Circulation. 2005;111:1097-1099
doi: 10.1161/01.CIR.0000158691.22229.75
(Circulation. 2005;111:1097-1099.)
© 2005 American Heart Association, Inc.
Dual Antiplatelet Therapy for Coronary Stenting
A Clear Path for a Research Agenda
Jane A. Leopold, MD;
Elliott M. Antman, MD
From the Whitaker Cardiovascular Institute, Boston University School of Medicine and Cardiovascular Division, Boston Medical Center (J.A.L.), and the Cardiovascular Division, Brigham and Womens Hospital (E.M.A.), Boston, Mass.
Correspondence to Elliott M. Antman, MD, Senior Associate Editor, Director, Samuel A. Levine Cardiac Unit, Cardiovascular Division, Brigham and Womens Hospital, 75 Francis St, Boston, MA 02115. E-mail eantman{at}rics.bwh.harvard.edu
Key Words: Editorials stents anticoagulants platelet aggregation inhibitors aspirin
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Introduction
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It was an important and indeed remarkable observation when several
trials reported the consistent finding that dual antiplatelet
therapy with aspirin and a thienopyridine was superior to aspirin
and oral anticoagulation for prevention of major adverse cardiac
events after deployment of a stent in a coronary artery.
1 A
major benefit of dual antiplatelet therapy was a lower rate
of stent thrombosis. The incidence of coronary stent thrombosis
in the modern era is reported to be approximately 1%, with an
increased likelihood of occurrence in high-risk patient or lesion
subsets. Although this rate may seem relatively low, stent thrombosis
is associated with major myocardial infarction (MI) in 60% to
70% of cases, resulting in an early mortality rate of 20% to
25%. With increased use of percutaneous coronary intervention
(PCI) as a revascularization strategy and implantation of stents
in coronary arteries with a small diameter, it is anticipated
that the number of patients at risk for stent thrombosis may
increase. It therefore continues to be important to construct
pharmacological regimens that minimize its occurrence. Several
risk factors for stent thrombosis have been identified, including
patient- and/or lesion-specific characteristics, procedure-related
factors, and inherent stent thrombogenicity.
2 These risk factors,
in turn, contribute to a state of enhanced platelet reactivity
and thrombus formation, which promotes abrupt vessel closure.
See p 1153
Although initial studies highlighting the benefits of dual antiplatelet therapy used aspirin and ticlopidine, clopidogrel is the thienopyridine of choice today because it is associated with a lower rate of intolerable side effects. It is noteworthy that clopidogrel as part of the dual antiplatelet regimen to support PCI has not undergone the type of extensive evaluation demanded of ACE inhibitors, angiotensin receptor blockers, or such devices as implantable cardioverter-defibrillators before they were recommended in practice guidelines for management of patients with ischemic heart disease. As a consequence, there is ongoing debate about the timing of clopidogrel administration, the appropriate loading dose, and the usefulness of concomitant glycoprotein (GP) IIb/IIIa antagonists in coronary stent procedures. Much of this controversy stems from the fact that clinical trials have not been explicitly designed to inform clinical practice. Instead, contemporary management strategies are a patchwork of individualized interpretation of the evidence, much of which centers around surrogate end points, such as inhibition of platelet aggregation, rather than hard clinical end points.
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Uncertainties About Pretreatment
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PCI-CURE (Clopidogrel in Unstable angina to prevent Recurrent
ischemic Events in patients undergoing Percutaneous Coronary
Intervention) was a nonrandomized, post hoc observational study
of a larger trial (CURE; Clopidogrel in Unstable angina to prevent
Recurrent ischemic Events) designed to compare clopidogrel with
placebo in patients with non-ST-segment-elevation acute coronary
syndromes (ACS) with planned conservative treatment. Sites routinely
practicing an early invasive strategy were excluded from the
trial; patients receiving GP IIb/IIIa inhibitors within 3 days
were excluded. PCI was performed on the basis of clinical indications,
such as refractory ischemia. Patients randomized to clopidogrel
were considered pretreated, whereas those who received placebo
were not. The median period of pretreatment was 6 days. For
the primary end point of cardiovascular death/MI/urgent target-vessel
revascularization, there was a nonsignificant reduction at 2
and 7 days and a significant reduction, from 6.4% to 4.5%, at
30 days favoring clopidogrel.
3
CREDO (Clopidogrel for Reduction of Events During Observation) is the only randomized trial to date that provides partially relevant information on the pretreatment questions. Patients with symptomatic coronary artery disease and evidence of ischemia who were referred for PCI or were thought to be at a high likelihood for requiring PCI were randomized to receive clopidogrel (300 mg) or matching placebo 3 to 24 hours before PCI. All subjects received clopidogrel at a 75-mg maintenance dose for 28 days. Thus, CREDO is really a comparison of administering a loading dose before PCI versus not administering a loading dose; however, there is no direct comparison of giving a loading dose before PCI versus at the time of PCI.4 The overall results of CREDO showed no statistically significant difference in the composite end point of death/MI/urgent target-vessel revascularization between those patients who received a loading dose before PCI versus those who did not. Subgroup analyses raise the possibility that patients who received the loading dose at least 6 or possibly as much as 15 hours before PCI had fewer events than those who did not receive a loading dose. Interpretation of these data is difficult, especially in light of a report that pretreatment with clopidogrel 300 mg before PCI versus administration of a loading dose at the time of PCI in patients undergoing elective PCI showed no difference in biomarker release or clinical end points.5 Further confusion was introduced by a report that patients receiving a loading dose of 600 mg of clopidogrel 2 to 3 hours before PCI in the ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) trial had the same rate of death/MI/urgent revascularization as those receiving that loading dose more than 12 hours before PCI.6
Pretreatment is not without risk. For patients who undergo CABG surgery within 5 days after being treated with clopidogrel, there is an increased risk of bleeding, a greater need for transfusions, and an increased length of hospital stay.7,8
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Uncertainties About the Optimal Loading Dose
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Because of the observation that acute thrombotic occlusion commonly
occurs during the first 24 to 48 hours after stent placement,
9 investigators have explored a number of clopidogrel regimens
to identify the optimum strategy to inhibit platelet aggregation
during this critical time period. In this issue of
Circulation,
Gurbel and colleagues
10 provide data on 300- and 600-mg loading
doses of clopidogrel with and without GP IIb/IIIa antagonism
with eptifibatide in the Clopidogrel Loading with Eptifibatide
to Arrest the Reactivity of Platelets (CLEAR PLATELETS) Study.
In this randomized study, they offer insight into the antiplatelet
efficacy of various regimens via elegant ex vivo platelet reactivity
studies and examine markers of myocardial necrosis to provide
a clinical correlation for their findings. The CLEAR PLATELETS
study shows, not unexpectedly, that the relative inhibition
of platelet aggregation is greatest when eptifibatide in combination
with clopidogrel is compared with clopidogrel alone, regardless
of the loading dose of clopidogrel administered at the time
of PCI. In addition, the release of cardiac biomarkers after
PCI was lower when eptifibatide was combined with either loading
dose of clopidogrel. In those patients not receiving eptifibatide,
a 600-mg clopidogrel loading dose after PCI was associated with
a slightly higher level of inhibition of platelet aggregation
compared with a 300-mg loading dose; however, the 600-mg clopidogrel
alone regimen was not associated with a clear difference in
biomarker release compared with 300 mg alone. Importantly, with
only 30 patients in each of the 4 treatment groups tested, the
CLEAR PLATELETS study is underpowered to make any definitive
observations about the rate of stent thrombosis or other clinical
events across the regimens tested.
What other evidence exists with regard to a 600-mg loading dose of clopidogrel? Angiolillo et al11 compared the antiplatelet efficacy of a clopidogrel 300-mg versus 600-mg loading dose, given after coronary stent placement, to determine whether the higher loading dose provided superior platelet inhibition. In their study of 50 patients, those treated with the 600-mg loading dose demonstrated a rapid, significant decrease in GP IIb/IIIa activation and P-selectin expression compared with patients treated with 300 mg; however, there was no difference in platelet aggregation between the groups when examined up to 48 hours after the procedure. In contrast, in the CLEAR PLATELETS study, patients who received the 600-mg loading dose of clopidogrel had a greater inhibition of platelet aggregation at all time points examined in the first 24 hours after stent placement compared with those given the 300-mg loading dose. The peak inhibitory effect of platelet aggregation occurred 8 hours after a 600-mg loading dose and 18 to 24 hours after a 300-mg loading dose.10 The reason for the observed differences between the 2 studies remains unclear.
Another argument used to support the use of a clopidogrel 600-mg loading dose stems from the observation that a number of patients are found to be poor responders to clopidogrel. Pharmacokinetic studies in healthy volunteers reveal vast interindividual variability in maximal platelet inhibition that correlates with peak plasma concentrations of unchanged clopidogrel and its metabolites.12 In a small series of 48 patients pretreated with clopidogrel 300 mg, 21 patients were identified as low responders, defined as a <40% inhibition of platelet aggregation. Baseline GP IIb/IIIa activation was found to be higher in low responders, and, although decreased after administration of clopidogrel, levels remained higher than those observed in patients who were classified as responders at 10 minutes and 4 and 24 hours after stent placement.13 Other studies have shown that after administration of a 300-mg loading dose of clopidogrel, platelet aggregation was only modestly inhibited in 40% of patients, with up to 8% of the study population demonstrating no effect on platelet aggregation.14 Investigators surmised that increasing the loading dose to 600 mg might decrease the number of patients who were nonresponders; however, when the clopidogrel loading dose was increased to 600 mg, there were still up to 5% to 11% of patients who fell into the category of clopidogrel nonresponders and another 9% to 26% of patients who were found to be semiresponders. Of note, this correlated with only 2 incidents of stent thrombosis in patients who were nonresponders.15 Compared with the 300-mg loading dose, more patients who received the 600-mg loading dose were found to be clopidogrel responders, but within each group, there was a significant interindividual response.11
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Uncertainties About the Need for Concurrent GP IIb/IIIa Inhibitor Administration
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The ISAR-REACT trial examined outcomes in 2159 low- to intermediate-risk
patients undergoing PCI who received a 600-mg loading dose of
clopidogrel and abciximab or placebo. When the groups were compared,
it was found that the addition of abciximab did not offer any
additional benefit with regard to reducing adverse events at
30 days.
16 The results of ISAR-REACT must be interpreted cautiously,
however, because the study was underpowered with regard to its
primary end point of death/MI/urgent target-vessel revascularization
and cannot exclude a 31% relative risk reduction with the addition
of abciximab. In contrast, the ISAR-SWEET (Intracoronary Stenting
and Antithrombotic Regimen: is abciximab a Superior Way to Eliminate
Elevated Thrombotic risk in diabetics) trial reported a clinical
benefit of abciximab coadministration in diabetic patients undergoing
PCI. In ISAR-SWEET, high-risk diabetic patients, treated similarly
to lower-risk patients enrolled in ISAR-REACT, who received
abciximab had a significantly decreased rate of restenosis and
target-vessel revascularization.
17 In the CLEAR PLATELETS study,
adjunctive GP IIb/IIIa antagonism with eptifibatide was shown
to decrease platelet aggregation and reduce markers of myocardial
necrosis after stent placement. The main difference between
ISAR-REACT, ISAR-SWEET, and the CLEAR PLATELETS study with regard
to clopidogrel administration was the timing of the 600-mg loading
dose. In the CLEAR PLATELETS study, clopidogrel was given at
the time of PCI, whereas a pretreatment regimen was used in
ISAR-REACT and ISAR-SWEET.
10 The results of these studies demonstrate
that the role of adjunctive GP IIb/IIIa antagonists in patients
treated with high loading doses of clopidogrel requires further
investigation.
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Clear Path for Next Research Agenda
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Although some clinicians have adopted a practice of pretreatment
with clopidogrel and some have also switched to a loading dose
of 600 mg of clopidogrel, it should be recognized that the evidence
base to support such decisions is far from robust. For example,
as a result of the lack of clinical data and inconsistent surrogate
end point data, a consensus statement by the American College
of Chest Physicians concluded, "...more information is needed
before higher-dose clopidogrel can be recommended on a routine
basis."
1 Many clinical decisions are being increasingly driven
by cost, with some healthcare systems citing the benefits of
pretreatment with high loading doses of clopidogrel as a way
to avoid the higher cost of intravenous GP IIb/IIIa infusions.
We believe that such decisions are premature, because they are
founded on incomplete evidence, and that therapeutic decisions
based on only partial data lead to suboptimal patient care with
potentially unanticipated adverse consequences.
Having established that dual antiplatelet therapy is a critical part of the antithrombotic strategy to support coronary stenting, we see a clear path for the next research agenda. Appropriately designed and powered clinical trials are needed to definitively settle the answers to questions such as the following.
- Is there a clinical benefit to pretreatment with a loading dose of a thienopyridine before PCI versus administration of a loading dose at the time of PCI? If so, what is the optimal timing of the pretreatment loading dose?
- Is there a clinical benefit to the use of a high loading dose versus a 300-mg loading dose of clopidogrel? If so, how does the use of a high loading dose influence the risk of bleeding?
- Will patients with different risk profiles (low versus intermediate) have the same clinical benefits from different loading doses and administration schedules of clopidogrel?
- Are there patient subgroups in whom interventionalists should plan to administer an intravenous GP IIb/IIIa infusion in addition to dual antiplatelet therapy to reduce the risk of clinical events both acutely and over the long term?
- What is the role of novel P2Y12 inhibitors, such as prasugrel (CS-747, LY640315), AZD6140, and cangrelor (AR-C69931MX), in patients undergoing coronary stenting?
Only after these questions are answered in adequately powered randomized clinical trials will we be able to determine an optimal antiplatelet regimen to support coronary artery stent placement.
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Disclosure
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The authors wish to disclose that Dr Antman is the recipient
of a research grant via The TIMI Study Group from Eli Lilly
and Co.
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Footnotes
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The opinions expressed in this article are not necessarily those
of the editors or of the American Heart Association.
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