Author + information
- Received December 1, 2016
- Revision received December 23, 2016
- Accepted January 2, 2017
- Published online March 20, 2017.
- Christopher M. O’Connor, MDa,b,∗ (, )
- David J. Whellan, MDc,
- Mona Fiuzat, PharmDa,
- Naresh M. Punjabi, MD, PhDd,
- Gudaye Tasissa, PhDa,
- Kevin J. Anstrom, PhDa,
- Adam V. Benjafield, PhDe,
- Holger Woehrle, MDf,g,
- Amy B. Blase, BSe,
- JoAnn Lindenfeld, MDh and
- Olaf Oldenburg, MDi
- aDuke University and Duke Clinical Research Institute, Durham, North Carolina
- bInova Heart and Vascular Institute, Falls Church, Virginia
- cThomas Jefferson University, Philadelphia, Pennsylvania
- dJohns Hopkins University, Baltimore, Maryland
- eResMed Science Center, ResMed Corp, San Diego, California
- fResMed Science Center, Martinsried, Germany
- gSleep and Ventilation Center Blaubeuren, Respiratory Center Ulm, Ulm, Germany
- hVanderbilt University, Nashville, Tennessee
- iHerz- und Diabeteszentrum NRW, Ruhr University Bochum, Bad Oeynhausen, Germany
- ↵∗Address for correspondence:
Dr. Christopher M. O’Connor, Inova Heart & Vascular Institute, 3300 Gallows Road, IHVI Administration, Suite 1225, Falls Church, Virginia 22042.
Background Sleep apnea is common in hospitalized heart failure (HF) patients and is associated with increased morbidity and mortality.
Objectives The CAT-HF (Cardiovascular Improvements With MV-ASV Therapy in Heart Failure) trial investigated whether minute ventilation (MV) adaptive servo-ventilation (ASV) improved cardiovascular outcomes in hospitalized HF patients with moderate-to-severe sleep apnea.
Methods Eligible patients hospitalized with HF and moderate-to-severe sleep apnea were randomized to ASV plus optimized medical therapy (OMT) or OMT alone (control). The primary endpoint was a composite global rank score (hierarchy of death, cardiovascular hospitalizations, and percent changes in 6-min walk distance) at 6 months.
Results 126 of 215 planned patients were randomized; enrollment was stopped early following release of the SERVE-HF (Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure) trial results. Average device usage was 2.7 h/night. Mean number of events measured by the apnea-hypopnea index decreased from 35.7/h to 2.1/h at 6 months in the ASV group versus 35.1/h to 19.0/h in the control group (p < 0.0001). The primary endpoint did not differ significantly between the ASV and control groups (p = 0.92 Wilcoxon). Changes in composite endpoint components were not significantly different between ASV and control. There was no significant interaction between treatment and ejection fraction (p = 0.10 Cox model); however, pre-specified subgroup analysis suggested a positive effect of ASV in patients with HF with preserved ejection fraction (p = 0.036).
Conclusions In hospitalized HF patients with moderate-to-severe sleep apnea, adding ASV to OMT did not improve 6-month cardiovascular outcomes. Study power was limited for detection of safety signals and identifying differential effects of ASV in patients with HF with preserved ejection fraction, but additional studies are warranted in this population. (Cardiovascular Improvements With MV ASV Therapy in Heart Failure [CAT-HF]; NCT01953874)
Sleep apnea is more common in patients with heart failure (HF) than in the general population, with a reported prevalence of 50% to 75% (1,2). There are 2 main types of sleep apnea: obstructive (OSA) and central (CSA). OSA is common in patients with HF with preserved ejection fraction (HFpEF), with a prevalence of 69% to 81% (3,4), and is independently associated with a worse prognosis (5), even when HF therapy is optimal (6). As cardiac function worsens, CSA and Cheyne-Stokes respiration increase in severity (1,3), with apnea-hypopnea index (AHI) >30/h in many patients with acute decompensation of HF (7,8). CSA worsening might be due to stimulation of stretch J-receptors by pulmonary congestion, which promotes hyperventilation and respiratory instability (9). The presence of CSA during HF admission is associated with an increased risk of morbidity and mortality including higher rates of HF rehospitalization (10,11), and often persists after successful management of the acute decompensation episode (8,12,13).
Noninvasive positive airway pressure therapy with adaptive servo-ventilation (ASV) is indicated for treatment of both CSA and OSA, and is more effective and better tolerated than continuous positive airway pressure when treating CSA in HF patients (14,15). The results of several small studies and meta-analyses showed ASV improved plasma B-type natriuretic peptide (BNP) concentration, left ventricular ejection fraction (LVEF), quality of life (QOL), functional outcomes, and mortality in patients with heart failure with reduced ejection fraction (HFrEF) and CSA (16–20). Conversely, the SERVE-HF (Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure) trial, the first large randomized trial of ASV in chronic stable HFrEF patients with predominant CSA, was neutral for the primary composite endpoint. There was a signal for increased mortality, especially cardiovascular (CV) death, in patients randomized to ASV, particularly in the subgroup of patients who had worse left ventricular function (21,22).
There are currently no data from large randomized trials on the effects of positive airway pressure therapy for sleep apnea in patients hospitalized for HF. However, observational data suggest that treating sleep apnea in the post-acute setting might reduce mortality risk (11). The CAT-HF (Cardiovascular Improvements With MV-ASV Therapy in Heart Failure) study investigated whether treatment of hospitalized HF patients with moderate-to-severe sleep apnea with ASV in addition to optimized medical therapy (OMT) was associated with improved 6-month cardiovascular outcomes compared with OMT alone (control).
The CAT-HF study was a randomized, controlled, multicenter clinical trial. The study design has been reported previously (23). In brief, hospitalized HF patients with either reduced or preserved ejection fraction and an AHI ≥15 events per h were randomized to usual care or active treatment in a 1:1 ratio. Two-hundred fifteen patients were intended to be randomized. At the time of discontinuation, 126 patients were randomized. The primary endpoint was a global rank composite endpoint of death, CV hospitalizations, and 6-min walk distance (6MWD). Secondary endpoints included changes in functional parameters, biomarkers, QOL, sleep, and breathing.
The study was funded by ResMed Corp (San Diego, California). The full study protocol was designed and conducted by an independent academic steering committee. The sponsor had nonvoting representation on the steering committee and did not participate in closed sessions in which trial recommendations were made. The data coordinating center (Duke Clinical Research Institute) was responsible for data management and statistical analysis. An independent data safety and monitoring committee monitored the trial conduct and the safety of study participants. The institutional review board at each study site approved the study, and all patients provided written informed consent. CAT-HF included core laboratories for biomarkers, echocardiography, sleep, and arrhythmias to evaluate substudy findings.
Patients and randomization
Patients were eligible if they were age ≥21 years and had a diagnosis of HFrEF or HFpEF with signs and symptoms of acute HF, had dyspnea at rest or with minimal exertion, elevated natriuretic peptide levels (BNP ≥300 pg/ml or N-terminal pro-BNP ≥1,200 pg/ml), and at least 1 additional sign or symptom (orthopnea, rales, congestion on chest radiograph, or pulmonary capillary wedge pressure ≥25 mm Hg). A complete listing of study inclusion and exclusion criteria has been published previously (23) and is in the Online Appendix. Data for the study came from 14 different health care centers.
Patients who met the study criteria signed informed consent. A type 3 cardiorespiratory polygraphy device (ApneaLink Plus, ResMed, San Diego, California) was used to assess eligibility based on the sleep apnea criteria of an AHI of ≥15 events per h (minimum evaluation time 3 h). Definitions for apneas and hypopneas were based on the American Academy of Sleep Medicine 2007 recommended scoring criteria (24). Patients who had moderate-to-severe sleep apnea (AHI ≥15/h) underwent ASV mask tolerability testing (second phase), in which they wore the mask with positive airway pressure being delivered for at least 2 h. Patients who satisfactorily completed the run-in phase were then randomized in a 1:1 ratio to the ASV group or control group. OMT was based on the most recent American College of Cardiology/American Heart Association guideline recommendations (25). Patients not meeting the criteria or not tolerating the run-in test were enrolled in a data collection registry (CAT-HF Registry). Randomization was stratified by LVEF as HFpEF (EF >45%) or HFrEF (EF ≤45%) and site using a permuted block design.
The primary endpoint was a composite global rank endpoint (26), which evaluates a rank order response (26) based on survival time, freedom from CV hospitalization, and improvement in functional capacity measured by change in 6MWD from baseline to 6 months. Patients who died within the first 6 months were assigned the lowest (worst) rank, assigned by the earliest death, and so forth. Among those alive at 6 months with cardiovascular hospitalization following randomization, the lowest (worst) rank was assigned to the patient with the earliest hospitalization. Finally, patients surviving without CV hospitalization were ranked based on percent change in 6MWD from baseline to 6 months. Secondary endpoints reported in this analysis include changes from baseline in sleep apnea parameters, functional capacity, recurrent hospitalizations or urgent clinic visits, cardiovascular and all-cause death, days alive and out of the hospital, biomarkers, QOL, sleep parameters, imaging parameters, and New York Heart Association (NYHA) functional class. Safety was evaluated by monitoring mortality and all-cause hospitalizations.
The primary analysis was based on the Wilcoxon-Mann-Whitney test, and therefore, the power calculation was approximated using the approach of Tang (27). Hypothesized differences between treatment groups were grouped across 5 categories. The hypothesized death or CV hospitalization differences were 25% for ASV versus 35% for control, and the hypothesized difference between groups in the percentage event free with a 6MWD improvement were 40% for ASV versus 20% for control. Assuming a 2-sided type I error of 0.05, the hypothesized differences provide 80% power with a sample size of 200 subjects. We planned to randomize a total of 215 subjects to achieve 200 evaluable subjects (100 per arm).
Descriptive summaries include mean ± SD for continuous variables; the number and frequency of subjects in each category are presented for nominal variables. Tests with a 2-sided p value <0.05 were considered statistically significant, unless otherwise specified. The primary analysis comparing change from baseline to follow-up in the ASV and control groups was conducted on an intention-to-treat (ITT) basis. A modified ITT (mITT) analysis was also conducted in which events that had already contributed to the global rank endpoint in the 26 HFrEF patients who were told to stop using ASV on May 13, 2015 (on the basis of the SERVE-HF results), were included, and if no event had occurred, the most recent 6MWD data before therapy cessation (May 13, 2015) were carried forward (i.e., baseline or 3-month values).
The primary analysis of the global rank endpoint was conducted using the Wilcoxon test. As a secondary analysis, and to support graphical presentation, a Cox proportional hazards model was used to test the significance of differences between the ASV and control groups overall for both pre-specified subgroups and interaction tests.
The steering committee made the decision to stop enrollment in CAT-HF when the results of the SERVE-HF study became available. Although the data safety and monitoring committee did not see a signal for harm in patients randomized to ASV in HFrEF subjects, there was a high degree of overlap in the patient populations with LVEF <45%. Therefore, enrollment in the CAT-HF study was stopped early and ASV treatment was stopped in patients with HFrEF, but remaining study visits were completed for data collection. HFpEF patients continued therapy to the end of the study. Full details of the early stopping decision and underlying rationale are provided in the Online Appendix.
A total of 126 patients were randomized at 13 clinical sites in the United States and 1 site in Germany from December 2013 to May 2015; 65 were assigned to the ASV group and 61 to the control group (Figure 1). Overall, the median patient age was 62 years, 26% were women, and 41% were Black. The majority of patients (n = 102; 81%) had HFrEF and 24 (19%) had HFpEF; 41% of patients had atrial fibrillation at baseline. There were no statistically significant differences in baseline characteristics between the control and ASV groups (Tables 1 and 2).
In the ASV group, the average device usage at 6 months was 2.7 h/day, compared with at least 3 h recommended in the study protocol. Additional details on adherence are described in the Online Appendix.
Overall prevalence of moderate-to-severe sleep apnea in all patients assessed was 65.4%. Sleep apnea severity, determined based on the AHI, decreased significantly from baseline in both groups (p = 0.0001), with a larger decrease in the ASV group (from 35.7 ± 17.1/h to 2.1 ± 2.2/h) compared with controls (from 35.1 ± 16.7/h to 19.0 ± 17.1/h; p = 0.0001 for between-group difference). Mean change in the AHI over time in the ASV and control groups is shown in Figure 2. ASV reduced AHI to levels considered normal at 1, 3, and 6 months.
Overall, the primary endpoint comparison was neutral, and there was no significant difference in the global rank endpoint between the ASV and control groups (p = 0.92) (Central Illustration). The rate of each event contributing to the primary endpoint in the ITT analysis, overall and by type of heart failure (HFrEF or HFpEF), is reported in Table 3. In the pre-specified analysis of the primary endpoint by LVEF strata, there was no statistically significant interaction between treatment groups and LVEF groups (Cox model interaction p = 0.10). However, the results were more favorable in the HFpEF subgroup (p = 0.036) (Figure 3). The results of other pre-specified subgroup analyses showed no significant differences between the ASV and control groups (Figure 3).
In the mITT analysis, the global rank endpoint (p = 0.91) was similar to that in the ITT analysis. Other results from the mITT analysis are shown in the Online Appendix.
Functional capacity, as indicated by the change in 6MWD, was similar in the ASV and control groups (Table 4). Also, there were no statistically significant differences between the ASV and controls groups with respect to the total number of cardiovascular hospitalizations (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 0.63 to 1.95), CV mortality (HR: 0.48; 95% CI: 0.09 to 2.59), all-cause mortality (HR: 0.54; 95% CI: 0.16 to 1.85), the number of days alive or out of hospital, biomarkers, daytime sleepiness, echocardiography parameters, and general QOL (Table 4). However, sleep apnea significantly improved in the ASV group versus controls, reflected by significantly greater decreases in the AHI and oxygen desaturation index, and patients in the ASV versus control group had statistically significant improvements in disease-specific quality of life (Kansas City Cardiomyopathy Questionnaire score) (Table 4). Changes in NYHA functional class during the study were not markedly different in the 2 groups (Online Table 1).
Although enrollment in the CAT-HF trial was stopped early, limiting statistical power, the results showed that sleep apnea commonly occurs in patients hospitalized for acute decompensation of HF, and is effectively controlled by the addition of ASV to optimized medical therapy. Alleviation of sleep apnea during ASV did not translate into improved clinical outcomes, with a neutral result for the primary global rank endpoint, although there was a suggestion of benefit in the subgroup of patients with preserved ejection fraction. CIs around the individual primary endpoint components were wide, precluding any definitive statement about the presence or absence of a safety signal such as that seen in the SERVE-HF trial.
Although the neutral primary endpoint result in the CAT-HF does mirror the main finding of the SERVE-HF trial (21), the 2 trials differed in several important ways. The CAT-HF trial included patients hospitalized with acute decompensation of HF regardless of LVEF, whereas the SERVE-HF trial enrolled chronic (≥12 weeks) stable HF patients with reduced ejection fraction, although these patients could have had a HF-related hospitalization ≥4 weeks before randomization. The type of sleep apnea also differed: CAT-HF patients had CSA, OSA, or coexisting CSA and OSA, whereas CSA was predominant in those enrolled in the SERVE-HF trial.
The results of the current study should be considered in the context of other treatments in patients with acute decompensated HF. Admission to the hospital with acute HF is a marker for worsening prognosis (28). Up to 50% of patients are rehospitalized within 6 months, and nearly one-third of these patients die within 1 year (29,30). The main goals of initial inpatient treatment are decreasing congestion and improving symptoms, with diuretics and intravenous vasodilators being the mainstay of therapy (28,31). There are a limited number of therapeutic trials of new pharmacological agents in this setting (32–36), and the majority have failed to show significant improvements in clinical outcomes and survival. Thus, management of comorbidities such as sleep apnea is an important option for improving patient outcome.
Perhaps the most interesting finding of CAT-HF was a pre-specified analysis showing a signal for improved outcomes with ASV therapy in the HFpEF subgroup. This finding is supported by ongoing analysis of data from SERVE-HF showing that the highest CV risk is evident in patients with the lowest EF (21), and that the response to ASV might be different in those with a higher ejection fraction. Although preliminary, the pre-specified subgroup analysis results from CAT-HF deserve further investigation given the differing presentations and epidemiology of HFpEF and HFrEF (37,38), the fact that there have been no improvements in survival for HFpEF patients over time (39), and that there are currently no evidence-based effective therapies for HFpEF, means that the focus is primarily on optimizing risk factors and treating comorbidities (38). One other randomized study has investigated ASV in patients with HFpEF and documented improvements in symptoms, diastolic function, arterial stiffness and the proportion of patients who did not experience cardiovascular events or rehospitalization for worsening HF (40). Similar results have been obtained in observational studies (41,42). Nevertheless, the positive results reported herein need to be tested in large, well-controlled clinical trials before any firm conclusions about the value of ASV in HFpEF can be drawn.
The results of the CAT-HF trial should be interpreted in light of several limitations. Most importantly, the trial was terminated early because of the unexpected safety signal reported in the SERVE-HF trial. This reduced the sample size and limited statistical power with respect to most endpoints. In addition, recommendation to discontinue ASV therapy in all patients with HFrEF, regardless of the type of sleep apnea, meant that patients with OSA were taken off treatment, limiting the ability to obtain useful data on the use of ASV in this group. The positive subgroup analysis findings around HFpEF patients and the global rank score were obtained in a small number of patients (n = 24) with broad CIs. Therefore, it is difficult to have confidence in the statistical hypothesis testing, and these findings regarding efficacy are at best hypothesis generating. Furthermore, adherence to ASV therapy was below the level recommended in the study protocol, which might have limited the ability of therapy to have an impact on the endpoints. It was interesting to note that AHI in the control group of the CAT-HF trial decreased at 6 months, although to a much lower extent than in the ASV group. Although effective management may not fully resolve sleep apnea, it may resolve in some patients and persist in others. Therefore, it may be appropriate that future studies focus on those with persistent sleep apnea. Finally, further analysis of CAT-HF data is needed to differentiate patients with different types of sleep apnea (i.e., OSA vs. CSA) and any associated variations in the response to ASV therapy in the setting of acute HF.
In this study of patients hospitalized with HF who have moderate-to-severe sleep apnea, the addition of ASV to optimized medical therapy did not improve 6-month cardiovascular outcomes compared with OMT alone. Study power was limited for detection of safety signals and for identifying differential effects of ASV in HFpEF patients, but additional studies in the latter group are warranted.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILL: ASV therapy (positive airway pressure) should be used cautiously in patients with HF and reduced left ventricular ejection fraction (≤45%) and predominantly central sleep apnea, but it may have a role in those with preserved ejection fractions.
TRANSLATIONAL OUTLOOK: Further studies are needed to identify patients with HF who benefit from ASV, focusing particularly on those with preserved ejection fractions.
The authors thank the patients who participated in the CAT-HF trial. Medical writing assistance was provided by Nicola Ryan, independent medical writer, funded by ResMed.
The CAT-HF trial was funded by ResMed Corp., San Diego, California. Drs. O’Connor, Whellan, Fiuzat, Punjabi, Anstrom, and Lindenfeld have received research funding from and are consultants for ResMed. Drs. Benjafield and Woehrle and Ms. Blase are employees of ResMed. Dr. Oldenberg is a consultant for ResMed; and has received speakers fees from and is on advisory boards for ResMed, LivaNova, Novartis, and Boehringer Ingelheim. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Akshay Suvas Desai, MD, MPH, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- 6-min walk distance
- apnea-hypopnea index
- adaptive servo-ventilation
- confidence interval
- central sleep apnea
- ejection fraction
- heart failure
- heart failure with preserved ejection fraction
- heart failure with reduced ejection fraction
- hazard ratio
- left ventricular ejection fraction
- modified intention-to-treat
- optimized medical therapy
- obstructive sleep apnea
- quality of life
- Received December 1, 2016.
- Revision received December 23, 2016.
- Accepted January 2, 2017.
- 2017 The Authors
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