It’s as if hospitals, clinicians, and the healthcare system itself were unprepared for such success as a powerful multiple-drug regimen emerged for hospitalized patients with heart failure with reduced ejection fraction (HFrEF).
Uptake in practice has been sluggish for the management strategy driven by a quartet of medications, each with its own mechanisms of action, started in the hospital simultaneously or in rapid succession over a few days. Key to the regimen, dosages are at least partly uptitrated in the hospital then optimized during close post-discharge follow-up.
The so-called four pillars of medical therapy for HFrEF, defined by a left ventricular ejection fraction (LVEF) of 40% or lower, include an SGLT2 inhibitor, a beta blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin-system (RAS) inhibitor — preferably sacubitril-valsartan (Entresto) or, as a backup, an ACE inhibitor or angiotensin receptor blocker (ARB).
Academic consensus on the strategy is strong. The approach is consistent with heart failure (HF) guidelines on both sides of the Atlantic and is backed by solid trial evidence suggesting striking improvements in survival, readmission risk, and quality of life.
In HFrEF, the four medications “clearly reduce all-cause mortality, are nonoverlapping and truly and fully additive, and their benefits are cumulative, incremental, and begin within days,” Gregg C. Fonarow, MD, University of California, Los Angeles, Medical Center, told theheart.org | Medscape Cardiology.
“Yet, when we look at their actual implementation in clinical practice, we’ve seen this slow and variable uptake.”
So, Why Is That?
The STRONG-HF trial tested a version of the multiple-drug strategy and demonstrated what it could achieve even without a contribution from SGLT2 inhibitors, which weren’t yet indicated for HF. Eligibility for the trial, with more than 1000 patients, wasn’t dependent on their LVEF.
Patients assigned to early and rapidly sequential initiation of a beta blocker, an MRA, and a RAS inhibitor, compared to a standard-care control group, benefited with a 34% drop (P = .002) in risk for death or HF readmission over the next 6 months.
Few doubt ― and the bulk of evidence suggests ― that adding an SGLT2 inhibitor to round out the four-pillar strategy would safely boost its clinical potential in HFrEF.
The strategy’s smooth adoption in practice likely has multiple confounders that include clinical inertia, perceptions of HF medical management as a long-term outpatient process, and the onerous and Kafkaesque systems of care and reimbursement in the United States.
For example, the drug initiation and uptitration process may seem too complex for integration into slow-to-change hospital practices. And there could be a misguided sense that the regimen and follow-up must abide by the same exacting detail and standards set forth in, for example, the STRONG-HF protocol.
But starting hospitalized patients with HFrEF on the quartet of drugs and optimizing their dosages in hospital and after discharge can be simpler and more straightforward than that, Fonarow and other experts explain.
The academic community’s buy-in is a first step, but broader acceptance is frustrated by an “overwhelming culture of clinical care for heart failure” that encourages a more drawn-out process for adding medications, said Stephen J. Greene, MD, Duke Clinical Research Institute, Durham, North Carolina. “We need to turn our thinking on its head about heart failure in clinical practice.”
The “dramatic” underuse of the four pillars in the hospital stems in part from “outmoded” treatment algorithms that clinicians are following, Fonarow said. And they have “no sense of urgency,” sometimes wrongly believing “that it takes months for these medications to ultimately kick in.”
For hospitalized patients with HFrEF, “there is an imperative to overcome these timid algorithms and timid thinking,” he said. They should be on “full quadruple therapy” before discharge.
“And for newly diagnosed outpatients, you should essentially give yourself 7 days to get these drugs on board,” he added, either simultaneously or in “very rapid sequence.”
What’s needed is a “cultural shift” in medicine that “elevates heart failure to the same level of urgency that we have in the care of some other disease states,” agreed Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital and Harvard Medical School, Boston.
Hospital as Opportunity
The patient’s 4 to 7 days in the hospital typically represent a “wonderful opportunity” to initiate all four drug classes in rapid succession and start uptitrations. But most hospitals and other healthcare settings, Vaduganathan observed, lack the structure and systems to support the process. Broad application will require “buy-in from multiple parties — from the clinician, from the patient, their caregivers, and their partners as well as the health system.”
Physician awareness and support for the strategy, suggests at least one of these experts, is probably much less of a challenge to its broad adoption than the bewildering mechanics of healthcare delivery and reimbursement.
“The problem is not education. The problem is the way that our healthcare system is structured,” said Milton Packer, MD, Baylor Heart and Vascular Institute, Dallas, Texas.
For example, sacubitril-valsartan and the SGLT2 inhibitors are still under patent and are far more expensive than longtime generic beta blockers and MRAs. That means physicians typically spend valuable time pursuing prior authorizations for the brand-name drugs under pressure to eventually discharge the patient because of limits on hospital reimbursement.
Clinicians in the hospital are “almost disincentivized by the system” to implement management plans that call for early and rapid initiation of multiple drugs, Vaduganathan points out.
One Change per Day
There’s no one formula for carrying out the quadruple drug strategy, Vaduganathan noted. “I make only a single change per day” to the regimen, such as uptitration or addition of a single agent. That way, tolerability can be evaluated one drug at a time, “and then the following day, I can make the next therapeutic change.”
The order in which the drugs are started mostly does not matter, in contrast to a traditional approach that might have added new drugs in the sequence of their approval for HFrEF or adoption in guidelines. Under that scenario, each successive agent might be fully uptitrated before the next could be brought on board.
Historically, Packer observed, “you would start with an ACE inhibitor, add a beta blocker, add an MRA, switch to sacubitril-valsartan, add an SGLT2 inhibitor — and it would take 8 months.” Any prescribed sequence is pointless given the short time frame that is ideal for initiating all the drugs, he said.
Hypothetically, however, there is some rationale for starting them in an order that leverages their unique actions and side effects. For example, Vaduganathan and others observed, it may be helpful to start an SGLT2 inhibitor and sacubitril-valsartan early in the process, because they can mitigate any hyperkalemia from the subsequent addition of an MRA.
That being said, “I don’t think we have firm evidence that any particular order is more efficacious than another,” Vaduganathan said. “It’s really about getting patients on all four drugs as quickly as possible, regardless of the sequence.”
Discussions about sequencing the drugs are “a distraction for our field,” Greene said. In trials, clinical benefit from the multiple-drug regimen has emerged almost right away once the drugs were on board. “The data clearly show that initiating all four, at least at low doses, gives the best bang for your buck and would be a high-yield strategy.”
Best evidence suggests that once all four agents have been started, attention can turn to uptitration, “with the beta blocker as the higher priority,” Green said. “The bottom line is to keep it simple: four drugs, simultaneously or within 1 week, and prioritize initiation at low doses to maximize tolerability.”
The four-drug approach yields survival and rehospitalization benefits even when uptitrations don’t reach prespecified goals, Fonarow observed. The SGLT2 inhibitors are started and maintained at the same dosage. But for the other three agents, uptitration should aim for the highest well-tolerated level, up to the target, even if the highest tolerated is the initial dosage.
“Challenging to Generalize”
The goal in STRONG-HF was to start and at least partly uptitrate a beta blocker, an MRA, and sacubitril-valsartan in the hospital and fully optimize their dosages within 2 weeks after discharge. Symptoms and laboratory biomarkers, including natriuretic peptides, were closely monitored at four in-person evaluations during the first 6 outpatient weeks.
But few believe the trial’s intensive drug regimen and post-discharge follow-up, as stipulated in the protocol, would be tolerated by current systems of care and reimbursement.
STRONG-HF “affirms the strategy in a rigorous, well conducted way,” Vaduganathan said, but would be “challenging to generalize to all healthcare systems.”
As a result, some in the field are “quick to almost disregard STRONG-HF in its entirety” and consider it “wishful thinking,” Greene said. Better that providers not become distracted by the precise details of its protocol.
At Duke, he said, “we see all our patients within 1 week of discharge to ensure they’re doing okay in terms of volume status and look for opportunities to escalate their guideline-directed medical therapy.”
But that can be done without in-person visits. A lot of the follow-up and uptitrations, Greene said, can be achieved by telephone or at virtual appointments in conjunction with regular laboratory testing. “That, I think, really is the path for the future, in this age when clinics are overwhelmed by in-person visits.”
Mildly Reduced and Preserved EF
STRONG-HF, in which patients were enrolled without regard to ejection fraction, suggests that its rapidly sequential drug regimen and intensive management protocol improves outcomes for patients with HF at any level of LVEF.
Those findings and others, along with DELIVER, EMPEROR-Preserved and other studies, make a tantalizing case for the quadruple drug approach in patients with HF and LVEF >40% ― that is, those with mildly reduced (LVEF >40% to <50%, HFmrEF) or preserved LVEF >50%, HFpEF) ejection fraction.
But the case isn’t solid enough to declare the four agents as core therapy for HF and LVEF >40%, observed Vaduganathan. Currently, SGLT2 inhibitors “are the only drug class that we are routinely implementing” in HFmrEF and HFpEF.
There have been suggestions of clinical benefit for such patients with sacubitril-valsartan and MRAs, especially in PARAGON-HF and TOPCAT, respectively. The evidence is stronger in HFmrEF than in HFpEF, but in either case it’s weaker than the clear-cut trial support for SGLT2 inhibitors in those HF categories.
Trials also suggest that in HF with LVEF >40%, clinical benefits from RAS inhibitors and MRAs taper off with increasing ejection fraction, especially into the >60% range.
In both HFmrEF and HFpEF, “I routinely try to get the patient on an SGLT2 inhibitor rapidly and then treat with some of the other agents on a more individual basis,” Vaduganathan said. An LVEF in the HFmrEF range, for example, would likely call for the addition of an MRA and sacubitril-valsartan.
Packer said he would likely recommend all four agents for patients with HF and LVEF up to 60%, which he considers a more appropriate definition of HFrEF. Their clinical benefits appear consistent across that LVEF range, he said, although they thin out somewhat at the higher end.
Evidence supporting the four pillars in HF with LV >40 and <60% is weakest for beta blockers, Packer noted, so arguably those drugs could be left out of the mix for patients with ejection fractions in that range.
Fonarow reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer. Greene discloses receiving research support from Amgen, AstraZeneca, Bristol-Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; serving on advisory boards or as consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Lilly, Bristol-Myers Squibb, Corteria, CSL Vifor, Cytokinetics, Lexicon, Roche Diagnostics, Merck, PharmaIN, Sanofi, scPharmaceuticals, Tricog Health, and Urovant Pharmaceuticals; and receiving speaker fees from Bayer, Boehringer Ingelheim, Cytokinetics, Lexicon, and Roche Diagnostics. Vaduganathan discloses receiving grant support, serving on advisory boards, or speaking for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and serving on committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Packer discloses relationships with 89bio, AbbVie, Actavis, Amarin, Amgen, AstraZeneca, Attralus, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacosmos, Reata, Regeneron, Relypsa, and Salamandra.
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