In‐hospital initiation of quadruple medical therapy for heart failure: making the post‐discharge vulnerable phase far less vulnerable

This article refers to 'Early and short-term intensive management after discharge for patients hospitalized with acute heart failure: a randomized study (ECAD-HF)' by D. Logeart et al., published in this issue on pages 219–226. Approximately one in four patients hospitalized for worsening heart failure (HF) are dead or rehospitalized within 30 days of discharge.1 This early post-discharge "vulnerable phase" has continued to be a major focus of HF care, with transitions of care, pre-discharge patient education, early post-discharge clinic visits and monitoring, and 30-day rehospitalization measures readily accepted as important goals by many health systems across the world.2 However, while rationale for these 'common sense' interventions may be intuitive, the widespread emphasis on these generic and empiric post-discharge strategies continues to be disproportionate to the evidence supporting them. Although multiple analyses do suggest benefits with various strategies, the supporting evidence is at best 'mixed' and far from definitive, and there are several examples (including randomized trials) where transitional care interventions have been shown ineffective for reducing clinical events.3-5 In fact, in some cases, seemingly benign interventions such as regular post-discharge telephone calls and alerting outpatient clinicians of patient discharge have been associated with increased risk of readmission.6 As we consider the current magnitude of healthcare resources devoted by many health systems to transitional care and early post-discharge follow-up, we should reflect on why the data for these well-intentioned strategies are not stronger. One plausible explanation is that the pure presence or absence of post-discharge patient contact matters less, whereas what occurs and is modified at each point of patient contact matters much more. In this context, for patients with HF with reduced ejection fraction (HFrEF), including those actively and recently hospitalized, use of comprehensive disease-modifying quadruple therapy stands as the cornerstone evidence-based intervention to reduce early and longer-term mortality and hospitalization7 (Figure 1). Benefits of each of these four medications [angiotensin receptor–neprilysin inhibitor (ARNI), beta-blocker, mineralocorticoid receptor antagonist (MRA) and sodium–glucose co-transporter 2 inhibitor] on risk of death and hospitalization accrue within days to weeks of initiation, with clinically significant benefits by 30 days.8 These early benefits are particularly relevant for patients hospitalized or recently hospitalized for HFrEF, since deferring or delaying initiation of any of these four medications exposes this exceptionally high-risk population to excess risk of death and clinical worsening.8 These sizeable reductions in mortality and morbidity are then coupled with data supporting in-hospital initiation as an evidence-based approach to drastically improve the early and long-term use, adherence, and persistence of medications.9 For example, in separate analyses of US clinical practice among patients eligible for therapy, not prescribing ARNI or MRA at time of hospital discharge carried >75% chance the patient did not receive the medication in the next 12 months.10, 11 Thus, while managing signs and symptoms of congestion, addressing comorbid conditions, coordinating care within multidisciplinary teams, and scheduling follow-up remain important components of in-hospital care, interventions explicitly focused on improving utilization of evidence-based medications likely constitute the most effective and efficient approach for reducing early, intermediate, and long-term post-discharge mortality and readmission. In this issue of the Journal, Logeart and colleagues present the results of the ECAD-HF (Early Care After Discharge of Heart Failure Patients) randomized trial, an open-label study evaluating the effect of intensive early post-discharge follow-up vs. usual care among patients hospitalized for HF across 22 centers in France.12 The trial enrolled patients across the spectrum of ejection fraction (EF) with all eligible patients having at least one of the following higher-risk features at discharge: prior HF hospitalization in the past 6 months before the index hospitalization, substantially elevated natriuretic peptides, moderate or worse kidney dysfunction, and/or systolic blood pressure ≤ 110 mmHg. Patients randomized to intensive post-discharge care received in-person consultations with HF specialists and a dietician at day 7 and day 14 post-discharge, with an additional consultation recommended at day 21. This was in addition to usual follow-up with a general practitioner and their regular cardiologist. Basic laboratory tests (serum electrolytes, kidney function, natriuretic peptides) were planned before each in-person patient visit, where the goal of each visit was to optimize patient care, including titration of HF medical therapy. By contrast, patients randomized to usual care were prescribed basic laboratory tests and encouraged to follow-up with their general practitioner within 7 days of discharge, and their regular cardiologist within 1 month. For the usual care group, it was encouraged that study investigators scheduled these appointments for patients, but this was not required. The primary trial endpoint was the composite of all-cause death or hospitalization, assessed as time-to-first event. Among 495 randomized patients (63% with EF ≤ 40%), there was no significant difference in the primary endpoint, with high rates of all-cause death or hospitalization at 6 months of 45%–47% regardless of randomized treatment arm. Similarly neutral findings were seen for all secondary clinical outcomes, with no significant interaction by reduced vs. preserved EF. The lack of clinical benefit with intensive early follow-up was observed despite overall strong adherence among those randomized to this strategy; >80% of patients were seen by the HF cardiologist at both day 7 and day 14, and >75% were seen by the dietician at either day 7 or 14. However, among patients with HFrEF, as compared with usual care, intensive follow-up was not able to generate any meaningful improvement in the use or dosing of medical therapy. The ECAD-HF investigators should be congratulated on this important randomized trial formally testing the hypothesis that intensive early post-discharge follow-up improves outcomes.12 It should also be emphasized that the patient population was particularly high risk, with median age 77 years, 44% with discharge blood pressure ≤ 110 mmHg, and a median discharge estimated glomerular filtration rate of 41–42 ml/min/1.73 m2. While in-hospital initiation of disease-modifying therapy did occur among some patients with EF ≤ 40% (i.e. admission and discharge rates of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker increased from ∼56% to 85%, beta-blocker from ∼62% to 93%, and MRA from ∼19% to 41%–48%), gaps at discharge remained and these gaps were not substantially bridged with enhanced transitions of care including early post-discharge follow-up. In an era of often limited resources and strong financial pressures, the results of the ECAD-HF trial raise further questions as to whether the general emphasis on presence vs. absence of post-discharge appointments should be redirected to more granular measures of post-discharge care, such as medication utilization. Nonetheless, limitations of the trial should be recognized. First, the study was a modestly sized programme that enrolled exclusively in France, and results may not necessarily generalize to other countries or health systems. Second, while adherence to the intensive follow-up arm confirmed a high level of patient exposure to the randomized intervention, such data were not available in the usual care arm. Although the authors assume based on prior data that ≤ 50% of such patients did not see their general practitioner within 1 month post-discharge (or their cardiologist within 3 months), higher than expected rates of follow-up in the usual care arm could have reduced differences in follow-up care between study groups, and pushed results towards the null. Third, although goals of follow-up care in the intensive strategy included titration of HF medications, the rationale and appropriateness of the specific medication decisions are unknown. Thus, while the authors document rates of interval medication changes between discharge and 6 months in the intensive group, the end result at 6 months among patients with EF ≤ 40% was utilization of therapy similar to usual care, with potential exception of even lower 6-month post-discharge use of MRA (34% vs. 42%). Likewise, it is unknown whether rates of use and dosing of evidence-based medications at 6 months reflect the maximally tolerated medication regimen or emergence of contraindications, vs. sub-optimal quality of care, clinical inertia, or other barriers to medication use. Nevertheless, in the context of minimal longitudinal and between group differences in medical therapy, it is unsurprising that there were no significant between group differences in clinical outcomes among the patients with HFrEF. In summary, as researchers and health systems continue to search for innovative approaches to reduce the burden of HF hospitalizations and improve post-discharge outcomes, we must recognize that data already support in-hospital initiation of quadruple medical therapy for HFrEF as an effective, practical, and patient-centered strategy9 (Figure 1). Diuresis and decongestion, pre-discharge planning, and post-discharge follow-up remain important and guideline-recommended. Yet, completion of these tasks should not distract from the role of HF hospitalization as a critical opportunity to initiate and augment mortality-reducing therapies, as well as the unfortunate reality that routinely deferring in-hospital initiation among eligible patients with HFrEF will lead to preventable deaths and readmissions. Rather, strategies of pre-discharge and post-discharge care should strive to be complementary to the overarching goal of providing all eligible patients with quadruple medical therapy, without delay, and subsequently titrating medications to maximally tolerated or target doses.8 As the ECAD-HF trial highlights, for purposes of improving outcomes, scheduling appointments and diligent early post-hospital follow-up may not be enough to make the post-discharge 'vulnerable phase' any less vulnerable, unless it translates to meaningful improvements in use of disease-modifying medical therapy. Conflict of interest: S.J.G. has received research support from the Duke University Department of Medicine Chair's Research Award, American Heart Association, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, and Pfizer; has served on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, and Cytokinetics; and serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck, and Vifor. J.B. has served as a consultant to Abbott, Adrenomed, Arena Pharma, Array, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, CVRx, Eli Lilly, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Sequana Medical, V-Wave Limited, and Vifor. G.C.F. reports research support from the National Institutes of Health, consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Medtronic, Merck, and Novartis.