Aggressive Therapy Recommendations Following the STRONG-HF Trials: Stephen J. Greene, MD

Recent advancements in medical therapy for heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) include 3 classes of therapy—sodium glucose cotransporter inhibitors (SGLTis), nonsteroidal mineralocorticoid receptor antagonists (nsMRA), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs).

In a Q&A with The American Journal of Managed Care^® (AJMC^®), the author of a recent viewpoint published in JAMA Cardiology, Stephen J. Greene, MD, an assistant professor in the division of cardiology advances heart failure and transplantation at Duke University Medical Center, discussed the definitive clinical benefits of these 3 classes of therapy and the benefits of a multidrug approach for treating HFmrEF and HFpEF.¹

The recent Safety, Tolerability, and Efficacy of Rapid Optimization of Heart Failure Therapies Trials (STRONG-HF; NCT03412201) evaluated the effectiveness of intensive care when compared with usual practice in the initiation and up-titration of HF medications after hospitalization. The trial results showed that patients in the high-intensity group, uptitrated to the recommended doses, saw a significant reduction in HF hospitalizations or all-cause death; however, there was a higher incidence of adverse events in this group too.²

Study authors suggest that the findings of the trial are likely to be followed up with updated recommendations for an aggressive approach to initiation and up-titration to optimize quadruple foundational therapy for patients with HFmrEF and HFpEF. As treatment strategies for HFmrEF and HFpEF continue to evolve, evidence supports the growing importance of multidrug therapy, with SGLTis, nsMRAs, and GLP-1 RAs offering complementary benefits.

The STRONG-HF trial underscores the potential of early, intensive optimization of therapies, though safety considerations remain key. In this Q&A, Greene shares his perspective on the latest advancements, the role of combination strategies, and what clinicians should consider when implementing emerging approaches to heart failure care.

AJMC: Given the limited trial data on concurrent administration of SGLT2 inhibitors, MRAs, and gastric inhibitory polypeptides(GIP)/GLP-1 receptor agonists, what key evidence or clinical experience most strongly supports rapid or simultaneous initiation of these therapies?

Greene: It is correct that there is no randomized trial testing simultaneous or rapid initiation of SGLT2i, nsMRA, or GIP/GLP1 RAs. Yet, we need to learn from our past struggles with the implementation of GDMT in HF and review the data we do have. We know that each of these 3 medications exerts clinical benefits within days to weeks of initiation, that the benefits of each are additive to each other, and that delaying initiation of medications leads to medications never being initiated or substantial delay.

We also have the STRONG-HF trial, which, while not with these 3 exact medications, showed that simultaneous initiation of ACEI/ARB, beta-blocker, and MRA substantially improved patients’ outcomes while coming with no price to pay on serious adverse events compared with usual care. You compare this with objective evidence for the "go slow, one move at a time" status quo approach? There is no scientific evidence that a routine approach of going slow carries any advantage. This approach is the approach that gives the huge gaps we see in real-world uptake of these medications.

AJMC: How do you envision implementing this rapid initiation strategy in diverse clinical settings, especially considering potential barriers like medication costs, patient adherence, and monitoring requirements?

Greene: Costs for branded medications remain a barrier for select patients, no doubt about it. But as a heart failure community, we need to first agree on the best approach to shoot for and make sure we are aligned on the goal. I strongly believe that simultaneous or rapid initiation of these medications should be the goal and that the benefits of this approach far outweigh the risks. That being said, assuming we agree on this goal, then the question is how we execute.

One thing to strongly consider is virtual visits. It may not be feasible from a patient or clinic perspective to have frequent in-person visits for an individual patient. But a lot of this can be done over the phone. Patients can get lab work as needed ordered for close to home, and assuming labs are ok and the patient feels ok, I think we need to be very comfortable titrating medications over the phone.

AJMC: Are there specific patient populations within HFmrEF and HFpEF who may benefit most from this approach, or conversely, for whom caution might still be warranted?

Greene: I think simultaneous or rapid initiation of SGLT2i, nsMRA, and GIP/GLP1RAs should be the routine approach for all patients with HFpEF who are eligible for these therapies. That being said, there could be select patients where a slower approach is needed, but we need to be careful that we do not "individualize" this so much that we substantially delay a therapy a patient is eligible for. While the speed of rapid initiation can be debated, such as simultaneous versus 1-week versus 2-week, the heart failure community should agree on what the "wrong answer" is.

The "wrong answer" is to start one medication today and then start the next medication in 3-6 months at the next clinic visit. I will argue strongly that this is the wrong answer, yet this is unfortunately our status quo approach.

AJMC: What are the most critical areas for future research to solidify the safety and efficacy of simultaneous combination therapy in heart failure with preserved or mildly reduced ejection fraction?

Greene: Clinical trials of this approach would certainly be helpful to further get clinicians comfortable with this, with these 3 medications specifically. Yet, we have to acknowledge that it is likely not practical to redo such trials every time we discover a new effective medication. We just had STRONG-HF show the efficacy and safety of simultaneous RASi, beta-blocker, and MRA. We have a trial in diabetic kidney disease showing the efficacy and safety of simultaneous SGLT2i and nsMRA. At some point, we just have to agree that this concept of simultaneous or rapid initiation is the default approach for patients with heart failure.

I would argue that at this point, the burden of proof should fall to those trying to justify going slow with one medication at a time. There are real risks of omission with delaying or omitting effective medications that have an early onset of benefit.

AJMC: How do you propose clinicians address patient hesitation or concerns about the complexity of initiating multiple medications simultaneously?

Greene: It is all about psychology with clinicians. Many are trained with the idea of "first, do no harm," and we inherently believe that starting multiple medications at the same time could increase the risk of side effects or be dangerous. Yet, I will argue that not starting proven medications is dangerous, especially for a condition like heart failure, where the prognosis is comparable to cancer. Every day in this country and around the world, many people are dying or going to the hospital without receiving medications proven to prevent these events. This would be the equivalent of saying that many cancer patients are dying without ever being started on chemotherapy. I would argue that patients and oncology would never accept that, yet this is what unfortunately happens routinely in heart failure care.

AJMC: In light of current guideline frameworks, what steps do you think are necessary to revise or update recommendations to incorporate this combined, rapid therapy approach?

Greene: Guidelines and expert consensus statements are already catching on to the concept of rapid sequence or simultaneous initiation of foundational medications for HF. My colleagues and I first proposed this approach for HFrEF in 2021. The US HF guidelines then mentioned it as a viable strategy when published in 2022. Then we have the STRONG-HF trial get published and incorporated within a new Class I recommendation for this approach in the European heart failure guidelines. Now that we have multiple definitively proven medications for HFpEF, it will be interesting to see what the next iteration of the guidelines says. Hopefully, they will incorporate the concept that we absolutely must be willing to initiate multiple medications at the same time or rapidly. Otherwise, real-world data shows that patients never get the opportunity to benefit from all the proven medications.

References

1. Greene SJ, Butler J, Fonarow GC. Simultaneous or rapid initiation of combination therapy for heart failure with preserved ejection fraction. JAMA Cardiol. 2025;10(5):407–408. doi:10.1001/jamacardio.2025.0038

2. Butler J, Talha KM, Fonarow GC. STRONG-HF and implementing heart failure therapies: Godspeed...with care. Circ. 2023;147(16):1189-1191. doi:10.1161/CIRCULATIONAHA.122.063811