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Show Notes

Pearl 1: Beta Blockers

  • Pathophysiology:
    • Many proposed mechanisms of action, however, the exact mechanism is unclear. Overall, thought to reverse deleterious neurohormonal effects of the sympathetic nervous system.
  • Outcomes and trial data:
    • Most trials were done over 20 years ago.
    • COMET Trial: The only trial that compared two beta blockers against each other.
      • Carvedilol extends survival compared to metoprolol tartrate.
      • The study was criticized for significantly under dosing metoprolol and using the short acting formulation (tartrate) instead of long acting (succinate).
    • The benefit of beta blockers appears to be a class effect.
      • A meta-analysis showed a significant reduction in mortality with use of beta-blocker compared to placebo.
      • While all beta blockers showed reduction in mortality, the largest mortality reduction was seen with carvedilol, although this was not statistically significant when compared to other beta blockers.
      • Beta blockers increased EF by a mean of 4.1%.
    • Beta blockade appears to be the most effective therapy for survival in patients with HFrEF (not acutely decompensated).
      • There is a 14% increase in all-cause mortality for every 10 bpm increase in HR above 80.
      • Resting HR > 80 bpm can cause myocardial dysfunction.
    • Patient counseling
      • Patients may experience lower blood pressure and heart rate, which is to be expected. However, they should inform their doctor if feeling lightheaded.
    • Pro tips in initiating
      • Controversy exists as to the optimal selection of a particular beta blocker.
        • Carvedilol is non-selective and acts on beta 1, beta 2 and alpha 1 thus it has afterload reduction properties.
        • Metoprolol acts only on beta 1 receptors and may be a better option if hypotension is a concern.
      • Few studies have answered the question of tolerability of beta blockers in heart failure
        • Avoid starting in acutely decompensated patients with evidence of poor perfusion and volume overload.

Pearl 2: ACE Inhibitors, ARBs and ARNIs

  • Pathophysiology
    • RAAS activation leads to systemic vasoconstriction, sodium retention, left ventricular remodeling and oxidative stress.
    • ACEI and ARBs act on different parts of the RAAS system but ultimately lead to inhibition of deleterious effects of aldosterone (vasoconstriction, inflammation, fibrosis, and arrythmogenesis).
    • ARNIs are newer combination pills composed of sacubitril (neprilysin inhibitor) and valsartan (ARB).
      • Sacubitril prevents the breakdown of natriuretic peptides (BNP, bradykinin, and adrenomedullin) leading to vasodilation, natriuresis, and decreased sympathetic tone.
      • Sacubitril also leads to increased levels of angiotensin which is why valsartan is added.
    • Outcomes and trial data
      • Earliest evidence for ACEI includes the CONSENSUS and SOLVD ARBs are thought to have a similar effect as shown in CHARM-Alternative.
      • PARADIGM HF Trial: treatment with ARNI reduces cardiovascular mortality, HF hospitalizations, and all-cause mortality when compared to enalapril. NNT was
        • PIONEER HF Trial: sacubitril-valsartan is safe to initiate in patients with acute decompensated HF.
        • ARNI therapy decreased NT-proBNP concentration compared to enalapril at 4 and 8 weeks without significantly different rates of medication related adverse events.
      • Patient Counselling
        • Most common side effects of ARNIs are hypotension and lightheadedness. Patients should monitor BP and inform their physician if BP <90/60 or if they are symptomatic.
      • Pro-tips in Initiating
        • Guidelines now support de-novo initiation of ARNIs, meaning that a patient does not need to be trialed on an ACEI or ARB before starting ARNI
        • Is the patient already on an ACEI?
      • There must be a 36-hour washout period required before prescribing ARNI if patient currently on ACEI
  • Higher rates of hypotension observed with ARNIs compared to ACEI/ARBs. Diuretic dose or other BP lowering medications may need to be lowered.
    • ARNI contraindicated in patients with prior history of angioedema related to previous ACEi/ARB.
  • In general, ARNI>ARB>ACEI however, medication choice should be individualized to each patient with attention to considerations such as hypotension and insurance coverage.
  • Titrate to the highest tolerated dose that the patient’s blood pressure, renal function and electrolytes will allow.

Pearl 3: MRAs

  • Pathophysiology
    • Aldosterone levels are upregulated via activation of the deleterious RAAS pathway in patients with HF and reach high levels (20x normal) in these patients, leading to vasoconstriction, cardiac remodeling and volume and sodium retention.
    • Eplerenone has a lower affinity for progesterone, androgen, and glucocorticoid receptors, leading to lower risk of sexual side effects.
    • Aldosterone blockade modulates fibrotic scar formation and may have a beneficial effect on cardiac arrhythmia.
  • Outcomes and trial data
    • RALES Trial: first to show mortality benefit with spironolactone in HFrEF.
    • EPHESUS Trial: mortality benefit in the use of eplerenone in the treatment of post MI LV dysfunction.
    • EMPHASIS-HF: Eplerenone  in HFrEF as it demonstrated reduced risk of death and hospitalization in patients with moderate systolic dysfunction and NYHA Class II symptoms.
  • Patient Counselling
    • Generally, MRAs do not have a marked effect on blood pressure.
    • Important to monitor kidney function and electrolytes with initiation and up titration.
  • Pro tips in initiating
    • MRAs are under prescribed because of the need for close lab monitoring for hyperkalemia with initiation and titration
    • Potassium binders can be used as adjuncts to mitigate hyperkalemia
      • However, insurance coverage of potassium binders may limit use
      • Discontinue MRA if Cr >2.5 in men and >2 in women, GFR <30 and potassium >5.

Pearl 4: SGLT2 Inhibitors

  • Pathophysiology
  • Inhibition of SGLT2 receptors leads to glycosuria and natriuresis owing to its antidiabetic and diuretic effects.
  • Outcomes and trial data
    • In 2008, the FDA began requiring every new diabetes drug to be tested in a CV outcomes trial. This led to the CANVAS and EMPA-REG Trials which showed reductions in composite primary outcomes of CV mortality, nonfatal MI, nonfatal stroke and reductions in HF hospitalizations among those with diabetes.
    • DAPA-HF trial: among patients with HFrEF with or without diabetes, initiation of dapagliflozin  decreased rates of CV death, worsening HF and all-cause mortality.
    • EMPEROR-Reduced Trial: empagliflozin reduced risk of CV death and HF hospitalization in patients with HFrEF regardless of diabetes status.
  • Patient Counseling
    • Risk of genital yeast infections and euglycemic DKA
  • Pro tips in initiating
    • Goal doses are 10 mg daily with both dapagliflozin and empagliflozin. Patients can be started on 10 mg daily and do not need to be up titrated.
    • Must ensure GFR >30 before initiation of dapagliflozin and >20 for empagliflozin
    • SGLT2 inhibitors are contraindicated in patients with type 1 diabetes given the increased risk of DKA
    • Prescribers may need to decrease diuretic doses when planning to initiate SGLT2 inhibitors
    • Prescribers may need to adjust patients’ diabetes regimen when starting SGLT2 inhibitors to prevent hypoglycemia.

Pearl 5: Approach to initiation of GDMT

  • The magnitude of the treatment benefit of each drug class is independent of that produced by other agents.
    • Addition of an additional drug class yields benefits that are greater in magnitude than up-titration of existing drug classes.
  • The conventional approach is to prescribe each agent in sequence. Prescribers generally have up titrated each drug class to target dosing before starting the next agent.
    • Start ACEI/ARB/ARNI → add beta- blocker → add MRA → add SGLT2 inhibitor
  • One recently published paper sets forth a proposal of a new algorithm for sequencing GDMT. This approach generally takes 4 weeks to achieve as opposed to >6 months with more traditional approaches. Up titration to target dose is pursued after all four drugs are introduced.
    • Start beta-blocker AND SGLT2 inhibitor → add ARNI → add MRA.
  • No head to head trials on which approach is best, prescriber style is also involved.
  • Individualize initiation of GDMT to each patient.



S: This is Dr. Shreya Trivedi, an internist at Beth Israel Deaconess Medical Center.

V: and Dr. Viktoria Mladenovik, a second-year internal medicine resident at Beth Israel Deaconess Medical Center.

S: And this is the CORE IM 5 Pearls Podcast, bringing you high-yield evidence-based pearls. Today we will be focusing on guideline-directed medical therapy in heart failure with a reduced ejection fraction.

S: So, let’s get into those pearls we’ll be covering in the episode. Test yourself by pausing after each of the 5 questions. Remember, the more you test yourself, the deeper your learning gains.

V: Pearl 1: Beta-blockers

S: Is one beta-blocker better than the other? How do you explain to patients what beta-blockers do?

V: Pearl 2: Ace inhibitors, ARBs, and ARNIs

S:  What is preferred: ACE, ARB or ARNI and why?

V: Pearl 3: Mineralocorticoid receptor antagonists

S:  What is the difference between spironolactone vs eplerenone? And when do you stop MRAs?

V: Pearl 4: SGLT2 inhibitors

S:  What’s the thought behind why SGLT inhibitors help in heart failure?

V: Pearl 5: Approach to initiation of GDMT

S:  Which meds do you start first and in which order?

Pearl 1 – Beta Blockers

S: Alright! Let’s get right into the first class of meds, Beta blockers. And particularly we are going to talk about — the evidence base is really for carvedilol, bisoprolol and metoprolol succinate.

V: You know, I feel like we all have this vague idea of how the beta blockers work– they decrease sympathetic drive on the heart– but is there an exact mechanism that’s been proven?

S: From what I’ve read there’s a lot of hand-wavy explanations about myocardial energy metabolism, improved remodeling and energy efficiency.

Dr. Katz: Ultimately at the end of the day, when you have 12 different mechanisms that are being proposed, that means that nobody fully understands it.

S: That’s Dr. Greg Katz, a cardiologist at NYU dropping some realness – regardless of if we understand the mechanism or not, what we do know is that beta-blockers work!

Dr. Motiwala: So, the ones that you’re going to hear about, like a Seminole papers for Metoprolol and Carvedilol or Merit HF for Metoprolol and Copernicus for Carvedilol. And I can’t, I can’t say that we’ve revisited the beta blocker benefits since then. The reduction mortality that was seeing based on those early trials has been accepted. And now any study that is looking for benefit on top of that is assumed to be on a background of accepted GMT of which beta blockers are cornerstone.

S: That’s Dr. Shweta Motiwala an advanced heart failure specialist at Beth Israel Deaconess Medical Center.  So we know beta blockers are good, but do we know if one is better than the other?

V:  So, what i found surprising was that there was only one trial that compared two beta blockers against each other and that was called the COMET trial. It showed that carvedilol was better in terms of survival than metoprolol tartrate.

S: Wait, did you say tartrate? I thought tartrate wasn’t part of GDMT?

V: Well yes that’s just one of the many things the COMET trial has been criticized for.

Dr. Katz: honestly, if you pull up the abstract of the Comet trial in our room of even non cardiologists, and you just make them read the abstract, as you are reading it, you’re going to, a lot of people will have this audible gas because they realize why it’s a crappy trial and an inadequate way of, uh, uh, of deciding that metoprolol tartrate, is not a great medication for heart failure. And so, in the abstract, they talk about the gold doses that they titrated people up to. And a good dose of carvedilol is 25 milligrams twice a day. And that was the goal dose in the Comet trial. A gold dose of metoprolol is 200 milligrams a day. 

S: But in the COMET trial, the goal dose that patients were on for metoprolol tartrate was only 50mg twice a day.

Dr. Katz: And so, it’s like an apples to half an apple comparison

V: You know on rounds sometimes we just accept these studies at face value as being evidence-based medicine, but we don’t always have the chance to dig deeper into the details and really analyze how they reached some of these conclusions.

Dr. Katz: And so don’t get me wrong. You’re not supposed to prescribe metoprolol tartrate for patients who have a reduced ejection fraction. And by commenting on the weaknesses of the COMET trial, I am not suggesting that you start prescribing it to your patients, but we should be aware as like evidence based physicians who are able to tolerate a little bit of nuance and uncertainty that the only trial that was ever done comparing beta blockers was designed pretty clearly to show that one was better than the other, not to ask the question about which one was better.

S: Wow mic drop – indeed but what we do know that at least three beta blockers – carvedilol, metoprolol succinate and bisoprolol do reduce mortality which is a win at least.

V: And of those the largest effect on mortality is actually with carvedilol.

S: I wonder why that was – is it just that carvedilol acts on both beta receptors AND alpha receptors and these patients on carvedilol get more benefit from better BP control?

Dr. Katz: So, for example, alpha blockade is going to lead to increase after load reduction. There’s the lack of beta selectivity that may have some other theoretical benefits. And then there’s the fact that  Carvedilol tends to improve your insulin sensitivity, whereas metoprolol, and some of the other cardio selective beta blockers tend to worsen your insulin sensitivity.

S: Really? I did not think I really appreciate that carvedilol can improve insulin sensitivity in our patients and more so, that other beta blockers ACTUALLY could contribute to some insulin resistance.

Dr. Katz: In general, I prefer Carvedilol over metoprolol succinate or bisoprolol. And the reason that I prefer Carvedilol is twofold. One. I think that the data shows that it’s on the whole, probably a little bit better with regards to morbidity and mortality long term. Number two, I buy the incremental benefit that you get from improving insulin sensitivity and the metabolic impacts of a beta blocker long term, uh, potentially having some, some negative consequences down the road.

S: Right, I like how Dr. Katz emphasizes that in the long-run that we could see negative metabolic effects with metoprolol succinate.

V: Yeah, I appreciate hearing how he weighs the pros and cons, let’s hear from Dr. Motiwala which ones she reaches for and when.

Dr. Motiwala So someone who has borderline blood pressure, more likely to reach for the Metoprolol, someone who needs blood pressure lowering, in addition to just the, the overall beta blocker effects, I’ll reach for the Carvedilol.

S: Now that we understand pros and cons of some of the beta-blockers, maybe the most important thing we can focus on is how we educate our patients on these meds and set them up for success.

Dr. Katz: And if you do a crappy job of explaining to your patients, why they need to be on the medications, they’re not going to take them because taking pills is not fun. And so, I have this conversation every single time, I have a new patient, a patient with a new reduction in their ejection fraction. And what I talk to them about is this is a really scary diagnosis. And we have a lot of treatment options that will improve the length of time that you live, and that will improve the quality of your life. And our job is going to be to work together, to find the group of these medications that you tolerate the best. And that makes you live the longest.  That means that in a perfect world, you’re going to be taking quite a few different medications because each of these medications work differently on your heart to help you live longer and help you feel better.

S: 100% agree. really do wonder how much we as clinicians contribute to “med nonadherence”  and ppl are left to their misconceptions, most common being “they just keep putting me on all these pills” and one of the most important things to set them for success is giving them a heads-up about what they can expect.

Dr. Motiwala: And you might see a lowering of your heart rate in addition to a lowering of the blood pressure. And all of that allows the heart to have to do less work by taking some demand off of it and allows it to recover. 

S: I like that a lot, taking the demand off your heart and allow it to recover – def going to steal that next time I give this spiel.

Dr. Katz: And we’re also going to try to get the doses of these medications up as high as we can possibly get them because the higher those doses are the longer you will live and we’re going to work together and it’s going to happen over a period of time. It’s not an instant success, but over time, we’re hopeful that you’ll be able to handle them well without any major side effects. And so, I only care about your blood pressure being low. If it makes you feel lightheaded. And if it doesn’t make you feel lightheaded, I’m not going to get scared by a number. And I’m not going to back off on those medications. 

S: And the number he is talking about is BPs and to that point I’m grateful for cardiology blessing because I do find myself little nervous when someone’s BP is already 100s/60s and we are up titrating their GDMT meds.

V: Yea, I have to admit I get a bit nervous too, but I remind myself of this study I recently came across for every 10 beats per minute increase in heart rate above 80, patients with HFrEF experience a 14% increase in ALL CAUSE MORTALITY! And that really puts it into perspective for me.

S: Wow that’s really motivating, got to take the stress off the heart and up titrate those beta blockers!

V: Ok let’s summarize, when you are deciding which beta blocker to reach for, carvedilol may have the greatest effect with some added benefit of improved insulin sensitivity but overall, you really want to tailor your choice to what your patients BP can tolerate.

S: And I think my biggest take away from all of this is how we really frame the GDMT conversation with your patients – give them a headsup on two things 1) we are going to up titrating as much as possible and we’re going to work as a team to do this, and 2) your BP may be lower and that’s okay but you need to let us know if they start to feel dizzy or lightheaded.

Pearl 2 – ACE-I, ARB, ARNI

S: Alright, next on deck. The ace inhibitors, angiotensin receptor blockers aka ARBs and the newest of the family, the angiotensin receptor-neprilysin inhibitors, also known as the ARNIs.

Dr. Motiwala: If you think about the path of physiology of heart failure to start, um, a lot of it is based on a maladaptive response that involves the renin angiotensin aldosterone system. 

V: Yep and all that aldosterone leads to vasoconstriction, inflammation and even fibrosis….

Dr. Motiwala: And eventually all of these things result in adverse cardiac remodeling kind of impairments and the relationship between the heart and the kidneys, and then eventually contribute to progression of disease. And so, the ACE inhibitors and the ARBs, which have been around for a long time, they interrupt these pathways in different places. They block the downstream effects and then ultimately improve outcomes.

S: And in recent years, a new player has come into the heart failure picture, the ARNIIIIs, which I think it’s funny Victoria because we say ARNIs but there is only one ARNI for the time being. But it was really the Paradigm trial that cemented this. It when it showed that ARNIs decreased risk of cardiovascular death or HF hospitalization even more than enalapril.

Dr. Katz:  So, there’s a ton of excitement after the paradigm trial for sacubitril, which is composed of two drugs sacubitril, which is a drug that blocks the degradation of BNP with Valsartan, which is an angiotensin receptor blocker. And so, if you think about what BNP does, it’s a natriuretic peptide, which means it makes you pee out sodium. If you inhibit its degradation, that means you pee out more sodium. And so, there’s a diuretic benefit from this medication. There’s also a cardiac remodeling benefit that at least has been shown in vitro.

Dr. Motiwala: Another thing that it does though, is it does increase the levels of angiotensin, which is bad. So, the ARB component of the ARNI blocks that effect. So, in combination, you ultimately increase the beneficial effects of this balanced system and decrease the deleterious effects.

S: That sounds beautiful – balance! but maybe why do I have a feeling Greg may point out some questionable study design here.

Dr. Katz: There are two parts of the way the paradigm trial was designed that are controversial. When we look back at it, the first part is the decision to have the comparator arm not be an equal dose of an ARB, and instead be a dose of ACE inhibitor, enalipril. The other issue with the paradigm trial is they had a really long run-in period that patients needed to be able to tolerate for several weeks before they were able to be in the trial. And so, by virtue of selecting for a group of patients who already tolerate the drug, you’re going to overestimate the treatment effect in the real world. And don’t get, this is not shady. Like drug run in periods are standard. It’s the way that lots of trials are designed. But we, as the prescribers in the real world need to be cognizant of the fact that when a run-in period like that exists, it necessarily overestimates the mortality benefit that we end up seeing just because of the way that it selects for patients who can tolerate the drug.

S: That’s really good food for thought – they compared it against an ACE not an ARB, but we obviously can’t dismiss the results but good to keep that in mind that the patients in the study were already able to tolerate 4 weeks of an ACE/ARB AND on a beta-blocker for 4 weeks prior to the study.

V: Maybe it is overestimated benefit BUT I’m still a big fan of ANRIs. You know, one thing that gets under my skin is how much hesitancy there is about starting ARNIs especially in someone with an acute exacerbation.

S: Yeah, I know people may defer to starting it outpatient when patients are not being actively diuresed.

V: So, the PIONEER study showed that its actually safe to start ARNIs in acutely decompensated patients and this was really game-changing.

S: I think this was a study that also showed that ARNI decreased NT proBNP concentrations by about a whopping 50% compared to enalapril dropping proBNPs by 25% ( after a couple a months).

V: Decreasing proBNP levels, even more reason to start ARNIs.

S: You really love ARNis Viktroria.

V: I do!

S: That brings a practical point that we often chart reviewing prior proBNPs when someone has questionable exacerbation and I wish EMRs came with a little asterisk on the proBNP level to indicate this proBNP was a drawn when pt was on an ANRI bc it can impact the proBNP level by up to 50%.

V: that would be nice – and now we can just start ARNIs de novo! Let’s hear a little bit more about what that actually means from Dr. Motiwala.

Dr.Motiwala: The newer recommendations have adopted, um, the option for de novo Arnie initiation or what is being referred to as a direct to ARNI approach. And the reason to do that is that we’ve seen that it is safe and feasible to start patients on an ARNI without demonstrating tolerance to ACE inhibitors or ARBs beforehand.

S: That sounds good! Thank you for the permission to just start an ARNI de novo!

Dr. Motiwala: However, sometimes when you’re starting these meds, the blood pressure isn’t high enough to necessarily tolerate the vasodilatation and the blood pressure lowering effects that even the lowest dose of the ARNI. And in those situations, if you first want to demonstrate tolerability and then gradually uptight trait, it is helpful to go first from an ACE inhibitor or an ARB.

S: Okay and if you are worried about the blood pressure want to do an ACE or ARB before the ANRI, how do you choose between the ACE or ARB?

Dr. Katz: when I’m starting my patients on some type of inhibition of the renal angiotensin system, I have gone from an ACE inhibitor as my first choice where I, I used to just start lisinopril on patients. And that would be what I would use, uh, to now I’ll start an ARB instead. And the reason for that is twofold. One is you have less cough and that’s a big deal because having a cough is annoying. And then the other reason is because it makes your switch to Entesto, Cubero Valsartan much easier because you don’t have to do the 36-hour washout period.

S: Right, so if the patient is already on an ACE, they need that 36 hour off the ACE before an ANRI can be started. That’s really to minimize the risk of angioedema. But if you are switching from an ARB to an ARNI, you thankfully don’t have to make patients go through a 36-hour washout period.

Dr. Katz: I would say we’re not completely moving away from ACE inhibitors, but if you have an equivalent medication that doesn’t cause a cough as frequently, it seems kind of like a no brainer to use that other medication. And so ACE inhibitors are definitely becoming less favored in my practice, in the practice of many others.  

V: So, it sounds like in general ARNIs are preferred over ARBs which are preferred over ACE-I.

S:  Yeah, I think that makes a lot of sense. So, say we do we do get our patients on one of these life-saving meds that blocks the RAAS system, we should all up titrate these meds as much as a the kidneys and potassium can tolerate.

Dr. Katz: in order to really up titrate these medications, you need the ability to order a basic metabolic panel and a basic understanding of what the side effects are going to be. And other than that, anybody could do it. But, uh, it there’s no the major flaw and the major thing that we should improve on is we need to do a better job of getting these patients on the right doses of life-saving medications.

V: Ok so, as we are trying to up titrate these life-saving medications up, what should we watch out for?

Dr. Katz: And so, I’ll have a soft cutoff of a systolic blood pressure under 110, I’m skeptical about starting it and a systolic blood pressure under 90. I definitely won’t. And in that 90 to 110 range, it’s really kind of like case by case basis. Sometimes you need to back off on the diuretic dose of the loop, diuretic that someone’s on because you’re getting the additional natriuretic and thus diuretic effect from the sacbitral portion of the drug.

V: Yes! This is one of my favorite moves in HF clinic! It’s easy to forget that diuretics themselves actually don’t have any mortality benefit.  If my patient appears otherwise euvolemic, I love cutting back on the diuretic to make more room for these lifesaving medications.

S: Okay so to recap this section- ACE, ARBS, ARNIs all do a decent job of inhibiting the badness of aldosterone. The ARNI has the advantage of preventing the breakdown of natriuretic peptides such as BNP which helps with vasodilation, peeing out more sodium and decreasing the sympathetic tone. If your pts BP can tolerate it, reach for an ARNI and you can start de novo now. If you have to choose btw ACE or ARB, go for the ARB because it doesn’t give you a cough and if you need to transition to an ARNI, you don’t have to wait for a 36-hour washout period from the last dose like you have to with ACEs.

Pearl 3: MRA

V: Now on to the next class of meds…what seems to be the sometimes forgotten step child of GDMT. The mineralocorticoid receptor antagonists, also known as MRAs.

Dr. Motiwala: So I think this is a drug class that is probably not given as much attention as it should be given in the treatment of half RAF and is probably not prescribed as much as it should be prescribed because it does have the same type of morbidity mortality benefit and the same order as that, that’s seen for RNs and beta blockers and SGLT two inhibitors. Um, so I’m, I’m a big fan and I think it should be used more.

Dr. Katz: The mineral corticoid receptor antagonists often feel very onerous to add on because they’re already on a drug that raises their potassium, and then you’re adding this other drug that also raises their potassium. And I, I know that there’s probably part of our, part of the way that we’re thinking about it internally, even if it’s not explicit where we’re like, I’m already blocking that renal angiotensin aldosterone system, why do I have to block it even more? And so, it’s, I like fully get that and I have that same inertia of how I’m doing it, but we need to be very forceful to remind ourselves to overcome that inertia, because these are amazing drugs that are really beneficial for our patients.

V: In prepping for this episode, I was blown away to find that in heart failure patients the RAAS system is on such overdrive — to the point that aldosterone levels can reach up to 20x higher than normal.

S: Wow! So maybe it’s not such a bad idea to block that damn Renin-angiotensin-aldo system as Dr. Katz says through as many different ways as we can.

Dr. Katz: The first reason is reverse cardiac remodeling and decreased fibrosis. The second is there seems really like there’s an antiarrhythmic effect. And so if you pull up the EPHESUS trial, it’s a post MI trial, uh, comparing eplerenone to placebo. And if you look at those Kaplan Meer curves, you see that the Kaplan Meer curves for sudden death and for overall death start separating instantly. And that suggests if there’s a reduction in sudden death from eplerenone versus placebo, that there’s an antiarrhythmic benefit. And so you need to think about the idea of starting an aldosterone antagonist, especially in these patients who are in this vulnerable period before they get an I C D as this is something that is potentially lifesaving in the short term, not just when we get the remodeling down the road.

S: So interesting! I think I’m sold!

V: Yeah, I knew aldosterone contributes to remodeling and scar formation but I did not know that blocking also could have antiarrhythmic effect.

S: It makes so much sense now since we know scar tissue is often the nidus for arrhythmias and you told us in pearl 2 before Viktoria that aldosterone cause fibrosis and that can certainly lead to that scar tissue.

V: Yep so with that, lets dive into the two options for MRAs, spironolactone and eplerenone. Most patients that I’ve come across are on spironolactone.

S: Yeah, same here, but I do wonder if spironolactone the best one for the patients?

Dr. Katz: comparing eplerenone to spironolactone, spironolactone has a risk of gynecomastia and also has some incidence of sexual side effects. Eplerenone does not seem to have those same issues with it, uh, because it’s more selective with the way that it’s inhibiting aldosterone. And that is really beneficial with the regards to patient tolerance. And, uh, and, and just the way that you’re talking to somebody on about the drugs. I have one drug that may make you have sexual side facts and may make you grow breasts that you wouldn’t otherwise have. And I have another drug that is equally effective but doesn’t do those things. It’s really hard to make the case that spironolactone is the one that we should go to. But for, I think for a lot of financial reasons, and what’s on hospital formulas, we end up not using as much eplerenone known as, uh, as perhaps we should.

S: I got curious and looked it up, if someone’s insurance doesn’t cover it, eplerenone retails for at least in US at about $100-150 for a month supply compare that to spironolactone which is basically about 10 bucks.

V: Whoa!

S: But with a GoodRx coupon goes bring eplerenone down $30-40 for a month supply but still.

V: Yeah, I wish we used eplerenone more – I bet our patients don’t bring up the embarrassing side effects to us.

S: Yeah, I can imagine how it impacts their lives — why don’t we transition to the last thing we wanted to cover, which is when do we stop the spironolactone and eplerenone.

V: Yeah, I feel like spironolactone is the first one to come off when a patient comes in with an AKI.

S: So per the most recent ACC expert consensus guidelines we generally need to stop MRAs once Cr is 2.5 men or 2 for women.

V: Another thing to watch out for is the potassium. When the K creeps up above 5, you can think about adding a potassium binder – I often try patormir or valtessa in heart failure clinic, but obviously if the K is persistently above 5, then sure peel off the spironolactone.

S: Okay so let’s recap big takeaways for MRAs, spironolactone or eplerenone – Yes, it’s another med that increase our patient’s K and block the RAAS system, but does decrease cardiovascular mortality and even studies have shown it has antiarrhythmic effect. When choosing between the two MRAs, eplerenone does not have the gynecomastia or sexual side effect but is more expensive. In terms of when to discontinue it, guidelines tell us hard stops for MRAs when Cr of 2.5 in men and 2.0 for women or if the K keeps creeping up persistently above 5 like Viktoria just told us.

Pearl 4: SGTL2 Inhibitors

S: On to the new kid on the block, the SGLT2 Inhibitors- empagliflozin and dapagliflozin.

V:  Its interesting how this discovery came to be. It all started back in 2008, when the FDA began requiring that every new diabetes drug be tested in a cardiovascular outcomes trial.

S: Interesting! Glad they required that.

V: Yeah, because that’s when we saw patients who were on SGLT2 inhibitors had lower rates of deaths, MI, stroke and hospitalizations, which are all things we want.

S:  And people started to wonder humm do the SGLTs show the benefit in patients who don’t have diabetes? And the answer YES! It did decrease morbidity and mortality regardless of if someone had diabetes or not.

V: Right, I sometimes get a quizzical looks from patients like “wait a minute, I don’t have diabetes or my diabetes is under control – why do you want to start on diabetes meds”

S: I try to give a handwavy explanation of why SGLTs are so effective.

Dr. Katz: There’s all of these hypothesis sees about it has an augmented diuretic effect, but then there are other analyses that sort of suggest that it’s not really the diuretic effect. 

S: Really it’s not the diuretic effect? I’m surprised that is not the explanation.

Dr. Katz: There’s this idea about shifting myocardial energy metabolism to maybe preferring ketotone bodies. It’s not, it’s not clear that that’s actually having, it’s kind of benefit what my, my personal hypothesis is that the hyper insulinemia associated with metabolic syndrome is really catastrophic. And that drugs that improve our glucose control by reducing our insulin needs are going to be beneficial from a cardiovascular perspective, partly by virtue of the reduction in hyper insulinemia.

And so there is something about hyperinsulinemia and hyperglycemia that is toxic to our cardiovascular system in the long term. And SGLT2 is definite will have an impact on that, even if they don’t have a huge role in reducing A1C. And so SGLT numbers are incredible. And if there’s only one thing I’m quoted in the podcast of saying, I want it to be that. 

S: ahhh.. so its fair to see Dr. Katz is obsessed with SGLT2 inhibitors. What about you Viktoria, are the ARNIs still your favorite? Or have SGLT2 taking their spot?

V: Nah ARNIs are still my favorite [laugh..] but one thing I really appreciate about SGLT2 inhibitors if they do have a potassium lowering effect which is great bc so many of other GDMT meds actually increase K.

S:  Right it’s beautiful equilibrium that if we can get patients on all these meds, then maybe the K sparing and lower effects all balance each other out.

V: Another balancing interaction that we have to be mindful about is starting an SGLT2 on a patient who’s already on a diuretic.

Dr. Motiwala: Because there is a bit of a diuretic effect to the SGLT two inhibitors, I often, especially in patients who have a low loop diuretic requirement, I will often decrease the loop diuretic dose or cut it completely depending on what their baseline doses and in those people, I really do want to know what’s happening with their renal function and their electrolytes at a one or two week interval.

V: I will say that, I’ve seen some clinicians  start SGLT2s  at 5 mg daily– which is half the goal dose– if they are unsure how the patient’s blood pressure or renal function will tolerate it and then go up to 10 mg daily.

S: So its a similar story with the SGLT2 inhibitors, which is to keep an eye on their kidney function if they giving you clues that they are getting a bit dehydrated.

V: Oh the kidneys! Right there are important GFR cutoffs to keep in mind with SGLT2 inhibitors. For empagliflozin the GFR cutoff is 30 and for dapagliflozin its 20.

Dr. Katz: If their GFR is less than 30, then the risk of a euglycemic ketoacidosis is prohibitively high, and you’re not supposed to start those medications. The other risks, as, as I mentioned, there’s the risk of euglycemic ketoacidosis. And so I always a counsel of patients that if you are feeling nauseated, if you are feeling unwell, if something, doesn’t it feel right after starting this medicine, you need to seek out medical care and you need to get your blood drawn so that we can see what’s going on. 

S: Speaking of DKA, right now SGLT2 inhibitors are contraindicated in patients with type 1 diabetes for the reason that that population is at a higher risk of DKA.

Dr Katz: The second is this signal for increased risk of genital yeast infections. And so the way that I’ll talk to a patient about that is I’ll say just in very plain English, if you have itching in your privates, you can’t be embarrassed about it and you need to speak up. And I saw one case of Fournier’s gangrene related to an SGLT2 inhibitor in a patient who probably just didn’t speak up for a while and had like some funny feelings going on in their nether regions for, for too long. But so you need to like de embarrass patients regarding the fact that if you have itching down, the, it is treatable and fixable, but we need to be aware of it.

S: To recap, SGLT2 inhibitors have cardioprotective benefits in patients with heart failure regardless of diabetes status. As someone on twitter put it, these meds are really heart and kidney meds, plus/minus diabetes meds. If you are worried about someone’s blood pressure room and getting dehydrated with the diuretic effect, you can lower their other diuretics or start at half the dose of SGLT2 and uptitrate.

Pearl 5: Approach to Initiation of GDMT

V: Ok, let’s get to my favorite part!! How do we start GDMT on a patient with newly reduced EF?

S: Ah yes! We know which meds to start BUT when is the best to start them … in what order isnt so straightforward.

V: Exactly! There are no head-to-head trials on which approach is best and there does appear to be some prescriber style involved. After all, medicine is an art isn’t it?

S: The conventional approach is to starting each med uptitirating to max dose and then starting the next med, generally starting with ACEI/ARB/ARNI, followed by beta blocker, then MRA and finally SGLT2 inhibitor.

V:  Yeah I’ve seen that too but more and more people are starting to change their practice, especially after a new paper by McMurray and Packer came out proposing a different approach.

Dr. Katz: He proposes is you start the beta blocker and the SGLT2 inhibitor as early as you can. And neither of those medicines is going to have a huge impact on blood pressure. And so almost everybody has a good ability to tolerate them pretty quickly. Then you start the ARNI (sacubitril- Valsartan). Then the next step after that is you add the minerality corticoid receptor antagonist. And there’s a lot of wisdom in doing that because you can get patients up to their target goal target. You can get patients up to their target doses a lot more quickly when they’re already on the low doses of the medicines. 

V: What’s amazing is that this approach generally takes 4 weeks to get patients on all 4 lifesaving meds,

S: 4 weeks! That’s pretty great

V: Yeah, when traditionally it would have taken more >6 months to get them on all these meds.

S: My dad recently went thru this and he just got tired from constant checkups and addition of meds and think he would have done better had he just had the SGLT2/B-blocoker started right away in the hospital and then the ARNI and MRA a couple weeks apart.

Dr. Katz: This is a stylistic thing. It’s not like we have high quality randomized control trial data demonstrating that we there’s a higher incidence of getting people up to the target doses of all of these medicines using one approach versus the other. Ultimately at the end of the day, the best approach is the one that gets results in your practice.

Dr. Motiwala: If you asked around, there is a big push these days to try to get patients on all four of these drugs at the same time, rapid sequence. And I think that that is a great goal. I think it is sometimes difficult to achieve if you have any concerns about hemodynamics stability or congestion or renal dysfunction or patient’s symptoms. And I do think that it’s difficult to start everything at once and then have someone say that they don’t feel good and then not know what to do with that. 

V: Thats a great point, I’ve definitely been in the situation where we’ve started multiple agents and suddenly the patient doesn’t feel well or another side effect pops up and we are scratching our heads as to which one it was.

S: Dr. Motiwala gave us another humble reminder that if the side effect is a creatine bump, to try adjust things that don’t have mortality benefit.

Dr. Motiwala: If I have a patient on all four of these meds, the RNA, a beta blocker, or an MRI, and an SGLT2 inhibitor, they’re also probably on a loop diuretic. And I see that there’s a little bit of an acute kidney injury that, you know, the patient’s feeling fine. I would first think about is the spironolactone causing a problem? Are they over diursed? Do we need to adjust their loop diuretic? Um, did we just start the SGLT2 inhibitor an hour? Are they a little bit dry? What are the other things that we could potentially optimize before we start discontinuing meds? And it usually involves adjusting a loop diuretic before, before touching the ARNI.

S: And not just the loop diuretic, scan the whole patient’s med list for other offenders.

V: I’m like a hawk when I see agents without any mortality benefit on my patients med list like amlodipine taking up precious blood pressure that I could put towards GDMT. In fact, I was recently on service and my attending said blood pressure is like money in heart failure and you really have to spend it wisely.

S: So to recap, Some experts favor starting patients on low doses of multiple agents upfront, like with an SGLT2/b-blocker then adding ANRI followed by an MRA and uptitrating as able. Others may take a more step wise approach with ARNI then B-blocker then MRA and then SGLT2 with the idea that if the patient has a side effect it may be easier to tell which one may the culprit. All have its pros and cons and gotta think what’s best for the patient and also what resources you have available to you to do this.


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