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Wow! Big news for HFpEF! Shall sacubitril/valsartan and spironolactone be FDA-approved for HFpEF?
FDA Advisory Panel has just voted today 12-1 to approve an expanded indication for sacubitril/valsartan based on PARAGON-HF trial (with a tantalizing RR=0.87 [0.75-1.01], p=0.06)
FDA Advisory Panel has just voted today 12-1 to approve an expanded indication for sacubitril/valsartan based on PARAGON-HF trial (with a tantalizing RR=0.87 [0.75-1.01], p=0.06)
There are two main subgroups showing the most benefit in PARAGON: women and LVEF under the median (57%). What the AdCom did not agree upon was how to define the population for whom the expanded indication would apply @HFpEF @SumeetMitter @dranulala @hvanspall @ShelleyZieroth
Do we use a LVEF cutoff for this expanded indication? The con is that LVEF is very variable, usually eyeballed and not a sensitive measurement of LV systolic function. The pro is that a cut off will facilitate implementation in clinical practice @paomorejon @lucreciamburgos
Which cut off? LVEF 57% was the median in PARAGON, but is undoubtedly an unusual figure, particularly difficult to define when eyeballing LVEF. Using 55% would simplify assessment but is technically not the value reported in the trial @drdargaray @j_alvarezgarcia @m_rivaslasarte
Excitingly, tomorrow Dec 16 will be the day when the AdCom will decide whether to expand the indication for spironolactone to include also HFpEF based on TOPCAT @ChristosArgyrop @Sglt2inhibitorL @FaiezZANNAD @DrRajivsankar @ersied727 @vbluml
TOPCAT is famously known to be a negative trial (HR 0.89 [0.77-1.04], p=0.14) when analyzed as a whole. However, there were marked geographical differences. Spironolactone was effective when excluding Russia and Georgia @RequenaIbanez @kevin_damman @rachkataria @kevin_damman
Lots have been written aout whether the patients in Russia&Georgia actually had HFpEF (much lower BNP) and whether were taking the drug (no canrenone -metabolite of spironolactone- in plasma, less marked hyperkalemia) @KevinShahMD @AlexNowbar
On the other hand, patients who qualified for the trial by prior HF hospitalization showed no treatment effect in either region (Russia-Georgia vs rest of the world), which undermines the explanation that different populations between two regions led to different outcomes.
Interestingly, the FDA noticed in documents that "Approval under this circumstance (negative results in RCT) is unusual but not unprecedented": enalapril on the basis of SOLVD-Prevention's secondary endpoint benefits and bivalirudin on the basis of post-hoc pooling of BAT studies
In summary, high promise of potential approval of two drugs for HFpEF: spironolactone -cheap and also used offlabel by some doctors in this indication- and sacubitril/valsartan
