Adjunctive Cilostazol Noninferior to Double-Dose Clopidogrel in All-Comer PCI Trial

CHICAGO, IL—The addition of cilostazol to standard dual antiplatelet therapy in patients receiving a drug-eluting stent (DES) is noninferior to doubling the dose of clopidogrel, according to 30-day results of the HOST-ASSURE trial presented March 25, 2012, at the annual American College of Cardiology/i2 Scientific Session.

Hyo-Soo Kim, MD, PhD, of Seoul National University Hospital (Seoul, South Korea), presented data from the trial, which randomly assigned patients to triple therapy with clopidogrel, aspirin and cilostazol (n = 1,879) or standard dual antiplatelet therapy (n = 1,876). Patients in both groups received 300 to 600 mg of clopidogrel plus 300 mg of aspirin before angioplasty. The triple therapy group also received a loading dose of 200 mg of cilostazol and then 100 mg of cilostazol twice daily added to dual antiplatelet therapy for 30 days after the procedure.

Triple Noninferiority

DES used in the study were the everolimus-eluting Promus Element (Boston Scientific, Natick, MA) and the zotarolimus-eluting Endeavor Resolute (Medtronic, Santa Rosa, CA) stents.

At 30 days, the cumulative incidence of the primary endpoint (a composite of cardiac death, nonfatal MI, definite or probable stent thrombosis, stroke and PLATO major bleeding) was 1.4% in the dual therapy group and 1.2% in the triple therapy group (P for noninferiority < 0.001).

In a landmark analysis of each individual component of the primary endpoint, there again was no difference between the 2 regimens. There also was no difference for any of the secondary clinical outcomes, including cardiac death, nonfatal MI, stroke, and major bleeding.

In a per-protocol analysis, a difference was observed in the incidence of spontaneous MI favoring the triple therapy group over the dual therapy group (0% vs. 0.3%; P = 0.021). However, for the primary endpoint, there was no difference for triple vs. double therapy (1.2% vs. 1.6%; P = 0.287).

Furthermore, in subgroup analysis no specific subgroup could be identified in which triple therapy or dual therapy was favored.

On-clopidogrel platelet reactivity analysis was performed in one-third of the patients 12 to 24 hours after the loading dose and at 30 days after initiation of maintenance therapy. At both time points, P2Y12 reaction units were significantly lower in the triple therapy group compared with the dual therapy group (table 1).

Table 1. P2Y12 Reaction Units

Dr. Kim noted that event rates were lower than expected, leading to the possibility that the study was underpowered. The expected rate of the primary endpoint based on previous studies was 3%. In addition, cardiac enzyme measurement was not mandated in the study protocol.

Panel co-chair George D. Dangas, MD, PhD, of Mount Sinai Medical Center (New York, NY), asked whether Dr. Kim’s group would consider performing genotyping since the high rate of resistance to clopidogrel in the Asian population may affect how the study is generalized to patients in the United States.

Cilostazol New to the West

Dr. Kim agreed that it will be important to replicate the results of triple therapy with cilostazol in other populations and that genotyping may be important.

Cilostazol is not familiar to many Western physicians because it was developed by a Japanese company that has neither marketed the agent widely outside Asia nor sponsored a large clinical trial of the drug. Dr. Kim said most clinical evidence supporting cilostazol’s benefit comes from investigator-initiated trials.

Panelist Philippe Gabriel Steg, MD, of Hopital Bichat-Claude Bernad (Paris, France), congratulated Dr. Kim on a carefully performed and important study, but added that it is not comparable to other studies of double-dose clopidogrel such as CURRENT-OASIS 7 because in that study, a double loading dose was mandated and the dual dose was only given for 1 week, as opposed to the 30 days in HOST-ASSURE. Dr. Steg explained that the reason for limiting the double dose to a week is that most of the benefit is seen upfront.

Dr. Kim said long-term follow up is planned as well as more detailed information on the stent groups.

Sources:

1. Kim H-S. Adjunctive cilostazol versus double dose clopidogrel after PCI with drug eluting stent: The HOST-ASSURE randomized trial. Presented at: American College of Cardiology Annual Scientific Session; March 25, 2012; Chicago, IL.
2. CURRENT-OASIS 7 investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010;363:930-942.

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