2) This program for #healthcare providers is supported by an unrestricted educational grant from Bayer. Statement of accreditation & faculty disclosures at https://t.co/0EkFYk4TZx. Prior programs in #PAH, still available for FREE CE/#CME, are at https://t.co/Z8M0L9k0hD.
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
4) The main consequence of #PAH is increased right ventricular (#RV) afterload, which can lead to right 🫀failure & ☠️. Fortunately, effective treatment options for PAH have improved outcomes.#pulmtwitter @MedTweetorials #FOAMcc
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
6) The pathobiology of #PAH involves several mechanisms contributing to vascular remodeling: 1) a dysfunctional pulmonary #endothelium, 2) a dysfunctional vascular smooth muscle, & 3) persistent #inflammation and immune dysregulation
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
🔓 https://t.co/bGVFigOF1T pic.twitter.com/XJ871KIUwJ
7b) The answer is D. Several drugs are approved worldwide under each category…but it is not as simple as it looked!
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
7d) The correct answer is b. (c. is acceptable, thank you for being honest!). This is the whole purpose of this #tweetorial.
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
9) Let’s have a closer look on the NO-sGC-cGMP pathway in PH, shall we? The next illustration will be discussed in more detail.
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
🔓 https://t.co/Rw1lQJfS4L pic.twitter.com/5OaUT1PaKf
11) Although the total #sGC expression is ⬆️, alteration of the redox state of sGC through oxidative stress may lead to ⬇️ levels of the NO-sensitive form of sGC. pic.twitter.com/2ZJRS4TzdF
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
13) ⬆️ NO level can be accomplished by inhalation of NO. In #PAH, this option is critical to identify “responders” to acute #vasoreactivity testing who will receive calcium channel blockers #CCB.
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
14b) #Sildenafil and #tadalafil are the two approved #PDE5i for the treatment of #PAH
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
16) Now you know everything on the role of NO-sGC-cGMP in #PAH! Let’s review the clinical evidence, and start with the NO pathway…
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
17b) The correct answer: c. The recent @escardio/@EuroRespSoc GL provide for 1st time a specific algorithm for responders to acute #vasoreactivity testing. Acute response is defined as
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
i. a decrease in #mPAP > 10mmHg +
ii. a mPAP < 40mmHg +
iii. ⬆️or no change in cardiac output
17d) If you answered a, you are on target! It is recommended to confirm long term response to CCB by RHC. A nice figure has been elaborated by the @escardio/@EuroRespSoc task force for GL – use it! pic.twitter.com/eeACAVjiQH
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
19a) Once upon a time…there was a very first trial combining sildenafil with another #PAH approved therapy (sometimes forgotten). What was this drug?
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
a. Bosentan
b. Macitentan
c. Epoprostenol
d. Another one (add name in comments)
19c) This was associated with a significant decrease in clinical worsening as shown in this KM plot, improved #haemodynamics and quality of life #QoL pic.twitter.com/wG9e85BMpT
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
20b) Of course a! #AMBITION compared initial combo with #ambrisentan + #tadalafil vs pooled monotherapy, resulting in a delayed time to clinical failure (HR 0.50 – 95% confidence interval [CI], 0.35-0.72; P<0.001).
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
🔓 https://t.co/1z4BCLUuVq pic.twitter.com/AVKyfJR2iV
20d) The combination of AMB + TAD was well tolerated, although more patients presented peripheral edema compared with both monotherapies. AMBITION set the stage of a new era in the management of #PAH
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
21b) Answer d of course! The study compared a double vs triple oral combination tx in pts with a new diagnosis of #PAH. Triple was no better to decrease PVR, improve 6MWD, or decrease #NTproBNP
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
🔓 https://t.co/Ywf8V0HTYv pic.twitter.com/lpd8l39I7K
22a) So where do we stand with combo #PDE5i + an #ERA?
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
a. initial combination therapy (low – intermediate risk status)
b. sequential combination therapy in patients not at goal
c. initial combination therapy with IV #prostanoids (high risk status)
d. all of the above
23) Large multicenter clinical trials with #riociguat are supporting the inclusion of the drug in the treatment algorithm of #PAH. In which specific setting?
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
a. Sequential combination on oral ERA background
b. Replacement of PDE5i
c. Both a and b
d. Initial combination therapy
25a) In PATENT-1, 443 #PAH patients were randomized to receive placebo vs #riociguat in individually adjusted doses up to 2.5 mg TID, or riociguat capped at 1.5 mg TID (for exploratory purposes). Background PAH therapy was allowed, with oral #ERA or non parenteral #prostanoids
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
26) The study population was predominantly female (79%), aged 51±17 y, mostly #iPAH (61%) or associated with #CTD (25%), in @WHO FC II (42%) or III (53%) on background therapy in 50% (44% ERA). Baseline #6MWD was 363±69 m
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
27b) Yes!–+ 36 m (95% CI, 20 to 52; P<0.001), on the basis of an analysis of the modified #ITT population with missing values imputed (last observed value carried forward or 0 m in case of clinical event)
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
🔓 https://t.co/DFhQEY5fzC pic.twitter.com/1hawQ6kTOy
29) Significant improvements were observed in #PVR (least-squares mean difference, –226 dyn · sec · cm–5; 95% CI, –281 to –170; P<0.001) and #NTproBNP. #TTCW was delayed in the active group vs placebo (⚠️) although the events were not adjudicated by an independent committee
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
31) In summary, #riociguat up to 2.5 mg TID significantly improved #6MWD, PVR and other efficacy EP in patients naïve form #PAH therapies or receiving #ERA/non parenteral #prostanoids. The benefit was sustained over time as observed in the #OLE
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
33) In #REPLACE, patients were not blinded to whether they switched to #riociguat or continued on a #PDE5i. This could have influenced how @WHO functional class was reported or influenced performance on the #6MWD.
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
35) Thus, the recommendation to switch a #PDE5i to #riociguat is less strong in the guidelines than the option to add #selexipag. Adding #selexipag is supported by the #GRIPHON #RCT
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
🔓 https://t.co/GSjg1jh2Rk
37) Let’s wrap up and see what the #ESC/#ERS GL say about the NO-#PDE5i–#sGC pathway…here is the “strategic” treatment algorithm. Evidence has been shown for #iPAH, #hPAH and #PAH associated with drugs/toxins and #CTD. pic.twitter.com/L8D5t4irQy
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
38b) But which #PDE5i? The wealth of evidence is in favor of #tadalafil (from large trials #PHIRST, #AMBITION, #TRITON, open label #OPTIMA) pic.twitter.com/Qge0Jlm9KP
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
39) Next step requires a reassessment, treatment decisions being based on a 4-strata evaluations. What are the options if low risk at 3-6 months is not achieved ?
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
a. Wait and see
b. + oral prostanoids receptor agonist
c. + IV prostanoids and consider transplantation
d. Not a
41a) What does the future hold? Novel tx for #PAH aims to explore 🆕 pathways but also ⬆️ safety/tolerability profiles of currently available compounds (big focus on inhaled therapies!). #MK_5475 is a small molecule designed for inhaled delivery via a dry-powder inhaler device
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
41c) The first cohort of 164 patients will be randomized in 4 arms (3 doses vs placebo) with #PVR at 12 weeks as primary endpointhttps://t.co/xbOrAlFaCV
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
43) That’s a wrap! 🔑 learnings:
— pulmmed_ce (@Pulmmed_CE) November 14, 2023
🫁 NO-PDE5i-sGCs important in #PAH
🫁 #PDE5i are widely used, especially in initial combo tx
🫁 #sGCs have a different mode of action, though lumped in the same pathway
🫁 switching from PDE5i to sGCs should be considered in pts not at goal
44) And WHEW!! That was like TEN #6MWT because you just earned a full HOUR of 🆓 CE/#CME! Claim your certificate now at https://t.co/ne0eLGwbYZ and then FOLLOW US for more expert-authored #MedEd! Thanks to outstanding faculty @jeanlucvachiery for joining our @pulmmed_ce team!
— pulmmed_ce (@Pulmmed_CE) November 14, 2023