James Januzzi, MD, Massachusetts General Hospital, Harvard Medical School

 Javed, the last couple of points I’d like to touch on before we close speak in part to the continued development of the space. There are a couple of therapies that you mentioned earlier that I’d like you to give a 30-second bullet on for each, which includes vericiguat and intravenous [IV] iron. In the landscape of therapies for our patients with heart failure with reduced EF [ejection fraction], where do these fit in? Do they fit in at this point? Where do you see them going in the future?

 Think about the journey of patients with heart failure. You have no heart failure, then you develop heart failure and you’re not on any therapy, so the risks are pretty high. Then you get started on the standard therapy and the risks come down—what we call residual risk—but it’s never back to not having heart failure. Then you start breaking through, you start developing worsening symptoms. Whatever therapy you were taking that kept you stable as an outpatient is not enough anymore. That is now an entity we call worsening heart failure.

We did the VICTORIA trial on vericiguat that had a positive result on the cardiovascular death and heart failure hospitalization primary end point. It was focused on people on standard therapy who developed worsening heart failure, either recent hospitalization or the need for outpatient IV diuretic. That therapy is now approved by the FDA for ejection fraction less than 45% and recent worsening heart failure because of improvement in cardiovascular death and heart failure hospitalization. Whether it should be given to people without worsening heart failure is something we are all questioning. Let’s see if we can generate some evidence.

I really like IV iron because this is a specific disease within heart failure that you’re treating. Iron deficiency should be in our minds dissociated from anemia. There are other causes of anemia, but iron deficiency, regardless of anemia, is associated with worse outcomes. Anemia reduces oxygen carrying capacity, but iron is also needed for ATP [adenosine triphosphate] generation in the mitochondria. You can have reduced energy production, regardless of anemia, as well. We had a lot of trials in the outpatient setting showing in the past that iron-deficient patients given IV iron improve quality of life and functional capacity. Now we have a 1-year outcomes trial called AFFIRM-AHF. When patients in the hospital setting with iron deficiency are given iron, you reduce the risk of rehospitalization in those patients. This was an outcomes trail, and not only a quality of life and functional capacity trial.

In whom would you suggest IV iron be considered? Can you give us a transferrin saturation number?

Yes. There is an issue of absolute iron deficiency or relative iron deficiency. If a patient has a transferrin saturation of less than 20%, that’s a good patient to get iron. But remember that oral iron therapy, unfortunately, does not get absorbed very well, so you have to give IV.

 Yes, I was going to actually ask, “Why don’t we just throw some iron sulfate into the medical program?” You just jumped ahead of that question. It’s a really important consideration that clinicians need to know, in part because patients with heart failure don’t absorb PO oral iron as well due to abnormalities of hepcidin.

I’m going to draw this to a conclusion and try to appeal to our viewers, which include a large number of community physicians, to remember that heart failure is a team sport. We need to work together in understanding how to identify these patients, how to initiate therapies, when to initiate therapies, and when to reach out for help. In the expert consensus document, I would ask you to have a look at 1 specific figure that focuses on recognizing heart failure, initiating the therapies, but then recognizing when patients are not responding and where you might need to kick it up a notch and refer to a heart failure specialist like Dr Butler.

There’s a simple acronym called I-NEED-HELP. Each letter refers to a different aspect of struggles in heart failure care that might help you recognize when to reach out to an advanced heart failure specialist. Not every patient with heart failure can be treated by a heart failure transplant specialist. The care of our patients most in need to reduce their risk for heart failure events is in your hands. The American College of Cardiology and the development of this expert consensus decision pathway document recognizes that. In addition to the document, there’s a smartphone application called TreatHF that summarizes all of the things that we just talked about in terms of the therapies, how to use them, when to use them, how to troubleshoot adverse effects, and other issues that come up in the course of the care of our patients with heart failure. It’s all in your hands, folks. We hope that the document is as useful to you as it is for us. Dr Butler and I both find it to be a really helpful piece of support for the care of our patients. 

I want to thank you all for watching HCPLive® Peers and Perspectives®. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peers and Perspectives® and other great content right in your inbox. Javed, thanks so much for spending time today.

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James Januzzi, MD, and Javed Butler, MD, MPH, MBA, discuss emerging agents, vericiguat and intravenous (IV) iron, in the treatment landscape for heart failure with reduced ejection fraction and advice for community physicians managing patients with heart failure. 

Emerging Agents for Heart Failure Treatment 

 Javed, we have a few more minutes. I wanted to get to some more philosophical, but very important topics that we touch on in the expert consensus document. One is the challenges of achieving optimal therapy in our more complicated cases, especially given the multiple drugs that we need to prescribe. For example, how do you approach an elderly patient? Does that differ from your general therapeutic approach?

The word elderly means a lot of things. The first and foremost thing I would say is that elderly means bias on our part as clinicians. There’s bias that somebody may not tolerate or benefit from a therapy. At least the benefit part has been taken off. We have never done a trial where we have given a therapy to an older person and they did not benefit. We have been doing that since the hypertension days where we thought that poor people have higher blood pressure, and that should be part of the physiology, and that’s not true. It’s the same thing with heart failure. When we do the secondary analysis, older patients benefit. We should definitely be treating these patients.

The issue of safety is real. Blood pressure, renal function, and all of these physiologic parameters that change with age are common traits. Some people may require the separation of times they take medications so that they’re not all at the same time. Maybe give a break of a couple of hours, take something at 8 in the morning and something at 11 in the morning so that not all the drugs are lowering the blood pressure at the same time. Go through the list of medications that they’re taking. If they’re taking a medication that does not play a role in improving morbidity or mortality, stop that medication. These people are taking a lot of medications. I would also say that if somebody is taking nitrates or amlodipine for no reason, we as clinicians know to stop those things. But then the patient takes so many over-the-counter things that we don’t even know what the hemodynamic effects are. Talking to the patients about all these nutraceuticals and whatnot. If you can stop those things, that becomes pretty important in older patients, as well.

Then there are social things: their hearing deficit, self-efficacy, whether they can take care of themselves, who’s the caregiver, whether they need home health, and social work. All of those things play into that. The last thing is that older people tend to have multiple comorbidities, so they tend to see multiple clinicians. You don’t want to have 1 set of clinicians doing 1 thing and the other set of clinicians doing something else. Communicating between the health care teams is also very important.

 Yes, that’s critically important and very useful advice. Adherence—a term that we used to call compliance, but we recognize that adherence speaks to a larger set of issues other than just the decision not to take a medication—to a therapy can be influenced by so many physiologic and social aspects of care. All need to be kept in mind. Working as a heart team in heart failure, including our colleagues who are specialists in other disease states, such as our kidney specialists and geriatricians, is so very important. Additionally, costs of care are something that we address in the expert consensus decision pathway document. This is obviously an increasing issue in modern medicine, particularly in the United States. We offer advice on how to manage the costs of care in order to reduce the burden on our patients. That’s an important factor that is built into the concept of adherence.

Cardiology experts discuss challenges in achieving the optimal therapy for patients with heart failure and the influence of patient lifestyle and medical factors. 

Challenges for Achieving Optimal Therapy in HF 

In the ACC [American College of Cardiology] Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment document, we take the experience from clinical trials in diabetes and heart failure, as well as our own experiences regarding for whom we would prescribe these drugs, in whom we might avoid them, and some important tips about what to expect when you use them. Javed, can you offer some clinical pearls about what to expect when you start an SGLT2 [sodium-glucose cotransporter-2] inhibitor in patients with heart failure?

 Yes. There are lessons learned about population, but you have to be very careful not to apply it to every single patient sitting in front of you. We are clinicians, and we should use our best judgment. If you look at the overall population data in the diabetes trial, there was a reduction in systolic blood pressure by about 4 or 5 mm Hg with the SGLT2 inhibitors. That is great because this is not an antihypertensive drug. These patients tend to be hypertensive, so that’s a benefit. Patients with reduced ejection fraction actually tend to have lower blood pressure. We have seen that with other vasoactive agents, as well. They don’t lower blood pressure as much, because by improving hemodynamic vasodilation, you improve cardiac efficiency.

We’re seeing with the SGLT2 inhibitors that the decrease in blood pressure that was seen in diabetes was not replicated. There was no statistically significant difference in blood pressure. Having said that, we shouldn’t be too careless with the person sitting in front of us who’s already orthostatic or may be older. We should take some caution. You already mentioned cutting down the dose of diuretics. Interestingly enough, in the overall population, you do not have to change the diuretic a lot, but I would still use caution when I’m seeing a person in front of me.

Yes, that’s an important nuance in the differences between SGLT2 inhibitors and sacubitril/valsartan. In our noncongested patients, we routinely will reduce loop diuretics in our patients for whom we initiate sacubitril/valsartan. With SGLT2 inhibitors, we tell them, “This may increase your diuresis. Weigh yourself, as you always should. Let us know if you‘re becoming dehydrated or losing too much weight.” You will see a rather exaggerated diuretic effect in about 1 in 10 patients. I have no idea how to explain that other than to say that SGLT2 inhibitors probably have multiple pathways that they‘re affecting, and in some patients, it’s the diuretic effect that is most obvious early on.

The other thing we warn patients about, and this is in the document as well, is that through their mechanism of action, sodium-glucose cotransporter-2 drugs increase the amount of glucose in the urine, which is particularly an issue for patients with diabetes. In a patient who doesn’t have diabetes, this is not an issue. But in those with higher circulating blood glucose levels, above 160 to 180 mg/dL is when you start seeing glycosuria developing. There is a risk for an increased rate of pelvic yeast infections. That’s typically vaginal yeast infections in women. In men, it is largely related to the lack of circumcision. It may be the one time that a heart failure cardiologist may be asking about circumcision, but it’s an important issue, because self-care and hygiene can help reduce the risk for these complications. A lot was made early on about the risks related to SGLT2 inhibitors in patients with peripheral arterial disease and the risk for amputation. We have discounted that quite heavily now. In fact, the FDA black box warning about risk for amputation on one of the SGLT2 inhibitors has been removed. These are actually a well-tolerated group of medications that should be added early as part of the fundamental therapeutic choice for our patients with heart failure with reduced ejection fraction.

Insights on approaching the initiation of SGLT2 inhibitors for the treatment of heart failure with reduced ejection fraction. 

Role of SGLT2 Inhibitor Therapy for HF Treatment 

 Javed, we’ve had a big change in the heart failure space in the last few years with respect to sodium-glucose cotransporter-2 inhibitors, or SGLT2 inhibitors, for the treatment of patients with heart failure. This is a therapy that was initially discovered by accident during clinical trials for the treatment of type 2 diabetes. We could probably give a complete hour on the discovery and mechanisms of action of SGLT2 inhibitors, but I’m going to ask you to give the 10,000-foot view of how we got here with SGLT2 inhibitors and your point of view about how they may work. Then we can talk about how we weave them into the care of our patients with heart failure.

That’s the story of serendipity on steroids. These were developed for diabetes. They help make you urinate glucose and decrease the absorption of glucose, so it’s a diabetes drug. Then in 2008, the United States FDA mandated that all newer therapies for diabetes should be assessed for their cardiovascular benefit. It was still a diabetes drug and it was tested for cardiovascular safety—not even benefit. Trials were done. And then with SGLT2 inhibitors, we were suddenly seeing substantial reductions in heart failure hospitalizations. We’re talking about 30% relative risk reduction, irrespective of any other characteristics. It doesn’t matter what your starting A1C [glycated hemoglobin] was, what your ending A1C was. There was no association with glycemic control. It doesn’t matter whether you have a history of heart failure. It doesn’t matter whether you have atherosclerotic cardiovascular disease or just risk factors. No matter how you slice and dice the data, there was a reduction in heart failure hospitalization. That was one realization that these drugs should maybe be used for heart failure as well.

The second realization was that, by that time, we had started to understand the pharmacodynamic effect beyond glycemic control. Most of the major organ systems that are associated with pathophysiology of development or progression of heart failure are beneficially impacted by SGLT2 inhibitors. Vascular function, aortic stiffness, endothelial function, cardiac structure and function, hypertrophy regression, diastolic function, fibrosis, renal function preservation, metabolism, and ATP [adenosine triphosphate] generation, no matter how you slice it, all benefit. Then there are a lot of more nuanced, subtle mechanisms of action as well, like lysosomal activity and autophagy.

The bottom line is that when they took a step back and looked at the pharmacodynamic effects of this drug, the question completely changed. The question was not how they improve cardiovascular outcomes. The question was, what does any of this have to do with diabetes? Perhaps we should look into all of these things, and these are cardiovascular risk-modifying agents, which are great diabetes drugs that you should absolutely use for glycemic control. But perhaps in the cardiovascular setting, we should test it irrespective of diabetes. So we started doing chronic kidney disease trials, heart failure with reduced ejection fraction [HRrEF], post-MI [post-myocardial infarction], and heart failure with preserved ejection fraction, without focusing on whether a person has diabetes.

Yes, it’s a remarkable story. The multitude of potential mechanisms of action remain so compelling, and yet still unanswered. There are more review articles on the mechanisms of action than mechanistic papers explaining what the most plausible candidates may be. These therapies preserve kidney function and lead to a certain degree of nature-resistant diuresis without activating the renin-angiotensin-aldosterone system [RAAS], but they’re much more than just a so-called smart diuretic. In fact, as you pointed out, there are now randomized data showing an impact on reverse cardiac remodeling. Earlier on I mentioned that therapies that improve ejection fraction in HFrEF are beneficial. Javed, what do we know about the impact of SGLT2 inhibitors on patients with heart failure with reduced EF? Let’s put the diabetes question completely aside. Let’s talk about them as a heart failure drug.

There are 2 large trials that have been published. DAPA-HF was dapagliflozin 10 mg vs placebo on standard of care, and EMPEROR-Reduced with empagliflozin. Both trials had baseline therapy that was excellent: 90%-plus use of diuretics, RAAS inhibitors, and β-blockers, and 70%-plus use of MRAs [mineralocorticoid receptor antagonists]. The beneficial effect that we’re seeing was on top of really good baseline medical therapies, so we can be rest assured that this is incremental benefit on top of that.

The primary end point of reduction in cardiovascular death and heart failure hospitalization, was positive in both trials. Recurrent heart failure hospitalizations, total heart failure hospitalization, renal function preservation, and quality of life scores were all improved in both of the trials. Then there were 2 big questions. Did this gamble of giving SGLT2 inhibitors to patients without diabetes pan out? Absolutely. Not only do patients without diabetes benefit from these agents, the magnitude of benefit and relative risk reduction is interchangeable in those with or without diabetes. One of my colleagues said, “Well, prediabetes, diabetes is a continuum. What about low glycemic epidemiology?” So DAPA-HF looked at it in 3 ways: diabetes, prediabetes, or no glycemic imbalance. Again, all 3 groups benefited.

On top of that, they also have data showing that being on dapagliflozin prevented onset of diabetes among people who didn’t have the diagnosis before. You’re talking about almost a 360-degree win. It’s quite remarkable. This experience has been one of the victories in recent heart failure therapy development. The observation in the diabetes trials was made, then the outcomes trials were rapidly developed, executed, and successful. Now we have a fourth major category of therapy in our armamentarium. That term is used all the time. We like to call them weapons. We now have a fourth major category of drug, the fourth pillar, that blocks a unique set of biological pathways to improve outcomes in our patients with heart failure with reduced ejection fraction.

Javed Butler, MD, MPH, MBA, reviews the historical background of using SGLT2 inhibitors and the impact on patients with heart failure with reduced ejection fraction. 

James Januzzi, MD, Massachusetts General Hospital, Harvard Medical School

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