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In patients implanted with long zotarolimus-eluting stents, triple antiplatelet therapy including cilostazol safely reduces 8-month late loss and restenosis compared with standard dual antiplatelet therapy. This benefit translates into less ischemia-driven revascularization at 1 year, according to a study published in the March 15, 2011, issue of the Journal of the American College of Cardiology.

The findings were first presented in September 2010 at the annual Transcatheter Cardiovascular Therapeutics symposium in Washington, DC.

For the DECLARE-LONG (Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients with Long Coronary Lesions) II trial, investigators led by Seong-Wook Park, MD, of Asan Medical Center (Seoul, South Korea), randomized 499 patients who underwent PCI of long coronary lesions (≥ 25 mm) at 10 South Korean centers to aspirin and clopidogrel with or without cilostazol (triple therapy, n = 250; dual therapy, n = 249). All patients received zotarolimus-eluting Endeavor stents (Medtronic Vascular, Santa Rosa, CA) measuring at least 30 mm.

Previous studies have suggested that the antiplatelet agent cilostazol, a phosphodiesterase III inhibitor, has antiproliferative properties, reducing intimal hyperplasia and restenosis.

Clear Impact on Late Loss

At 8 months, quantitative coronary angiography (performed in about 85% of both groups) showed reduced in-stent late loss, the primary endpoint, as well as reduced in-segment late loss with triple therapy. Both in-stent and in-segment binary restenosis rates also were lower with the addition of cilostazol (table 1).

Table 1. Quantitative Angiographic Outcomes at 8 Months

IVUS analysis of 122 patients (65 on triple therapy, 57 on dual therapy) at 8 months confirmed the angiographic benefit of triple therapy. For example, percent intimal hyperplasia volume was lower with cilostazol (22.1 ± 9.9% vs. 27.1 ± 13.2% for dual therapy; P = 0.017).

At 12-month follow-up, there were no differences in rates of death, MI, or Academic Research Consortium-defined stent thrombosis between the groups. However, ischemia-driven TLR and TVR were nearly halved in the triple therapy arm. The incidence of MACE (death, MI, and ischemia-driven TLR) also trended in favor of triple therapy, although the difference was driven almost entirely by reduced repeat revascularization (table 2).

Table 2. Clinical Outcomes at 1 Year

With regard to safety, there was no difference between the 2 groups in rates of TIMI major (2.4% vs. 0.8%; P = 0.16), minor (0.4% vs. 0.4%; P = 0.99), or minimal (4.4% vs. 5.6%; P = 0.53) bleeding. On the other hand, headache was more common in patients receiving triple therapy (4.4% vs. 0.8%; P = 0.01), who also were more likely to stop taking the study drug (18.8% vs. 12.2%; P = 0.02), primarily because of headache, skin rash, or gastrointestinal problems.

Even with DES implantation, restenosis remains a significant clinical problem in patients with complex lesions, and these and previous findings suggest that cilostazol would be a valuable option in such patients, the authors write.

Data Ethnically Limited

Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), agreed that the study results are “consistent with older datasets that suggested there might be an effect of cilostazol on restenosis.” But in a telephone interview with TCTMD, he pointed out that “there are also other studies that have been contradictory, and suggested instead an effect on stent thrombosis.

“The problem is that all these studies have been pretty small and have not been geographically or ethnically diverse,” he commented. “If you only study one ethnic group, you never know if their particular genotype or other factors are the reason why the drug works. And of course when the studies are small, there’s always the risk that the findings can’t be duplicated. For both those reasons, we need a large multicenter study to figure out what cilostazol adds to contemporary intervention.”

One hitch is that cilostazol is off patent and thus there is little financial incentive to invest in a major trial, he added.

Mandated Angiography Raises Doubts

Dr. Bhatt also pointed to another important study limitation. “We don’t know if the protocol-mandated angiography drove some of the subsequent TVR procedures,” he said. “If there were no protocol-mandated angiograms or surrogate endpoints like late loss and restenosis, I’d feel a lot more confident that the reduction in TVR really is a clinically important effect.”

Cilostazol faces other drawbacks. In addition to “a pretty significant rate of discontinuation because of side effects,” the drug is contraindicated in patients with heart failure, Dr. Bhatt noted. “That’s a bit of an issue because patients with bad CAD may also have left ventricular dysfunction.”

Although there are “tantalizing” signals regarding cilostazol’s effect on both restenosis and stent thrombosis, American physicians remain fairly skeptical about the data thus far, Dr. Bhatt reported, largely because they are limited to East Asian populations.

In the meantime, he said, it would not be unreasonable to try cilostazol in patients implanted with DES who experience repeated symptomatic restenosis, and it would be useful to have an oral antirestenotic agent available for cases where BMS are preferred.

However, the evidence for wider use is not there yet, Dr. Bhatt concluded, stressing that the current trial should be viewed more as “hypothesis-generating than definitive.”

Study Details

All patients received aspirin (200-mg loading dose followed by 200 mg daily indefinitely) and clopidogrel (300-mg loading dose followed by 75 mg daily for ≥ 12 months). The dosage of cilostazol/placebo was: 200-mg loading dose in 2 tablets, and 100 mg twice daily for 8 months.

The 2 groups had similar anatomic and procedural characteristics.

 

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Source:
Lee S-W, Park S-W, Kim Y-H, et al. A randomized, double-blind, multicenter comparison study of triple antiplatelet therapy with dual antiplatelet therapy to reduce restenosis after drug-eluting stent implantation in long coronary lesions: Results from the DECLARE-LONG II (Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients with Long Coronary Lesions) trial. J Am Coll Cardiol. 2011;57:1264-1270.

 

 

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