Optimizing Heart Failure Therapies During Hospitalization

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Circulation

Circulation. 2023;147:1189–1191. DOI: 10.1161/CIRCULATIONAHA.122.063811 April 18, 2023 1189

PERSPECTIVE

STRONG-HF and Implementing Heart Failure Therapies: Godspeed … With Care

Javed Butler , MD, MPH, MBA; Khawaja M. Talha , MBBS; Gregg C. Fonarow , MD

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apid optimization of quadruple foundational therapy for heart failure (HF) with reduced ejection fraction comprising β-blockers, angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotrans- porter-2 inhibitors has been advocated recently. HF hospitalization has been identified as an optimal time for initiation and uptitration of medications, not only because the patients are at a high risk but also because this encounter occurs in a setting of close surveillance under the care of a team of clinicians that lasts several days, all facilitating rapid initiation and titration of therapy. Transitions of care are associated with a potential for loss to follow-up or lack of prescription of therapies that were planned but not initiated in the hospital. Both the American and European guidelines recommend in- hospital initiation of guideline-directed medical therapy and multiple experts have proposed algorithms for rapid initiation and titration of these drugs.

STRONG-HF (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies)¹ was an open-label, randomized trial that evaluated the effectiveness of intensive care versus usual practice for the initiation and uptitration of HF medications after hospitalization. Partici- pants in the intensive care group underwent uptitration of therapies to recommended dosing within 2 weeks of discharge and were followed over 2 months with at least 4 outpatient visits for close assessment. At 90 days, a higher proportion of patients in the high-inten- sity group had been uptitrated to recommended doses (renin-angiotensin antagonists, 55% versus 2%; β- blockers, 49% versus 4%; MRA, 84% versus 46%). A significant reduction in HF hospitalizations or all-cause

death was reported in the intensive care group (15.5%

versus 23.3%; adjusted risk difference, 8.1%; risk ratio, 0.66 [95% CI, 0.50, 0.86]). At 90 days, there was a higher incidence of adverse events in the intensive care group (41% versus 29%) including hypotension (5%

versus <1%), hyperkalemia (3% versus 0%), and renal impairment (3% versus <1%). However, the risk of serious adverse events was similar in both groups (16%

versus 17%).

The findings of this trial have important implications for clinical practice. The study provides randomized evi- dence to support the notion that an approach to initiate and optimize HF therapy rapidly with close follow-up is superior to usual practice where there is a lag in or absence of drug optimization and patients are not moni- tored as closely.

The results of this trial should be embraced by the clinical community as they underscore the importance of timely use of guideline-directed medical therapies for HF. However, appropriate caution in its implementation should be exercised. A pertinent example is that of the RALES trial (Randomized Evaluation of Aldac- tone Study)² that evaluated the effectiveness of spironolactone in HF with reduced ejection fraction. The study was stopped early for efficacy because spironolactone reduced the risk of all-cause mortality (relative risk, 0.70 [95% CI, 0.60, 0.82]) and HF hospitalizations (relative risk, 0.65 [95% CI, 0.54, 0.77]). MRAs have a risk of hyperkalemia if not managed appropriately. The RALES study found low rates of serious hyperkalemia in the spironolactone (14 events [2%]) and placebo (10 events [1%]) groups, which may be attributable to the use of study protocol–guided doses and close surveillance in a trial setting.

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

Correspondence to: Javed Butler, MD, MPH, MBA, Baylor Scott and White Research Institute, 3434 Live Oak St, Dallas, TX 75204. Email [email protected] For Sources of Funding and Disclosures, see page 1191.

Key Words: heart failure ◼ mineralocorticoid receptor antagonists ◼ therapeutics

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April 18, 2023 Circulation. 2023;147:1189–1191. DOI: 10.1161/CIRCULATIONAHA.122.063811 1190

Butler et al STRONG-HF Implementation

Juurlink et al³ subsequently analyzed prescription rates of MRA and hospitalizations and deaths attributable to hyperkalemia before and after the RALES publication using a population-based database of hospitalized patients ages >65 years in Canada. The prescription rate of MRA was relatively constant among patients hospitalized for HF from 1994 to 1999 but increased 5-fold after the RALES publication. This increase in MRA use was accompanied by a 3-fold increase in the risk of hyperkalemia-related hospitalizations and deaths. The authors postulated that the findings could be explained by a lack of close monitoring of serum potassium levels and dif- ferences in patient characteristics that may predispose patients to hyperkalemia-related events; however, details of such data were not reported. Shah et al.⁴ performed a retrospective analysis of monitoring patterns for serum potassium level and renal function in patients with HF who were prescribed spironolactone after the publication of the RALES trial and showed that one-third of patients who were prescribed spironolactone did not undergo laboratory testing in the first 3 months after initiation. Of those who did, 15% developed hyperkalemia and 6%

developed severe hyperkalemia within 3 months, compared with a hyperkalemia incidence of 2% reported in the spironolactone arm of the RALES trial over 2 years.

These findings highlight that the RALES trial may have grossly underestimated the risk of spironolactone-asso-

ciated hyperkalemia and that a substantial proportion of patients do not undergo laboratory surveillance after initiation of spironolactone in routine practice.

These data remind clinicians that in the absence of individualization of therapeutic approach and close monitoring, medical therapy may cause harm. Although MRAs have been shown to be implemented safely with appropriate monitoring, the aforementioned studies had a great effect on practice and MRAs continue to be underpre- scribed because of fear of hyperkalemia. The CHAMP- HF registry (Change the Management of Patients with Heart Failure)⁵ recently reported that only 33% of the eligible ambulatory HF population in the United States were prescribed an MRA, compared with 73% and 67%

of patients prescribed renin-angiotensin antagonists and β-blockers, respectively.

The STRONG-HF trial findings likely will be followed by recommendations for an aggressive approach to initiate and uptitrate therapy during and after hospitalization. If done as in the trial, this approach can be expected to improve outcomes. However, similar to the RALES trial and its subsequent community-level uptake, safety reported in the STRONG-HF trial was in the context of a specific trial protocol (Figure). The STRONG-HF trial provides a framework for implementation of HF therapies and in-hospital initiation of foundational medical therapy recommended by guidelines,

FRAME OF REFERENCE

Figure. Illustration of the trial protocol, baseline characteristics, and main findings of RALES and its subsequent population- wide implementation.

The effects of the population-level implementation of the STRONG-HF trial (Safety, Tolerability, and Efficacy of Rapid Optimization, helped by NT-proBNP Testing, of Heart Failure Therapies) are yet to be determined. MRA indicates mineralocorticoid receptor antagonist; and RALES, Randomized Aldactone Evaluation Study.

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Circulation. 2023;147:1189–1191. DOI: 10.1161/CIRCULATIONAHA.122.063811 April 18, 2023 STRONG-HF Implementation

1191 Butler et al

yet postdischarge titration needs to be individualized and early follow-up monitoring and care should be emphasized. It is important to implement the learning from the STRONG-HF trial adapted to the patient characteristics as well as the health care setting. Patients with HF have adverse outcomes in large part because of suboptimal care that can be mitigated easily. It will be a travesty if the STRONG-HF trial results are ignored or are implemented recklessly, leading to predictable side effects and intolerances that will set a negative dynamic against rapid guideline-directed medical therapy implementation, which is avoidable. The potential in terms of improved health status, reduction in HF hospitalizations, and lives saved create a call to action for a successful implementation journey globally.

ARTICLE INFORMATION Affiliations

Department of Medicine, University of Mississippi Medical Center, Jackson (J.B., K.M.T.). Baylor Scott and White Research Institute, Dallas, TX (J.B.). Ahmanson- UCLA Cardiomyopathy Center, Division of Cardiology, University of California Los Angeles (G.C.F.).

Sources of Funding

None.

Disclosures

Dr Butler is a consultant to Abbott, Adrenomed, American Regent, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, CVRx, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, and Vifor. Dr Fonarow is a consultant to Abbott, Amgen, AstraZeneca, Bayer, Cyto- kinetics, Eli Lilly, Janssen, Medtronic, Merck, Novartis, and Pfizer. K.M. Talha has no disclosures.

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