Meta-analysis: Triple Therapy with Cilostazol Lowers TLR, TVR With No Extra Bleeding

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Adding the antiplatelet drug cilostazol to standard therapy with clopidogrel and aspirin lowers repeat revascularization rates with no increase in bleeding in patients who receive drug-eluting stents (DES), according to a meta-analysis appearing online June 22, 2012, ahead of print in the International Journal of Cardiology.

Researchers led by Ryota Sakurai, MD, PhD, of the University of Tokyo Hospital (Tokyo, Japan), pooled data from 3,590 patients in 8 trials that randomized DES patients to dual antiplatelet therapy with (n = 1,800) or without (n = 1,790) the selective phosphodiesterase III inhibitor cilostazol. Follow-up was anywhere from 1 to 24 months. The analysis included trials such as DECLARE-LONG, which found that triple therapy with cilostazol reduces late loss and restenosis in long lesions, and CILON-T, which found no clinical benefit from adding the drug to dual therapy.

The risk of TLR and TVR was roughly 42% lower with triple therapy, while adverse events including death, MI, and stent thrombosis were similar between groups (table 1).

Table 1. Clinical Outcomes

 

The number needed to treat with cilostazol was 33 to prevent a single TLR event, and 25 to prevent a single TVR event.

Rates of both bleeding and major bleeding were also similar between groups. However, drug discontinuation rates were higher with triple therapy, primarily because of minor adverse events such as rash and GI side effects, which were twofold and threefold higher, respectively, with cilostazol (table 2).

Table 2. Bleeding and Minor Adverse Events

The number needed to treat with cilostazol for both rash and GI side effects was 33, while the number needed to treat for drug discontinuation with cilostazol was 9. On subsequent linear regression analysis, the researchers found that publication bias may have contributed to the drug discontinuation finding (P = 0.127).

Side Effects a ‘Real-World’ Issue

Dr. Sakurai and colleagues note that cilostazol’s effects in reducing TLR and TVR may be multifactorial, stemming from induced apoptosis of vascular smooth muscle cells as well as leukocyte activation after coronary stenting. Nevertheless, “the accumulation of minor side effects may cause a critical situation due to cilostazol termination in a larger number of patients in real-world settings,” they warn.

At the very least, “concurrent prevention or treatments for rash and GI side effects seem reasonable strategies for patients on [triple antiplatelet therapy],” they advise.

TLR Reduction Not Enough to Warrant Routine Use

According to Gary L. Schaer, MD, of Rush University Medical Center (Chicago, IL), the current results will not affect his management of patients. “I think there probably is some antiproliferative effect of cilostazol—a number of studies have suggested this,” he told TCTMD in a telephone interview. “The meta-analysis shows with some confidence that there’s a reduction in TLR, but there’s no effect on hard events like MI and death, and then you pay a price in terms of tolerability.”

Dr. Schaer noted that he uses cilostazol in his own practice “fairly commonly” to treat peripheral vascular disease patients with claudication, the indication for which the agent is approved. “The drug works pretty well in about 50 to 60% of patients in my experience,” he said. “But maybe 20% who derive some benefit don’t tolerate the drug and will have to come off of it.”

He does not see a role for cilostazol as a routine part of antiplatelet therapy for DES patients. “I would not be sending my typical DES patient home on triple therapy,” Dr. Schaer said. “There might be an occasional patient who you determine can’t continue on antiplatelet therapy although they still need it, and they might not tolerate clopidogrel or prasugrel. And occasionally you get a rare DES patient who can’t take aspirin.”

A Potential Niche for Cilostazol

Dr. Schaer explained that reducing the risk of stent thrombosis in patients unable to take dual antiplatelet therapy is his biggest concern. “There might be a benefit to adding cilostazol if the antiplatelet effect could reduce that risk, but this meta-analysis doesn’t add to our understanding of that at all,” he said.

A particular niche that cilostazol might occupy is for patients who are “serial restenosers,” Dr. Schaer noted, who develop significant re-narrowing and ischemic symptoms even after multiple DES implantations. “We still have these patients every now and then [who have] a high risk of intimal hyperplasia, and I might try cilostazol based on the signal that’s indicated in this meta-analysis,” he said.

In terms of the study itself, Dr. Schaer pointed out that the 7.3% TLR rate in the dual therapy arm seems unusually high compared with what would be expected with current, third-generation DES. “TLR rates, if anything, are lower than 4%,” he said. “I suspect to some extent it’s oculostenotic and not ischemia-driven TLR.”

In addition, cilostazol has mainly been studied in Asian populations. For instance, all of the trials in the current meta-analysis were conducted in South Korea.

 

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Source:
Sakurai R, Koo B-K, Kaneda H, et al. Cilostazol added to aspirin and clopidogrel reduces revascularization without increases in major adverse events in patients with drug-eluting stents: A meta-analysis of randomized controlled trials. Int J Cardiol. 2012;Epub ahead of print.

 

Disclosures:

• Drs. Sakurai and Schaer report no relevant conflicts of interest.

 

Related Stories:

• Adjunctive Cilostazol Noninferior to Double-Dose Clopidogrel in All-Comer PCI Trial
• Meta-Analysis: Adjunctive Cilostazol Lowers Repeat Revascularization After PCI
• Cilostazol Reduces Repeat Revascularizations for Long Lesions

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