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Dual antiplatelet therapy plus cilostazol improves outcomes in certain patients

Jairia Dela Cruz
5 days ago

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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Most Read Articles
Roshini Claire Anthony, 11 Jun 2018

Patients who received a combination of ticagrelor plus aspirin within 24 hours of undergoing coronary artery bypass grafting (CABG) had significantly improved saphenous vein graft patency rates 1 year post-procedure compared with those who only received aspirin, according to findings of the DACAB* trial.

10 Jun 2018
Treatment with rituximab (RTX) is well tolerated and leads to stability or improvement in pulmonary function or severity of interstitial lung disease (ILD) on computed tomography (CT) in most patients, a recent study has shown.
10 Jun 2018
The dual-action antibody directed against epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), duligotuzumab, does not appear to provide survival advantage compared with cetuximab in patients with RAS exon 2/3 wild-type metastatic colorectal cancer treated with the FOLFIRI regimen, according to the results of a phase II trial.
Jairia Dela Cruz, 09 Jan 2017
The sulfonylurea glimepiride may pose an increased risk of hypoglycaemia in a subgroup of elderly type 2 diabetes (T2D) patients with lower β-cell function when added to a metformin regimen, according to a post-hoc analysis of data from the GENERATION* trial.