Day 5 on service at @MGHHeartHealth. No better time than now to think about the favorite drug of @AndrewJSauer...spironolactone.

The story of how the drug was discovered is interesting, and gave a hint as to the fact the drug would eventually become a pillar of HF care.
The first mineralocorticoid synthesized was deoxycorticosterone (DOC). Simultaneously, aldosterone was discovered. Both exerted powerful sodium retention effects. This was in the early 1950s.

Simultaneously, people began to recognize that pts with HF retained salt and water...
Recognizing that Na/water retention in HF resembled that of DOC/aldo treatment, efforts began on the synthesis of ways to block their effects with a family of compounds called 17-spironolactones.

one had potent anti-mineralocorticoid effects, and was dubbed "aldactone".
But the use of spiro for HF took a back seat as the drug was mostly employed for aldosteronism, hypertension, PCOS, and other steroid-hormone mediated processes.

It wasn't until recognition that aldo causes myocardial/vascular fibrosis that spiro was explored in the RALES trial.
The results from RALES are likely well-known to many of you, but the trial was terminated early (with the issues that come with that) due to overwhelming efficacy, with a 30% reduction in death and 35% reduction in HF hospitalization.
Of course, do not forget that similar benefits were seen with eplerenone in the EMPHASIS-HF trial of somewhat less severe HF. Recall that eplerenone is a more selective MRA, without gynecomastia when compared to spiro.
So here are the things to remember clinically:

1. Both spiro and eplerenone are effective antihypertensives outside of HF, but they cause very little BP lowering in those with HF. Thus, together with SGLT2i, MRAs are important therapies to add even when the pressure is low.
2. Both spiro and eplerenone may cause hyperkalemia. Everyone knows this. But how often should you monitor for it?

The recommended monitoring for potassium and creatinine is 1 week after initiation, monthly for the first 3M, quarterly for a year, and then every 6 months.
3. Your patient has hyperkalemia. What now?

First, do not over-react to a K of 5.5 ("elevated" in the MGH lab system). Though high, the risk from low K is actually greater.

But what should you do about it?
First, I find it incredible how a simple intervention may make all the difference: review the foods your patient is eating. Providing a low K list of foods addresses about HALF of the cases that I see of hyperkalemia.

What about other meds to treat the K?
I will start with a low dose of a thiazide diuretic (being mindful about risk for hypotension; I lower loop diuretic when I do this), or I will turn to a potassium binder.

I DO NOT stop the spiro/eplerenone, nor do I lower other #GDMTworks.
4. Can other #GDMTworks help to preserve use of MRAs? Yes! It was recently shown that use of SGLT2i lead to greater likelihood of persistence on MRA in the EMPEROR program owing to lowering of risk for hyperkalemia. This is from EMPEROR-Preserved:
Benefits of SGLT2i were also additive to MRA. Again from EMPEROR-Preserved.
5. Sounds good...what's the down side?

First, spiro may cause gynecomastia, which may be uncomfortable and lead to resistance to taking it or alternatives. Education is critical. Gynecomastia may take months to reverse so early recognition and intervention is important.
Second, when optimizing GDMT it is not unusual to be able to reduce loop diuretics...good, right? Except loops promote kaluresis. So if you reduce/stop them, you must monitor K to avoid risk for hyperkalemia, which may emerge!
In the end, among the "four pillars" spironolactone/eplerenone are about as well tolerated as they come. If there was a way to more easily monitor K, this would likely ensure more use in HF. With emerging home K testing options, it will likely make that a reality.

#GDMTworks

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More from @JJheart_doc

Nov 22
Day 6 on service at @MGHHeartHealth and we're running on fumes. But Thanksgiving is just around the corner, so all is well.

At the request of Dr. @CoronaryDoc, a thread on appropriate use of natriuretic peptides.

There's a time to measure them. And a time not to.
Just a reminder of NP biology:

NP genes are highly conserved across species. Your ANP is only one amino acid different than the ANP of a rat, for example.

In addition to being conserved across species, the three CV NPs (ANP, BNP, CNP) have structural similarities.
In addition to having a common ring structure responsible for their biologic effect, all three CV NPs (A, B, C) are synthesized as pre-pro-peptides, and are processed by corin/furin to liberate an N-terminal pro-peptide and a biologically active C-terminal fragment. Image
Read 23 tweets
Nov 20
Day 4 on service @MGHHeartHealth. 4 thoughts on beta blockers.

Don’t worry @AndrewJSauer, MRA are coming tomorrow.

@cardiojaydoc02 @AHajduczok
One: begin your target BB at the start. I don’t know how the culture of starting short acting metoprolol “for titration” came from but it’s not supported by any science, uses a drug that failed in the MDC trial, and may actually be harder to titrate due to on/off effects.
Two: if you use carvedilol, scan the med list for other alpha blockers and d/c them. Carvedilol has alpha blocking effects, so if you d/c the other it’s likely to “buy” more BP, and won’t be noticed. Remember—tamsulosin (used for BPH) is an alpha blocker…
Read 5 tweets
Oct 10
Here's a question that you might not have considered: how did the dose for #sacubitril/valsartan in #HFrEF get chosen?

Out today is a paper in @JACCJournals led by @RezaMohebiMD that addresses some questions about sac/val dose in HFrEF.

a 🧵

jacc.org/doi/epdf/10.10…
It's a little known fact that prior to the PH3 PARADIGM trial, a PH2 study in HFrEF was not performed--normally PH2 studies provide target doses for the pivotal outcomes trials.

So how was the dose of sacubitril/valsartan chosen??
The target dose of 97/103 mg twice daily was selected to achieve serum concentrations of valsartan = to those in Val-HeFT and VALIANT while simultaneously achieving 90% neprilysin inhibition in normal individuals.
Read 17 tweets
Oct 2
Presented today as late-breaking data at #HFSA2022 and posted online @CircAHA, new data from PROVE-HF regarding impact of #sacubitril/valsartan on #mitralregurgitation in #HFrEF.

Thanks to @DukeHFDoc for presenting in my absence.

What did we find? A 🧵...
It is well-known that MR severity is an important determinant of symptoms and prognosis in those with HFrEF.

Thanks to work from @LindenfeldJoann and @GreggWStone in the COAPT trial, it is also known that repair of MR may improve outcome in HFrEF.
Based on the COAPT and MITRA-FR results, current recommendations are to "optimize" #GDMT prior to decisions on repair of MR. Why?

Thanks to the reverse remodeling effects of #GDMT, MR severity may be reduced, avoiding need for MV repair.

What is known about sac/val and MR?
Read 19 tweets
Jan 13
What happens to BNP when a person is started on #sacubitrilvalsartan?

#BNP should go up, right?

Thanks to work by @pmyhre in our group, we have some new and interesting data.

A 🧵, read on! 👇
When the #PARADIGM-HF study was published, one of the things immediately noticed was the increase in BNP that occurred after being started on sacubitril/valsartan.

This is because through effect of sacubitril, neprilysin is inhibited. Why might this lead to an increase in BNP?
#Neprilysin is a ubiquitous metalloproteinase that assaults BNP (among other targets including ANP and CNP) and cleaves it in numerous places as shown.

Note that in BNP, there are cleavage sites that involve numerous places where immunoassays for measurement of BNP may bind.
Read 17 tweets
May 18, 2021
In one month, I've diagnosed more cases of ATTR cardiomyopathy than I did in 10 years. If you don't look for it, you won't find it.

A micro-tweetorial...

What should you look for?

@HannaGaggin @frederickruberg
--unexplained mild "LVH"
--PAF that has little explanation
--spinal stenosis
--carpal tunnel
--orthostatic hypotension
--bruising
--lack of EF response to #GDMTworks
--Diuretic sensitivity
--Higher biomarkers "than they should be"
Why are biomarkers higher in amyloid? It has mainly to do with direct myocardial toxicity of the amyloid protein, and NOT congestion/ischemia in most cases.

hs-cTn is almost universally elevated.

Both NPs and hs-cTn are prognostic, regardless of their 'decoupling' from HF/MI.
Read 5 tweets

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