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Dual antiplatelet therapy plus cilostazol improves outcomes in certain patients

Jairia Dela Cruz
13 Jun 2018

Intensifying antiplatelet treatment with adjunctive cilostazol appears to be safe and effective for patients with low clopidogrel response, improving outcomes without increasing the risk of major bleeding, according to the results of the CREATIVE* trial.

“Although high post-treatment platelet reactivity is associated with increased adverse events, simply intensified P2Y12 inhibitor treatment [such as clopidogrel] might not improve clinical outcomes,” researchers said. “As a selective reversible phosphodiesterase type 3 inhibitor, cilostazol owns unique antithrombotic and vasodilatory properties, which contribute to the improvement of clinical outcomes.”

CREATIVE randomized 1,078 patients at high thrombotic risk and undergoing percutaneous coronary intervention (PCI) to receive either of the following antiplatelet therapies for 1 year: standard antiplatelet therapy (clopidogrel 75 mg daily plus aspirin 100 mg daily; STANDARD group), double-dose clopidogrel (clopidogrel 150 mg daily plus aspirin 100 mg daily; DOUBLE group) or dual antiplatelet therapy with adjunctive cilostazol (100 mg twice per day; TRIPLE group).

The primary outcome of major adverse cardiac and cerebrovascular events (MACCEs) at 18 months following PCI occurred in 52 patients (14.4 percent) in the STANDARD group, 38 (10.6 percent) in the DOUBLE group and 30 (8.5 percent) in the TRIPLE group. [Circulation 2018;137:2231-2245]

On Cox analysis, the TRIPLE strategy demonstrated superiority over standard DAPT (absolute difference, –5.9 percent; hazard ratio [HR], 0.550; 95 percent CI, 0.349–0.866), whereas no significant difference was observed between the DOUBLE and STANDARD treatment groups (absolute difference, –3.8 percent; HR, 0.720; 0.474–1.094).

Safety data revealed that the rates of major bleeding (Bleeding Academic Research Consortium grade ≥3) were similar across the TRIPLE, DOUBLE and STANDARD treatment groups (2.53 percent vs 3.34 percent vs 1.93 percent, respectively). 

Meanwhile, the rate of Bleeding Academic Research Consortium–defined minor bleeding in the DOUBLE group, but not in the TRIPLE group, was markedly increased than in the STANDARD group (27.4 percent with DOUBLE treatment and 23.6 percent with TRIPLE treatment vs 20.3 percent; p=0.031 and p=0.146, respectively).

“The present study, to our knowledge, is the first randomized trial to demonstrate that adjunctive cilostazol could improve the long-term clinical outcomes in in patients with low responsiveness to clopidogrel,” researchers said, adding that although the double-dosage clopidogrel strategy showed a trend of reduced MACCE rates, it did not yield significant improvement in clinical outcomes.

Multiple functions of cilostazol are believed to contribute to outcome improvements in the study population. As pointed out by researchers, cilostazol possesses unique antithrombotic and vasodilatory properties, as well as inhibits platelet aggregation induced by ADP, arachidonic acid, collagen and epinephrine.

“TRIPLE strategy could bring additive elevation of intracellular cAMP (cyclic adenosine monophosphate) through both [an] increase in cAMP production by clopidogrel and inhibition of cAMP degradation by cilostazol,” they explained.

Researchers acknowledged several study limitations, including the single-centre design, premature discontinuation of the study drug, which occurred more commonly in the DOUBLE and TRIPLE groups, and the inclusion of East Asian PCI patients only.

*Clopidogrel Response Evaluation and AnTi-platelet InterVEntion in High Thrombotic Risk PCI Patients

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