ACC 2019 Day 2: primary results of the AUGUSTUS trial, Ticagrelor vs DAPT and more
Reported from ACC.2019 in New Orleans
Francesco Costa reports live on late-breaking trials of interest for the interventional community presented at ACC 2019: AUGUSTUS, GLASSY, TICAGRELOR REVERSAL, DEFINE PCI and MRUSMI.
On day two the convention center is packed full since the very start: many discussions have been connected to the early “leakage” of information regarding the results of the two TAVI trials, PARTNER 3 and Evolut Low risk. Nonetheless, the main tent is full at 8 AM for the presentation of the two trials, giving a strong message to the community in support of the importance of live presentations. While the results have been anticipated, the excitement was palpable, and the audience concluded the presentation in a standing ovation applause. Prof. Braunwald, part of the Panel during the discussion, defined this as a “historical moment” in cardiology, “one that we will tell our children, I was there”.
AUGUSTUS: the pharmacological treatment of patients undergoing coronary stenting
Late breaking clinical trials continued with a series of many important studies in various domains. It was also an especially important day for the pharmacological treatment of patients undergoing coronary stenting as the results of the AUGUSTUS trial have been presented for the first (very first in this case) time.
Let’s examine the study design and results in detail:
The study included 4,614 patients with atrial fibrillation undergoing PCI or suffering an acute coronary syndrome (both medically managed or undergoing PCI). This study had a factorial 2x2 design, so patients at the moment of the inclusion underwent two randomizations: first randomization was to Apixaban 5mg b.i.d. vs. vitamin K antagonist (VKA) comparing through the type of oral anticoagulant; the second randomization was to Aspirin 81mg vs. Placebo comparing through the strategy of triple therapy vs. dual therapy.
The main inclusion criteria were the presence of non-valvular AF or flutter with indication for OAC and the novel presentation with an ACS or the need for coronary stenting. Patients were enrolled in the study within 14 days from those index events. Main exclusion criteria were the need for OAC due to conditions other than AF (e.g. prosthetic mechanical heart valve), severe renal insufficiency (e.g. CrCl<30 mL/min) or prior intracranial haemorrhage.
The study was designed and powered to show first non-inferiority of the first randomization strategy with respect to bleeding (primary endpoint: ISTH major or clinically relevant non-major bleeding), and in the case this was reached, superiority was also tested. Among roughly 500 hospitals worldwide, the population ultimately included and followed for 6 months after the index event in the study had a moderate-high ischemic risk (CHA2DS2-VASc score mean 3.9) and bleeding risk (HAS-BLED score mean 2.9). Most of the patients have been treated with the P2Y12 inhibitor clopidogrel (92.6%).
The study showed a significant 31% reduction of the primary endpoint with Apixaban vs. VKA. The magnitude of this effect corresponded to an absolute reduction of 4.2% during 6 months of follow-up with a number needed to treat to prevent bleeding of 24. Importantly, treatment with Apixaban was also associated to a significant 50% reduction of stroke and re-hospitalization. On the other hand, with respect to the second randomization, patients undergoing a path of dual therapy by skipping aspirin were associated to a 47% reduction of bleeding, with a number needed to treat of 14.
The presenter, Dr. Renato Lopes from the Duke Clinical Research Institute, ultimately concluded that Apixaban is superior to VKA in this scenario and that a strategy with dual therapy is safer than triple therapy. The manuscript has been simultaneously published in the New England Journal of Medicine (read our Journal Club review here). The trial had very positive reactions both during the presentation and online on Twitter. While now evidence of a class effect for the superior safety of NOACS vs. VKA in patients undergoing stent appear evident from the three trials so far presented, many remain concerned regarding the routine implementation of a dual therapy strategy.
In the AUGUSTUS, as also in the other two trials, a trend towards an excess of MI and stent thrombosis was seen when avoiding aspirin, and importantly these trials alone are not powered to detect differences in this more rare events. Another important point to stress is that in all these trials, including AUGUSTUS there was a screening time in which patients were treated with triple therapy before being included. This time was 7 days in AUGUSTUS. Hence this consideration will be important at the time of translation of these results to clinical practice as the risk of stent thrombosis peaks during the first weeks after implantation.
LIVE on #Periscope: #LBCT#AUGUSTUS#ACC19https://t.co/FIOeysLG4i
— mirvat (مرفت عبدالله الأصنج) (@mirvatalasnag) March 17, 2019
#AUGUSTUS trial at #ACC19 shows superiority of Apixaban vs. VKA with 31% bleeding reduction & superiority of Dual Tx vs. Triple tx (irrespect of OAC type) with 47% bleeding reduction @PCRonline@sbrugaletta@hect2701@DFCapodanno@Ortega_Paz@mmamas1973@mirvatalasnag@ACCinTouchpic.twitter.com/Y3TAWpvr8v
— Francesco Costa (@Costa_F_8) March 17, 2019
Other studies of interested presented during ACC 2019
During day 2 of the conference several other studies caught my attention and would definitely deserve some attention from the interventional cardiovascular community:
- GLASSY, a sub-study of the GLOBAL LEADERS trial in which blinded event adjudication was performed evaluating the impact of Ticagrelor monotherapy vs standard DAPT. Ticagrelor monotherapy ultimately showed non-inferiority as compared to DAPT, and a reduction of MI and ST was evident at landmark analysis beyond 12 months.
- TICAGRELOR REVERSAL: data regarding the first reversal agent of Ticagrelor, tested in a phase 1 setting, showed a consistent reversal of platelet inhibition in roughly 5 minutes after infusion. The study has been simultaneously published in the NEJM.
- DEFINE PCI: a study evaluating the measurements and effects of iFR measured after stenting.
- MRUSMI: evaluated the effect of sonothrombolysis during primary percutaneous coronary intervention. The authors studied this interesting strategy ultimately finding a reduction of the primary endpoint and a better ejection fraction at cardiac MRI with the experimental treatment. The study has been simultaneously published in JACC.
It was an exciting day at the conference, with good science and novel enthusiasm for the importance of in-person scientific conferences.
Read more about Late Breaking trials presented at the ACC.19
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