Getting Ready for a Heart Failure Polypill, Well Before the Data Are In

Well ahead of its availability, and even before randomized trials have shown that it works, experts are laying the groundwork for the introduction of a polypill to treat patients with heart failure.

A new paper in JACC: Advances delves into the factors that may affect implementation of a polypill for heart failure with reduced ejection fraction (HFrEF)—assuming one proves safe and effective—and outlines strategies for an eventual rollout.

The idea is to do this conceptual work now rather than waiting for the therapies to work their way through clinical trials and become commercially available, so that delays in adopting the polypill can be reduced if it’s available.

This exercise “just reinforces the idea, in addition to previous data showing therapeutic inertia and reluctance to use other single-pill combination therapies for cardiovascular diseases, that we need to plan in advance. We need to be strategic in how we design the heart failure polypill and how we implement it, and what strategies and what messages we provide with that,” said Justin Chen, MD (WashU Medicine, St. Louis, MO), one of the lead authors along with Colette DeJong, MD (Stanford University, CA).

Though guideline-directed medical therapy (GDMT) for HFrEF has evolved dramatically over the past several years—with four pillars of treatment now recommended—studies have shown time and again that most patients aren’t being treated with quadruple therapy.

One strategy that has been proposed to overcome barriers to treatment is the use of polypills, or fixed-dose combination therapies, designed to boost adherence, ease pill burden, and streamline care. Such an approach was shown to be beneficial for the secondary prevention of atherosclerotic CVD in the SECURE trial, which demonstrated that a polypill containing aspirin, atorvastatin, and ramipril reduced the risk of major cardiovascular events compared with usual care.

Overcoming Barriers to Treatment

This new paper builds on prior work from these researchers that identified key factors around the design and implementation of an anticipated polypill for HFrEF by examining how those factors interact with each other, developing an implementation bundle to address potential barriers to adoption, and estimating how those measures may improve patient care.

The researchers used information from in-depth interviews with nine HFrEF patients from diverse racial backgrounds (mean age 57.6 years; 44.4% women) and 22 healthcare providers (mean age 46.1 years; 59.1% women), including primary care physicians, hospitalists, cardiologists, and nurse practitioners. The study was conducted at Washington University in St. Louis and the University of California San Francisco.

An overarching theme that emerged was that “there are a lot of current barriers to excellent HFrEF care and that the polypill can help to address some of those barriers, but not all of them,” Chen said.

[A polypill] is not a magical pill that’s going to solve all of our problems. Justin Chen

After identifying the barriers to adoption of innovations like a HFrEF polypill and potential steps that can be taken to address them, “the third step was to illustrate how those strategies would come together as a package to support the effective and safe use of a polypill, understanding that there are also limitations in what kinds of strategies can be employed in different healthcare settings,” he said. “This could be a list or a package of strategies that providers can consider when they implement a HFrEF polypill once it’s shown to be effective.”

It’s important to understand, Chen said, that a future fixed-dose combination therapy containing multiple types of GDMT is “not a magical pill that’s going to solve all of our problems.”

Cost will be a key issue to address, as polypills are typically more expensive than the individual generic components. “We need to try to get insurance to support payment programs or coverage for this polypill in the very beginning, and the whole goal is to know what those barriers are in advance so that once this does come out and come out to market that we can get it into the hands of the people that need it the most in the quickest and safest way possible,” Chen said.

The design of a polypill is another critical consideration because the types of medications that are included will determine how easy it will be to titrate the doses to accommodate individual patients’ needs. The makeup of the pill comes into play, too, when trying to convince clinicians to use it—if physicians are reluctant to use a mineralocorticoid receptor antagonist on its own, for example, then they will also be hesitant to use a polypill containing one.

At least initially, Chen indicated, a HFrEF polypill may best be thought of as a population-level versus a precision-medicine strategy, one that will help address the dismal rates of patients receiving four-pillar GDMT. “This single-pill combination, heart failure polypill will be useful at the very beginning with initiation, making sure they get at least low doses of all four guideline-directed medical therapies until they’re able to follow up with their primary care doctor, cardiologist, or heart failure specialist in that gap where they’re so vulnerable,” he said.

Then, “as the capacity to create more-tailored polypills for HFrEF are available, we can start building more towards that precision strategy as well,” Chen added.

HFrEF Polypills Still Several Years Away

Research into HFrEF polypills is still in the relatively early stage, with results from pilot RCTs starting to come out. At the upcoming American Heart Association 2025 Scientific Sessions, for instance, Ambarish Pandey, MD (UT Southwestern Medical Center, Dallas, TX), will present results from the phase II POLY-HF study, which tests the feasibility and effectiveness of polypill-based strategy for treating HFrEF.

Five years from now, larger phase III trials will likely be ongoing, Chen predicted. It took about 10 years for the polypill for secondary prevention of atherosclerotic CVD studied in the SECURE trial to make it through phase III testing, he noted. “So, there is time and there’s still a lot of formative work that needs to come out [for the HFrEF polypill] to provide that preponderance of data and evidence that people will be like, ‘Hey, yes, this is a thing that we need to do.’”

Pandey, speaking with TCTMD, said that Chen and his colleagues “have come up with an implementation road map that could be used to guide uptake of these therapies if these were to show that they’re clinically effective and get adopted.”

The main obstacles to bringing a HFrEF polypill to market are, first, showing that it works to improve adherence to GDMT and/or clinical outcomes and, second, figuring out who will pay for a more-expensive fixed-dose combination therapy, Pandey said. Concerns about how to titrate the doses of a polypill will need to be addressed as well, he said, noting that POLY-HF used multiple versions of the polypill with different doses of the component medications. It was made with an encapsulation-based approach, “so the pharmacist can actually create any kind of polypill based on what the prescription regimen by the provider is,” said Pandey.

Ultimately, he predicted, “if we have a successful clinical study that demonstrates that there is better adherence, better outcomes with these polypills, it could become an important treatment strategy” several years down the road.

In an accompanying editorial, Quan Bui, MD, and Max Jason, MD (both from UC San Diego Health, La Jolla, CA), say this new paper “makes an important contribution to the field of implementation science in cardiovascular medicine. It integrates proactive implementation planning, a welcomed departure from the traditional model in which implementation is considered only after clinical trial completion.”

The fundamental question, however, is whether polypills are the solution to the tricky problem of increasing use of GDMT for patients with HFrEF, they add. These patients often need frequent dose adjustments, and fixed-dose combinations can have limitations when it comes to managing side effects or accounting for contraindications or variability in cost.

“As such, a polypill may be best suited in resource-limited environments or a narrow subset of ‘Goldilocks’ patients, those with [optimal] blood pressure and minimal comorbidities,” Bui and Jason write.

In addition, there’s still a need for large-scale validation of polypills in diverse HFrEF populations, they say.

“In the meantime, we should prioritize implementation of proven, multifaceted strategies that are already available and cost-effective,” they advise. “Multidisciplinary GDMT clinics, protocol-driven titration algorithms, and patient-centered decision support tools have demonstrated efficacy in increasing GDMT uptake.”

Right now, “the solution to optimizing GDMT is not a magic pill; it is the commitment to implement what we already know works,” Bui and Jason say.