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252 Antithrombotic Drug Therapy in Cardiovascular Disease
recognition and treatment, mortality from ICH is as high as 60%. Additional bleeding complications
may occur in the gastrointestinal tract, retroperitoneum, or at intravenous or intra-arterial access sites.
Hypersensitivity reaction to lytic agents occurs only with streptokinase, as it is a bacterial protein and
is antigenic. These events are usually not life threatening if recognized and treated promptly.
Lytic Use in the Elderly
Elderly patients represent a high-risk group for thrombolytic therapy as the rate of ICH is higher
among patients > 75 years of age and the mortality rate from ICH in these patients is as high as 90%.
There is controversy in the literature, however, regarding just how much higher the risk is among
elderly patients, as reports are conflicting. An observational study
(10) from the Medicare database
found patients older than 75 years had an increased risk of death at 30 days with fibrinolytic therapy
(RR
= 1.38, 95% CI: 1.12–1.71, p = 0.003). However, an updated meta-analysis of nine randomized
trials
(11) found the risk reduction with fibrinolysis in patients older than 75 years was 16%
(OR
= 0.84, 95% CI: 0.72–0.98, p < 0.05). The only randomized trial to specifically address manage-
ment of STEMI in the elderly found that elderly patients treated with PCI had significantly lower
30-day and 1-year mortality rates than elderly patients treated with fibrinolysis (12). However, a
recent study suggested that fibrinolytic therapy may be safe in the elderly if a reduced dose of enoxa-
parin is used (13). Nevertheless, it appears reasonable to conclude that wherever available, primary
PCI should be the treatment of choice in the elderly.
Contraindications
Recent cerebrovascular accident (including hemorrhagic stroke), intracranial neoplasm, active
internal bleeding, and suspected aortic dissection are the only absolute contraindications to lytic
therapy. There are a number of relative contraindications, including severe hypertension, remote
ischemic stroke, non-compressible vascular puncture sites, among others (see Table
4). The presence of
one absolute contraindication or one or more relative contraindications should favor PCI, even if this
means delaying reperfusion.
Adjunctive Therapies
Antiplatelet Agents
The benefits of aspirin in the treatment of acute MI are well established. Aspirin should be admin-
istered as quickly as possible when the diagnosis of STEMI is made. Aspirin should be given by
mouth, chewable if possible, and non-enteric coated, in a dose of at least 162–325 mg. The evidence
for this practice is founded on the landmark ISIS-2 trial (International Studies of Infarct Survival)
which showed a significant mortality benefit for aspirin (14). Since that study numerous others in
acute MI and NSTEMI have shown benefit.
More recently, trials have been completed evaluating the use of clopidogrel in addition to aspirin.
The CLARITY trial compared clopidogrel to placebo in 3,491 patients, finding a 36% reduction in
a composite endpoint of death, recurrent MI, or occluded infarct artery at early angiography (15).
The larger COMMIT trial had a similar finding, with 9% reduction in death, reinfarction, or stoke
with the addition of clopidogrel to aspirin (16). Therefore, early administration of clopidogrel, with
an oral loading dose of 300 mg except in those older than 75 years of age, is recommended for
patients with STEMI.
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253Fibrinolysis and Facilitated PCI
Antithrombotic Agents
When used as an adjunct to t-PA, intravenous unfractionated heparin (UFH) has been shown to
improve late patency. This is likely due to its antithrombin effects, as thrombin activity is paradoxi-
cally increased after fibrinolysis. Intravenous heparin was used successfully in conjunction with
accelerated t-PA in the GUSTO I trial to improve infarct artery patency and outcomes. However, in
the same trial, there was no benefit to intravenous heparin with streptokinase. The use of unfraction-
ated heparin as adjunctive therapy with reteplase and tenecteplase was validated in the the GUSTO
III and ASSENT 2 trials, respectively. The dose of heparin recommended in the AHA/ACC guidelines
is a bolus of 60 U/kg bolus (maximum, 4,000 units), followed by 12 U/kg/h (maximum, 1,000 U/h).
The goal activated partial thromboplastin time (aPTT) should be adjusted to 50–70 s.
Low-Molecular-Weight Heparins
Low-molecular-weight heparin (LMWH) has recently been shown to improve upon outcomes
obtained with adjunctive UFH use. Because UFH is neutralized by activated platelets, it cannot inhibit
clot-bound thrombin. However, enoxaparin, a low-molecular-weight heparin, overcomes this disadvan-
tage due to consistent bioavailability and diminished inhibition by platelet factor 4. In addition, there
is a reduced incidence of heparin-induced thrombocytopenia with LMWH. Table 5 summarizes the
observations from trials of anticoagulants in STEMI.
The ASSENT 3 trial (17) found that patients treated with full-dose TNK and enoxaparin had a
lower 30-day risk of death or MI compared to full-dose TNK and UFH (6.8% vs. 9.1%; p = 0.02). The
ENTIRE-TIMI 23 (Enoxaparin as Adjunctive Antithrombin Therapy for ST-Elevation Myocardial
Infarction) demonstrated that patient enoxaparin was superior to UFH in a similar trial design to
Table 4
Contraindications and cautions for use of fibrinolytic agents to manage myocardial infarction
Absolute contraindications
Previous hemorrhagic stroke at any time; ischemic stroke within 3 months
Known intracranial neoplasm, structural cerebral vascular lesion or closed-head injury within 3 months
Active bleeding or bleeding diathesis (excluding menses)
Suspected aortic dissection
Relative contraindications
Severe, uncontrolled hypertension at presentation (blood pressure > 180/110 mmHg) or history of chronic
severe hypertension
History of ischemic stroke > 3 months, dementia, or known intracerebral pathologic condition not covered
in contraindications
Current use of anticoagulants, the risk increases with increasing INR
Traumatic or prolonged (>10 min) CPR or major surgery (<3 wk)
Noncompressible vascular punctures
Recent (within 2–4 wk) internal bleeding
For streptokinase or anistrepeplase: prior exposure (more than 5 days prior) or prior allergic reaction
Pregnancy
Active peptic ulcer
CPR cardiopulmonary resuscitation, INR international normalized ratio
Adapted from Antman EM, Anbe DT, Armstrong PW, et
al. (2004) ACC/AHA guidelines for the management of patients
with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute
Myocardial Infarction). J Am Coll Cardiol 44:E1–E211
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254 Antithrombotic Drug Therapy in Cardiovascular Disease
ASSENT 3. The rate of major hemorrhage was slightly less with adjunctive enoxaparin compared to
UFH. However, the EXTRACT-TIMI 25 trial showed that the primary benefit of enoxaparin was in
prevention of reinfarction, rather than in survival. Although the EXTRACT-TIMI 25 trial did not have
a primary PCI group, among patients who had subsequent PCI after lytics, enoxaparin appeared to be
superior to UFH without increased bleeding events (13).
Fondaparinux
Fondaparinux is a synthetic factor X inhibitor that has been studied in acute MI. The OASIS-6 trial
evaluated fondaparinux with fibrinolytics and appeared to demonstrate benefit versus placebo/UFH in
terms of death and re-infarction at 30 days (9.7% vs. 11.2%; HR
= 0.86) without an increased risk
in bleeding
(18). However, in the primary PCI subset, there was no benefit and a significant increase in
guiding catheter thrombosis was noted which has limited its widespread use.
Glycoprotein IIb/IIIa Inhibitors and Direct Thrombin Inhibitors
Sustained tissue-level reperfusion occurs in only 25% of patients who receive lytics. In addition,
there is paradoxically increased activity of platelets after lytic therapy, and this activation may be an
important mediator in vessel reocclusion. Glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors are potent
antiplatelet agents which block the final common pathway of platelet aggregation, and so may be
useful in conjunction with lytics. The GUSTO V trial found that the addition of abciximab to half-
dose r-PA did not reduce mortality, but did reduce the rate of reinfarction and complications after MI
(19). The ASSENT 3 trial also found similar reduction in reinfarction with abciximab and half-dose
TNK (17). However, this reduction in reinfarction came at a high cost in the elderly, with almost twice
the level of ICH among patients receiving combination therapy. Therefore, age > 75 can be considered
a contraindication to combination GP IIb/IIIa and lytics.
Direct thrombin inhibitors have failed to show a significant benefit over heparin during fibrinolysis
in acute MI, and outside of the realm of heparin-induced thrombocytopenia, do not appear to play a
significant role in the treatment of acute MI with lytics.
RESCUE ANGIOPLASTY
The use of PCI in the setting of failed reperfusion with fibrinolytic therapy has been called rescue
angioplasty. The clinical determination of successful reperfusion can be difficult to determine as reso-
lution of chest pain can occur for reasons other than reperfusion, such as blunting of pain with narcotic
analgesics. Serial 12-lead ECGs can be a more reliable measure of reperfusion, with resolution of
Table 5
Summary of findings from trials of enoxaparin and fondaparinux for STEMI
Pharmacologic agent 30-Day efficacy Safety Use during PCI
Enoxaparin Appears superior to UFH
with fibrinolysis
Increased risk of
serious bleeds
Can be used to support
PCI after fibrinolysis
Fondaparinux Appears superior to placebo/UFH in
fibrinolysis. Trend toward worse
outcomes with primary PCI
Trend toward
decreased risk
of serious bleeds
Increased risk of cath-
eter thrombosis when
used alone
PCI percutaneous coronary intervention, UFH unfractionated heparin
Adapted from
(3)
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255Fibrinolysis and Facilitated PCI
ST-segment elevation by more than 70% correlating with effective tissue level reperfusion and clinical
outcomes. In a small number of patients, resolution of chest pain with an accompanied run of
accelerated idioventricular rhythm (AIVR) indicated successful reperfusion.
Infarct-related artery patency at 90
min following lytic administration has been shown to correlate
with long-term survival. If reperfusion is not evident after 90
min, a prompt decision should be made
regarding the use of emergency angiography and PCI. High-risk patients with large infact size, severe
congestive heart failure, or unstable cardiac rhythms after lytic administration should not await clini-
cal assessment of reperfusion, but instead should be taken to immediate PCI.
The RESCUE (Randomized Evaluation of Salvage Angioplasty with Combined Utilization of
Endpoints) trial (20) showed that patients with a large anterior MI and unsuccessful thrombolysis
(TIMI 0 or 1 flow) can benefit from rescue PCI. The REACT trial showed that when lytics fail,
treatment with rescue PCI is associated with a 50% reduction in death, reinfarction, stroke, and
severe heart failure
(21). Although not technically “rescue angioplasty,” the strategy of early inva-
sive approach among STEMI patients treated with lytic therapy has been evaluated in several
small trials, including GRACIA I, Capital AMI, and SIAM III (22–24). These trials showed a
reduction in revascularization events in the early invasive group, and a trend toward fewer deaths
and reinfarctions.
The conclusion which may be drawn from these trials is that an early angiography strategy (within
24
h) may be a reasonable approach in all patients who undergo lytic treatment, with emergent PCI
in those patients where reperfusion at 90
min is not achieved or hemodynamic or electrical instability
are present.
FACILITATED PCI
Evidence from PCI trials has shown that a patent infarct artery at the time of presentation to the
catheterization laboratory is associated with improved procedural success and decreased mortality
(25). The success of lytics in improving infarct artery patency created interest in combining the use
of lytic therapy with immediate PCI. The combination of an initial pharmacologic regimen with
planned primary PCI has been termed “facilitated PCI.” The theoretical advantages include earlier
reperfusion, improved hemodynamic stability, enhanced procedural success, smaller infarct size, and,
hopefully, improved survival. The disadvantages may include increased bleeding risk when combining
lytics with PCI. A number of different facilitated PCI strategies have been proposed, including high-dose
heparin, early glycoprotein IIb/IIIa inhibitor use, full-dose or reduced-dose fibrinolytics, and combi-
nation fibrinolytics and glycoprotein IIb/IIIa inhibitors.
Full-Dose Lytics
Although previously studied in a smaller number of patients, the largest study to date to evaluate
full-dose fibrinolytic therapy was ASSENT-4 PCI (Assessment of Safety and Efficacy of a New
Treatment Strategy with PCI). This trial evaluated tenecteplase plus PCI versus primary PCI alone.
Higher in-hospital mortality (6% vs. 3%; p = 0.01) and higher primary composite endpoints (18.6%
vs. 13.4% ; p = 0.0045) with full-dose fibrinolytics led to premature termination of this trial (26). As
a result of this trial the practice of full-dose thrombolytic therapy prior to PCI is not recommended.
The reason for the excess mortality and other endpoints was appeared to be an excess in stroke and rein-
farction, possibly representing a prothrombotic, post-fibrinolytic milieu.
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256 Antithrombotic Drug Therapy in Cardiovascular Disease
Half-Dose Lytics + Glycoprotein IIb/IIIa Inhibitor or Glycoprotein IIb/IIIa
Inhibitor Alone
The first combination therapy trial, ADVANCE-MI, evaluated eptifibatide, a glycoprotein IIb/
IIIa inhibitor, together with bolus-dose TNK. This trial included 146 patients and evaluated 30-day
outcomes. The result was better initial TIMI 3 flow with facilitated PCI, but no improvement in
final ST-segment resolution and a non-significant increase in mortality
(27). Subsequently, a large
meta-analysis of multiple, small randomized trials confirmed that primary PCI is a superior strategy
to facilitated PCI with respect to the endpoints of death, reinfarction, target vessel revascularization
(28). This meta-analysis recommended that use of such regimens be limited to the setting of rand-
omized trials.
The most definitive randomized control trial to date designed to answer the questions about facili-
tated PCI was recently published. The FINESSE (Facilitated Intervention with Enhanced Speed to
Stop Events) (29) trial assessed the effects of half-dose reteplase plus abciximab, abciximab alone, or
placebo on outcomes in patients undergoing PCI for STEMI. The lytic plus glycoprotein IIb/IIIa arm
had greater infarct-related artery patency at the time of cardiac catheterization, although the composite
primary endpoint of death or complications of MI at 90 days was no different between the three
strategies (9.8% half-dose fibrinolytic + GP IIB/IIIA inhibitor, 10.5% GP IIb/IIIa inhibitor alone, and
10.7% placebo; P
= NS). Although the endpoints were similar, bleeding rates were higher with the
half-dose lytic
+ IIB/IIIA inhibitor strategy.
Although not technically “facilitated PCI” per se, there is evidence that early administration of a
glycoprotein IIb/IIIa inhibitor may be beneficial. The On-TIME 2 trial evaluated the prehospital
initiation of tirofiban in patients with STEMI undergoing primary PCI
(30). This trial documented
improved residual ST-segment elevation at one hour post-PCI. There was also a trend toward improved
survival at 30 days with early tirofiban but the study was not powered for clinical endpoints.
As a result of the lack of data showing benefit for facilitated PCI regimens, current guidelines
recommend the use of facilitated PCI only with regimens other than full-dose lytics when patients are
at high risk but PCI is not immediately available within 90
min and bleeding risk is low (3). The current
emphasis for research and resources allocation should now be placed on improving transfer times and
overall door-to-balloon times, as facilitated PCI, although intellectually appealing, has not solved the
dilemma of prolonged PCI times.
REFERENCES
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2. Schomig A, Mehilli J, Antoniucci D et al (2005) Mechanical reperfusion in patients with acute myocardial infarction
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4.
Keeley EC, Boura JA, Grines CL (2003) Primary angioplasty versus intravenous thrombolytic therapy for acute myocar-
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5. Nallamothu BK, Bates ER (2003) Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial
infarction: is timing (almost) everything? Am J Cardiol 92(7):824–826
6. Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Gruppo
Italiano per lo Studio della Streptochi-nasi nell’Infarto Miocardico (GISSI) (1987) Lancet 2(8564):871–874
7. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO
investigators (1993) N Engl J Med 329(10):673–682
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257Fibrinolysis and Facilitated PCI
8. A comparison of reteplase with alteplase for acute myocardial infarction. The Global Use of Strategies to Open
Occluded Coronary Arteries (GUSTO III) Investigators (1997) N Engl J Med 337(16):1118–1123
9. Van De Werf F, Adgey J, Ardissino D et al (1999) Single-bolus tenecteplase compared with front-loaded alteplase in
acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 354(9180):716–722
10.
Thiemann D (2000) Primary angioplasty vs thrombolysis in elderly patients. JAMA 283(5):601–602
11.
Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality
and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists’ (FTT)
Collaborative Group (1994) Lancet 343(8893):311–322
12.
de Boer MJ, Ottervanger JP, van’t Hof AW, Hoorntje JC, Suryapranata H, Zijlstra F (2002) Reperfusion therapy in
elderly patients with acute myocardial infarction: a randomized comparison of primary angioplasty and thrombolytic
therapy. J Am Coll Cardiol 39(11):1723–1728
13.
Antman EM, Morrow DA, McCabe CH et al (2006) Enoxaparin versus unfractionated heparin with fibrinolysis for
ST-elevation myocardial infarction. N Engl J Med 354(14):1477–1488
14.
Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute
myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group (1988)
Lancet 2(8607):349–360
15.
Sabatine MS, Cannon CP, Gibson CM et al (2005) Addition of clopidogrel to aspirin and fibrinolytic therapy for myo-
cardial infarction with ST-segment elevation. N Engl J Med 352(12):1179–1189
16. Chen ZM, Jiang LX, Chen YP et al (2005) Addition of clopidogrel to aspirin in 45, 852 patients with acute myocardial
infarction: randomised placebo-controlled trial. Lancet 366(9497):1607–1621
17. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the
ASSENT-3 randomised trial in acute myocardial infarction (2001) Lancet 358(9282):605–613
18. Yusuf S, Mehta SR, Chrolavicius S et al (2006) Effects of fondaparinux on mortality and reinfarction in patients with
acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 295(13):1519–1530
19. Topol EJ (2001) Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced
fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet
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20.
Ellis SG, da Silva ER, Heyndrickx G et al (1994) Randomized comparison of rescue angioplasty with conservative
management of patients with early failure of thrombolysis for acute anterior myocardial infarction. Circulation
90(5):2280–2284
21.
Gershlick AH, Stephens-Lloyd A, Hughes S et al (2005) Rescue angioplasty after failed thrombolytic therapy for acute
myocardial infarction. N Engl J Med 353(26):2758–2768
22. Fernandez-Aviles F, Alonso JJ, Castro-Beiras A et al (2004) Routine invasive strategy within 24 hours of thrombolysis
versus ischaemia-guided conservative approach for acute myocardial infarction with ST-segment elevation (GRACIA-1):
a randomised controlled trial. Lancet 364(9439):1045–1053
23.
Scheller B, Hennen B, Hammer B et al (2003) Beneficial effects of immediate stenting after thrombolysis in acute
myocardial infarction. J Am Coll Cardiol 42(4):634–641
24. Le May MR, Wells GA, Labinaz M et al (2005) Combined angioplasty and pharmacological intervention versus throm-
bolysis alone in acute myocardial infarction (CAPITAL AMI study). J Am Coll Cardiol 46(3):417–424
25. Stone GW, Cox D, Garcia E et al (2001) Normal flow (TIMI-3) before mechanical reperfusion therapy is an independent
determinant of survival in acute myocardial infarction: analysis from the primary angioplasty in myocardial infarction
trials. Circulation 104(6):636–641
26.
Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute
myocardial infarction (ASSENT-4 PCI): randomised trial (2006) Lancet 367(9510):569–578
27. ADVANCE MI Investigators (2005) Facilitated percutaneous coronary intervention for acute ST-segment elevation
myocardial infarction: results from the prematurely terminated ADdressing the Value of facilitated ANgioplasty after
Combination therapy or Eptifibatide monotherapy in acute Myocardial Infarction (ADVANCE MI) trial. Am Heart J
150(1):116–122
28. Keeley EC, Boura JA, Grines CL (2006) Comparison of primary and facilitated percutaneous coronary interventions for
ST-elevation myocardial infarction: quantitative review of randomised trials. Lancet 367(9510):579–588
29. Ellis SG, Tendera M, de Belder MA et al (2008) Facilitated PCI in patients with ST-elevation myocardial infarction. N
Engl J Med 358(21):2205–2217
30. Van’t Hof AW, Ten Berg J, Heestermans T et al (2008) Prehospital initiation of tirofiban in patients with ST-elevation
myocardial infarction undergoing primary angioplasty (On-TIME 2): a multicentre, double-blind, randomised control-
led trial. Lancet 372(9638):537–546
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Part V
Antithrombotic Therapy in International Cardiology
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14 Antithrombotic Therapy in Percutaneous
Coronary Intervention
Adrian W. Messerli
Co n t e n t s
Introduction
Antiplatelet Therapy
Antithrombin Therapy
Fondaparinux
Special Populations
Future Directions
References
Ab s t r A c t A comprehensive understanding of periprocedural anticoagulation is an important component
of interventional cardiovascular medicine. Rapid and ongoing advancement in adjunctive pharmacother-
apy has made percutaneous coronary intervention (PCI) considerably safer, thereby facilitating the rapid
international growth. Nevertheless, debate regarding the optimal pharmacologic ingredients and potency of
anticoagulation for PCI persists. This chapter will review the specific value of antiplatelet and anticoagu-
lant therapy to prevent thrombotic complications during PCI, targeting the most contemporary evidence
available for each. The focus will be on agents that are routinely available and commonly used.
Key words:
Antiplatelet; Antithrombotic; Antithrombin; Intervention; Platelets; Stents; Thrombosis
INTRODUCTION
For good reason, there are no universally accepted guidelines for periprocedural anticoagulation.
Logically a number of variables must be taken into account prior to prescribing an antithrombotic
regimen for any individual procedure. Patients undergoing PCI in the midst of an acute coronary
syndrome (ACS) frequently require more aggressive antithrombotic and platelet aggregation inhibition
than lower-risk patients undergoing elective PCI for stable angina pectoris. Similarly, generalizing
antithrombotic regimen to a wide spectrum of catheter-based therapeutic devices is unreasonable. A level
of anticoagulation that is safe and effective for routine angioplasty and stent placement may not be
sufficient for devices with longer intracoronary dwell times such as brachytherapy or atherectomy
From: Contemporary Cardiology: Antithrombotic Drug Therapy in Cardiovascular Disease
Edited by: A.T. Askari and A.M. Lincoff (eds.), DOI 10.1007/978-1-60327-235-3_14
© Humana Press, a part of Springer Science+Business Media, LLC 2010
261
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Antithrombotic Drug Therapy in Cardiovascular Disease
catheters. Perhaps most importantly, risk is a relatively subjective metric; different interventional
cardiologists will have different definitions of high-risk lesions and high-risk patients. Nonetheless,
the compilation of recently released randomized clinical trial data does provide for several broader
recommendations.
ANTIPLATELET THERAPY
Aspirin
Aspirin, or acetylsalicylic acid (ASA), is the stalwart antiplatelet therapy for any percutaneous
catheter-based procedure. Approximately, 35 million patients in the United States take ASA
chronically
(1). The Antithrombotic Trialists meta-analysis (2), which included over 200,000
ASA-treated patients, confirmed definitively that ASA is protective in patients specifically at risk
for atheroembolic events, those with a prior history of stable or unstable angina, myocardial inf-
arction, peripheral arterial disease, ischemic stroke, and/or atrial fibrillation. The ISIS-2 study
affirmed the cardioprotective role of ASA in the setting of acute STEMI; a 23% reduction in
mortality was observed versus placebo
(3). Numerous other randomized controlled trials noted
decreased mortality rates when ASA (75–325
mg) was given to hospitalized patients with an
ACS
(4–7).
Aspirin exerts its antiplatelet effect by acetylating and inactivating a key moiety of cyclooxygenase-I
(COX-I), thereby preventing the formation of thromboxane A2 from arachidonic acid
(1). In platelets,
this effect is irreversible and persists for the circulating lifespan of the mature platelet, or roughly
seven days. Although no trials have been published that specifically compare low dose versus higher
doses of ASA in the setting of PCI, the ability of ASA to inhibit platelet aggregation and prevent
thrombotic cardiovascular events makes its administration essential from both risk-benefit and cost-
benefit standpoints. The available studies examining ASA administration in the setting of percutaneous
coronary intervention are older, frequently included dipyridamole as a comparator or adjunct therapy
(8), and revealed a significant reduction in their respective primary endpoints (ST-elevation myocardial
infarction or acute vessel closure) in patients administered ASA. As such, an ASA is and should be
routinely given to any nonallergic patient undergoing PCI.
Oral ASA achieves an appreciable antiplatelet effect within 60
min of administration (1). Chewed
nonenteric-coated ASA has a more rapid bioavailability than swallowed tablets
(1). While a lower-
dose regimen is entirely effective and appropriate in the chronic condition, in an acute setting at least
325
mg should be given 2 h before intervention whenever possible (9). For elective PCI, ASA 325 mg
should be administered at least 24 h before the proposed procedure (9).
The issue of ASA resistance (10,11) has recently confused physicians, specifically regarding
appropriate dosing and loading time. Data suggest that between 5 and 60% of patients demonstrate
some ASA antiplatelet resistance. In most of these studies, ASA efficacy was determined by effect on
bleeding times, or by ability to inhibit platelet aggregation measured by whole blood aggregometry
or a rapid platelet function assay. A recent study suggests, however, that aspirin resistance in platelets
may be overestimated by these relatively nonspecific methods (12). Arachidonic-acid-induced light
transmittance platelet aggregation (LTA) and thromboelastography (TEG) were performed in 223
patients (n = 203 undergoing PCI; n = 20 with a history of stent thrombosis) reportedly compliant with
long-term daily ASA therapy. ASA resistance, defined as >20% aggregation by LTA or >50% aggre-
gation by TEG, was noted in only one patient, suggesting that the true incidence may be quite low.
Until the clinical impact and definition of ASA resistance are better defined, the subject has to be
considered largely academic (see Chap. 24).
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Antithrombotic Therapy in Percutaneous Coronary Intervention
Thienopyridines
The two thienopyridines FDA-approved for clinical use are ticlopidine (Ticlid) and clopidogrel
(Plavix)
(13). Thienopyridines inhibit the platelet P
2Y12
type ADP receptor at the adenyl cyclase-
coupled receptor site, leading to attenuation of platelet aggregation in response to ADP excreted by
activated platelets
(13) (Fig. 1). ASA and clopidogrel have been studied in comparison with one
another, but thienopyridines and ASA most likely exert complementary and synergistic antiplatelet
effects
(13).
Clopidogrel is preferentially prescribed both in and outside of the catheterization laboratory for
several reasons. First, ticlopidine has a more toxic side effect profile, including agranulocytopenia
(1% of patients) or thrombotic thrombocytopenic purpura (0.01%)
(14). Due to these potential adverse
effects, white blood cell count monitoring is advisable for patients taking ticlopidine. In addition,
clopidogrel loading, either with 300
mg or 600 mg oral boluses, is generally better tolerated than
ticlopidine loading. Finally, ticlopidine is conventionally prescribed as a twice-daily drug, while
clopidogrel needs to be taken once daily.
Dual antiplatelet therapy utilizing both ASA and a thienopyridine is currently the most effective
regimen for prevention of acute thrombosis after coronary stent placement. The benefit of dual
antiplatelet therapy in reducing stent thrombosis was initially demonstrated in a trial of 517 patients
undergoing acute or elective stenting
(15). Patients who received ASA and ticlopidine were significantly
less likely to experience a primary endpoint (death, MI, CABG or repeat PCI) than those receiving
ASA, intravenous unfractionated heparin, and phenprocoumon (1.5% vs. 6.2%, respectively). These
data were confirmed in a subsequent randomized clinical trial that compared ASA alone, ASA and
ticlopidine, or ASA and coumadin in 1,653 low-risk patients undergoing stent placement (16). The
primary endpoint, comprising death, target lesion revascularization, subacute stent thrombosis, or MI,
was only 0.5% in the ASA and ticlopidine group, versus 3.6% in the ASA alone group, and 2.7% in
the ASA and coumadin group solidifying the role of post-PCI dual antiplatelet therapy
Clopidogrel: Dosing and Timing Prior to PCI
A growing body of evidence indicates that high loading doses of clopidogrel (300–600 mg) given
two or more hours prior to an interventional procedure may reduce acute ischemic events at the time
Fig. 1. Mechanism of action of antiplatelet drugs
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