ITALIC Published: No Benefit to Long-Term DAPT After Stenting
Among good responders to aspirin, rates of bleeding and thrombotic events are similar after DES implantation whether patients receive either 6 or 24 months of dual antiplatelet therapy (DAPT), according to a study published in the March 3, 2015, issue of the Journal of the American College of Cardiology.
Findings from the ITALIC/ITALIC+ study, which was stopped early due to slow recruitment, were previously presented at the 2014 American Heart Association Scientific Sessions in November.
Martine Gilard, MD, PhD, of Brest University (Brest, France), and colleagues randomized 1,850 good aspirin responders to DAPT lasting 6 months (n = 926) or 24 months (n = 924) after DES implantation (Xience V; Abbott Vascular). Patients were at European and Middle Eastern sites during 2 periods under the same protocol, from November 2008 to December 2010 and from January 2012 to November 2013.
Both study arms had similar baseline characteristics—one-third of patients had a history of type 2 diabetes, a quarter had previous revascularization, and about half presented with ACS. Two or more lesions were stented in more than half of patients, with a mean stent length of about 37 mm.
Within 1 year of stenting, 24.2% of patients in the 6-month arm did not adhere to the study—8.9% stayed on DAPT longer, while the remainder stopped earlier. About 5% of the 24-month group stopped early. There was no difference between the groups with regard to the primary endpoint (death, MI, repeat emergency TVR, stroke, or TIMI major bleeding), its individual components, or stent thrombosis at 12 months (table 1). As such, noninferiority for the primary endpoint was established for 6- vs 24-month DAPT (absolute risk difference 0.11%; P for noninferiority = .0002).
Additionally, outcomes did not differ based on DAPT duration among the 792 high-risk ACS patients included in the study.
Identifying Who Benefits
“There is no doubt that long-course aspirin attenuates the risk of MI, stroke, and vascular-related deaths in patients with cardiovascular disease,” Dr. Gilard and colleagues write. “The major controversy about aspirin therapy is why certain patients do not show benefit with such therapy and how they might be identified.”
Future studies should “seek to identify the specific clinical characteristics associated with benefit or harm related to shorter or longer durations of DAPT following deployment of various types of coronary stents,” they conclude.
Defining ‘Individualized’ Therapy
In an editorial accompanying the study, Robert W. Yeh, MD, of Massachusetts General Hospital (Boston, MA); Laura Mauri, MD, of Brigham and Women’s Hospital (Boston, MA); and Dean J. Kereiakes, MD, of the Christ Hospital Heart and Vascular Center (Cincinnati, OH), point out several limitations that “bias toward the null for noninferiority”—lack of power, lower-than-expected event rates, and imbalanced study medication compliance.
They also write that the “95% confidence interval surrounding the primary endpoint is wide, allowing for a > 2-fold increase in events in the short-duration treatment group without negating the noninferiority claim.” Lastly, the very low event rate may indicate an atypical patient population not representative of routine clinical practice.
Incorporating the data from this trial into a meta-analysis with prior trials may be “tempting,” the editorialists acknowledge. However, they caution, “the post hoc aggregation of underpowered trials with variable study populations, protocols, methodologies, and endpoints not infrequently provides results that are proven incorrect by a subsequent, adequately-powered, randomized, controlled clinical trial.”
In a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), echoed their thoughts. “When you aggregate underpowered trials, you can get very funky results,” he said.
“The decision to continue DAPT beyond any time point must involve a balance of risks,” the editorialists conclude, adding, “The risk of bleeding must not be discounted, despite the magnitude of antithrombotic benefits (often nonstent-related) observed in the DAPT Study.” But advice to “individualize” treatment, they write, is not enough guidance for practitioners.
“Among patients without prior episodes of severe/moderate bleeding who tolerated DAPT to 1 year, significant ischemic event benefit is accrued by extending DAPT through 30 months if not longer,” they write. “In this context, the bleeding risk appears to be acceptable.”
Optimal Duration ‘Fluid’
ITALIC/ITALIC+ is one of 10 recent trials looking at the same question of longer vs shorter DAPT after stenting, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital, told TCTMD in a telephone interview. “The data are pretty consistent at this point…. If the purpose of the dual antiplatelet therapy is just for the stent, it doesn't seem that longer durations are better than shorter durations. In fact, it seems like the bleeding risk in general outweighs any benefit with respect to stent thrombosis.”
Future studies will need to sort out the optimal duration of DAPT, he said, but “it's a very fluid answer, depending on the type of patient and their ischemic risk, their bleeding risk, their comorbidities, the type of stent they got, and their coronary anatomy.... It's a mistake, for example, to say that everyone who got a stent should be on DAPT forever.”
He said that the upcoming PEGASUS trial, to be presented at the 2015 American College of Cardiology/i2 Scientific Session, might give further guidance on this issue.
1. Gilard M, Barragan P, Noryani AAL, et al. 6- versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. J Am Coll Cardiol. 2015;65:777-786.
2. Yeh RW, Mauri L, Kereiakes DJ. Dual antiplatelet therapy duration following coronary stenting [editorial]. J Am Coll Cardiol. 2015;65:787-790.
- The study was funded by Abbott Vascular.
- Drs. Gilard and Brener report no relevant conflicts of interest.
- Dr. Yeh reports serving on the advisory board of Abbott Vascular, serving as a consultant for Gilead Sciences and Merck, and receiving a salary from Harvard Clinical Research Institute.
- Dr. Mauri reports receiving research grants from Abbott Vascular, Biotronik, Boston Scientific, Bristol-Myers Squibb, Cordis, Daiichi Sankyo, Eli Lilly, Medtronic, and St. Jude Medical.
- Dr. Kereiakes reports serving as a consultant for Abbott Vascular, Ablative Solutions, Boston Scientific, Harvard Clinical Research Institute, and REVA Medical.
- Dr. Bhatt reports receiving research funding from AstraZeneca, Bristol-Myers Squibb, Eisai, and Sanofi-Aventis.