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C O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

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Cardiovascular Outcomes WithMinute Ventilation–Targeted AdaptiveServo-Ventilation Therapy in Heart FailureThe CAT-HF Trial

Christopher M. O’Connor, MD,a,b David J. Whellan, MD,c Mona Fiuzat, PHARMD,a Naresh M. Punjabi, MD, PHD,d

Gudaye Tasissa, PHD,a Kevin J. Anstrom, PHD,a Adam V. Benjafield, PHD,e Holger Woehrle, MD,f,g Amy B. Blase, BS,e

JoAnn Lindenfeld, MD,h Olaf Oldenburg, MDi

ABSTRACT

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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 ¼ 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 ¼ 0.10 Cox model); however, pre-specified subgroup analysis suggested a positive effect of ASV in patients

with HF with preserved ejection fraction (p ¼ 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)

(J Am Coll Cardiol 2017;69:1577–87) © 2017 The Authors. Published by Elsevier on behalf of the American College of

Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/

licenses/by-nc-nd/4.0/).

m the aDuke University and Duke Clinical Research Institute, Durham, North Carolina; bInova Heart and Vascular Institute,

lls Church, Virginia; cThomas Jefferson University, Philadelphia, Pennsylvania; dJohns Hopkins University, Baltimore, Mary-

d; eResMed Science Center, ResMed Corp, San Diego, California; fResMed Science Center, Martinsried, Germany; gSleep and

ntilation Center Blaubeuren, Respiratory Center Ulm, Ulm, Germany; hVanderbilt University, Nashville, Tennessee; and the

rz- und DiabeteszentrumNRW, Ruhr University Bochum, Bad Oeynhausen, Germany. The CAT-HF trial was funded by ResMed

rp., San Diego, California. Drs. O’Connor, Whellan, Fiuzat, Punjabi, Anstrom, and Lindenfeld have received research funding

m and are consultants for ResMed. Drs. Benjafield and Woehrle and Ms. Blase are employees of ResMed. Dr. Oldenburg is a

sultant for ResMed; and has received speakers fees from and is on advisory boards for ResMed, LivaNova, Novartis, and

ehringer Ingelheim. All other authors have reported that they have no relationships relevant to the contents of this paper to

close. Akshay Suvas Desai, MD, MPH, served as Guest Editor for this paper.

nuscript received December 1, 2016; revised manuscript received December 23, 2016, accepted January 2, 2017.

ABBR EV I A T I ON S

AND ACRONYMS

6MWD = 6-min walk distance

AHI = apnea-hypopnea index

ASV = adaptive servo-

ventilation

CI = confidence interval

CSA = central sleep apnea

CV = cardiovascular

EF = ejection fraction

HF = heart failure

HFpEF = heart failure with

preserved ejection fraction

HFrEF = heart failure with

reduced ejection fraction

HR = hazard ratio

ITT = intention-to-treat

LVEF = left ventricular ejection

fraction

mITT = modified intention-

to-treat

OMT = optimized medical

therapy

OSA = obstructive sleep apnea

QOL = quality of life

O’Connor et al. J A C C V O L . 6 9 , N O . 1 2 , 2 0 1 7

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S leep apnea is more common in patientswith heart failure (HF) than in the gen-eral population, with a reported preva-

lence of 50% to 75% (1,2). There are 2 maintypes of sleep apnea: obstructive (OSA) andcentral (CSA). OSA is common in patientswith HF with preserved ejection fraction(HFpEF), with a prevalence of 69% to 81%(3,4), and is independently associated witha worse prognosis (5), even when HF therapyis optimal (6). As cardiac function worsens,CSA and Cheyne-Stokes respiration increasein severity (1,3), with apnea-hypopneaindex (AHI) >30/h in many patients withacute decompensation of HF (7,8). CSAworsening might be due to stimulation ofstretch J-receptors by pulmonary congestion,which promotes hyperventilation and respi-ratory instability (9). The presence of CSAduring HF admission is associated with anincreased risk of morbidity and mortalityincluding higher rates of HF rehospitalization(10,11), and often persists after successfulmanagement of the acute decompensationepisode (8,12,13).

SEE PAGE 1588

Noninvasive positive airway pressure therapy withadaptive servo-ventilation (ASV) is indicated fortreatment of both CSA and OSA, and is more effectiveand better tolerated than continuous positive airwaypressure when treating CSA in HF patients (14,15).The results of several small studies and meta-analyses showed ASV improved plasma B-type natri-uretic peptide (BNP) concentration, left ventricularejection fraction (LVEF), quality of life (QOL), func-tional outcomes, and mortality in patients with heartfailure with reduced ejection fraction (HFrEF) andCSA (16–20). Conversely, the SERVE-HF (AdaptiveServo-Ventilation for Central Sleep Apnea in SystolicHeart Failure) trial, the first large randomized trial ofASV in chronic stable HFrEF patients with predomi-nant CSA, was neutral for the primary compositeendpoint. There was a signal for increased mortality,especially cardiovascular (CV) death, in patientsrandomized to ASV, particularly in the subgroup ofpatients who had worse left ventricular function(21,22).

There are currently no data from large randomizedtrials on the effects of positive airway pressure ther-apy for sleep apnea in patients hospitalized for HF.However, observational data suggest that treatingsleep apnea in the post-acute setting might reduce

mortality risk (11). The CAT-HF (Cardiovascular Im-provements With MV-ASV Therapy in Heart Failure)study investigated whether treatment of hospitalizedHF patients with moderate-to-severe sleep apneawith ASV in addition to optimized medical therapy(OMT) was associated with improved 6-month car-diovascular outcomes compared with OMT alone(control).

METHODS

The CAT-HF study was a randomized, controlled,multicenter clinical trial. The study design has beenreported previously (23). In brief, hospitalized HFpatients with either reduced or preserved ejectionfraction and an AHI $15 events per h were random-ized to usual care or active treatment in a 1:1 ratio.Two-hundred fifteen patients were intended to berandomized. At the time of discontinuation,126 patients were randomized. The primary endpointwas a global rank composite endpoint of death,CV hospitalizations, and 6-min walk distance(6MWD). Secondary endpoints included changes infunctional parameters, biomarkers, QOL, sleep, andbreathing.

The study was funded by ResMed Corp (San Diego,California). The full study protocol was designed andconducted by an independent academic steeringcommittee. The sponsor had nonvoting representa-tion on the steering committee and did notparticipate in closed sessions in which trial recom-mendations were made. The data coordinating center(Duke Clinical Research Institute) was responsible fordata management and statistical analysis. An inde-pendent data safety and monitoring committeemonitored the trial conduct and the safety of studyparticipants. The institutional review board ateach study site approved the study, and all patientsprovided written informed consent. CAT-HFincluded core laboratories for biomarkers, echocar-diography, sleep, and arrhythmias to evaluate sub-study findings.

PATIENTS AND RANDOMIZATION. Patients wereeligible if they were age $21 years and had a diagnosisof HFrEF or HFpEF with signs and symptoms of acuteHF, had dyspnea at rest or with minimal exertion,elevated natriuretic peptide levels (BNP $300 pg/mlor N-terminal pro-BNP $1,200 pg/ml), and at least 1additional sign or symptom (orthopnea, rales,congestion on chest radiograph, or pulmonary capil-lary wedge pressure $25 mm Hg). A complete listingof study inclusion and exclusion criteria has beenpublished previously (23) and is in the Online

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Appendix. Data for the study came from 14 differenthealth care centers.

Patients who met the study criteria signedinformed consent. A type 3 cardiorespiratory polyg-raphy device (ApneaLink Plus, ResMed, San Diego,California) was used to assess eligibility based on thesleep apnea criteria of an AHI of $15 events per h(minimum evaluation time 3 h). Definitions for ap-neas and hypopneas were based on the AmericanAcademy of Sleep Medicine 2007 recommendedscoring criteria (24). Patients who had moderate-to-

FIGURE 1 Study Flow

Assessed for eligibility(n=9,396)

Assessed for sleep apnea(n=373)

Randomized (n=126)

Allocated to ASV(n=65)

Analyzed for global rankendpoint(n=65)

Analyzed for gloendpoin

(n=61)

• Withdrew consent (n=4)*• Lost to follow-up (n=1)*• Physician decision (n=1)*• Other (n=2)*

• Withdrew conse• Lost to follow-u• Physician decisi• Other (n=2)*

Allocated to c(n=61)

Flow of patients through the CAT-HF (Cardiovascular Improvements Wit

consent or were lost to follow-up were included in the global rank endp

hypopnea index; ASV ¼ adaptive servo-ventilation; HF ¼ heart failure; P

severe sleep apnea (AHI $15/h) underwent ASVmask tolerability testing (second phase), in whichthey wore the mask with positive airway pressurebeing delivered for at least 2 h. Patients who satis-factorily completed the run-in phase were then ran-domized in a 1:1 ratio to the ASV group or controlgroup. OMT was based on the most recent AmericanCollege of Cardiology/American Heart Associationguideline recommendations (25). Patients notmeeting the criteria or not tolerating the run-in testwere enrolled in a data collection registry (CAT-HF

bal rankt

Completed registryassessment

(n=230)

Lost to follow-upfor registry

(n=17)

nt (n=2)*p (n=2)*

on (n=O)*

ontrol

Excluded (n=9,023) • No signs/symptoms of HF (n=1,835) • No prior diagnosis of HF (n=813) • Oxygen saturation ≤85% (n=758) • Current PAP therapy (n=735) • Chronic dialysis (n=594) • Other exclusion criteria (n=4,288)

Entered in registry (n=247) • AHI <15/h (n=123) • Did not tolerate ASV (n=14) • Declined/other (n=110)

h MV-ASV Therapy in Heart Failure) study. *Subjects who withdrew

oint analysis up to the point that they left the study. AHI ¼ apnea-

AP ¼ positive airway pressure.

TABLE 1 Baseline Characteristics

ASV (n ¼ 65) Control (n ¼ 61)*

Age, yrs

Mean 61 � 14 63 � 13

Median 62 (52–71) 65 (55–73)

Male 49 (75) 44 (72)

Body mass index, kg/m2

Mean 32.3 � 9.0 31.4 � 8.6

Median 31.3 (25.8–36.7) 28.7 (25.3–35.9)

White 35 (54) 34 (56)

NYHA functional class

I 3/63 (5) 3/60 (5)

II 19/63 (30) 11/60 (18)

III 32/63 (51) 43/60 (72)

IV 9/63 (14) 3/60 (5)

LVEF, %

Overall

Mean 30.5 � 15.4 33.7 � 15.7

Median 30 (17–40) 30 (20–45)

Reduced LVEF (#45%)

Mean 24.4 � 10.0 28.1 � (10.6)

Median 20 (15–32) 26.5 (18.0–40.0)

Preserved LVEF (>45%)

Mean 55.0 � 5.8 59.1 � 8.0

Median 55 (50–55) 55 (50–65)

Comorbid conditions

Diabetes mellitus 35 (54) 34 (56)

Hypertension 52 (80) 56 (92)

COPD 12 (19) 11 (18)

Ischemic HF etiology 26 (40) 18 (30)

Atrial fibrillation 26/63 (41) 26 (43)

Implanted device

Pacemaker 3 (5) 6 (10)

ICD 26 (40) 15 (25)

NT-proBNP, pg/ml

Mean 3,469 � 4,232 6,056 � 8,402

Median 2,537 (949–4,608) 2,998 (1,261–7,390)

6MWD, m

Mean 221 � 123 196 � 115

Median 200 (134–310) 175 (108–268)

Concomitant medications

ACEI or ARB (HFrEF only) 39/52 (75) 38/50 (76)

Beta-blocker (HFrEF only) 47/52 (90) 46/50 (92)

Aldosterone agonist 33 (51) 29 (48)

Loop diuretic 58 (89) 53 (87)

Values are mean � SD, median (interquartile range), n (%), or n/N (%). *p > 0.05 for all com-parisons between ASV and control groups.

6MWD ¼ 6-min walk distance; ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼angiotensin receptor blocker; ASV ¼ adaptive servo-ventilation; COPD ¼ chronic obstructivepulmonary disease; HF ¼ heart failure; HFrEF ¼ heart failure with reduced ejection fraction; ICD ¼implantable cardioverter-defibrillator; LVEF ¼ left ventricular ejection fraction; NT-proBNP ¼N-terminal B-type natriuretic peptide; NYHA ¼ New York Heart Association.

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Registry). Randomization was stratified by LVEF asHFpEF (EF >45%) or HFrEF (EF #45%) and site usinga permuted block design.

ENDPOINTS. The primary endpoint was a compositeglobal rank endpoint (26), which evaluates a rank

order response (26) based on survival time, freedomfrom CV hospitalization, and improvement in func-tional capacity measured by change in 6MWD frombaseline to 6 months. Patients who died within thefirst 6 months were assigned the lowest (worst) rank,assigned by the earliest death, and so forth. Amongthose alive at 6 months with cardiovascular hospi-talization following randomization, the lowest(worst) rank was assigned to the patient with theearliest hospitalization. Finally, patients survivingwithout CV hospitalization were ranked based onpercent change in 6MWD from baseline to 6 months.Secondary endpoints reported in this analysis includechanges from baseline in sleep apnea parameters,functional capacity, recurrent hospitalizations or ur-gent clinic visits, cardiovascular and all-cause death,days alive and out of the hospital, biomarkers, QOL,sleep parameters, imaging parameters, and New YorkHeart Association (NYHA) functional class. Safety wasevaluated by monitoring mortality and all-causehospitalizations.

SAMPLE SIZE. The primary analysis was based on theWilcoxon-Mann-Whitney test, and therefore, the po-wer calculation was approximated using the approachof Tang (27). Hypothesized differences betweentreatment groups were grouped across 5 categories.The hypothesized death or CV hospitalization differ-ences were 25% for ASV versus 35% for control, and thehypothesized difference between groups in the per-centage event free with a 6MWD improvementwere 40% for ASV versus 20% for control. Assuminga 2-sided type I error of 0.05, the hypothesizeddifferences provide 80% power with a sample size of200 subjects. We planned to randomize a total of 215subjects to achieve 200 evaluable subjects (100 perarm).

STATISTICAL ANALYSIS. Descriptive summariesinclude mean � SD for continuous variables; thenumber and frequency of subjects in each categoryare presented for nominal variables. Tests with a2-sided p value <0.05 were considered statisticallysignificant, unless otherwise specified. The primaryanalysis comparing change from baseline to follow-upin the ASV and control groups was conducted on anintention-to-treat (ITT) basis. A modified ITT (mITT)analysis was also conducted in which events that hadalready contributed to the global rank endpoint in the26 HFrEF patients who were told to stop using ASV onMay 13, 2015 (on the basis of the SERVE-HF results),were included, and if no event had occurred, the mostrecent 6MWD data before therapy cessation (May 13,2015) were carried forward (i.e., baseline or 3-monthvalues).

TABLE 2 Respiratory Characteristics at Baseline

ASV (n ¼ 65) Control (n ¼ 61)*

ESS score 9.2 � 5.7 10.4 � 6.1

AHI, events/h

Mean 35.7 � 17.1 35.1 � 16.7

Median 31 (22-48) 33 (20-48)

CSA† 47 (72) 48 (79)

Oxygen desaturation index, events/h

Mean 36.8 � 18.0 34.6 � 14.7

Median 32 (23–53) 34 (23–46)

Time with oxygen saturation <90%, min

Mean 156.3 � 140.5 122.2 � 128.3

Median 123 (37–238) 80 (34–183)

Values are mean � SD, median (interquartile range), or n (%). *p > 0.05 for allcomparisons between the ASV and control groups. †The sleep core lab classifiedsleep apnea by manually scoring central and obstructive apneas and hypopneas.

AHI ¼ apnea-hypopnea index; CSA ¼ central sleep apnea; ESS ¼ EpworthSleepiness Scale; other abbreviations as in Table 1.

FIGURE 2 Change in AHI

40

30

35

20

25

15

10

5

00 1 2 3 4 5 6

Mea

n AH

I (ev

ents

/h)

ControlASV

Months on Study

Change in mean AHI over time in the ASV and control groups. events/h ¼ events per hour;

other abbreviations as in Figure 1.

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The primary analysis of the global rank endpointwas conducted using the Wilcoxon test. As a sec-ondary analysis, and to support graphical presenta-tion, a Cox proportional hazards model was used totest the significance of differences between the ASVand control groups overall for both pre-specifiedsubgroups and interaction tests.

The steering committee made the decision to stopenrollment in CAT-HF when the results of the SERVE-HF study became available. Although the data safetyand monitoring committee did not see a signal forharm in patients randomized to ASV in HFrEF sub-jects, there was a high degree of overlap in the patientpopulations with LVEF <45%. Therefore, enrollmentin the CAT-HF study was stopped early and ASVtreatment was stopped in patients with HFrEF, butremaining study visits were completed for datacollection. HFpEF patients continued therapy to theend of the study. Full details of the early stoppingdecision and underlying rationale are provided in theOnline Appendix.

RESULTS

A total of 126 patients were randomized at 13 clinicalsites in the United States and 1 site in Germany fromDecember 2013 to May 2015; 65 were assigned to theASV 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 ofpatients (n ¼ 102; 81%) had HFrEF and 24 (19%) hadHFpEF; 41% of patients had atrial fibrillation atbaseline. There were no statistically significant dif-ferences in baseline characteristics between the con-trol and ASV groups (Tables 1 and 2).

In the ASV group, the average device usage at6 months was 2.7 h/day, compared with at least 3 hrecommended in the study protocol. Additional de-tails on adherence are described in the OnlineAppendix.

Overall prevalence of moderate-to-severe sleepapnea in all patients assessed was 65.4%. Sleep apneaseverity, determined based on the AHI, decreasedsignificantly from baseline in both groups(p ¼ 0.0001), with a larger decrease in the ASV group(from 35.7 � 17.1/h to 2.1 � 2.2/h) compared withcontrols (from 35.1 � 16.7/h to 19.0 � 17.1/h;p ¼ 0.0001 for between-group difference). Meanchange in the AHI over time in the ASV and controlgroups is shown in Figure 2. ASV reduced AHI tolevels considered normal at 1, 3, and 6 months.

PRIMARY ENDPOINT. Overall, the primary endpointcomparison was neutral, and there was no significantdifference in the global rank endpoint between theASV and control groups (p ¼ 0.92) (CentralIllustration). The rate of each event contributing tothe primary endpoint in the ITT analysis, overall andby type of heart failure (HFrEF or HFpEF), is reportedin Table 3. In the pre-specified analysis of the primaryendpoint by LVEF strata, there was no statisticallysignificant interaction between treatment groups andLVEF groups (Cox model interaction p ¼ 0.10). How-ever, the results were more favorable in the HFpEFsubgroup (p ¼ 0.036) (Figure 3). The results of otherpre-specified subgroup analyses showed no

CENTRAL ILLUSTRATION Cardiovascular Effects of Adaptive Servo-Ventilation Therapy in Heart Failure:Primary Endpoint

O’Connor, C.M. et al. J Am Coll Cardiol. 2017;69(12):1577–87.

This trial considered whether adaptive servo-ventilation (ASV) improved cardiovascular (CV) outcomes in hospitalized heart failure (HF) patients with moderate-to-

severe sleep apnea. The primary endpoint was a composite global rank score of hierarchy of death, CV hospitalizations, and change in 6-min walk distance (6MWD) at

6 months in patients randomized to ASV plus optimized medical therapy or optimized medical therapy alone (control). There was no significant difference in the

primary endpoint, although pre-specified subgroup analysis suggested a positive effect of ASV in patients with HF with preserved ejection fracture (HFpEF). 6MWD

Better implies 6-month event-free survival and an improvement from baseline in 6MWD >50%; 6MWD Worse implies 6-month event-free survival and a decrease

from baseline in 6MWD or missing 6MWD at 6 months. HFrEF ¼ heart failure with reduced ejection fraction.

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significant differences between the ASV and controlgroups (Figure 3).

In the mITT analysis, the global rank endpoint(p ¼ 0.91) was similar to that in the ITT analysis. Otherresults from the mITT analysis are shown in theOnline Appendix.

SECONDARY ENDPOINTS. Functional capacity, asindicated by the change in 6MWD, was similar in theASV and control groups (Table 4). Also, there were nostatistically significant differences between the ASVand 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), CVmortality (HR: 0.48; 95% CI: 0.09 to 2.59), all-causemortality (HR: 0.54; 95% CI: 0.16 to 1.85), the num-ber of days alive or out of hospital, biomarkers, day-time sleepiness, echocardiography parameters, andgeneral QOL (Table 4). However, sleep apnea signifi-cantly improved in the ASV group versus controls,reflected by significantly greater decreases in the AHIand oxygen desaturation index, and patients in theASV versus control group had statistically significantimprovements in disease-specific quality of life

TABLE 3 Primary Endpoint Events at 6 Months (Intention-to-Treat Analysis)

Incidence

Overall HFrEF HFpEF

ASV (n ¼ 65) Control (n ¼ 61) ASV (n ¼ 52) Control (n ¼ 50) ASV (n ¼ 13) Control (n ¼ 11)

Death at 6 months 4 (6) 7 (11) 3 (6) 7 (14) 1 (8) 0 (0)

CV hospitalization (excluding deaths) 24 (37) 17 (28) 22 (42) 12 (24) 2 (15) 5 (45)

6MWD worse* 12 (18) 13 (21) 9 (17) 9 (18) 3 (23) 4 (36)

6MWD same* 18 (28) 13 (21) 12 (23) 11 (22) 6 (46) 2 (18)

6MWD better* 7 (11) 11 (18) 6 (12) 11 (22) 1 (8) 0 (0)

Wilcoxon p value 0.92 0.70 0.12

Wilcoxon interaction p value 0.22

Cox p value 0.74 0.40 0.036

Cox interaction p value 0.10

Values are n (%). Subjects were classified as “Worse” if the 6MWD at 6 months had decreased from baseline; subjects alive without CV hospitalization and missing 6MWD wereclassified as 6MWD Worse. Subjects were classified as Same if the 6MWD at 6 months was better than baseline by no >50%. Subjects were classified as Better if the 6MWDincreased by >50% from baseline to 6 months. *For the subset of patients alive and without cardiovascular hospitalization at 6 months.

6MWD ¼ 6-min walk distance; CV ¼ cardiovascular; HFpEF ¼ heart failure with preserved ejection fraction; other abbreviations as in Table 1.

FIGURE 3 Global Rank Endpoint: Hazard Ratios

Group HR 95% CI P-value

OverallAge (yrs)

≥75<75

Sex

Race 0.80

0.89

0.10

0.54

0.38

0.38

Region

EF

Obesity

Afib

Etiology

ASV Better<--- Control Better--->0.125

Based on global rank order endpoint (using Cox model analysis)The p-value is from the test statistic for testing the interaction between treatment and any subgroup variable

0.25 0.5 1 2

0.97

0.22MaleFemale

WhiteNon-White

USAGermany

PreservedReduced

0.361.18

0.14, 0.930.80, 1.76

Obese (BMI ≥30)Non-obese (BMI <30)

1.220.95

0.73, 2.050.58, 1.56

YesNo

0.881.22

0.50, 1.560.76, 1.96

IschemicNon-ischemic/other/uncertain

1.260.92

0.68, 2.330.59, 1.42

1.041.02

0.69, 1.570.53, 1.99

1.061.06

0.891.36

0.46, 2.430.71, 1.57

0.59, 1.350.68, 2.75

1.081.00

0.67, 1.740.59, 1.69

1.06

Hazard Ratio Overall and by Sub-groups (with no censoring)

0.75, 1.51 0.74

Primary endpoint result: global rank endpoint in the ASV and control groups, including scores for 6MWD, cardiovascular hospitalization (CV hosp), and death. Results

are shown for all patients, patients with heart failure with reduced ejection fraction (HFrEF), and patients with heart failure with preserved ejection fraction (HFpEF).

6MWD Better implies 6-month event-free survival and an improvement from baseline in 6MWD of >50%. 6MWD Worse implies 6-month event-free survival and a

decrease from baseline in 6MWD or missing 6MWD at 6 months. Afib ¼ atrial fibrillation; BMI ¼ body mass index; CI ¼ confidence interval; EF ¼ ejection fraction; HR ¼hazard ratio; other abbreviations as in Figure 1.

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TABLE 4 Secondary Endpoints at 6 Months

ASV Control p Value

Change in 6MWD*, m

Mean 22.6 � 131.3 61.2 � 117.4 0.22

Median 52 (�65 to 100) 47 (4 to 159)

CV hospitalization 34 (52.3) 27 (44.3) 0.37

CV death 2 (3.1) 4 (6.6) 0.43

All-cause death 4 (6.2) 7 (11.5) 0.29

Days alive and out of hospital

Mean 144.0 � 48.3 152.6 � 43.5 0.050

Median 167 (135 to 176) 173 (151 to 179)

Sleep-disordered breathing

Change in AHI, /h <0.001

Mean �33.7 � 16.9 �17.9 � 22.3

Median �31.6 (�46.9 to �21.5) �16.0 (�32.0 to �5.0)

Change in ODI, /h 0.017

Mean �28.3 � 17.5 �16.3 � 20.5

Median �27.0 (�40.0 to �17.0) �18.0 (�32.0 to �8.0)

Sleep quality and sleepiness

Change in ESS score 0.59

Mean �1.6 � 5.6 �2.1 � 5.1

Median �1.0 (�5.0 to 2.0) �2.0 (�4.5 to 0.5)

Change in PSQI score 0.59

Mean �2.7 � 5.0 �3.3 � 4.9

Median �2.5 (�5.5 to 0.50) �3.0 (�6.0 to 0.5)

Biomarkers

Change in NT-pro-BNP, pg/ml 0.053

Mean 172.7 � 3,429.1 �1,069.9 � 6,768.2

Median �143.0 (�1,383.7 to 701.0) (�775.0 to �9.7)

Change in troponin I ultrasensitive, ng/ml 0.82

Mean �13.32 � 32.08 �14.08 � 41.82

Median �3.11 (�7.58 to �0.05) �3.51 (�10.28 to 0.23)

Change in hs-CRP, mg/l 0.79

Mean 0.03 � 0.60 0.29 � 1.61

Median �0.03 (�0.22 to 0.27) �0.04 (�0.22 to 0.30)

Change in creatinine,mg/dl

Mean 0.18 � 0.66 0.08 � 0.38

Median 0.25 (�0.25 to 0.60) 0.05 (�0.20 to 0.30)

Continued on the next page

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(Kansas City Cardiomyopathy Questionnaire score)(Table 4). Changes in NYHA functional class duringthe study were not markedly different in the 2 groups(Online Table 1).

DISCUSSION

Although enrollment in the CAT-HF trial was stoppedearly, limiting statistical power, the results showedthat sleep apnea commonly occurs in patients hospi-talized for acute decompensation of HF, and iseffectively controlled by the addition of ASV to opti-mized medical therapy. Alleviation of sleep apneaduring ASV did not translate into improved clinicaloutcomes, with a neutral result for the primary global

rank endpoint, although there was a suggestion ofbenefit in the subgroup of patients with preservedejection fraction. CIs around the individual primaryendpoint components were wide, precluding anydefinitive statement about the presence or absence ofa safety signal such as that seen in the SERVE-HFtrial.

Although the neutral primary endpoint result inthe CAT-HF does mirror the main finding of theSERVE-HF trial (21), the 2 trials differed in severalimportant ways. The CAT-HF trial included patientshospitalized with acute decompensation of HFregardless of LVEF, whereas the SERVE-HF trialenrolled chronic ($12 weeks) stable HF patientswith reduced ejection fraction, although these pa-tients could have had a HF-related hospitalization$4 weeks before randomization. The type ofsleep apnea also differed: CAT-HF patients hadCSA, OSA, or coexisting CSA and OSA, whereas CSAwas predominant in those enrolled in the SERVE-HFtrial.

The results of the current study should be consid-ered in the context of other treatments in patientswith acute decompensated HF. Admission to thehospital with acute HF is a marker for worseningprognosis (28). Up to 50% of patients are rehospi-talized within 6 months, and nearly one-third of thesepatients die within 1 year (29,30). The main goals ofinitial inpatient treatment are decreasing congestionand improving symptoms, with diuretics and intra-venous vasodilators being the mainstay of therapy(28,31). There are a limited number of therapeutictrials of new pharmacological agents in this setting(32–36), and the majority have failed to show signifi-cant improvements in clinical outcomes and survival.Thus, management of comorbidities such as sleepapnea is an important option for improving patientoutcome.

Perhaps the most interesting finding of CAT-HFwas a pre-specified analysis showing a signal forimproved outcomes with ASV therapy in the HFpEFsubgroup. This finding is supported by ongoinganalysis of data from SERVE-HF showing that thehighest CV risk is evident in patients with the lowestEF (21), and that the response to ASV might bedifferent in those with a higher ejection fraction.Although preliminary, the pre-specified subgroupanalysis results from CAT-HF deserve further inves-tigation given the differing presentations and epide-miology of HFpEF and HFrEF (37,38), the fact thatthere have been no improvements in survival forHFpEF patients over time (39), and that there arecurrently no evidence-based effective therapies forHFpEF, means that the focus is primarily on

TABLE 4 Continued

ASV Control p Value

Echocardiography parameters

Change in LVEF, %† 0.71

Mean 3.812 � 6.318 4.953 � 9.501

Median 1.913 (�0.583 to 5.657) 2.373 (�0.857 to 9.433)

Change in LVESVI† 0.39

Mean �9.016 � 21.169 �8.621 � 16.213

Median �6.436 (�14.930 to 4.419) �12.430 (�17.914 to �0.418)

Change in E/e0 ratio‡

Patients withpreserved EF

0.25

Mean �2.124 � 9.011 �4.567 � 6.729

Median 0.284 (�4.421 to 3.725) �5.022 (�8.203 to �2.715)

Patients with reducedEF

0.55

Mean �3.183 � 9.555 �2.567 � 13.741

Median �3.110 (�8.037 to 4.383) �2.854 (�4.623 to 2.311)

Quality of life

Change in KCCQ score 0.053

Mean 20.28 � 28.30 24.74 � 29.02

Median 20.96 (5.76 to 35.03) 22.92 (3.13 to 40.36)

Change in DASI score 0.42

Mean 3.73 � 13.40 5.24 � 14.50

Median 2.75 (�4.88 to 8.10) 5.50 (�2.50 to 11.75)

Change in PHQ-9 score 0.08

Mean �2.8 � 6.7 �4.6 � 6.7

Median �2.0 (�5.0 to 0.0) �6.0 (�9.0 to 1.0)

Change in EQ-5D-5Lindex score

0.49

Mean 0.07 � 0.23 0.03 � 0.22

Median 0.05 (�0.04 to 0.20) 0.07 (�0.05 to 0.15)

Values are mean � SD, median (interquartile range), or n (%). *Complete case analysis based on the subset with6-month 6MWD. †In patients with reduced EF. ‡In patients with preserved EF.

DASI ¼ Duke Activity Status Index; EQ-5D-5L ¼ EuroQol-5D-5L; EF ¼ ejection fraction; hs-CRP ¼ high-sensitivity C-reactive protein; KCCQ ¼ Kansas City Cardiomyopathy Questionnaire; LVESVI ¼ left ventricularend-systolic volume index; ODI ¼ oxygen desaturation index; PHQ-9 ¼ Patient Health Questionnaire-9; PSQI ¼Pittsburgh Sleep Quality Index; other abbreviations as in Tables 1 and 2.

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optimizing risk factors and treating comorbidities(38). One other randomized study has investigatedASV in patients with HFpEF and documented im-provements in symptoms, diastolic function, arterialstiffness and the proportion of patients who did notexperience cardiovascular events or rehospitalizationfor worsening HF (40). Similar results have been ob-tained in observational studies (41,42). Nevertheless,the positive results reported herein need to be testedin large, well-controlled clinical trials before any firmconclusions about the value of ASV in HFpEF can bedrawn.

STUDY LIMITATIONS. The results of the CAT-HF trialshould be interpreted in light of several limitations.Most importantly, the trial was terminated earlybecause of the unexpected safety signal reported inthe SERVE-HF trial. This reduced the sample size andlimited statistical power with respect to most end-points. In addition, recommendation to discontinueASV therapy in all patients with HFrEF, regardless ofthe type of sleep apnea, meant that patients with OSAwere taken off treatment, limiting the ability toobtain useful data on the use of ASV in this group.The positive subgroup analysis findings aroundHFpEF patients and the global rank score were ob-tained in a small number of patients (n ¼ 24) withbroad CIs. Therefore, it is difficult to have confidencein the statistical hypothesis testing, and these find-ings regarding efficacy are at best hypothesis gener-ating. Furthermore, adherence to ASV therapy wasbelow the level recommended in the study protocol,which might have limited the ability of therapy tohave an impact on the endpoints. It was interesting tonote that AHI in the control group of the CAT-HF trialdecreased at 6 months, although to a much lowerextent than in the ASV group. Although effectivemanagement may not fully resolve sleep apnea, itmay resolve in some patients and persist in others.Therefore, it may be appropriate that future studiesfocus on those with persistent sleep apnea. Finally,further analysis of CAT-HF data is needed to differ-entiate patients with different types of sleep apnea(i.e., OSA vs. CSA) and any associated variations inthe response to ASV therapy in the setting ofacute HF.

CONCLUSIONS

In this study of patients hospitalized with HF whohave moderate-to-severe sleep apnea, the addition ofASV to optimized medical therapy did not improve6-month cardiovascular outcomes compared with

OMT alone. Study power was limited for detection ofsafety signals and for identifying differential effectsof ASV in HFpEF patients, but additional studies inthe latter group are warranted.

ACKNOWLEDGMENTS The authors thank the pa-tients who participated in the CAT-HF trial.Medical writing assistance was provided by NicolaRyan, independent medical writer, funded byResMed.

ADDRESS FOR CORRESPONDENCE: Dr. ChristopherM. O’Connor, Inova Heart & Vascular Institute, 3300Gallows Road, IHVI Administration, Suite 1225, FallsChurch, Virginia 22042. E-mail: christopher.oconnor@inova.org.

PERSPECTIVES

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.

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KEY WORDS 6-min walk distance, acuteheart failure, HFpEF, mortality, sleep apnea

APPENDIX For a list of the trialinvestigators, committees, and participatinginstitutions, and an expanded Methods section,please see the online version of this paper.