ACUTE CORONARY SYNDROMES G A R Y S.

WALTER A. TAN, MD, MS D A V I D J. MOLITERNO, M D

Section of Interventional Radiology, Pittsburgh Medical Director, Angiographic Core
Vascular Institute, University of Pittsburgh Laboratory, Department of Cardiology,
Medical Center-Shadyside, Pittsburgh Cleveland Clinic

Aspirin, ticiopidine, and Clopidogrel in

acute coronary syndromes: Underused
treatments could save thousands of lives
ABSTRACT aspirin
HE O R A L ANTIPLATELET A G E N T S ,
in particular, have the best benefit-to-
Aspirin is the cornerstone of therapy for unstable angina risk ratio and the best cost-benefit ratio of any
and acute myocardial infarction and the foundation on of the therapies for acute coronary syndromes,
which other therapies are added, both in the short term and have become the cornerstone of thera-
and the long term. Yet, despite clear data, aspirin is py.1.2 The ISIS-2 trial3 showed that aspirin
woefully underused or is often used late. Prompt and streptokinase were approximately equally
administration of aspirin could save thousands of lives each beneficial, with approximately 24 lives saved
year. Ticiopidine and clopidogrel have a synergistic effect per 1,000 patients treated. This translates into
when used with aspirin, and can also have a role in treating less than $20 spent for each premature death
patients who are aspirin-resistant or have diffuse prevented by aspirin, vs about $2,000 for
streptokinase.
atherosclerosis.
Yet a sizable number of patients who
KEY POINTS should receive aspirin do not receive it. While
physician adherence to guidelines is improv-
The benefits of antiplatelet drugs in the treatment and ing,4 as recently as 1995 the Health Care
prevention of acute coronary syndromes outweigh the risks, Financing Administration reported that 39%
of patients 65 years or older did not receive
although a few precautions are advisable.
aspirin within 2 days of an acute MI. 5
Aspirin (or another antiplatelet drug)
Patients with aspirin resistance may be more vulnerable to should be given promptly. Eisenberg and
adverse vascular events. Topol6 showed a time gradient for deaths pre-
vented by aspirin even within the first 12
Ticiopidine and clopidogrel have been proved to be hours of presentation for chest pain related to
effective as adjuncts to aspirin for preventing subacute myocardial infarction (MI). This is not sur-
stent thrombosis. prising given the rapid pharmacokinetics of
these agents, and in light of the large body of
Timely administration of these agents during acute evidence demonstrating greater myocardial
coronary syndromes is critical. salvage with prompt therapy in acute coronary
syndromes. Yet a 1994 study7 found that only
45% of patients presenting to four hospital
emergency departments with acute Mis
received aspirin at all, and of these, 78%
received it more than 30 minutes after arrival
and 54% received it after 1 hour.
With approximately 2 million patients
admitted each year for acute coronary syn-

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 ASPIRIN, TICLOPIDINE, AND CLOPIDOGREL TAN AND MOLITERNO

dromes, by simply giving aspirin to virtually all name aspirin in 1899. It is no small irony that
candidates promptly, potentially 10,000 pre- the company had to give the public assurances
mature deaths a year could be prevented in the that the compound had no adverse effects on
United States alone. It is incumbent upon the heart.19
caregivers to maximize this opportunity to Aspirin was first noted to cause a bleeding
decrease the mortality rate in this common tendency in 1891. Its use in coronary artery
and frequently fatal condition. disease was first reported in 1953 by Craven.20
In this paper we review the utility, risks, and Today, aspirin is the most widely used drug for
optimal use of currently available oral ischemic vascular diseases.18
antiplatelet agents: aspirin, ticiopidine, and
clopidogrel. The glycoprotein Ilb/IIIa inhibitors Aspirin's mechanism of a c t i o n
and other classes of agents used in treating acute Aspirin prevents conversion of arachidonic
coronary syndromes will be covered in future acid to prostaglandin H 2 , which is the first
issues. step in prostaglandin synthesis and the subse-
quent production of thromboxane A 2 (a
• ROLE OF PLATELETS potent vasoconstrictor and inducer of platelet
IN ACUTE CORONARY SYNDROMES aggregation) and prostacyclin (which has the
opposite effects).11 Aspirin does this by acety-
Basic and clinical research has firmly estab- lating the serine residue of the enzyme
lished that platelets play a central role in trig- prostaglandin H 2 synthase (PGHS, also
gering and perpetuating acute coronary syn- known as cyclooxygenase), irreversibly inacti-
dromes.8-17 The cascade of events that leads vating it.22 Since platelets, unlike endothelial
to the formation of a coronary thrombus typi- cells, have no nucleus, they cannot regenerate
cally begins when an atherosclerotic plaque PGHS, and their ability to aggregate is
ruptures or is otherwise disrupted, exposing impaired for the duration of their lifespan.23
the subendothelium to the circulating blood Approximately 10% to 15% of circulating
(FIGURE 1 ) . 1 7 When dormant platelets come platelets are replaced each day; therefore,
Aspirin into contact with factors present in the suben- platelet aggregation takes several days to
dothelial matrix and the lipid-rich core of the recover as new platelets are supplied by the
reaches its plaque, they adhere to the vessel wall and bone marrow.24 However, during the interval,
peak effect become "activated," ie, they: platelets can still be activated by substances
• Change their shape from smooth and other than thromboxane A 2 , notably adeno-
in 30 disc-shaped to irregular with pseudopods sine diphosphate, thrombin, and epinephrine.
minutes • Release a number of prothrombotic Aspirin has other effects that may be salu-
substances from their granules that activate tary: it attenuates leukocyte rolling, cytokine
and recruit neighboring platelets production, monocyte adhesion, thrombo-
• Up-regulate a number of different cell genicity of atherosclerotic plaques, oxidant
surface receptors. stress, nicotine-induced endothelial cell acti-
If enough platelets are involved, they coa- vation, hypoxia-induced vasoconstriction,
lesce with thrombin and fibrin to form a activity of nitric oxide inhibitors, activation of
hemostatic plug, resulting in myocardial fibroblastic cells, and vascular smooth muscle
ischemia or infarction. cell proliferation.
Aspirin is rapidly absorbed in the stomach
M ASPIRIN and upper intestine, achieving detectable plas-
ma levels as early as 15 minutes after inges-
Hippocrates used willow bark, which contains tion, with onset of platelet inhibition evident
salicylates, for its analgesic properties circa within minutes thereafter.23
400 BC. Native Americans used willow bark
as well.18 Acetylsalicylic acid was synthesized Trials of aspirin in unstable angina
by Hoffman in the late 1800s, and introduced or n o n - Q - w a v e Ml
for treating rheumatism and fever by the Aspirin is a cornerstone of therapy for unsta-
Farbenfabriken Bayer company under the ble angina or non-Q-wave MI. Several studies

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• Blocking t h e cascade o f p l a t e l e t a g g r e g a t i o n
W h e n vascular e n d o t h e l i a l cells are d a m a g e d , platelets b i n d t o t h e vessel w a l l a n d u n d e r g o a c t i v a t i o n
a n d d e g r a n u l a t i o n , releasing a n u m b e r of substances t h a t a c t i v a t e a n d recruit o t h e r platelets. Aspirin,
t i c i o p i d i n e , clopidogrel, a n d g l y c o p r o t e i n llb/llla inhibitors block t h e process in d i f f e r e n t ways.

Platelet
A r a c h i d o n i c acid
(cyclooxygenase)
ASPIRIN prevents conversion of
arachidonic acid t o e n d o p e r o x i d a s e ,
Endoperoxidase (PGH2)"^ t h e r e b y p r e v e n t i n g p r o d u c t i o n of
Prostacyclin (PGI 2 )
t h r o m b o x a n e A 2 f o r t h e life of t h e

O t h e r prostaglandins
Thromboxane A2 ^
V ^DP
p l a t e l e t . H o w e v e r , e n d o t h e l i a l cells
can c o n t i n u e t o p r o d u c e
t h r o m b o x a n e A 2 , a n d platelets can
E p i n e p h r i n e is,, ,. still release o t h e r p r o t h r o m b o t i c
w Thrombin substances.
Serotonin V-AV
TICLOPIDINE A N D C L O P I D O G R E L
prevent adenosine diphosphate
Activated (ADP) f r o m b i n d i n g t o its receptor.
platelets H o w e v e r , platelets can still b e
activated by o t h e r agonists such as
thrombin and epinephrine.

GLYCOPROTEIN llb/llla I N H I B I T O R S
block t h e f i n a l c o m m o n p a t h w a y of
Fibrinogen p l a t e l e t a g g r e g a t i o n by p r e v e n t i n g
g l y c o p r o t e i n llb/llla receptors f r o m
cross-linking w i t h f i b r i n o g e n .

G l y c o p r o t e i n llb/llla receptors

CCJM
© 1999

FIGURE 1 ADAPTED FROM SHARIS PJ, C A N N O N CP, LOSCALZO J. THE ANTIPLATELET EFFECTS OF TICLOPIDINE A N D CLOPIDOGREL. A N N INTERN M E D 1 9 9 8 ; 1 2 9 : 3 9 4 - 4 0 5 .

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 ASPIRIN, TICLOPIDINE, AND CLOPIDOGREL TAN AND MOLITERNO

Selected studies of oral a n t i p l a t e l e t agents

in a c u t e c o r o n a r y s y n d r o m e s
AGENT STUDY POPULATION TIMING NUMBER NEEDED
OF BENEFIT TO TREAT'

Aspirin Theroux et al 25 Unstable angina 1 week 12

RISC26 Unstable angina 3 months 10
or non-Q-wave Ml
ISIS-23 Acute Ml 5 weeks 42
Tidopidine Balsano et al 54 Unstable angina 6 months 16
Clopidogrel CAPRIE^s History of stroke, Ml, 2 years 200+
or peripheral vascular
disease

*To prevent one death or Ml, except for the CAPRIE study (which included cerebrovascular accidents) and ISIS-2
(vascular deaths only)
tCompared with aspirin

have shown that it can reduce the incidence formed a meta-analysis of eight randomized
of death or MI by approximately half in these clinical trials of aspirin in acute MI involving
conditions. For example: nearly 16,000 patients.27 In aggregate, these
• Theroux et al25 conducted a random- trials demonstrated that aspirin reduced the
ized trial in patients admitted to the hospital incidence of reinfarction by one third and the
In unstable with unstable angina. At 1 week, the inci- composite endpoint of MI, stroke, or vascular
dence of fatal or nonfatal MI was 11.9% in death by one fourth, translating into 36 major
angina, aspirin patients who received placebo, compared with cardiovascular events prevented over 2 years
reduces death 3.3% in those who received aspirin (P = .012) per 1,000 treated patients (NNT = 28).
and 1.6% for those who received both aspirin Of interest, one of the trials in this analy-
or Ml by half and heparin (P = .001). At 30 days, the rates sis, the Second International Study of Infarct
were 16.1%, 5.8%, and 3.3%, respectively. Survival (ISIS-2),3 found aspirin nearly as
Another useful way to look at the data is effective as streptokinase in reducing vascular
the "number needed to treat" (NNT)—the mortality in patients with suspected MI. At 35
number of patients that need to be treated to days, aspirin had reduced the rate of vascular
prevent one event. In this study, the NNT with mortality by 23%, compared with 25% for
aspirin for the 1-week data was only 12 ( T A B L E 1 ) . streptokinase (FIGURE 2 ) . Combining the two
• The Research Group on Instability in agents yielded a 42% reduction in mortality
Coronary Artery Disease in Southeast Sweden compared with placebo. Similarly, a study in
(RISC) showed a similar benefit for aspirin in 11,630 patients with recent Mis 28 found
up to 90 days of follow-up of men with unsta- aspirin approximately as effective as clopido-
ble angina or non-Q-wave MI. 26 grel: at 1.9 years the rate of ischemic stroke,
MI, or vascular death was 4-84% in the clopi-
Trials of aspirin dogrel group vs 5.03% in the aspirin group (P
in acute myocardial infarction = . 6 6 ) . ( T A B L E 2 lists the relative advantages,

Aspirin serves as the linchpin of therapy for disadvantages, and costs of aspirin, ticlopi-
acute MI and the foundation on which other dine, and clopidogrel.)
therapies are added, both in the short term
and the long term. For example, the Trials of aspirin in a n g i o p l a s t y
Antiplatelet Trialists' Collaboration per- In a trial in patients undergoing percutaneous

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 Aspirin and streptokinase provide similar b e n e f i t
in a c u t e m y o c a r d i a l i n f a r c t i o n : t h e ISIS-2 t r i a l
Placebo infusion: Placebo tablets:
1029 vascular d e a t h s 1016 vascular deaths
1000 r- (12.0%) 1 0 0 0 r - ( 1 1 . 8 % )

03 03
ÜJ <u
- a ~o
—
800 800
J5
3
u u
l/l l/l
(C (0
> >
600 600
Streptokinase: Aspirin:
QJ
7 9 1 vascular d e a t h s <v
8 0 4 vascular d e a t h s
-O (9.2%) -Q (9.4%)
E 400 E 400
3
C C
01 <u
> >

200 j u 200
3 3
£
3
E
3
U
_L U

14 21 28 35 14 21 28 35
Days Days

FIGURE 2. Cumulative vascular m o r t a l i t y in days 0 t h r o u g h 35 a f t e r myocardial infarc-

t i o n in patients t r e a t e d w i t h placebo, streptokinase, or aspirin. N o t e t h e similar b e n e -
fit w i t h aspirin c o m p a r e d w i t h streptokinase.
F R O M ISIS-2 INVESTIGATORS. R A N D O M I S E D TRIAL OF I N T R A V E N O U S STREPTOKINASE, O R A L ASPIRIN, BOTH, OR NEITHER A M O N G 1 7 , 1 8 7 CASES The Physician's
OF SUSPECTED A C U T E M Y O C A R D I A L INFARCTION: ISIS-2 ( S E C O N D INTERNATIONAL STUDY OF INFARCT SURVIVAL) COLLABORATIVE GROUP.
LANCET 1 9 8 8 ; 2 : 3 4 9 - 3 6 0 . Health Study
found no excess
transluminal coronary angioplasty, half of Bleeding. Aspirin increases the risk of
Gl bleeding
whom had unstable angina, Barnathan and gastric bleeding in a dose-related manner. A with aspirin
colleagues29 reported an incidence of clinical- slight excess risk has been observed even at a
ly significant coronary thrombosis of 10.7% in low dose (75 mg/day), which is doubled with
patients who received placebo compared with a daily dose of 300 mg, and is increased five-
1.8% in those who received aspirin (P = fold at doses of 1,800 mg or more.25'51 The risk
.005). appears to be greatest during the first week,
In another study,30 the incidence of after which most patients may develop gastric
periprocedural Q-wave Mis was 6.9% in adaptation.52'55
patients receiving placebo compared with Of note: no excess in gastric complica-
1.6% in patients randomized to receive aspirin tions was seen in the Physician's Health
and dipyridamole combined before the proce- Study,54 in which healthy subjects took 325
dure (P = .01). mg of aspirin every other day as primary pre-
vention. However, this was in the context of a
Safety issues with aspirin relatively healthy population cohort.
While the benefits of aspirin in the treatment If necessary, one can consider prophylac-
and secondary prevention of acute coronary tic therapy with misoprostol or a proton pump
syndromes far outweigh the risks, a few pre- inhibitor (eg, omeprazole, lansoprazole) for
cautions are in order, especially since this patients at increased risk of gastrointestinal
treatment is lifelong. bleeding.

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 ASPIRIN, TICLOPIDINE, AND CLOPIDOGREL TAN AND MOLITERNO

TABLE 2

Advantages, disadvantages,
and costs of oral a n t i p l a t e l e t agents
AGENT ADVANTAGES DISADVANTAGES COST
(30-DAY SUPPLY)*

Aspirin Well established Weak antiplatelet effect $1

Safe Allergy
Inexpensive Gastrointestinal intolerance
Gastrointestinal upset
(main side effect)
Bleeding
Nonresponders
Ticlopidine Decreases stent thrombosis Rare but life-threatening $130
(with aspirin) neutropenia and thrombotic
thrombocytopenia purpura
Expensive
Clopidogrel To date, safer than aspirin Relatively new $100
Proven for peripheral vascular Gastrointestinal upset
disease Expensive
Effective for secondary prevention
and for stenting

* Average wholesale price

Some people
Aspirin resistance. A n emerging body of more vulnerable to adverse vascular
may become evidence suggests that people differ widely in events.37'38 It is possible that aspirin resistance
resistant to their response to aspirin. Valettas et al35 gave is a marker of proclivity to thrombotic events
aspirin 325 mg/day to 29 healthy subjects for a and may not be amenable to a simple increase
aspirin week and then used flow cytometry to measure in aspirin dose.
platelet activation in response to in vitro stim- At present there are no recommendations
ulation. The mean value was 30% platelet about monitoring platelet inhibition in
activation, compared with 92% at baseline patients on long-term aspirin therapy.
prior to aspirin intake. However, the investi- However, if a patient has diffuse atherosclero-
gators observed a wide distribution of sis or recurrent events, most physicians would
response: 13 subjects had less than 25% reduce the dose of aspirin and add clopidogrel,
platelet activation, but 12 had between 25% or switch to clopidogrel alone.
and 50%, and 4 had more than 50%.
Moreover, some people may become resis- Aspirin dosage r e c o m m e n d a t i o n s
tant to aspirin with treatment. Helgason36 fol- The dose of aspirin required to suppress
lowed 306 stroke patients who were taking platelet function is lower than that needed for
aspirin over 33 months with serial aggregation analgesia. Indeed, the R I S C study,26 discussed
studies. Seventy four percent of these patients above, used doses of 75 mg/day. However, only
had complete platelet inhibition initially, but one randomized study has compared aspirin
33% lost some degree of platelet inhibition doses in acute coronary syndromes: the Duke
over time. Eight percent remained aspirin- University Clinical Cardiology Study II
resistant even when doses were increased to (DUCCS-II). 39 In this study, 162 thrombolyt-
1,300 mg/day. ic-eligible MI patients received either 81 or
Patients with aspirin resistance may be 325 mg of aspirin daily. There were no differ-

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 TABLE 3

Effect and dosage of a n t i p l a t e l e t agents

AGENT ONSET PEAK % INHIBITION DURATION RECOMMENDED
OF ACTION EFFECT OF PLATELET OF ANTIPLATELET DOSAGE
AGGREGATION' EFFECT (DAYS)

Aspirin Minutes < 30 min43 20 5-7 Loading dose: 325 mg

chewed, then 150-325 mg
daily in the hospital, then
80-325 mg daily at home
Ticlopidine 1 - 2 hours 5 days66 4067 5-749 Loading dose: 500 mg,
then 250 mg twice a day
for 2 weeks*
Clopidogrel 1 - 2 hours68 5 days 40 5-7 Loading dose: 300 mg,
then 75 mg daily

"With 5 nmol/L ADP stimulation

f Asadjunct for intracoronary stenting

ences between the outcomes of the two groups ADENOSINE DIPHOSPHATE

with regard to death, stroke, shock, vessel ANTAGONISTS
patency, or global left ventricular function.
However, the study's small sample size pre- Ticlopidine (Ticlid) and clopidogrel (Plavix)
cludes any definitive conclusions. are thienopyridine derivatives that block
Given the central role of antiplatelet adenosine diphosphate (ADP)-mediated
therapy as demonstrated by the large-scale platelet aggregation without affecting the Obtain a CBC
platelet glycoprotein Ilb/IIIa drug trials,40^2 cyclooxygenase pathway.49 This blockade is
and the recognition that individual responses thought to inhibit fibrinogen from binding to
10 days after
to low aspirin doses may vary considerably, we the glycoprotein Ilb/IIIa receptor.50 In addi- starting
recommend giving 325 mg of chewable (regu- tion, ticlopidine may interfere with binding of
lar) aspirin for acute coronary syndromes fol- von Willebrand factor to platelet recep-
ticlopidine to
lowed by 150 to 325 mg/day during the hospi- tors.51'52 The end effect is an irreversible and look for
tal stay (TABLE 3).43,44 A maintenance dose of noncompetitive inhibition of platelet func-
80 to 325 mg daily should be prescribed indef- tion. Both of these agents have a synergistic
neutropenia
initely for secondary prevention, unless there effect when used with aspirin and are typical-
are compelling contraindications such as ly added to aspirin (although this combina-
proven aspirin allergy, aspirin-induced asth- tion remains to be proven in a clinical trial for
ma, or bleeding ulcers. This is similar to the clopidogrel). Maximal bioavailability is
recommendation from the Agency for Health achieved when they are taken after meals.
Care Policy and Research that patients with
unstable angina receive a loading dose of 325 Ticlopidine
mg initially followed by a daily dose of 150 to Ticlopidine was first used extensively for cere-
325 mg.45 brovascular disease, in which it was shown to
One possible but uncommon condition in be superior to aspirin in specific patient sub-
which aspirin may not be mandatory is dilat- sets in the Ticlopidine Aspirin Stroke Study
ed cardiomyopathy with angiographically nor- (TASS).53 At 3 years, 17% of patients taking
mal coronary arteries. The reason: some retro- ticlopidine had died or suffered a second
spective data suggest that aspirin might inter- stroke, compared with 19% of those taking
fere with the action of angiotensin-converting aspirin (P = .048).
enzyme inhibitors.46-48 In the only randomized trial of ticlopidine

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 ASPIRIN, TICLOPIDINE, AND CLOPIDOGREL TAN AND MOLITERNO

in acute coronary syndromes, Balsano et al54 clopidogrel during angioplasty. However, a

randomized 652 patients with unstable angina laboratory experiment using vessels from pigs
to receive either ticlopidine or conventional in a milieu of high shear stress indicated that
therapy (which did not include aspirin at that clopidogrel may be more effective than aspirin
time—only beta blockers, calcium antago- in preventing stent thrombosis.59 Recently,
nists, and nitrates). A t 6 months, 7.3% of the Clopidogrel Aspirin Stent International
patients taking ticlopidine had died of a vas- Cooperative Study (CLASSICS), 60 indicated
cular cause or suffered a nonfatal MI, com- that the two drugs likely produced equivalent
pared with 13.6% of those receiving conven- outcomes, but clopidogrel was more tolerable
tional therapy alone, a 46% risk reduction (P and patients complied better with taking it.
= .009). (The study was not powered to compare effi-
Ticlopidine came into wide use in cardio- cacy outcomes.)
vascular medicine as an adjunct to aspirin to A n ongoing placebo-controlled trial,
prevent stent thrombosis in coronary inter- Clopidogrel for Reduction of Events During
ventions. Schomig and coworkers55-56 found Observation (CREDO), is testing the efficacy
the combination of ticlopidine and aspirin of giving clopidogrel before angioplasty.
better than aspirin plus anticoagulant therapy Patients receiving clopidogrel before the pro-
in preventing acute stent thrombosis, MI, and cedure will continue therapy for 1 year, where-
repeat interventions. Registry data also show as those randomized to receive placebo before
that giving ticlopidine before percutaneous the procedure will receive clopidogrel after-
coronary angioplasty improves the short-term ward for 1 month.
outcomes.57 A widely-used regimen is ticlopi- At the Cleveland Clinic, before angio-
dine 500 mg as an oral loading dose followed plasty, we give a loading dose of 300 mg of
by 250 mg twice a day. If possible, the loading clopidogrel (preferably at least 2 hours before
dose should be given 3 days before the proce- the procedure, based on an anticipated near-
dure, because ticlopidine achieves its maximal maximal antiplatelet effect by 2 hours),61 and
effect in 4 days.58 If the patient receives an continue with 75 mg daily for a month (along
Stop tidopidine intracoronary stent, the maintenance dose is with lifelong aspirin therapy) if the patient
250 mg twice a day for 2 to 4 weeks, along receives a stent.
or clopidogrel with lifelong aspirin.
1 week before Safety issues
Clopidogrel w i t h ticlopidine a n d clopidogrel
elective surgery
Clopidogrel, a congener of ticlopidine, is Bleeding. Although the newer agents
increasingly being used as an alternative to have not been as well-studied as aspirin, the
ticlopidine. Currently, it is used in acute coro- same considerations of bleeding risk apply to
nary syndromes if the patient has aspirin resis- them.
tance, allergy, or intolerance, or following The incidence of gastrointestinal hemor-
intracoronary stent placement. rhage may be slightly lower with ticlopidine or
Evidence of clopidogrel's safety and effica- clopidogrel than with aspirin, because the new
cy comes from the CAPRIE trial,28 which agents do not inhibit prostaglandin synthesis.
included 19,185 patients with recent MI, For example, in the CAPRIE study,28 the inci-
ischemic stroke, or symptomatic peripheral dence of severe gastrointestinal hemorrhage
vascular disease who were randomized to was 0.71% with aspirin compared with 0.49%
receive clopidogrel 75 mg daily or aspirin 325 with clopidogrel (P < .05).
mg daily. At 3 years, the incidence of death, If a patient requires surgery, keep in mind
MI, or cerebrovascular accident was a modest that ticlopidine and clopidogrel irreversibly
9% lower in patients taking clopidogrel com- inhibit platelets for the lifespan of the platelet.
pared with aspirin. The only patient subgroup Hence, we recommend that these drugs be
in which clopidogrel was clearly better than stopped about a week before any elective
aspirin was the group with peripheral vascular surgery if the patient is stable from a coronary
disease. standpoint. In cases of urgent surgery, platelet
We have only limited data about using transfusions can be given if significant bleed-

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 L J

ing occurs. Aprotinin has been shown in an • A PUBLIC HEALTH NOTE

animal study to reduce the prolonged bleeding ON THE IMPORTANCE OF USING ASPIRIN
time observed with clopidogrel, but whether
this can reduce bleeding in clinical practice is Coronary artery disease is still the most com-
uncertain. mon cause of death in the United States. Each
Thrombotic thrombocytopenic purpura, year more than 1.5 million Americans suffer a
which may be life-threatening, has been myocardial infarction.64.65
reported at an estimated rate of 1 case per As we have noted throughout this paper,
4,814 persons exposed to ticlopidine, and can the oral antiplatelet agents, and aspirin in par-
occur up to 19 days after ticlopidine is ticular, are the cornerstone of therapy for
stopped.62 Keep this condition in mind, acute coronary syndromes, and for good rea-
because prompt plasmapheresis may be life- son. They are effective, reducing the rate of
saving. O n the other hand, follow-up for up to death or MI by one third to one half, depend-
3 years in the CAPRIE study has not uncov- ing on the situation. The number patients
ered any excess incidence of thrombotic who need to be treated to prevent one event
thrombocytopenic purpura with clopidogrel.28 is remarkably low: as few as 10, according to
Neutropenia has been reported to occur some studies. The agents are inexpensive,
in approximately 1% of patients taking ticlo- aspirin costing only pennies per dose. And
pidine. This condition usually resolves if the although the agents do pose risks, they have
drug is stopped. We recommend obtaining a the best benefit-to-risk ratio and the best cost-
complete blood count about 10 days after benefit ratio of any of the therapies for acute
starting ticlopidine specifically to look for coronary syndromes.
neutropenia. In light of this evidence, physicians
Treatment resistance. There is also should be certain that nearly every patient
emerging evidence of interindividual variabil- suspected of having unstable angina or an MI
ity of response to ticlopidine,63 as there is to gets an aspirin tablet expeditiously and consis-
aspirin. tently. S&

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