Triple antiplatelet therapy with aspirin, clopidogrel, and cilostazol lowers platelet aggregation more than standard dual therapy or even a high maintenance dose of clopidogrel in patients receiving drug-eluting stents (DES) for acute myocardial infarction (AMI), according to a study appearing online January 26, 2010, ahead of print in Circulation: Cardiovascular Interventions.

Adding cilostazol to dual antiplatelet therapy may protect against CV events, especially in patient populations more likely to carry genetic alleles that cause poor response to clopidogrel, added the study authors.

Researchers led by Jin-Yong Hwang, MD, PhD, of Gyeongsang National University Hospital (Jinju, South Korea), randomized 90 AMI patients who had received DES to 3 different antiplatelet regimens—all of which included aspirin—for 30 days:

• Standard dual therapy (clopidogrel 75 mg daily)
• High-maintenance dose (clopidogrel 150 mg daily)
• Triple therapy (clopidogrel 75 mg daily plus cilostazol 100 mg twice daily)

At 30 days, there was more inhibition of maximal platelet aggregation as assessed by light transmittance aggregometry (LTA; the primary endpoint) in patients receiving triple therapy vs. each of the other 2 groups. This was also true for percentage platelet inhibition as measured by the VerifyNow P2Y12 assay (table 1).

Table 1. Platelet Inhibition at 30 Days

^a P < 0.001 for triple vs. standard therapy and triple therapy vs. high maintenance dose.

^b P < 0.001 for triple vs. standard therapy; P = 0.034 for triple therapy vs. high maintenance dose.

Other measures of platelet reactivity, such as late aggregation and P2Y12 reaction units were also improved in the triple therapy group, although the difference between the triple therapy and high-maintenance groups was not significant for reaction units (table 2).

Table 2. Platelet Reactivity at 30 Days

^a P < 0.001 for triple vs. standard therapy; P = 0.001 for triple therapy vs. high maintenance dose.
^b P < 0.001 for triple vs. standard therapy; P = 0.085 for triple therapy vs. high maintenance dose.

Fewer patients had high post-clopidogrel platelet reactivity (20 μM ADP-induced maximal aggregation > 50%) in the triple-therapy group (13.3%) compared with the standard therapy (76.7%) and high maintenance dose groups (56.7%; P < 0.001) at 30 days.

All of the regimens were generally well tolerated, and there were no major CV or bleeding events in any group at 30-day follow-up. The incidence of minor bleeding was low and equivalent between the groups: 3% in the standard therapy group, 0% in the high maintenance dose group, and 3% in the triple therapy group (P = 1.000).

Achieving Balance

According to Dr. Hwang and colleagues, “this study showed that triple antiplatelet therapy may result in greater ADP-induced platelet inhibition than a high-[maintenance dose of] clopidogrel of 150 mg daily in patients with AMI. If triple antiplatelet therapy achieves the optimal balance between adequate platelet inhibition and acceptable adverse effect rates, it could be a welcome option for patients with AMI.”

Study coauthor Young-Hoon Jeong, MD, PhD, also of Gyeongsang National University Hospital, added that cilostazol’s unique method of action makes it a good complementary therapy with clopidogrel. “Cilostazol acts by selective dual inhibition of phosphodiesterase type 3 and adenosine uptake. Unlike other antiplatelet agents, cilostazol not only inhibits platelet aggregation but also has beneficial effects on ischemia-reperfusion injury, inflammatory and oxidative stress, endothelial dysfunction, and control of neointmal hyperplasia,” he said in an e-mail communication with TCTMD. “Although large-scale studies are needed, adjunctive cilostazol with dual antiplatelet therapy conceptually can be a more ideal therapy compared with other intensified antiplatelet therapies.”

Clinical Confirmation Needed

In a telephone interview with TCTMD, Neal S. Kleiman, MD, of the Methodist DeBakey Heart and Vascular Center (Houston, TX), cautioned that the study results should not be overinterpreted. “Their point is if you add cilostazol to clopidogrel, you get more inhibition of platelet activity than you would with just high dose clopidogrel,” Dr. Kleiman said. “There is good reason to think that this might mean something clinically, particularly in high-risk patients, such as those with long or multiple stents, lots of thrombus, or poor results after stenting, but we don’t know yet. This looks great in vitro, but we need to see this proven clinically.”

Dr. Jeong indicated that in South Korea, cilostazol is often used as adjunctive therapy in high-risk PCI patients. While it is not used as frequently in the United States, Dr. Kleiman noted that the drug is still being used. “I’ve used cilostazol probably a handful of times, maybe 10 or so,” he said, all with good results. “I would bet that US clinicians are using it from time to time.” In the United States, cilostazol is approved for the symptomatic relief of peripheral arterial disease.

It’s in the Genes?

According to Dr. Jeong, cilostazol may be particularly useful in patients who are more likely to carry the mutant CYP2C19 allele that predisposes to worse response to clopidogrel. In the paper, the study authors note that East Asians are more likely than whites to carry this genetic polymorphism (roughly 60% vs. 30%). Because cilostazol is activated by different enzymes from clopidogrel, “its effect may be consistent irrespective of the carriage of CYP2C19 mutant allele,” Dr. Jeong said.

Dr. Kleiman, though, was more skeptical. “Everyone likes to raise the question of genetic differences,” he said. “I think we make more out of that than we should. More Asians have the polymorphism, but the rate is not dramatically higher.”

Juggling Antiplatelets

A more important question, according to Drs. Jeong and Kleiman, is how to potentially decide between using cilostazol and the newer antiplatelet agents prasugrel and ticagrelor.

“Although prasugrel is not currently available in Korea, the degree of platelet inhibition by prasugrel is somewhat higher, in my opinion, compared with adjunctive cilostazol,” Dr. Jeong said. “However, we must not neglect the beneficial role of the pleiotropic effects of cilostazol. Also, atherothrombosis originates from multiple causes. Using only platelet inhibition [with prasugrel] cannot guarantee better outcomes.”

Dr. Kleiman was more pragmatic. “Number one is bleeding,” he said. “It doesn’t look like there’s a significant increase in bleeding with cilostazol, so if you’re worried about bleeding with prasugrel or the short half-life of ticagrelor, adjunctive cilostazol might be an option. But in the absence of any clinical data, it’s tough to say.”

Disclosures:

• The study was partly supported by grants from the Research Foundation of Gyeongsang National University Hospital.
• Dr. Jeong reports receiving lecture honoraria from Sanofi-Aventis, Daiichi Sankyo, and Otsuka.
• Dr. Kleiman reports receiving research grants from Sanofi-Aventis and Eli Lilly.

Related Stories:

• Trials DECLARE Benefits of Cilostazol Persist Long Term
• Study Suggests That Cilostazol Reduces Restenosis After Carotid Stenting
• Triple Antiplatelet Therapy with Cilostazol Reduces Death After Primary PCI