Frederik H. Verbrugge Profile picture
May 18, 2023 20 tweets 15 min read Read on X
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! Image
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. Image
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 Image
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 Image
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! Image
Higher UNa & greater total natriuresis
✅Associated with higher chance of successful #decongestion (no more than trace edema and no ascites/pleural effusion) Image
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? Image
Consequently, patients with better natriuresis has a shorter length of stay
✅4.5 days shorter for UNa ≥100 versus <50 mmol/L Image
As shown in other studies, better natriuretic response to #diuretics was associated with better clinical outcome (death or heart failure readmissions) Image
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):
🪦 &🏥 Image
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
Also read this other analysis from the #ADVOR, eloquently discussed by my friend & partner in crime @PieterMartensMD :


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… Image
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

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

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More from @FH_Verbrugge

Feb 28
Reviewing current evidence on #hyponatremia in #heartfailure together with our bright visiting fellow @GiulioMonde!

Tweetorial 👇

link.springer.com/article/10.100…
#hyponatremia in #heartfailure 🟰 mainly dilutional: ➡️Impaired water excretion & extracellular volume expansion!

However, we tend to underestimate the depletional component due to chronic potassium and magnesium losses
➡️Intracellular dehydration
➡️Intracellular sodium shift Image
Replenishing potassium & magnesium stores alone actually increases serum Na in depletional hyponatremia!
K & Mg go intracellular ➡️Na goes back extracellular

Best K level probably ~4.5 mmol/L
3.5-4.0 mmol/L: K deficit ~ 200 mmol (!), so be aggressive!

pubmed.ncbi.nlm.nih.gov/28866674/
Image
Read 14 tweets
Mar 16, 2023
Teaming up again with the great @VerwerftJan to share our experience with #echoCPET in #HFpEF. This hot-of-the-press paper @ESC_Journals demonstrates myriad of opportunities for diagnosis & treatment, far beyond #SGLT2i only. Tweetorial below!

@SarahStroobant2 @HerbotsLieven Image
We have recently described our set-up for a dedicated #dyspnoeaclinic in detail @JACCJournals



In #HFpEF, early & correct diagnosis are important, #phenotyping is everything. There are a lot of mechanisms for dyspnoea involved Image
Current @ESC_Journals paper goes one step further: "In patients with confirmed HFpEF or probability >90% according to well-validated HFpEF scores (both are complimentary in our view), why #echoCPET within a dedicated #dyspnoea clinic? What is the impact of findings?" Image
Read 9 tweets
Nov 6, 2022
Really proud moment for me today, presenting 1st time in a Featured Science session @AHAScience.

Deeper insight in #ADVOR trial with key contributions from @WilfriedMullens @PieterMartensMD @JeroenDauw @petra_nijst @EvelyneMeekers among many others. Proudly 🇧🇪!
Tweetorial below!
From #ADVOR population, we included 462 or 89% of patients with 2 correctly performed consecutive urine collections and urine sodium concentration (UNa) available.

Natriuresis:
- UNa [mmol/L] ~ diuretic efficiency
- Total natriuresis [mmol] ~ ECV & interstitial Na buffer removed
#Acetazolamide, after multivariate adjustment, was strongest predictor of #natriuresis in #ADVOR:
UNa + 16 mmol/L
Total natriuresis +115 mmol

👊 within 2 days !!!
👍 much stronger than effect on urine output itself

"#acetazolamide keeps the urine salted"
Read 9 tweets
Oct 9, 2022
What is your take on #vasodilators in acute #HeartFailure? The upcoming November issue of #EHJACVC will bring you a PRO/CON "Vasodilator therapy in acute heart failure revisited"

As our PRO paper was published in advanced access, a sneak preview Tweetorial below...

@EHJACVCEiC
First some background...
Current @escardio guidelines state (IIb, B): "In patients with AHF and a systolic blood pressure (SBP) >110 mmHg, intravenous vasodilators may be considered as an initial therapy to improve symptoms and reduce congestion."
Only 1 flowchart has them in...
So far, I consider this a fair recommendation... In hyper/normotensive pulmonary oedema, they might be helpful in some cases, with their main benefit a reduced need for (non-)invasive ventilation!

Beautiful (older) trial by Gad Cotter on this: thelancet.com/journals/lance…
Read 14 tweets
Sep 7, 2022
Don't miss our monthly educational review #EHJACVC @ESC_Journals!

This month by the great @ArgaizR: fluids in #AKI
Co-starring: @ThinkingCC @khaycock2

Extremely proud that our journal offers a platform to 3 great clinicians & Twitter educators. I always learn from them... Image
A strong argument is made to switch mainstream thinking in #AKI away from the fallacious concept of fluid responsiveness in all to a primary assessment of fluid tolerance.

Probably the most important thing I have learned on Twitter: #VExUS Image
Why do I like #VExUS so much? Because it really changed my everyday practice... Portal vein became part of my standard #echocardiography assessment.

And that's what we want to achieve with this review, offer something directly applicable at your bedside! Image
Read 5 tweets
Aug 27, 2022
For those who can't get enough from #ADVOR, below the promised Tweetorial!

Acetazolamide in acute #HeartFailure w volume overload on background high-dose loop diuretics:
👍Increases diuresis & natriuresis
👍More euvolemia after 3 days & discharge
👍⬇️LOS
#ESCCongress #Cardiology
First, the unsung hero's of this trial, done with a little bit over 2 million €, bargain for largest diuretic #RCT ever!
@KatrienTartagl2 & her team, with only 3FTE, they ran the most successful trial in #AHF
@PieterMartensMD & @JeroenDauw who did most fieldwork
👏
How did we come up with the idea? Actually, cause we all love #physiology. Credits go to Prof. Em. Paul Steels who teached us all how kidneys work.
@GLW_UHasselt

65% of sodium is reabsorbed in the proximal tubules, can be up to 85% in #HeartFailure
Read 12 tweets

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