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"From Lab to Life" is a cutting-edge podcast that bridges the gap between groundbreaking medical research and real-world clinical practice. Hosted by leading experts in the healthcare field, each episode delves into the latest innovations in medicine, offering insights on how scientific discoveries translate into practical solutions for patient care. From emerging therapies to case-based discussions, this podcast equips healthcare professionals with the knowledge they need to bring the future of medicine into their daily practice. Join us as we explore the journey from the lab to life.
Welcome to Advancing Worsening Heart Failure Treatment, exploring cutting edge therapies and addressing disparities. I'm doctor Bob Underwood, and I am joined today by my esteemed colleague, who is the director of Mount Sinai Heart and the 1st doctor Valentine Fooster professor of cardiovascular medicine at Icahn School of Medicine in New York, doctor Deepak Bhatt. Doctor Bhatt's relevant financial relationships can be found at iridiumce.com/ hf. This educational activity is supported by an independent educational grant from Merck, Sharp, and Dome. We would like to thank them for their support of this initiative.
Dr.Bob Underwood:This learning objective for this program is summarize the novel heart failure medications and their treatment indications for heart failure with reduced ejection fraction or HFREF, and heart failure with preserved ejection fraction, which we more commonly refer to as HFEF. Doctor Bott, thanks for joining us today.
Dr.Deepak Bhatt:It's great to be with you.
Dr.Bob Underwood:Absolutely. And so to start off, can you give us some information on the different classes of medications for heart failure?
Dr.Deepak Bhatt:Absolutely. So they're generally speaking, 4 classes of medications, beta blockers, drugs that target angiotensin, things like ACE inhibitors, angiotensin receptor blockers, RNA, mineral, corticoid receptor antagonists, or MRAs as they're sometimes abbreviated and sodium glucose, co 2 inhibitors, SGLT 2 inhibitors as they're often referred to. The ACE inhibitors, RNA, MRA also along with the angiotensin receptor blockers or ARBs target the renin angiotensin aldosterone system or RA system. The SGLT 2 inhibitors block uptake of glucose to the proximal tubules of the kidney. This leads to excretion of glucose and sodium in the urine with resulted in atherotic and diuretic effects.
Dr.Deepak Bhatt:But it's not just that. Sometimes people think, oh, it's just the sugar and salt in the urine. And that's part of it, but it's also an improvement in cardio energetics. Yeah. There's a heart failure benefit with the SGLT 2 inhibitors, including reductions in the composite of cardiovascular death and hospitalization for heart failure in some cases, even in CV death, alone as an endpoint, especially in sicker heart failure patients.
Dr.Deepak Bhatt:And these benefits are seen both in patients with diabetes, the SGLT2 inhibitors were initially developed for diabetes, but also in patients with heart failure without diabetes, quite important. And also in patients you are alluding to have ref and have peth in both those types of heart failure. So pretty remarkable and relatively still new development with the SGLT2 inhibitors as heart failure drugs, not just diabetes drugs anymore. The glucagon like peptide 1 receptor agonist or the GLP-one receptor agonist as they're often called, were originally used to treat type 2 diabetes, really good diabetes drugs, pretty good, glycemic control in fact that they provide. But in the context of this conversation, they were also found to protect against cardiovascular events in person with diabetes, at least some of the drugs in the class, not every drug in the class, and also provide cardiovascular benefits in people that were overweight or obese with established cardiovascular disease.
Dr.Deepak Bhatt:So very important. And also found to have benefit in patients with HFpEF that were overweight or obese in improving things like the Kansas City Cardiomyopathy questionnaire in terms of how patients feel and BNP levels. This was shown in the step HFpEF trial.
Dr.Bob Underwood:Yeah. Absolutely. And we'll dig a deeper dive into that particular class of medicine here in a little bit. Really some great stuff coming out. So cecubatrialvalsartan is approved for patients with chronic heart failure.
Dr.Bob Underwood:So can you describe the clinical trials that led to best approval, noting specific differences in left ventricular ejection fraction among these trials?
Dr.Deepak Bhatt:Yeah, absolutely. So Sacubutrivalsartan is an ARTI I mentioned before this class of Asian. And right now it's actually in terms of what's available, the only, drug in that class. There are clinical trials that support its use in HFrEF and, to an extent in HFEF. It does have some labeling there, where the data are stronger for HFEPF.
Dr.Deepak Bhatt:And even in the HFEPF patients, it's ones that have lowish, ejection fraction where there seems to be benefit. But at any rate, the paradigm heart failure trial examined sacubutrovalsartan versus enalapril in patients with left ventricular ejection fraction less or equal to 35%. So these were folks with a history of heart failure, elevated natriuretic peptides, trial examined cardiovascular deaths and hospitalization for heart failures, well designed, well done trial. And the primary endpoint showed a significant 20% relative risk reduction and pretty sizable absolute risk reduction as well. And the end point I mentioned for Sacagbutrovalvastatinib versus enalapril.
Dr.Deepak Bhatt:So that's pretty good in its own, right? But there was also a lower rate of death in those that were randomized to Sacagbutrovalvastatinib versus enalapril. So really important results, overall. There was also the pioneer heart failure trial that examined patients with LVEF of less than equal to 40%, comparing sacubutrovalvastart with enalapril. And this was looking at patients that had come in with worsening heart failure and fluid overload.
Dr.Deepak Bhatt:Patients were enrolled 24 hours to 10 days after initial presentation at a hospital. The primary endpoint here wasn't so much a clinical one. It was change in NT proBNP, but, there were exploratory endpoints to look at clinical endpoints, things like cardiovascular deaths and hospitalization for heart failure. Bottom line, the biochemical endpoint reduction in T proBNP was significantly better, in the Sacubutro Wellsartan arm. And in terms of hospitalization for heart failure, or I should say rehospitalization for heart failure, that was also lower in patients randomized to Sacubutro Wellsartan.
Dr.Deepak Bhatt:And the final trial I'll mention at least right now is PARAGON Heart Failure. This was in patients with an ejection fraction greater than or equal to 45%. So half path, but again, one can debate in that range, whether it was truly patients with, slightly reduced ejection fraction or truly preserved. It was an admixture. Here was a comparison of sacubutrialvalsartan and valsartan.
Dr.Deepak Bhatt:Again, patients with heart failure. And this was a trial that examined once more cardiovascular deaths and hospitalization for heart failure. So heart failure related endpoints. And here, the primary endpoint was lower with Sacobutro, valsartan, about 13% lower, but the p value was right on the fence, 0.059. So strictly speaking, a trial that was not statistically significant, but the treatment effect, if one is willing to go beyond the p value there did appear to be driven by reductions in heart failure, hospitalization, and appeared to be in patients in the lower range of EF within that sort of low normal range that was enrolled in the trial.
Dr.Deepak Bhatt:So I think when viewed and if this were the only trial of Sacubutro valsartan, then I don't know that we could hang our hat on it, but coupled with the other trials I mentioned, particular paradigm heart failure, looks like if the EF is low or lowish, there's a degree of benefit with shakbutrovalvesartan. Most mark where the EF is truly low, that is half ref.
Dr.Bob Underwood:Yeah. Yep. Great trials. And I think you're right. Looking at them in combination with one another really supportive.
Dr.Bob Underwood:So how have these clinical trials informed which patients can be treated with succubitrofloxet valsartan?
Dr.Deepak Bhatt:Yeah. Great question. So the drug is now approved. It's indicated to reduce the risk of cardiovascular death that heart failure hospitalizations in patients with chronic heart failure. And the benefits are more evident in patients with an EF that's below NOBL.
Dr.Deepak Bhatt:So that's really where it fits in. And it's one of the 4 pillars now, I think of heart failure therapies, While one can make an argument to use drugs like ACE inhibitors and ARBs, really now assuming that cost isn't prohibitive or there are side effect issues, if the patient can instead be on an ARNI, that's probably the way to go and provides the absolute best care along with the other pillars of heart failure therapy. That is beta blockers, SGLT 2 inhibitors, neural corticoid receptor antagonists.
Dr.Bob Underwood:Sure. So you've also done some work with SGLT 2 inhibitors. So can you describe the 3 SGLT 2 inhibitors available for the treatment of heart failure and the clinical trials that led to the approval of these medications?
Dr.Deepak Bhatt:Sure. I mean, there are a lot of trials. There's been an explosion of data with the SGLT two numbers. Once more, these were approved available great data as diabetes drugs for the most part to several drugs in the class. But now specifically, let's talk about heart failure and 3 drugs that I think are most relevant are dapagliflozin, empagliflozin, and sotagliflozin.
Dr.Deepak Bhatt:Sotagliflozin isn't SGLT trinibre, but it's also an SGLT1 inhibitor. So it's got a little bit of a different mode of action, but they all share the SGLT2 inhibition. And most would say they're all part of that class, but the SGLT1 might add a little bit something different in terms of reduction in atherosclerotic events, but that may be a topic for another day. But as far as dapagliflozin goes, it was studied in DAPA heart failure and in deliver in patients essentially with HFrEF and HFF respectively. Dapagliflozin was compared with placebo.
Dr.Deepak Bhatt:These are patients again with heart failure class 2, the 4 elevated NT proBNP. So they have real heart failure evidence of it. The primary endpoint was once more are these composites of heart failure related endpoints. In this case, heart failure, hospitalization, urgent visits for heart failure, cardiovascular death, and dapagliflozin significantly reduced that endpoint in the DAPA heart failure trial of patients with EF less or equal to 40%. It was a hazard ratio of about 0.74 statistically significant.
Dr.Deepak Bhatt:And the deliver trial with an EF greater than 40%, there has ratio of 0.82. So again, statistically significant. So similar or significant degree of risk reduction. And for that reason, dapagliflozin is indicated to reduce the risk of cardiovascular death and hospitalization due to heart failure in patients with heart failure. As far as epagliflozin goes, that was studied in EPRA reduced and EPRA Preserved, HFref and HFpEF respectively, trials of epigliflozin versus placebo.
Dr.Deepak Bhatt:Again, patients with heart association class 2 to 4, primary endpoint, similar endpoint of cardiovascular death or heart failure hospitalization. Once more in both trials, they were positive. That is an EMPEROR reduced a significant reduction, has ratio of about 0.7, statistically significant in the EMPEROR Preserve trial. Again, that's the one with EFs greater than 40%, hazard ratio of around 0.79, once more statistically significant. Therefore, emagliflozin is indicated to reduce the risk of cardiovascular death than hospitalization due to heart failure in patients with heart failure.
Dr.Deepak Bhatt:And then finally, sotagliflozin was studied in SOLUS worsening heart failure, sotagliflozin versus placebo. Here, the trial was patients specifically also with diabetes and admitted with acute decompensated heart failure. We actually intended to ultimately enroll patients, without diabetes as well, but the trial ended before we had a chance to do that. The primary outcome was the composite of total events consisting of cardiovascular deaths, hospitalization for heart failure, urgent heart failure visits. The primary outcome once more is significant benefit, has a ratio 0.67, very statistically significant.
Dr.Deepak Bhatt:And I'll point out that in terms of numbers needed to treat, it was about 4 patients that needed to be treated for about a year to prevent one event. So it just shows that in a very high risk population, such as those admitted with acute decompensated heart failure and soloist really large, not only relative risk reductions, but absolute risk reductions. And for that reason, sotagliflozin is indicated in adults with heart failure to reduce the risk of cardiovascular death, hospitalizations for heart failure, or ocean heart failure visits. Importantly, the label doesn't actually just say diabetes, even though our trial actually included patients with diabetes. There's another trial of sotagliflozin where there was a reduction in heart failure, but also in MACE atherosclerotic events.
Dr.Deepak Bhatt:Maybe that's due to the SGLT1 mechanism that was scored trauma that was patients with chronic kidney disease. So that's the story in a nutshell for SGLT2 inhibitors and the setting of heart failure.
Dr.Bob Underwood:And some just wonderful information about that particular class of medication. So let's make a transition over to aldosterone agonist. What can you tell us about some of the medications that are available and how they work?
Dr.Deepak Bhatt:Yeah. Absolutely. So this is, again, one of the four pillars of heart failure care. Spironolactone is the agent with the most evidence in terms of being around for a while and being effective, certainly in patients with heart failure with reduced ejection fraction, lots of older data and trials that support that. Despite that lots of registries show that it's under utilized in the context of HFREF.
Dr.Deepak Bhatt:But what about HFpEF? There's more recent data for spironolactone from the top cap study or the top cap trial, spironolactone versus placebo. This was patients with an EF grade or equal to 45% that had heart failure. The primary outcome was death from cardiovascular causes, aborted cardiac arrest, hospitalization for heart failure. And the trial, strictly speaking overall was not positive.
Dr.Deepak Bhatt:The hazard ratio was 0.89, but the P value wasn't significant. So, that makes it a little tough to go beyond the primary endpoint. There was, I would say a signal of benefit on components of the endpoint, like hospitalization for heart failure, where it looked like it was lower. There were some post hoc analyses that were done that suggested maybe there is a benefit if you excluded certain countries where it looked like there were protocol violations and maybe the patients that got admitted didn't really have heart failure. And maybe those, countries and the sites in those countries were doing some funny stuff in terms of trial conduct.
Dr.Deepak Bhatt:So if you're willing to draw out those particular countries, it looked like the remaining countries, there was a significant benefit. So with some caveats, it looks like there's probably something there, but need more data. There's more research going on though, with respect to MRAs, melocorticoid receptor, antagonist and heart failure receptor. The FIND ARTS trial is investigating a non steroidal neural corticoid receptor antagonist, spironolactoid is a steroidal one. The agent being studied there is phenerinone in patients with HFpEF.
Dr.Deepak Bhatt:So that trial will hopefully report out sometime not too far in the future. And we'll know with greater certainty whether this class of agents truly does work in HFpEF.
Dr.Bob Underwood:Thanks for that. So the last medication we'll discuss in this section is GLP 1 receptor agonists or semaglutide. So would you describe the results of the step half pheff clinical trial for us?
Dr.Deepak Bhatt:Sure. And I'm glad we're talking about the GLP one receptor agonist again, and you specifically said semaglutide. I think it's right. Sometimes doctors like to talk about classes of agents with the SGLT 200 Brazil seem pretty good with respect to heart failure reductions With the GLP 1 receptor agonist, not all of them provide cardiovascular benefits. So really not fair to talk about them as a class.
Dr.Deepak Bhatt:They're all great diabetes drugs, but not necessarily all great cardiac drugs. Exactly why that's a topic for another day. But with respect to semaglutide, it was studied in the STEP HFEF study. So looking at patients with heart failure with preserved ejection fraction EF greater than equal to 45%. These different trials have slightly different cut points for exactly what HFEF is, but here it's what I just said.
Dr.Deepak Bhatt:And here semaglutide was compared versus placebo. Patients had a BMI of 30 or more, so they are obese. And the primary outcome was change from baseline in the KCCQ, that's the Kansas City Cardiomyopathy questionnaire, a way of seeing how are patients with heart failure feeling, how are they doing? So not sort of a hard endpoint like cardiovascular death or hospitalization for heart failure, but an important patient centric endpoint. Also change in body where it was examined.
Dr.Deepak Bhatt:Other secondary outcomes were things like 6 minute walk distance and looking at some clinical endpoints as part of the composite along with some of the other endpoints that I already alluded to. And bottom line is there was a significant difference benefit with the semaglutide with respect to KCCQ that is in terms of how patients felt. It was a change that was felt to be clinically significant, not just statistically significant. There was also a change in body weight that was significant with semaglutide that is consistent with what was already done with the ability of this drug to cause a substantial amount of weight loss. So that is something patients obviously like.
Dr.Deepak Bhatt:Sometimes it can help with adherence. There are also improvements in the 6 minute walk distance and also in the composite of clinical and other endpoints that I alluded to. So overall positive trial, not a clinical endpoint outcome trial per se, but still lots of other clinically relevant endpoints being favorably influenced. And semaglutide is approved for adults with type 2 diabetes, either alone or if they also have cardiovascular disease. It's also approved for chronic weight management in folks with a BMI greater than 30 or equal to 27 with other comorbidities.
Dr.Deepak Bhatt:So a useful addition to the argumentarium. Yeah. Great drug for diabetes, for obesity, for folks at elevated cardiovascular risk with obesity. And also now it turns out for heart failure preserved ejection fraction. Once more with the caveat that this wasn't a classic cardiovascular outcome trial looking at heart end points.
Dr.Bob Underwood:Right. Right. But definitely some good indications for that particular medication in multiple categories. So let's move on. So 2022 American Heart Association, American College of Cardiology or ACC, and the Heart Failure Society of America, HFSA released updated guidelines.
Dr.Bob Underwood:So what can you tell us are the big takeaways for the 2022 guidelines?
Dr.Deepak Bhatt:Yeah, absolutely. It really centers upon the 4 pillars of care for heifera. Obviously you're gonna use diuretics, even though in general, they're not been shown to reduce things like mortality. Although it sort of depends what you call a diuretic, but the 4 pillars beyond just decongesting patients are ARNEs ACE inhibitors or angiotensin receptor blockers should use one of those. And as I said, with a preference towards ARNI's, assuming lead cost or side effects are an issue, beta blockers are another pillar.
Dr.Deepak Bhatt:The mineralocorticoid receptor antagonists are yet another pillar and they do have a diuretic effect obviously. That's why when I was alluding to diuretics, I really meant things like the loop diuretics haven't been shown to influence hard endpoints. They're used just for deep congestion. The MRAs are a bit special that way. The SGLT2 inhibitors are the latest addition to the 4 pillars of care.
Dr.Deepak Bhatt:So those are the 4 pillars of care, very strong evidence based, guideline endorsement, so forth. In clinical practice beyond that, if patients are all 4 pillars of care, optimally dosed to the extent they can tolerate without side effects and so forth, still having problems with symptomatic heart failure readmissions for heart failure, then agents such as ericiguat are potential additions to the armamentarium for patients with heart failure, reduced ejection fraction. Now with patients with heart failure, more in that mid range of ejection fraction, not quite HFF, not quite HFF, there as well as SGLT2 inhibitors would be recommended. And there is likely a role for RNAs, ACE inhibitors, ARBs, mineralocorticoid receptor antagonists, especially if they're at that lower range of what we're saying is mid range. So, and if they're closer to abnormal, there does seem to be benefit.
Dr.Deepak Bhatt:The same seems to be true of beta blockers as well. And in HFpEF, the evidence is really strong as for SGLT2 inhibitors. One can consider RNAs and MRAs. As I said, there are some caveats to the data where with respect to RNA, as I alluded to, the trial was clearly statistically significant, but there were a lot of signals of positivity. And with respect to MRAs, again, top cat strictly speaking, not statistically significant, but if you're willing to go on this post hoc analysis, it looked like there might be something there as well for drug that's generic and relatively cheap.
Dr.Deepak Bhatt:So this is really, I think the key things to remember the possibilities for HFREF and HFEF, we've come a long way in terms of medical therapy and options that are evidence based.
Dr.Bob Underwood:Yeah. The 2,292 guidelines have a huge amount of information. And so thanks for summarizing your key takeaways. I think people will find that really, really valuable. As we close anything else you'd like to add for this particular segment?
Dr.Deepak Bhatt:I think the most important point is that medicine is ever static, and that seems to be especially true with heart failures, but so much new data that's come out. And I think it's important to try to stay on top of all of the data because it really can benefit patients in terms of how they feel, in terms of how they do, in terms of heart endpoints, like hospitalization for heart failure and even cardiovascular death in some cases all cause mortality. The approaches do involve polypharmacy. One does need to be mindful of side effects and and cost and that sort of thing. But having said that, in HFREF, we really are trying to embrace the 4 pillars of care, starting therapy as quickly as possible, again, assuming it's tolerated.
Dr.Deepak Bhatt:And with HFpEF, it's a new day with data really showing clear benefit of SGLT 2 inhibitors and potential benefit of at least a couple other classes where SGLT 2 inhibitors may not be enough. So lots of reasons to be optimistic these days in the care of our heart failure patients.
Dr.Bob Underwood:Yeah. It's great advances. Really is. So doctor Bhatt, thank you so much for this informative discussion. For me, it's been an honor to learn from you today.
Dr.Bob Underwood:So we'd also like to thank Merck for their support of this program. And for the listeners, please claim your CME credit by filling out the evaluation and the post test. And don't miss our next and final episode of this series where we will again be speaking with doctor Aaron Michos from Johns Hopkins. And be sure to follow Iridium on x, Facebook, and LinkedIn to see the corresponding MedEd threads. Thanks so much for being on.