Elsevier

The Lancet

Volume 382, Issue 9892, 17–23 August 2013, Pages 614-623
The Lancet

Articles
Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study

https://doi.org/10.1016/S0140-6736(13)61170-8Get rights and content

Summary

Background

The relation between platelet reactivity and stent thrombosis, major bleeding, and other adverse events after coronary artery implantation of drug-eluting stents has been incompletely characterised. We aimed to determine the relation between platelet reactivity during dual therapy with aspirin and clopidogrel and clinical outcomes after successful coronary drug-eluting stent implantation.

Methods

ADAPT-DES was a prospective, multicentre registry of patients successfully treated with one or more drug-eluting stents and given aspirin and clopidogrel at 10–15 US and European hospitals. We assessed platelet reactivity in those patients after successful percutaneous coronary intervention using VerifyNow point-of-care assays, and assigned different cutoffs to define high platelet reactivity. The primary endpoint was definite or probable stent thrombosis; other endpoints were all-cause mortality, myocardial infarction, and clinically relevant bleeding. We did a propensity-adjusted multivariable analysis to determine the relation between platelet reactivity and subsequent adverse events. This study is registered with ClinicalTrials.gov, number NCT00638794.

Findings

Between Jan 7, 2008, and Sept 16, 2010, 8665 patients were prospectively enrolled at 11 sites, of which 8582 were eligible. At 1-year follow-up, stent thrombosis had occurred in 70 (0·8%) patients, myocardial infarction in 269 (3·1%), clinically relevant bleeding in 531 (6·2%), and death in 161 (1·9%) patients. High platelet reactivity on clopidogrel was strongly related to stent thrombosis (adjusted HR 2·49 [95% CI 1·43–4·31], p=0·001) and myocardial infarction (adjusted HR 1·42 [1·09–1·86], p=0·01), was inversely related to bleeding (adjusted HR 0·73 [0·61–0·89], p=0·002), but was not related to mortality (adjusted HR 1·20 [0·85–1·70], p=0·30). High platelet reactivity on aspirin was not significantly associated with stent thrombosis (adjusted HR 1·46 [0·58–3·64], p=0·42), myocardial infarction, or death, but was inversely related to bleeding (adjusted HR 0·65 [0·43–0·99], p=0·04).

Interpretation

The findings from this study emphasise the counter-balancing effects of haemorrhagic and ischaemic complications after stent implantation, and suggest that safer drugs or tailored strategies for the use of more potent agents must be developed if the benefits of greater platelet inhibition in patients with cardiovascular disease are to be realised.

Funding

Boston Scientific, Abbott Vascular, Medtronic, Cordis, Biosensors, The Medicines Company, Daiichi-Sankyo, Eli Lilly, Volcano, and Accumetrics

Introduction

The occurrence of stent thrombosis after coronary artery implantation of drug-eluting stents is associated with high rates of myocardial infarction and death.1 Dual anti-platelet therapy with aspirin and an adenosine diphosphate (ADP)-receptor inhibitor is presently recommended for at least 1 year after drug-eluting stent implantation since most episodes of stent thrombosis occur within this period.2 Aspirin inhibits cyclo-oxygenase-1, a key enzyme involved in the conversion of arachidonic acid to thromboxane A2, an important agonist that amplifies platelet aggregation. Clopidogrel, the most widely used ADP-receptor inhibitor, undergoes a two-step metabolic transformation before binding to the platelet P2Y12 ADP receptor.3 The conversion of clopidogrel to its active metabolite is regulated by the CYP450 system, and the presence of genetic polymorphisms partly determines the extent to which clopidogrel inhibits ADP-induced platelet activation.4, 5 Results from pharmacodynamic studies in patients treated with clopidogrel have shown wide variability in platelet responsiveness, and high platelet reactivity on clopidogrel has been linked to stent thrombosis and adverse cardiovascular events after stenting.5, 6, 7, 8, 9, 10, 11, 12 Variability in platelet responsiveness to aspirin has also been described, although its association with cardiac events and stent thrombosis is less clear.13, 14, 15, 16

Previous studies examining the relation between platelet reactivity and stent thrombosis have been limited in size, and have often enrolled a stable, elective population in whom event rates were low.17 Additionally, the effect of platelet reactivity on major bleeding, the occurrence of which has been associated with mortality, has been incompletely characterised, with previous studies reporting conflicting results.6, 17, 18, 19 We therefore undertook a large-scale, prospective, multicentre registry study designed to determine the relation between platelet reactivity during dual therapy with aspirin and clopidogrel and subsequent adverse events after successful coronary drug-eluting stent implantation.

Section snippets

Study design and patients

ADAPT-DES was a prospective, multicentre registry specifically designed to determine the relation between platelet reactivity and subsequent clinical events in patients with coronary artery disease treated with aspirin and clopidogrel after successful drug-eluting stent implantation. We planned to enrol 11 000 patients at 10–15 US and European hospitals. Consecutive patients at every centre successfully treated with one or more drug-eluting stents approved by the US Food and Drug Administration

Results

Between Jan 7, 2008, and Sept 16, 2010, 8665 patients in whom drug-eluting stents were successfully implanted were prospectively enrolled at 11 hospitals in the USA and Germany (enrolment was terminated before the planned 11 000 patient target for financial constraints; appendix). 82 (0·9%) patients were excluded because platelet function testing was done before the protocol-required glycoprotein IIb/IIIa inhibitor washout period. Thus, the final study population consisted of 8582 patients (

Discussion

The principal findings from the present prospective, multicentre study, the largest investigation so far examining the relation between platelet reactivity and ischaemic and haemorrhagic complications after coronary drug-eluting stent implantation, are: (1) high platelet reactivity on clopidogrel was an independent predictor of 1-year stent thrombosis and myocardial infarction after drug-eluting stent placement, but was also protective against clinically relevant bleeding; (2) ischaemic and

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The names of the investigators, institutions, and research organisations participating in the Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents (ADAPT-DES) study appear in the appendix

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