cardiomet-ce

Please help us spread the word that we have posted an "encore" CE/#CME-accredited tweetorial from #AHA24 here on BlueSky! First post at bsky.app/profile/card...

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25) Thank you for joining us for this update from #AHA2024! You may now proceed to cardiometabolic-ce.com/antithrombot... and collect your 🆓CE/#CME certificate! Thanks as always to @SidPatel (and to @sameralsaid!) for leading us through these hot-off-the-presses data!

24) @sidpatel & the #TIMI investigators further commented that if shown to be effective for prevention of ischemic events in ongoing Ph 3 trials, FXI inhibitor tx may be especially attractive for pts requiring #OAP – a subset of patients typically at much higher risk for bleeding.

23) The authors concluded that #abelacimab tended to provide a greater absolute risk reduction for 🩸 in pts on #antiplatelet therapy than a conventional #DOAC, even beyond the difference seen in #AZALEA for pts treated overall. The #FXI hypothesis continues to be strengthened!

22) The authors did note some limitations of this analysis, and pointed out that a Phase 3 study for efficacy AND safety of abelacimab is underway (#LILAC #TIMI-76, NCT05712200).

21) That same difference was present when considering #MB alone, and also when looking at net clinical benefit #NCB (composite of ischemic #SSE, MB, and all-cause death). Remarkable consistency favoring a #FXI-targeted approach!

20b) The interesting finding is that the addition of #OAP therapy to #anticoagulation created another differential between #rivaroxaban & #abelacimab: adding #OAP to riva significantly ⬆️ 🩸, but adding OAP to abelacimab did not!

20a) So let’s look at the primary endpoint—centrally adjudicated combination of major 🩸 and clinically relevant non-major 🩸 #CRNMB by anticoagulant, stratified by concomitant #OAP. Overall, pts on #rivaraxaban had a higher bleeding rate. But we knew that already!

19) The pts receiving #OAPs were, as would be expected, more likely to be male and more likely to have “hard” markers of #ASCVD—higher rates of prior diagnoses of #MI, #CAD, & #PAD. Keep in mind these pts ALL also had #AFib with mod-high risk of #stroke.

18) The methodology of this preplanned secondary analysis of #AZALEA was straightforward, and indeed the cohort on concomitant #OAP comprised a quarter of the enrollments. Most were on #ASA monotherapy:

17b) A particularly appealing potential of a #FXI/XIa-targeted #anticoagulant is the ⬇️ bleeding risk they seem to offer vs #DOACs. Might this translate to patients on concomitant #OAPs?

17a) At #AHA2024, Samer Al Said @sameralsaid reminded us that #AF and #ASCVD / #CAD are all too common a combination, especially in older patients, for whom concomitant #OAP and currently available #OAP may create particularly ⬆️ bleeding risk.

16) Use of one of these agents was NOT an exclusion criterion in #AZALEA, but pts taking #OAPs on entry & randomization were prospectively tracked as a separate cohort of interest for 🩸complications. That was the subject of today's presentation.

15) But what about those pts w/#AF who also have #CAD or have a #coronary #stent & therefore take oral antiplatelets #OAPs--including plain ol' #ASA, but also #P2Y12 inhibitors—drugs that carry an independent bleeding risk that is ⬆️in pts also taking a currently approved #OAC.

14) This dramatic reduction in bleeding occurred despite robust inhibition of #FXI, which at the 150mg monthly dose (the dose carried forward, BTW, into #LILAC #TIMI-76) was associated with near-total inhibition:

13) The 🩸reduction with investigational #abelacimab compared with on-label #rivaroxaban was indeed impressive:

12) This trial was terminated prematurely due to a substantial reduction in bleeding with abelacimab as per the independent #DMC statement:

11) Need an #AZALEA refresher? You can still earn credit by reviewing our live #tweeetorial from #AHA23 at cardiometabolic-ce.com/antithrombot.... AZALEA was a Ph 2 comparison of #abelacimab vs #rivaroxaban in pts w/#AF + mod/high risk of #stroke.

10) So @SidPatelMD was in the room here at #AHA24 for @cardiomet_CE as @TIMIStudyGroup #fellow Samer Al Said @sameralsaid presented a second preplanned analysis from #AZALEA TIMI_71, looking at concomitant use of #OAPs with either #abelacimab or #rivaroxaban.

Asundexian versus Apixaban in Patients with Atrial Fibrillation - PubMed Among patients with atrial fibrillation at risk for stroke, treatment with asundexian at a dose of 50 mg once daily was associated with a higher incidence of stroke or systemic embolism than treatment...

9) Another small molecule, #asundexian, was being studied vs #apixaban for #SPAF in #OCEANIC_AF, but that trial was prematurely terminated due to inferior efficacy of the #FXIa inhibitor. See pubmed.ncbi.nlm.nih.gov/39225267/ & discussion by @CMichaelGibson at cardiometabolic-ce.com/antithrombot....

8b) New approaches for #stroke ⬇️ in #AFib have been #MAb against #FXI and small molecule inhibitors of #FXIa. Leading candidate from each of these categories currently in Ph 3 trials: MAb #abelacimab in #LILAC #TIMI-76 & small molecule #milvexian in #LIBREXIA_AF.

8a) Since #FXI was identified as a potential target for #anticoagulation with less bleeding risk (supported by genomic & epidemiologic studies of ppl with inborn FXI deficiency & by animal studies), multiple approaches to inhibition of FXI zymogen or #FXIa activity are being studied.

7) This allows us to see a potential way to "divide and conquer" this process UPSTREAM of the common pathway: by specifically inhibiting (only) #FXI:

6) Envisioning this requires rewiring our traditional thinking about the #coagulation cascade:

5) If we were to specifically & solely impact the INTRINSIC pathway, either at #FXI or #FXII (NB so far anti-FXII approaches haven't worked), we could #uncouple the intersecting processes of (physiologic) #hemostasis & (pathologic) #thrombosis.

4b) That brings up the concept of a #hemostasis-sparing #anticoagulant, as we have discussed in prior programs. Specific #FXI/#FXIa inhibitors might be just that, as they would impact only the intrinsic #coagulation pathway.

4a) Use of #DOACs is indeed complicated to some extent by enzyme-related drug-drug interactions #DDI with, e.g., #SSRIs & #SNRIs, but especially by a pt's need for con meds that ALSO ⬆️bleeding, such as #ASA, #OAPs, & #NSAIDs. An anticoagulant that reduces bleeding might be easier to use.

3c) Which of these con meds can be used only w/caution with #DOACs for #stroke prevention in #AF?
a. #NSAIDs
b. colchicine
c. P2Y12 inhibitors
d. a & c
Answer in the comments!

3b) Which is FALSE about #FXI/XIa-targeted agents in development?
a. multiple #MOAs are being tested
b. both FXI & FXIa are potential 🎯s
c. Pts on #OAPs are excluded from FXI/XIa #AF trials
d. a Ph 2 trial of a FXI inhibitor was stopped early for superior safety v a DOAC
Answer in the comments!