Is Triple Antiplatelet Therapy After PCI the Way Forward?

March 16, 2010

March 16, 2010 (Atlanta, Georgia) — Triple antiplatelet therapy--with cilostazol (Pletal, Otsuka America) plus clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and aspirin--was not associated with a significant reduction in clinical outcomes after drug-eluting-stent placement vs clopidogrel and aspirin alone in the CILON-T study. But triple therapy did improve posttreatment platelet reactivity, and the trial was underpowered for hard clinical events.

Dr Hyo-Soo Kim

The trial was presented at the American College of Cardiology (ACC) 2010 Scientific Sessions. Lead investigator Dr Hyo-Soo Kim (Seoul National University Hospital, Korea) commented: "The most important result of this study is that posttreatment platelet reactivity was the key determinant of major adverse cardio- and cerebrovascular events, such as cardiac death, heart attack, or ischemic stroke, and we showed that platelet hyporesponsiveness is a problem even with triple antiplatelet therapy."

Time to Use Platelet Tests to Guide Therapy?

"Our study also suggests that it is time to select which antiplatelet agents we should use by guidance from posttreatment platelet-reactivity tests," Kim concluded.

But moderators of the session said it may be too soon to make such a definitive statement on this issue. Dr Robert Harrington (Duke Clinical Research Institute, Durham, NC) said: "I am not sure that this hypothesis is correct--that by decreasing platelet responsiveness on an assay we are going to reduce outcomes. I don't think we know the answer to that yet."

He commented to heartwire later: "Multiple studies (including the cilostazol one presented today) have shown association between platelet activity and outcomes. That's not new. What's needed is to see if changing therapy based on that functional platelet knowledge changes clinical outcomes. GRAVITASis one trial testing this."

Dr Franz Joseph Neumann (Technical University of Munich, Germany) said he "partially agreed" with Kim's statement about using platelet-reactivity tests to guide therapy. "This study adds more evidence linking platelet reactivity to outcomes. But we need studies showing that actively lowering platelet reactivity with higher doses of clopidogrel or changing to prasugrel will result in improved clinical outcome. These are under way, and we will have data on this very soon."

Commenting on this issue for heartwire , Dr Peter Berger (Geisinger Clinic, Danville PA) said he thought the CILON-T study illustrated why platelet-function testing is in fact not yet ready to guide clinical decision making. "Cilostazol reduced aggregability, and yet it did not improve outcomes. It is a little hard for me to imagine how the study provides strong evidence linking aggregability and outcome or can be used to guide clinical decision making," he argued.

The CILON-T Study

In the CILON-T trial, 960 coronary disease patients were given either standard therapy of aspirin and clopidogrel or a triple antiplatelet regimen of aspirin, clopidogrel, and cilostazol for six months after drug-eluting-stent placement.

Although the addition of cilostazol has been shown to reduce late loss in a few small clinical trials, the effect of cilostazol on platelet reactivity and ischemic vascular events after drug-eluting-stent implantation has not previously been tested in a large prospective randomized trial, Kim explained.

Results showed that cilostazol did improve posttreatment platelet reactivity, as measured by P2Y12-receptor reaction units (PRU).

Platelet Reactivity in CILON-T Trial

  Cilostazol + clopidogrel + aspirin Clopidogrel + aspirin p

reaction units (PRU)

210.7 255.7 <0.001

But clinical events were not significantly reduced in the triple therapy group.

Clinical events in CILON-T trial

Primary end point Cilostazol + clopidogrel + aspirin (%) Clopidogrel + aspirin (%) p
Cardiac death, nonfatal MI, ischemic stroke, and target lesion revascularization 8.5 9.2 0.73

Kim said he believed the reason that they did not show a reduction in events with the triple therapy regimen was because there were still many patients with high levels of platelet reactivity (PRU >265 units) even after triple antiplatelet therapy.

He showed data demonstrating that platelet reactivity as measured by PRU was directly correlated with clinical outcome and that patients in the lowest tertile of platelet reactivity (PRU values of 0 to 184 units) had zero clinical events (cardiac death, nonfatal MI, ischemic stroke).

"Based on these results, we believe that PRU measurements may be useful in predicting risks after drug-eluting-stent implantation and that if PRU readings are high, a third antiplatelet drug should be considered," Kim concluded.

Shortcomings of the Study

Discussing the study after the presentation, Harrington said: "Although in this study they did show a better platelet response with triple therapy, there were not better clinical outcomes with triple therapy. So that raises for me a series of questions. Was this a large enough trial? Perhaps not. Did it have the right end point? Was six months of follow-up enough? Also, there was a low event rate, so the study was underpowered to see an effect on clinical outcomes."

He also raised the issue that cilostazol might not be the ideal agent to use in a triple antiplatelet therapy regimen. "This drug does have side effects, particularly gastrointestinal effects, and it increases heart rate, which may be problematic and may tip an antiplatelet benefit into harm," he added.

Neumann commented: "I think they were unlikely to have shown a benefit on the composite end point used, which included restenosis. Antiplatelet drugs do not generally reduce restenosis rates, so it would have been very difficult to attain a positive result. And the study was not powered for hard clinical end points."

Dr Dean Kereiakes (Christ Hospital Heart and Vascular Center, Cincinnati, OH) told heartwire : "The problem with this study for me is that we don't know whether it is applicable to non-Asian populations. The clopidogrel loss-of-function alleles are more prevalent in the Asian population. There may have been a 40% prevalence of this in Kim's study, which was conducted in South Korea, and so the results are not easily extrapolated to the US population."

Other Agents for Triple Therapy?

Commenting on the study for heartwire , Dr Paul Gurbel (Sinai Center for Thrombosis Research, Baltimore, MD) said he thought that it was reasonable to include target vessel revascularization in the end point, as previous studies have suggested reduced restenosis rates with cilostazol. "But the problem with this drug is tolerability, and for that reason it isn't used much in the US," he added.

But Gurbel believes the idea of using other agents to boost the effect of clopidogrel is a valid one. His group presented a study at the ACC meeting showing that St John's wort actually increases the inhibition of platelets by clopidogrel by upregulating CYP450 activity. "This was just a pilot study, but it is a provocative idea," he said.

"You can also improve activity of clopidogrel by being aware of other drugs that the patient is taking--high-dose stains, proton-pump inhibitors, and calcium blockers may all affect clopidogrel's activation," Gurbel noted.

Answers on What to Do in Clopidogrel Hyporesponders Coming Soon

On the association of platelet reactivity with outcomes, Gurbel agreed with Harrington that Kim's statement about using platelet-function tests to guide therapy was premature. "Basically, this trial did what many others have done before--it just correlated platelet function with outcomes. They did not personalize antiplatelet therapy. To make a statement like this, you need to test all your patients for their platelet response to clopidogrel and then randomize the hyporesponders to different treatment options and see whether outcomes are different. There are three trials under way doing just that," he noted.

These three trials are the GRAVITAS study (randomizing to high-dose vs normal-dose clopidogrel), the TRIGGER PCItrial (randomizing to normal dose clopidogrel or prasugrel) and the ARCTICstudy (where the doctor can choose which treatment to use).


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