Heart Failure Podcast

Quadruple Therapy in Heart Failure With Reduced Ejection Fraction: Don't Back Down

Michelle M. Kittleson, MD, PhD; Biykem Bozkurt, MD


January 10, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Michelle M. Kittleson, MD, PhD: Welcome to Medscape InDiscussion. I'm your host, Dr Michelle Kittleson. Today is the first episode of our 12-part series, where we first look at the six core challenges and issues affecting patient care, while the final six episodes tackle special concerns.

We're kicking off the series with the topic of quadruple therapy for patients with heart failure with reduced ejection fraction, also known as HFrEF. What advances have there been in guideline-directed medical therapy? What role do older therapies play today? What barriers are in the way of helping patients realize the benefit of recent advances?

For expert guidance, we've invited Dr Biykem Bozkurt. She is professor of medicine at Baylor College of Medicine in Houston, Texas. In addition to being the current editor-in-chief of JACC: Heart Failure, she's the past president of the Heart Failure Society of America and vice chair of the recent ACC/AHA/HFSA Heart Failure Guidelines. Welcome, Biykem. I'm delighted to have you here.

Biykem Bozkurt, MD: Thank you, Michelle. It's a pleasure to be with you.

Kittleson: Before we dive into the most exciting topic, I'd love to have you tell the listeners how you knew you wanted to work with patients with heart failure. How did your career trajectory unfold?

Bozkurt: Oh, this is a very important question for me and for my career trajectory. Throughout my training in internal medicine and cardiology, I was always drawn toward heart failure; the ability to be able to follow the patient through the continuum of their journey at the bedside in the ICU, with innovation and implementation ranging all the way from hemodynamics to pathophysiology and physiology, was very exciting. I also had great role models, who were master clinicians and truly transformative scientists who were leading the way. Thus, I was drawn to heart failure, and I am truly thrilled to be in the field.

Kittleson: And the field is truly thrilled to have you. I love that story. We're going to move on now to this very exciting topic of GDMT — guideline-directed medical therapy — for HFrEF. I think if there's one thing clinicians need to know, it's the amazing advances in GDMT for HFrEF. Tell us, what defines optimal GDMT?

Bozkurt: First and foremost, initiation and optimization of quadruple — quadruple meaning four classes of therapies — is the foundation of HFrEF therapy. This entails initiation and optimization of beta-blockers, mineralocorticoid receptor antagonists (MRAs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and renin-angiotensin-aldosterone system (RAAS) inhibition with either an angiotensin receptor-neprilysin inhibitor (ARNI) in patients with New York Heart Association (NYHA) class 2 to 3 heart failure and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with NYHA class 2 to 4 heart failure.

In the guidelines, we have specified that these agents can be initiated simultaneously at low doses or sequentially. That is driven or initiated according to patients' specific [characteristics] and etiology, not according to the historical sequence of the clinical trials. It's critical for these four classes of medications to be initiated as early as optimally possible, because we do see significant improvements in cardiovascular death and heart failure hospitalization as early as within 1 month of initiation of these agents. Thus, time is of the essence for us to optimize therapies. Just having ACE inhibitors and beta-blockers is not adequate. The new agents — the new models of care that entail SGLT2 inhibitors and an ARNI — have demonstrated significant incremental benefits when added to background therapy. So, it's more important than ever for us to optimize the therapies.

The second step in the guidelines is optimization of doses. Doses are very important because, as we know with beta-blockers and ACE inhibitors, there is evidence that optimization of doses translates into outcome benefits.

We also have evidence that these agents, these newer modalities of treatment, are associated with improvement in quality of life, as well as in renal outcomes. Both ARNIs and SGLT2 inhibitors are associated with reduction in the decline of eGFR [estimated glomerular filtration rate] slope. They do have renal benefits, and thus we would be able to see not only the efficacy but also the safety of initiation of these agents. I think from the patient's perspective, patient-reported outcomes, there is benefit.

Finally, there is also evidence of reversal of remodeling — meaning there is improvement in EF [ejection fraction] and reduction in LV [left ventricular] volume. So, before consideration of devices such as ICD [implantable cardioverter defibrillator] and CRT [cardiac resynchronization therapy], it is critical for clinicians to optimize the doses of these agents. Thus, the patient can have full benefit from [prevention of] cardiovascular death, heart failure hospitalization, and quality of life — real effects — as well as reversal of remodeling.

Kittleson: I don't think anyone could have said it better. If you want your patients to feel better, live longer, have healthier kidneys, and potentially improve their heart function — [give quadruple therapy with] an ARNI, an evidence-based beta-blocker, an MRA, and an SGLT2 inhibitor. Perfect.

Now, you touched on this issue of old-school therapy. We are very grateful to the ACE inhibitor consensus trial of 1987, which changed the world of heart failure. Patients can live longer when you give them an ACE inhibitor, and we know that beta-blockers came along soon after. So, tell our listeners why they should overcome therapeutic inertia and go for quadruple therapy. Isn't it okay if patients are doing fine on their ACE inhibitor and beta-blocker?

Bozkurt: It certainly is not fine, and that is the greatest emphasis we would like to disseminate to all our clinicians. This is very similar to assuming a patient with active cancer is stable and not optimizing therapy with their chemotherapy or other cancer disease-modifying regimen.

Heart failure is a deadly disease. We lose about half of our patients in a couple of years. These agents — the newer modalities, specifically, SGLT2 inhibitors and an ARNI — when added on the background therapy with ACE inhibitors and beta-blockers have resulted in significant improvement in outcomes in hard endpoints, such as cardiovascular death and heart failure hospitalizations, as early as 30 days. Not initiating new therapies would be a great disservice, precluding the opportunities for our patients to have better outcomes in terms of cardiovascular death and heart failure hospitalizations.

Thus, it's critical for us not to have inertia, not to assume stability. We emphasize not to use the terminology stable, because stable creates inertia and complacency, and a false presumption that the patient is doing well. Actually, any patient with active heart failure, regardless of their NYHA class, should have optimization of their therapies, because this is a deadly disease and these newer modalities of treatment have been associated with better outcomes.

Kittleson: Amazing. I love the analogy you made between heart failure and cancer. Heart failure is a deadly disease; now, there's a lot of hope involved. These therapies are transformative and minimally toxic — very well tolerated. That is the best cry to move forward with overcoming therapeutic inertia.

When we think about the sources of therapeutic inertia, one of them, as you said, is a false sense of complacency. The other might be the perception of side effects that may not actually be barriers. So, if we [consider] hypotension or renal dysfunction, tell me what you think are truly contraindications and what we can overcome with optimization.

Bozkurt: This is a great question, Michelle. I think more than ever, we now have an armamentarium of medications with fewer side effects. This is very important for our clinicians to hear. SGLT2 inhibitors, when compared with placebo, are not associated with hypoglycemia, ketoacidosis, hypotension, or any adverse effects on the kidney. If anything, beneficial effects on the kidney are seen — that is, improvement in renal outcomes and slowing the decline of eGFR in patients with heart failure, regardless of diabetes. It is critical for us to recognize that these agents, the SGLT2 inhibitors, are very safe and easy to use, because they usually entail one dose in patients with heart failure and can actually enable initiation of other agents, such as MRAs. ARNIs, when compared [with other agents], such as ACE inhibitors, are associated with less worsening renal function, less hyperkalemia, and thus are quite effective and safe to initiate in heart failure patients. These agents have been studied in large-scale trials demonstrating efficacy and safety. Thus, these new agents actually help us initiate MRAs, help us initiate these agents in patients with chronic kidney disease.

Bozkurt: The blood pressure profile with SGLT2 inhibition is very safe, and there is no evidence of hypotension. An ARNI also is quite safe, regardless of the severity of the heart failure — the NYHA class. Thus, as a compendium — as a group of medications that facilitate and enable initiation of each other — we have a better group of medications that allow us to initiate these safely. I think our reliance on having to check labs and having to chase potassium is going to be less. Thus, it's going to be a better, probably an easier, way to initiate these agents. The new agents, such as SGLT2 inhibitors, are only one dose. An ARNI, beta-blockade, or ACE inhibitors may require a few steps. An MRA is only one or two steps, so thus overall, I think it's simpler. I know the number sometimes gives the impression of many medications, but keep in mind — I am going to again give the analogy of cancer, when we have bundled chemotherapy or bundled treatment regimens, and also ischemic heart disease, when we have a group of medications that we have to use — our clinicians feel quite comfortable with the number of medications. So, imagine this as a complementary menu that facilitates and enables initiation of each other and also has an effective profile when used together.

Kittleson: That's perfect. We need to remember that [number] one, these medicines are very well tolerated in clinical trials. And number two, the benefits are incredible — time-sensitive, early benefits, as well as long-term benefits.

Say your patient has a blood pressure of 90/60 mm Hg and feels amazing. Are you scared to up their dose of the ARNI, or do you say to yourself that because the afterload reduction will be offset by the increase in cardiac output, the sacubitril-valsartan will be beautifully tolerated? I'm not going to predict that my patient is going to fail this therapy; I'm going to test them and see what happens. Tell me your approach.

Bozkurt: Excellent question, Michelle. It's never the number of the blood pressure; it never is the number. It is, in essence, the symptoms. A significant proportion of our patients will have these numbers that vary.

First is, in the absence of any symptoms of hypotension/presyncope, these blood pressure values vary from time to time according to perhaps, the severity of the illness, because the more severe the heart failure is, the lower the blood pressure may be. Or, as we augment, as we optimize our GDMT, we will see these numbers coming down a little bit, which in essence is demonstrating its efficacy. We do not back down. We should not back down in optimization of therapies. The numbers by themselves should not be a preclusion, should not be a contraindication for optimization of therapies.

A small percentage of patients who may have true hypotension symptoms and/or orthostatic symptoms, which is rare, will need to be evaluated for very advanced heart failure. Keep in mind, patients with advanced heart failure, who have the higher absolute risk for bad outcomes, are the ones who benefit from these agents. Disease modification is critical in these patients because they have very high mortality rates.

I think that more than ever, we need to look at the whole patient. We need to look at the patient's journey and prognosis and recognize that these disease-modifying agents can change their trajectory, can help them get better, can improve their symptoms. Quite often when initiated, these agents change the disease trajectory. So, a number is never a contraindication.

Kittleson: Amazing. It comes back to that old rule of medicine that we all learned: Look at the patient; don't look at the number. Put the number in context. I love that.

So, tell me your approach, then, to renal function. Sometimes when you start these agents, you might see a slight bump in the creatinine before you see, over time, a slowing of any progressive decline. How do you approach that? How do you have the courage to not be swayed by an early bump in creatinine?

Bozkurt: This is important. We need to recognize that RAAS inhibition, as well as SGLT2 inhibitors, is associated with an expected transient rise in creatinine, which is not something that is associated with adverse outcomes. If anything, it is a reflection of their efficacy in glomerular hypertension. These agents — both the ARNI and SGLT2 inhibitors — have been associated with slowing the progression of chronic kidney disease. So, seeing a rise in creatinine is not something that the clinicians should fear, but [instead] should expect and recognize that this is related to the efficacy of the medication and will be associated with better outcomes in the long run in a significant proportion of patients. The only group of patients in whom these agents have not been studied in large-scale trials are individuals with an eGFR < 20 mL/min per 1.73 m2.

Kittleson: Again, look at the patient; don't look at the lab value. If you have a patient who has a bump in creatinine and they otherwise look well, you're reassured. If they otherwise look like they're declining regarding their symptoms, then you're going to be worried about them regardless of what their creatinine is. That is such a good lesson.

What I want to go on to now are some of the medical barriers to implementation. What about systems, barriers regarding frequent visits, frequent lab draws? What are ways to overcome these system-based sources of therapeutic inertia?

Bozkurt: We have learned during the time of COVID that we can do telehealth and virtual visits. I think the new models of care right now entail a variety of different options. We are at a juncture where we could be innovative and recognize the critical importance of time, and of us having to optimize these therapies as quickly as possible, preferably within 4 weeks.

How to optimize, how to uptitrate, can vary from practice to practice or within systems. I would encourage clinicians to utilize the resources that are available in their community, including multidisciplinary team–based care, where care coordination can be implemented with clinicians, with advanced practitioners, with telehealth — with the first visit happening postdischarge as quickly as within 7 days, but subsequently maybe virtually or even enabling patient self-titration. These agents, which demonstrate quite a reliable safety [profile], can allow us to uptitrate without having to rely on the traditional models of care, which always entailed a face-to-face visit in the past and sometimes labs. Now, we have enough evidence that uptitration is safe.

Bozkurt: We recently heard from the STRONG-HF trial at the American Heart Association (AHA) Scientific Sessions, where they were able to optimize ACE inhibitors, beta-blockers, and MRAs within 2 weeks to the optimal doses, which was associated with significant improvement in all-cause mortality and heart failure hospitalizations. Thus, I think the concept right now is that time is of the essence. Utilize resources in your system. You could use different models of care, including telehealth, virtual visits, and sometimes even patient uptitration, depending on their own self-assessment, and even remote monitoring. We now have newer modalities with the ability to monitor patients with digital health or remote implantable monitoring devices. I think these newer concepts will help us optimize therapies without having to rely on face-to-face visits.

Kittleson: So, we can say that the one and only one silver lining of the pandemic is now our ability to do telehealth for frequent follow-up and monitoring of our patients. I'm so glad you brought up this STRONG-HF trial, because I think it put a lot of theory into practice. Number one, it's feasible to do rapid uptitration with close monitoring. Not only is it feasible, but at 180 days of follow-up, there's actually an effect size — a 15% vs 23% difference in the incidence of heart failure, hospitalization, and death. I think that was a more stunning effect size than any of us thought we'd get. It really affirms the importance of quadruple therapy for HFrEF.

Bozkurt: I do agree, and I think one other important thing that will facilitate implementation, is recognition that the kidney also benefits from the quadruple therapy. In the past, as heart failure clinicians, we always used to fear the outcome on the kidney. One important concept that I'm going to share with our clinicians is that we need to probably not utilize the acute kidney injury concept as often as it's being implemented in clinical practice, especially for hospitalized patients with heart failure. Decongestion, when implemented with an effective diuretic and/or decongestion strategy during the hospitalization, if associated with a transient rise in creatinine, is not associated with bad outcomes. If anything, successful decongestion is associated with better outcomes, as well as RAAS inhibition and SGLT2 inhibitors now being associated with transient increases in creatinine but better outcomes in terms of heart failure and kidney outcomes. I think this underscored the importance of us recognizing that not every rise in creatinine — either during hospitalization or with effective therapies — is AKI. Acute kidney injury is probably an entity that should be spared for entities that are associated with true kidney injury in the setting of heart failure. Initiation of GDMT is not associated with acute kidney injury, and decongestion is a successful target that we should all try for in our hospitalized patients with heart failure.

Kittleson: That's amazing. I can't think of a more important take-home point for our listeners.

So, what we've learned today is that [number one]: Use optimal quadruple therapy for patients with HFrEF that involves an ARNI, evidence-based beta-blocker, MRA, and SGLT2 inhibitor. Number two: Don't have a false sense of complacency. Move forward. These medications are incredibly well tolerated, and your patients will feel better, be less likely to be hospitalized, live longer, and potentially have an improvement in heart function. Finally, we know this approach is not only feasible but it does reap rewards, based on the newest STRONG-HF trial that was presented at the AHA [Scientific Sessions] on November 2022.

Thanks for joining us in this 12-part conversation in heart failure. We are so lucky to have Dr Bozkurt with us today.

Bozkurt: Thank you.

Kittleson: There's so much more ahead in the next episodes. I'm Dr Michelle Kittleson, for Medscape InDiscussion.


2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines

Effects of Enalapril on Mortality in Severe Congestive Heart Failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)

Prescribing SGLT2 Inhibitors in Patients With CKD: Expanding Indications and Practical Considerations

Safety, Tolerability and Efficacy of Up-titration of Guideline-Directed Medical Therapies for Acute Heart Failure (STRONG-HF): A Multinational, Open-Label, Randomised Trial

Follow Medscape on Facebook, Twitter, Instagram, and YouTube


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.