Pivotal Clinical Trials Shaping HF Treatment Landscape


The panel explores clinical evaluations, such as the PROVE-HF study and PARADIGM-HF trial.

Ryan Haumschild, PharmD, MS, MBA: Discuss the results of the PARADIGM-HF trial (NCT01035255) and how it has changed the treatment landscape. In practice, are you starting to see an overall shift to ARNI [angiotensin receptor-neprilysin inhibitor] therapies based on the positive results of this trial?

Jim Januzzi, MD: Thanks for the question. There’s definitely a shift toward sacubitril/valsartan, which is the only angiotensin receptor-neprilysin inhibitor available. The uptake has been modest, though, in part because the drug is more expensive than previous therapies, including ACE [angiotensin-converting enzyme] inhibitors and ARBs [angiotensin receptor blockers]. But the preponderance of data is clear that sacubitril/valsartan is superior to an ACE inhibitor or ARB.

The PARADIGM-HF study was a trial of sacubitril/valsartan vs enalapril in people with ejection fractions [EFs] of 40% or less. In this study, the treatment with sacubitril/valsartan was associated with a 20% reduction in the primary end point of cardiovascular death or heart failure hospitalization. But in addition to the primary end point, there was also a 20% reduction in mortality, including sudden death, which is quite interesting and probably relates to the fact that regardless of the background therapy that a person receives prior to being put on sacubitril/valsartan, there’s some degree of reverse remodeling with improvement of the ejection fraction and a lowering of risk for an arrhythmic complication. Quality of life and the 6-minute walk distance were improved. This was a 500-foot home run supporting the use of sacubitril/valsartan instead of an ACE inhibitor or ARB.

There have been subsequent studies since PARADIGM, including the PIONEER-HF study (NCT02554890) looking at the role of the drug for patients with decompensated heart failure with reduced ejection fraction. We performed the PROVE-HF study (NCT02887183), which was a prospective study of 800 individuals with heart failure with reduced EF treated with sacubitril/valsartan, where we showed profound reverse remodeling with improved ejection fraction and improvements in health status regardless of background therapy. For all of these reasons, the guidelines have elevated sacubitril/valsartan to a class 1 level A recommendation. However, they concede that some patients are either unable or unwilling to take sacubitril/valsartan, and in that situation, another inhibitor of the renin-angiotensin system, such as an ACE inhibitor or ARB, would be recommended. I try to simplify things. I don’t see any reason to start with an ACE inhibitor or ARB in a patient with newly diagnosed reduced ejection fraction heart failure. I lead with sacubitril/valsartan unless there’s a reason not to.

Ryan Haumschild, PharmD, MS, MBA: Excellent. I appreciate your incorporating the study and your best practice. Dr Anderson, you do a great job treating your patients as well, so I’m curious about your thoughts. How did your practice change after the PARADIGM study came out? As part of the new 2022 guidelines, they recommend switching patients to an ARNI when appropriate or feasible. In your practice, how do you define feasible? Maybe working off some of the points that Dr Januzzi made, when do you feel like a patient isn’t feasible to make that transition?

John E. Anderson, MD: That’s a great point. Dr Januzzi said “when appropriate.” It’s appropriate in every patient with heart failure with reduced ejection fraction, so that’s our job. We need guideline evidence-based therapy and recommendations. There’s never a time, at least in my experience, that it isn’t appropriate. Feasible also isn’t that difficult. Most of our patients, particularly patients with longstanding hypertension and diabetes, have been on ACEs or ARNIs. This usually isn’t a new therapy for them. It has the same potential to lower blood pressure.

You have to have the same cautionary tale you do with all your patients. You start with the moderate dose, increase as necessary, and make sure they’re in contact with you. If they have any lightheadedness, you change other drugs or decrease the doses of other drugs as you’re building up this particular medication. But this isn’t any different in primary care from what we’ve done for years using antihypertensive therapies. It’s a matter of awareness. I agree with Dr Januzzi; I’m seeing a lot more patients on ARNI therapy, particularly when they’re coming out of the hospital, and particularly when they’re coming back from the cardiologists. Our primary care colleagues have been much slower on the uptake, but the word is out. When you have guidelines that say, “This is what you should do,” primary care listens.

Ryan Haumschild, PharmD, MS, MBA: I’d like to follow up on that point, Dr Anderson, because you made a great one in terms of who’s being a little delayed and who’s adding the therapy. When we think about patients coming for an inpatient hospital stay, that postdischarge period can be vulnerable. We’ve talked about that as a group. That’s the time to make sure we have good intervention. Follow-up visits with the specialist sometimes don’t occur until months after. Dr Januzzi mentioned that the PIONEER heart failure trial found that inpatient initiation of ARNI therapy was high value compared with delay of initiation. Dr Anderson, do you feel like some of the hospitalists are looking to make the switch from an ACE or ARB to ANRIs in the inpatient setting? Are they looking for that specialist to make the switch on the outpatient in that transition-of-care clinic? What has been your experience? What have you seen across the different areas in which you practice?

John E. Anderson, MD: As someone who did inpatient/outpatient for 27 years, I’ve done both sides of that fence. In our institution, the hospitalists and cardiologists work in tandem. They have a great communication set. It’s rare for me to see a patient with heart failure, especially new onset heart failure, who doesn’t have cardiologist consultation with it. They’re making the transition, and in that particular study you referenced, even with week 1, you see NT-proBNP levels improving. This isn’t going to take you 2 months to see a benefit, at least by that particular biomarker. It’s in concert. There are also times in primary care when I have older patients who don’t want to see their cardiologist. They haven’t been hospitalized, but they’re appropriate for ARNI therapy, and we’re making those transitions off ACEs and ARBs before hospitalization or before repeat hospitalization. It takes both of us and the communication between the specialists to do this right.

Transcript edited for clarity.

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