ATLANTA, GA—Triple antiplatelet therapy with cilostazol added to clopidogrel and aspirin lowers platelet reactivity compared with standard dual therapy in patients receiving drug-eluting stents (DES), but these results do not translate to fewer ischemic events, according to late breaking trial data presented Monday, March 15, 2010, at the American College of Cardiology/i2 Summit.
For the CILON-T (Influence of CILostazol-based triple antiplatelet therapy ON ischemic complications after drug-eluting stenT implantation) trial, researchers led by Hyo-Soo Kim, MD, PhD, of Seoul National University Hospital (Seoul, Korea), randomized 915 patients receiving DES for indications ranging from stable angina to acute MI to receive triple therapy with cilostazol (n = 457) or standard dual therapy (n = 458).
Co-primary endpoints for the trial were platelet reactivity—assessed by P2Y12 reaction units (PRU) via the VerifyNow assay (Accumetrics, San Diego, CA)—and major adverse cardiac and cerebrovascular events (MACCE) at 6 months.
At both hospital discharge and 6 months, platelet reactivity was reduced in triple therapy patients (table 1).
Table 1. Platelet Reactivity
|
Triple Therapy
(n = 457)
|
Dual Therapy
(n = 458)
|
P Value
|
Hospital Discharge, PRU
|
206.6
|
232.1
|
< 0.001
|
6 Months, PRU
|
210.7
|
255.7
|
< 0.001
|
In addition, on Cox regression analysis, high PRU level (for every increase in tertile) was an independent predictor of MACCE (composite of cardiac death, MI, ischemic stroke, TLR) at 6 months (adjusted HR 1.63; 95% CI 1.12-2.37).
However, the same relationship did not hold for cilostazol and MACCE (adjusted HR 0.88; 95% CI 0.50-1.56), and patients taking triple therapy with cilostazol did not have lower rates of the composite or any of its components compared with patients on dual therapy (table 2).
Table 2. Clinical Outcomes at 6 Months
|
Triple Therapy
(n = 457)
|
Dual Therapy
(n = 458)
|
P Value
|
MACCE
|
8.5%
|
9.2%
|
0.73
|
Cardiac Death
|
0
|
0.7%
|
0.25
|
MI
|
0.9%
|
0.7%
|
0.73
|
Ischemic Stroke
|
1.1%
|
0.9%
|
0.75
|
TLR
|
6.6%
|
7.2%
|
0.79
|
Patients receiving triple antiplatelet therapy also had equivalent rates of all-cause death (0.9% vs. 1.3%; P = 0.75) and stent thrombosis (0.7% vs. 1.1%; P = 0.73) compared with patients receiving dual therapy at 6 months.
Clinical outcomes remained equivalent even after stratifying patients by high, middle, and low PRU values. The was only 1 subgroup that showed any difference: women with higher PRU values showed an increased risk of adverse events (HR 3.41; 95% CI 1.12-10.4).
Safety Signals with Cilostazol
In terms of other safety endpoints, major and minor bleeding events were low and equivalent between the 2 groups. Meanwhile, drug discontinuation rates were higher in the triple therapy patients (6.6% vs. 0.7%; P < 0.001), as was heart rate at 6 months (73.3 ± 12.0 bpm vs. 68.4 ± 13.7 bpm; P < 0.001). The increase in heart rate was most pronounced in women on triple therapy.
“Triple antiplatelet therapy achieved lower post-treatment platelet reactivity than dual antiplatelet therapy, but this did not necessarily reduce MACCE within 6 months after DES implantation,” Dr. Kim said. The cause of this, he noted, was the substantial number of patients who responded poorly even to triple therapy. But irrespective of the antiplatelet regimen, “the patients with PRU under 120 did not develop any thrombotic event like cardiac death, myocardial infarction, or ischemic stroke,” he added.
The main conclusion from the study, Dr. Kim said, is that a “tailored decision on the adjunctive use of cilostazol according to post-treatment platelet reactivity can be helpful to reduce adverse clinical outcomes in patients who undergo DES implantation.”
Asking the Big Questions
Commenting on the study, Robert A. Harrington, MD, of Duke University Medical Center (Durham, NC), noted that the disparity between the platelet reactivity outcomes and the clinical outcomes left him with questions regarding the size of the trial as well as the choice of endpoints.
“And then I would ask: Is cilostazol the right drug to think about as an alternative agent?” Dr. Harrington continued. “There were issues with discontinuation for side effects, and the increase in heart rate has been noted with cilostozal and other drugs like it, which may be problematic because that might tip some of the benefits of drugs like cilostazol toward actual harm.”
Support for Platelet Reactivity Testing
The most important question of all, he added, is: “Are we actually sure the hypothesis is the correct one? Are we sure that by decreasing platelet responsiveness based on an assay that we’re going to improve patient outcomes? I don’t think we know the answer to that.”
In response, Dr. Kim maintained that “it is time to prescribe antiplatelet agents based on guidance from post treatment platelet inhibition measured by VerifyNow or [light transmittance aggregometry].”
Franz-Josef Neumann, MD, of the Heart Center (Bad Krozingen, Germany) was largely in agreement. “I think it’s most likely we can guide antiplatelet therapy based on PRU,” he commented. “The threshold for events is even the same as in many other studies, so that’s very reassuring, but I think we need data from a randomized study showing that if you correct [platelet reactivity], you can improve outcomes.”
Study Details
Patients in the study were aged 62 years, with high rates of hypertension. About a third of the patients had diabetes, and DES use was roughly split between Taxus (Boston Scientific, Natick, MA) and Endeavor (Medtronic, Minneapolis, MN).
Source:
Kim HS. CILON-T late breaking trial: Randomized prospective trial of dual vs. triple antiplatelet therapy after DES implantation. Presented at: American College of Cardiology Annual Scientific Session/i2 Summit; March 15, 2010; Atlanta, GA.
Disclosures:
- Dr. Kim reports no relevant conflicts of interest.
- Dr. Harrington reports receiving consulting fees/honoraria from WebMD, Astra Zeneca, Schering Plough, Baxter, Otsuka, Maryland Research Institute, Merck, The Medicines Company, TheHeart.org, Regado, Luitpold, Sanofi-Aventis, CSL Behring, Novartis, and Lilly, and receiving research grants from Portola, Schering Ploush, Bristol-Myers Squibb, GlaxoSmithkline, Merck, Millennium, AstraZeneca, The Medicines Company, and Baxter.
- Information regarding conflicts of interest was not available for Dr. Neumann.
Related Stories: