Thread by @FH_Verbrugge

Read our latest analysis from the #ADVOR trial @JACCJournals. Deeper dive into the relationship of #natriuresis with decongestion & clinical outcomes after diuretic therapy in acute #heartfailure! Tweetorial below...

authors.elsevier.com/a/1h4wr2d9GHwT…

@PieterMartensMD @WilfriedMullens

First, look at detailed #ADVOR protocol below:
onlinelibrary.wiley.com/doi/full/10.10…

We did 2 consecutive urine collections:
1. Randomization => First morning (<24 h)
2. First morning => Second morning (=24 h)

If in those 2 collections, cumulative urine output <3.5 L ➡️ Failed decongestion!

Allocation to #acetazolamide clearly increased:
✅total urine output (+12.6%)
✅total natriuresis (+26.9%)

In relative terms: effect on natriuresis > urine output, UO🚫significant after 1st diuretic dose, natriuresis remained high!

*Normalized UO to 24 h for collection 1.

Moreover, allocation to #acetazolamide by a landslide strongest predictor of both urine #sodium concentration (UNa) AND total #natriuresis (molecules excreted)!
For instance, 5-8x bigger impact than an eGFR change of 10 mL/min/1.73m²

Be wary: total natriuresis and UNa not the same!

Total natriuresis tracks well with UO
➡️Amount of extracellular volume (ECV) DURABLY removed (150 mmol Na ~ 1 L ECV)

❗️Urine is usually HYPOTONIC (UNa <150 mmol/L)
➡️Part of UO reflects #dehydration rather than #decongestion

No such strong correlation between UNa & UO!

UNa:
➡️Only partly reflects decongestion
➡️Also reflects neurohumoral activation
➡️Best measurement of sodium avidity

Thus, #acetazolamide
✅Keeps sodium content of urine high, therefore allowing better decongestion for same UO!

Higher UNa & greater total natriuresis
✅Associated with higher chance of successful #decongestion (no more than trace edema and no ascites/pleural effusion)

From 1st morning, patients w higher UNa (less Na avidity): significantly greater clinical decongestion!

UNa ≥80 ideal cut-off, indicating excellent response!

❗️Intriguingly, effect of #acetazolamide on decongestion🚫significant after adjustment for natriuresis➡️Mediation?

Consequently, patients with better natriuresis has a shorter length of stay
✅4.5 days shorter for UNa ≥100 versus <50 mmol/L

As shown in other studies, better natriuretic response to #diuretics was associated with better clinical outcome (death or heart failure readmissions)

Now the intriguing part:
Good natriuretic response (UNa ≥80 mmol/L):
➡️Similar outcome loop diuretic monotherapy & combination with acetazolamide

❗️Many more patients with #acetazoalmide had UNa ≥80 mmol/L (NNT = only 7!)

Poor natriuretic response (UNa <80 mmol/L):
🪦 &🏥

Also, for people that are so concerned about the non-significantly🔼90-day 🪦 with #acetazolamide in #ADVOR:
* Notice LATE occurrence of this effect (45 days after randomization or >30 days after acetazolamide was stopped)
* Mostly in patients with a poor natriuretic response

My interpretation is that by the play of chance, patients in the #acetazolamide arm were probably slightly sicker.

Illustrated as well by slightly higher baseline dose of loop diuretics (80 vs. 60 mg furosemide equivalents).

Conclusion:
1. Upfront combination of #acetazolamide with loop diuretics in acute #heartfailure helps to keep sodium content of urine high.
2. Strong natriuresis ~ better (and more durable?) decongestion!
3. Natriuretic response ~ clinical outcomes

➡️UNa+ guided diuretic therapy

@JeroenDauw @petra_nijst @EvelyneMeekers @jozinetm @kevin_damman @Filippatos @AlexMebazaa

Also read this other analysis from the #ADVOR, eloquently discussed by my friend & partner in crime @PieterMartensMD :

https://twitter.com/PieterMartensMD/status/1655293571363110912

It shows nicely that after 48 h treatment with monotherapy loop diuretics, almost every patient develops "contraction alkalosis"

We need to rename "contraction alkalosis" to "neurohumoral alkalosis", as it is not a sign of hypovolemia per se.

Thus:
➡️Minor congestion requiring 1 or 2 doses of diuretics probably does not need #acetazolamide
➡️In case of any prolonged treatment: UPFRONT!!!

This is a BIG difference with #thiazides, which have shown to break diuretic resistance, can wait until this occurs!

The effect of #acetazolamide resides in braking the neurohumoral system, so need to treat upfront rather than bail-out, which is how #ADVOR was set up!

For the #physiology fans, here's the paper in which we discussed the proximal nephron hypothesis, leading to the #ADVOR trial @ESC_Journals :

onlinelibrary.wiley.com/doi/full/10.10…

Doing a pilot on UNa guided therapy incorporating ALL diuretic classes (#DECONGEST):
clinicaltrials.gov/ct2/show/NCT05…
@SVanhentenrijk

Don't miss out on:
- ENACT-HF at #Heartfailure2023 in Prague

https://twitter.com/JeroenDauw/status/1658810146460409856

- PUSH-HF, by @jozinetm & @kevin_damman @escardio 2023 in Amsterdam