Antithrombotics for Acute Coronary Syndrome

Posted by Jeff Berk; BOLT International

 

Been a while, kids.  Lots of meeting, including AACR/EORTC in the Peeps Democratic Republic of Kalifornia, San Francisco, and then ASH in ditto ditto ditto, San Diego.  The Dark Side owns all that wisdom, so I can’t really say much.  But we are doing a Multiple Myeloma Thought Leader Panel for syndication right now, as we speak, and that should be a pretty good review of bortezomib, lenalidomide, pomalidomide, elotuzumab, carfilzomib (tough break, Millennium/Takeda, no accelerated approval – FDA doesn’t think that your peripheral neuropathy data is so much better than weekly Velcade.  If it’s any consolation, there are a lot of hematologists who were more impressed than FDA.  But read our report when it comes out in early January – not everybody’s going to bail on Velcade just because the next pretty possibility struts by).

 

So I’ll get onto antithrombotics in a minute.  First I want to share a note that i received yesterday from a blog-reader.  It’s kind of self-explanatory:

 

Name: Brent Sterling Morris

Email: brentsmorris@cs.com

Message Subject:  melanoma blog

 

Message:

How dare you mix in your assinine political views with information about your rather stupid political views. how repubulican of you. jerk!

 

I think brent was a little flustered.  I mean, and y’all can help me with this…  Shouldn’t he be demanding that I stop mixing my asinine (I’m pretty sure this is a more republican spelling than brent’s) political views with something other than my stupid political views?  I mean, what he wrote just doesn’t make any sense to me.  And isn’t republican spelled “republican”, and not the way brent spelled it (btw, i don’t always capitalize.  and i NEVER capitalize democrat, democratic, etc.  so chill on that point, will ya?).

 

So brent, waah, waah, waah.

So there’s no better way to convince a gun hating liberal, a complete stranger no less, that guns are COOL than to take them out in the Arizona desert and hand them a full auto Uzi.  That would be the one in her left hand.  Just LOOK at that smile!

 

 

 

Okay, on to business…

There have been a number of negative trials of late, most recently the Ph-II REDEEM study with dabigatran, looking at the combination of an antithrombotic with dual antiplatelet therapy.  There has also been one surprizingly positive Ph-III trial, ATLAS2, which demonstrated a survival advantage for rivaroxaban 2.5 mg bid.  At AHA there was a lot of talk about Xarelto (rivaroxaban) as part of triple therapy (aspirin, clopidogrel + RIVA) as post hospital maintenance for the treatment of acute coronary syndrome.  We ran BOLT’s Cardiology Thought Leader Panel #13 2011-12 right after the meeting, and the intersection of antithrombotics and antiplatelets for ACS was the key topic.  We asked six internationally recognized Thought Leaders in the treatment of ACS to discuss the ramifications of the ATLAS2 results.  They did so considering other triple therapy trials, newer antiplatelets such as ticagrelor, formulary decision makers, and the overall importance of stroke reduction vs. bleeding risk.   The Panel also enriches their past discussion on the use of antithrombotics in prevention of strokes in the patients with atrial fibrillation (SPAF).

 

I usually tease you with sort of the beating around the bush discussion, because I’m a Republican jerk and want to sell my intellectual property for profit.  But in honor of the coming into the neighborhood of MY LORD JESUS CHRIST, and in dishonor of brent sterling whatever his name was, here’s the reason why ATLAS2 was a positive trial while all other triple therapy (dual antiplatelet + an antithrombotic) trials have been failures.  Enjoy, and MERRY CHRISTMAS!

ps… if you’re “dark side” and want to spend your 2011 budget, you can buy this from the BOLT website.  Go to the BOLT home page and click on the buy now tab.

pps…  we’re cool, right brent what’s yer name?  tee hee hee.

 

  • The best theory that we heard for why rivaroxaban was successful in ATLAS2, while apixaban, basically the same drug, failed in APPRAISE2, is that the APPRAISE2 DSMB saw a little excess bleeding, got spooked and stopped the trial early, while ATLAS2, which also had excess bleeding, was allowed to run its course.  The reason that this matters is that the longer the ATLAS2 patients were on the study, the more likely they were to drop the non-aspirin antiplatelet.  This reduced the bleeding risk.  What the trial ultimately showed is that the benefit of rivaroxaban in ATLAS-2 really kicks in when the survival curves really start to separate out around one year.

 

“Well, considering that rivaroxaban and apixaban have essentially the same mechanism of action with relatively little to distinguish them it seems to be all about dose and pattern of administration, which is essentially dose.  So I don’t doubt that there is a dose of apixaban that could have achieved the same result.  It is a little bit of a study design too.  Apixaban chose a somewhat higher risk population of patients.  If I recall we initiated therapy a little bit earlier, although that is probably not so important.  There is also plenty of chance.  There is also the fact that the apixaban study was stopped early.  I think that really hurt them because quite some part of the benefit in rivaroxaban comes from the effect of the drug against single antiplatelet therapy.  The longer you wait after an ACS event the more likely patients are to go back on single antiplatelet therapy at which point the drug starts to get really effective.  It is just easier to exert an antithrombotic effect against a single antiplatelet than against the dual.  So that the benefit of rivaroxaban in ATLAS-2 the curves really start to separate out around one year.  I think that is probably, although no one has confirmed that, but I think that is probably coinciding with the time going back to single antiplatelets.  Apixaban never got to get that kick because they never got out that far, or if they did it was only in a very few patients.  So they got unlucky.  I think it is a little bit of that.  Their dose is probably too high, which is a little bit why they got unlucky.  They got excess bleeding and their DSMB blew the whistle.  In retrospect when you look at the results it probably shouldn’t have stopped the trial at that point.  It is too bad for them if they did”.

 

 

 

 

Drugs discussed in this report include:

 

Company Generic Brand
AstraZeneca ticagrelor Brilinta
Bayer-Schering / Janssen rivaroxaban Xarelto
Boehringer Ingelheim dabigatran Pradaxa
Bristol-Myers Squibb warfarinclopidogrel CoumadinPlavix
BMS / Pfizer apixaban Eliquis
Daiichi-Sankyo edoxaban Lixiana
Eisai atopaxar
Lilly / Daiichi-Sankyo prasugrel Effient
Merck vorapaxar
Novartis / Portola elinogrel
Portola  betrixaban (PRT054021)FXa antidote
Sanofi-Aventis enoxaparinotamixaban Lovenox
The Medicines Company cangrelor

 

Categories: acute coronary syndrome, antiplatelets, Antithrombotics, Cardiovascular, DVT/PE, SPAF
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