Time Stamps

  • 01:54 Pearl 1 – Recap of GDMT and CKD
  • 09:15 Pearl 2 – Hydralazine and Isosorbide Dinitrate 
  • 20:59 Pearl 3 – Ivabradine 
  • 25:47 Pearl 4 – Inpatient vs Outpatient Initiation of GDMT
  • 30:55 Pearl 5 – Ejection Fraction Recovery 


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Show Notes

Pearl 1: Quadruple-therapy in CKD

What additional considerations are warranted when using these medications for patients with CKD?  for patients with CKD?

    • Beta blockers:
    • ACE inhibitors, ARBs, and ARNIs:
      • May cause a temporary increase in creatinine (~30%)
        • Long-term nephroprotective effects
      • There is no absolute creatinine-based contraindication to initiation
      • Subsequent dose-adjustment may be required based on follow-up:
        • Blood pressure 
        • Potassium levels
      • Consider potassium binders if necessary (check out our episode on hyperkalemia in CKD)
    • Mineralocorticoid antagonists (MRAs):
      • If Creatinine > 2.5 mg/dl, avoid initiating an MRA, but do not discontinue if they patient is already on it as CKD progresses
    • SGLT2 inhibitors:
      • If GFR < 20, don not initiate SGLT2i therapy, but may be ok to continue
      • PRACTICAL TIP! Starting SGLT2 inhibitors and MRAs together may provide a buffer against hyperkalemia.
  • As CKD progresses to stage 3, using these medications becomes increasingly challenging!
  • Consider the difference between initiating and continuing a medication:
    • Initiating:
      • Uncertainty about how a patient will respond to a new drug and whether it will be well-tolerated.
    • Continuing:
      • Patient already demonstrated they can tolerate that agent in the long-term and doses can be adjusted if adverse effects occur
    • Always keep therapeutic inertia in mind, which can manifest in both continuing effective medications and hesitating to initiate new ones 

Pearl 2: Hydralazine/Isosorbide Dinitrate

  • Pathophysiology:
    • Vasodilators
      • Reduce peripheral resistance → Lower blood pressure
  • Outcomes and trial data:
    • V-HeFT trial (1986) 
      • Trend towards improved survival among patients with systolic heart failure who were treated with hydralazine and isosorbide dinitrate
    • A-HeFT trial (2004) 
      • Combination of hydralazine and isosorbide dinitrate improve survival and reduce hospitalization among black patients with HFrEF 
    • V-HeFT II Trial 
      • Enalapril had a more favorable effect on 2-year survival than a combination of hydralazine plus isosorbide dinitrate. 
    • Hydralazine and isosorbide dinitrate can be considered if:
      • Initiation of first-line therapy (ACE-I, ARB, or ARNI) is contraindicated 
        • Drug intolerance Renal insufficiency) 
      • Blood pressure goals are not met on first-line therapy alone 
    • Current guidelines recommend initiation for self-identified African American patients who are otherwise receiving optimal medical therapy to:
      • Improve symptoms 
      • Reduce morbidity and mortality.
  • Patient Counseling:
    • Vasodilatory effects  can lead to headaches 
    • Require 3 times daily dosing
      • Short half-lives
    • Lab monitoring is NOT required
      • Do not affect renal function
  • Pro tips:
    • If caring for a patient on hydralazine/isosorbide dinitrate, always look back at the chart to investigate the reason they are not on preferred first line agents and continually re-evaluate!

Pearl 3: Ivabradine

  • Pathophysiology:
    • Lowers HR
      • Selectively inhibits  cardiac pacemaker current called the “funny channel”
        • “Funny channel” controls the spontaneous diastolic depolarization in the SA node
  • Outcomes and trial data:
    • SHIFT Trial 
      • Addition of ivabradine to patients who had a resting HR >/ 70 bpm despite maximal beta blockade → reduced rates of hospitalization
  • Patient Counseling:
    • Start only if the patient is on maximally tolerated doses of beta blockers
    • Does not affect blood pressure or kidney function
  • Pro tips: 

Pearl 4: Inpatient vs Outpatient Considerations

  • 1 in 4 annual cardiovascular deaths are due to heart failure
  • CHAMP-HF registry (2016-2018): 
    • ONLY 1% of eligible patients were simultaneously on target doses of ACEi/ARB/ARNI, BB, and MRA therapy
  • Safety, Tolerability and efficacy of Rapid Optimization (STRONG-HF Trial):
    • Simultaneous initiation of all 4 GDMT agents is: 
      • Safe 
      • Well tolerated
      • Rapidly effective 
      • Overcomes inertia 
    • Specifically, the protocol aimed for optimal dosing at 2 weeks after discharge, and 4 outpatient visits over 6 weeks to monitor clinical status
    • Outcome: Rapid initiation of all 4 GDMT agents is
        • Safe
        • Well tolerated
        • Rapidly effective 
      • 40-50% of patients on all max dose GDMT compared to only 5% with usual care! 
        • With better readmission and mortality rates
  • There is no substantial overlap in effect of the GDMT meds, thus it is important to utilize each in combination!

Pearl 5: Patient Expectations on EF Recovery


Dr. Shreya Trivedi: Welcome to the Core IM 5 Pearls Podcast, bringing you high-yield evidence-based pearls.  This is Dr. Shreya Trivedi, an internist at Beth Israel Deaconess Medical Center. 

Dr. Viktoria Mladenovik: And Dr. Viktoria Mladenovik, cardiology fellow at Beth Israel Deaconess Medical Center.

Dr. Shreya Trivedi: Today we will be focusing on guideline directed medical therapy aka GDMT in heart failure with reduced ejection fraction, Part 2!

Dr. Viktoria Mladenovik: Shreya, let’s get right into it! We got a lot of good ground to cover.

Dr. Shreya Trivedi: Yes, yes! Test yourself by pausing after each of the 5 questions. Remember, the more you test yourself, the deeper your learning gains.

Dr. Viktoria Mladenovik: Pearl 1 – Recap of GDMT and CKD

Dr. Shreya Trivedi: With progressive CKD, what GDMT medications can you start, continue, or stop?

Dr. Viktoria Mladenovik: Pearl 2 – Hydralazine and Isosorbide Dinitrate 

Dr. Shreya Trivedi: What does the data on hydral/isosorbid tell us and what does it not tell us, and what are the medication’s limitations?

Dr. Viktoria Mladenovik: Pearl 3 – Ivabradine 

Dr. Shreya Trivedi: What do you do if your patient’ s heart rate is still above 70 despite maximal beta blockade? 

Dr. Viktoria Mladenovik: Pearl 4 – Inpatient vs Outpatient Initiation of GDMT

Dr. Shreya Trivedi: What are the pros and cons of starting GDMT inpatient versus outpatient?

Dr. Viktoria Mladenovik: Pearl 5 – Ejection Fraction Recovery 

Dr. Shreya Trivedi: Do you still keep patients on GDMT once their EF recovers? 

Dr. Shreya Trivedi: I am so excited about Part 2 to shine light on some of the medications that don’t get as much attention, but before we do that, let’s do some spaced repetition. Why don’t we review the quadruple GDMT we talked about in Part 1? But I thought we could kick it up a notch and review them a bit in the context on advanced chronic kidney disease, CKD.

Dr. Viktoria Mladenovik: Shreya, I’m so glad we are talking about this! Because in clinical practice, you’ll see so many notes that say “we can’t start an ACE or an ARB due to CKD” or we “Can’t start an SGLT-2  inhibitor because the creatinine is too high.” 

Dr. Shreya Trivedi: Yep, lets relook at the GDMT meds and when we can start them, stop them, is okay to continue them as kidney disease progresses and for that let’s hear from Dr. Greg Katz, a cardiologist at NYU.

Dr. Greg Katz: When I think about the goal of treatment for many heart failure patients, it’s quadruple therapy. Get them on a beta blocker, get them on an ACE, an ARB, an ARNI  get them on a mineralocorticoid receptor antagonist and get them on an SGLT-2. So you have those four pillars of therapy. And what’s really, really nice about beta blockers is they don’t affect kidney function, they don’t affect GFR. And so with a beta blocker, you feel totally comfortable pushing that dose as long as the patient is not orthostatic. And it doesn’t matter what their creatinine is because creatinine is not affected by the beta blocker. When it comes to the ACEs, the ARNIs and the ARBs, then you’re expecting a 30% rise in their creatinine, even if in the long term it’s nephro protective. And there’s no absolute cutoff for when I wouldn’t start those medications, but I am watching their kidney function on the metabolic panel. I am watching their potassium, and I’m making sure that the patient is not orthostatic when I’m thinking about either continuing it or increasing those doses. 

Dr. Viktoria Mladenovik: Okay, so beta blockers don’t affect kidney function, therefore we can continue them as long as the patient can tolerate it from a blood pressure standpoint. 

Dr. Shreya Trivedi: Yep! And then with ACE, ARB, ARNIs, we expect that creatinine to go up. There is certainly less data we get to CKD stage 5, but you can start/continue that RAAS blockade as long as the blood pressure and potassium allows. And that’s where you can think about potassium binding drugs, right? So you can make sure to get this neurohormonal blockade for your patients heart and for their kidneys. And we do a whole episode on hyperkalemia and management that goes over all that!

Dr. Greg Katz: When it comes to the MRIs and the SGLT-2’s, you have a little bit more of a numerical obstacle when it comes to those medications. And so it’s often quoted that if the creatinine is over 2.5, the mineralocorticoid receptor antagonist shouldn’t be started, but it probably can be continued. And with the SGLT-2  inhibitor, the GFR of 20 is probably your cutoff for when you can’t start it, but you can continue it. And at the end of the day, patients don’t fit into these precise boxes very frequently. But it’s good to have numbers in general because it gives us a sense of when do I need to be most worried about somebody and when should I really be double checking what that up-to-date article says before I put the order in or before I sign that the prescriptions to go to the pharmacy? 

Dr. Shreya Trivedi: One thing that made me pause that he said is, we can probably continue that MRA and SGLT-2 as CKD progresses, which I really appreciated since I often find myself squeamish when CKD stage 3 or 5.

Dr. Viktoria Mladenovik: Absolutely!

Dr. Greg Katz: Stage 3 is where I think that you are both faced with your most challenging clinical decisions, but you also have the most opportunity to change the trajectory of their kidney disease. And so you need to look at Stage 3 patients as a real opportunity for you to slow down the decline in their GFR that’s going to necessarily happen over time. If somebody’s already on it, if somebody is already on a medication and they’re tolerating that medication and we know what the side effects of these drugs are. A mineralocorticoid receptor antagonist raises potassium and it lowers blood pressure. An SGLT-2 inhibitor has the risk of genital urinary tract infections, both bacterial and fungal, and it also has the risk of euglycemic DKA. And if you know what the risks of a medication are and you have a patient who is on the medication and is not having those side effects, you need to feel comfortable or you should feel comfortable continuing a medication that a patient is very clearly tolerating. And so there’s a very big difference between introducing something into somebody’s biology and just continuing them. And therapeutic inertia is powerful in both directions. It’s powerful in the way that we can continue patients on medications that are working for them, but it’s also powerful in the way that it holds us up from putting medications on a patient’s med list that they would actually benefit from.

Dr. Shreya Trivedi: Therapeutic interia! Oh, I love thinking about that and how I do a bat my eyes when I see on an ARB or SGLT inhibitor in a patient with stage 4 CKD or even end-stage renal disease, but ultimately I have relief that we can continue if the patient is not having side effects.

Dr. Greg Katz: There’s pretty clear data for ACE inhibitors, for angiotensin receptor blockers, for SGLT-2  inhibitors, that those drugs are nephro protective and they slow the progression of chronic kidney disease. And that data is pretty clear. It’s been replicated over and over and over again. And one of the nice things about the overlap between the cardiovascular system and the renal system is blood pressure is a target of therapy for both of them. And the heart doesn’t pumping against high blood pressure just like the kidney doesn’t receiving high blood pressure. And for a patient who has chronic kidney disease, I try to not just be creatinine centric and I try to think about what are the commonalities between what’s going to help their cardiovascular function and what’s going to be nephro protective. And so blood pressure reducing the pressure that the glomerulus faces. Thinking about ACE inhibitors, angiotensin receptor blockers, SGLT-2 inhibitors as being things that will preserve renal function even if they transiently make the blood test look worse.

Dr. Shreya Trivedi: Exactly, exactly. So as a recap of our recap and spaced repetition, I think the big takeaway here is to have that intestinal fortitude, as Dr. Katz would say, to push through that creatinine when we see it looking a bit worse and managing the hyperkalemia with potassium binders and doing our best to start and continue the B-blocker, ACE/ARB/ARNI, MRA, SGLT inhibitors in our patients with heart failure with reduced ejection fraction. 

Dr. Viktoria Mladenovik: And with that we will leave you with this last little practical tip from Dr. Katz.

Dr. Greg Katz: I will often for a patient especially who has a patient who has borderline renal function, who I’m worried about hyperkalemia, I will start the SGLT-2 inhibitor along with the mineralocorticoid receptor antagonist because of the way that SGLT-2 inhibitors protect against hyperkalemia. And neither of those medications has a big role in what the glomerular perfusion is. And you know, you do see a small rise in creatinine when you start either of those medications, just anecdotally, even if it’s not proven in the lab, but starting them together gives you a little bit of a buffer against hyperkalemia, which is one of the things that you’re really worried about with these things. 

Dr. Viktoria Mladenovik: Okay, now with that recap of GDMT in the context of CKD, lets get to the B team meds. These are the meds that get a bit less of the limelight! Why don’t we get started with hydralazine and isosorbide dinitrate, also known as, isordil.

Dr. Shweta Motiwala: Hydralazine and isordil are essentially in combination used for vasodilatation. So they lower blood pressure by causing vasodilatation. And in that way, similar to the other agents, they remove some of the stress from the heart. The way that they’re used typically are as additional agents on top of the medications that we’ve already discussed. So in patients who are already on max tolerated doses of the ARNI, the beta blocker, the MRA and the SGLT-2 inhibitor, if they need additional hypertension management, hydralazine and isordil are good agents to add on. They’re also used in patients who are unable to tolerate one or more of those classes of medications, either due to renal dysfunction issues or electrolyte issues or side effects. 

Dr. Shreya Trivedi: That’s Dr. Shweta Motiwala, a cardiologist at USCF. And so its a Class I recommendation to use hydral/isordil in patients who self-identify as African American after the other GDMT is maxed. Now, we wanted to make sure we address the challenging nature of this recommendation and the trials they’re based on upfront. 

Dr. Viktoria Mladenovik: Exactly, so we wanted to address these studies head on and reconceive their takeaways, and we invite discussion from people of all perspectives and backgrounds on this issue.

Dr. Greg Katz: I very much worry about the over extrapolation of trial data like we have that will lead to differences in how different groups of people are treated. And after we were talking about it, I re-read all the papers. It actually kind of blew my mind what re-looking at them, where the path that I kind of went down. I learned a ton. I talked to, I don’t know, half a dozen people, maybe more.

Dr. Shreya Trivedi: So, I really appreciated his nuanced read of what the data really does tells us and what the data does not tell us.

Dr. Viktoria Mladenovik: All the data we have for isosordil and hydral initially comes from the V-HeFT trial, which was published all the way back in 1986. 

Dr. Shreya Trivedi: And to help keep the trials straight, V in V-HEFT stands for vasodilatator therapy. 

Dr. Greg Katz: If you look at V-HeFT, what did V-HeFT look at? They looked at isosorbide hydralazine, they looked prazasin, and they looked at placebo and they found that the long acting nitrate and hydralazine combination had sort of a trend towards being better. And it looks like it was better compared to prazasin and it looks like it was better compared to placebo. But then if you look at the subgroup analysis of that, which wasn’t published till a few years later, they really sort of separate out self identified African Americans versus everybody else. And most, that’s a VA trial. So it’s mostly people who identify as African American and people who identify as white.

Dr. Shreya Trivedi: Two big caveats that should keep anyone from applying those trial results to current day is that number 1, that the V-HeFT was done back in 1986, as Viktoria mentioned, and the standard of care then was digoxin and diuretic. I mean there wasn’t even data on beta-blockers then. 

Dr. Viktoria Mladenovik: Yeah! It was a very different era.

Dr. Shreya Trivedi: And then number 2, we know that subgroup analysis, which was done from V-HeFT, is hypothesis generating, right? So thats why A-HeFT was designed. And the A in A-HeFT standing for African American. 

Dr. Greg Katz: Isosorbide dinitrate and hydralazine to a placebo in a group of patients who are self-identified as African American. They were a VA population. And a VA population is different than the population that many people who don’t work in VAs treat, but they compared isosorbide nitrate and hydralazine to a placebo. And what they found was that in self-identified African Americans, isosorbide hydralazine, compared to placebo leads to a mortality benefit.

Dr. Shreya Trivedi: So much to unpack there. 

Dr. Viktoria Mladenovik: And the first thing to keep in mind when interpreting these results, is that the VA population back in 2004 were rock stars when it comes to GDMT. 

Dr. Shreya Trivedi: Over 90% on ACE or ARB, 80% on beta-blockers and about half on an mineralocorticoid receptor agonists!

Dr. Greg Katz: And what I was so struck by rereading A-HeFT and looking at what the other guideline directed medical therapy they were on, and it was really good. And so to see a benefit of isordil and hydralazine on top of pretty good medical therapy tells you that there’s a there there, and you can’t blow off that result.

Dr. Shreya Trivedi: On top of at least 2-3 GDMT, we found hydral/isosorbid showed a mortality benefit ,but the second thing to unpack here is that A-HeFT  trial was ONLY done in the African American population.

Dr. Greg Katz: A literal read of the data tells you that there’s probably a benefit in this subgroup on top of our current GDMT, but I don’t think that a literal read of the data tells you that there’s no benefit in anybody else. Where the evidence that hydralazine and isosorbide dinitrate doesn’t work in patients who identify as other races? I kept looking at this data and I’m like, where’s the data that shows that nobody really benefits from this drug? And you’re left with a subgroup analysis from V-HeFT and the fact that A-HeFT only included people who self-identified as one specific race.

Dr. Shreya Trivedi: And the last thing that I found really nuanced and thought-provoking is thinking back what may be a confounder, and that it might be the etiology of the cardiomyopathy.

Dr. Greg Katz: The other thing that’s notable about A-HeFT is the proportion of patients who had ischemic cardiomyopathy was much lower than the proportion of patients who have ischemic cardiomyopathy in most other clinical trials. And so the majority of patients had either hypertensive cardiomyopathy or idiopathic cardiomyopathy. And so maybe the right distinction isn’t based on self-identification of race, but etiology of cardiomyopathy because that’s often not separated out in the clinical trials. 

Dr. Viktoria Mladenovik: So maybe its the fact that a lot more of the patients had hypertensive cardiomyopathy or idiopathic cardiomyopathy that was a confounder and maybe hydral/isordil works better in those etiologies.

Dr. Shreya Trivedi: Yeah! Exactly and the last very practical consideration about applying the A-HeFT trial to current practices is just looking at the fine print of the doses that were used. 

Dr. Viktoria Mladenovik: So, I was totally shocked when I realized how high the target doses of hydral and isordil were in the study. They titrated hydral up to total 225 mg and isordil up to 120 mg daily. I mean, Shreya, when I start these inpatient, I’m usually reaching for like 10 mg TID of each! 

Dr. Greg Katz: And then you add to the fact that the nitrate titration is often limited by headache, and that these are three times a day medications. And you end up in a situation where the narrow, narrow cross section of patients who are indicated for it can tolerate it and who you can titrate it up for. It’s such a small fraction that. !e like it because again, they don’t affect the creatinine. It’s really easy to prescribe a three times a day medicine. It’s really hard to take a three times a day medicine. If you have a patient who for whatever reason cannot be on an ACE inhibitor or an ARB or an ARNI, then sure it is totally fine to add in the long acting nitrate and hydralazine combo and try to titrate it up as much as you possibly can. 

Dr. Viktoria Mladenovik: So when I meet a patient who happens to have hydral/isodil along with their laundry list of meds, what do you think, Shreya? Should I rock the boat a little bit and change things up? 

Dr. Shreya Trivedi: Yeah! You know, Viktoria, when I find myself in these situations, I try to give this person the benefit of the doubt that someone really thought about their GDMT and there is some reason I don’t know about why their GDMT ended up this way versus that way. But we really probed our cardiologist on what they would do when they see hydral/isosorbid on med rec, but not other GDMT meds.

Dr. Shweta Motiwala: So sometimes you can find a good reason and sometimes it’s that someone tried a low dose of something and there was some side effect and it wasn’t clear what it was. And then it just got pulled forward in the patient history as an intolerance to whatever the medication was that was tried. Even in people who borderline renal function, I will, if there isn’t a compelling reason not to, if a patient comes to me on hydralazine and isosorbide dinitrate, I will try to get them on some of the other agents that we spoke about. And I can think of a particular patient who had some renal dysfunction and was then committed at some point to hydralazine and isosorbide. And I swore by it. And then, you know, over time, the renal function kind of stabilized. Her creatinine was in the 2s, but it wasn’t getting any worse. And so in collaboration with an outpatient nephrologist, we decided to try to do this cross titration. And she is now completely off of her three times a day, hydralazine and three times a day, isordil and on maximum dose Entresto. And it’s, so it takes a little bit of digging. It takes a little bit of communication with, um, other treating clinicians to figure out what issues came up in the past, and then not always, but sometimes you can actually get people on better meds. 

Dr. Shreya Trivedi: What a great story and again there is good data for this. Not to add another trial into the mix but when ACE and ARBs actually came out, there was another trial that came out V-HeFT II, that looked at enalapril vs. hydral/iso, and of course hydral/iso was inferior to the ACE inhibitor! 

Dr. Viktoria Mladenovik: So maybe the take away here is next time you find yourself caring for a patient with hydral and isosodil on their medication list, take a quick look back at the chart and investigate the reason they are not on preferred first line agents.

Dr. Shreya Trivedi: So to summarize this pearl on hydral/isordil. This works by vasodilating. The con is that your titration is going to be limited by headaches and blood pressure room on top of the the other GDMT and its a 3 times a day medication, but one pro is that doesn’t affect the kidney function or potassium directly. And then we’ll let Dr. Katz summarize his take away on his close read of what literature does and does not tell us.

 Dr. Greg Katz: It’s pretty clear to me that ACE inhibitors or ARBs or ARNIs are better than treating somebody with hydralazine and isosorbide by itself.  But the additive nature of a long acting nitrate plus hydralazine and the effect that that will have on nitric oxide and vasodilation and blood pressure control and yada yada, like all of the pathophysiologic theories about why that would be better, I’m honestly not fully persuaded, that won’t work in self-identified white patients or self-identified Hispanic patients or self-identified Asian patients who don’t have ischemic cardiomyopathies and have hypertensive cardiomyopathy. And what I took away from rereading those trials is if I have room to treat somebody’s blood pressure and they have a reduced ejection fraction, maybe anybody would benefit from that. And yes, I will be probably more aggressive in somebody who has a hypertensive cardiomyopathy or an idiopathic cardiomyopathy. 

Dr. Shreya Trivedi: Okay, next player on the B team! Ivabradine! Speaking of the B team, I am getting flashbacks to being the slowest kid in gym and being called last or second to last.

Dr. Viktoria Mladenovik: Oh man! Bad memories! But to understand ivabradine’s story, it really comes back to the idea we talked about in Part 1. That heart rate should be thought of as a therapeutic target in heart failure. 

Dr. Shreya Trivedi: Yeah! And studies have even shown us that in patients with left ventricular dysfunction, who have a heart rate greater than 70 bpm, they are at an increased risk of cardiovascular death and increase in hospitalization for HF compared to those with resting HR below 70. 

Dr. Shweta Motiwala: What we know is that there are, there are a lot of beneficial effects of beta blockers that aren’t directly related to heart rate reduction, but we also know that the lower the heart rate, the better the outcomes in heart failure. And so Ivabradine, I would think of as an add on medication or an adjunctive agent to be used in patients who need additional lowering of the heart rate after they’re already on either the optimal dose of a beta blocker or the maximum tolerated dose of the beta blocker due to other potential side effects.

Dr. Viktoria Mladenovik: Okay, so it looks like the key is to only consider ivabradine, once GDMT is optimized, particularly when the patient is on maximally tolerated doses of beta blockade. 

Dr. Shreya Trivedi: Viktoria, can you remind us again, how exactly does ivabradine work? 

Dr. Viktoria Mladenovik: Shreya, how could we forget! Ivabradine inhibits the “funny current” and thereby controls diastolic depolarization of the sinoatrial node and lowers heart rate. 

Dr. Shreya Trivedi: Ah yes, the funny current! I honestly haven’t thought about that since med school! 

Dr. Viktoria Mladenovik: And so, data for ivabradine comes from SHIFT Trial. And in this trial patient had to be on stable GDMT for at least 4 weeks before initiating ivabradine. The greatest benefit was reduction in heart failure hospitalization. 

Dr. Shweta Motiwala: The main trial that looked at Ivabradine, the SHIFT trial, it resulted in a significant reduction in heart failure hospitalizations, but we haven’t seen the same type of benefit in terms of mortality.

Dr. Shreya Trivedi: Okay, so we are looking at less heart failure hospitalizations here when ivabradine was added. But I’m curious, how many of the patients in the SHIFT trial were on optimal doses of beta blockers in the background? 

Dr. Viktoria Mladenovik: So that’s where one criticism comes in. It turns out only about 25% of the participants were on optimal doses of beta blockade and only about half were on half of the target dose. 

Dr. Shreya Trivedi: That is a valid criticism, since we know the mortality benefit of beta-blockers goes even beyond reduction of heart rate, right? And so its really important that we up titrate them as much as possible before we add that ivabradine.  

Dr. Viktoria Mladenovik: Well they did cite that up titration of the beta-blocker was limited by things like hypotension and fatigue.  

Dr. Shreya Trivedi: Ah, I see! So things we do run into real life, but yeah it does make us wonder did the underuse of beta-blockers in lowering that heart rate play into that ivabradine got to come in and save the day, and maybe the SHIFT trial kind of overstated its benefits because we were underusing beta-blockers. 

Dr. Viktoria Mladenovik: Yeah, thats great food for thought in interpreting the results in a more nuanced way.

Dr. Shreya Trivedi: Either way, the takeaway is we are going to try to max out those beta-blockers as much as possible before we give ivabradine. But I guess, Viktoria, before we go ahead and prescribe, are there particular cases we should avoid starting ivabradine? 

Dr. Shweta Motiwala: They should be in sinus rhythm. They cannot be in persistent atrial fibrillation or flutter, and they shouldn’t have pre-existing conduction abnormalities. So any concern for heart block or sinus node dysfunction, those would be people who I would not consider this in.

Dr. Viktoria Mladenovik: And the reason why a patient has to be in sinus rhythm goes back to the mechanism. 

Dr. Shreya Trivedi: Oh yeah, you told us ivabradine blocks the funny current in the sinoatrial node. So if the patient is not in sinus, I guess there’s no point in using a med that works on the sinus node!

Dr. Viktoria Mladenovik: Exactly! The last point I’ll bring up is a positive one. Ivabradine doesn’t affect blood pressure and is not limited by renal function. 

Dr. Shreya Trivedi: Ah, two big wins! So let me try to recap what I am taking away. I think when I see a patient who is on maximally tolerated doses of beta blocker, but their resting heart rate is still above 70 bpm, I’ll consider adding ivabradine since it may reduce heart failure hospitalizations. I will have to make sure the patient is in sinus rhythm but don’t have to worry about blood pressure or kidney function.

Dr. Viktoria Mladenovik: So lets we’ve stabilized our patient who came in with an acute heart failure exacerbation. And we are now nearing discharge. Enter the debate we’ve all had with the team at some point! What do we start now and what do we save for the outpatient setting? 

Dr. Greg Katz: New diagnosis of heart failure, they have a low EF, we get them started on a beta blocker, an ACE and or an ARB. Maybe we start Sacubitril-Valsartan and then we have this conversation on rounds of, should we start the mineralocorticoid receptor antagonist? And there’s always somebody who says, I think that we should just defer it to the outpatient setting. Do you know how hard it is to do that from the outpatient setting? You start the prescription. And so you’re typing into your EMR. You send the prescription, and then you need to tell the patient, I’m gonna check your blood work in a week to see what happens to your potassium and see what happens to your creatinine. And so you need to send them for blood work in a week. And then part of you is worried. They’re not gonna get the blood worker they’re gonna get into done too late. And then the blood work comes to your inbox. And then the potassium is 5.6. And so you have to call the patient on the phone and then you get a voicemail or a non-working number. 

Dr. Shreya Trivedi: Oh, I appreciate this so much! I’ve had so many friends care for a patient after being discharged from the hospital with a long list of to-dos, transitional items, and just feeling like “wait why didn’t the team just start the MRA inpatient?!” and then I also try to remind them the inpatient setting is also madness and constant pressure to discharge patients as early as possible. 

Dr. Viktoria Mladenovik: Absolutely! There is varying comfort starting a new medication right before discharge. Do you keep the patient for a little bit to see if any side effect starts or repeat a K  but I also understand where Dr. Katz is coming from that if possible prioritize starting as much as you can in the inpatient setting.

Dr. Greg Katz: If you have the opportunity to start in the inpatient setting where you can check labs a day or two later, please, please, please do that because it’s your golden opportunity in the inpatient setting to have the chance to get as many of these lifesaving medications started for your patients as you possibly can. And it’s just so, so, so much easier to do it when they’re in the hospital than when they’re at home.

Dr. Viktoria Mladenovik: And it can make a huge difference since the  NNT to prevent only 1 death over the next year is just 4! And this is for patients on all 4 classes of GDMT. This is mind-blowing, Shreya!  

Dr. Shreya Trivedi: And in our last episode, we brought up a good point that, if you start all 4 agents at once, even at low doses, and the next day, the patient isn’t feeling so great, we might not know which one is the culprit?  

Dr. Viktoria Mladenovik: So thats a great point but that was before the publication of the STRONG-HF trial (Safety, Tolerability and efficacy of Rapid Optimization (STRONG-HF Trial). This definitely got eyeballs on how quickly we can initiate all 4 GDMT. As quickly as within 2 weeks of discharge

Dr. Eugene Yurditsky: What the investigators did is they said, let’s compare usual care to GDMT initiation and titration informed by local practices. And this was a multinational trial. Or let’s randomize patients to a very aggressive protocolized approach to GDMT initiation and titration. And what they said is that they wanted by two weeks patients who were discharged with a diagnosis of heart failure from the hospital to be on full dose GDMT. And just to kind of take a sidebar here, full dose GDMT is really high stuff. So we’re talking about lisinopril 40, losartan 150, carvedilol at least 25 milligrams twice a day, or Toprolol XL 200 milligrams. These doses are a lot higher than what we very commonly wind up seeing in patients who get admitted and certainly higher than patients get discharged. As the punchline, what the investigators found is that looking at 180 days, the rate of heart failure readmissions and mortality as a combined outcome was lower. And it was also really impressive about the study is that if you look towards 90 days to see which patients or how many patients were actually on full dose GDMT, you’ll find that somewhere between the forties to fifties percent mark at, at about two weeks, people were on full dose beta blockers, full dose ACE inhibitors or ARBs. Whereas by contrast, people who were randomized to usual care we’re talking about 5% or less. So that really informs us that we’re pretty bad at getting people onto full dose GDMT therapy.

Dr. Viktoria Mladenovik: Whoa, 40-50% on all max dose GDMT compared to only 5% with usual care! 

Dr. Shreya Trivedi: And better readmission and mortality outcome, too! What a win!

Dr. Viktoria Mladenovik: And so basically the STRONG-HF Trial showed that rapid initiation of all 4 GDMT agents is safe, well tolerated, rapidly effective, and overcomes inertia. 

Dr. Shreya Trivedi: So to summarize, its interesting that, despite the number of evidenced-based treatments we have in heart failure, with usual standard of care, patients are less likely to be on all four GDMT meds. And maybe some of that is due to clunky medical system or the resources we have (probably a lot of it). Right? In the STRONG-HF trial they had people to see these patients to see at least 4 times within like 6 weeks of discharge, which is awesome. But if we can, we do have this golden opportunity to at least try to get patients on as many of the 4 classes of GDMT, as possible, while they are under a closer eye in the hospital setting. 

Dr. Shreya Trivedi: So last but not least, over time, patients on guideline directed medical therapy can have complete recovery of their ejection fraction (as defined by EF >/50%), partial recovery (EF 40-50%), or no recovery of their EF (where their EF </ 40%). But does everyone who is on GDMT have their EF recover? And if so, if our patients EF does recover, do still have to be on GDMT?

Dr. Greg Katz: Whenever I’m talking to patients, I get the question all the time. So if I go on these medicines, is my heart gonna get better? And the answer to that question is I hope so, but I don’t know. And I’m also doing my hardest work to make sure that there isn’t a reversible medical cause that there’s something else I can treat differently that will help it get better. I hope that their, at that their EF is gonna get better. Not everybody gets better. And if you look at the kind of sum total of it, about a third of them will fully recover, a third will partially recover, and a third won’t. That that’s not a perfect estimate, but that’s kind of how I think about it in my mind. 

Dr. Viktoria Mladenovik: And I looked into this more and the studies I came across had a wide range of improved EF. That’s anywhere from 10% to 40%. Thats probably because a lot of this was based on both observational and clinical trial dataset and also the fact that there are variable etiologies of heart failure.

Dr. Greg Katz: The other kind of big part of heart failure is you need to think about the underlying etiology and you need to make sure you’re working that up appropriately. 

Dr. Shreya Trivedi: Yeah and so we often see the highest rates of EF recovery are in tachycardia induced cardiomyopathy and those caused by hypo or hyperthyroidism. The second highest rates have been noted with dilated cardiomyopathies that are associated with immune responses. So the ones we see in peripartum cardiomyopathy, viral myocarditis, and the systemic inflammatory response syndrome, SIRS. 

Dr. Viktoria Mladenovik: So that’s good news if the EF does recover, but then what do we do with the patients GDMT once their EF is improved? 

Dr. Greg Katz: And then the other question that comes up is if their heart does get better, do they need to be on those medicines forever? And there are two schools of thought with that. One school of thought is, well, your EF is better. You don’t need the meds anymore. Why don’t you stop them? It’s nice to take less meds. But the other school thought, which is the one that I I’m kind of more persuaded by is that there is something about your phenotype that means that with the right insult, your EF is gonna drop. And it is very clear from all of the data that EF is a really good predictor of mortality. It’s not a great predictor of exercise tolerance or what you’re able to do physically, but it’s a really good predictor of mortality. And so if keeping you on these medicine that you’ve clearly tolerated well enough that you were able to be on them so that your EF got better, you can probably keep going with them. And so in the absence of somebody having real issues with their medicines, I’m of the belief that should probably keep people on these meds forever even if their EF gets better.

Dr. Viktoria Mladenovik: So that’s great! Because I’ve certainly had patients come into clinic and we tell them that their ejection fraction got better. And their first question is, well can I stop taking my meds? But I found it really important to take the time to educate the patient, because as as Dr. Katz said with the right insult the EF will drop again without meds, and there is not mortality benefit of just being on GDMT meds. 

Dr. Shreya Trivedi: One caveat, one our reviewers noted is how practice with what to do with GDMT varies depending on the insult. So for example, with peripartum cardiomyopathy that completely improves, if the person wants to get pregnant again, they can’t really be on any GDMT, so clinicians may start to peel meds off after 6 months or so with careful monitoring. 

Dr. Viktoria Mladenovik: Absolutely! We know that the ACEs, ARBs, and ARNIs are teratogenic! But similarly, tachymyopathy, which is how the cool cardiologists say tachycardia induced cardiomyopathy, if you fix the tachycardia, oftentimes I’ve seen the GDMT taken off and people do fine, as long as they maintain normal sinus rhythm.

Dr. Greg Katz: I know that if I had myocarditis and my EF dropped and I got put on heart failure meds, and my EF got better, or if I was diagnosed tomorrow with a non-ischemic cardiomyopathy, and no secondary cause was found, and I was started on all of these medicines and my EF got better, I would wanna stay on them because I don’t want my EF to drop again. And I think that you reduce the chances as much as possible. You minimize the chance that someone’s gonna get worse again, if you keep them on the cardioprotective medications and there’s no right answer to that question, that is a hundred percent, like, what do you think is the, the right thing to do? But at the end of the day, you need to make a decision. And so you’re left with making a decision in the realm of really incomplete information.

Dr. Shreya Trivedi: And at least with that incomplete information, at least the data we have so far has shown that even among patients who’s EF fully recovers, a large portion will develop recurrent left ventricular dysfunction and heart failure events. And so per the most recent 2022 guidelines, GDMT should be continued even when EF improves and fully recover!

Dr. Viktoria Mladenovik: That’s a wrap for today’s episode! 

Dr. Shreya Trivedi: If you found this episode helpful, please share with your team and colleagues. Give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us! This episode will count for CME credit with the American College of Physician so click on the link in the show notes, answer 3 questions and get CME Credit.

Dr. Viktoria Mladenovik: Thank you to all the educators and mentors! Thank you to our peer reviewers Dr. Susan Mcilvene, Dr. Randy Goldberg, and Dr. Daniel Kirshenbaum. 

Dr. Shreya Trivedi: Thank you to Daksh Bhatia for the audio editing and Ivanna Tang for the accompanying graphics. As always we love hearing feedback, email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.