Four Pillars, Fast? Rapid Sequencing of HF Drugs Faces an Uphill Battle

No other aspect of cardiology research has seen as many blockbuster trials over the last decade as heart failure, even as the total number of patients afflicted continues to rise. Since the range of new therapeutic options all act on different disease pathways, leading physicians now propose that the four “foundational” drugs should be rapidly—even simultaneously—initiated. They say this “four-pillar” approach, especially if it’s applied when a patient is first diagnosed in the hospital, will radically curb deaths and rehospitalizations in the burgeoning population of heart failure patients with reduced ejection fraction (HFrEF).

The problem? Despite all the theoretical reasons why rapid sequencing of all four drugs should work, it has never actually been tested. And there’s no broad agreement on how swiftly, and in what order, this sequencing should be done.

Gregg Fonarow, MD (University of California, Los Angeles), first took the stage at the 2020 Heart Failure Society of American meeting last year to propose that all four guideline-directed medical therapies (GDMT)—an angiotensin receptor-neprilysin inhibitor (ARNI), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a sodium-glucose cotransporter 2 (SGLT2) inhibitor—should be started simultaneously, or as close to that as possible.

But speaking with TCTMD last week, he acknowledged that such a strategy has not been studied: the newer agents were tested on a background of “standard” therapy, typically ACE inhibitors and beta-blockers. “There has not been a trial that has said, compared to delaying all of these therapies, we'll start them all simultaneously,” Fonarow admitted.

Instead, there has been a “layered approach” in all of the pivotal trials that paved the way for the newer agents. PIONEER-HF, he pointed out, randomized patients already taking beta-blockers and MRAs to early initiation of sacubitril/valsartan (Entresto; Novartis) versus enalapril. The SOLOIST trial tested the SGLT1/2 inhibitor sotagliflozin (Zynquista; Sanofi Aventis/Lexicon—not yet approved in the United States) in hospitalized patients with diabetes and acute HF who were already taking beta-blockers, diuretics, and renin-angiotensin-aldosterone system (RAAS) inhibitors. In both trials, Fonarow stressed, benefits were seen within the first 30 days and continued to accrue.

“We have seen the incremental benefits, and we know they're safe and well-tolerated,” he noted.

Fonarow cited a paper he co-authored last year, led by Muthiah Vaduganathan, MD (Brigham and Women’s Hospital, Boston, MA), and published in the Lancet. In it, the authors acknowledge that the newer drug classes were studied against different background therapies, so the benefits of using them in tandem are not known. Combining data from the pivotal EMPHASIS-HF, PARADIGM-HF, and DAPA-HF (of an MRA, ARNI, and SGLT2 inhibitor, respectively), their analysis suggested that the aggregate treatment effects of all three agents on top of long-standing, conventional care could extend survival up to 6 years, while also reducing hospital admissions.

“We're really talking about a substantial extension of life with this approach and getting started as soon as possible to begin getting those quality years back is so important,” Fonarow said.

Stephen Greene, MD (Duke Clinical Research Institute, Durham, NC), agreed, noting that inclusion criteria for the recent HFrEF trials specified that patients be “on good background therapy of preexisting, approved GDMTs.” That said, he conceded, “there's been no trial of a simultaneous approach versus a conventional approach.” Yet Greene also pointed out that there is no evidence background therapy alters the efficacy of the newer therapy, adding that these subgroup analyses have been done: “An SGLT2 inhibitor works just as well in terms of relative risk reduction for mortality and hospitalization whether the patient is on an ARNI or not on an ARNI, whether they're on a beta-blocker or not on a beta-blocker.”

Moreover, as Fonarow, Greene, and Javed Butler, MD (University of Mississippi Medical Center, Jackson), observe in a viewpoint published in JAMA Cardiology earlier this year, a similar approach to what they are proposing is already the norm when a patient is hospitalized with an acute MI.

“A garden-variety STEMI patient might be in hospital for 2 to 5 days,” said Greene, “and in that short period of time, aside from the statin and the dual antiplatelet therapy, we're going to start pretty routinely an ACE inhibitor, a beta-blocker, and an MRA, all before the patient goes home. And that's a very compressed time line.”

Different Approaches

The past year has witnessed a flurry of proposals for how to initiate all four drugs, stat, with a shift away from getting one agent to full strength before adding another.

In their viewpoint, Greene and colleagues propose that all four drugs be initiated on day one of a HF hospitalization, at low doses for the ARNI, beta-blocker, and MRA (the SGLT2 inhibitor being a standard dose). In their pitch, uptitration of the beta-blocker is given priority. “This strategy could be tested in randomized clinical trials, but available evidence suggests the benefits of this strategy outweigh the risks,” they write.

We're really talking about a substantial extension of life with this approach and getting started as soon as possible to begin getting those quality years back is so important. Gregg Fonarow

Other HF heavyweights Milton Packer, MD (Baylor Heart and Vascular Institute, Houston, TX), and John McMurray, MD (University of Glasgow, Scotland), who led many of the field’s major trials of the past decade, have also advocated for starting patients on all four foundational HF drugs within 2 to 4 weeks.

They laid out their “three-step” formula in Circulation in late 2020 and fleshing it out in the European Journal of Heart Failure this past summer. Their recommendation? Begin with simultaneous initiation of a beta-blocker and an SGLT2 inhibitor and within 2 weeks start an ARNI (or, if hypotension is a concern, start with valsartan alone before switching to the combination drug). Next, layer on the MRA such that all four drugs are initiated within 4 weeks, and only then increase the dose of each drug towards the target dose as tolerated.

Yet another proposal for rapid sequencing was set out by Klaus Witte, MD (University of Leeds, England), and colleagues in the BMJ in March 2021. For most patients, they write, low-dose ARNI and an SGLT2 inhibitor are the best place to start, followed within a few days by a low-dose beta-blocker and MRA, and then uptitrated. “While others have suggested that initiation with beta-blocker alongside SGLT2 inhibitor might be more optimal,” they write, “we believe that the exact sequence of initiation is unimportant, as long as all four pillars are introduced within the first few weeks of diagnosis.”

That’s all well and good, but none of these strategies are backed up by data, Nathan Mewton, MD, PhD (Hôpital Cardio-Vasculaire Louis Pradel, Lyon, France),  stressed to TCTMD. “I'm convinced that all patients should be on four drugs, because each drug actually has a specific pathophysiologic pathway targeted, so that's my personal conviction. But what I'm much more reluctant to consider is everybody giving his or her recipe for how to do it when they haven't tested it. With this, I'm not that comfortable.”

What’s notable is that many of the voices calling for more-rapid initiation of the newer, more-expensive agents on top of the older generics are the clinical trialists who led to pivotal studies; they have a vested interest in seeing these agents succeed, but they also understand the drugs and benefits more intimately than their peers. On the other hand, notes Mary Norine Walsh, MD (St. Vincent Heart Center, Indianapolis, IN), “some of the clinical trial leaders have less current experience in busy clinics and on busy inpatient services. They’re not dealing with the day-to-day barriers as much as others are.”

Explaining the Status Quo

What all of the four-pillar proposals seem to agree on is that the status quo falls short when it comes to getting HFrEF patients on medications proven to help.

“It doesn't matter how many trials we do, it doesn't matter how many guidelines people write, it doesn't matter how many presentations we give at national or international meetings: physicians are not prescribing these drugs,” Packer told TCTMD. “We have spent decades generating evidence, and the evidence is really powerful because it comes from multiple trials for each member of the class of drugs. Yet in clinical practice, the uptake of these drugs is awful. The percentage of patients who are getting all four drugs in the US right now is probably less than 5% or 10%, and the number who are getting these drugs at an appropriate dose is even less than that.”

It doesn't matter how many trials we do, it doesn't matter how many guidelines people write, [or] how many presentations we give at national or international meetings: physicians are not prescribing these drugs. Milton Packer

Even worse, for the minority of physicians who are actually aiming to prescribe the four agents, they are moving much too slowly, Packer continued. “If it takes 6 or 9 months for a physician to prescribe the four foundational drugs, then during that period of time there are patients who are dying and being hospitalized for heart failure, who would not have died or been hospitalized.”

Mewton agreed. “There's a whole generation of physicians saying: what's the point in getting those drugs added as fast as possible? At least one-third of heart failure specialists are not going to change or budge the way they implement [medications],” he said. “They know that those drugs are effective, but the timing, to them, is not that much of a concern. [They] prefer waiting and doing it slowly, their way.”

Most physicians tend to start patients on HF drugs that are most familiar to them, which typically means the order in which they were developed and approved for use, because the fear of side effects looms large.

“There are many leaders in the field who imagine, I think, because most patients that are referred to them have very advanced heart failure, that the majority of these patients are coming in with blood pressures under 80 and reduced cardiac index,” Fonarow said. “The concept of starting all of these vasoactive-type medications all at once perplexes them a little bit, and there are certainly comorbid conditions [to consider]. But there's never been communication outside of a few passionate individuals of this sense of urgency.”

The Need for Speed

Indeed, most of the recent HFrEF guideline updates are mum on expediency. A 2021 update to the American College of Cardiology’s Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment sticks with the traditional framework of adding agents based largely on their historical usage (beta-blocker, ACE/ARNI, MRA, then SGLT2) within a recommended time frame of 3 to 6 months.

The Canadian Cardiology Society (CCS) heart failure guidelines, released in April 2021, come closest to embracing the rapid, simultaneous approach. They recommend that all four drug classes be started (in the absence of contraindications), that they be titrated “as soon as feasible” after diagnosis, that it’s “reasonable” to aim for concurrent titration, and that the goal is maximal titration within 3 to 6 months. Notably, the CCS document states: “The [writing] committee acknowledges lack of evidence favoring one particular titration strategy for guideline-directed medical therapy (GDMT) over another.”

There's a whole generation of physicians saying: what's the point in getting those drugs added as fast as possible? Nathan Mewton

Released in August, the 2021 European Society of Cardiology heart failure guidelines describe the “cornerstone therapies” in HFrEF as the “triad of an ACE inhibitor/ARNI, a beta-blocker, and an MRA.” And while SGLT-2 inhibitors made their debut in this year’s update, they are recommended for HFrEF patients “already treated” with the other three class I therapies. No mention is made of escalated timing.

“We need to treat heart failure with the sense of urgency it deserves, including leveraging and realizing that the benefits of these drugs start accruing within days to weeks of initiation,” Greene stressed. “Any delay, aside from increasing the risk of the next medication never being started, really exposes your patient to excess risk of death, worsening heart failure, and worsening patient-reported quality of life.”

Prohibitive Costs

As Mewton put it, however, there is a big difference between a patient “on paper” and a patient “in reality,” with major, real-life barriers to getting GDMT prescribed and maintained.

First and foremost are the costs of the medications, said Walsh, along with the tough conversations these warrant—not to mention navigating the labyrinthine pathways to financial assistance for medications.

“To try to go with all four medicines all at once is just rough from a shared decision-making standpoint,” she said. “You can fairly easily get people on an ACE/ARB, beta-blocker, aldosterone-inhibitor, no problem, because they're all generic. But the ARNI, sacubitril/valsartan, and the SGLT2s are not generic and many patients have significant co-pays, which we only find out about in the outpatient setting.”

A recent analysis estimated that annual out-of-pocket costs for SGLT2 inhibitors starts at about $1,000, while another put that amount at $1,600 for ARNIs.

For all the good intentions of starting patients on the four foundational drugs while hospitalized, it’s not uncommon to see a patient again 3 months later only to learn that they dropped their ARNI because they couldn’t afford it, Walsh said.

And it’s not just the cost to individual patients, but their collective cost, Packer observed.

“Many people ask me, why is it so much more difficult for a heart failure drug to get accepted than a drug for cancer? Many drugs, novel drugs, for cancer are really expensive: $200,000, $300,000, $400,000 a year,” he said. By contrast, the novel heart failure drugs, before discounts, cost $4,000 to $6,000 per year. “And the answer is because most cancer drugs that cost tens and hundreds of thousands of dollars have a very small target population, maybe 10,000 or 50,000 or 75,000 people. . . . In contrast, there are 6 million people in the United States that have heart failure. The insurers do the math.”

For this reason, third-party payers may require cumbersome preauthorization requirements, Packer noted, and physicians aren’t paid to prescribe drugs. “If that preauthorization form is six pages long, and you have to do it for every patient that you have with heart failure, you're not going to do that,” he said, “because filling out those forms costs you money.”

To try to go with all four medicines all at once is just rough from a shared decision-making standpoint. Mary Norine Walsh

“Prior authorization and co-pay issues are huge,” Walsh agreed. When sacubitril/valsartan first came out, the amount of time spent on the paperwork for the heart failure nurses at her hospital was the equivalent of a half-day’s work. And while that paperwork has eased, there remain some patients with a Medicare supplement that doesn’t cover as much as other plans, and “there are many patients who are paying full freight for drugs,” she added. “Some of these practical things are really important.”

You can’t simply tell patients they need to be on four or five medications without understanding the implications of cost, said Walsh.

Other Barriers

Despite financial barriers, costs alone don’t fully explain physician inertia, said Greene.

“Cost is certainly an issue, particularly for our newer therapies, but at the same time, we need to recognize that the gaps in use,” he said. “And this clinical inertia where we have very few medication changes over time, it’s really applied to the spectrum of evidence-based HFrEF therapies, including our generic older therapies.”

The CHAMP-HF registry showed that only two out of three patients eligible for an MRA in the United States actually get the drug, only one in three are prescribed a beta-blocker, and the number is even lower for ACE/ARB/ARNI, Greene said. “While certainly costs will remain a barrier for certain patients and certain therapies, I think the overwhelming evidence suggests that we can do better and a lot of that is on clinicians and also patient education, independent of cost barriers.”

Setting also plays a key role, Walsh noted. It’s one thing to initiate a host of new medications while a patient is in the hospital, with an entire team focused on optimizing patient care, including physicians, pharmacy, labs, nurses, and social workers, but initiating all four drugs in the outpatient setting is a completely different ballgame.

We just can't [lapse] into that sense of complacency or lose our sense of urgency for at least trying a medication that's proven to help them. Stephen Greene

“We're very aggressive,” Walsh said. “We push hard. But I have yet to prescribe, in the outpatient setting, more than one drug [at a time].” Even “back in the day,” she said, “I didn’t even prescribe an ACE and a beta-blocker at the same time,” because patient uptake was so poor.

“I think it's really important to remember that every patient's different, every situation is different,” she said. It’s one thing to start a single, new agent and deal with an adverse reaction. “But if you've started a lot of drugs all at the same time, and the patient has some type of side effect that is it's very untoward and they can't continue on, [then] you have no idea where you are.”

Moreover, she said, while GDMT was the comparator for all of the big trials forming the basis for this new, four-pillar approach, none of those studies ensured that patients were optimized on all available agents prior to randomization. The much smaller COAPT trial, she noted, was an outlier in this regard in that patients had to be maxed out on medical therapy to be considered for a MitraClip (Abbott). As such, it remains an open question whether side effects would loom larger when all HFrEF medications are prescribed; it’s also plausible that benefits demonstrated in the trials will be smaller when background therapy is maximized. 

Physicians should keep, as a goal, getting to maximum doses of the four cornerstone drugs, plus or minus ivabradine (Corlanor; Amgen), though how fast that’s done and in what setting needs to be individualized to the patient, Walsh said. The key is to ensure that the delay between agents isn’t weeks or months, she stressed, but days. In her practice, uptitration is done by phone within days of the initial dosing.

Mewton urged physicians to rethink patient visits: “We must challenge ourselves every time and get rid of this false idea that the ‘patient seems stable.’ Heart failure is everything but a stable disease. We should try to challenge our therapies, drug prescriptions, instructions, and encouragements at each visit with the patient.” He says he now challenges himself at every appointment and has changed the name of the appointments from “HF consults” to “HF optimizations.”

The Path Forward

Many, like Fonarow, Greene, and Packer, believe that physicians can do a better job of explaining the risks of heart failure to their patients and peers—particularly the nonspecialists.

The risk of dying or being rehospitalized after an initial heart failure hospitalization is 50% within the first 100 days, said Fonarow. With coronary heart disease, “people talk about being at ‘intermediate’ risk if your risk is between 1% and 2% per year, for any type of event,” he said. With heart failure, “we're talking about one in two patients in the first hundred days. It’s phenomenal. It’s off the scale.”

The hospital admission, said Greene, should serve as a reminder that heart failure is serious and potentially lethal, which makes it an opportune moment to be aggressive with medications.

“Both clinicians and patients can get this false sense of security when they see an outpatient is NYHA class II and they haven't been in the hospital recently and they are feeling okay,” Greene said. “That ignores the fact that sudden death is one of the number-one reasons for death in stable heart failure patients and also just the inherently high-risk these patients face despite stable symptoms. We just can't [lapse] into that sense of complacency or lose our sense of urgency for at least trying a medication that's proven to help them.”

In the years to come, when more of the newer agents are generic, many of the cost barriers will fade. That might open the door to a polypill approach, along the lines of those trialed in hypertension and primary prevention, which would help with polypharmacy, several experts told TCTMD.

For now, said Walsh, it’s important to bring patients into the decision-making. “I have a pitch that I tell patients which is: ‘Eventually this will be generic, but it's not today. This medication, compared to the one you’re on, will help you live longer, stay out of the hospital, and feel better. And those are all really important things, we agree, don't we? Yes.’ And then we say, okay, here we go.”

In the meantime, trials that address physician inertia and pave the way for swift or simultaneous prescribing—and show the benefit of doing so—will be critical.

Mewton said he’s applied for funding for a clinical trial that would test the rapid sequencing of all four drugs at low doses with the aim of tracking NT-proBNP reductions and drug status/adherence at 2 months. Here, he explained, the order or “recipe” in which they are layered is less important than seeing whether physicians prove successful in getting patients on all four foundational drugs swiftly, then uptitrating to maximal doses. That, in and of itself, be a “quite significant” achievement, he said. 

Walsh advocates for a collaborative approach involving pharmacy and nursing, in particular, and patient-centric algorithms to make sure that follow-up goes to plan, guided by lab results as needed. “I’ve always been a firm believer in team-based care,” said Walsh, “and this is where team-based care and algorithms that we set up with physician oversight can really drive us away from that therapeutic inertia and toward the goal of getting not just all four or five drugs started, but at max-tolerated doses.”

Packer made the case for a different kind of clinical trial than the high-profile investigational drug trials that have packed conference rooms and made headlines in heart failure over the last decade.

“I think we're spending too much time on evidence generation and we're not spending enough time on implementation,” Packer said bluntly. “We are spending enormous amounts of money doing large-scale trials and these large-scale trials are wonderful, they're amazing. And when they show a positive result, there's a real celebration.

“But it’s physicians and academics that are doing the celebrating,” he continued. “Are patients benefiting? Are they celebrating? Are they actually getting these drugs? And the answer is no, they're not, they're not getting drugs. And so there's a major disconnect between this celebration at a meeting and the celebration at a patient level in the physician's office and at the patient’s home, where they can spend time quality time with their family, for long periods of time. That's where the celebration needs to occur.”

That doesn’t mean there isn’t a need for new drugs, said Mewton. “If you look at all the recent trials with SGLT2 inhibitors and [other] successful drugs, in the intervention groups, patients are still dying and still having HF decompensations,” he said. There means there’s still room for new research, and new agents. “New therapies just push the boundaries further; they don’t erase them. For me, all these new drugs are like new colors on my painter’s palette. The more colors we have, the more opportunities we’ll have for personalized medicine.”