Improving Physical Activity and Exercise Capacity in Heart Failure. Taking the First Step is Always the Hardest

This article refers to ‘Rationale and study design of OUTSTEP-HF: a randomised controlled study to assess the effect of sacubitril/valsartan and enalapril on physical activity measured by accelerometry in patients with heart failure with reduced ejection fraction’ by F. Edelmann et al., published in this issue on pages 1724–1733. The pivotal PARADIGM-HF trial previously demonstrated that sacubitril/valsartan (S/V), compared to enalapril, led to a 20% reduction in the relative risk of the composite of cardiovascular death or hospitalization for heart failure (HF) among ambulatory HF patients with a left ventricular ejection fraction (LVEF) ≤40% and New York Heart Association (NYHA) functional class II–IV symptoms.1, 2 As a result of these data, both the U.S. Food and Drug Administration and the European Medicines Agency approved S/V and the American College of Cardiology/American Heart Association/Heart Failure Society of America3 and the European Society of Cardiology-Heart Failure Association4 updated their recommendations to include initiating and/or switching HF with a reduced ejection fraction (HFrEF) patients from a conventional renin–angiotensin system antagonist (i.e. enalapril) to an angiotensin receptor–neprilysin inhibitor (ARNi) (i.e. S/V). More recently, the PIONEER-HF trial showed that in-hospital initiation of S/V vs. enalapril was safe, well-tolerated, and led to a nearly 45% reduction in HF readmissions within 8 weeks of discharge.5, 6 However, despite the impressive improvements in clinical outcomes seen with S/V vs. enalapril, there are very limited existing data examining its effects on supplementary endpoints including functional status and health-related quality of life (HRQoL). In this issue of the Journal, Edelmann et al.7 describe the rationale and study design as well as the baseline characteristics of the patients enrolled in the ongoing randOmized study using acceleromeTry to compare Sacubitril/valsarTan and Enalapril in Patients with Heart Failure (OUTSTEP-HF) trial. OUTSTEP-HF (ClinicalTrials.gov Identifier: NCT02900378) is a prospective, multicentre, double-dummy, active-controlled, randomized clinical trial (RCT) planning to enrol an estimated 600 ambulatory patients with symptomatic HFrEF in 19 European countries. Key inclusion criteria included chronic HF with NYHA functional class II–IV symptoms and a LVEF ≤40%, an elevated natriuretic peptide or prior hospitalization for HF (12 months), stable background medical therapy (4 weeks) including a minimal daily dose of an angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) of at least 2.5 mg/day enalapril, a willingness to wear the accelerometer continuously for the duration of the study, and living freely and independently where they are primarily self-responsible for their daily schedule. Participants are excluded if they have a recent acute decompensation (4 weeks) manifested by signs and symptoms and requiring intravenous therapy, prior treatment with S/V, known intolerance and/or contraindications to either study drug, and a number of additional potential safety concerns. Eligible patients are then randomized 1:1 to receive S/V vs. enalapril both titrated to target dose. The co-primary endpoints are the changes from baseline to week 12 in exercise capacity based on daily non-sedentary daytime physical activity as measured by accelerometry using a continuously worn wrist-based device and 6-min walk distance (6MWD). Additional secondary endpoints include sleep parameters, signs and symptoms of HF, and patient- and provider-reported questionnaires for HRQoL. At the time of publication, recruitment has been completed for the OUTSTEP-HF trial and the study is currently in follow-up. A total of 764 patients were screened and 621 were randomized with 310 randomly assigned to S/V and 311 randomly assigned to enalapril. Patients had a mean age of 67 ± 11 years, 21% were women, 57% had an ischaemic aetiology of HF, and an astonishing 99% of patients reported NYHA functional class II/III symptoms. The prevalence of both cardiac and non-cardiac comorbidities was high and patients were exceptionally well-treated with guideline-directed medical therapy for HFrEF including beta-blockers (92%), ACEi/ARB (97%), and mineralocorticoid receptor antagonists (67%). In general, compared to the pivotal PARADIGM-HF approval trial, the patients enrolled in OUTSTEP-HF were similar with the exception that they were older, had a higher prevalence of atrial fibrillation, and were more likely to have symptomatic (i.e. NYHA functional class II–IV) HFrEF by virtue of the eligibility criteria. The OUTSTEP-HF investigators should be commended for undertaking a well-designed RCT enrolling a high-risk cohort of symptomatic HFrEF patients, utilizing traditional and novel endpoints for physical activity, and incorporating a range of patient-reported outcomes to better understand the impact of S/V vs. enalapril on HF-related morbidity. It is worth noting that more than 80% of patients who underwent screening were ultimately enrolled in this study, suggesting that the eligibility criteria were streamlined and reflective of real-world clinical practice. Indeed, the subjects enrolled in OUTSTEP-HF were astonishingly similar in terms of baseline characteristics to PARADIGM-HF with the exception that they were older and more symptomatic. This is the ideal target population as advancing age in HFrEF is often characterized by multimorbidity, frailty, and functional limitations.8 It is somewhat discouraging that only ∼20% of study participants were women but female subjects have historically proven difficult to recruit and typically been underrepresented in RCTs.9 Finally, OUTSTEP-HF does not tackle the potential impact of S/V on signs and symptoms, physical activity, and/or HRQoL in patients with HF with a preserved ejection fraction (HFpEF), although the PARAGON-HF trial suggested there may be an expanded role for ARNi therapy in select subgroups of HFpEF patients (i.e. women and borderline LVEF) and with respect to certain patient-centred outcomes (i.e. NYHA functional class and HRQoL).10, 11 The pairing of novel measures for physical activity with traditional endpoints for functional status (i.e. 6MWD) is a unique aspect of the study design that merits further mention. Although not the primary objective of the OUTSTEP-HF study, this feature will for the first time in a sizable HFrEF population allow wearable-derived metrics for daily activity to be cross-validated with 6MWD, which has been well-studied in multiple chronic cardiopulmonary conditions and served as the gold standard for functional capacity in clinical research. In addition, accelerometers have the advantage of providing ‘real-time’ and continuous measures of frequency, intensity, and duration of activity. However, there are several potential pitfalls to leveraging data from wearables in this specific patient population. First, the thresholds used in this study to define sedentary vs. non-sedentary activity levels were based on an elderly population of healthy controls and may differ for patients with symptomatic HFrEF. Second, the gait speed is slower in older patients, particularly those with chronic medical conditions, and there is the potential that physical activity may not be comprehensively captured by the device and devices typically cannot distinguish between load-bearing vs. non-load-bearing activities. Third, and most importantly, although the investigators required patients to ‘continuously’ wear the device on their non-dominant wrist, prior RCTs using accelerometers have been challenged by incomplete data and how to handle missingness (i.e. censoring and/or imputation) in the statistical analysis plan.12 Finally, although S/V vs. enalapril has previously been shown to lead to an early improvement in N-terminal pro B-type natriuretic peptide and clinical outcomes, the timing of any theoretical benefit on physical activity is unclear, and more importantly this study will not address whether the effects are sustained over time.5, 6 OUTSTEP-HF will also evaluate a number of patient-centred outcomes including sleep parameters, signs and symptoms of HF, and HRQoL. A secondary analysis of the PARAGIDM-HF trial has previously shown that S/V improved signs and symptoms of congestion to a greater extent than enalapril and this improvement was associated with better HRQoL and reduced risk of cardiovascular morbidity and mortality.13 OUTSTEP-HF will provide additional supportive evidence for the role of S/V vs. enalapril on clinical congestion in a high-risk HFrEF population enriched for signs and symptoms of HF. Although the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score deteriorated in both treatment arms during follow-up in the PARADIGM-HF trial, it worsened to a greater degree in patients receiving enalapril.14 However, the baseline KCCQ was administered at randomization following the sequential single-blind run-in periods after patients may have been treated with both study medication for up to 10 weeks, potentially minimizing the between-group difference. In addition, while the KCCQ score improved in S/V-treated patients when zero values were not imputed for patients who died, the magnitude of the between-group difference was greatly diminished suggesting that the KCCQ analyses were confounded by the competing risk of death. Thus, improving HRQoL remains an unmet need15, 16 and OUTSTEP-HF will reveal the first insights into the short-term effects of S/V vs. enalapril on HRQoL in symptomatic HFrEF patients not previously exposed to ARNi therapy. In summation, the OUTSTEP-HF trial is poised to provide important insights into the expected distribution of values for novel accelerometry-based measurements and cross-validate these metrics against the traditional and historical gold standard for assessing functional capacity (i.e. 6MWD). Furthermore, this study will be the first assessment of S/V vs. enalapril on sleep parameters, signs and symptoms of HF, and HRQoL in an ambulatory population of highly symptomatic HFrEF patients who are truly ARNi naïve. Thus, OUTSTEP-HF will advance the general knowledge on expected physical activity in symptomatic HFrEF and extend the evidence base on the relative benefits of S/V vs. enalapril on several traditional and emerging patient-centred outcomes in this at-risk cohort. Additional research is necessary to understand the durability of the effects of S/V vs. enalapril on exercise capacity as well as the impact of ARNi therapy on functional outcomes among the subset of patients with mid-range or preserved LVEF. Conflict of interest: A.P.A. reports having received research support and reimbursement for travel from Novartis Pharmaceuticals Corporation. O.C. has received research grants from Servier, Novartis, and Vifor and reports other support from Boehringer Ingelheim.