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The drug cilostazol may be a valuable addition to standard dual antiplatelet therapy, resulting in reduced restenosis in high-risk patients undergoing drug-eluting stent (DES) implantation, particularly with sirolimus-eluting devices, according to a new report published online July 23, 2013, ahead of print in the American Journal of Cardiology.

To assess the efficacy of add-on cilostazol with various DES types in patients with diabetes or long coronary lesions, Seung-Whan Lee, MD, PhD, of Asan Medical Center (Seoul, South Korea), and colleagues pooled data from 3 prospective, randomized trials:

• DECLARE-DIABETES
• DECLARE-LONG I
• DECLARE-LONG II

A total of 1,399 patients underwent implantation with a sirolimus-eluting stent (SES; n = 450), a paclitaxel-eluting stent (PES; n = 450), or a zotarolimus-eluting stent (ZES; n = 499). Seven hundred patients received triple antiplatelet therapy (aspirin, clopidogrel, and cilostazol), while 669 received dual antiplatelet therapy (aspirin and clopidogrel).

Follow up angiography was mandatory at 6 months in DECLARE-DIABETES and DECLARE-LONG I, and at 8 months or earlier in DECLARE-LONG II as indicated by clinical symptoms or evidence of myocardial ischemia.

Triple Therapy Outperforms

Overall, patients on the triple antiplatelet regimen had significantly lower in-segment and in-stent late loss and restenosis at follow up, regardless of stent type (table 1).

Table 1. Angiographic Outcomes

Triple therapy also resulted in decreased in-segment and in-stent late loss for each type of DES used. Specifically, researchers reported absolute reductions of in-segment late loss of 0.13 mm with SES (P < 0.001) and 0.15 mm with ZES (P = 0.006) and PES (P = 0.010). Similar decreases were also seen for in-stent late loss, with absolute reductions of 0.13 mm (P = 0.002), 0.11 mm (P = 0.045), and 0.11 mm (P = 0.062), respectively.

The SES and the ZES groups experienced significantly lower rates of in-segment restenosis with triple therapy than dual therapy. No such effect was seen with PES (table 2).

Table 2. In-Segment Restenosis by Stent Type

Similarly, the frequency of in-stent restenosis with triple therapy was lower in the SES and ZES groups but not the PES group.

Logistic regression analysis showed a significant interaction between stent type and antiplatelet therapy in both in-segment and in-stent restenosis (P = 0.004). Post hoc bootstrap resampling indicated that the combination of SES and triple therapy resulted in the greatest relative risk reduction for in-segment restenosis compared with ZES (P = 0.001) and PES (P < 0.001).

Investigators did not observe an interaction between antiplatelet therapy and stent type for any clinical outcomes at 1 year, including death, MI, ischemia-driven TLR or TVR, stent thrombosis, major adverse cardiac events or major bleeding.

Clinical Implications

In an e-mail correspondence with TCTMD, Dr. Lee said that despite the proven efficacy of bypass surgery in patients with multivessel disease, diabetes, and higher Syntax scores, improved efficacy and safety profiles of newer generation DES have allowed physicians to easily favor PCI for complex lesions.  

While newer generation DES have excellent restenosis rates and safety profiles compared to early-generation devices, “restenosis is still a major drawback,” said Dr. Lee. “As the complexity of lesion[s] increase, [the] restenosis rate also increase[s].”

However, many clinical trials show that newer generation DES have similar efficacy as SES in terms of late loss, restenosis, and clinical outcomes of up to 1 year, said Dr. Lee. Using add-on cilostazol might help improve DES efficacy even with newer generation devices, he said. 

The SES is a potent reducer of neointimal hyperplasia, added Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), in an e-mail correspondence. However, “in my mind, it’s uncertain whether the differential effect of cilostazol among patients treated with SES was due to play of chance—there were very low rates of restenosis overall in that arm—or actual truth,” he noted.

Overall, the study demonstrates a modest additive effect of cilostazol in further decreasing angiographic late loss when added to early generation DES, Dr. Kirtane observed. The incremental late loss reduction was approximately 0.10 mm, “but whether these effects translate into meaningful reductions in clinical target lesion revascularization are unknown, particularly given the frequency of routine angiographic follow-up in the included trials,” he said.

Additionally, the role of cilostazol with newer-generation DES is difficult to predict, but the agent might be recommended for cases of DES in-stent restenosis, Dr. Kirtane said, adding “I don't see many clinicians wanting to use this regimen up front, even given these data.”

Cilostazol: Lost in Translation

Most clinical trials of cilostazol, with the exception of CREST (Carotid Revascularization Endarterectomy versus Stenting Trial) have been conducted in Korea, Japan and China, noted Dr. Lee. Although cilostazol is not popular the United States, the Asian experience suggests it “may be beneficial beyond [its] antirestenostic effects,” he said. 

But cilostazol is mainly unpopular in the United States because adding yet another agent to an already complex drug regimen in PCI patients, which typically would include aspirin, a P2Y12 antagonist, beta-blocker, statin, and possibly other agents such as ACE inhibitors, is difficult, Dr. Kirtane explained. Furthermore, there remain concerns about potentially increased bleeding complications associated with the drug, he added.

Source:

Lee S-W, Ahn J-M, Han S et al.  Differential impact of cilostazol on restenosis according to implanted stent type (from a pooled analysis of three DECLARE randomized trials). Am J Cardiol. 2013;Epub ahead of print. 

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