Meta-Analysis: Adjunctive Cilostazol Lowers Repeat Revascularization After PCI

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Adding the drug cilostazol to dual antiplatelet therapy reduces the need for repeat revascularization between 6 months and 1 year after percutaneous coronary intervention (PCI). While triple therapy does not exert positive effects on death or myocardial infarction (MI) rates, it also does not appear to raise the risk of major bleeding, according to a meta-analysis published online March 1, 2012, ahead of print in the American Journal of Cardiology.

Avi Shimony, MD, and colleagues at McGill University (Montreal, Canada), identified 12 randomized controlled trials (n = 5,655) that evaluated dual antiplatelet therapy with or without cilostazol. Studies ranged in size from 60 to 1,212 patients. Two included only BMS and 6 only DES, while 4 used both stent types or did not specify.

Follow-up durations ranged from 1 to 24 months. Data were pooled using random-effects models and stratified into short-term (1 month), mid-term (6-12 months), and long-term (≥ 12 months) follow-up.

Cilostazol did not appear to reduce TLR at 1 month, but a difference became apparent between 6 and 12 months. In the single study that evaluated TLR beyond 1 year (n = 900), risk was lower in patients receiving adjunctive cilostazol (table 1).

Table 1. TLR Risk: Adjunctive Cilostazol vs. Dual Antiplatelet Therapy

TVR risk was similarly reduced at mid-term follow-up, though only a trend favoring cilostazol was observed at long-term follow-up.

Triple therapy did not affect the risks of death or MI at any follow-up duration, nor did it increase major bleeding in the 4 trials that assessed that endpoint (RR 1.63; 95% CI 0.58-4.57). Details on drug discontinuation could not be pooled because of inconsistency among trials, but of the 7 studies reporting such data, 6 found that patients receiving adjunctive cilostazol were more likely to stop treatment. Discontinuation rates ranged from 0 to 19% with cilostazol and from 0 to 11% with aspirin and clopidogrel alone.

“Taken together, the lack of change in bleeding, myocardial infarction, and mortality could suggest that the dose of cilostazol was too low to have the biologic activity required to significantly reduce stent thrombosis, despite improvements in symptom-driven reinterventions,” Dr. Shimony and colleagues write. “Additional investigation into optimal dosing is required.”

Cilostazol dosing varied among the trials. Six studies included a loading dose of 200 mg and 1 of 400 mg. Maintenance doses were typically 100 mg twice daily, though 2 trials administered only 50 mg twice daily with no loading dose.

‘Jury Is Still Out’

In an e-mail communication, Dr. Shimony pointed out that the current meta-analysis is the first to pool clinical outcomes and to incorporate data from 5 recently published trials. The 2 most recent trials, CILON-T and DECLARE-II, had mixed results. CILON-T showed positive effects on platelet reactivity but not clinical outcomes in DES patients at 6 months. DECLARE-LONG II, meanwhile, found that triple therapy decreased TLR and TVR at 1 year in patients receiving zotarolimus-eluting stents. Both studies were published in the Journal of the American College of Cardiology in 2011.

Sunil V. Rao, MD, of Duke University Medical Center (Durham, NC), told TCTMD in an e-mail communication that the new meta-analysis is not enough to change minds about triple therapy in either direction. “I think that this paper is going to reinforce the practice of people who are believers in cilostazol and will not persuade those who are not believers in cilostazol,” he said.

“Given the lack of a clear efficacy signal and a plausible mechanism to explain it, the jury is still out on cilostazol. But maybe the verdict will come” March 25, 2012, when the HOST ASSURE trial is presented at this year’s American College of Cardiology (ACC)/i2 Summit in Chicago, IL, Dr. Rao suggested. In the meantime, he expressed skepticism that triple therapy will become widespread “[g]iven that the best ways to reduce TVR and TLR are appropriate patient selection and DES.”

Dr. Shimony commented that one reason why cilostazol has not been widely adopted into clinical practice may be that the drug has predominately been studied in Asian populations.

“One can argue that this issue might have biased our results since this population has a greater prevalence of the CYP2C19 polymorphism, leading to an attenuated clopidogrel response,” he said, noting that even so, 1 North American trial showed reduced restenosis with cilostazol. “Hopefully, our study will provide the necessary sway and a ‘boost’ for conducting large clinical trials in diverse populations.”

BMS vs. DES?

But David Antoniucci, MD, of Careggi Hospital (Florence, Italy), characterized the inclusion of studies using BMS in the meta-analysis as a “major concern.”

Cilostazol has the most impact when paired with BMS, which have higher late loss than DES. “A significant impact of this drug seems unlikely in patients receiving last-generation DES,” Dr. Antoniucci said in an e-mail communication with TCTMD, adding that in fact, cilostazol could prove useful in the BMS population.

But Dr. Antoniucci concluded that the reductions in repeat revascularization observed by this meta-analysis are not enough to justify triple therapy as a whole, since there were no significant benefits over the long-term.

Dr. Shimony also noted that “whether this drug is especially beneficial in patients treated with BMS and not DES deserves further investigation.” That being said, “TVR and TLR are major clinical surrogates for restenosis,” he stressed. “Symptoms are important, and patients seek treatment for [symptoms that] bother them.”

 

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Source:
Friedland SN, Eisenberg MJ, Shimony A. Meta-analysis of randomized controlled trials on effect of cilostazol on restenosis rates and outcomes after percutaneous coronary intervention. Am J Cardiol. 2012;Epub ahead of print.

 

 

Related Stories:

• Cilostazol Reduces Repeat Revascularizations for Long Lesions
• Cilostazol Improves Platelet Reactivity, Not Clinical Outcomes in DES Patients
• CILON-T Published: Cilostazol Reduces Platelet Reactivity, Not Events
  

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