Implementing medical therapy during worsening heart failure

Graphical Abstract

Medical therapy to reduce risks during and after worsening HF

AMI, acute myocardial infarction; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction; NPs, natriuretic peptides

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This editorial refers to ‘In-hospital initiation of angiotensin receptor–neprilysin inhibition in acute heart failure: the PREMIER trial’, by A. Tanaka et al., https://doi.org/10.1093/eurheartj/ehae561.

Heart failure (HF) is a relapsing and remitting syndrome characterized by intermittent episodes of worsening HF, which often require acute care and result in hospitalization. Worsening HF episodes are prognostically important and increase the likelihood of cardiovascular death in patients across the spectrum of left ventricular ejection fraction (LVEF). Recently, several new pharmacotherapies have been evaluated and found to be effective in improving clinical outcomes among chronic, ambulatory HF populations. These therapies, including sacubitril/valsartan, mineralocorticoid receptor antagonists (MRA), and sodium-glucose-co-transporter (SGLT) inhibitors, have shown broad efficacy even at higher LVEF ranges. Secondary analyses from these trials have established that patients enrolled in the hospital or shortly thereafter might derive greater absolute benefits from these therapies.^1–3 These observations have raised interest in whether such therapies should be routinely implemented earlier in the trajectory of worsening HF, even during an worsening HF hospitalization. For example, in the PIONEER-HF⁴ trial enrolling hospitalized patients with HF and reduced ejection fraction (HFrEF), treatment with sacubitril/valsartan during worsening HF episodes lowered natriuretic peptide levels and improved clinical outcomes. Pooled data with the adjacent HF with mildly reduced or preserved ejection fraction (HFmrEF or HFpEF) population in PARAGLIDE-HF⁵ suggested that the clinical benefit of this therapy in worsening HF might extend to a broader EF range (<60%). However, these trials were modest in size and enrolled North American populations only. Whether findings are generalizable to global populations remained largely unknown.

In this issue of the European Heart Journal, Tanaka and colleagues⁶ expand our understanding of the potential efficacy and safety of sacubitril/valsartan during worsening HF in the PREMIER trial. PREMIER was an investigator-initiated, multicentre, prospective, randomized, open-label, pragmatic trial conducted across 44 sites in Japan. Eligible patients were required to have recent hospitalization for worsening HF (within 7 days of randomization) and elevated natriuretic peptide levels; patients could be enrolled across the full spectrum of LVEF and inclusive of both de novo and acute on chronic presentations of worsening HF. Patients were considered stabilized from worsening HF if they had a systolic blood pressure ≥100 mmHg, no increase in intravenous diuretics, and no initiation of intravenous vasodilators or inotropes. The primary endpoint of the study was the proportional change in the geometric means of NT-proBNP levels from baseline to week 8. A total of 400 patients were equally randomized to continue renin-angiotensin-system inhibitor or switch to sacubitril/valsartan. The investigators found patients randomized to sacubitril/valsartan had greater reductions in natriuretic peptide levels by week 8 compared with those randomized to continue renin-angiotensin-system inhibitors (−45% vs. −32%). This treatment effect was strongest in patients with reduced ejection fraction (LVEF ≤ 40%).

Despite these encouraging findings, several important points should be noted. Unlike North American studies of sacubitril/valsartan in worsening HF, all patients in PREMIER were required to be on renin-angiotensin-system inhibitors before randomization. Whether this inclusion led to preferential enrolment of patients who may be more likely to tolerate the hemodynamic effects of sacubitril/valsartan should be considered. Prior studies have found treatment-related hypotension rates are highest in those with LVEF in the normal range. In addition, site investigators were discouraged from initiation of MRAs and SGLT inhibitors during the study; this practice may not generalize globally, particularly given strong, consistent evidence for SGLTi across the spectrum of LVEF and HF chronicity. Furthermore, similar to the rationale posed in this study for conducting a validation of prior North American findings, the findings of PREMIER may also not be readily extrapolated to other populations in Asia. The modest sample size and low event rates preclude the ability to discern if the reduction in natriuretic peptide levels with sacubitril/valsartan would translate into improved clinical outcomes. Notably, target doses of sacubitril/valsartan were achieved infrequently (13.6%) in the PREMIER study, compared with the PIONEER-HF (55.2%) and PARAGLIDE-HF (39.1%) trials.

Initiating disease-modifying pharmacotherapy during an acute worsening HF episode has several theoretical advantages. First, in-hospital initiation during worsening HF naturally selects patients who are at high risk for recurrent events and death. Consistently, effective pharmacotherapies in HF have had greater absolute risk reductions in patients actively or recently hospitalized for HF. Second, ambulatory visits are periodic, infrequent, and often too brief to fully explain the risks and benefits of new pharmacotherapy. Hospitalization affords greater time and exposure to multidisciplinary care teams (physicians, pharmacists, nursing), allowing for more robust education regarding the benefits and risks of new additional HF therapy and the opportunity for greater shared decision-making; these advantages may promote the ability to implement multiple therapies over a short period of time and may improve adherence in follow-up. Third, HF therapies may have overlapping effects on hemodynamics, kidney function, and electrolytes; close monitoring is often difficult or inaccessible outside the hospitalized setting. Frequent monitoring during the acute episode of care may more readily identify those with early intolerance. Finally, in the hospital, cost and access barriers can often be prospectively assessed and potentially mitigated even before pharmacotherapy initiation; this leads to greater transparency for patients, avoids post-prescription administrative burdens for ambulatory providers, and may help build trust among patients and their healthcare systems.

How do the findings of PREMIER fit into a broader puzzle of HF therapeutics initiated during or shortly after worsening HF? (Graphical Abstract). The findings here largely mirror those seen in the PIONEER-HF and PARAGLIDE-HF trials, which both enrolled participants from North America. Collectively, these trials establish the efficacy and safety of sacubitril/valsartan on surrogate measures of disease progression in a global population currently or recently hospitalized with worsening HF. Mirroring the data from the chronic HF trials of sacubitril/valsartan, the benefit-to-risk ratio appears particularly favourable in patients with an LVEF below normal.

Robust data has shown consistent efficacy and safety of the SGLT inhibitor class for the treatment of worsening HF across the spectrum of LVEF. The relative benefits of SGLT inhibition in the SOLOIST-WHF⁷ trial are consistent with those seen in chronic HF trials of SGLT inhibition; given the elevated baseline risk, larger absolute benefits in clinical outcomes and health status improvements were observed. EMPULSE⁸ also established an overall improvement, including better patient-reported health status in over 500 patients enrolled globally. A dedicated large global trial evaluating clinical outcomes with SGLT2i in worsening HF is ongoing; the results, if consistent, would solidify this class as a major pillar in worsening HF care across LVEF. Data on other medical therapies, including beta-blockers and MRA, in worsening HF has been limited to smaller trials or trial subsets. B-CONVINCED established the relative non-inferiority of a strategy of beta-blocker continuation vs. discontinuation during worsening HF episodes in those without beginning or overt cardiogenic shock,⁹ though larger placebo-controlled trials that assess clinical outcomes in worsening HF are generally missing. MRAs have strong recommendations for the treatment of chronic HFrEF and after acute MI; though previously, trials in acute HF have been small.¹⁰ However, nearly half of patients in the recently completed FINEARTS-HF trial of patients with HFmrEF or HFpEF were enrolled within months of a worsening HF event¹¹; the overall encouraging results of this trial establish non-steroidal MRAs as a potential central therapy in worsening HF. Dedicated secondary analyses of recently hospitalized patients will further clarify the potential role of this therapy. A late-phase trial of this therapy in worsening HF is also currently enrolling (NCT06008197) together with an implementation trial of finerenone and SGLTi in patients hospitalized for HF (NCT06024746). Finally, in patients with worsening HFrEF well treated on conventional disease-modifying pharmacotherapy, additional treatments, including vericiguat and intravenous iron may provide incremental benefit in select populations.¹²

All in all, we are no longer in an era where the treatment for worsening HF is limited to decongestion with conventional diuretic strategies alone; several components of chronic HF treatments can be safely implemented during or early after worsening HF. This benefit is punctuated by the findings from STRONG-HF,¹³ reporting that early intensive implementation of medical therapy during and immediately following worsening HF led to improvements in clinical outcomes within 180 days. However, pervasive implementation gaps remain, and discovery science in HF is rapidly evolving, particularly in HFmrEF and HFpEF. Novel implementation studies are needed that prioritize in-hospital initiation during acute worsening episodes of care and prospectively evaluate medication adherence, quality of life, and clinical outcomes. Such programmes may utilize the unique access to multidisciplinary care teams that hospitalization provides, including empowering pharmacists and other providers to more actively nudge high-quality care.¹⁴ Doing so will ensure we can provide PREMIER care for our patients experiencing worsening HF.

Declarations

Disclosure of Interest

A.S.B. has received research grant support to his institution from the National Institutes of Health/National Heart, Lung, and Blood Institute, National Institutes of Health/National Institute on Aging, American College of Cardiology Foundation, and the Centers for Disease Control and Prevention, and consulting fees from Sanofi Pasteur, Merck, and Novo Nordisk.

M.V. has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics.

References

Author notes