RE-CLOSE: Low Responsiveness to Clopidogrel and Sirolimus- or Paclitaxel-Eluting Stent Thrombosis

Luis Gruberg, MD, FACC


Medscape Cardiology 

These findings raise some intriguing questions: Should we screen all patients for platelet reactivity? Should platelet-resistant patients be placed on a higher dose of clopidogrel or a different medication altogether?

Presenter: David Antoniucci, MD (Careggi Hospital, Florence, Italy), on Behalf of the RE-CLOSE Investigators

Dual antiplatelet therapy with aspirin and clopidogrel is the standard treatment for patients who undergo percutaneous coronary intervention with stent placement. Previous studies have shown that patients who undergo vascular brachytherapy or are treated with drug-eluting stents are at an increased risk for late-stent thrombosis, which subsequently led to the requirement for prolonged use of dual antiplatelet therapy in these patients.

Stent thrombosis, however, also can occur in patients treated with aspirin and clopidogrel, suggesting that platelet aggregation nonresponsiveness to clopidogrel could be the cause. Previous studies that have tried to show this association were retrospective and/or underpowered. The Low Responsiveness to Clopidogrel and Sirolimus- or Paclitaxel-Eluting Stent Thrombosis (RE-CLOSE) trial analyzed platelet reactivity in patients treated with drug-eluting stents.

Study Design

Secondary endpoint: Composite of cardiac mortality and definite or probable stent thrombosis.

Consecutive patients treated with a drug-eluting stent were assessed prospectively for platelet reactivity. All patients were treated with clopidogrel for 6 months. Blood samples for platelet reactivity assessment were obtained 12-18 hours from clopidogrel loading with 600 mg. Platelet-rich plasma was stimulated with 10 micromoles (mcmol) of adenosine diphosphate (ADP), and aggregation was assessed with light transmission aggregometry. Patients with platelet aggregation by 10 mcmol ADP ≥ 90th percentile of controls were defined as nonresponders.


A total of 804 patients were included in the study, of which 699 were responders and 105 were classified as nonresponders. Nonresponders tended to be older, had a higher incidence of diabetes and unstable angina, and had a significantly lower ejection fraction compared with patients who were classified as responders ( Table 1 ).

There were also differences in baseline procedural characteristics. Nonresponders had a lower incidence of thrombotic lesions and generally had significantly longer lesions than responders ( Table 2 ).

At 6-month follow-up, the overall rate of definite and/or probable stent thrombosis was 3.1% and was significantly higher in the nonresponder group vs the responder group (2.3% vs 8.6%, P < .001). The majority of cases presented as late stent thrombosis (Figure 1). Nonresponders also had a significantly higher rate of cardiac death, as well as the composite of cardiac death and stent thrombosis than responders (Figure 2).

Figure 1.

RE-CLOSE: timing of stent thrombosis.

Figure 2.

RE-CLOSE: cardiac mortality with and without stent thrombosis (secondary endpoints).

Cox predictors of stent thrombosis included nonresponsiveness to clopidogrel acute myocardial infarction, total stent length, and ejection fraction per 1% increase ( Table 3 ).


  1. Nonresponsiveness to clopidogrel is a strong, independent predictor of stent thrombosis in patients treated with drug-eluting stents.

  2. Alternative revascularization strategies or pharmacologic strategies with an increasing dose of clopidogrel or other antiplatelet agents should be considered to reduce the risk for ischemic events.


The results of the RE-CLOSE trial suggest that a substantial percentage of patients treated with stents have some type of nonresponsiveness (resistance) to clopidogrel. Patients who were prospectively classified as nonresponders were found to be at a 3-fold increased risk of developing subacute and late stent thrombosis.

Obviously, this finding raises some intriguing questions: Should we screen all patients for platelet reactivity? Should nonresponders be placed on a higher dose of clopidogrel or on a different medication altogether? The final results of this trial will enable us to understand the complex interaction between resistance to platelet aggregation and stent thrombosis.


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