral vascular disease; no difference between the treatment groups wasfound among the subjects who had ischemic stroke as their qualifying event.

In a subgroup analysis, Ringleb and colleagues [136] found that clopidog-

rel was superior among patients who had ischemic symptoms. Several trials

have compared clopidogrel with other antithrombotic agents in patients

who had ischemic heart disease, with clopidogrel added to aspirin in some

instances [127,137140]. Overall, data suggest that clopidogrel is slightly

more effective than aspirin in preventing recurrent ischemic events among

high-risk persons, although the difference is modest.

Because its antiplatelet effects occur rapidly when the agent is adminis-tered with a loading dose of 300 to 600 mg, clopidogrel has become a stan-

dard intervention for treating patients who have acute myocardial ischemia.

However, the efficacy of clopidogrel in the emergency management of acute

ischemic stroke has not been tested on a large-scale basis [141]. Current

guidelines do not recommend use of clopidogrel for emergency treatment

of stroke, and advise that antiplatelet agents not be initiated within 24 hours

after treatment with intravenous tPA [9].

Prasugrel

Prasugrel is a new thienopyridine that was recently tested in patients who

had ischemic heart disease. This potent antiplatelet agent may be tested in

a wide range of patients who have ischemic vascular disease. It seems to

have advantages over clopidogrel [142].

Pharmacology

Like ticlopidine and clopidogrel, prasugrel is a prodrug that is inactive invitro [143,144]. The medication rapidly and irreversibly binds the platelet

P2Y12 receptor and blocks ADP-induced platelet activation and aggrega-

tion. Morel and colleagues [145] found that it inhibited ADP-induced plate-

let aggregation at a higher level than clopidogrel.

Prasugrel was estimated to be 10 to 100 times more potent than either

clopidogrel or ticlopidine [143]. Wiviott and colleagues [146] found that



17/31

60 mg of prasugrel resulted in a greater inhibition of platelet aggregation

than a 600-mg loading dose of clopidogrel. They also found that a daily

dose 10 mg of prasugrel had more effect on platelet function than 150 mgof clopidogrel. Another study found that a 60/10 mg regimen of prasugrel

has greater inhibition of platelet aggregation than a 600/75 mg regimen of

clopidogrel [147]. A study comparing clopidogrel and prasugrel in normal

volunteers found the platelet inhibitory actions of prasugrel to be similar,

but that the range of responses was smaller with prasugrel [148].

Safety

Serious bleeding seems to be more frequent with prasugrel than the otherthienopyridine medications [149]. No differences in the rates of intracranial

bleeding were found with prasugrel or clopidogrel; however, older persons

who experienced stroke may be at higher risk for bleeding with this agent.

Stopping the combination of prasugrel and aspirin may be associated with

rebound platelet activation [150].


A clinical trial compared aspirin and prasugrel with aspirin and clopidog-rel in the treatment of patients who had acute coronary artery syndromes

and underwent endovascular treatment [149]. The group of patients

receiving prasugrel experienced significant reductions in myocardial

infarction, urgent revascularization operations, and stent thrombosis. No

differences in the rate of nonfatal stroke were found between the treatment

groups. No trials have tested prasugrel in the long-term prevention of ische-

mic events or in persons at high risk for ischemic stroke. Additional research

on the short- or long-term administration of prasugrel is warranted.

Other antiplatelet agents

A Canadian trial tested sulfinpyrazone alone and in combination with

aspirin [52]. The medication, which is a uricosuric agent that has antiplatelet

effects, was not found to be as effective as aspirin and further study was

abandoned.

Cannon and colleagues [151] tested AZD6140, a reversible oral adenosine

diphosphate receptor antagonist, in patients who had nonST segment ele-

vation myocardial infarction. Compared with clopidogrel, AZD6140 wasassociated with a slight increase in minor bleeding and is now being tested

in a large clinical trial.

Indobufen, an anti-inflammatory agent that also inhibits cyclo-oxygenase,

was also evaluated but found to be less effective than ticlopidine [152,153].

Cilostazol increases the cyclic adenosine monophosphate induction of

platelet aggregation [122,154]. It has been used in combination with aspirin



18/31

and clopidogrel to treat patients who have coronary artery disease [155].

The combination was associated with a reduction in adverse cardiac events.

Cilostazol in combination with aspirin was compared with clopidogrelcombined with aspirin in patients undergoing stenting of the coronary

arteries [156]. The cilostazol therapy was superior to the combination of

aspirin and clopidogrel for preventing restenosis of the arteries. Cilostazol

has also been studied in secondary ischemic stroke prevention. In a pla-

cebo-controlled trial, Gotoh and colleagues [157] found it to be effective

and safe.

A clinical trial comparing trifusal with aspirin found it to have no net

benefit [158]. Several orally administered glycoprotein IIb/IIIa receptor

blockers were tested in nonstroke populations, but high rates of bleedingand mortality were reported [159161]. The glycoprotein IIb/IIIa receptor

blockers also may induce thrombocytopenia. These agents have not been

tested subsequently for long-term prevention. Valencia and colleagues

[162] found that the combination of eptifibatide, aspirin, and clopidogrel

could be given safely to patients who underwent recent coronary artery

angioplasty and stenting.

Combinations of antiplatelet agents

Because the antiplatelet agents inhibit aggregation through different

mechanisms, the facts that their actions could be synergistic and that a com-

bination of medications would be more effective in preventing thromboem-

bolic disease and ischemia than would each agent administered alone have

a natural appeal. In addition, because the actions of the antiplatelet agents

could be complementary to the inhibition of coagulation factors by oral

anticoagulants, this antithrombotic combination could be given to especially

high-risk patients.

Potential indications for combinations of antiplatelet agents or antiplate-

let agents and anticoagulants could include emergency treatment for

patients experiencing crescendo or recent TIA, recent stroke, acute myocar-

dial ischemia, or unstable angina; adjunctive treatment of patients undergo-

ing endovascular interventions; or management of patients who have very

high-risk cardiac circumstances, such as those who have prosthetic valves.

The combination of medications also may be used if a patient has ischemic

symptoms despite treatment with an individual antiplatelet agent or

anticoagulant.

Several recent clinical trials have focused on testing combinations of

antiplatelet agents rather than performing head-to-head comparisons of

the efficacy and safety of the medications. Although combinations of med-

ications may be more effective in preventing ischemia, they probably will be

associated with a higher risk for serious bleeding complications than among

persons taking one medication. Thus, the potential benefit in preventing



19/31

ischemia must be weighed against the risk of serious hemorrhage, including

intracranial bleeding.

Oral anticoagulants and antiplatelet agents

The use of warfarin and an antiplatelet agent is relatively common among

patients who have cardiovascular disease. Johnson and colleagues [163]

found that approximately 40% of patients taking warfarin also were receiv-

ing an antiplatelet agent. Most of these patients have symptomatic coronary

artery disease and risk factors for cardioembolic stroke, such as atrial fibril-

lation or a dilated cardiomyopathy. These patients also had symptomatic

artery disease and recent endovascular interventions.

Data on the safety and efficacy of oral anticoagulants and antiplatelet

agents are limited. Most experience involves the administration of aspirin,

and most studies involved subjects who had symptomatic heart disease or

were considered at high risk for cardioembolic stroke. Testa and colleagues

[164] found the combination of warfarin and aspirin to be comparable to

that of aspirin and clopidogrel in preventing death, bleeding adverse experi-

ences, and recurrent myocardial infarction among persons who had symp-

tomatic coronary artery disease.

The combination of warfarin and single or dual antiplatelet therapy

(most commonly aspirin and/or clopidogrel) was evaluated among patients

undergoing coronary artery stenting [165]. No major increase in bleeding

complications or decline in ischemic events was noted. However, Khurram

and colleagues [166] found that combining warfarin, clopidogrel, and aspi-

rin was associated with more serious bleeding complications than treatment

with just two antiplatelet agents. Delaney and colleagues found adding

aspirin to warfarin to be associated with a marked increase in the risk for

gastrointestinal bleeding.

OConnor and colleagues [168] found that the combination of fixed-dose

warfarin and 81 mg of aspirin was inferior to aspirin 160 mg/d in preventing

stroke among patients who experienced recent myocardial infarction. Aspi-

rin was also added to adjusted-dose warfarin to prevent thromboembolic

events among patients who had prosthetic heart valves. A common scenario

would be to add aspirin after a patient has an embolic stroke, despite treat-

ment with warfarin at a therapeutic level of anticoagulation.

One study administering low-dose aspirin (100 mg/d) in conjunction with

anticoagulants to reach an international normalized ratio of approximately 2.5

showed that the combination may be as effective as higher-intensity anticoagula-

tion in preventing embolic events among persons who have mechanical cardiac

valves [169]. A systemic review found that the combination of low-dose aspirin

(7581 mg) and warfarin is effective in lowering the risks for embolic events or

stroke among persons who have prosthetic heart valves [170]. Dipyridamole

was also used as an adjunct to oral anticoagulants to lower the risk for embolic

events among high-risk patients who have mechanical heart valves [171].



20/31

Dipyridamole has been shown to have additive effects on inhibiting plate-

let aggregation among patients taking aspirin [172]. Because the data on the

efficacy of dipyridamole as a monotherapy are limited, most trials of dipyr-idamole in stroke prevention (immediate or sustained-release formulation)

have focused on its combination with aspirin [173,174]. Two European stud-

ies found that the combination of aspirin and dipyridamole was superior to

placebo, with one showing that the combination was more effective than

either medication given as a monotherapy [59,175].

Subsequently, an investigator-initiated trial of dipyridamole and aspirin

found that the combination was more effective than aspirin monotherapy

in preventing stroke among high-risk patients who had symptomatic cere-

brovascular disease [92]. Bleeding complications were not a major problem.These three trials provide solid evidence that the combination of aspirin

and dipyridamole is an effective choice for stroke prophylaxis among high-

risk persons. Indirect evidence suggests that the combination is more

effective than clopidogrel in preventing stroke [176]. The large international

PRoFESS trial compared the combination of sustained-release dipyrida-

mole and aspirin with clopidogrel [177].

Studies tested the efficacy of the combination of ticlopidine and aspirin

primarily in the treatment of patients who had acute heart disease [95,96].

These studies showed that the combination was more efficacious in prevent-ing arterial occlusion and ischemic symptoms than aspirin monotherapy. Al-

though interest in the use of ticlopidine has waned, primarily because of

concerns about safety, research continues on the efficacy of combining aspi-

rin and ticlopidine [178].

Serebrauany and colleagues [179] found that adding clopidogrel to an

81-mg dose of aspirin had more effects on platelet function than adding clo-

pidogrel to a 325-mg dose. Clopidogrel provides further inhibition of plate-

let function among patients undergoing long-term treatment with aspirin

[180], which is associated with an increased risk for bleeding complications.For example, Delaney and colleagues [167] found that combining clopidog-

rel and aspirin was associated with an approximately doubled risk for gas-

trointestinal bleeding compared with either medication alone. A trial

comparing the safety and efficacy of combining aspirin and clopidogrel ver-

sus clopidogrel alone among patients who experienced recent TIA or stroke

found that the combination was associated with an increased risk for major

bleeding complications [181].

Another large trial compared the efficacy of adding clopidogrel to aspirin

versus aspirin alone in a broad range of subjects who had symptomatic ath-erosclerotic disease or asymptomatic patients at high risk for ischemic events

[182]. Overall the trial did not show a reduction in ischemic events associ-

ated with the combination therapy, although a trend among the subgroup

of symptomatic persons may have favored the combination.

A second trial that enrolled only subjects who had a history of TIA or

stroke was unable to show that adding aspirin to clopidogrel was superior



21/31

to clopidogrel alone in preventing recurrent ischemic events [181]. The

combination of aspirin and clopidogrel was tested against monotherapy

with aspirin in a series of patients who had symptomatic carotid stenosis.The marker of success was a reduction in microembolic signals detected

with transcranial Doppler ultrasonography [183]. The combination reduced

the number of recurrent events compared with aspirin. Kennedy and

colleagues [116] tested the efficacy of the combination of clopidogrel and

aspirin for emergency treatment of patients who experienced recent TIA.

Although a modest increase in bleeding complications was noted with the

combination, the frequency of stroke within 90 days was 10.8% for patients

treated with aspirin only and 7.1% among those treated with both medica-

tions. Another trial is testing the combination of clopidogrel and aspirin fortreating patients who have recent TIA [114].

A German study that surveyed outcomes in 7559 patients found that the

combination of clopidogrel and aspirin was superior to aspirin alone in pre-

venting death, nonfatal recurrent myocardial infarction, and nonfatal stroke

among patients who had acute ST-elevation myocardial infarction [115].

These changes were found regardless of reperfusion strategy (thrombolysis

or endovascular treatment). The combination of medications was associated

with a higher risk for bleeding than aspirin alone (7.1% versus 3.4%). Bhatt

and colleagues [184] concluded that the combination of clopidogrel andaspirin was superior to aspirin alone among patients in the CHARISMA

trial who had symptomatic atherosclerotic disease.

The combination of clopidogrel and aspirin is often prescribed for

patients undergoing endovascular interventions [185,186]. Fares and col-

leagues [187] concluded that the combination of clopidogrel and aspirin is

justified in high-risk patients, but the exact dose regimen and duration of

treatment has not been established. Another analysis concluded that adding

clopidogrel to aspirin results in a small reduction in all-cause mortality in

patients who had ST-elevation myocardial infarction and a modestreduction in stroke or recurrent myocardial infarction in patients who had

symptomatic cardiovascular disease [188,189]. The combination was not

associated with an excess rate of intracranial or fatal hemorrhages.

The combination of clopidogrel and aspirin has been compared with

adjusted dose warfarin in the treatment of patients who have atrial fibrilla-

tion [190,191]. Not only was the combination found to be less effective than

adjusted-dose oral anticoagulant treatment, the frequency of bleeding events

was higher among patients taking the combination of aspirin and

clopidogrel.

Summary

Antithrombotic therapy is a major component of ischemic stroke preven-

tion. Oral anticoagulants are typically reserved for patients who have

a known cardioembolic source. Antiplatelet agents are the most widely



22/31

prescribed medications for preventing first or recurrent stroke among

patients who have arterial diseases. They also are prescribed to patients

who have cardiac sources of embolization, either as an adjunct to oral anti-coagulants or as an alternative for patients who have contraindications to

oral anticoagulants.

Because of its well-studied side-effect profile, widespread availability, and

low cost, many regard aspirin as the first-line agent for preventing ischemic

cardiovascular disease, including stroke. In general, the desired dose of

aspirin is 50 to 325 mg/d. No evidence shows that higher doses of aspirin

are more effective, but larger doses may be associated with an increased

risk for upper gastrointestinal side effects.

The 2008 American Heart Association/American Stroke Associationevidence-based guideline update [192] indicates that aspirin, aspirin plus sus-

tained-release dipyridamole, or clopidogrel may be used as initial long-term

therapy for recurrent ischemic stroke prevention if anticoagulants are not

indicated. However, some reserve antiplatelet agents other than aspirin

for patients who experience aspirin failure, those at high risk for recurrent

events, or those unable to tolerate aspirin.

The other commonly prescribed antiplatelet agents are clopidogrel and the

combination of aspirin and sustained-release dipyridamole. The combination

of aspirin and clopidogrel has not been shown to be superior to either agentalone and has a higher risk for causing major bleeding, including

intracerebral hemorrhage. A recent large trial showed that the efficacy of clo-

pidogrel was approximately the same as that of sustained-release dipyrida-

mole plus aspirin. Therefore, evidence shows that either clopidogrel

monotherapy or the combination of aspirin and sustained-release dipyrida-

mole is a reasonable choice for patients who are not treated with aspirin alone.

References

[1] Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke:

a guideline from the American heart association/American stroke association stroke

council: cosponsored by the atherosclerotic peripheral vascular disease interdisciplinary

working group; cardiovascular nursing council; clinical cardiology council; nutrition,

physical activity, and metabolism council; and the quality of care and outcomes research

interdisciplinary working group: the American academy of neurology affirms the value of

this guideline. Stroke 2006;37:1583633.

[2] Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with

ischemic stroke or transient ischemic attack: a statement for healthcare professionals

from the American heart association/American stroke association council on stroke:co-sponsored by the council on cardiovascular radiology and intervention: the American

academy of neurology affirms the value of this guideline. Stroke 2006;37:577617.

[3] Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the

prevention of recurrent ischemic stroke. N Engl J Med 2001;345:144451.

[4] Algra A. Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of

arterial origin (ESPRIT): a randomised controlled trial. Lancet Neurol 2007;6:11524.



23/31

[5] Algra A, De Schryver EL, van Gijn J, et al. Oral anticoagulants versus antiplatelet therapy

for preventing further vascular events after transient ischemic attack or minor stroke of

presumed arterial origin. Stroke 2003;34:2345.

[6] Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for

symptomatic intracranial arterial stenosis. N Engl J Med 2006;353:130516.

[7] Antiplatelet trialists collaboration collaborative overview of randomised trials of

antiplatelet therapyi: prevention of death, myocardial infarction, and stroke by prolonged

antiplatelet therapy in various categories of patients. BMJ 1994;308:81106.

[8] Assadian A, Eidher U, Senekowitsch C, et al. Antiplatelet therapy prior to carotid

endarterectomystill room for improvement. Vasa 2006;35:96100.

[9] Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of

adults with ischemic stroke: a guideline from the American heart association/American

stroke association stroke council, clinical cardiology council, cardiovascular radiology

and intervention council, and the atherosclerotic peripheral vascular disease and quality

of care outcomes in research interdisciplinary working groups: the American academy of

neurology affirms the value of this guideline as an educational tool for neurologists. Stroke

2007;38:1655711.

[10] Craven LL. Prevention of coronary thrombosis and cerebral thrombosis. Mississippi Valley

Medical Journal 1956;78:2135.

[11] Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs. Chest 2001;119:39S63S.

[12] Awtry EH, Loscalzo J. Aspirin. Circulation 2000;101:120618.

[13] Brandon RA, Eadie MJ. The basis for aspirin dosage in stroke prevention. Clin Exp Neurol

1987;23:4754.

[14] Heavey DJ, Barrow SE, Hickling NE, et al. Aspirin causes short-lived inhibition of brady-

kinin-stimulated prostacyclin production in man. Nature 1985;318:1868.[15] Capone ML, Sciulli MG, Tacconelli S, et al. Pharmacodynamic interaction of naproxen

with low-dose aspirin in healthy subjects. J Am Coll Cardiol 2005;45:1295301.

[16] Cryer B, Verlin RG, Cooper SA, et al. Double-blind, randomized, parallel, placebo-

controlled study of ibuprofen effects on thromboxane B2 concentrations in aspirin-treated

healthy adult volunteers. Clin Ther 2005;27:18591.

[17] Zhao J, Qi R, Wu W, et al. Protective effects of aspirin against oxidized LDL-induced

inflammatory protein expression in human endothelial cells. J Cardiovasc Pharmacol

2008;51:327.

[18] Cyrus T, Sung S, Zhao L, et al. Effect of low-dose aspirin on vascular inflammation, plaque

stability, and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation

2002;106:12827.[19] Gomes I. Aspirin: a neuroprotective agent at high doses? Natl Med J India 1998;11:147.

[20] Hohlfeld T, Weber AA, Junghans U, et al. Variable platelet response to aspirin in patients

with ischemic stroke. Cerebrovasc Dis 2007;24:4350.

[21] Patrono C, Rocca B. Aspirin: promise and resistance in the new millennium. Arteroscler

Thromb Vasc Biol 2008;28:52532.

[22] Pamukcu B, Oflaz H, Onur I, et al. Clinical relevance of aspirin resistance in patients with

stable coronary artery disease: a prospective follow-up study (PROSPECTAR). Blood

Coagul Fibrinolysis 2007;18:18792.

[23] Assadian A, Lax J, Meixner-Loicht U, et al. Aspirin resistance among long-term aspirin

users after carotid endarterectomy and controls: flow cytometric measurement of aspirin-

induced platelet inhibition. J Vasc Surg 2007;45:11427.[24] Sanderson S, Emery J, Balin T, et al. Narrative review: aspirin resistance and its clinical

implications. Ann Intern Med 2005;142:37080.

[25] Coma-Canella I, Velasc A. Variability in individual responsiveness to aspirin: clinical

implications and treatment. Cardiovasc Hematol Disord Drug Targets 2007;7:27487.

[26] Barnes GD, Li J, Kline-Rogers E, et al. Dual antiplatelet agent failure: a new syndrome or

clinical nonentity. Am Heart J 2007;154:7325.



24/31

[27] Chen WH, Cheng X, Lee PY, et al. Aspirin resistance and adverse clinical events in patients

with coronary artery disease. Am J Med 2007;120:6315.

[28] Gurbel PA, Bliden KP, DiChiara J, et al. Evaluation of dose-related effects of aspirin on

platelet function: results from the aspirin-induced platelet effect (ASPECT) study.

Circulation 2007;115:315664.

[29] Patel D, Moonis M. Clinical implications of aspirin resistance. Expert Rev Cardiovasc Ther

2007;5:96975.

[30] Fitzgerald DJ, Maree A. Aspirin and clopidogrel resistance. Hematology Am Soc Hematol

Educ Program 2007;2007:11420.

[31] Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory

detection. J Thromb Haemost 2007;5:2307.

[32] Alberts MJ, Bergman DL, Molner E, et al. Antiplatelet effect of aspirin in patients with

cerebrovascular disease. Stroke 2004;35:1758.

[33] Helgason CM, Bolin KM, Hoff JA, et al. Development of aspirin resistance in persons with

previous ischemic stroke. Stroke 1994;25:23316.

[34] Helgason CM, Tortorice KL, Winkler SR, et al. Aspirin response and failure in cerebral

infarction. Stroke 1993;24:34550.

[35] Rao GH, Michiels JJ. Aspirin resistance: does it exist? Semin Thromb Hemost 2007;33:

2104.

[36] Patrono C, Bachmann F, Baigent C, et al. Expert consensus document on the use of anti-

platelet agents: the task force on the use of antiplatelet agents in patients with atheroscle-

rotic cardiovascular disease of the European society of cardiology. Eur Heart J 2004;25:

16681.

[37] Sze PC, Reitman D, Pincus MM, et al. Antiplatelet agents in the secondary prevention of

stroke: meta-analysis of the randomized control trials. Stroke 1988;19:43642.[38] Petty GW, Brown RD Jr, Whisnant JP, et al. Frequency of major complications of aspirin,

warfarin, and intravenous heparin for secondary stroke prevention. Ann Intern Med 1999;

130:1422.

[39] CAST (Chinese Acute Stroke Trial) collaborative group CAST: randomised placebo-

controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet

1997;349:16419.

[40] International stroke trial collaborative group the international stroke trial (IST):

a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients

with acute ischaemic stroke. Lancet 1997;349:156981.

[41] Steering committee of the physicians health study research group final report on the aspirin

component of the ongoing physicians health study. N Engl J Med 1989;321:12935.[42] He J, Whelton PK, Vu B. Aspirin and risk of hemorrhagic stroke. J Am Med Assoc 1998;

280:19305.

[43] CLASP collaborative group low dose aspirin in pregnancy and early childhood

development: follow up of the collaborative low dose aspirin study in pregnancy. Br J Obstet

Gynaecol 1995;102:8618.

[44] Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary

prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293304.

[45] Patrono C. Prevention of myocardial infarction and stroke by aspirin: different mecha-

nisms? Different dosage? Thromb Res 1998;92:S712.

[46] Hart R, Halperin J, McBride R. Aspirin for the primary prevention of stroke and other

major vascular events. Arch Neurol 2000;57:32632.[47] Hennekens CH, Schneider WR. The need for wider and appropriate utilization of aspirin

and statins in the treatment and prevention of cardiovascular disease. Expert Rev Cardio-

vasc Ther 2008;6:95107.

[48] Goldstein LB, Rothwell PM. Primary prevention and health services delivery. Stroke 2007;

38:2224.



25/31

[49] Ambrosi P, Villani P, Bouvenot G, et al. Antiplatelet therapy for primary prevention in

diabetes. Diabete Metab 2006;32:2S526.

[50] De Berardis G, Sacco M, Evangelista V, et al. Aspirin and Simvastatin Combination for

Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D): design of a randomized

study of the efficacy of low-dose aspirin in the prevention of cardiovascular events in

subjects with diabetes mellitus treated with statins. Trials 2007;8:2130.

[51] Morimoto T, Nakayama M, Saito Y, et al. Aspirin for primary prevention of

atherosclerotic disease in Japan. J Atheroscler Thromb 2007;14:15966.

[52] The Canadian cooperative study group a randomized trial of aspirin and sulfinpyrazone in

threatened stroke. N Engl J Med 1978;299:539.

[53] Fields WS, Lemak NA, Frankowski RF, et al. Controlled trial of aspirin in cerebral

ischemia. Part II: surgical group. Stroke 1978;9:30919.

[54] Fields WS, Lemak NA, Frankowski RF, et al. Controlled trial of aspirin in cerebral ische-

mia. Circulation 1980;62:V906.

[55] The SALT collaborative group Swedish aspirin low-dose trial (SALT) of 75 mg aspirin

as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991;338:

13459.

[56] The Dutch TIA study group. The Dutch TIA trial: protective effects of low-dose aspirin and

atenolol in patients with transient ischemic attacks or nondisabling stroke. Stroke 1988;19:

5127.

[57] United Kingdom Transient Ischaemic Attack (UK-TIA) aspirin trial: interim results.

UK-TIA Study Group. Br Med J 1988;296:31620.

[58] Taylor DW, Barnett HJM, Haynes RB, et al. Low-dose and high-dose acetylsalicylic acid

for patients undergoing carotid endarterectomy: a randomised controlled trial. Lancet

1999;353:217984.[59] Diener HC, Cunha L, Forbes C, et al. Dipyridamole and acetylsalicylic acid in the second-

ary prevention of stroke. J Neurol Sci 1996;143:113.

[60] Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after

cerebral ischaemia. J Neurol Neurosurg Psychiatr 1996;60:1979.

[61] Adams HP Jr, Bendixen BH. Low- versus high-dose aspirin in prevention of ischemic

stroke. Clin Neuropharmacol 1993;16:485500.

[62] Johnson ES, Lanes SF, Wentworth CE, et al. A metaregression analysis of the dose-

response effect of aspirin on stroke. Arch Intern Med 1999;159:124853.

[63] Kasner SE, Lynn MJ, Chimowitz MI, et al. Warfarin vs aspirin for symptomatic intracra-

nial stenosis: subgroup analyses from WASID. Neurology 2006;67:12758.

[64] Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin forsymptomatic intracranial arterial stenosis. N Engl J Med 2005;352:130516.

[65] Multicentre Acute Stroke TrialItaly (MAST-I) group randomised controlled trial of strep-

tokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet

1995;346:150914.

[66] Berge E, Abdelnoor M, Nakstad PH, et al. Low molecular-weight heparin versus aspirin in

patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised

study. Lancet 2000;355:120510.

[67] Berge E, Sandercock P. Anticoagulants versus antiplatelet agents for acute ischaemic

stroke. Cochrane Database Syst Rev 2002;(4):CD003242.

[68] Bath PM, Lindenstrom E, Boysen G, et al. Tinzaparin in Acute Ischaemic Stroke (TAIST):

a randomised aspirin-controlled trial. Lancet 2001;358:6834.[69] Wong KS, Chen C, Ng PW, et al. Low-molecular-weight heparin compared with aspirin for

the treatment of acute ischaemic stroke in Asian patients with large artery occlusive disease:

a randomised study. Lancet 2007;6:40713.

[70] Roden-Jullig A, Britton M, Malmkvist K, et al. Aspirin in the prevention of progressing

stroke: a randomized controlled study. J Intern Med 2003;254:58490.



26/31

[71] Stein PD, Alpert JS, Dalen JE, et al. Antithrombotic therapy in patients with mechanical

and biological prosthetic heart valves. Chest 1998;114:602S10S.

[72] di Marco F, Grendene S, Feltrin G, et al. Antiplatelet therapy in patients receiving aortic

bioprostheses: a report of clinical and instrumental safety. J Thorac Cardiovasc Surg

2007;133:1597603.

[73] Brueck M, Kramer W, Vogt P, et al. Antiplatelet therapy early after bioprosthetic aortic

valve replacement is unnecessary in patients without thromboembolic risk factors. Eur

J Cardiothorac Surg 2007;32:10812.

[74] Homma S, Sacco R, Di Tuillo M, et al. Effect of medical treatment in stroke patients with

patent foramen ovale. Patent foramen ovale in cryptogenic stroke study. Circulation 2002;

105:262531.

[75] Mas J-L, Cabanes L, Coste J, et al. Patent foramen ovale, atrial septal aneurysm, and

recurrent stroke. N Engl J Med 2002;346:13312.

[76] The atrial fibrillation investigators. The efficacy of aspirin in patients with atrial fibrillation.

Analysis of pooled data from 3 randomized trials. Arch Intern Med 1997;157:123740.

[77] The SPAF III Writing Committee for Stroke Prevention in Atrial Fibrillation Investigators.

Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with as-

pirin. Stroke Prevention in Atrial Fibrillation III Study. JAMA 1998;279:12737.

[78] Petersen P, Boysen G, Godtfredsen J, et al. Placebo-controlled, randomised trial of

warfarin and aspirin for prevention of thromboembolic complications in chronic atrial

fibrillation. The Copenhagen AFASAK study. Lancet 1989;1:1759.

[79] Petersen P. Thromboembolic complications in atrial fibrillation. Stroke 1990;21:413.

[80] Mant J, Hobbs FR, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an

elderly community population with atrial fibrillation (the Birmingham atrial fibrillation

treatment of the aged study, BAFTA): a randomised controlled trial. Lancet 2007;370:493503.

[81] Rash A, Downes T, Portner R, et al. A randomised controlled trial of warfarin versus

aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO). Age Ageing

2007;36:1179.

[82] Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an

elderly community population with atrial fibrillation (the Birmingham atrial fibrillation

treatment of the aged study, BAFTA): a randomised controlled trial. Lancet 2007;370:

493503.

[83] Rivey MP, Alexander MR, Taylor JW. Dipyridamole: a critical evaluation. Drug Intell

Clin Pharm 1984;18:86980.

[84] Fleck JD, Biller J. Choices in medical management for prevention of acute ischemic stroke.Curr Neurol Neurosci Rep 2001;1:338.

[85] Theis JG, Deichsel G, Marshall S. Rapid development of tolerance to dipyridamole-

associated headaches. Br J Clin Pharmacol 1999;48:7505.

[86] Humphreys DM, Street J, Schumacher H, et al. Dipyridamole may be used safely in

patients with ischaemic heart disease. Int J Clin Pract 2002;56:1217.

[87] Diener HC, Darius H, Bertrand-Hardy JM, et al. Does early high dosage dipyridamole in

prevention of secondary stroke induce cardiac events? Z Kardiol 2001;90:34851.

[88] De Schryver EL, ESPRIT Study Group. Dipyridamole in stroke prevention: effect of dipyr-

idamole on blood pressure. Stroke 2003;34:233942.

[89] The Persantine-Aspirin Reinfarction Study (PARIS) research group. The Persantine-

Aspirin Reinfarction Study. Circulation 1980;62:V858.[90] The American-Canadian co-operative study group persantine aspirin trial in cerebral

ischemia. Part II: endpoint results. Stroke 1985;16:40615.

[91] The ESPS group. The European stroke prevention study. Lancet 1987;2:13514.

[92] ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischae-

mia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367:1665.

[93] Sacco R. European Stroke Conference, Nice France, May 14, 2008.



27/31

[94] Hass WK, Easton JD, Adams HP Jr, et al. A randomized trial comparing ticlopidine

hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine

aspirin stroke study group. N Engl J Med 1989;321:5017.

[95] Gent M, Blakely JA, Easton JD, et al. The Canadian American ticlopidine study (CATS) in

thromboembolic stroke. Lancet 1989;1:121520.

[96] van de Loo A, Nauck M, Noory E, et al. Enhancement of platelet inhibition of ticlopidine

plus aspirin vs aspirin alone given prior to elective PTCA. Eur Heart J 1998;19:96102.

[97] Goods CM, al-Shaibi KF, Liu MW, et al. Comparison of aspirin alone versus aspirin plus

ticlopidine after coronary artery stenting. Am J Cardiol 1996;78:10424.

[98] Harker LA. Therapeutic inhibition of platelet function in stroke. Cerebrovasc Dis 1998;

8(Suppl 5):818.

[99] Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationships among dose,

effectiveness, and side effects. Chest 1998;114:470S88S.

[100] Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999;100:166772.

[101] Iqbal M, Goenka P, Young MF, et al. Ticlopidine-induced cholestatic hepatitis: report of

three cases and review of the literature. Dig Dis Sci 1998;43:22236.

[102] Persoz CF, Cornella F, Kaeser P, et al. Ticlopidine-induced interstitial pulmonary disease:

a case report. Chest 2001;119:19635.

[103] Love BB, Biller J, Gent M. Adverse haematological effects of ticlopidine. Prevention,

recognition and management. Drug Saf 1998;19:8998.

[104] Hung MJ, Wang CH, Cherng WJ. Granulocyte colony stimulating factor treatment for

delayed recovery of ticlopidine-related neutropenia. Int J Clin Pract 2002;56:701.

[105] Bennett CL, Weinberg PD, Rozenberg-Bendror K, et al. Thrombotic thrombocytopenia

purpura associated with ticlopidine. Ann Intern Med 1998;128:5414.

[106] Steinhubl SR, Tan WA, Foody JM, et al. Incidence and clinical course of thromboticthrombocytopenic purpura due to ticlopidine following coronary stenting. EPISTENT

Investigators. Evaluation of platelet IIb/IIIa inhibitor for stenting. J Am Med Assoc

1999;281:80610.

[107] Medina PJ, Sipols JM, George JN. Drug-associated thrombotic thrombocytopenic

purpura-hemolytic uremic syndrome. Curr Opin Hematol 2001;8:28693.

[108] Janzon L. The STIMS trial: the ticlopidine experience and its clinical applications. Swedish

ticlopidine multicenter study. Vasc Med 1996;1:1413.

[109] Gorelick PB, Richardson D, Kelly M, et al. Aspirin and ticlopidine for prevention of

recurrent stroke in black patients: a randomized trial. JAMA 2003;289:294757.

[110] Gorelick PB, Richardson D, Kelly M, et al. Aspirin and ticlopidine for prevention of

recurrent stroke in black patients. JAMA 2006;289:294757.[111] CAPRIE steering committee a randomised, blinded, trial of clopidogrel versus aspirin in

patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:132939.

[112] Helft G, Osende JI, Worthley SG, et al. Acute antithrombotic effect of a front-loaded reg-

imen of clopidogrel in patients with atherosclerosis on aspirin. Arterioscler Thromb Vasc

Biol 2000;20:231621.

[113] Pache J, Kastrati A, Mehilli J, et al. Clopidogrel therapy in patients undergoing coronary

stenting: value of a high-loading-dose regimen. Catheter Cardiovasc Interv 2002;55:43641.

[114] Meyer DM, Albright KC, Allison TA, et al. LOAD: a pilot study of the safety of loading of

aspirin and clopidogrel in acute ischemic stroke and transient ischemic attack. J Stroke

Cerebrovasc Dis 2008;17:269.

[115] Zeymer U, Arntz H, Darius H, et al. Efficacy and safety of clopidogrel 600 mg administeredpre-hospitally to improve primary percutaneous coronary intervention in patients with

acute myocardial infarction (CIPAMI): study rationale and design. Cardiology 2007;108:

26572.

[116] Kennedy J, Hill MD, Ryckborst KJ, et al. Fast Assessment of Stroke and Transient

Ischaemic Attack to Prevent Early Recurrence (FASTER): a randomised controlled pilot

trial. Lancet Neurol 2007;6:9619.



28/31

[117] Lev EI, Arikan ME, Vaduganathan M, et al. Effect of caffeine on platelet inhibition by

clopidogrel in healthy subjects and patients with coronary artery disease. Am Heart J

2007;154:694.e1694.e7.

[118] Saw J, Brennan DM, Steinhubl SR, et al. Lack of evidence of a clopidogrel-statin interac-

tion in the CHARISMA trial. J Am Coll Cardiol 2007;50:2915.

[119] Trenk D, Hochholzer W, Frundi D, et al. Impact of cytochrome P450 3A4-metabolized

statins on the antiplatelet effect of a 600-mg loading dose clopidogrel and on clinical

outcome in patients undergoing elective coronary stent placement. Thromb Haemost

2008;99:17481.

[120] Wenaweser P, Windecker S, Billinger M, et al. Effect of atorvastatin and pravastatin on

platelet inhibition by aspirin and clopidogrel treatment in patients with coronary stent

thrombosis. Am J Cardio 2007;99:3536.

[121] Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of

clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole

Clopidogrel Aspirin) study. J Am Coll Cardiol 2008;51:25660.

[122] Kim JY, Lee K, Shin M, et al. Cilostazol could ameliorate

Documents

Use of Anti Platelet Agents for Prevention[1]