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More data starting to emerge about pretreatment, switching DAPT after PCI
SAN DIEGO — More information is needed regarding how to pretreat patients with dual antiplatelet therapy before PCI, but recent research has provided more evidence as to how to switch from one therapy to another after patients undergo PCI, according to two presentations at TCT 2018.
Pretreatment with DAPT
There may be some confusion as to the definition of pretreatment, as it may pertain to before angiography or diagnosis, before PCI or both, Giuseppe Tarantini, MD, PhD, FESC, professor and director of interventional cardiology at University of Padua in Italy, said during the presentation.
“Actually, pretreatment should mean before angiography or diagnosis,” Tarantini said. “This is because if we go on dual antiplatelet therapy before PCI, this is a preloading and this is part of the downstream strategy. It’s not an upstream strategy.”
In a systematic review and meta-analysis published in JAMA in 2012, researchers found that there is a gradient between coronary disease severity and the favorable impact of pretreatment with DAPT.
According to the presentation, some of the limitations of the meta-analysis was the trials included such as the PCI CURE trial. In this trial, ACS was designed for noninvasive management, as 57% were not treated with catheterization. PCI was performed in 21% of patients with a median time to the procedure of 10 days.
“That means that in this case, the pretreatment was a real upstream treatment,” Tarantini said during the presentation. “The other treatment was done before any diagnosis in this case.”
Another trial in the meta-analysis — the CREDO trial — found that patients may benefit from pretreatment if they received clopidogrel at least 6 hours before PCI.
“This trial is completely different because in this case, the coronary anatomy was known prior to PCI. This is not a pretreatment or upstream trial. This is a preloading trial, which means a downstream trial.”
Prior evidence has determined that in patients with non-STEMI, clopidogrel has shown a flawed superiority for upstream compared with downstream. Treatment with prasugrel (Effient, Daiichi Sankyo/Eli Lilly) favors downstream vs. upstream. The comparison of upstream vs. downstream is currently unsettled with ticagrelor (Brilinta, AstraZeneca), as there is no overall advantage for patients with STEMI, according to the presentation. Glycoprotein IIb/IIIa inhibitors are part of the downstream strategy and has been previously given a IIIa recommendation when coronary anatomy is not known.
In European Society of Cardiology guidelines for the treatment of patients with ACS published in the European Heart Journal in 2015, there was no recommendation for or against pretreatment, and optimal timing for ticagrelor or clopidogrel has not been adequately investigated, Tarantini said.
In a 2017 focused update published by the ESC in the European Heart Journal, pretreatment with a P2Y12 inhibitor was given a Ia recommendation in patients with known coronary anatomy who will undergo PCI.
“In this case, it’s one indication, but this is not pretreatment,” Tarantini said. “This is not an upstream strategy. It is again preloading and this is a downstream strategy.”
Treatment with ticagrelor or clopidogrel received a IIa C recommendation as soon as patients are diagnosed with non-ST-elevation ACS.
Tarantini and colleagues are currently conducting the DUBIUS trial, in which 2,520 patients with non-STEMI are assigned an upstream strategy with ticagrelor or a downstream strategy. Patients in the downstream group will then be assigned prasugrel or ticagrelor if they undergo PCI. The primary endpoints are net adverse clinical events at 30 days, defined as MI, CV death, stroke or Bleeding Academic Research Consortium (BARC) types 3, 4 or 5.
Upstream pretreatment has been shown to be ineffective in patients who were stable in studies including PRAGUE-8 and ARMYDA-5.
In ESC guidelines published in the European Heart Journal earlier this year, pretreatment for clopidogrel received a IIb C recommendation for patients in whom the probability of PCI is high. For peri-interventional treatment, a Ia recommendation was given for clopidogrel for elective stenting, and cangrelor (Kengreal, Chiesi) may be considered with a IIb A recommendation in P2Y12 inhibitor-naive patients who are undergoing PCI, according to the presentation.
Switching DAPT after PCI
Switching from one P2Y12 inhibitor to another is sometimes required based on patient characteristics, clinical setting, side effects, concomitant therapies, cost and the mandated switch from IV to an oral P2Y12 antagonist, Matthew J. Price, MD, FACC, FSCAI, director of the cardiac catheterization laboratory at Scripps Clinic in La Jolla, California, and assistant professor at Scripps Translational Science Institute in La Jolla, said during the presentation.
“While clinical data for switching is for the most part lacking, strategies that we think are optimal can be derived from incorporating the known mechanisms of action of these drugs and pharmacodynamic studies of switching,” Price, a member of the Cardiology Today’s Intervention Editorial Board, said. “In addition, whether or how to switch can be influenced by the timing of the switch, that is whether the switch occurs in the acute or chronic setting may influence the strategy due to the relative risk of thrombotic events.”
When determining how to switch DAPT in patients after PCI, it is critical to consider the binding mechanism, the half-life of the active metabolite, the receptor occupancy and the offset of action, according to the presentation.
“Stepping back, we can come up with what we think are rational ways to switch these agents,” Price said.
In an international expert consensus published in Circulation in 2017, researchers defined three ways of switching DAPT based on pharmacodynamic considerations. Escalation is switching from a less intensive oral P2Y12 inhibitor to a more intensive treatment, such as from clopidogrel to prasugrel or ticagrelor, and de-escalation can be switching from prasugrel or ticagrelor to clopidogrel, according to the presentation. Change is switching from one more intensive agent to another such as prasugrel to ticagrelor.
Timing of the switch was also discussed in the expert consensus and defined in four ways: acute (< 24 hours from event), early (1 day to 30 days from event), late (between 30 days and 1 year from event) and very late ( 1 year from event).
In a study published in the Journal of the American College of Cardiology in 2010, researchers assessed the effects of switching from clopidogrel to prasugrel. Patients who were given a loading dose of prasugrel to a maintenance dose of clopidogrel had a greater magnitude of P2Y12 inhibition compared with switching to a maintenance dose.
In the RESPOND trial published in Circulation in 2010, patients who were on a maintenance dose of clopidogrel and were given a loading dose of ticagrelor had a rapid onset of inhibition.
Based on the expert consensus recommendations, switching in acute and early phases from clopidogrel to prasugrel or ticagrelor should be done with a loading dose regardless of when the last dose of clopidogrel was given. During late and very late phases, it was determined to be reasonable to escalate from clopidogrel to prasugrel or ticagrelor without a loading dose.
In the RECOVERY trial published in the Journal of the American College of Cardiology in 2012, researchers assessed patients who were given a maintenance dose of prasugrel or clopidogrel. It took 7 to 9 days for the effect of prasugrel to wear off. Ticagrelor has a rapid offset within the first 2 days, according to the presentation.
In the CAPITAL OPTI-CROSS study published in Thrombosis and Haemostasis in 2017, patients who were given a loading dose of clopidogrel when stopping ticagrelor had a divergence in platelet reactivity between strategies at 24 and 48 hours.
“In the acute phase, this may make a difference,” Price said.
In the SWAP-4 study published in Circulation earlier this year, researchers found that platelet reactivity increases with clopidogrel. In addition, initiating the switch with a loading dose of clopidogrel 12 hours after the last dose of ticagrelor provides greater levels of inhibition during the first 48 hours vs. starting a maintenance dose of clopidogrel.
The expert consensus recommendation mentions that there is a lack of group consensus on how to de-escalate from prasugrel to clopidogrel, although it is reasonable to de-escalate with a loading dose in the acute phase and a maintenance dose in the last phase. Avoiding a gap in platelet inhibition can be done when de-escalating from ticagrelor to clopidogrel with a loading dose, especially during the acute phase. It is also reasonable to de-escalate from ticagrelor to clopidogrel without a loading dose if the reason for the switch is related to a bleeding event, according to the presentation.
When changing therapy, the expert consensus recommendation suggests a loading dose of prasugrel when switching a patient from ticagrelor. Patients who are switching from prasugrel to ticagrelor are recommended to take either a loading dose of ticagrelor or straight to a maintenance dose, according to the presentation. – by Darlene Dobkowski
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Disclosures: Price reports he has received grant or research support from Daiichi Sankyo and has received consultant fees or honoraria from Abbott Vascular, AstraZeneca, Boston Scientific, Chiesi USA, Medtronic and W.L. Gore and Associates. Tarantini reports he received honoraria or consultant fees from Abbott, AstraZeneca, Boston Scientific, Chiesi, Edwards Lifesciences, Gada, Medtronic, Philips Healthcare, Sanofi Aventis and St. Jude Medical.