Mounting evidence over the safety and efficacy of shorter-term dual antiplatelet therapy (DAPT) regimes for high bleeding risk (HBR) patients undergoing percutaneous coronary intervention (PCI) was welcomed by panellists taking part in a US Food and Drug Administration (FDA) town hall debate during the recent TCT Connect 2020 meeting (14–18 October, virtual), but speakers noted that a number of key questions must be answered in future clinical trials.
DAPT—the dual-use of aspirin and a P2Y12 receptor inhibitor after PCI—is known to reduce recurrent ischaemic events, but comes at the expense of an increased risk of major bleeding in some patients. Recent clinical trials on newer generation drug-eluting stents (DESs) have shown an acceptable safety profile with a short course of DAPT, but the optimal DAPT duration in HBR patients undergoing PCI remains unknown.
During the TCT session, Adrian Magee from the FDA’s Center for Devices and Radiological Health (CDRH, Silver Spring, USA) presented the US regulatory view on short duration DAPT in HBR patients. “I believe what is well established in 2020 is that high bleeding risk patients undergoing PCI are a heterogeneous patient subset comprising approximately 15–45% of current PCIs,” Magee commented. He noted that accumulating trial data suggest that DES placement followed by three- or one-month DAPT post-PCI may be safe in selected HBR patients.
Magee said that the US regulatory focus is to encourage the performance of robust clinical trials to evaluate the safety and effectiveness of new devices or treatment strategies. “The FDA strives to balance the need for scientific rigour with the sponsor and clinical practice realities in accordance with our ‘least burdensome’ principals and to provide guidance to study sponsors regarding labelling claims that may be considered following trial completion and analysis,” he noted, commenting that randomised trials provide the best assessment of benefit versus risk, but noting that single-arm studies may be acceptable if supported by other strong clinical data.
Turning to short duration DAPT studies, Magee said: “A significant reduction of the rate of major bleeding would provide strong support for shorter DAPT duration post-PCI, and the FDA recommends, of course, a standard definition. For the primary bleeding endpoint BARC [Bleeding Academic Research Consortium] 3 or 5 is well established to be associated with severe bleeding. Other BARC categories should be presented as secondary endpoints.
“Target lesion revascularisation may be an important endpoint particularly if it is a comparison of two different stent designs and FDA would prefer to see this as a separate endpoint.
“For regulatory approval FDA recommends studying a one-month or three-month clear population, which is a post-procedural blanking period. From a regulatory standpoint this is a more rigorous comparison and preferred.”
Magee added that while good progress has been made in understanding the risks faced by HBR patients undergoing PCI, knowledge gaps do remain. “Future studies should focus on balancing the bleeding and ischaemic trade-offs faced by individual HBR patients,” he said. Other “knowledge gaps” he highlighted included which single antiplatelet drug should be used following DAPT, whether there is a net benefit for a single antiplatelet agent post-PCI, and the possible benefit or risk of medical therapy versus PCI in the HBR patient population.
Following Magee, Roxana Mehran (Icahn School of Medicine, New York, USA) offered a clinician’s perspective on HBR and short duration DAPT clinical trials, and outlined some of the published data. Mehran described HBR patients as a “common group of patients in the cath lab”, commenting: “We see it really every day and we have to make important decisions on these patients.”
“DAPT is the cornerstone [of treatment],” she said, adding that for some patients this therapy can be required for up to three years. “There is no question that there is an improvement of ischaemic events, but, in high-risk patients there is an increase of bleeding events, this is an important trade-off.”
Mehran then offered an overview of the clinical trials to have offered data into treatment of HBR patients, beginning with the LEADERS FREE trial which compared the BioFreedom (Biosensors) drug-coated stent (DCS) to a bare metal stent. “[LEADERS FREE] showed that DCS was efficacious in reduction of target lesion revascularisation but the safety endpoint with one month of DAPT was superior in DCS compared to BMS,” she noted.
Other studies highlighted by Mehran include the TWILIGHT study, assessing ticagrelor monotherapy, after three months of aspirin plus ticgrelor in patients after PCI, who were intended to be treated with ticagrelor and aspirin for twelve months; STOP DAPT-2 which showed that one-month DAPT followed by Clopidogrel monotherapy, was superior to 12-month therapy at preventing net adverse ischaemic events; and ONYX ONE, which compared a durable polymer drug-eluting stent (Resolute Onyx, Medtronic) to a polymer-free drug-coated stent (BioFreedom) in patients at high risk of bleeding and treated with one-month DAPT, finding the former to be non-inferior in HBR patients treated with one-month DAPT. “This non-inferiority is important,” Mehran said, adding that this ”does bring the Onyx stent into the milieu of treating HBR patients.”
Mehran also pointed to the XIENCE Short DAPT clinical trials, results of which she presented during a later TCT session, finding that a shorter course DAPT (either one or three months) after PCI using the XIENCE everolimus-eluting stent platform (Abbott) is non-inferior to standard DAPT up to 12 months.
Looking to the horizon, Mehran noted that the MASTER DAPT trial, comparing short versus prolonged DAPT following PCI with Terumo’s Ultimaster or Ultimaster Tansei drug-eluting bioresorbable polymer stents, will be the largest prospective trial in the area to date. It is expected that findings of MASTER DAPT will be presented in 2021.
Despite this mounting evidence, Mehran said a number of unanswered questions on short duration DAPT exist. These, she said, include whether there are device-related differences in HBR patients with current generation DES, what is the optimal duration of DAPT post PCI in HBR patients, as well as approaches to patients requiring oral anticoagulants.
Following her presentation, Mehran opened the session out for discussion, asking Mitchell Krucoff (Duke Clinical Research Institute, Durham, USA) the direction he would like to see future research heading, to which he commented that he would like to see further research on drug selection and the duration of drug therapy. “I think we have a lot more work to do on the pharmaceutical side, and as we do that dichotomising the groups who require oral anticoagulants from some of the other HBR groups may also be an important aspect of how we design trials,” Krucoff said.
“I think the problem is that now there will be a multiplication of small trials that will address a single question, and probably be inconclusive,” said Davide Capodanno (University of Catania, Catania, Italy) who was asked to comment, following his recent authorship of a paper on the issue in the Journal of the American College of Cardiology (JACC), on how the design of future trials could answer some of the unanswered questions around short duration DAPT. “What we need is a large trial, perhaps multifactorial, that addresses simultaneously the two very important questions for me, which are the short versus long DAPT in HBR patients, and maybe which monotherapy [is favourable]—clopidogrel or aspirin—I think these are the burning questions.”
However, according to Robert Byrne (Mater Private Hospital, Dublin, Ireland)—who presented at TCT Connect 2020 the findings of the COBRA-REDUCE randomised trial of 14-day DAPT using the COBRA PzF stent (CeloNova)—awaiting a “perfect” clinical trial may prove to be fruitless. “If we are waiting for the perfect clinical trial to be done, we are probably not going to get there,” he said. “It is not an area where a one-size-fits-all approach is going to work. All of the factors mentioned so far are going to be relevant—using a high performance stent, using optimal techniques; many of these elderly patients have really calcific disease, they require extensive, carefully planned PCI with calcium modification [and] with intravascular imaging, and it is only when you see the end result that the operator can give a steer on whether this is a candidate for a shorter duration of DAPT than another patient.”