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Clinicians who prescribe heart failure meds are holding the best hand they’ve ever had, but with so much underuse and suboptimal dosing in actual practice, it seems many may not appreciate the value of their cards. But a major randomized trial that has captured the field’s attention may embolden them to go all in.

Results showed that a strategy of early, rapid uptitration of multiple guideline-directed meds in patients hospitalized with heart failure, compared with a usual-care approach, cut their 6-month risk for death or HF readmission by a steep 34% (P = .002).

The drugs had been started and partly uptitrated in the hospital with the goal of full uptitration within 2 weeks after discharge.

Patients well tolerated the high intensity, researchers said. Their quality-of-life scores improved (P < .0001) compared to the usual-care group, and adverse events were considered few and manageable in the international trial with more 1000 patients.

Safety on the high-intensity strategy depended on close patient monitoring at frequently planned clinic visits along with guidance for the uptitrations from clinical signs and natriuretic peptide levels, observed Alexandre Mebazaa, MD, zolpidem prescription PhD, University of Paris and Public Hospitals of Paris, France.

Mebazaa is principal investigator on the trial, called STRONG-HF, which he presented November 7 at the American Heart Association (AHA) Scientific Sessions 2022, held in Chicago and virtually. He is also lead author on the study’s same-day publication in The Lancet.

The high-intensity strategy’s superiority emerged early in the trial, which was halted early on the data safety monitoring board’s recommendation, with about 90% of follow-ups completed. The board “felt it was unethical to keep patients in usual care,” Mebazaa said at a press conference.

A Dramatic Change

The next step, he said, will be to educate the heart failure community on the high-intensity care technique so it can swiftly enter clinical practice. Currently in acute heart failure, “very few patients are monitored after discharge and treated with full doses of heart failure therapies.”

Adoption of the strategy “would be a dramatic change from what’s currently being done,” said Martin B. Leon, MD, NewYork-Presbyterian/Columbia University Irving Medical Center, New York City, who moderated the press conference.

Only an estimated 5% of patients with HF in the United States receive full guideline-directed medical therapy, Leon said, “so the generalizability of this strategy, with careful follow-up that has safety involved in it, is absolutely crucial.”

But the potential impact of this high-intensity approach on resource use is unknown, raising questions about how widely and consistently it could be implemented, said Leon, who is not connected with STRONG-HF.

The trial called for in-hospital initiation of the 3 distinct drug classes that, at the time, were the core of guideline-directed HF therapy, with uptitration to 50% of recommended dosage by hospital discharge, and then to 100% within 2 weeks later.

The meds included a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin-system inhibitor (RASI). The latter could be an ACE inhibitor, angiotensin-receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI).

How About a Fourth Drug?

Conspicuously absent from the list, for contemporary practice, was an SGLT2 inhibitor, a class that entered the HF guidelines well after STRONG-HF was designed. They would undoubtedly join the other three agents were the high-intensity strategy to enter practice, potentially changing its complexity and safety profile.

But Mebazaa and other experts don’t see that as a big challenge and would expect a smooth transition to a high-intensity approach that also includes the SGLT2 inhibitors.

STRONG-HF was necessary in part because many clinicians have been “reluctant” to take full advantage of three agents that had been the basis of guideline-directed therapy, he told theheart.org | Medscape Cardiology.

That reluctance stemmed from concerns that beta-blockers might worsen the heart failure, ACE inhibitors could hurt the kidneys, or MRAs might cause hyperkalemia, Mebazaa said. The STRONG-HF high-intensity regimen, therefore, demanded multiple clinic visits for close follow-up.

But the SGLT2 inhibitors “are known to be rather safe drugs, at least much safer than the three others,” he said. So, it seems unlikely that their addition to a beta-blocker, RASI, and MRA in patients with HF would worsen the risk of adverse events.

John G.F. Cleland, MD, PhD, agrees. With addition of the fourth agent, “You may need to be a little bit more careful with renal function, just in that first couple of weeks,” he told theheart.org | Medscape Cardiology. “But I think it would be easy to add an SGLT2 inhibitor into this regimen. And in general, there’s no titration with an SGLT2 inhibitor, so they’ll all be on full dose predischarge.”

Given the drugs’ diuretic-like action, moreover, some patients might be able to pull back on their loop diuretics, speculated Cleland, from the University of Glasgow’s School of Health and Wellbeing, Glasgow, Scotland.

The prospect of a high-intensity strategy’s wide implementation in practice presents both “challenges and opportunities,” Amanda R. Vest, MBBS, MPH, Tufts University School of Medicine, Boston, Massachusetts, told theheart.org | Medscape Cardiology.

“There may be additional challenges in terms of ensuring we avoid hypotension or acute kidney injury in the uptitration phase,” said Vest, who is medical director of her center’s cardiac transplantation program but not connected with STRONG-HF.

“But it also gives us opportunities,” she added, “because there are some patients, especially in that vulnerable postdischarge phase, who are actually much more able to tolerate introduction of an SGLT2 inhibitor than, for example, an ACE inhibitor, ARB or ARNI — or maybe a beta-blocker if they’ve been in a low cardiac-output state.” Effective dosing would depend on “the personalization and skill of the clinician in optimizing the medications in their correct sequence,” Vest said.

“It’s challenging to think that we would ever get to 100% uptitration,” she added, “and even in this excellent study, they didn’t get to 100%.” But as clinicians gain experience with the high-intensity strategy, especially as the SGLT2 inhibitors are included, “I think we can reasonably expect more progress to be made in these uptitration skills.”

No Restrictions on LVEF

The researchers entered 1078 patients hospitalized with acute HF in 14 countries across Africa, Europe, the Middle East, and South America, and randomly assigned them to the high-intensity management strategy or usual care.  

About 60% of the patients were male and 77% were White. There were no entry restrictions based on left ventricular ejection fraction (LVEF), which exceeded 40% in almost a third of cases.

In the high-intensity care group’s 542 patients, the three agents were uptitrated to 50% of the maximum guideline-recommended dosage prior to hospital discharge, and to 100% within 2 weeks after discharge. Symptoms and laboratory biomarkers, including natriuretic peptides, were monitored closely at four planned clinical visits over the following 6 weeks.

The 536 patients assigned to usual care were discharged and managed according to local standards, their meds handled by their own primary care doctors or cardiologists, the published report notes. They were re-evaluated by STRONG-HF clinicians 90 days after discharge.

The number of clinic visits in the first 90 postdischarge days averaged 4.8 in the high-intensity care group and 1.0 for those receiving usual care. Full uptitration was far more likely in the high-intensity care group: 55% vs 2% for RASI agents, 49% vs 4% for beta blockers, and 84% vs 46% for MRAS.

They also fared significantly better on all measured parameters associated with decongestion, including weight, prevalence of peripheral edema, jugular venous pressure, NYHA functional class, and natriuretic peptide levels, the researchers said.

The primary endpoint of 180-day death from any cause or HF readmission was met by 15.2% of the high-intensity care group and 23.3% of usual-care patients, for an adjusted risk ratio (RR) of 0.66 (95% CI, 0.50 – 0.86, P = .0021).

Subgroup analyses saw no significant interactions by age, sex, race, geography, or baseline blood pressure, renal function, or LVEF. Patients with higher vs lower baseline natriuretic peptide levels trend toward better responses to high-intensity care (P = .08)

The COVID Effect

The group performed a sensitivity analysis that excluded deaths attributed to COVID-19 in STRONG-HF, which launched prior to the pandemic. The high-intensity strategy’s benefit for the primary endpoint grew, with an adjusted RR of 0.61 (95% CI, 0.46 – 0.82, P = .0005). There was no corresponding effect on death from any cause (P = .15).

Treatment-related adverse effects in the overall trial were seen in 41.1% of the high-intensity care group and in 29.5% of those assigned to usual care.

The higher rate in the high-intensity care arm “may be related to their higher number of [clinic] visits compared to usual care,” Mebazaa said. “However, serious adverse events and fatal adverse events were similar in both arms.”

Cardiac failure was the most common adverse event, developing in about 15% in both groups. It was followed by hypotension, hyperkalemia, and renal impairment, according to the published report.

Cleland cautioned that the risk of adverse events would potentially be higher should the high-intensity strategy become common clinical practice. The median age in STRONG-HF was 63, which is “10 to 15 years younger, on average, than the population with recently admitted heart failure that we see. There’s no doubt that older people have more multimorbidity.”

STRONG-HF was funded by Roche Diagnostics. Mebazaa discloses receiving grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics; honoraria for lectures from Roche Diagnostics, Bayer, and Merck, Sharp & Dohme; and consulting for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and to being a co-inventor on a patent involving combination therapy for patients having acute or persistent dyspnea.

Vest reports modest relationships with Boehringer Ingelheim, Corvia, and CareDx; and receiving research grants from the American Heart Association and the National Institutes of Health. Cleland discloses receiving honoraria from Idorsia; and research grants from Vifor Pharma, Medtronic, Bayer, and Bristol-Myers Squibb. Leon had no disclosures.

American Heart Association Scientific Sessions 2022: Featured Science 4, Emerging Heart Failure Science. STRONG-HF: Successful Post-Discharge Management of Heart Failure. Presented November 7, 2022.

The Lancet. Published online November 7, 2022. Abstract

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org, follow us on Twitter and Facebook.

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