More DAPT Duration Data, More Calls to Tailor to Individual Patients

Trials and subanalyses of shorter dual antiplatelet therapy (DAPT) duration following PCI continue to trickle in from the major cardiology meetings—today’s from TCT 2021—amid growing consensus that the “categories” of bleeding or ischemic risk matter less than tailoring antiplatelet intensity and duration to individual patients.

In a new ACS analysis from MASTER DAPT, which focused on patients at high bleeding risk (HBR), the shorter DAPT regimen tested did not appear to increase the risk of ischemic events and was associated with a lower risk of bleeding. Meanwhile, a separate analysis combining patients from the STOPDAPT-2 and STOPDAPT-2 ACS trials found that clopidogrel monotherapy after 1-month DAPT, as compared with 12 months of aspirin and clopidogrel, cut the risk of major bleeding without increasing CV events. However, its presenters did flag a numerical increase in CV events in ACS patients.

Both analyses were presented as part of a late-breaking clinical science session earlier today.

The new data build on studies going back more than a decade seeking to find the sweet spot for limiting stent-related adverse events without upping the risk of bleeding. Protracted DAPT was mandated for drug-eluting stents, early on, to mitigate the risk of stent thrombosis, but newer generations of stents with different designs and coatings have cut that risk dramatically.

Moderating a panel discussion following the press conference presentation of both analyses, Ajay Kirtane, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, NY), asked panelists how they put all of the emerging data together clinically.

“At the end of it all,” said Anna Sonia Petronio, MD (Azienda Ospedaliero Universitaria Pisana, Pisa, Italy), “you should tailor the therapy with the patient and not look to certain categories as a first objective.”

Luca Testa, MD, PhD (IRCCS Policlinico S. Donato, Milan, Italy), agreed, noting that bleeding has now moved into the center of the discussion; with newer-generation stents, the device itself is no longer the focus.

“We’ve finally got to the idea that bleeding is probably even more important than the fear of the ischemic events [and] considering the recent data, that's probably the real scenario we should take care of,” he said. “I’m very happy, because we’ve actually dropped the idea of giving dual antiplatelet therapy to our patients for 6 months or 12 months, or even longer, but we were afraid about the stents, about the devices.”

What’s clear now, Testa added, is “the concept should be the patient. I totally agree with Anna Sonia: we need to tailor the therapy.”

Ischemic Risk in MASTER DAPT

Full results from both MASTER DAPT and STOPDAPT-2 ACS were released this past summer at the European Society of Cardiology (ESC) Congress 2021, as reported by TCTMD. 

MASTER DAPT, looking specifically at DAPT duration in post-PCI patients at high risk for bleeding, including one-third who were taking oral anticoagulation, showed that 1 month of DAPT was noninferior to 3 months or more for both net adverse clinical events (NACE) and major adverse cardiac or cerebrovascular events (MACCE), although bleeding was less common with the shorter regimen.

Today Pieter Smits, MD, PhD (Maasstad Hospital, Rotterdam, the Netherlands), presented the prespecified ACS analysis from the 4,579-patient MASTER DAPT trial. In all, 914 of the patients randomized to the abbreviated DAPT strategy had had a prior MI in the last 12 months; 1,381 had not. In the nonabbreviated DAPT arm, those numbers were 866 and 1,418.

For the primary endpoint of NACE, overall event rates were lower for patients with no prior MI, regardless of DAPT duration, but in both the prior MI and no prior MI groups, there were no significant differences between patients randomized to shorter versus more-standard DAPT.

A similar pattern was seen for MACCE and for the individual components of the endpoint, suggesting that even in patients at higher risk for ischemic events, the shorter DAPT regimen did not appear to put them at risk.

Instead, clinically relevant nonmajor or major bleeding—not surprisingly—was the only endpoint for which a difference was seen between the DAPT arms, with higher bleeds of this caliber in the longer DAPT duration patients, both in those who’d had a prior MI and in those who hadn’t.

“NACE and MACCE rates did not differ between an abbreviated—median 34 days—and a nonabbreviated—median 193 days—DAPT strategy,” Smits concluded. Moreover, “there was no signal towards increased ischemic risk in the abbreviated DAPT population presenting with recent acute myocardial infarction.”

STOPDAPT-2 Total Cohort

Results for nearly 6,000 patients were combined to make up the STOPDAPT-2 “total cohort,” of whom nearly one-third were categorized as high risk for bleeding. Both HBR and non-HBR patients were randomized to 1 month or 12 months of DAPT.

As Yuki Obayashi, MD, and Ko Yamamoto, MD (both Kyoto University Hospital, Japan), showed in a joint presentation at TCT, the shorter DAPT regimen was noninferior for the primary endpoint of CV death, MI, stent thrombosis, and TIMI major/minor bleeding as well as a secondary CV endpoint which omitted bleeding. Major bleeding, again not surprisingly, was higher for the 12-month regimen.

In a series of subanalyses zeroing in on ACS versus chronic coronary syndrome (CCS), HBR versus no HBR, and complex PCI versus noncomplex, the results largely echoed the overall cohort findings. The only one to stand out, said the investigators, was the treatment-by-subgroup interaction in the ACS/CCS analysis.

“Given the numerical increase in cardiovascular events with clopidogrel monotherapy after 1-month DAPT in ACS patients, further studies would be warranted to explore the optimal antithrombotic strategies in ACS patients,” Yamamoto concluded.

On the other hand, he stressed, the effects of 1-month DAPT relative to 12-month DAPT for cardiovascular and bleeding events were consistent regardless of HBR and complex PCI. “Complex PCI might not be an appropriate determinant for DAPT durations after PCI,” he said.

Further Considerations

During the press conference, Kirtane pointed out that in the early days of drug-eluting stents and the requirement for protracted DAPT, surgeons pushed back, concerned about patients who might need to head unexpectedly to surgery, cardiovascular or otherwise.

“When I trained, there was a surgeon who used to refer to Plavix as ‘FP,’ and I’ll leave it to your imagination what that means, because it used to make everybody bleed,” said Kirtane. Is that still a concern, he asked cardiothoracic surgeon Michael Borger, MD, PhD (Leipzig Heart Center, Germany).

“Certainly the [sooner] we can stop the dual antiplatelet therapy, from a surgeon’s perspective, the better,” Borger replied. “Having said that, we know that there's a lot of patients that present with initial treatment for the acute coronary syndrome, and then later require surgery but cannot wait long enough to stop the dual antiplatelet therapy.”

“To be honest,” Borger continued, “I don't see it as a big problem for cardiac bypass surgery. With some of the other [antiplatelets], prasugrel for example, that's a big problem. But not Plavix, in my view. If you're going to be doing a big aortic operation or some sort of redo surgery, maybe, but for straightforward coronary bypass surgery, I really don't see it as too much of an issue.”

Kirtane also noted that both analyses at TCT used a NACE-type endpoint—something he urged the field to move away from. “When you're mixing ischemic events going one way  . . .  with bleeding events going the other way, it biases towards the null,” he said. “Frankly, the NACE thing is really, really hard to get around and understand so I would strongly encourage people, especially as we start getting into more and more trials in this space, to get away from that NACE endpoint and really separate out the bleeding from the ischemic endpoints. Otherwise, it's just very, very muddy and the confidence intervals are wide and you really can’t make definitive conclusions.”

Worth considering too, he said, is that extended DAPT has been shown to reduced non-stent-related myocardial infarction, uttering a phrase that was scarcely heard at the TCT meeting a decade ago: “It's not just only about the stent.”

Following Smits’ late-breaking presentation, discussion circled briefly around the stent and bioresorbable polymer used in MASTER DAPT (Ultimaster; Terumo), and whether shortening DAPT duration would apply just to this device or others. Smits said that he himself believes other stents would also need to be investigated to be sure.

Kirtane, however, noted that in many ways the data presented today, and at ESC, offer reassurances for a strategy many cardiologists are already using. “Honestly, we've been doing it for high-bleeding-risk patients up-front, because we’ve sort of come full circle to the point where we recognize now that bleeding is a really important clinical endpoint for patients. So as long as we can do that and feel comfortable about the safety, which is why this study is important—[showing we don’t incur] an ischemic risk penalty by doing it—then of course we would do it.

Worth considering too, Kirtane added, is that extended DAPT has been shown to reduced non-stent-related myocardial infarction, uttering a phrase that was scarcely heard at the TCT meeting a decade ago: “It's not just only about the stent.”