Treatment of sleep-disordered breathing in heart failure impacts cardiac remodeling: Insights from the CAT-HF Trial

doi:10.1016/j.ahj.2018.03.026

American Heart Journal

Volume 201, July 2018, Pages 40-48

https://doi.org/10.1016/j.ahj.2018.03.026 Get rights and content

Abstract

Background

Sleep-disordered breathing (SDB), including central and obstructive sleep apnea, is a marker of poor prognosis in heart failure (HF) and may worsen cardiac dysfunction over time. Treatment of SDB with adaptive servoventilation (ASV) may reverse pathologic cardiac remodeling in HF patients.

Methods

The Cardiovascular Improvements with Minute Ventilation-targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) trial randomized patients with acute decompensated HF and confirmed SDB to either optimal medical therapy (OMT) or treatment with ASV and OMT. Patients with reduced ejection fraction (HFrEF) or preserved EF (HFpEF) were included. Echocardiograms, performed at baseline and 6 months, assessed cardiac size and function and evaluated cardiac remodeling over time. The CAT-HF trial was stopped early in response to the SERVE-HF trial, which found increased mortality among HFrEF patients with central sleep apnea treated with ASV.

Results

Of the 126 patients enrolled prior to trial cessation, 95 had both baseline and 6-month echocardiograms (77 HFrEF and 18 HFpEF). Among HFrEF patients, both treatment arms demonstrated a significant increase in EF: +4.3% in the ASV group (.0004) and +4.6% in OMT alone (P = .007) and a significant decrease in LV end-systolic volume index: −9.4 mL/m² in the ASV group (P = .01) and −8.6 mL/m² in OMT alone (P = .003). Reductions in left atrial (LA) volume and E/e’ were greater in the ASV arm, whereas patients receiving OMT alone demonstrated more improvement in right ventricular function. HFpEF patients treated with ASV also had a decrease in LA size that was greater than those receiving OMT alone. Although there were significant intragroup changes within the ASV + OMT and OMT-alone groups, there were no significant intergroup differences at 6 months.

Conclusions

Significant reverse LV remodeling was seen among HFrEF patients with SDB regardless of treatment allocation. Substantial reductions in LA volume among HFrEF and HFpEF patients receiving ASV suggest that ASV treatment may also improve diastolic function and warrant further investigation.

Section snippets

Study design and patient selection

The study design of the CAT-HF trial has been previously published.¹⁷ Briefly, CAT-HF was a multicenter trial that randomized patients with acute decompensated heart failure and confirmed SDB to either treatment with ASV and optimal medical therapy (OMT) or OMT alone. SDB classification and severity were evaluated using a type 3 cardiorespiratory polygraphy test with a respiratory effort sensor signal that classified patients as having either central or obstructive sleep apnea (ApneaLink Plus,

Results

Over 18 months, 126 heart failure patients were enrolled in the CAT-HF trial. Of these, 102 had HFrEF and 24 patients had HFpEF. Analyses of cardiac remodeling in HFrEF and HFpEF were analyzed separately. Among HFrEF patients, 52 were randomized to receive ASV + OMT, and 50 received OMT alone. Within these treatment groups, 40 patients in the ASV + OMT arm and 37 patients in the OMT-alone arm had paired baseline and 6-month echocardiograms that were adequate for quantitative analysis (Figure 1).

Discussion

In this study, we performed a comprehensive evaluation of cardiac remodeling in a multicenter trial of heart failure and SDB in which patients were randomized to treatment with ASV and OMT or OMT alone. Among HFrEF patients, we found that substantial reverse LV remodeling occurred over 6 months regardless of treatment allocation. However, compared with patients receiving OMT alone, the HFrEF patients treated with ASV + OMT had a greater reduction in E/e’ and indexed LA volume, suggesting that

Conclusions

In conclusion, HFrEF patients with SDB demonstrated substantial reverse cardiac remodeling during the CAT-HF trial. Specifically, EF increased and LV volumes decreased significantly irrespective of whether patients were treated with ASV + OMT or OMT alone. However compared with OMT alone, both HFrEF and HFpEF patients receiving ASV + OMT therapy had greater reductions in LA volumes, which suggest that ASV therapy may impact diastolic function and warrant further investigation given the scarcity

References (33)

T.D. Bradley et al.
Obstructive sleep apnoea and its cardiovascular consequences
Lancet
(2009)
T.E. Herrscher et al.
High prevalence of sleep apnea in heart failure outpatients: even in patients with preserved systolic function
J Card Fail
(2011)
A. Paulino et al.
Prevalence of sleep-disordered breathing in a 316-patient French cohort of stable congestive heart failure
Arch Cardiovasc Dis
(2009)
R.N. Khayat et al.
In-hospital testing for sleep-disordered breathing in hospitalized patients with decompensated heart failure: report of prevalence and patient characteristics
J Card Fail
(2009)
T. Kasai et al.
Obstructive sleep apnea and heart failure: pathophysiologic and therapeutic implications
J Am Coll Cardiol
(2011)
B. Shivalkar et al.
Obstructive sleep apnea syndrome: more insights on structural and functional cardiac alterations, and the effects of treatment with continuous positive airway pressure
J Am Coll Cardiol
(2006)
S. Javaheri et al.
Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure
J Am Coll Cardiol
(2007)
R. Khayat et al.
Central sleep apnea is a predictor of cardiac readmission in hospitalized patients with systolic heart failure
J Card Fail
(2012)
D.G. Kramer et al.
Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a meta-analytic approach
J Am Coll Cardiol
(2010)
M.A. Konstam et al.
Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment
JACC Cardiovasc Imaging
(2011)

B.K. Sharma et al.

Adaptive servoventilation for treatment of sleep-disordered breathing in heart failure: a systematic review and meta-analysis

Chest

(2012)

M. Fiuzat et al.

Lessons learned from a clinical trial: Design, rationale, and insights from The Cardiovascular Improvements with Minute Ventilation-targeted Adaptive Sero-Ventilation (ASV) Therapy in Heart Failure (CAT-HF) Study

Contemp Clin Trials

(2016)

C.W. Yancy et al.

2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

J Am Coll Cardiol

(2013)

C.M. O'Connor et al.

Cardiovascular outcomes with minute ventilation-targeted adaptive servo-ventilation therapy in heart failure: the CAT-HF trial

J Am Coll Cardiol

(2017)

R.M. Lang et al.

Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

J Am Soc Echocardiogr

(2015)

W.A. Zoghbi et al.

Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography

J Am Soc Echocardiogr

(2003)

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Cardiac remodeling is a life-long process in hypertrophic cardiomyopathy (HCM), and if uncontrolled, would cause substantial morbidity and mortality. Sleep apnea (SA) is a common comorbidity in HCM. This study aimed to investigate the relationship between SA and cardiac remodeling in a large series of patients with HCM.
A total of 606 patients with HCM who underwent sleep evaluations at Fuwai Hospital were included. Parameters of cardiac remodeling were evaluated by echocardiographic studies.
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Severity of SA is independently associated with cardiac remodeling indicating a trend toward enlarged chamber size and thinned wall. Clinical trials are required to determine whether treatment of SA improves cardiac remodeling and long-term outcomes in patients with HCM.
Diagnostic and therapeutic approach of central sleep apnea in heart failure – the role of adaptive servo-ventilation. A statement of the Portuguese society of pulmonology and the Portuguese sleep association
2023, Pulmonology
Citation Excerpt :
Nevertheless, it allowed to conclude that significant reverse left ventricular (LV) remodelling was observed among HFrEF patients with SDB, regardless of treatment allocation. Substantial reductions in left atrial volume among HFrEF and HFpEF patients receiving SV suggests that SV treatment may also improve diastolic function and warrant further investigation.16 A proof-of-concept study showed that treatment of sleep apnoea with SV leads to reduction in atrial fibrillation burden compared with OMT alone, without an increase in ventricular tachycardia/ventricular fibrillation (VT/VF) events.
It is known that patients with heart failure (HF) have an increased risk of developing central sleep apnoea (CSA), with Cheyne-Stokes respiration. The development of servo-ventilation aimed to treat CSA and improve the quality of life (QoL) of these patients. A large randomized clinical study, SERVE-HF, was conducted in order to test this theory in patients with HF and reduced ejection fraction (HFrEF). The results from this trial seemed to indicate that, in these patients, there was no beneficial effect of the assisted ventilation in CSA treatment. More surprisingly, an increased rate of all-cause or cardiovascular mortality was observed. This has led to dramatic changes in clinical practice, with decreased frequency of servo-ventilation prescription across Europe, including Portugal, due to changes in the guidelines. However, SERVE-HF was conducted only in severe systolic HF patients with CSA, and caution must be taken when extrapolating these results to HF patients with preserved ejection fraction or CSA patients without HF.
The study also showed poor adherence, methodological and statistical gaps, including study design, patient selection, data collection and analysis, treatment adherence, and group crossovers, which have not been discussed in the trial as potential confounding factors and raise several concerns. Moreover, the adaptive servo-ventilation (ASV) device used in SERVE-HF was unable to lower the minimum support pressure below 3 mm H₂0, and this has been suggested as one of the probable contributing reasons to the excess mortality observed in this study. This limitation has since been solved, and this ASV device is no longer used.
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The effect of obstructive sleep apnea on readmissions and atrial fibrillation after cardiac surgery
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With the compounded increase in morbidity as a consequence of OSA and atrial fibrillation, such patients are likely vulnerable to readmission. Studies examining the effects of OSA on normal physiology have linked it to adverse cardiac remodeling [36–38], which likely explains the predisposition to atrial fibrillation and worse outcomes. Such studies have also established the benefits of CPAP treatment in facilitating reverse remodeling and decreasing recurrences of atrial fibrillation [36–38].
To understand the effect of obstructive sleep apnea on readmission rates and post-operative atrial fibrillation in the cardiac surgical population.
Retrospective cohort study.
Administrative database consisting of 2007–2014 data from California, Florida, New York, Kentucky, and Maryland from the State Inpatient Databases, Healthcare Cost and Utilization Project.
A total of 506,604 patients ≥18 years old who underwent coronary artery bypass grafting surgery (CABG) and/or valve surgery were included in the study. After excluding for death during the index hospitalization and missing data, 396,657 patients remained for 30-day readmission analysis.
None.
Primary outcomes were unadjusted rates and adjusted odds of 30-day readmission. Secondary outcomes included post-operative atrial fibrillation and readmission diagnoses. Bivariate associations were assessed between OSA status, covariates and potential confounders, and outcomes. Odds ratios (OR) with 95% confidence intervals (CI) were estimated. Statistical significance was assessed at p < 0.05.
The overall 30-day readmission rate was 17.2%, with a rate of 19.6% vs. 17.1% in the OSA vs. non-OSA group (p < 0.001). Patients with OSA had higher odds of 30-day readmission (OR = 1.08, 95% CI 1.06–1.11) and higher odds of developing post-operative atrial fibrillation (OR = 1.04, 95% CI 1.01–1.08) compared to non-OSA patients. The most common reason for readmission was atrial fibrillation (38.6%), with OSA patients presenting with atrial fibrillation more frequently than their counterparts (41.7% vs. 38.4%, p < 0.001).
Patients with OSA are at increased risk of 30-day readmission and post-operative atrial fibrillation following cardiac surgery compared to those without OSA. Although the importance of OSA is increasingly recognized, it remains a significant risk factor for post-operative readmissions and morbidity. Further research is needed to optimize perioperative management of patients with OSA, but these results highlight the importance of this disease on patient outcomes and healthcare costs.
Effects of obstructive sleep apnea on myocardial injury and dysfunction: a review focused on the molecular mechanisms of intermittent hypoxia
2024, Sleep and Breathing
Positive Airway Pressure Therapy Adherence and Health Care Resource Use in Patients With Obstructive Sleep Apnea and Heart Failure With Preserved Ejection Fraction
2023, Journal of the American Heart Association
Non-invasive positive pressure ventilation for central sleep apnoea in adults
2022, Cochrane Database of Systematic Reviews

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: Larry A. Allen, MD, MHS, served as guest editor for this article.

: Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01953874

: Funding sources: The CAT-HF Trial was funded by ResMed Corp.

: Relationships with Industry: Duke Clinical Research Institute was the recipient of research grants from ResMed Corp. M. Daubert has received research support from ResMed Corp. D. Whellan has received consulting fees and research support from ResMed Corp. H. Woehrle was employed by ResMed and has received consulting fees and research support from ResMed Corp. K. Anstrom has received research support from ResMed Corp. J. Lindenfeld has received consulting fees and research support from ResMed Corp. A. Blase is employed by ResMed. A. Benjafield is employed by ResMed. M. Fiuzat has received consulting fees and research support from ResMed Corp. O. Oldenburg has received consulting fees and research support from ResMed Corp. C. O'Connor has received consulting fees and research support from ResMed Corp. The other authors report no relevant relationships with industry to disclose.

View full text

Clinical InvestigationTreatment of sleep-disordered breathing in heart failure impacts cardiac remodeling: Insights from the CAT-HF Trial

Abstract

Background

Methods

Results

Conclusions

Section snippets

Study design and patient selection

Results

Discussion

Conclusions

Lancet

J Card Fail

Arch Cardiovasc Dis

J Card Fail

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Card Fail

J Am Coll Cardiol

JACC Cardiovasc Imaging

Chest

Contemp Clin Trials

J Am Coll Cardiol

J Am Coll Cardiol

J Am Soc Echocardiogr

J Am Soc Echocardiogr

Clinical Investigation
Treatment of sleep-disordered breathing in heart failure impacts cardiac remodeling: Insights from the CAT-HF Trial