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ABSTRACT & COMMENTARY
By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco, Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SOURCE: Mauri L, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-2166.
Dual antiplatelet therapy (DAPT) following coronary stenting is essential for the prevention of stent thrombosis, which can occur due to a response to the vascular scaffold, as well as to the local inflammation that occurs after angioplasty. DAPT after drug-eluting stent (DES) implantation is currently recommended for at least 12 months in the United States and for 6 months in Europe. Concern over very late stent thrombosis (occurring later than 1 year) with DES prompted a collaborative effort between the FDA and device and pharmaceutical manufacturers to study the efficacy of DAPT beyond 1 year in these patients.
The DAPT trial, whose results were published in the New England Journal of Medicine following a presentation at the American Heart Association meeting in November, enrolled patients following treatment with drug-eluting and bare metal stents. There were 22,866 patients who received DES initially registered. From that number, more than half dropped out before 1 year. Some of these were not eligible because they had experienced ischemic or bleeding events or had demonstrated nonadherence to therapy. Others withdrew consent or were otherwise unable to be randomized. In the end, 9961 patients underwent randomization at 12 months to receive either continued thienopyridine or placebo for up to 33 months. More than 95% of these patients were included in clinical follow up at 30 months.
During the period from randomization at 12 months to analysis at 30 months, patients receiving continued thienopyridine showed a significantly lower incidence of both stent thrombosis (0.4% vs 1.4%, P < 0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs 5.9%, P < 0.001). Among MACCE events, myocardial infarction (MI), in particular, was lower in the continued thienopyridine group. MI not related to stent thrombosis accounted for just over half of this benefit, presumably indicating an advantage in preventing events distant from the stented region. As might be expected, these benefits came at the cost of higher rates of moderate and severe bleeding (2.5% vs 1.6%; hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.21 to 2.16; P = 0.001), although severe and fatal bleeding (by GUSTO and BARC criteria) were not significantly increased. All-cause mortality was slightly higher in the continued DAPT group (2.0% vs 1.5%; HR, 1.36; P = 0.05), with non-cardiovascular death accounting for the difference. Interestingly, bleeding-related deaths were not the sole contributor; cancer-related deaths were significantly greater (31 vs 14, P = 0.02) in the group receiving continued thienopyridines. The authors concluded that treatment beyond 1 year with dual antiplatelet therapy has measurable benefits in terms of ischemic outcomes, but at the expense of higher rates of bleeding.
Back in 2006, the interventional cardiology world was shaken by data suggesting increased rates of late and very late stent thrombosis with first-generation DES. The current post-percutaneous coronary intervention (PCI) antiplatelet recommendations, as well as the DAPT trial itself, were born of these concerns. However, over the past several years, multiple studies with second- and third-generation DES have focused on the shorter end of the time scale, comparing 12 months of thienopyridine to 6-, 3-, or even 1-month durations. The majority of these smaller and shorter-term studies have shown non-inferiority of the shorter durations of therapy. Although the European Society of Cardiology guidelines currently recommend 6 months of treatment post-stent, Abbott’s Xience DES has had CE Mark labeling for at least 3 months since 2012, and Medtronic updated its European labeling for the Resolute Integrity stent to state that "patients who interrupt or discontinue DAPT medication one month or more after stent implantation are considered at low risk…."
What then are we to make of these results, and how will they change practice? In an accompanying editorial, Dr. Antonio Columbo wisely argues that the time course following DES implantation should be divided into an early "mandatory" period and a later "possibly beneficial" phase. A bevy of smaller studies (PRODIGY, RESET, OPTIMIZE, and, most recently, ISAR-SAFE) have focused on the "mandatory" period, and have, for the most part, shown that low-risk patients do not show an undue hazard from shorter durations of thienopyridine. The DAPT study focuses on the later, possibly beneficial, period, and does so with a rigorous study design and large sample size. The results show convincingly that there is a small but real benefit to longer-term therapy in terms of preventing both thrombosis of the stented segment and acute coronary syndromes involving other vessels.
In examining the results, we should ask ourselves: Who were the patients in this trial and how do they compare with our patient population? The DAPT trial evaluated patients who were relatively adherent and had already completed a year of thienopyridine without adverse events. In many ways, this focuses on patients who were already in a relatively low-risk category. Patients who had ischemic events in the first year post-PCI were not evaluated, but one might reasonably expect an even higher benefit to longer-term therapy in such patients.
It should be pointed out that the newer non-thienopyridine agent, ticagrelor, was not included in the DAPT study. Also at issue is the apparent differential response among the different stent types in the study. For example, the difference between thienopyridine and placebo groups was most marked with the older paclitaxel-eluting stents, and was less striking with more contemporary stent platforms.
As with many issues in medicine, an individualized approach is needed when evaluating the duration of antiplatelet therapy for any particular patient. Tailored therapy that compares bleeding risk with known risk factors for MI and stent thrombosis is likely to be the best tactic, and this requires intimate knowledge of the each patient’s risk profile and stent anatomy. Patients with low propensity for bleeding, who are at higher risk of ischemic complications, including patients with acute coronary syndrome with multiple or complex stents, now have data to support longer-term therapy.