Targeting the Vulnerable Phase of Heart Failure: Initiate Novel Therapies in Stable Patients Prior to Hospitalization

This article refers to ‘Chronic exposure to ivabradine reduces readmissions in the vulnerable phase after hospitalization for worsening systolic heart failure: a post-hoc analysis of SHIFT’, by M. Komajda et al., published in this issue on pages 1182–1189. While long-term survival following hospitalization for heart failure (HF) remains persistently poor and comparable with that of many cancers, the early post-discharge period carries particularly high risk of poor outcomes and has been termed the ‘vulnerable phase’.1 Despite available therapies and quality improvement initiatives, early mortality and rehospitalization rates may reach 15% and 30%, respectively, within 90 days post-discharge.2 Early readmissions are generally linked to congestion, while late readmissions may be related to progressive HF. Unfortunately, for patients hospitalized with HF and reduced ejection fraction (HFrEF), no treatments have been definitively proven to improve post-discharge outcomes other than optimization of chronic HF therapies.1 Indeed, discovery of evidence-based treatments and care strategies that specifically improve outcomes during the vulnerable phase following HF hospitalization have been challenging. For instance, patients undergo major transitions in care and are often elderly or with multiple cardiovascular and non-cardiovascular co-morbidities that each carry risks of death and readmission. Moreover, it is conceivable that pharmacological and non-pharmacological interventions during hospitalization for some patients may be ‘too late’ to reverse HF progression or may not be well tolerated in this tenuous high-risk cohort.3 Accordingly, initiating new therapies and optimizing doses of existing medications in well-compensated patients in the chronic phase of HF may be an important mechanism for improving downstream outcomes, including post-discharge event rates following hospitalization for worsening HF. In this editorial, we discuss (i) the optimal timing of initiation of novel therapies in HF and (ii) the importance of studying recurrent hospitalizations in contemporary clinical trials of HF. In this issue of the journal, Komajda et al.4 present a post hoc analysis from the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) study investigating the efficacy of chronic exposure to ivabradine, a selective If channel blocker, in reducing early subsequent rehospitalization following a hospitalization for HF. The investigators analyzed 1186 outpatients with stable, symptomatic HFrEF (≤35%) enrolled in SHIFT who experienced at least one hospitalization for HF during study follow-up, and demonstrated that early recurrent hospitalizations at 1, 2, and 3 months post-discharge were significantly lower in ivabradine-treated patients.4 The authors raise the intriguing question of whether ivabradine may be of clinical use in the post-discharge vulnerable phase. This study reinforces their prior work5, 6 demonstrating that ivabradine initiated in the chronic phase is well-tolerated and reduces risk of index hospitalization and recurrent hospitalizations, and prolongs the time interval between clinical events. Nonetheless, limitations of the current analysis should be recognized. Patients included in this analysis were on stable doses of ivabradine well before the index hospitalization, and the current data do not inform the clinical utility of ivabradine initiation during or soon after the index HF hospitalization. Thus, these data in isolation are unable to support any benefit of the drug specific to the post-discharge vulnerable phase. In addition, by virtue of SHIFT being a chronic HF trial, comprehensive patient data at the time of the first HF hospitalization were not available. Instead, baseline characteristics collected during the stable chronic HF phase in SHIFT are provided, but are likely not indicative of clinical status at the time of hospitalization weeks to months later. Similarly, multivariate modelling included baseline covariate data, and is thus unlikely to fully account for risk differences between the ivabradine and placebo cohorts at the time of hospitalization. Heart rate is a viable target during the early post-discharge phase,7 and ivabradine remains a promising agent in this population. Indeed, despite treatment with beta-blockers, the majority of hospitalized HFrEF patients may have a discharge heart rate >70 b.p.m.8 The IMPACT-HF (Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure) trial demonstrated the safety of early initiation of the beta-blocker, carvedilol, prior to hospital discharge;9 however similar data are not available validating the safety of routine use of ivabradine during the vulnerable phase. As such, ivabradine should not be initiated in patients who are haemodynamically tenuous and may rely on heart rate augmentation to maintain sufficient cardiac output. Careful selection of potential drug candidates is required to optimize the risk–benefit calculation. Since early readmissions after HF hospitalization are frequently caused by worsening congestion, thorough assessment of congestive status at the early post-discharge follow-up visit is mandatory. Clinicians should ensure resolution of subclinical or ‘haemodynamic’ congestion, which represents elevated filling pressures in the absence of overt signs and symptoms of HF and can be provoked via dynamic manoeuvres (e.g. 6-min walk test, orthopnea assessment, and presence of minimal orthostatic changes).10, 11 Available clinical and biomarker parameters may be effectively used to identify high-risk, but well-compensated patients free from subclinical or ‘haemodynamic’ congestion10, 11 who may be appropriate candidates for ivabradine initiation. At this time, it is reasonable to consider ivabradine according to the general SHIFT inclusion criteria: symptomatic ambulatory HFrEF patients with persistently high heart rates (≥70 b.p.m. in sinus rhythm) who have clinically stabilized after recent hospitalization for HF within the last year. Moving forward, future prospective studies with ivabradine will be necessary to determine its clinical effects when initiated during or shortly after hospitalization for HF. The present study by Komajda et al.4 further reinforces the utility and importance of repeated event analyses in assessing drug effects and therapeutic value in HF.12 HF is characterized by recurrent hospitalizations, but efficacy endpoints in trials often only consider first hospitalization in the case of ambulatory chronic HF trials, or rehospitalization in the case of hospitalized HF trials. Repeated event analyses may improve the detection and quantification of treatment effects, and make traditional endpoints more patient-centred. Recent analyses from DIG ( Digitalis Investigation Group),13, 14 CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure),15 CHARM (Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity)-Preserved,12 and SHIFT5, 6 provide important insight into the longitudinal effects of drug therapy over time. To our knowledge, the ongoing PARAGON-HF (Prospective Comparison of ARNi with ARB on Management of Heart Failure with Preserved Ejection Fraction) trial is the first phase III HF trial to include both first and recurrent HF hospitalizations within a composite primary endpoint (ClinicalTrials.gov identifier: NCT01920711). Major therapeutic goals of the vulnerable phase include amelioration of congestion and prevention of HF progression over time. Although hospitalization itself appears to augment risk slightly for recurrent clinical events, it is fundamentally only a ‘location of care’ and may serve as a strong and clinically useful marker to identify an at-risk population.16 The individual patient's risk profile, regardless of presence of a recent hospitalization, most closely correlates with subsequent mortality.16 As such, initiating and optimizing long-term drug and device therapies in appropriately selected, stable, high-risk patients regardless of hospitalization status may be the more prudent and durable strategy to reduce overall hospitalization burden in this complex population. Nevertheless, dedicated trials of novel therapies during or soon after hospitalization for HF represents a practical means of enriching trial populations with high-risk patients with a large unmet therapeutic need. At this juncture, ivabradine should be considered in stable patients with HFrEF during the vulnerable phase with persistently high heart rates and resolved clinical and ‘haemodynamic’ congestion. Patients with persistent congestion post-discharge should undergo further decongestion and be considered for digoxin, which has been shown to improve haemodynamics and reduce the need for hospitalization in high-risk patients.13, 14 Once clinical stability and euvolemia are established, ivabradine should be considered. There is an ongoing need for safe and effective therapies during the vulnerable phase of HF and ivabradine may be a good choice in patients without clinical and ‘haemodynamic’ congestion. Conflict of interest: M.G. reports receiving consultant fees from Abbott Laboratories (modest), Astellas (modest), Astra Zeneca (modest), Bayer Schering Pharma AG (significant), CorThera, Inc. (modest), Cytokinetics, Inc. (modest), DebioPharm SA (significant), Errekappa Terapeutici (Milan, Italy) (modest), GlaxoSmithKline (modest), Johnson & Johnson (modest), Medtronic (significant), Merck (modest), Novartis Pharma AG (significant), Otsuka Pharmaceuticals (significant), PeriCor Therapeutics (significant), Protein Design Laboratories (modest), Sanofi-Aventis (modest), Sigma Tau (significant), and Solvay Pharmaceuticals (significant). All other authors report no conflicts of interest related to this work.