Platelets are important in the pathogenesis of atherosclerosis, arterial thrombosis, acute coronary syndromes, and in acute vessel occlusion following percutaneous coronary intervention. Because of the significant impact of platelets on coronary disease, much energy has been invested into research to better understanding platelet physiology and into developing antiplatelet medications. This focus of intense research has led to clinical trials evaluating their safety and efficacy. The use of antiplatelet medications has offered continued improvement in clinical outcomes and procedural success. This review will help clinicians become more familiar with the pharmacology of antiplatelet medications and will briefly review clinical trials supporting their clinical safety and efficacy during percutaneous coronary interventions.
Dr. Simpson received his MD from East Carolina University
(ECU) School of Medicine, Greenville, NC. He is currently in the
ECU Deptartment of Cardiology.
Antiplatelet therapy is continuing to become an integral part of
pharmacotherapy during percutaneous coronary interventions (PCI).
The ongoing development of novel antiplatelet therapies continues
to improve procedural and clinical outcomes during PCI. This review
will provide clinically relevant information regarding commonly
used antiplatelet drugs and the clinical research supporting their
use during PCI.
Aspirin blocks the formation of prostaglandin endoperoxides and
thromboxane A2 by inhibiting prostaglandin G/H synthase and the
cyclo-oxygenase pathway. In an anucleate platelet, this is a
permanent effect. Aspirin prior to PCI reduces the risk of abrupt
coronary vessel closure by 50% to 75%.
Other benefits of aspirin therapy include: the prevention of
coronary artery disease and stroke; improved outcome in chronic
stable angina, unstable angina, and acute myocardial infarction
; and the maintenance of saphrenous vein graft patency after
coronary artery bypass surgery.
The risk of bleeding is increased with aspirin.
There has been no proven beneficial effect regarding
The optimal dose, timing, and duration of administration of
aspirin are unknown. The standard regimen consists of 325 mg at
least 24 hrs prior to an elective intervention and continuing
indefinitely. For emergency procedures, 4 baby aspirins should be
chewed and swallowed (81 mg each). For patients who are allergic to
aspirin, begin clopidogrel, 75 mg daily beginning 3 to 5 days prior
to the intervention.
Aspirin does have its limitations. It does not block platelet
aggregation caused by thrombin, catecholamines, adenosine
diphosphate (ADP), serotonin, or shear stress. Recent studies
suggest that 8% to 12% of patients with coronary artery disease may
be unresponsive to the antiplatelet effects of aspirin.
Bedside platelet functioning may assist in identifying those
Ticlopidine is a thienopyridine that blocks ADP-induced platelet
activation by interfering with the signaling between the
low-affinity platelet ADP receptor and the subsequent processes of
platelet activation, including activation of the platelet
glycoprotein (GP) IIb/IIIa receptor. Ticlopidine also inhibits
platelet aggregation in response to collagen, thrombin, and shear
stress by inhibiting ADP amplification mechanisms for platelet
activation. Thienopyridines, such as ticlopidine and clopidogrel,
are much more effective than aspirin in inhibiting shear-induced
platelet activation, which is an important cause of thrombosis in
coronary artery disease. In a randomized trial of percutaneous
transluminal coronary angioplasty (PTCA), ticlopidine (250 mg bid)
resulted in fewer ischemic complications than aspirin plus
dipyridamole (2% vs. 5%).
Several other trials have demonstrated superiority of aspirin plus
ticlopidine versus aspirin plus warfarin in reducing ischemic and
hemorrhagic complications following stenting. These trials include
(Intracoronary Stenting and Antithrombotic Regimen), FANTASTIC
(Full Anticoagulation versus Aspirin and Ticlopidine), and MATTIS
(Multicenter Aspirin and Ticlopidine Trial after Intracoronary
Stenting). Ticlopidine has also been shown to reduce the risk of
death and nonfatal MI in unstable angina,
prevent stroke in patients with transient ischemic attacks (TIAs),
and has been used for aspirin-allergic or intolerant patients.
The recommended dosage of ticlopidine is 250 mg PO bid for at
least 3 days prior to intervention to obtain maximal antiplatelet
effect. The onset of action is 48 to 72 hours, and full
antiplatelet effects are evident in 5 to 7 days. Oral loading of
500 mg PO bid for 48 hours may accelerate the antiplatelet effects
and may provide some benefit in emergency situations. The
antiplatelet effects subside over 1 to 2 weeks. The benefits of
ticlopidine beyond 2 weeks after stenting is questionable.
An important side effect of ticlopidine is reversible
neutropenia, which occurs in 0.5% to 2% of patients after 4 weeks
It is recommended that a complete blood count be monitored every 2
weeks during the first few months of therapy. Ticlopidine has an
associated incidence of thrombotic thrombocytopenic purpura
estimated at 0.02%. Most cases occur during the 3rd or 4th week of
therapy. Complaints of nausea, vomiting, and diarrhea associated
with ticlopidine can usually be minimized by taking it with food.
The use of ticlopidine has been greatly diminished because of its
side effect profile compared with that of clopidogrel.
Clopidogrel is another thienopyridine derivative, analogous to
ticlopidine, which blocks ADP-induced platelet activation by
irreversibly modifying the ADP receptor. Compared with ticlopidine,
clopidogrel has a longer duration of action, a faster onset of
action, and is associated with fewer hematologic effects. In a
randomized blinded trial, Clopidogrel versus Aspirin in Patients at
Risk of Ischemic Events (CAPRIE),
there was no difference in neutropenia between aspirin and
clopidogrel. In the Clopidogrel Aspirin Stent International
Cooperative Study (CLASSICS)
trial of patients undergoing elective stenting, clopidogrel was
tolerated better than ticlopidine without sacrificing clinical
efficacy. The combined use of aspirin plus clopidogrel in acute
coronary syndromes was recently evaluated in the CURE (Clopidogrel
in Unstable angina to prevent Recurrent Events) trial. There was a
highly significant 20% relative reduction in the primary composite
end points of cardiovascular death, MI, or stroke. Benefits were
noted within 30 days and increased further beyond 30 days,
demonstrating the importance of long-term therapy.
There was a 1% increase in major bleeding with clopidogel that was
controlled easily with transfusions with no increase in fatal
bleeding. This suggests that patients with acute coronary syndromes
should be considered for antiplatelet therapy with aspirin plus
The dosage of clopidogrel is 75 mg daily. The full antiplatelet
effect is achieved in 5 days. A loading dose of 300 mg was used in
the CLASSICS, CREDO (Clopidogrel for Reduction of Events During
extended Observation), and CURE studies. The ideal dose and
duration of clopidogrel plus aspirin following stenting should be
answered by the CREDO study.
The most frequent side effects of clopidogrel (¾ 5% of cases)
include purpura, diarrhea, rash, and pruritis. Clopidogrel is not
associated with an increased risk of neutropenia, so routine
hematologic monitoring is not required. A recent report documented
1 case of suspected thrombotic thrombocytopenic purpura (TTP) among
3000 patients exposed to clopidogrel. The overall incidence of TTP
is substantially lower than that associated with ticlopidine.
Clopidogrel is metabolized in the liver but has little impact on
hepatic enzyme induction. Caution is recommended when clopidogrel
is used in combination with nonsteroidal anti-inflammatory drugs or
warfarin due to increased risk of bleeding.
Dipyridamole increases platelet c-AMP and causes direct release
of prostacyclin from the endothelium, but its antiplatelet
mechanism of action is incompletely understood.
The half-life of dipyridamole is 10 days and it is metabolized
primarily in the liver. In PTCA patients, 2 studies of parenteral
dipyridamole plus aspirin reported fewer ischemic complications
compared with aspirin alone, but a randomized trial of oral
dipyridamole failed to demonstrate benefit.
The oral dose of dipyridamole is 75 mg bid for 6 months. Side
effects of dipyridamole include exacerbation of angina, headaches,
hypertension, and tachycardia. The risk of GI bleeding increases
with the use of aspirin. At the present time, dipyridamole is not
recommended routinely for coronary intervention.
Activation of the platelet GP IIb/IIIa receptor complex
constitutes the final common pathway for platelet aggregation and
is a critical event in arterial thrombosis. Potent GP IIb/IIIa
receptor antagonists have been shown to improve event-free survival
in a variety of interventional and noninterventional settings. The
agents abciximab, eptifibatide, and tirofiban have been evaluated
more thoroughly than others and are the most widely used.
Abciximab is a noncompetitive antagonist that binds 1:1 to the
GP IIb/IIIa receptor molecule to induce a conformational change
that renders its fibrinogen-binding site inactive. From a clinical
standpoint, noncompetitive inhibitors have a longer biological
half-life, more cross-reactivity with other cell-surface receptors,
and more permanent binding than competitive inhibitors.
Abciximab has been studied in several large-scale,
placebo-controlled randomized trials in PTCA, stenting, acute MI,
and acute coronary syndromes.The PTCA trials were: EPIC (Evaluation
of Platelet IIb/IIIa Inhibition for Prevention of Ischemic
Complication), EPILOG (Evaluation in PTCA to Improve Long-term
Outcome with Abciximab GP IIb/IIIa Blockade), and CAPTURE (c7E3 Fab
Antiplatelet Therapy in Unstable Refractory Angina). EPISTENT
(Evaluation of Platelet IIb/IIIA Inhibitor for Stenting) was a
trial in stenting.
Three trials in acute MI were: ADMIRAL (Abciximab before Direct
angioplasty and stenting in Myocardial Infarction Regarding Acute
and Long-term follow-up); RAPPORT (ReoPro and Primary PTCA
Organization and Randomized Trial); CADILLAC (Controlled Abciximab
and Device Investigation to Lower Late Angioplasty Complications);
and GUSTO IV ACS (Global Utilization of Streptokinase and t-PA for
occluded coronary arteries trial IV in Acute Coronary Syndromes).
The TARGET trial (Do Tirofiban and ReoPro Give similar Efficacy
Trial) has recently been completed. EPIC, EPILOG, EPISTENT, and
CAPTURE all demonstrated 35% to 57% reduction in the primary end
point (death, MI, TLR) favoring abciximab. Although EPIC reported
more bleeding complications with abciximab, EPILOG demonstrated
that low-dose, weight-adjusted heparin (70 U/kg to achieve an ACT
200 to 250 seconds) plus abciximab could reduce the risk of
bleeding significantly without sacrificing efficacy. Furthermore,
benefits observed in high-risk PTCA patients in EPIC were extended
to high- and low-risk PTCA and stent patients in EPILOG and
EPISTENT. Importantly, EPIC continues to demonstrate sustained
benefit of abciximab at 30 days, 6 months, and 3 years.
EPILOG has shown persistent benefit at 1 year
; and EPISTENT reported sustained benefit at 6 months
and at 1 year (mortality 1% vs. 2.4%).
Angiographic restenosis was also lower in diabetics treated with
In contrast to the abciximab bolus 12-hour infusion utilized in
EPIC, EPILOG, and EPISTENT, CAPTURE patients received 18- to
24-hour infusion before and a 1-hour infusion after the
intervention; initial benefit at 30 days was not sustained at 6
suggesting that a 12-hour infusion after intervention may be
important for prolonged clinical benefit.
In patients with acute MI undergoing primary PTCA or stenting,
three trials of abciximab have reported inconsistent results: In
abciximab was associated with a nonsignificant 17% reduction in
late major adverse cardiac events (MACE) after primary PTCA. In
abciximab was associated with a significant 47% reduction in late
MACE after primary stenting. In CADILLAC,
patients were randomized to primary PTCA versus stenting, with or
without abcximab. Similar to RAPPORT, the 21% reduction in late
MACE was not significant, and in contrast to ADMIRAL, abciximab
offered no incremental benefit after primary stenting. The TARGET
trial reported significantly better results for abciximab compared
with tirofiban for stent patients (death, MI, or urgent
revascularization at 30 days), especially those presenting with an
acute coronary syndrome.
The recommended dose for abciximab for percutaneous intervention
is an IV bolus of 0.25 µg/kg/min, followed by an constant infusion
of 0.125 µg/kg/min (max 10 µg/min), for 12 hours post-intervention.
All patients should receive standard aspirin therapy. The
recommended heparin dose is 70 U/kg IV to maintain an ACT of 200 to
250 seconds. No further heparin is needed postintervention, and
sheaths should be removed when ACT is 150 to 175 seconds. Abciximab
does not need to be discontinued for sheath removal.
A number of safety concerns have been raised about the use of GP
IIb/IIIa antagonists in general and about abciximab in particular.
Most of these concerns are related to the risks of bleeding
complications, the potential requirement for emergency coronary
artery bypass graft (CABG) surgery, severe thrombocytopenia, and
potential drug reactions. Virtually all of these concerns are
readily prevented and/or treated and are not felt to be significant
obstacles to the use of GP IIb/IIIa inhibitors.
Independent predictors of bleeding include MI, low body weight,
old age, longer procedural times, repeat PTCA, and failed
intervention. In abciximab trials utilizing low-dose heparin, early
sheath removal, and ACT 200 to 250 seconds (EPILOG, CAPTURE, and
EPISTENT), there were no reported differences in major or minor
bleeding compared with placebo. Importantly, patients do not have a
higher incidence of intracranial hemorrhage when treated with
abciximab compared with placebo.
Thrombocytopenia is a potential safety concern with GP IIb/IIIa
antagonists, which may increase bleeding complications.
The incidence of thrombocytopenia appears to be higher with
abciximab compared with tirofiban and eptifibatide. The incidence
of mild thrombocytopenia (<100,000/mm
) was 2.6% to 5.6% and severe thrombocytopenia (<50,000/mm
) was 0.9% to 1.6%.
Unlike heparin-induced thrombocytopenia (HIT), abciximab-associated
thrombocytopenia responds within days of discontinuing the drug and
responds quickly to platelet transfusions. In contrast, severe
thrombocytopenia after abciximab retreatment (which is 2 to 3 times
more frequent than after first time use) may not respond promptly
to platelet transfusions. If retreatment with abciximab is
performed, early platelet counts should be obtained with rapid
discontinuation of the drug if platelet count falls.
The risk of bleeding during emergency CABG is potentiated by
abciximab and heparin.
The hemostatic defect due to abciximab is largely reversible with
platelet transfusions, but the benefit is not immediate or complete
due to persistent platelet-bound abciximab. Transfused platelets
serve as a "sink" to remove excess drug from affected platelets,
and it may take 3 hours to completely reverse the antiplatelet
In the EPIC, EPILOG, and EPISTENT trials,
the risk of major bleeding or blood transfusion in emergency CABG
patients receiving antecedent abciximab was similar to that of
those receiving placebo, although abciximab patients required more
Eptifibatide is a synthetic cyclic K-G-D
(lysine-glysine-aspartic acid) heptapeptide and a competitive
antagonist for GP IIb/IIIa receptor. Unlike abciximab, eptifibatide
has a short half-life (2.5 hours),
is very specific for the GP IIb/IIIa receptor, and does not
cross-react with the vitronectin receptor. Platelet function
returns to normal within 4 hours after drug discontinuation.
The use of eptifibatide during coronary intervention was studied
in the IMPACT-II (Integrilin to Minimize Platelet Aggregation and
Coronary Thrombosis), PURSUIT (Platelet glycoprotein IIb/IIIa in
Unstable angina: Receptor Suppression Using Integrilin Therapy),
and ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor
with Integrin Therapy) trials. In IMPACT-II, there was a
nonsignificant 19% reduction in the composite primary end point
(death, MI, revascularization, or bailout coronary stent) at 30
days in the low-dose and high-dose eptifibitide groups.
There was no difference in major bleeding or blood transfusion. In
PURSUIT, 10,948 patients with unstable angina or non-Q-wave MI
received aspirin and intravenous (IV) heparin and were randomly
assigned to eptifibitide (180 µg/kg bolus and 2.0 µg/kg/min
infusion) or placebo.
In a subgroup of 1250 patients undergoing percutaneous intervention
within 72 hours of randomization, eptifibitide reduced the 30-day
incidence of death and MI by 31% (
= 0.01). In ESPRIT, the dose of eptifibatide was further modified
to include a second bolus, 10 minutes after the first.
In an elective coronary stent population, this second bolus was
associated with a 37% reduction in ischemic events at 48 hours,
which persisted at 30 days and at 6 months.
The FDA-approved dose of eptifibitide is 135 µg/kg immediately
before intervention followed by a continuous infusion of 0.5
µg/kg/min for 12 to 24 hours. The current recommended dose due to
the concerns of IMPACT-II and the favorable response in PURSUIT is
180 µg/kg IV bolus X 2 (10 minutes apart) followed by a constant
infusion at 2.0 µg/kg/min.
Eptifibitide was not associated with an increased risk of major
bleeding in IMPACT-II, PURSUIT, and ESPRIT. In contrast to
abciximab, there may be less need to reduce the heparin dose, there
is no known immune response, and the incidence of thrombocytopenia
is similar to placebo. Eptifibatide should be discontinued in
patients requiring emergency CABG. Antiplatelet effects resolve in
4 to 6 hours and platelet transfusion is ineffective. Drug
clearance is longer in renal impaired patients.
Tirofiban is a synthetic, small molecule nonpeptide competitive
antagonist of the GP IIb/IIIa receptor. Similar to eptifibatide, it
is rapidly reversible, highly selective, and does not cross-react
with the vitronectin receptor.
In the RESTORE trial,
2139 patients with acute coronary syndromes undergoing PTCA or
directional coronary atherectomy receiving aspirin and heparin were
randomized to tirofiban (10 µg/kg bolus, 0.15 µg/kg/min infusion)
or placebo for 36 hours. There was a 40% reduction in death, MI,
and urgent revascularization (5.2% vs. 8.7%,
= 0.002) at 2 days, 30% reduction at 7 days (6.9% vs. 9.8%,
= 0.016), and a 24% reduction at 30 days (8.0% vs. 10.5%,
= 0.16). The composite end point (death, MI, and revascularization)
at 6 months was similar to placebo (24.1% vs. 27.1%,
= 0.11). The TARGET trial was a direct head-to-head comparison of
tirofiban versus abciximab in 4812 stent patients. Overall
tirofiban was less effective than abciximab, with a 26% relative
increase in the primary end point of death, MI, and urgent
revascularization at 30 days (7.5% vs. 6.0%,
= 0.037). In the TACTICS-TIMI-18 (Treat Angina with Aggrastat
[tirofiban] and determine Cost of Therapy with Invasive or
Conservative Strategy-Thrombolysis In Myocardial Infarction) trial,
2220 patients with unstable angina or non-ST-elevation MI received
aspirin, heparin, beta-blockers, and tirofiban upon hospital
admission, followed by randomization to invasive management
(catheterization within 4 to 48 hours and revascularization where
feasible) versus conservative management (catheterization only for
spontaneous or provocable ischemia). The primary end point of the
trial (death, MI, or rehospitalization for ACS at 6 months) was
reduced by 18% in the invasive arm (15.9% vs. 19.4%,
= 0.025). The beneficial effect was most pronounced in the patients
with positive troponins (14% vs. 24%).
The dosage of tirofiban used in RESTORE and TARGET was 10 µg/kg
bolus followed by an infusion of 0.15 µg/kg/min. In the PRISM-PLUS
(Platelet receptor inhibition in ischemic syndrome management in
patients limited by unstable signs and symptoms) trial, the dose
was slightly different, a 0.4 µg/kg/min loading infusion for 30
minutes, followed by a 0.1 µg/kg/min maintenance infusion. In
practice, physicians favor the high-dose regimen for patients
undergoing coronary intervention. Therapy is usually continued for
12 to 24 hours after the completion of the procedure.
With tirofiban, there was no increase in major bleeding
complications in the clinical trials,
and, as with eptifibatide, there is no known immune response and
the overall incidence of thrombocytopenia is low. If patients
require emergency CABG, tirofiban should be discontinued;
antiplatelet effects will resolve in 6 hours, but platelet
transfusion is ineffective. Clearance is longer in patients with
Trials of oral GP IIb/IIIa antagonists have been disappointing
without obvious explanation. In the EXCITE (Evaluation of oral
xemilofiban in controlling thrombotic events) trial,
7232 patients undergoing coronary intervention were randomized to
xemilofiban or placebo. The primary end point (death, MI, and
urgent intervention) was similar at 30 days and 6 months, although
there appeared to be a benefit in diabetics. In OPUS (Orboifiban in
Patients with Unstable coronary Syndrome)-TIMI 16, 10,302 patients
with unstable ischemic syndromes were randomized to oral orbofiban
Enrollment was terminated because of excess 30-day mortality in the
low-dose orbofiban group, although patients who underwent PCI
appeared to benefit from orbofiban.
Antiplatelet medications have made, and will continue to make, a
significant impact on PCI. After review of the evidence, the
supported recommendations regarding antiplatelet medication and PCI
(unless contraindicated) would be as follows: 1) all patients
undergoing PCI should receive aspirin; 2) all patients receiving
stents should be placed on clopidogrel; 3) the data is compelling
for the routine use of IV GP IIb/IIIa antagonists during PCI with
stenting and especially high risk PCI; 4) the routine use of GP
IIb/IIIa antagonists during acute MI with primary stent is
controversial; 5) there is potential benefit for the use of
abciximab during acute MI (rescue PTCA after failed lytic therapy),
but further study is needed; and 6) rescue use of GP IIb/IIIa
antagonists after failed/suboptimal intervention has not been
prospectively studied. Several small reports suggest potential
benefit for "rescue use" in thrombus-containing lesions, stent
thrombosis, and abrupt closure, but suggest less benefit in
degenerated vein grafts.