Latest Post-DES Drug Trial Tests Aspirin Monotherapy After 1 Month of DAPT

The latest effort to hone the antiplatelet regimen following elective PCI is a new twist on an old idea: dual antiplatelet therapy (DAPT) followed by aspirin monotherapy, albeit on a very different time line than what was originally used when drug-eluting stents first came to market.

The hypothesis going in to One-Month DAPT, which was presented by Myeong-Ki Hong, MD, PhD (Yonsei University College of Medicine, Seoul, Korea), during the virtual American Heart Association 2020 Scientific Sessions, was that 1 month of aspirin plus a P2Y12 inhibitor followed by aspirin monotherapy would be noninferior to the standard regimen of 6 to 12 months of DAPT for the composite endpoint of cardiovascular events or major bleeding at 1 year.

Complicating matters, the 1-month group was treated with the BioFreedom stent (Biosensors), while the 6-to-12-month group was treated with the BioMatrix (Biosensors) or Ultimaster (Terumo) stents. The study included 3,020 elective PCI patients treated at one of 23 South Korean centers.

After 12 months, the primary endpoint occurred in 5.9% of the 1-month DAPT group and in 6.5% of the 6-to-12-month DAPT group, with the shorter-duration regimen meeting the bar set for noninferiority (P < 0.001), but not for superiority. Key clinical outcomes, including both ischemic and bleeding outcomes, were not statistically different between groups.

“To our knowledge, this study is the first randomized trial comparing 1-year clinical outcomes of 1-month DAPT followed by aspirin monotherapy after polymer-free, drug-coated stent implantation versus currently recommended DAPT after next-generation DES implantation in a diverse group of patients, both high bleeding risk and non-high bleeding risk,” Hong concluded. “DAPT for 1 month followed by aspirin monotherapy was not inferior to 6 to 12 months of DAPT in terms of 1-year outcomes among patients receiving a DES.”

Some Caveats

After the first-generation drug-eluting stents were approved, regulatory agencies extended DAPT recommendations to 12 months out of concern for stent thrombosis, with many physicians recommending lifelong aspirin thereafter. Current guidelines recommend 6 to 12 months of DAPT, though as newer DES have emerged with better healing and lower risks of stent thrombosis than seen with the earliest devices, trials have attempted to redefine the best antiplatelet regimen. Most of those have seen aspirin dropped, and a newer, more-potent antiplatelet continued over the longer term.

Róisín Colleran, MB BCh (Mater Private Hospital, Dublin, Ireland), discussing One-Month DAPT, called it “a timely trial for which there was an unmet clinical need,” amid a recent surge of monotherapy trials that, by contrast, dropped aspirin.

A number of trial quirks make it tricky to see how these results fit in, however. The fact that the two DAPT-duration study arms also involved different stents “without a factorial design . . . does make interpretation a little bit more difficult,” Colleran pointed out, particularly since the BioFreedom stent has been shown in recent studies to have lower efficacy in terms of target lesion revascularization as compared with contemporary DES.

“Reverse noncompliance” to DAPT assignment also raises questions, she continued. In the trial, 17% of patients assigned to 1 month of DAPT actually continued taking dual therapy beyond 4 weeks and in some cases for the duration of the trial. Moreover, the primary hypothesis was designed as an intention-to-treat analysis, but in Colleran’s view, that may have biased the results towards inferiority, “so in this respect a per-protocol analysis would have been preferable.”

Lastly, she noted, a full 75% of patients randomized to longer-duration DAPT ended up receiving 12 months of dual therapy, “even though 60% of patients presented with stable angina. So this wouldn't really be standard practice in the US or Europe where 6 months of DAPT would be recommended.”

Commenting on the study for TCTMD, both Michelle O’Donoghue, MD, MPH (Brigham and Women’s Hospital, Boston, MA), and Ajay Kirtane, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), raised a number of similar concerns to Colleran. They also questioned use of a primary endpoint that combined ischemic and bleeding events, which adds another layer of complexity in interpreting the findings.

Kirtane reeled off the names of other trials that have endeavored to shorten DAPT duration, including SMART-DATE, STOPDAPT-2, SMART CHOICE, GLOBAL LEADERS, TWILIGHT, and TICO. As noted by Colleran, the thrust of so many of these recent trials has been dropping aspirin and continuing instead with more-potent P2Y12 monotherapy. As such, Kirtane said, Hong et al’s study is something of a throwback to some of the earliest thinking in this space, when it was aspirin continued over the longer term. It is also “largely confirmatory,” he said, since the BioFreedom stent is already approved outside the US for 1 month of DAPT.

And while many of the recent trials have explored prolonged monotherapy using newer, more potent P2Y12 inhibitors, Hong clarified to TCTMD in an email that the second antiplatelet drug in his trial was clopidogrel in most patients.

O’Donoghue agreed. “There have been so many of these types of study designs trying to look at different durations of dual antiplatelet therapy,” she said. “Overall, I think that the weight of the evidence supports the concept that for lower-risk patients who are undergoing elective PCI in the setting of stable angina for noncomplex lesions, using newer-generation stents, you can probably ‘get away with’ shorter durations of dual antiplatelet therapy. Whereas in higher-risk patients, by and large, the weight of the evidence suggests that extending treatment with a P2Y12 inhibitor lowers risk of ischemic events but comes with a price of an increased risk of bleeding.”

Lower-Risk Patients

Both O’Donoghue and Kirtane stressed that Hong et al’s trial enrolled a relatively low-risk patient cohort. In subgroup analyses presented today by Hong, the only group to demonstrate a signal of different outcomes, according to antiplatelet regimen, was patients with ACS who had higher rates of the primary endpoint if they were treated with the shorter DAPT regimen  as compared with the longer course (7.2% vs 6.2%). This pattern was reversed for patients with stable angina (5.1% vs 7.6%; P = 0.013 for interaction).

“The exclusion of patients with MI is very important to emphasize,” Kirtane said. “While I hate to focus too heavily upon subgroups, the fact that longer was favored in the ACS subgroup with a weakly positive interaction term suggests that for ACS/MI patients, longer duration of P2Y12 inhibition likely remains favored.”

Discussing the decision to continue aspirin rather than use a more-potent antiplatelet agent during a morning press conference, Hong pointed out that in daily clinical practice, patients are more resistant to taking clopidogrel or a stronger P2Y12 receptor blocker, particularly if they have episodes of minor bleeding. “We also have to think of the price of the drug,” he said. “And, as we know, the original concept of dual antiplatelet therapy [after DES] was DAPT followed by aspirin monotherapy, not the P2Y12 receptor blocker. . . . I think aspirin monotherapy is more comfortable to the physician and the patient.”

Asked whether, on the basis of these results, he felt comfortable using 1 month of DAPT followed by aspirin monotherapy, Hong told TCTMD that he believes the trial “provides sufficient data of safety and efficacy [with] 1-month DAPT followed by aspirin monotherapy in elective PCI.” That said, he continued in an email, “simple lesions rather than complex lesions [would be] more highly recommended by our study.”