Thread by @cardiomet_CE

Don’t miss a new accredited #tweetorial launching TOMORROW here on @cardiomet_CE. #Cardiologist, #SoMe education advocate, and true #Renaissance man @CMichaelGibson will be discussing a novel #aspirin prep that has PK/PD like plain #ASA . . .

. . . but a different site of absorption--with greater predictability than ECASA. DON'T MISS IT!! @DLBHATTMD @cpcannon @AnnMarieNavar @DrM_ODonoghue @DrMarthaGulati @practicalcardio @GuyattGH @DrMauricioCohen @SVRaoMD @ASPCardio @PlateletDoc @stephanamayer #FOAMed #CardioTwitter

1) Welcome to a #tweetorial where we’ll explore how changing the formulation of #aspirin & where it's absorbed in the GI tract can ⬇️the risk of acute GI injury, but still maintain predictable absorption. This program is accredited for 0.50h CE/#CME. I am @CMichaelGibson. #FOAMed

2) This tweetorial is supported by an educational grant from PLx Pharma, and is intended for healthcare professionals. Faculty disclosures are listed at cardiometabolic-ce.com/disclosures/ and similar programs on #antiplatelets, still available for credit, are at cardiometabolic-ce.com/category/plate….

3) There has been SO much #hullabaloo about the updated (draft) @USPSTF primary #cardiovascular event protection #guidelines for #ASA, released 10/12/21 & available at uspreventiveservicestaskforce.org/uspstf/draft-r…. There is in fact rational thinking & reasonable evidence to support the conclusions ...

4) ... that aspirin use for the primary prevention of CVD events in adults ages 40-59y who have a 10%+ 10-year CVD risk has a SMALL net benefit, and that initiating #ASA use for primary prevention of CVD events in adults age 60+ has NO net benefit. This is because ...

5) ... risk for #gastrointestinal bleeding, #intracranial hemorrhage & hemorrhagic #stroke, w/ or w/o ASA use, ⬆️with age. Other risk factors include ♂️ sex, #diabetes, past #GI issues (such as #pepticulcer), liver disease, smoking, & ⬆️ #bloodpressure. ASA ⬆️that risk.

6) Unfortunately, press around these guidelines was interpreted too broadly and was applied by many well-meaning patients to their high-risk situation, as well as those on ASA for #secondaryprevention, which the guidelines don't address at all! See

https://twitter.com/AnnMarieNavar/status/1448786614050766854

7) So in this #accredited #tweetorial (#FOAMed), let's set the record straight! Let's start with the mechanism of action of ASA: It irreversibly blocks the cyclooxygenase (COX) activity of the prostaglandin H synthases 1 and 2, also known as COX-1 and COX-2. This causes ...

8) ... upstream block of prostanoid biosynthesis and, ultimately, inhibition of thromboxane A2 (TXA2) and prostacyclin (PGI2) generation. Mature platelets express only COX-1 & produce TXA2 in response to many stimuli. Vascular endothelial cells express both COX-1 & COX-2 ...

9) ... & represent the main site of PGI2 generation. Low-dose ASA selectively inhibits COX-1 activity; higher doses inhibit both COX-1 & COX-2.

10) Long story short:

11) So plain ASA can cause acute GI tract injury & ⬆️"nuisance" as well as major bleeding (think gums, bruisability), but generally WORKS unless the patient stops taking it ("pseudoresistance", as above) BECAUSE OF GI issues and nuisance bleeding. Alas, ASA follows the old maxim:

12) You can’t give a pt an #antithrombotic without ⬆️bleeding risk over baseline. But some patients (think high-risk primary #CVD prevention and many secondary CVD prevention pts) NEED an #antithrombotic effect. It's a positive benefit:risk balance! But if they DON'T TAKE IT ...

13) ... Hello, GI upset! ... it doesn't give them that needed protection. Who benefits?

14) So if selected patients benefit from ASA, but don't take it because of GI upset, what can we do? Lower dose? Doesn't yield effective platelet inhibition. Longer interval between doses? Same. Enteric coating? GI absorption--and therefore effect--is erratic.

15) Why does ASA cause GI injury anyway?

16) So what if we could complex ASA with phospholipids (PL-ASA) and thereby maintain gastric hydrophobicity? Animal models suggest that in this case ASA exposure to GI lumen would be largely delayed until it exits the stomach.

17) So maybe we can reduce the risk of GI injury BUT . . . will the ASA be absorbed? Look at the graph below. The curves represent "standard" ASA, PL-ASA, and enteric-coated ASA. This study was done in obese diabetic patients, with dosing for 3d. Which one do you think is ECASA?

Mark your answer!

18) Return tomorrow and check your answer, then buckle up for more learning. @MedTweetorials @DLBHATTMD @cpcannon @gcfmd @hvanspall @DrMarthaGulati @ProfSNicholls @HanCardiomd @DrDebCroyNP @DrToniyaSingh @Dr_DanMD @gina_lundberg @limbsalvagedr @baileyannRN @cardioPCImom

19) Welcome back! We are talking #ASA for #cardiovascular event risk reduction & changing the pill so that the risk of GI injury is reduced. This is your source for CE/#CME-accredited, serialized education on Twitter! I am @CMichaelGibson.

20) Yesterday's poll? That graph appeared (with the legend not hidden) in Bhatt DL, Grosser T, Dong J-F, et al. JACC 2017;69:603-12. And absorption of PL-ASA (blue line) was 5X higher than that of ECASA (gray line) (p<0.0001). And it sure looks like PL-ASA (mostly absorbed ...

21) … post-stomach) & "plain" ASA (black line, absorbed in stomach) overlap. For you #PK geeks, AUC of plasma conc's after 325 mg dosing were: PL-ASA (2523), plain ASA (1964), ECASA (456). So yes, it's absorbed. Is there less injury to the gastric mucosa w/ PL-ASA? Take a look:

22) So we have good absorption (better than ECASA) & we have less gastric injury than plain aspirin with PL-ASA, BUT . . . do we have the desired #antplatelet effect? Again, take a look:

23) So, it appears that PL-ASA might help reduce GI injury in chronic use, whether part of #DAPT or not. That's critical, whether after #ACS/#PCI or after #stroke/#TIA, especially during the early "vulnerable" periods during which the #antithrombotic effect ..

24) ... of ASA is generally perceived as providing a benefit:risk balance with respect to bleeding risk. Protecting the GI mucosa is particularly important then! But there is ANOTHER fly in the ointment!

25) Because in this #tweetorial we are talking primarily about secondary prevention (see what I did there??), which isn't provided with 325mg like these data we have considered. We use 81mg! Will the absorption and the effect be similar to ECASA at a low dose?

26) You're in luck! You see, @TCTConference was last week and there are NEW data to share! Thanks to @FFranchiMD et al, we have 🥁(drum roll please)

27) Take your best shot: what did they find?
(a) faster absorption PL-ASA > ECASA
(b) more complete absorption PL-ASA > ECASA
(c) less potent inhibition of #platelet aggregation PL-ASA < ECASA
(d) a & b

28) Mark your response and return tomorrow for the answer, a wrap-up of this program, and your link to FREE CE/#CME--#physicians #nurses #Pharmacists #PAs #NPs. Nod to @mvaduganathan @hvanspall @HannahBeba @JavedButler1 @JJheart_doc @AmitGoyalMD @cardiojaydoc02 @DBelardoMD

29) Welcome back! I am @CMichaelGibson and you are just a few clicks away from getting FREE CE/#CME for following along this #tweetorial on the impact of pre-associating #ASA with lipid and reducing gastric injury! Do you think the PK/PD of PL-ASA matched up with ECASA?

30) So let's quickly review. Plain ASA is assoc'd with risk of mucosal damage in the UGI tract. Enteric coated aspirin (ECASA) was designed to ⬇️GI injury (and thereby ⬆️tolerance and 🤞hopefully ⬆️ adherence by bypassing stomach & releasing ASA in ...

31) ... the duodenum. Arguably, it is #standardofcare in secondary prevention of #cardiovascular events, but it is more unpredictable in absorption & #antiplatelet effect than plain ASA. PL-ASA is a novel FDA-approved, liquid-filled phospholipid-ASA capsule, designed to ...

32) ... be absorbed like plain ASA but in the duodenum. Seems to work with a 325mg dose. What about 81mg? Let's look at the PK findings from @TCTConference presentation:

33) What about #pharmacodynamics? The PD marker is again platelet aggregation, this time measured by light transmission aggregometry (#LTA) ... & PL-ASA looks good, showing PL-ASA more potent & earlier inhibition compared to ECASA.

34) So, let's summarize: The ongoing (occasionally heated) discussion abt #ASA for primary prevention of #CV events in MOST patients is a subject for another #tweetorial. The use of #ASA 81mg for secondary prevention--at least early on after #ACS/#PCI or ischemic stroke/#TIA ...

35) But the favorable benefit:risk equation for early ASA in these patients can't work if the pt won't take the ASA--which is most often due to #GI upset. A number of new approaches have been suggested (see @DLBHATTMD & @md_pollack (🔓10.1016/j.amjcard.2020.12.019) such as ...

36) ... an inhaled nanoparticle ASA prep, admin'd with a dry powder inhaler & an ASA-loaded solid lipid microparticle formulation, but those aren't in the clinic anytime soon--if ever. PL-ASA is a novel, FDA-approved phospholipid-ASA formulation in a liquid-filled capsule ...

37) ... that has been shown to be bioequivalent to plain ASA, yields faster & more complete absorption after a single 81mg dose & more predictable #antiplatelet effect compared to ECASA. Time--and maybe some registry data—will address whether ...

38) ... less GI injury + great PK&PD … does that equate to better adherence and potentially better outcomes?

39) And that's it! You made it! Claim your 0.5h CE/#CME at cardiometabolic-ce.com/plts10/ now, & FOLLOW US for more accredited #tweetorials in #cardiometabolic medicine! Also JOIN US at @ckd_ce for more FREE credit focused on--you guessed it--#CKD! Til next time, I am @CMichaelGibson.