Triple antiplatelet therapy consisting of cilostazol added to clopidogrel and aspirin does not improve clinical outcomes in patients who receive drug-eluting stents (DES) compared with standard dual antiplatelet therapy. However, the triple regimen does reduce platelet reactivity, which is correlated with thrombotic events, according to a study published in the January 18, 2011, issue of the Journal of the American College of Cardiology. 

Findings of the CILON-T (influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial were first presented at the American College of Cardiology/i2 Summit in March 2010 in Atlanta, GA.

For the trial, investigators led by Hyo-Soo Kim, MD, PhD, of Seoul National University Hospital (Seoul, South Korea), randomized 915 patients to triple antiplatelet therapy with cilostazol (n = 457) or standard dual therapy (n = 458) for 6 months. All patients had received a DES for indications ranging from stable angina to acute MI.

On-treatment platelet reactivity was assessed using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) at discharge and at 6 months. Patients receiving triple therapy showed reduced levels of P2Y12 reaction units (PRU) at both time points (table 1).

Table 1. Platelet Reactivity

 
Percent platelet inhibition also was lower at discharge and at 6 months between the 2 groups (P < 0.0001 for both time points).

At 6 months there were no differences between the 2 groups in the incidence of the primary outcome, the composite of cardiac death, nonfatal MI, clinically driven TLR, and ischemic stroke. Rates of the individual endpoints and stent thrombosis also were similar (table 2).

Table 2. Clinical Outcomes at 6 Months

Subgroup analyses based on clinical and angiographic characteristics found no differences in clinical outcome between the treatment groups except for female patients, who experienced a higher rate of adverse events on triple therapy (HR 3.41; 95% CI 1.12-10.4).

To explore the influence of on-treatment platelet reactivity on clinical outcomes, the researchers stratified patients into tertiles of PRU value at discharge:

• Low: < 184
• Middle: 184-264
• High: > 264

Outcomes Linked to PRU Level

The risk of hard clinical events rose with PRU level, with a trend toward a worse primary outcome in the high vs. the low tertile (P = 0.077) and a clear difference for the composite of cardiac death, nonfatal MI, and ischemic stroke (P = 0.037). However, there was no correlation between PRU level and TLR (P = 0.486). On the other hand, the tertile distribution of percentage inhibition was not associated with thrombotic complications (P = 0.133).

Receiver-operator characteristic curve analysis showed that on-treatment PRU assessed at discharge was able to discriminate between patients with and without thrombotic events (area under the curve 0.670; 95% CI 0.579-0.762; P = 0.043). In addition, a PRU ≥ 252.5 was determined to be the optimal cutoff value, with a 99.3% negative predictive value.

In Cox regression analysis, lesion length (≥ 28 mm; HR 1.90; 95% CI 1.05-3.43) and PRU level at discharge (every increase in tertile; HR 1.63; 95% CI 1.12-2.37) were independent predictors of the primary outcome, but use of cilostazol was not (HR 0.88; 95% CI 0.50-1.56).

At 6 months patients on triple therapy had a higher heart rate than those on dual therapy (73.3 ± 12.0 beats/min vs. 68.4 ± 13.7 beats/min; P < 0.001) despite more frequent use of beta blockers. About 6.6% of triple-therapy patients stopped cilostazol due to adverse reactions compared with only 0.7% in the dual-therapy group who stopped study drugs. Bleeding did not differ between the 2 groups. The most common side effects were palpitations (2.8%), headache (2.4%), and GI distress (0.7%).

Interestingly, PRU levels in the dual-therapy group increased significantly at 6 months compared with discharge levels. Because this backsliding was not seen in the triple-therapy group, the finding suggests that cilostazol may overcome delayed hyporesponsiveness to clopidogrel, the researchers say.

Possible Explanations for Negative Finding

The discrepancy between the negative clinical findings in this study and the cilostazol advantage observed in some smaller randomized trials may arise from several possible explanations, Dr. Kim and colleagues suggest:

• Unlike CILON-T, the earlier trials enrolled only high-risk populations such as diabetics or patients with long lesions. Moreover, those trials had angiographic endpoints and were underpowered to assess clinical differences between the antiplatelet regimens.
• In the current study, LDL cholesterol was tightly controlled by statins. This can reduce platelet reactivity and neointimal hyperplasia and may have diluted the potential benefit of cilostazol.
• Use of more effective second-generation zotarolimus-eluting stents in about half of CILON-T patients may have minimized the potential antirestenotic benefit of cilostazol.
• Cilostazol is associated with increased heart rate, and in the relatively high proportion of ACS patients in CILON-T, this side effect may have contributed to increased event rates.

Importantly, the investigators observe, although overall the triple-therapy group had a lower mean PRU level than the dual-therapy group, almost one-third of patients in the former were in the highest PRU tertile.

“These hyporesponders to [triple antiplatelet therapy] may be the toughest group, one that has little additional benefit from cilostazol therapy and also the target population in need of another adjunctive or alternative pharmacologic intervention,” the authors write. “These findings suggest that not the antiplatelet regimen but the achievement of low [on-treatment platelet reactivity] is important.”

In an accompanying editorial, David Antoniucci, MD, of Careggi Hospital (Florence, Italy), says that the available data suggest that triple antiplatelet therapy is unlikely to overcome clopidogrel resistance. “It is still unknown whether more potent antiplatelet agents, such as prasugrel or ticagrelor, [which] provide a more predictable in vitro platelet aggregation inhibition, will replace clopidogrel in all patients receiving DES,” he adds.

“In the meantime, the possibility to tailor effectively antiplatelet therapy under the guidance of in vitro tests should be considered as an attractive option,” he concludes.

Platelet Reactivity May Not Be a Modifiable Risk Factor

In a telephone interview with TCTMD, Sunil V. Rao, MD, of Duke University Medical Center (Durham, NC), granted that the finding that triple therapy reduced platelet reactivity without generally improving clinical outcomes appears somewhat paradoxical. “But I think we have put too much faith in platelet reactivity as a modifiable risk factor,” he said. “Clearly, it’s a risk marker, and I’m certainly not saying that platelet inhibition is not important. But these processes are more complex than we give them credit for.”

For example, he pointed out that the association between platelet inhibition and improved outcomes seen in the PLATO and TRITON trials involved ACS patients. “I think there’s a distinct difference between the ACS population and the non-ACS population, and event rates are so low in the latter that it’s hard to show differences [in outcome] regardless of what antiplatelet strategy you’re looking at,” he observed, adding that in CILON-T 43% of the study population had stable angina and 43% were in the amorphous “unstable angina” category.

Moreover, “there may be unmeasured confounders—perhaps other biological pathways that have not yet been elucidated—that run alongside increased platelet reactivity” and influence outcome, Dr. Rao said. “There is a lot of circumstantial evidence to suggest that platelet reactivity may be a modifiable risk factor, but I don’t think it has been proven yet,” he added.

Where Is the Evidence for Platelet Function Testing?

Dr. Rao disagreed with the editorialist’s suggestion that using functional testing to tailor antiplatelet therapy is “an attractive option.” “I don’t think it’s [a clinical] option yet. I don’t see data that tell me that titrating to any level of PRU or light transmittance aggregation percentage of platelet reactivity is associated with any better outcomes or safety for that matter,” he said.

However, it would be wrong to conclude from the current findings that cilostazol is useless, Dr. Rao added. “We need to be very careful about condemning or praising therapies based on studies that are too small to show differences.” And given considerable experience with the drug in PAD patients, Dr. Rao did not believe its side effects were a barrier to use. Nonetheless, he noted, any kind of triple therapy has a strike against it, both because patients are often already on multiple medications and because the more complex the regimen, the more difficult adherence becomes.

Despite being “unimpressed” by results in the literature thus far, Dr. Rao said there may yet be a role for cilostazol in PCI. “But if you really believe it works, you should test it just as you would any new drug for PCI. Do a larger pivotal phase III trial,” he asserted, adding, “Some of these smaller, one-off trials are very interesting, but they leave us with more questions than answers.”

Study Details

Loading doses of aspirin (300 mg) and clopidogrel (300 mg or 600 mg) were given to all patients not previously exposed. Daily aspirin (100 mg) and clopidogrel (75 mg) were continued for 6 months. The triple therapy group received a loading dose of cilostazol (200 mg) followed by 100 mg twice daily for 6 months in addition to standard dual therapy.

There were no significant baseline clinical, angiographic, or procedural differences between the treatment groups. Discharge medications were similar except that ACE inhibitors and angiotensin receptor blockers were more frequently prescribed in the dual-therapy group. 

 

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Sources:
1. Suh J-W, Lee S-P, Park K-W, et al. Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease: Results of the CILON-T (Influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial. J Am Coll Cardiol. 2011;57:280-289.

2. Antoniucci D. No role for triple antiplatelet therapy? J Am Coll Cardiol. 2011;57:290-291.

 

 

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