Shift to ‘personalized’ DAPT after PCI must balance complex bleeding, ischemic risks
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For adults who undergo PCI with a drug-eluting stent, recommendations for dual antiplatelet therapy have evolved from a standard 1-year duration for most patients to a more nuanced approach that balances risks for ischemia and bleeding.
One-year DAPT, aspirin plus a P2Y12 inhibitor, was considered a cornerstone of treatment after PCI with a bare-metal stent and then first-generation DES to reduce risk for spontaneous MI and stent thrombosis. Improved second-generation DES, with better polymers and smaller struts, sharply reduced that thrombotic risk; trial data favored shorter-term DAPT (less than 1 year) in those cases. Other data now suggest long-term single antiplatelet therapy with a P2Y12 inhibitor works just as well as long-term DAPT for CV protection while reducing bleeding risk.
The data have sparked uncertainty among cardiologists about how best to manage patients after PCI, including the optimal duration of DAPT, ideal escalation and de-escalation strategies and which drug to use for long-term antiplatelet monotherapy.
“We have a huge number of DAPT studies, and the messages given are not always consistent,” Marco Valgimigli, MD, PhD, FESC, deputy chief of interventional cardiology at Cardiocentro Ticino Institute, Lugano, Switzerland, told Cardiology Today. “First, it is difficult for the clinicians to know about all these studies. Second, even if you want to put the energy into reading all of them, you may be more confused than before. The reason why is because DAPT duration depends on patient characteristics.”
In a review published in the Cleveland Clinic Journal of Medicine in June 2021, Travis M. Howard, MD, and Umesh N. Khot, MD, both of the department of cardiovascular medicine and the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at Cleveland Clinic, wrote that the current trend for DAPT is toward shorter treatment in view of lower rates of late and very late stent thrombosis with newer DES and the risk for bleeding with DAPT; however, some patients at high risk for ischemic events and low risk for bleeding may benefit from longer treatment.
“There is no doubt that DAPT is a hot topic because every day we have a question about this,” Roxana Mehran, MD, FACC, FACP, FCCP, FESC, FAHA, FSCAI, professor of medicine and director of interventional cardiovascular research and clinical trials at the Zena and Michael A. Weiner Cardiovascular Institute at the Icahn School of Medicine at Mount Sinai, told Cardiology Today. “Our patients are faced with a conundrum of how to balance the higher bleeding risk of DAPT that comes with the protection against ischemic events. That is one of the biggest areas of concern. We still do not know the best possible approach, because it is different for every patient.”
Optimal DAPT duration ‘unsettled’
In a systematic review and meta-analysis published in Circulation in October 2020, Cardiology Today Intervention Section Editor Deepak L. Bhatt, MD, MPH, FACC, FAHA, MSCAI, FESC, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, and colleagues assessed data from 24 randomized controlled trials conducted through September 2019 that compared short-term (< 6 months) DAPT followed by aspirin or P2Y12 monotherapy with 12-month DAPT and extended term (> 12 months) DAPT after PCI with DES. The coprimary endpoints were MI and major bleeding, which constituted the net clinical benefit. Many of the original DAPT studies were conducted with patients predominantly with chronic coronary syndrome; the updated trial-level meta-analysis was designed to reflect new data that included patients with ACS and trials assessing up to 3 months of DAPT followed by discontinuation of aspirin rather than the P2Y12 inhibitor.
“The optimal duration of DAPT after PCI remains unsettled,” the researchers wrote.
Compared with 12-month DAPT, researchers found the net clinical benefit favored short-term DAPT followed by P2Y12 inhibitor monotherapy instead of aspirin in select patients; however, extended-term DAPT has a role for patients with low bleeding risk but with higher ischemic risk such as ACS.
“The real contribution of this analysis is it shows there are some patients in particular who do seem to benefit from longer durations of DAPT, and that is ACS patients,” Bhatt told Cardiology Today. “It is not fair to lump all DAPT patients together. Someone coming in with stable angina vs. ACS — that matters when talking about DAPT. The ACS patient is much more likely to benefit from longer-duration DAPT than someone with stable angina. For the higher-risk patient, it makes sense to give them the ‘insurance,’ the extra protection of DAPT, while doing other things like lifestyle modification and appropriate lipid, BP and glucose control.”
Best de-escalation strategies
Monotherapy with a P2Y12 inhibitor after a minimum period of DAPT is an emerging approach to reduce bleeding risk after PCI. To assess what might be the best therapy de-escalation strategy, Mehran and colleagues designed the TWILIGHT study, published in The New England Journal of Medicine in 2019, to examine the effect of ticagrelor (Brilinta, AstraZeneca) alone compared with ticagrelor plus aspirin in patients at high risk for bleeding or ischemic events who had undergone PCI.
“Often when we move to single antiplatelet therapy, we drop the P2Y12 inhibitor,” Mehran said. “TWILIGHT tried to answer the question of can we keep the P2Y12 inhibitor on board and just drop aspirin to reduce bleeding while maintaining ischemic protection? If we are aiming for 12-month DAPT in complex patients, maybe we could drop aspirin earlier and still have the same benefit with keeping a potent P2Y12 inhibitor agent [ticagrelor] for a longer period of time.”
In TWILIGHT, after 3 months of DAPT with ticagrelor plus aspirin, participants without a major bleeding or ischemic event continued to take ticagrelor and were randomly assigned to receive aspirin or placebo for 1 year. The primary endpoint was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. The study demonstrated that ticagrelor monotherapy lowered bleeding risk without raising ischemic risk compared with continued DAPT.
“Our view was we would be able to preserve the ischemic protection but at a very large benefit of reducing bleeding complications, and we proved exactly that,” Mehran said. “There was a 45% reduction in BARC 2, 3 and 5 bleeds. There was absolutely no difference in ischemic events between the two treatment groups, and we also proved with a substudy within TWILIGHT that there was no difference in the blood thrombogenicity on and off aspirin in the presence of ticagrelor. It was a game changer on so many levels.
“What we learned from TWILIGHT and other studies that came after is that potent P2Y12 inhibitor monotherapy can work in selected patients where you could preserve the ischemic benefit of prolonged DAPT and reduce bleeding, which is tremendous,” Mehran said.
Benefit persists with shortened DAPT
The MASTER DAPT study, published in NEJM in August 2021, showed that DAPT for just 1 month after PCI lowered bleeding rates and was noninferior for ischemic events compared with 3-month DAPT among participants at high bleeding risk. Randomization occurred 1 month after PCI, after which the abbreviated therapy group stopped DAPT, and the standard therapy group continued DAPT for at least 2 more months. DAPT consisted of aspirin and a P2Y12 inhibitor; single antiplatelet therapy consisted of either of those.
In new 15-month data from the MASTER DAPT trial presented at the European Society of Cardiology Congress in August, researchers reported that the benefits of early deintensification of DAPT persisted beyond 12 months compared with standard treatment. However, researchers also observed that during routine care, prior allocation to standard treatment was a major driver for more intense antiplatelet therapy beyond 1 year.
Ischemic risk — but not bleeding risk markers — also affected the decision-making of continued intensified long-term antiplatelet therapy, according to Valgimigli, who led the MASTER DAPT study.
“We took that extra 3-month phase into account when planning MASTER DAPT because we thought all patients would stop DAPT after 12 months and we would see the treatment effects after all groups stopped,” Valgimigli said. “The big surprise was that was not the case. There was an incredible proportion of patients in the control group which continued DAPT beyond 1 year. If you consider that we selected only patients at high bleeding risk, and guidelines state DAPT should never exceed 6 months in high bleeding risk, and some patients should not exceed 1 week, that is an incredible finding.”
‘Bleeding risk should dominate ischemic risk’
Guidelines recommend patients not on oral anticoagulation should discontinue DAPT; however, in MASTER DAPT, more than 15% of participants not on oral anticoagulation were still on DAPT at 15 months in the standard DAPT arm, Valgimigli said.
Similarly, although guidelines recommend patients prescribed oral anticoagulation should discontinue single antiplatelet therapy if free from recurrent ischemic events or repeat interventions, more than one-fourth were still on single antiplatelet therapy in the standard DAPT arm compared with 14% of the abbreviated treatment group.
“We also looked into the drivers — why did clinicians choose to continue DAPT?” Valgimigli told Cardiology Today. “Interestingly, that decision-making was driven by the perceived ischemic risk of the patient on clinical grounds. So, diabetes, HF. Not PCI complexity. Bleeding risk features did not play any role in the decision-making. This is a mindset that needs to be changed. We have evidence showing that bleeding risk takes a toll. The bleeding risk should dominate ischemic risk in decision-making with respect to DAPT duration. In practice, it is absolutely the opposite. People do not even assess bleeding risk.”
Future role of aspirin debated
Data from more recent trials have led to a shift in the way cardiologists think about the role of aspirin, Khot told Cardiology Today.
“Because aspirin was where we started, we thought we would build everything on top of aspirin,” Khot said. “What we are learning more and more ... is that aspirin is not benign in terms of bleeding risk. Should we shift to more of a monotherapy model, where patients just stay on the clopidogrel or ticagrelor? That will be a big question in the coming years.”
Mehran said many unanswered questions remain, including what the chronic maintenance therapy should be after PCI.
“Should it be aspirin forever? Or should it be a P2Y12 inhibitor forever?” Mehran said. “I believe that is a very important question.”
Bhatt agreed.
“We have been dropping the P2Y12 inhibitor, but maybe we should drop the aspirin and continue the P2Y12 inhibitor,” Bhatt said. “That has been studied with ticagrelor and clopidogrel, both good options for antiplatelet monotherapy. Both seem to be evidence-based strategies.”
Older data suggest that strategy could be effective. The CAPRIE trial, published in The Lancet in 1996, demonstrated long-term administration of clopidogrel to patients with atherosclerotic vascular disease was more effective than aspirin in reducing combined risk for ischemic stroke, MI or vascular death; the overall safety profile of clopidogrel was at least as good as that of medium-dose aspirin.
“CAPRIE did show that for high-risk secondary prevention, clopidogrel was modestly superior to aspirin,” Bhatt said. “In a sense, we are going back in time to something proven in a large, randomized trial. There will be more momentum in patients where DAPT is being abbreviated to de-escalate to P2Y12 inhibitor monotherapy therapy instead of aspirin. More research along those lines will be helpful.”
Additionally, Mehran said researchers and clinicians still do not understand which antiplatelet regimen is best in whom — and for how long.
“The level of understanding escalation and de-escalation of antiplatelet therapy at different times is very important,” Mehran said. “Whether you need to do this as guided by platelet function or genetic testing or unguided still needs to be determined in a large-scale clinical trial. There are many more questions and it is scary that we do not have all the answers, given that so many of our patients need these therapies.
“At the end of the day, we may come to a place where artificial intelligence will help us identify patients for different prescriptions, but then allow us to continue to improve on those recommendations with close monitoring,” Mehran said. “For now, we are using our best guess.”
- References:
- CAPRIE Steering Committee. Lancet. 1996; doi:10.1016/S0140-6736(96)09457-3.
- Howard CE, et al. J Am Heart Assoc. 2019;doi:10.1161/JAHA.119.012639.
- Howard TM, et al. Clevel Clin J Med. 2021;doi:10.3949/ccjm.88a.20113.
- Khan SU, et al. Circulation. 2020;doi:10.1161/CIRCULATIONAHA.120.046308.
- Mehran R, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1908419.
- Valgimigli M, et al. J Am Coll Cardiol. 2021;doi:10.1016/j.jacc.2021.08.074.
- Valgimigli M, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2108749.
- For more information:
- Deepak L. Bhatt, MD, MPH, FACC, FAHA, MSCAI, FESC, can be reached at dlbhattmd@post.harvard.edu; Twitter: @dlbhattmd.
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