GDMT Uptake Remains Dismal in HFrEF: What’s the Right Fix?

Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) has expanded dramatically in recent years, but getting patients on all four pillars remains a challenge.

Indeed, study after study after study after study affirm that most patients who are eligible to be treated with foundational GDMT are not receiving it. Generally, most get a beta-blocker, but fewer than half are put on a mineralocorticoid receptor antagonist (MRA) and even less get prescribed an angiotensin receptor-neprilysin inhibitor (ARNI) or sodium-glucose cotransporter 2 (SGLT2) inhibitor.

Efforts to improve the situation include things like alerts within the electronic health record (EHR), educational initiatives aimed at both physicians and patients, and specialized GDMT clinics have yielded mixed success. But there’s a long way to go, according to HF specialists contacted by TCTMD.

A brief report published in JAMA Cardiology in early October underscores the seriousness of the issue. Researchers estimate that, worldwide, about 1.19 million deaths could be avoided each year through optimization of GDMT in all eligible patients, with even partial improvements in medication use associated with smaller but still substantial benefits.

It “really quantifies from a public health standpoint the phenomenal impact, given the risk of these patients and the current size of the treatment gap, and what this could actually mean if we could overcome these barriers,” said Gregg Fonarow, MD (University of California, Los Angeles), senior author of the study.

The number of lives that could be saved with optimal GDMT use is “a staggering amount, and governments need to pay attention to this,” Shelley Zieroth, MD (University of Manitoba, Winnipeg), a past president of the Canadian Heart Failure Society, told TCTMD. “These are lifesaving, disease-modifying therapies, and our patients need rapid access to them.”

Clinical Inertia Shoulders Much of the Blame

Experts have debated why it’s so hard to get patients on optimal GDMT. Multiple trials have established beyond a doubt that patients with HFrEF, who have a very high risk for poor outcomes, including death, see improvements in symptoms and function as well as reductions in mortality and other endpoints when they’re put on all four drugs.

It’s critical for the heart failure community to come together and agree on the main underlying reason so solutions can be developed, according to Stephen Greene, MD (Duke Clinical Research Institute, Durham, NC), who noted that issues like drug costs, intolerance to medications, or pill burden have been proposed as explanations.

“I’m not saying that those issues aren’t there for select patients, but we need to come together and agree that if you’re looking at the one unifying reason why we have widespread systemic underuse of GDMT, the dominant reason is a culture of clinical inertia and underappreciation of risk,” he said. That’s an argument supported by a study based on physician surveys that he and his colleagues published recently in JACC: Heart Failure.

If you’re looking at the one unifying reason why we have widespread systemic underuse of GDMT, the dominant reason is a culture of clinical inertia and underappreciation of risk. Stephen Greene

The magnitude of a HFrEF patients’ risk may be underestimated if they have improving symptoms despite not being on all four pillars of GDMT, which can lead to physicians not intensifying treatment, Fonarow said. This failure to act, he added, “has essentially lethal consequences.”

Akshay Desai, MD (Brigham and Women's Hospital, Boston, MA), cited some other possible factors playing into the underuse of GDMT, including the difficulty of getting patients access to potentially costly medications that may require prior authorization, which creates a disincentive for physicians to make the effort. Prescribing physicians may also be concerned about adverse effects when adding more medications or increasing dosage. Patients might be reluctant to take more drugs, with accompanying costs and potential side effects, when they’re feeling well, he added.

But at least some of the issue is related to clinical inertia, Desai agreed. “I think there is the myth of a stable heart failure patient that leads people to become a little complacent about the project of optimizing medical therapy.”

Contributing to this inertia is that clinicians have become accustomed to the usual way of administering HF treatment in the past—starting one medication at a time, at a low dose, and then intensifying gradually across subsequent visits.

“If you’re only seeing patients back at 2-month intervals, it’s going to take a year or more, even without inertia, to get those medications on board, and patients go on to have events or die before then,” Fonarow said, adding that this approach “doesn’t make therapy better tolerated and doesn’t get the job done, but yet many clinicians adhere to that because that’s how they were kind of taught to use the medications.”

Also, said Christopher O’Connor, MD (Inova Heart and Vascular Institute, Falls Church, VA), a past president of the Heart Failure Society of America (HFSA), there’s pressure to get patients who are improving out of the hospital as quickly as possible, so physicians may not have the time to add and titrate all components of GDMT before discharge, especially if there are concerns about side effects.

“So it kind of gets pushed down the ladder a little bit and people say, ‘Well, I’ll initiate it as an outpatient.’ But then you realize if you take that strategy, it doesn’t happen,” O’Connor said.

The STRONG-HF Approach

Asked about how to address the underuse of GDMT, several physicians pointed to the approach tested in the STRONG-HF trial—namely, in-hospital initiation of all recommended medications followed by rapid uptitration to full doses within 2 weeks. At the time of the trial, GDMT for HFrEF encompassed renin-angiotensin-system (RAS) blockers, beta-blockers, and MRAs, with SGLT2 inhibitors not yet approved or in widespread use. Compared with usual care, this approach safely improved measures of congestion and quality of life and lowered the rate of all-cause death or HF readmission at 180 days.

“That hospitalization serves as a teachable moment for guideline-directed medical therapy,” Fonarow said, noting that when therapies are started in the hospital, patients have 85% to 90% adherence at 1 year. On the flip side, he said, if they’re not started in the hospital, 85% to 90% of patients remain untreated through the next year of follow-up.

“Having hospital-based systems and programs like Get With The Guidelines – Heart Failure to ensure the initiation of these therapies and early follow-up from the hospital is also something that is evidence-based, guideline-recommended, and very useful,” Fonarow said.

O’Connor also pointed to a hospitalization in a patient with HFrEF as a critical moment in the course of the disease. “It gives you five observation days to look at the patient and talk about their medicines and their care and do education. You don’t get that in a clinic visit. So I think the first step is to really utilize the hospitalization to get patients on as many of the four pillars as you can and hopefully all four.”

Then, it’s important to have systems in place to get patients back for early—and frequent—follow-up, he said, acknowledging that that isn’t common in the current US system.

Multidisciplinary HF Care and Virtual Consults

Several physicians pointed to the utility of multidisciplinary heart failure teams, which can include navigators guiding patients through the process of GDMT uptitration, as a way to improve care.

“Having a team-based approach is really important, where you have physicians involved and heart failure physicians involved, but a lot of the actual conduct can be done by advanced practice providers,” O’Connor said.

Use of these multidisciplinary programs has been associated with improved outcomes and greater use of GDMT. In the GEstIC study, for example, patients admitted to such a clinic saw declines in all-cause and HF hospitalizations, as well as urgent HF visits, in the year after versus before admission, and that reduces healthcare costs.

“The challenge is the availability of those programs and access,” Fonarow said. “It’s only a very small proportion of patients with heart failure that are getting to see heart failure specialists and multidisciplinary teams, and there’s a lot of structural challenges around expanding that. So the key question becomes: is there a way of making a sustainable and scalable type of approach where you get access to expertise like that to get the meds initiated?”

These are lifesaving, disease-modifying therapies, and our patients need rapid access to them. Shelley Zieroth

One way to expand access to specialized heart failure care, particularly for patients who live in rural areas, is through virtual consultations.

Greene argued that a standard in-person visit as part of routine follow-up for chronic heart failure “is on average very low value,” pointing to data showing few medication chances, inadequate physical exams, and poor prediction of risk.

“Instead, you can envision a lot of this could be done remotely,” he said. Laboratory tests, including NT-proBNP, can be performed at a site near the patient, and then discussion about the results and how the patient is feeling, as well as GDMT optimization, can take place via telehealth.

“There’s always going to be a role for in-person visits for select patients that are particularly high risk or not doing well. And of course, that’s the patient that needs a lot of physician judgment, but for a lot of our standard routine follow-up patients, a lot of this I think could be optimized [virtually] in the outpatient setting. And that could just be one method of getting quad therapy for HFrEF on board as quickly as possible,” Greene said.

Mark Schuuring, MD, PhD (University of Twente, Enschede, The Netherlands), and his team recently reported results from a proof-of-principle trial, ADMINISTER, that evaluated the impact of virtual consults. Patients with HFrEF were randomized to usual care or a strategy of digital consults consisting of data sharing between patients and clinicians on drug use, home-measured vital signs, and Kansas City Cardiomyopathy Questionnaire scores; patient education with text-based learning; and the provision of guideline recommendations for clinicians.

A GDMT score incorporating all nonconditional class 1 indications for HFrEF therapy significantly increased in the digital consults group after 12 weeks of follow-up. Even so, “there’s so much room for improvement,” Schuuring said. Although the rate of optimal medical therapy was significantly higher with digital consults versus usual care (28.2% vs 6.9%), most patients didn’t reach that goal.

Other studies have examined the impact of virtual strategies, too. A study conducted at Brigham and Women’s Hospital called IMPLEMENT-HF showed that a virtual care team-guided strategy—with a CV-trained physician and pharmacist—for patients in the hospital also improved use of GDMT, with a near doubling in new drug initiations and intensification of one or more GDMT components.

Other Digital Solutions

Schuuring is lead author of a European consensus statement on digital solutions for optimizing GDMT for heart failure that was published earlier this year. The document  reviews various options, including digital consults, remote monitoring, interrogation of cardiac implantable electronic devices, clinical decision support systems, and others.

Further research is needed, but digital solutions will play a central role in improving use of GDMT in patients with HFrEF, Schuuring predicted. It’s “a way to make it scalable because we will not get more staff to do that. It’s a labor-intensive task,” he said, adding that these types of approaches also “can bring a mirror, a nudge,” to get clinicians thinking about GDMT optimization. “We want it to be positive—it’s not punishing when you’re not doing it, but it’s supporting in a positive way where there’s room,” said Schuuring.

Some trials, such as BETTER CARE-HF and PROMPT-HF, have evaluated the impact on GDMT use of adding pop-up alerts to the EHR.

“What we see is that they move the needle a little bit, but not maybe as dramatically as we might hope in terms of closing the gap in prescription,” Desai said.

Researchers are also exploring the possibility of incorporating artificial intelligence to improve the situation by identifying untreated but eligible patients and then guiding physicians through the process of getting them on optimal GDMT.

A recent study published in JACC: Heart Failure, for instance, evaluated a method for automated identification of patients with HFrEF at hospital discharge using a deep learning-based approach, with the idea that these patients could then be targeted for improved quality of care, including optimization of GDMT. Performance was high for identifying HFrEF from clinical notes in the electronic health records. “This strategy improved the classification of patients with HFrEF compared with the chart diagnosis codes and identified discernible gaps in guideline-directed therapies in practice,” the authors write.

The GDMT Clinic Model

Another approach tried in some centers is the creation of dedicated outpatient clinics focused on optimizing GDMT, much like the anticoagulation clinics set up for patients with atrial fibrillation.

Fonarow and Greene both participated in TEAM-HF, a study that evaluated the impact of such a clinic staffed by nurse practitioners, physician assistants, and pharmacists under the supervision of general cardiologists in the Massachusetts General Hospital system. Patients referred to the clinic underwent rapid uptitration of GDMT, with the proportion on four-drug treatment rising from 21% to 88% through a median of about 16 weeks. Patients in the clinic also were more likely than those getting usual care to achieve at least 50% of the target dose of each class of medication, with accompanying improvements in HF symptoms, NT-proBNP levels, LVEF, and the severity of mitral regurgitation.

“Extracting the project of medical optimization from routine practice and into dedicated clinics or implementation models seems to be effective,” Desai said, noting that this strategy can be undertaken using a virtual program, a brick-and-mortar clinic, or a combination of the two.

Financial Incentives May Help

Some physicians raised the prospect of using different reimbursement or compensation structures to incentivize greater use of GDMT since the prescription of medications is not as clearly reimbursed as procedures and physicians trying to work through a large number of visits may not have the time to adequately address it.

O’Connor described an effort, tested within a large outpatient cardiology practice with 10 locations throughout northern Virginia, that identified use of ARNI and MRA in eligible HFrEF patients as a quality metric and then linked that to the group’s clinician compensation as a way to improve GDMT use. As reported in JACC: Heart Failure, after implementation of the project, ARNI use rose from 31% to 67% and MRA use increased from 28% to 66%.

There is the myth of a stable heart failure patient that leads people to become a little complacent about the project of optimizing medical therapy. Akshay Desai

Over time, the medical community can expect to see a shift from the current system to more value-based payment frameworks, Desai said. Yet “even now in our risk-based contracts, there’s more attention to this,” he added. “The incentives are better structured for clinicians to do what is needed to keep patients well and out of the hospital because in some sense the system benefits in that situation. In a fee-for-service model, less so, because each hospitalization is still a revenue opportunity for the system.”

With value-based payment, Desai said, “it becomes a little easier to incentivize clinicians around performance because on a population scale, the higher the utilization of these therapies in aggregate, the lower your rates of hospital admission, readmission, and in general, the better the health of the population.”

He added, however, that “much of the work we do in heart failure longitudinal care is done because we know it’s important and not because it provides any revenue for the institution.”

Filling the Education Gap

A key step in boosting use of GDMT in HFrEF cited by several physicians is improving education around these medications for clinicians, who might have misperceptions about the benefits, contraindications, and the potential for adverse effects.

“If there are misperceptions, which there are so commonly, that’s where the education gap is,” Fonarow said. Many clinicians, for example, might think that they can’t initiate or uptitrate a beta-blocker or start an SGLT2 inhibitor or MRA if a patient’s blood pressure is too low, but “the clinical trials and clinical experience show that is the absolutely not the case,” he said.

A prior study Fonarow was involved in demonstrated that adverse events do occur frequently in heart failure trials, but that the rates with components of GDMT were no higher than with placebo. “Much of what’s attributed to an adverse event or side effect of the medication is the underlying heart failure or the comorbid conditions,” he explained, adding that “there is a lot of education needed about the appropriate use of these medications and the necessary adjustments that can be made.”

As for the benefits of these medications, there are data underscoring the value in getting patients on all of them, Fonarow said. He pointed to an analysis that estimated that giving patients quadruple therapy with sacubitril/valsartan, a beta-blocker, an MRA, and an SGLT2 inhibitor would extend survival by up to 6.3 years compared with conventional therapy with an ACE inhibitor/ARB and beta-blocker in patients with HFrEF.

To help with education, HFSA put together an optimal medical therapy program for practicing clinicians and others involved in the care of patients with heart failure to teach them about therapies, dosing, and prescription optimization, Fonarow noted. It’s also important, he said, to ensure that trainees are exposed to education about GDMT for heart failure, to continue to explore digital support strategies at the point of care, and to educate patients themselves.

Much of what’s attributed to an adverse event or side effect of the medication is the underlying heart failure or the comorbid conditions. Gregg Fonarow

Feedback to clinicians might be an important part of improving GDMT, and an optimal medical therapy (OMT) score, with thresholds for suboptimal, acceptable, and optimal usage based on the use and target dosing of GDMT, could be used to compare clinical practices and trials on the adequacy of their treatments. “This is like a report card that could be used to help motivate clinicians and investigators to do a better job with GDMT,” O’Connor said.

It remains important to deliver education through various means, whether that’s meeting symposia, podcasts, e-blasts, or webinars, Zieroth said. For every CME session on GDMT she participates in, “the room is still full, and people are still asking questions about utilization, safety follow-ups, and getting the important reassurance that all four pillars of therapy in combination are safe to apply.”

Fonarow said he and Clyde Yancy, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), are co-directing the American Heart Association’s version of IMPLEMENT-HF, a quality improvement initiative across seven regions of the US geared toward optimizing inpatient heart failure management, with a strong educational component. Through a systematic approach, they worked with about 100 healthcare systems to improve implementation of GDMT.

“We’re preliminarily able to show quadruple therapy going from about 17% use up to 60% use and importantly at 30-day follow-up, that therapy persisting in the higher rates of use,” Fonarow said. “So on a large scale, this can be done through essentially a national collaborative with professional societies working with multidisciplinary teams at different health systems to really make a meaningful difference.”

The ‘Moon Shot’ for Heart Failure

Though several different strategies have been tried to achieve gains in GDMT use, their impacts have varied.

“Generally speaking, for every positive study, there’s oftentimes a neutral study. And even when studies are positive, they usually have modest absolute benefit,” Greene said. Research should continue, he said, because “we really haven’t hit the silver bullet with a lot of these things, in my opinion.”

Desai stressed the importance of continuing to look for ways to get patients on GDMT, noting that “medical optimization pays really substantial dividends for patients.” Similar therapies are proving themselves for patients who have heart failure with preserved ejection fraction, too, and additional classes of medications, like the glucagon-like peptide-1 receptor agonists, may be helpful in the HF population as well, he added.

“We are starting to evolve a systematic approach to therapy for patients with heart failure across the EF spectrum, and I think the patients will benefit if clinicians begin to feel the urgency and implement the data that’s increasingly driven by the evidence in clinical practice,” Desai said.

The discussion should go in a positive direction, he said. “We spend a lot of time in heart failure talking about the gaps in therapy, and the message has almost become a little tired and clinicians are feeling a little browbeaten by the message, which is that we just aren’t doing what we should be doing. I think it’s time to move the conversation forward [and start] thinking about ways in which we can partner with payers, partner with allied colleagues in nursing and pharmacy, partner with healthcare systems and institutions to solve this problem.”

Fonarow pointed out that HFrEF, despite having a poor prognosis on par with some malignancies, isn’t handled with the same urgency, even with several well-tolerated, effective medications that cost substantially less than cancer therapies. “There’s just this dramatic contrast in the way heart failure patients are approached,” he said.

Indeed, Zieroth said, “we have disease-modifying therapies and devices now that can improve their outcomes and improve their quality of life and we need to create the moon shot for heart failure as much as we do the moon shot for cancer care.”