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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Clinical efficacy of clopidogrel across the whole spectrum of indications: percutaneous coronary intervention

Hussam Hamdalla and Steven R. Steinhubl*

Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY, USA

* Corresponding author: 900 S. Limestone Street, 326 C.T. Wethington Building, Lexington, KY 40536-0200, USA. Tel: +1 859 323 8040; fax: +1 859 323 6475. E-mail address: steinhubl{at}uky.edu


   Abstract
Top
 Abstract
Introduction
 Clopidogrel treatment prior to...
 Long-term therapy following PCI
 Conclusion
 References
 
Over the past few decades, the interventional cardiology field has witnessed remarkable progress that demanded an evolution in the adjunctive antithrombotic therapy. Antiplatelet therapy has evolved from simply aspirin into the current use of dual- or even triple-antiplatelet therapy to attenuate the periprocedural ischemic events. Our knowledge and understanding of the use of the current antiplatelet therapy has been further refined with recent landmark trials involving clopidogrel. Dual antiplatelet therapy, with aspirin and clopidogrel, has become standard of care following PCI with stenting. Several trials including PCI-CURE, CREDO and the ISAR trials have established the benefit of pretreatment with clopidogrel in PCI. Although the use of a prolonged course of dual antiplatelet therapy is currently driven primarily by the wide use of drug-eluting stents, it also has been proven to significantly decrease recurrent thrombotic events in the year following PCI unrelated to the target lesion. In this paper we review some of the recent information on the early and long-term use of clopidogrel in the percutaneous coronary intervention patient.

Key Words: Clopidogrel • Antiplatelet therapy • Percutaneous coronary intervention • Cardiovascular disease • Acute coronary syndrome • PCI-CURE • CREDO • PCI-CLARITY


   Introduction
Top
 Abstract
 Introduction
Clopidogrel treatment prior to...
 Long-term therapy following PCI
 Conclusion
 References
 
The introduction of balloon angioplasty in 1977 by Gruntzig1 marked the beginning of a new era in percutaneous coronary interventions (PCI). However, as balloon angioplasty was increasingly utilized, it was met with high rates of abrupt vessel closure and restenosis. Stents were consequently pioneered to curtail the early ischaemic complications and improve the long-term restenosis. After the prohibitively high rates of stent thrombosis in the first few consecutive implants with heparin and aspirin alone, the antithrombotic and antiplatelet regimen evolved into unfractionated heparin intravenously and streptokinase intracoronary for anticoagulation as well as starting aspirin and dipyridamole the day before and continuing them following the procedure.2 Prolonged anticoagulation with warfarin up to 6 months following stent implantation was added to aspirin to avoid subacute stent thrombosis, which was as high as ~18% in some series.2,3 Ticlopidine became the first thienopyridine to be introduced more than 30 years ago but it has only been over the last 10 years that dual antiplatelet therapy with a thienopyridine plus aspirin has developed into the standard of care in the PCI patient.

Clopidogrel, like ticlopidine, irreversibly inhibits one of the platelet's ADP receptors: the P2Y12 receptor. Clopidogrel rapidly overcame ticlopidine as the thienopyridine of choice among cardiologists with its better tolerability, lower side effect profile, and faster onset of action.4,5 A multitude of randomized and observational studies over the past decade have helped identify and define the role of clopidogrel in the PCI patient today. Although much is known, a surprising number of unknowns remain.


   Clopidogrel treatment prior to PCI
Top
 Abstract
 Introduction
 Clopidogrel treatment prior to...
Long-term therapy following PCI
 Conclusion
 References
 
Aspirin and thienopyridines synergistically inhibit platelet function and their combination initiated before PCI appears to be superior to aspirin alone. Unlike aspirin, which can achieve maximal antiplatelet effects within minutes of a chewed loading dose, the thienopyridines require hours to days, depending upon the agent and the dose.6–9 Early observational reports suggested lower thrombotic events during PCI in patients who were started on dual antiplatelet therapy with ticlopidine few days before the intervention.10 In the PCI-Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE), there was a significant reduction in the combined endpoint of cardiovascular death, recurrent MI, and revascularization associated with pretreatment with 300 mg clopidogrel.11 This subset of patients from the CURE trial were treated for a median of 10 days before the PCI and subsequent analysis found no difference in the benefit on the basis of the duration of pretreatment, but the shortest interval analysed was 48 h,12 so it was unclear whether the benefit was attributable to the loading dose or the prolonged pretreatment course. Subsequently, the Clopidogrel for Reduction of Events During Observation (CREDO) was the first randomized, placebo-controlled trial to prospectively evaluate the benefit of pretreatment with a clopidogrel-loading dose initiated 3–24 h prior to a non-emergent PCI.13 Although, overall, no significant reduction in the combined endpoint of death, MI, and urgent target revascularization at 28 days was observed, the timing of pretreatment appeared to influence the clinical benefit. Subsequent analysis found that the 300 mg loading dose of clopidogrel needed to be given more than 15 h before the coronary intervention to significantly reduce the periprocedural ischaemic events.14 More recently, the PCI-Clopidogrel as Adjunctive Reperfusion Therapy (PCI-CLARITY) added the ST-elevation myocardial infarction (STEMI) patients to the broad population of patients suggested to benefit from pretreatment with clopidogrel. The addition of a 300 mg of clopidogrel to thrombolytic therapy in patients with STEMI who underwent PCI for a median of 3 days after receiving lytics and study drug was associated with a highly significant reduction in the odds of death, MI, or stroke at 30 days (OR, 0.59; 95% CI 0.43–0.81; P=0.001).15 Importantly, the reduction in ischaemic events seen in PCI-CURE, CREDO, and PCI-CLARITY was a reflection of the pretreatment effect, as all these patients were started on open-label thienopyridine following PCI.

The optimal dose and timing of pretreatment to achieve near-maximum benefit with clopidogrel during PCI remains controversial. Von Beckerath et al.8 studied three loading doses of clopidogrel and was able to demonstrate a faster and more potent inhibition of platelet aggregation associated with a 900 or 600 mg loading dose compared with the 300 mg dose. Interestingly, the 900 mg loading dose did not provide a higher level of inhibition of platelet aggregation at 4 h compared with the 600 mg dose.

A series of studies have explored the clinical benefit of adding a Gp IIb/IIIa inhibitor such as abciximab to a 600 mg loading dose of clopidogrel. In the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) study, the addition of abciximab to a 600 mg loading dose more than 2 h before coronary intervention provided to clinical benefit consistent with a clopidogrel-loading dose.16 Likewise, the Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) Study reproduced similar findings in diabetic patients.17 Furthermore, in the Intracoronary Stenting or Angioplasty for Restenosis Reduction in Small Arteries (ISAR-SMART 2), patients with small coronary artery intervention also did not derive any clinical benefit with abciximab if they received a 600 mg clopidogrel-loading dose.18 However, these studies enrolled only patients with relatively stable coronary artery disease (CAD) and the findings should only be applied to similar patients. In contrast, patients presenting with acute coronary syndrome (ACS) documented by either ST depression or elevated troponin were enrolled in the ISAR-REACT 2 trial and were randomized to a Gp IIb/IIIa or placebo after receiving 600 mg clopidogrel-loading dose at least 2 h prior to PCI.19 Among patients who had an elevated troponin level, further reduction in the relative risk of ischaemic events (a combination of death, MI, or urgent target revascularization) at 30 days was achieved with Gp IIb/IIIa compared with placebo (RR 0.71, CI 0.54–0.95; P=0.02). An analysis of all these ISAR trials documents the lack of any benefit with the addition of abciximab to 600 mg loading dose of clopidogrel when given more than 2 h before PCI in troponin-negative patients (Figure 1).


Figure 0501
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  		Figure 1 A combined analysis of the ISAR-REACT, ISAR-SWEET, ISAR-SMART 2, and the troponin-negative patients in the ISAR-REACT 2.

 
Patients on chronic therapy with clopidogrel presenting for a PCI pose a different question, that is, whether they would benefit from reloading with clopidogrel. Kastrati et al.20 evaluated similar patients on chronic clopidogrel therapy and showed that a 600 mg loading dose achieved further inhibition of platelet aggregation beyond the levels that were achieved in naïve patients. The clinical significance of the higher level of platelet inhibition still needs to be established in prospective randomized trials. Recently, findings from the PCI-Clopidogrel as Adjunctive Reperfusion Therapy (PCI-CLARITY) provided support to this concept.15 In a post hoc analysis study, patients received the blinded 300 mg loading dose of clopidogrel at enrollment and were subsequently reloaded with open-label clopidogrel at the time of PCI had the lowest number of ischaemic events.21 However, the timing and dose of clopidogrel needed for reloading as well as the clinical scenario in which it would be beneficial still need to be further delineated in future studies.


   Long-term therapy following PCI
Top
 Abstract
 Introduction
 Clopidogrel treatment prior to...
 Long-term therapy following PCI
Conclusion
 References
 
Dual antiplatelet therapy in the immediate post-PCI period was initially aimed at primarily preventing stent thrombosis. Early durations of 14–30 days were arbitrarily chosen with this in mind; however, the benefit of dual antiplatelet therapy following PCI extends beyond the first 30 days. In PCI-CURE, the combination of aspirin and clopidogrel was given for a mean of 8 months after PCI in those assigned to the clopidogrel arm. The combined endpoint of cardiovascular death and MI was reduced at the end of follow-up in the clopidogrel-assigned patients, compared with the placebo, who received open-label thienopyridines for only 2–4 weeks following PCI (RR 0.75; 0.56–1.00; P=0.047).11 There was a 34% reduction in the combined endpoint at 30 days following PCI and a 21% further reduction between 30 days and end of follow-up. Similarly in CREDO, patients who were randomized to the 300 mg loading dose were also assigned to clopidogrel long-term therapy. Overall, the combined benefit of pretreatment and prolonged clopidogrel up to 1 year in CREDO was associated with a 27% (95% CI 3.9–44.4) relative reduction in the combined primary endpoint compared with those assigned to routine therapy of no pretreatment followed by 4 weeks of dual antiplatelet therapy. Continuation of dual therapy beyond 30 days resulted in further divergence between the two arms (Figure 2), with a 37% reduction in the risk of the combined endpoint between 29 days and 1 year in the clopidogrel arm compared with the placebo (HR 0.63; CI 0.4–0.98; P=0.04).22 Collectively, both the PCI-CURE and CREDO taken together support the long-term therapy with clopidogrel following PCI. As none of the long-term benefit of prolonged clopidogrel was associated with a reduction in restenotic events, the current use of drug-eluting stents would not be expected to diminish the benefit of continued therapy, and in fact, owing to continued concerns about late stent thrombosis, is likely to be of even greater benefit than in the populations previously studied.


Figure 0502
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  		Figure 2 Kaplan–Meier estimates of death, myocardial infarction, or stroke from day 29 to 1 year on the basis of randomized treatment assignment in the CREDO trial.

 
Whether it is beneficial to continue clopidogrel and aspirin beyond 1 year after a PCI remains unclear. A number of case reports have highlighted that at least some DES-treated patients are at risk for stent thrombosis even beyond 1 year. Beyond this, although, is the question of whether the continuation of dual antiplatelet therapy beyond 1 year continues to decrease non-target lesion ischaemic events. Clearly, there is no pathophysiological basis for assuming the benefit seen in CURE and CREDO would end at 1 year. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial was designed to evaluate long-term treatment with clopidogrel extending beyond 1 year in a wide range of patients.23 Patients who had documented atherosclerotic disease or multiple risk factors for vascular disease were randomized to either a 75 mg clopidogrel daily or placebo, on a background of daily aspirin, and were followed up for a median of 28 months. In the overall trial, there was no difference in the effect of clopidogrel therapy compared with placebo (6.8 vs. 7.3% P=0.22); however, patients who had documented atherosclerotic disease had a small but significant reduction in the combined endpoint of cardiovascular death, MI, or stroke with clopidogrel therapy (6.9 vs. 7.9% P=0.046). Further analysis of the CHARISMA trial needs to be performed before any definite recommendations on chronic therapy with clopidogrel can be made.


   Conclusion
Top
 Abstract
 Introduction
 Clopidogrel treatment prior to...
 Long-term therapy following PCI
 Conclusion
References
 
The body of evidence accumulated over the past decade establishes convincingly the role of dual antiplatelet therapy using aspirin and clopidogrel in a broad spectrum of cardiovascular patients. The CREDO trial, PCI-CURE subset analysis, and ISAR studies support the benefit of early treatment with clopidogrel before PCI. The combined analysis of these studies clearly indicates that adequate inhibition of platelet function with clopidogrel and aspirin alone can be achieved in troponin-negative patients without a need for a Gp IIb/IIIa inhibitor on board. Although treatment with a loading dose prior to PCI is designated a class I recommendation by the American College of Cardiology (ACC) and American Heart Association (AHA), most data suggest that the majority of patients do not receive adequate pretreatment prior to PCI, especially in the ACS population.

The concept of variability in responsiveness to clopidogrel is attracting more attention in recent years. The expanded and widespread use of drug-eluting stents in the past few years associated with more unprotected left main and bifurcation lesions stenting made this more of a concern with the catastrophic consequences of subacute stent thrombosis in these high risk patients. The recent ACC/AHA guidelines even suggest documenting >50% inhibition in such patients and consider increasing clopidogrel to 150 mg daily if not, although there are essentially no clinical data to guide this.24 Novel and more potent platelet ADP-receptor antagonists including the thienopyridine prasugrel, the reversible oral agent AZD6140, and the parenteral cangrelor are all being investigated in the on-going phase 3 studies.25–27 These agents hold the potential for significant improvements in the management of the PCI patient beyond the proven benefit of clopidogrel.

Conflict of interest: H.H. has received honoraria for speaking for AstraZeneca and Novartis. S.R.S. has served as a consultant for Sanofi-Aventis, The Medicines Company, Eli Lilly and AstraZeneca.


   References
Top
 Abstract
 Introduction
 Clopidogrel treatment prior to...
 Long-term therapy following PCI
 Conclusion
 References
 

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