Author + information
- Laurent Bonello, MD, PhD∗ (, )
- Françoise Dignat-George, PhD and
- Marc Laine, MD
- ↵∗MARS Cardio Cardiology Department, Hopital Universitaire Nord, Chemin des Bourrely, 13015 Marseille, France
We read with great interest the RECLOSE 3 (REsponsiveness to CLOpidogrel and Stent Thrombosis 3) study reported by Valenti et al. (1) in which the authors investigated the clinical efficacy of prasugrel in clopidogrel nonresponders undergoing percutaneous coronary intervention (PCI) with drug-eluting stents. As stated by the authors, clopidogrel nonresponse or high on-treatment platelet reactivity (HTPR) after a clopidogrel loading dose has been identified as a major risk factor for recurrent ischemic events in acute coronary syndrome patients undergoing PCI. It is associated with an increased risk of cardiovascular (CV) death, myocardial infarction, and stent thrombosis (2). Consistent with the results of this study, a meta-analysis by Aradi et al. (3) suggested that HTPR was associated with a 3.35-fold increase in CV mortality. This issue is very relevant because a large majority of patients undergoing PCI are currently treated with clopidogrel despite its limitations.
However, the RECLOSE 3 trial has methodological limitations that distort its conclusion. First, as stated by the authors, it is a historical cohort comparison with the RECLOSE 2 (REsponsiveness to CLOpidogrel and Stent Thrombosis 2) trial, which represents the “control” group of clopidogrel nonresponders. However, the RECLOSE 2 trial was already an interventional trial in which clopidogrel nonresponders had an increase in their clopidogrel maintenance dose in order to reach a platelet reactivity (PR) <70% on an adenosine diphosphate test. This group of patients therefore cannot represent a valid clopidogrel nonresponders group. Second, the RECLOSE 3 trial population, unlike that of the RECLOSE 2 trial, included stable patients who are at low risk of events and in whom HTPR has limited prognosis implications (4). This could skew the results despite adjustments, and they should have been excluded from the analysis.
Third, in the present study, there are 2 limitations to the antiplatelet therapy protocol proposed. First, no prasugrel loading dose was used. It is well demonstrated that most events related to HTPR are early events, including periprocedural events, and therefore a prasugrel loading dose should have been used to optimize PR inhibition (3). In addition, the duration of dual antiplatelet therapy is not provided. After publication of the DAPT trial, it could be postulated that a difference in the duration of dual antiplatelet therapy between the 2 groups may have contributed to the observed difference in outcome (5).
Another major limitation lies in the fact that bleeding events were not reported. In fact, prasugrel is associated with a significant increase in major bleeding events in ACS patients undergoing PCI, which could offset its potential benefit on ischemic events. Balancing ischemic and bleeding events is critical to improve outcomes in patients undergoing PCI.
Finally, several studies have investigated the potential of PR monitoring in order to improve the outcome in patients with HTPR undergoing PCI. However, although small studies had promising results, large-scale randomized trials failed to show any difference in outcome. An adequately designed and powered trial is still warranted to provide a safe and efficient alternative to clopidogrel in patients with HTPR. Selection of patients and of the intervention to overcome HTPR will be critical in this lasting odyssey.
Please note: Dr. Bonello has received honoraria from AstraZeneca and Eli Lilly and research grants from AstraZeneca. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Valenti R.,
- Marcucci R.,
- Comito V.,
- et al.
- Tantry U.S.,
- Bonello L.,
- Aradi D.,
- et al.,
- Working Group on On-Treatment Platelet Reactivity