Cilostazol as Safe as Double-Dose Clopidogrel in Patients Undergoing PCI with DES

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Adjunctive cilostazol is noninferior to double-dose clopidogrel in patients undergoing percutaneous coronary intervention (PCI), according to a study published in the September 1, 2013, issue of JACC: Cardiovascular Interventions.

For the HOST-ASSURE (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Safety & Effectiveness for Drug-Eluting Stents & Antiplatelet Regimen) trial, Hyo-Soo Kim, MD, PhD, of Seoul National University Hospital (Seoul, South Korea), and colleagues randomized 3,755 patients slated for PCI with DES to antiplatelet therapy with cilostazol (Otsuka Pharmaceuticals, Seoul, South Korea; n = 1,879) or double-dose clopidogrel (600 mg, n = 1,876). Procedures were conducted at 40 South Korean sites from June 2010 to November 2011.

Patients in both groups received 300 mg 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.

Data were previously presented in March 2012 at the annual American College of Cardiology/i2 Scientific Session in Chicago, IL.

Noninferiority Proven

At 1-month follow-up, cilostazol showed noninferiority to double-dose clopidogrel with regard to the primary endpoint of net clinical outcome—the combination of cardiac death, nonfatal MI, stent thrombosis, stroke, and PLATO major bleeding (P for noninferiority = 0.005; table 1).

Table 1. Clinical Outcomes at 1 Month

 

Triple Therapy
(n = 1,879)

Dual Therapy
(n = 1,876)

HR (95% CI)

P Value

Net Clinical Outcome

1.2%

1.4%

0.85 (0.49-1.48)

0.566

Cardiac Death

0.4%

0.4%

1.14 (0.41-3.15)

0.798

Nonfatal MI

0.4%

0.7%

0.54 (0.21-1.35)

0.185

Stroke

0.1%

0.2%

0.67 (0.11-3.99)

0.656

Definite/Probable Stent Thrombosis

0.2%

0.4%

0.57 (0.17-1.95)

0.371

PLATO Major Bleeding

0.4%

0.4%

1.00 (0.38-2.66)

0.999

 
There were also no differences in PLATO minor bleeding, TLR, and TVR between the treatment groups. Results were also confirmed in subgroup analyses and a 1-week landmark analysis.

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 between triple and dual therapy (1.2% vs. 1.6%; P = 0.002 for noninferiority; HR 0.73; 95% CI 0.42-1.30).

Platelet reactivity was measured using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) in a subgroup of 1,356 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 lower in the triple therapy group compared with the dual therapy group (table 2).

Table 2. P2Y12 Reaction Units

Time After Loading Dose

Triple Therapy
(n = 1,879)

Dual Therapy
(n = 1,876)

P Value

12-24 Hours

173 ± 97

214 ± 93

< 0.001

30 Days

169 ± 80

192 ± 80

< 0.001

 
‘Maybe’ Applicable to United States

“This study was performed to generate evidence of a rationale for using [triple antiplatelet therapy] in high-risk situations as is done by many Asian physicians,” Dr. Kim and colleagues write.

While the study was “underpowered to concretely prove that [triple antiplatelet therapy] is noninferior to [dual therapy],” they acknowledge, “the adjunctive use of cilostazol in addition to conventional dual antiplatelet therapy showed comparable rates of clinical outcome and seems to be noninferior to doubling the maintenance dose of clopidogrel in this broad PCI population receiving exclusively drug-eluting stents with regard to net clinical outcome at 1 month.”

In a telephone interview with TCTMD, Gary L. Schaer, MD, of Rush University Medical School (Chicago, IL), said that while he is aware of the potent antiplatelet qualities of cilostazol, he has mainly seen it used in patients with claudication to improve walking distance. “I don’t think [cilostazol is commonly used] in the United States in the setting of PCI, but . . . the concept that it might have some benefits in an antiplatelet regimen after PCI certainly is a reasonable question,” he commented.

In an accompanying editorial, Carl J. Lavie, MD, of the University of Queensland School of Medicine (New Orleans, LA), and James J. DiNicolantonio, PharmD, of Wegmans Pharmacy (Ithaca, NY), ask if the findings “even matter” in the United States. “The answer is a resounding ‘maybe.’”

Drs. Lavie and DiNicolantonio explain: “The Asian population and those from Korea, as in the present study, may be particularly resistant to clopidogrel’s antiplatelet effects, with a greater prevalence of high on-treatment platelet reactivity, which is associated with an increased risk of MACE following PCI.”

New Drugs Cannot Be Beat

However, more potent antiplatelet agents available in the United States, such as prasugrel and ticagrelor, may be preferred by physicians, the editorial states.

“Considering cost restraints, [triple therapy] with aspirin, clopidogrel, and cilostazol appears to be a viable alternative to DAPT and even [double-dose clopidogrel],” they write. “Clearly, this therapy should be compared with DAPT with the newer agents, as opposed to just clopidogrel, and the efficacy of [triple antiplatelet therapy] should be studied with aspirin and cilostazol added to the newer therapies to determine if further clinical efficacy can be enhanced without producing nondesirable increases in bleeding complications.”

Dr. Schaer agreed with the editorial, saying HOST-ASSURE likely will not change US clinical practice. Although he does not see many South Korean patients in his practice, Dr. Schaer said his approach for these patients would be to not use cilostazol but rather ticagrelor or prasugrel and to potentially give the double dose of clopidogrel to those that “might be at higher risk for having the loss-of-function allele.”

In an e-mail communication with TCTMD, Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), said, “It's just so hard to advocate for triple therapy given the number of medications most stent patients are already on, not to mention the potential compliance issues.”

Study Details

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).

 


Sources:
1. Park KW, Kang S-H, Park JJ, et al. Adjunctive cilostazol versus double-dose clopidogrel after drug-eluting stent implantation: The HOST-ASSURE randomized trial (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Safety & Effectiveness of Drug-Eluting Stents & Anti-platelet Regimen). J Am Coll Cardiol Intv. 2013;6:932-942.

2. Lavie CJ, DiNicolantonio JJ. Cilostazol—A forgotten antiplatelet agent, but does it even matter [editorial]? J Am Coll Cardiol Intv. 2013; 2013;6:943-944.

 

 

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Disclosures
  • The study was sponsored by the Ministry of Health and Welfare, Republic of Korea, and supported by a grant from the Innovative Research Institute for Cell Therapy, Seoul National University Hospital, and an unrestricted grant from Boston Scientific Korea.
  • Drs. Kim, DiNicolantonio, Kirtane, and Schaer report no relevant conflicts of interest.
  • Dr. Lavie reports serving as a speaker and consultant for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer.

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