Patient-Reported Outcomes for Heart Failure with Preserved Ejection Fraction: Conducting Quality Studies on Quality of Life

This article refers to ‘Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity’ by Y.N.V. Reddy et al., published in this issue on pages 1009–1018. Compared with heart failure (HF) with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF) has seen minimal therapeutic progress and there remain no therapies definitively proven to improve clinical outcomes.1, 2 However, aside from high risk for mortality and hospitalization, HFpEF patients experience substantial morbidity and impairments in quality of life (QOL), the severity of which are comparable to patients living with end-stage renal disease.3 Combined with high rates of depression, low levels of activity, and significant time spent away from home in hospitals and healthcare facilities, these collective data paint a bleak picture for the daily life and clinical course of a typical HFpEF patient.3, 4 Although improving patient QOL is critical across the spectrum of HF, it is increasingly becoming a focal point in HFpEF. For perspective, when one considers drug development for HFrEF, the bar for ‘successful’ drug development is becoming increasingly high. Aside from the sheer number of medications, the level of effectiveness of existing HFrEF therapies is substantial, as most are proven to various degrees to meaningfully reduce cardiovascular mortality, decrease hospitalizations, reduce symptoms, and improve QOL.1, 2 Thus, aside from regulatory approval, a novel HFrEF therapy may need to simultaneously improve all or most of these domains to garner reasonable uptake in a competitive marketplace where medication costs and polypharmacy are carefully scrutinized. The landscape for HFpEF drug development stands in stark contrast. In HFpEF, a drug that meaningfully improves QOL without adverse effects on mortality or hospitalization would represent a major therapeutic breakthrough. This view has been reflected in ongoing HFpEF drug development programmes. For example, stemming from the favourable Kansas City Cardiomyopathy Questionnaire (KCCQ) signal in SOCRATES-PRESERVED, the phase 2b VITALITY-HFpEF (Evaluate the Efficacy and Safety of the Oral sGC Stimulator Vericiguat to Improve Physical Functioning in Daily Living Activities of Patients With Heart Failure and Preserved Ejection Fraction) trial is among the first HFpEF trials using a patient-reported outcome (PRO) [i.e. KCCQ Physical Limitation Score (KCCQ-PLS)] as the primary endpoint.5, 6 Likewise, the U.S. Food and Drug Administration (FDA) recently issued an industry guidance statement that improvement in symptoms without a favourable effect on mortality or HF hospitalizations may be a basis for HF drug approval.7 KCCQ and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) are now recognized by the FDA as medical device development tools to be used within clinical trial endpoints evaluating HF medical devices or drugs.8 As we consider the particular importance of understanding QOL in HFpEF, the article by Reddy et al.9 in this issue of the Journal is a timely addition to the literature. The Authors explored the relationships between patient-reported QOL and various markers of HFpEF severity using data from three National Heart Lung and Blood Institute sponsored trials.9 QOL was assessed by two instruments: the MLHFQ in one trial (score range 0–105, lower scores better) and KCCQ Overall Summary Score (KCCQ-OSS) in the remaining two trials (score range 1–100, higher scores better). To allow combination for the primary analysis, both score distributions were converted into tertiles. The ‘QOL worst’ group reported severe impairment, with KCCQ-OSS ≤45 or MLHFQ score >57. This group was also the youngest, with higher body mass index (BMI), greater prevalence of diabetes, and lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. After adjustment for age, sex and BMI, poor QOL was associated with worse physical capacity and activity levels, assessed by peak oxygen uptake (VO2), 6-min walk distance (6MWD) and actigraphy, but was not associated with NT-proBNP (N-terminal pro-B-type natriuretic peptide), indices from resting echocardiography, or prior HF hospitalization. The Authors conclude that QOL is more robustly tied to measures of functional capacity and daily activity levels, rather than elevations in NT-proBNP and prior HF hospitalization, and that this finding has important implications for the design of HFpEF clinical trials targeting symptom improvement. Indeed, NT-proBNP elevation and/or prior HF hospitalization are frequently used within eligibility criteria for typical HFpEF trials. Although these parameters may be helpful in enriching the population with patients at higher risk for mortality and hospitalization events, the current data suggest these criteria are not helpful in identifying patients with particularly impaired QOL. Moreover, these data provide insight regarding determinants of impaired QOL. Acknowledging that directionality and causality of relationships cannot be confirmed, QOL appears most intimately tied to functional capacity. This observation is consistent with a recent study of patient-reported goals, where HF patients reported independence and mobility as among their top priorities.10 Although the Authors are to be congratulated for this novel work, caveats and important questions regarding use of PROs in HFpEF clinical trials remain. First, the practical utility of correlating different variables with QOL is of uncertain significance. QOL can be measured directly and just as easily as many potential surrogates. Since surrogate endpoints are riddled with challenges in use and interpretation, directly measuring the ‘gold standard’ outcome is preferable whenever possible.11 While surrogates for mortality and hospitalization endpoints are appealing given the larger sample sizes and longer follow-up times needed to accrue events, important differences in QOL can be directly detected with modest sample sizes. Indeed, the sample size necessary to study differences in QOL is comparable to that required for any potential surrogate measures, such as echocardiographic, natriuretic peptide level, or functional capacity measures (e.g. 6MWD, peak VO2). Thus, functional capacity, imaging, and laboratory endpoints may be best viewed as complementary, rather than surrogates, to PROs. Second, the study by Reddy et al. was cross-sectional. While understanding associations between QOL and other factors at study baseline is important, QOL and HF status are dynamic and inferences from a single baseline value may be limited. For both clinical care and trial design, understanding associations with longitudinal changes in QOL to identify patients at risk for QOL deterioration may be more valuable. Specifically, such longitudinal information could have important implications for study power and selection criteria for HFpEF trials using QOL endpoints. Likewise, while other studies support the potential benefits of weight loss in HFpEF, the cross-sectional association between baseline obesity and QOL does not directly address the prospect of weight loss to improve PROs in HFpEF.12 Third, in the broader context, it is imperative to define how much of a change in QOL score or functional capacity is necessary to make a patient feel noticeably better. A 5-point change in KCCQ-OSS has been correlated with a relevant change in health status among patients with HFrEF, but the minimal clinically important difference (MCID) in the HFpEF population is less clear.13, 14 Moreover, it is unclear whether the meaningfulness of a given magnitude of numerical improvement varies with the baseline level of the measure, and whether absolute vs. relative improvement should be emphasized. For example, a 50 m increase in 6MWD may have more impact on wellbeing in a patient whose baseline 6MWD is 100 m compared with a patient whose baseline 6MWD is 400 m. Interpreting QOL scores or functional capacity in the context of patient global assessment facilitates clinical interpretation and may improve communication with patients regarding benefits of therapy. The ongoing VITALITY-HFpEF trial will characterize the MCID of KCCQ-PLS, categorizing patients as responders and non-responders and further informing future interpretation of the KCCQ-PLS as a trial endpoint. Fourth, for trials focused on QOL and functional capacity, questions regarding the true degree of overlap between obesity and HFpEF are increasingly relevant. While the current study and many others suggest a very high proportion of HFpEF patients are obese, the prevalence of diagnosed or undiagnosed HFpEF in a general population with obesity is less certain. Prior work has shown that therapeutic weight loss can significantly improve exercise capacity and symptoms in obese HFpEF, but the degree to which these observed benefits are due to ‘improvement in HFpEF’ vs. alternative benefits from weight reduction are less clear.12 Indeed, even in obese patients without a diagnosis of HFpEF, therapeutic weight loss results in significant improvements in QOL and physical activity.15 Thus, future studies are encouraged to work towards isolating the independent effects of HFpEF and obesity on patient-centred endpoints, including comparing and contrasting the longitudinal patterns of such measures among patients with obesity alone as compared with obese and non-obese HFpEF. Central to such studies will be the continued characterization of the true prevalence of ‘sub-clinical’ or undiagnosed HFpEF in obese patients. Prior work from Reddy and colleagues suggested this prevalence is substantial and that benefits of weight loss in obese individuals may work via a HFpEF mechanism.16 Specifically, the authors previously highlighted that significant abnormalities in invasive haemodynamics are present even among obese patients without a formal HFpEF diagnosis, and that weight reduction was associated with improvement in such parameters.16 In conclusion, this new work by Reddy et al. focuses on the important issue of QOL faced by millions of HFpEF patients worldwide and enhances our understanding of key factors at play. While these results are an important addition to the literature, caution must be exercised in that factors associated with QOL should not be viewed as surrogates, but rather as complementary to PROs such as the KCCQ. Maintaining a focus on the direct measurement of PROs will ensure that future HFpEF trials remain patient-centred. Indeed, in the setting of persistent challenges with HFpEF trials evaluating ‘hard’ clinical endpoints and recent regulatory guidance for HF trial endpoints, clinical trials focused on patient-reported QOL may be the most expedient means of bringing new meaningful therapies to the HFpEF community. Conflict of interest: M.S.K. has nothing to disclose. J.B. has received research support from the NIH, PCORI and the European Union; and serves as a consultant for Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squib, CVRx, G3 Pharmacautical, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Relypsa, StealthPeptide, SC Pharma, Vifor, and ZS Pharma. S.J.G. has received a Heart Failure Society of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis; has received research support from Amgen, Bristol-Myers Squibb and Novartis; serves on advisory boards for Amgen and Cytokinetics; and serves as a consultant for Amgen and Merck.