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(Circulation. 2005;111:1097-1099.)
© 2005 American Heart Association, Inc.

Editorial

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 Women’s 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 Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail eantman{at}rics.bwh.harvard.edu

Key Words: Editorials • stents • anticoagulants • platelet aggregation inhibitors • aspirin

	Introduction

Top Introduction Uncertainties About Pretreatment Uncertainties About the Optimal... Uncertainties About the Need... Clear Path for Next... Disclosure References

 
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.

	Uncertainties About Pretreatment

Top Introduction Uncertainties About Pretreatment Uncertainties About the Optimal... Uncertainties About the Need... Clear Path for Next... Disclosure References

 
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

	Uncertainties About the Optimal Loading Dose

Top Introduction Uncertainties About Pretreatment Uncertainties About the Optimal... Uncertainties About the Need... Clear Path for Next... Disclosure References

 
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 colleagues¹⁰ 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

	Uncertainties About the Need for Concurrent GP IIb/IIIa Inhibitor Administration

Top Introduction Uncertainties About Pretreatment Uncertainties About the Optimal... Uncertainties About the Need... Clear Path for Next... Disclosure References

 
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.

	Clear Path for Next Research Agenda

Top Introduction Uncertainties About Pretreatment Uncertainties About the Optimal... Uncertainties About the Need... Clear Path for Next... Disclosure References

 
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.

1. 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?
   
2. 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?
   
3. Will patients with different risk profiles (low versus intermediate) have the same clinical benefits from different loading doses and administration schedules of clopidogrel?
   
4. 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?
   
5. 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.

	Disclosure

Top Introduction Uncertainties About Pretreatment Uncertainties About the Optimal... Uncertainties About the Need... Clear Path for Next... Disclosure References

 
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.

	Footnotes

 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction Uncertainties About Pretreatment Uncertainties About the Optimal... Uncertainties About the Need... Clear Path for Next... Disclosure References

 

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