Duration of antiplatelet therapy following intracoronary stenting: are changes needed?
Deutsches Herzzentrum and Technische Universität, Lazarettstr. 36, 80636 Munich, Germany
* Corresponding author. Tel: +49 89 1218 4577; fax: +49 89 1218 4053. E-mail address: kastrati{at}dhm.mhn.de
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Abstract |
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 Top Abstract IntroductionRandomized trials of duration...Dual-antiplatelet therapy in the...ConclusionsFundingReferences |
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This review addresses the question of whether established guidelines for the duration of dual-antiplatelet therapy (DAT) following intracoronary stenting need to be updated. Current recommendations for the optimal duration of DAT following percutaneous coronary intervention are limited by an inadequate evidence base. While the Percutaneous Coronary Intervention–Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO) studies showed reductions in ischaemic events with prolongation of DAT out to 9–12 months, both the main CURE and CREDO studies showed an excess of major bleeding and are limited in generalizability by study design characteristics. Concerns regarding the rates of delayed acute stent thrombosis following drug-eluting stent (DES) implantation are integral to any debate on the optimal duration of DAT. The most reasonable conclusion from a number of divergent reports is that the evidence for an increased rate of stent thrombosis with DES therapy is conflicting. The Intracoronary Stenting and Antithrombotic Regimen: Safety And eFficacy of a 6-month DAT after drug-Eluting stenting (ISAR-SAFE) trial should help answer whether DAT should be routinely extended beyond 6 months post-DES implantation. Two other studies, ISAR-REBOUND and ISAR-CAUTION, are evaluating the effect of abrupt vs. tapered cessation of clopidogrel therapy on predefined in vitro and clinical endpoints and should shed further light on the existence and clinical significance of a rebound phenomenon following clopidogrel discontinuation.
Key Words: Dual-antiplatelet therapy • Drug-eluting stent • Clopidogrel • Percutaneous coronary intervention
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Introduction |
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TopAbstractIntroductionRandomized trials of duration...Dual-antiplatelet therapy in the...ConclusionsFundingReferences |
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Recent controversies regarding the risk of delayed acute stent thrombosis in patients receiving drug-eluting stent (DES) therapy has brought into sharp focus the issue of duration of antiplatelet therapy following percutaneous coronary intervention (PCI).1 Effective pharmacological interventions targeted at inhibiting the evolutionarily evolved systems of haemostasis and thrombosis may be expected to increase the risk of haemorrhage. As such, the application of any effective antithrombotic or antiplatelet therapy to a particular patient carries with it a defined tipping point where treatment risk exceeds benefit. Unfortunately, we do not know the point at which the risk of excess bleeding events from dual-antiplatelet therapy (DAT) outweighs the benefits in reducing acute ischaemic events.
Aspirin therapy before PCI, and lifelong thereafter, is considered the standard of care and will not be addressed further in this review.2,3 The issue of duration of concomitant thienopyridine therapy is more complex and requires detailed consideration of the available evidence.
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Randomized trials of duration of dual-antiplatelet therapy |
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TopAbstractIntroductionRandomized trials of duration...Dual-antiplatelet therapy in the...ConclusionsFundingReferences |
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Current guideline recommendations regarding the optimal duration of DAT cannot be guided by evidence-based medicine. The 2005 European Society of Cardiology guidelines on PCI recommends clopidogrel therapy for 3–4 weeks post-implantation of a bare-metal stent (BMS), 6–12 months after implantation of a DES, 12 months after vascular brachytherapy, and a duration of 9–12 months if a stenting procedure follows the presentation of an acute coronary syndrome (ACS).2 On the other hand, a focused update of the 2005 American College of Cardiology/American Heart Association/Society of Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) PCI guidelines recommends that patients who receive a BMS should ideally be treated with clopidogrel for 12 months post-PCI (minimum, 1 month) and stresses that all patients who receive a DES should be given clopidogrel for at least 12 months in the absence of an increased risk of bleeding.3
We know from the Percutaneous Coronary Intervention–Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) trial that there is a 31% relative risk reduction in ischaemic events—from 12.6 to 8.8%—following an extension of clopidogrel therapy for a mean of 8 months beyond standard 4-week treatment after PCI.4 However, we must recognize that PCI-CURE was not a true PCI trial but rather a subset analysis of a larger study. In fact, the main trial showed that the reduction in ischaemic events (9.3 vs. 11.4%; odds ratio, 0.80 for clopidogrel vs. placebo; P = 0.001) was clearly offset by an increased risk of major bleeding events (3.7 vs. 2.7%; odds ratio, 1.36 with clopidogrel; P = 0.001), a finding that may be expected to result in marginal, if any, net clinical benefit—although such an analysis was not presented.5 The Clopidogrel for the Reduction of Events During Observation (CREDO) investigators also reported a significant reduction in ischaemic events in patients undergoing elective PCI who received clopidogrel for up to 12 months (8.5 vs. 11.5%; odds ratio, 0.73 for clopidogrel vs. placebo; P = 0.02), although again there was a clear signal of an excess of major bleeding (8.8 vs. 6.7%; odds ratio, 1.31; P = 0.07).6 It should be noted that both trials tested dual hypotheses—loading plus prolongation vs. no loading and standard (4-week) therapy—without employing a factorial design. As such, the ascription of benefit to prolongation of therapy alone is not without its concerns. Interestingly, these trends are neatly mirrored when the intensity of DAT is increased.
The TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN With Prasugrel–Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) showed that ischaemic outcome events can be further reduced in moderate- to high-risk patients if prasugrel is substituted for clopidogrel as the second antiplatelet drug (12.1 vs. 9.9%; odds ratio, 0.81 for prasugrel vs. clopidogrel; P = 0.001) with therapy continued for 6–15 months post-PCI, although again at the expense of an increase in major bleeding (2.4 vs. 1.8%; odds ratio, 1.32; P = 0.03).7 Further information on DAT—this time in a cerebrovascular disease cohort—is provided by the Management of ATherothrombosis with Clopidogrel in High-risk patients with recent transient ischaemic attack or ischaemic stroke (MATCH) trial, which showed a 2.6% absolute increase in serious bleeding with 18 months of dual- vs. single-antiplatelet therapy (in this instance without a reduction in the ischaemic endpoint)—an example of a study where the tipping point was clearly exceeded.8 So, we should realize that, in addition to potential benefit to the patient, the prolongation of DAT is associated with significant harm.
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Dual-antiplatelet therapy in the drug-eluting stent era |
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TopAbstractIntroductionRandomized trials of duration...Dual-antiplatelet therapy in the...ConclusionsFundingReferences |
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Concerns regarding the rates of delayed acute stent thrombosis are integral to any debate on the optimal duration of DAT. If there is an increased risk, our tipping point is changed and we need to respond. We previously conducted a meta-analysis of 14 trials comparing the outcomes of patients treated with sirolimus-eluting stents and BMS, and found no excess risk of stent thrombosis over 5 years (Figure 1).9 However, an increase in first-time stent thrombosis is observed with BMS during the first 18 months. This is a frequent finding in studies comparing BMS with DES. Does it mean that 4-week DAT following BMS is insufficient? Unfortunately, we do not know. Registry data have reported a steady occurrence of late stent thrombosis out to 3 years at
0.6% per annum, without evidence of a diminishing effect10 and suggested possible excess mortality with DES compared with BMS treatment.11 However, pooled analysis performed subsequent to the adoption of the uniform Academic Research Consortium (ARC) criteria12 reported no difference in rates.13 Furthermore, there is some evidence to suggest differences between DES platforms in the observed rates of late stent thrombosis, with a possible excess of events with the Taxus® (Boston Scientific Corp, Natick, MA, USA) platform compared with Cypher® (sirolimus-eluting stent, Cordis Corp, Miami, FL, USA) stents.14,15 Overall, the most reasonable conclusion is that the evidence for an increased rate of stent thrombosis with DES treatment is conflicting.
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Against this uncertain background, what light can we shed on the issue of the benefits of extending DAT beyond 6 months after DES? Airoldi et al.16 looked at the thrombosis rate with and without clopidogrel and found that within the first 30 days, the risk of stent thrombosis was significantly greater for patients who stopped clopidogrel (4.2%) than for patients who continued to receive it (0.9%). While this excess risk continued out to 180 days, discontinuation of clopidogrel therapy after 6 months did not predict the occurrence of stent thrombosis. This may be an indication that 6 months of therapy is sufficient, but at best it is a signal. On the other hand, an observational study from the Duke Heart Center, based on a landmark analysis of event-free patients, appeared to show that ongoing clopidogrel use beyond 6 and even 12 months continued to predict lower rates of death and myocardial infarction (MI).17
It is to be hoped that a definitive answer will be provided by the Intracoronary Stenting and Antithrombotic Regimen: Safety And eFficacy of a 6-month DAT after drug-Eluting stenting (ISAR-SAFE) trial. This randomized, multicentre, double-blind study is scheduled to recruit 6000 patients and will compare 6 and 12 months of clopidogrel therapy (Figure 2A). Patients receiving clopidogrel therapy 6 months after DES are eligible for inclusion; this is designated as time zero. The primary endpoint will be a composite of death, MI, stent thrombosis (definite or probable, according to ARC criteria), stroke, and major bleeding, and will be assessed at 9 months post-enrollment (i.e. 15 months after intervention). Exclusion criteria include left main stem stenting and prior history of stent thrombosis.
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The question of a so-called rebound effect is also of significant interest and the subject of a recent retrospective cohort study by Ho et al.18 focusing on outcomes following clopidogrel discontinuation in patients with ACS. The patients were divided into two groups: half received medical therapy and half had undergone PCI. The mean duration of clopidogrel therapy was 302 days in the medical group and 278 days in the PCI group. While the results were consistent across the subgroups, the number of events in the PCI patients (the group that is of interest to us) decreased as the time interval from stopping clopidogrel increased. It may be argued that this is not surprising, in that if a patient is deriving benefit from clopidogrel therapy, the most likely response to its discontinuation is the occurrence of events soon after stopping treatment rather than later. Nonetheless, the conclusion that there was a higher incidence of death and acute MI during the initial 90-day period after stopping clopidogrel may represent a significant finding. This indication, together with the results of prior physiological studies, lends some further weight to the possibility of a rebound phenomenon after thienopyridine discontinuation.
This is an issue that we aim to address further in the Intracoronary Stenting and Antithrombotic Regimen: REBOUND (ISAR-REBOUND) trial. This study was designed to investigate platelet function in two groups of patients: patients who stop clopidogrel therapy abruptly (as in conventional clinical practice) and patients who taper clopidogrel therapy at discontinuation (reducing it first to alternate-day dosing, then every 3 days, then every 4 days). The primary endpoint is platelet aggregation as determined by light aggregometry. The hypothesis under study is that the group with tapering will show less platelet aggregation after stopping clopidogrel.
In view of the importance of assessing whether an in vitro difference in platelet reactivity translates into a real effect on clinical events, its larger sister study, the Intracoronary Stenting and Antithrombotic Regimen: CAUTION in Discontinuing Clopidogrel Therapy (ISAR-CAUTION) study, plans to randomize 3000 patients in a double-blind fashion to tapering or abrupt cessation of thienopyridine therapy. The primary endpoint will be assessment 3 months after randomization of a composite of cardiac death, MI, stent thrombosis, stroke, major bleeding, or rehospitalization for ACS. The key inclusion criterion is a planned interruption of chronic clopidogrel therapy after DES implantation. It could be at 6, 12, or 24 months. The time when the physician decides to stop clopidogrel is the right time to enter the ISAR-CAUTION trial. The treatment scheme for the study is shown in Figure 2B. The duration of clopidogrel treatment is not known in advance because all patients are eligible at the time a decision is made to stop clopidogrel. Taken together, these two trials should provide enough evidence to confirm or refute the existence of a rebound phenomenon after cessation of clopidogrel therapy. Whether these results can be extrapolated to the treatment of patients with newer thienopyridines, in whom a suggestion of a similar rebound effect has already been reported,19 remains to be studied.
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Conclusions |
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There is clinical equipoise on the issue of optimal DAT treatment duration following PCI. What is really needed before more definitive changes to guideline recommendations can be made are the results from ongoing randomized controlled trials that are investigating this matter in a scientific manner.
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R.A.B. received grant support from the Irish Board for Training in Cardiovascular Medicine sponsored by A. Menarini Pharmaceuticals. Financial support provided by Daiichi Sankyo, Inc. and Eli Lilly and Company.
Conflict of interest: A.K. has received lecture fees from Bristol-Meyers Squibb, Cordis, Eli Lilly and Company, Medtronic and sanofi-aventis, LLC. R.A.B. declares no conflict of interest.
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