Randomized Comparisons of Double-Dose Clopidogrel or Adjunctive Cilostazol versus Standard Dual Anti-platelet in Patients with High Post-Treatment Platelet Reactivity: Results of the CREATIVE Trial (Clopidogrel Response Evaluation and AnTi-platelet InterVEntion in High Thrombotic Risk PCI Patients)
Background—Patients undergoing percutaneous coronary intervention (PCI) react differently to antiplatelet drugs. Those with low responsiveness to clopidogrel have a higher risk of cardiac ischemic events. The goal of this study is to conduct a head-to-head comparison of the safety and effectiveness of intensified antiplatelet therapies (either double-dose clopidogrel [DOUBLE] or adjunctive cilostazol [TRIPLE]) and conventional strategy (STANDARD) in post-PCI patients.
Methods—In this single-center, randomized, controlled trial, we used thromboelastography (TEG), a platelet function test, to select 1078 PCI patients at high thrombotic risk and compared the intensified antiplatelet therapies with standard antiplatelet therapy. The primary outcome was the incidence of major adverse cardiac and cerebrovascular events at 18 months post-PCI, defined as a composite of all-cause death, myocardial infarction, target vessel revascularization or stroke. Bleeding Academic Research Consortium (BARC) deﬁned bleeding complications (types 1, 2, 3, or 5) were the safety endpoints.
Results—The primary endpoint occurred in 52 patients (14.4%) in STANDARD group, 38 patients (10.6%) in DOUBLE group and 30 patients (8.5%) in TRIPLE group (HR: 0.720, 95%CI: 0.474-1.094, DOUBLE vs. STANDARD; HR: 0.550, 95%CI: 0.349-0.866, TRIPLE vs. STANDARD). No significant difference in the rates of major bleeding (BARC grade≥3) was found in DOUBLE group (3.34% vs. 1.93% in STANDARD, P=0.133) and TRIPLE group (2.53% vs 1.93% in STANDARD, P=0.240). The rate of BARC-defined minor bleeding increased in DOUBLE group (27.4% vs. 20.3% in STANDARD, P=0.031), but not in TRIPLE group (23.6% vs. 20.3% in STANDARD, P=0.146).
Conclusions—In patients with low responsiveness to clopidogrel, as measured by thromboelastography, the intensified antiplatelet strategies with adjunctive use of cilostazol significantly improved the clinical outcomes without increasing the risk of major bleeding. Decreased trend of negative outcomes could be observed in patients with double dosage of clopidogrel, but the difference was not significant.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov Unique Identifier: NCT01779401.
- Received August 19, 2017.
- Revision received January 9, 2018.
- Accepted January 17, 2018.