April 06, 2011

April 6, 2011 (New Orleans, Louisiana) — A small trial testing the appropriate duration of dual antiplatelet therapy suggests that some patients can stop clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) after just six months following drug-eluting-stent implantation. Although the study was not powered for hard clinical end points, such as death, MI, or stent thrombosis, investigators report that one-year rates of target vessel failure (TVF) were equivalent among patients treated with six- and 12-months of dual antiplatelet therapy.

"The take-home message from our study is that, at least in low-risk, nondiabetic patients treated with second-generation drug-eluting stents, we can safely discontinue clopidogrel at about six months, especially if the patient is at high risk for bleeding or is anticipating some surgery," said lead investigator Dr Hyeon-Cheol Gwon (Sungkyunkwan University School of Medicine, Seoul, Korea) during a morning press conference announcing the results.

Presenting the results of the EXCELLENT trial today during the late-breaking clinical-trials session at the American College of Cardiology 2011 Scientific Sessions, Gwon acknowledged that hard clinical end points are what really matters when it comes to the question of stopping clopidogrel or prasugrel (Effient, Eli Lilly/Daiichi Sankyo) but said that the updated 2009 clinical guidelines already make allowances--based on expert clinical opinion--that certain, low-risk patients can stop taking thienopyridine therapy after six months. These new data provide support for that recommendation but on the whole are hypothesis-generating, and clinicians will need to wait for larger clinical trials, said Gwon. Other experts recommend at least 12 months of dual antiplatelet therapy following drug-eluting-stent implantation.

Commenting on the trial during a panel discussion, Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) took issue with the trial design, particularly the selection of TVF as the primary end point. Importantly, Kaul also noted that there was no statistically significant reduction in the risk of TIMI major bleeding and that without a clear benefit--and TVF going in the wrong direction in the diabetic and sirolimus-eluting-stent subgroups--there is little support for stopping treatment at six months.

"Clinically, the way we make decisions is that I'm willing to accept some degree of inferiority, given some ancillary advantage in terms of safety and even cost," said Kaul. "Cost is an argument and convenience is an argument, but the bleeding, the safety end point, is not borne out by this data."

The EXCELLENT Trial

The EXCELLENT trial is a 2X2 factorial study that randomized 722 patients with coronary artery disease to dual antiplatelet therapy for six months and 721 patients to dual antiplatelet therapy for one year. In the first randomization, patients were treated with the everolimus-eluting stent (Xience V/Promus, Abbott Vascular/Boston Scientific) or the sirolimus-eluting stent (Cypher Select, Cordis), and the primary end point of that analysis was the effect on late lumen loss, findings that were presented last year at TCT 2010.

Regarding the primary end point of TVF, a composite of cardiac death, MI, or target vessel revascularization at 12 months, investigators observed no statistically significant difference between patients randomized to dual antiplatelet therapy for six months and those treated with dual therapy for one year. For those treated with clopidogrel and aspirin for six months, the rate of TVF was 4.7%, while it was 4.4% for those treated with dual antiplatelet therapy for 12 months, a difference that met statistical criteria for noninferiority. There was no difference between the two durations in terms of other end points, including cardiac death, MI, stent thrombosis, or TIMI major bleeding, as well as in the combined safety end point of death, MI, stent thrombosis, stroke, or TIMI major bleeding.

Among different subgroups, there was no difference in the primary end point when patients were stratified by age, left ventricular ejection fraction, or complexity of disease. There was a significantly increased risk of TVF--more than threefold--among diabetes patients treated with aspirin and clopidogrel for just six months and a trend toward an increased risk among patients treated with the sirolimus-eluting stent who received dual antiplatelet therapy for six months.

Trials Getting Harder to Do . . . 

Speaking with heartwire , Dr David Kandzari (Piedmont Heart Institute, Atlanta, GA) said the overall results--showing that there doesn't appear to be a difference among patients treated with six or 12 months of dual antiplatelet therapy--fit with other observational data. That said, all these studies are limited by sample size, and for that reason not too much emphasis should be placed on the overall findings, as well on the signal of risk among sirolimus-eluting-stent patients treated with dual antiplatelet therapy for six months.

EXCELLENT included just 1500 patients, said Kandzari, but noted that such trials are becoming difficult to complete because limited numbers of patients are maintaining adherence to study protocol. For patients randomized to dual antiplatelet therapy for six months, doctors are keeping patients on clopidogrel or prasugrel for longer durations, not because of any adverse-driven events, but because they don't believe there is a downside to keeping them on the drugs. He noted that in trials such as the Scripps Evaluation of Antiplatelet Therapies for Intermediate Duration With the Endeavor Stent (SEASIDE), a 900-patient study evaluating six-month dual antiplatelet therapy in patients treated with the zotarolimus-eluting stent (Endeavor, Medtronic), patients are continuing on with both aspirin and the thienopyridine.

"What we're finding in trials like SEASIDE is that just 60% of our patients are stopping dual antiplatelet therapy at six months," said Kandzari. "The outcomes are exceptional, but it's an issue of their primary physicians recommending that they continue on treatment. It's a notion of, 'Well, you're doing fine on it, you can afford it, and you're not having bleeding problems, so you might as well stay on it.' In some ways, it's a case of treating ourselves instead of the patient based on the evidence."

Like Gwon and the EXCELLENT investigators, Kandzari noted that in learning when it is appropriate to stop clopidogrel or prasugrel will need hard clinical end points, but trials designed around end points such as stent thrombosis, as well as death and MI, will require 15 000 to 20 000 patients. The Dual Antiplatelet Therapy (DAPT) trial comparing 12 vs 30 months of dual antiplatelet therapy among 15 000 patients who have been treated with drug-eluting stents is currently under way. That study, led by Dr Laura Mauri (Harvard Clinical Research Institute, Boston, MA) and Dr Dean Kereiakes (Christ Hospital Heart & Vascular Center/Lindner Research Center, Cincinnati, OH), is powered to assess the primary end points of differences in stent-thrombosis rates and major adverse cardiovascular and cerebrovascular events (MACCE), while the primary safety end point for DAPT is major bleeding. An additional 5000 patients treated with bare-metal stents will also be enrolled.

The EXCELLENT study was sponsored by grant support from the Korean government, Abbott Vascular, and Boston Scientific. Gwon reports consulting for Cordis and Medtronic and receiving research grants from Abbott and Medtronic.

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