Heterogeneity of health status treatment response with sacubitril/valsartan: insights from the CHAMP-HF registry

Introduction

The primary treatment goal for patients with heart failure with reduced ejection fraction (HFrEF) is to improve their survival and to optimize their health status—their symptoms, function, and quality of life.¹ Sacubitril/valsartan has been shown to improve both outcomes,² and we recently demonstrated that a very large health status response [≥20-point improvement in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score] occurs in about one in five patients shortly after initiating this medication.³

Methods

To better identify patients whose health status may be more likely to improve than others, we used data from CHAMP-HF—an ongoing, observational registry of 140 US clinics that enrolled 5026 outpatients with chronic HFrEF.⁴ Health status was measured using the KCCQ-12 Overall Summary Scale (KCCQ-OS), an extensively validated, disease-specific patient-reported outcome measure that ranges from 0 to 100 (higher scores are better) and where a ≥20-point improvement has been established as a very large improvement in patients' health status.^{3, 5}

We used the previously reported cohort of 508 patients newly initiated on sacubitril/valsartan, in whom 104 (20.5%) experienced a ≥20-point change in KCCQ score within 3 months.³ Because those with a baseline score > 80 were not eligible to improve by ≥20 points, we excluded 174 patients, leaving a final analytic cohort of 334 patients. To compare the clinical characteristics of those who markedly improved with those who did not, we used hierarchical multivariable logistic regression, with site as a random effect to account for clustering of patients at the same site. Thirteen patient-level characteristics were considered, including sociodemographic (age, sex, race, and household income), clinical (chronic obstructive lung disease, chronic kidney disease, diabetes mellitus, depression, and number of hospitalizations within the past 12 months), haemodynamic (systolic blood pressure), and medication [angiotensin-converting enzyme/angiotensin receptor blocker (ACE/ARB) and loop diuretic] characteristics, as well as baseline KCCQ-12 score. Non-linear associations for continuous variables were assessed. Calculated odds ratios (ORs) reflect the odds of any predictor being associated with a very large improvement in the KCCQ-OS.

Results

The median (25th and 75th percentiles) patient follow-up between enrolment and post-angiotensin receptor neprilysin inhibitor KCCQ-12 was 61 (33–136) days. A total of 104/334 (31.1%) of patients achieved the primary endpoint. Table S1 and Table 1 present the characteristics of those who did and did not experience a very large KCCQ-OS improvement, as well as the univariate and multivariable-adjusted ORs of a very large improvement, respectively. Following multivariable adjustment, the only patient characteristic associated with very large health status improvements was worse baseline health status. The higher the score, the less likely patients were to attain a very large benefit from sacubitril/valsartan—with a non-linear relationship—such that those with a KCCQ-12 score of 0–60 points had an OR = 0.86/5-point higher score (CI 0.79, 0.93) and those with a KCCQ-12 score of 60–80 points had an OR = 0.61/5-point higher score (0.45–0.82). No other patient characteristics were associated with very large health status improvements (P > 0.05).

Conclusions

Although all patients may derive a survival or hospitalization benefit from sacubitril/valsartan, we sought to identify patient characteristics associated with a very large, early health status treatment response. We found that only poorer baseline health status was associated with such improvement. In fact, the worse the health status, the greater the observed treatment benefit. This suggests that it is not possible to readily identify patients who are more likely to derive a very large health status benefit from sacubitril/valsartan and that a trial of therapy—particularly in those with worse symptoms, function and quality of life—and assessing treatment response is likely to be the best prospective strategy. Notably, there was no significant difference in health status outcomes by heart failure aetiology (ischaemic vs. non-ischaemic). Our study should be interpreted with the understanding that our model was developed to predict patient characteristics associated with large health status improvement and not meant to estimate causal treatment effects. We also cannot exclude regression to the mean, as we only studied patients initiated on sacubitril/valsartan, and we recognize that those with worse health status may be more likely to demonstrate regression to the mean. Interestingly, patients previously on ACE/ARB were less likely to experience a very large health status benefit; while these findings were not statistically significant, the mechanism remains unclear. To that end, further studies in larger patient cohorts will be needed to extend and validate our findings and to determine whether patients' health status improvements are sustained over a period of prolonged clinical follow-up.

Conflict of interest

Drs. Y. Khariton and M. Nassif are supported by the National Heart, Lung, and Blood Institutes of Health Under Award Number T32HL110837; the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Khariton had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. John A. Spertus discloses grant funding from NIH, ACCF, Bayer, Novartis, and Abbott Vascular. He serves on the Scientific Advisory Board for United Healthcare and the Board of Directors for Blue Cross Blue Shield of Kansas City. He is a consultant for Novartis, Amgen, AstraZeneca, Jansssen, Merck, and Bayer. He has intellectual property rights for the Kansas City Cardiomyopathy Questionnaire and an equity interest in Health Outcomes Sciences. Dr. Laine Thomas reports research funding from Novartis Pharmaceuticals Corporation. Dr. Gregg C. Fonarow reports research support from the National Institute of Health, consulting for Abbott, Amgen, Bayer, Janssen, Medtronic, and Novartis and serving on the Get With The Guidelines Steering Committee. Dr. Javed Butler has received research support from the National Institutes of Health and the European Union and serves as a consultant for Amgen, Bayer, Boehringer Ingelheim, Cardiocell, CVRx, Gilead, Janssen, Medtronic, Merck, Novartis, Relypsa, and ZS Pharma. Dr. Nancy M. Albert reports consulting for Novartis and Boston Scientific and receiving honoraria from Novartis. Dr. Carol I. Duffy is an employee of Novartis. All other authors have reported no relationships to disclose relevant to the contents of this manuscript.

Funding

CHAMP-HF and this study was funded by the Novartis Pharmaceuticals Corporation.