Antiplatelet Agents

ASPIRIN WAS THE ONLY ANTIPLATELET AGENT
available from the 1970s to the 1980s. Today we now
have more than five agents available. These cardioactive
drugs are useful in the prevention of thrombi in coronary
arteries and those arteries that supply the brain, but they
are much less effective in preventing thrombi that occur in
veins. Antiplatelet agents are used in virtually all patients
with coronary artery disease to manage the acute and
chronic phases of the disease as well as its complications.

I. MECHANISM OF ACTION
Coronary thrombosis is known to be the major cause of
coronary artery occlusion resulting in fatal or nonfatal
acute myocardial infarction. Antiplatelet agents are
named this because they inhibit platelet aggregation,
which plays a major role in coronary thrombosis, myocardial
infarction, and cardiac death.

Platelets clump on to atherosclerotic plaques, causing
occlusion of the artery, and/or embolize downstream.
The occlusion of these vessels may induce fatal arrhythmias
and cardiac death. In patients with unstable angina,
angioscopy has confirmed the presence of platelet clumps
attached to the surface of eccentric atheromatous plaques
that jut into the lumen of arteries causing partial to
near complete occlusion. The atheromatous plaques may
become fissured or rupture exposing a ‘‘porridge/gruel’’
like substance or substances that are highly thrombogenic.
(See also the chapter Atherosclerosis/Atherothrombosis.)
However, antiplatelet agents are not expected to prevent
all forms of thrombotic events.
After plaque rupture the formation of a platelet-rich
thrombus requires three essential steps:
1. Platelet adhesion: This occurs shortly after an atheromatous
plaque has ruptured and the process of
adhesion is mediated by the platelet glycoprotein IIb
receptor through its interaction with von Willebrand
factor.
2. Platelet activation: The smooth discoid platelet
assumes a spiculated form, thus increasing the surface
area of the platelet membrane where thrombin is generated.
Figure 1 illustrates the complex and orchestrated
processes that lead to platelet aggregation along with
stimulatory and inhibitory drugs and substances.
3. Platelet aggregation: Platelet activation converts the
glycoprotein IIb/IIIa receptor into a form that can
bind fibrinogen and aggregation occurs.

II. INDICATIONS
Antiplatelet agents are of proven value in the management
of non-ST segment elevation myocardial infarction;
stable and unstable angina; post coronary artery bypass
graft (CABG), coronary artery stents, cerebral transient
ischemic attacks (TIAs); and lone atrial fibrillation in
individuals younger than 65.

III. AVAILABLE ANTIPLATELET AGENTS
Currently used antiplatelet agents include aspirin, clopidogrel
(ticlopidine still has a role, see Section III.B),
dipyridamole plus aspirin, and platelet glycoprotein
IIb/IIIa receptor blockers

A. Aspirin
Acetylsalicylic acid irreversibly acetylates the enzyme
cyclooxygenase. This enzyme is necessary for the conversion
of platelet arachidonic acid to thromboxane A2,
a powerful platelet-aggregating agent. Cyclooxygenase is
inhibited by all nonsteroidal anti-inflammatory drugs
(NSAIDs), aspirin transfers the acetyl group to the
enzyme that is irreversibly inactivated. Other NSAIDs
such as ibuprofen act as reversible inhibitors of cyclooxygenase.

Most important, both the use of aspirin and the administration
of nitroglycerin sublingually also contribute to
the prevention of fatal and nonfatal heart attacks. It is
important for individuals to realize that a rapid-acting
aspirin formulation such as two 80- to 81-mg chewable
aspirins taken soon after the onset of chest pain has been
shown to cause a 25% reduction in fatal and nonfatal
myocardial infarction, whereas nitroglycerin has no effect
on prevention. Nitroglycerin ameliorates the pain of stable,
mild angina and its use has been overvalued.
A recent study by Gum et al. demonstrated the natural
history of aspirin resistance and documented a greater than
threefold increase in the risk of major adverse events
associated with aspirin resistance. Fortunately this form
of resistance is rare and occurred in less than 5% of the
326 stable cardiovascular patients administered aspirin.

B. Clopidogrel
Clopidogrel is a thienopyridine derivative and an anolog
of ticlopidine; the drug inhibits platelet aggregation
by inhibiting adenosine diphosphate (ADP) induced platelet
activation and inhibits platelet fibrinogen binding.
Clopidogrel is more effective than ticlopidine, but is
considerably less toxic. Clopidogrel prevents platelet
degranulation and the release reaction which produces
prothrombotic substances. This drug selectively and
irreversibly prevents ADP from binding to the platelet
ADP receptor and inhibits the transformation of the
glycoprotein IIb/IIIa receptor to the form that binds
fibrinogen and links platelets. Clinical studies confirm the
drug’s effectiveness.

Platelet Glycoprotein IIb/IIIa Receptor
Blockers
There are approximately 75,000 glycoprotein IIb/IIIa
receptors on the surface of each platelet. Antagonism of
these receptors blocks the final common pathway for
platelet aggregation — the binding or fibrinogen to the
platelet glycoprotein receptors; platelet aggregation caused
by thrombin, thromboxane A2, ADP, collagen, and shearinduced
platelet aggregation is prevented. Unfortunately,
these agents do not affect platelet activation and degranulation,
unlike ADP receptor antagonists which are active
at much earlier stages of the atherothrombotic cascade.

1. Abciximab (ReoPro)
This widely used platelet receptor blocker inhibits both
alpha IIb3 receptor and alpha v beta 3 receptors. Several
randomized clinical trials have documented the beneficial
effects when used for patients undergoing urgent PCI.
This drug is not recommended for patients who are not
scheduled for urgent PCI. Dosage would include 0.25 mg/
kg IV bolus over at least 1 minute, immediately followed
by IV infusion of 0.125 mgram/kg/minute for 18–24 h,
concluding 1 h after PCI.

2. Eptifibatide (Integrilin)
This platelet receptor blocker has actions that are similar
to abciximab. In a randomized clinical trial (PURSUIT), a
significant benefit was observed in patients who underwent
PCI within 72 h with no benefit at 30 days in those
without PCI. In another large trial (TACTICS), eptifibatide
was beneficial only in patients with acute coronary
syndromes treated with early invasive PCI. In another
trial (TARGET), the drug caused less protection from
major ischemic events than abciximab. In the trial PRISMPLUS,
eptifibatide reduced events at seven days but not
at six months. Dosage would be IV bolus of 135 mgram/kg
followed by an infusion of 0.5 mgram/kg/minute for a
further 20–24 h after PCI.
3. Tirofiban (Aggrastat)

This platelet receptor blocker shows specificity toward
alpha IIbb 3 receptor and has a shorter biological half-life
than abciximab and eptifibatide. Tirofiban and eptifibatide
are indicated only in patients in whom immediate PCI is
not planned. In this population of patients the combination
of clopidogrel and aspirin may prove to be more
efficacious at 30 days and 1 year follow up. A meta-analysis
of randomized clinical trials with these three agents with
the exception of abciximab used as indicated for PCI
planned within 24 h indicates that nondiabetic patients
had no survival benefit.


In a large randomized trial (TACTICS) patients were
treated with tirofiban for 48 h plus aspirin and heparin
and randomized to either invasive therapy (coronary
angiography and revascularization) or conservative strategy.
It is claimed that at 6 months there was a significant
reduction in death or MI ( p¼0.0498; p¼0.05) This
p¼0.05 is hardly the level of significance required to
recommend a treatment strategy to the population at
large. In clinical medicine it is essential to achieve a significance
level of p <0.02 to be meaningful in terms of saving lives. 4. Oral Agents Several randomized clinical trials have shown no benefit with oral agents that included orbofiban (in the OPUS trial), sibrafiban (in SMPHONY, and xemilofiban (in the EXCITE trial) caused excess mortality, usually sudden death, and approximately a 30% increase in mortality. In five large randomized trials oral platelet receptor blockers showed a consistency toward increased mortality when compared with placebo. A 37% increase in mortality was observed in a meta-analysis of four large trials. Thirty days after commencement of one trial there was a 40% higher incidence of MI associated with these agents. Except for the proven beneficial defects of abciximab for patients undergoing primary PCI, the IV agents, also have not been a major success in terms of causing significant improvement in survival at 6 months, and they cause a significantly high excess in the incidence of major bleeding. The partial effectiveness of oral and IV agents may relate to the fact that they do not affect platelet activation and degranulation; processes that occur very early in the stage of the platelet thrombotic process. Several randomized clinical trials in progress should indicate which platelet receptor blocker is best for acute clinical situations and the role for clopidogrel combined with aspirin in patients stratified to receive PCI versus conservative therapy.

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