According to an estimate by the American Heart Association (AHA), 5.1 million American adults suffered from heart failure (HF) in 2014 [
Forty percent to half of patients with chronic heart failure (CHF) and impaired left ventricular function go on to develop sleep-disordered breathing (SDB), either obstructive or central sleep apnea (OSA or CSA) [
Perhaps because of limitations in sample size, incomplete data reporting, and population differences, not all studies on NPPV have yielded positive results in terms of cardiac function improvement. For instance, Pepperell et al. found no difference in change in left ventricular ejection fraction (LVEF) between ASV treated patients and controls [
We therefore sought to explore in a meta-analysis if adult patients with CHF would benefit from NPPV in improving cardiac function, in the form of cPAP or ASV, as compared to standard medical treatment (SMT).
A systematic literature review was undertaken on January 26th, 2015, using PubMed, OVID, and EMBASE databases. To retrieve the largest number of potentially related studies, the following terms were used individually: “noninvasive positive pressure ventilation,” “continuous positive airway pressure,” “bilevel positive airway pressure,” “adaptive servo-ventilation,” and “heart failure.” Articles were first screened by title and abstract, and reviews, meta-analyses, guidelines, letters, case reports, clinical trials in children, newborns, or postsurgical patients, and animal experiments were excluded. Three studies with full texts not written in English also were excluded.
The following criteria then were used to identify potentially suitable studies in a second screen: the trials were (a) well-designed randomized controlled trials (RCTs), quasirandomized controlled trials (qRCTs), and nonrandomized controlled trials; (b) enrolled subjects were adults older than 18 years and diagnosed with chronic heart failure, with or without sleep-disordered breathing (SDB); and (c) the intervention was noninvasive positive pressure ventilation (NPPV) in the form of continuous positive airway pressure (cPAP), adaptive servoventilation (ASV), or bilevel positive airway pressure (BiPAP), plus standard medical treatment (SMT), while the control treatment was SMT plus sham-NPPV or SMT only; and (d) left ventricular ejection fraction (LVEF) must be included in the study outcomes.
After the above-mentioned screening, the authors obtained the full text articles and read them carefully and independently. Articles meeting the following criteria were excluded: (a) follow-up period was less than 4 weeks; (b) number of study participants was less than 10; (c) crossover-design was excluded if data before washout were not reported or unavailable; (d) outcome LVEF was only reported by a descriptive conclusion (original data or processed data were not reported or available); and (e) subjects from subgroup analysis of the other clinical trials were repeatedly counted. In addition, we excluded articles including BiPAP from the final analysis because BiPAP worsens, rather than improves, central apneas [
Two authors extracted data independently. Descriptive data include first author, publication year, study design, duration of study arms, duration of washout (if applicable), type of control used, HF inclusion criteria, SDB inclusion criteria, proportion of male patients, mean age, and mean BMI (if available). For outcome data, the mean together with standard deviation (SD) at baseline and end-trial time point was extracted for the NPPV and control arms. Standard error of the mean (SEM) was converted into SD. The change in mean was calculated as end-trial value minus baseline value. Variables reported in interquartile range were converted into mean using the method provided in the
Two authors (Chenqi Xu and Hao Jiang) conducted the analyses using Review Manager version 5.2 (Nordic Cochrane Center). The pooled estimate of mean weight difference (MWD) or risk ratio (RR) with their 95% CI was calculated using random effect model or fixed effect model according to heterogeneity among studies.
In a search of the PubMed database, 1478 potential articles were identified. After applying the prespecified exclusion and inclusion criteria, the full texts of 75 articles were read, yielding 23 eligible studies. During data extraction and analysis, 4 additional studies were excluded for different reasons: Smith et al. (2007) [
Characteristics of 19 studies included in meta-analysis.
Study | Length of follow-up | Location | Ventilator mode | Ventilator parameters | Ventilator connection method | Patients | Control | Trial | Control | Results |
---|---|---|---|---|---|---|---|---|---|---|
Arzt et al. 2005 | 3 months | Germany | CPAP | CPAP: 8 to 12 cm H2O | Face mask | CHF with CSA | Nasal oxygen treatment | 14 (NP), 64.0 ± 2 | 10 (NP), 65.0 ± 2 | Ventilatory efficiency LVEF |
Bradley et al. 2005 | 2 years | Canada | CPAP | CPAP: 10 cm H2O | Face mask | CHF with CSA | SMT | 128 (125/3), 63.2 ± 9.1 | 130 (123/7), 63.5 ± 9.8 | Effect of CPAP on CSA and LVEF Death rates |
Egea et al. 2008 | 3 months | Spain | CPAP | NP | Face mask | CHF with SA | Sham-CPAP | 28 (24/4), 64.0 ± 0.9 | 32 (29/3), 63.0 ± 1.6 | AHI and LVEF |
Ferrier et al. 2008 | 6 months | New Zealand | CPAP | NP | Face mask | CHF with OSA | SMT | 19 (16/3), 58.5 ± 11.2 | 7 (3/4), 60.3 ± 4.3 | LVEF, SBP, BNP, LVESD, LVEDD |
Granton et al. 1996 | 3 months | Canada | NCPAP | CPAP: 10 to 12.5 cm H2O | Nasal mask | CHF with CSR-CSA | SMT | 9 (NP), 58.3 ± 2.2 | 8 (NP), 58.0 ± 2.0 | MIP and MEP, LVEF, dyspnea |
Haruki et al. 2011 | 6 months | Japan | ASV | EPAP: 5 cm H2O | Face mask | CHF | SMT | 15 (11/4), 67.0 ± 11.0 | 11 (8/3), 67.0 ± 14.0 | LVEF, LVEDV, LVESV |
Hastings et al. 2010 | 6 months | United Kingdom | ASV | NP | Face mask | CHF with SA | SMT | 11 (NP), 61.3 ± 10.0 | 8 (NP), 64.5 ± 8.0 | AHI, LVEF, BNP |
Johnson et al. 2008 | 6.9 ± 3.3 months | Canada and United States | CPAP | CPAP: 10.6 ± 1.6 cm | Nasal mask | CHF with OSA | SMT | 7 (7/0), 61.0 ± 12.0 | 5 (5/0), 62.0 ± 9.0 | Stroke volume, LVEF, LVEDV, LVESV |
Joho et al. 2012 | 3.5 ± 0.8 months | Japan | ASV | EPAP: 4-5 cm H2O IPAP: 3–10 cm H2O | Face mask | CHF with CSA | SMT | 20 (18/2), 62.0 ± 11.0 | 12 (10/2), 68.0 ± 9.0 | LVEF, LVDd, LVDs, BNP, MSNA |
Kaneko et al. 2003 | 1 month | Canada | CPAP | CPAP: 8.9 ± 0.7 cm H2O | NP | CHF with OSA | SMT | 12 (11/1), 55.9 ± 2.5 | 12 (10/2), 55.2 ± 3.6 | BP, HR, LVESD, LVEDD, LVEF |
Koyama et al. 2010 | 1 month | Japan | ASV | EPAP: 4 cm H2O | NP | CHF with SDB | SMT | 10 (8/2), 68.4 ± 4.0 | 7 (4/3), 71.4 ± 7.6 | AHI hs-CRP BNP LVEF |
Koyama et al. 2011 | 12 months | Japan | ASV | EPAP: 5 cm H2O | NP | CHF with SDB | SMT | 27 (23/4), 74.8 ± 7.6 | 16 (13/3), 75.4 ± 6.4 | eGFRhs-CRP, LVEF |
Mansfield et al. 2004 | 3 months | Australia | CPAP | CPAP: 8.8 ± 1.4 mm Hg | Nasal mask | CHF with OSA | SMT | 28 (28/0), 57.2 ± 1.7 | 27 (24/3), 57.5 ± 1.6 | LVEF, UNE |
Naughton et al. 1995 | 1 month | Canada | NCPAP | CPAP: 10 to 12.5 cm H2O | Nasal mask | CHF with CSR-CSA | SMT | 12 (NP), 61.0 ± 3.2 | 12 (NP), 56.6 ± 3.2 | LVEF effect of NCPAP on CSA |
Oldenburg et al. 2011 | 12 months | Germany | ASV | EPAP: 4-5 cm H2O | Face mask | CHF with CSR | SMT and CPAP noncompliance | 56 (54/2), 67.7 ± 9.5 | 59 (52/7), 62.5 ± 11.8 | NT-proBNP |
Pepperell et al. 2003 | 1 month | United Kingdom | ASV | EPAP: 5 cm H2O | NP | CHF with CSR | Subtherapeutic ASV | 15 (15/0), 71.4 ± 8.6 | 15 (14/1), 70.9 ± 7.9 | Osler test BNP |
Tkacova et al. 1997 | 1 month | Canada | CPAP | CPAP: 10 to 12.5 cm H2O | Nasal mask | CHF with CSR-CSA | SMT | 9 (NP), 61.0 ± 1.9 | 8 | LVEF, ANP, MRF |
Usui et al. 2005 | 1 month | Canada | CPAP | CPAP: 7.5 ± 0.5 cm H2O | NP | CHF with OSA | SMT | 8 (8/0), 55.0 ± 2.0 | 9 (7/2), 52.2 ± 4.1 | MSNA, BP, HR, LVEF |
Yoshihisa et al. 2011 | 6 months | Japan | ASV | EPAP: 4–10 mm Hg | NP | CHF with CSR-CSA | SMT | 23 (20/3), 60.8 ± 13.7 | 37 (29/8), 60.5 ± 16.7 | LVEF BNP cardiac systolic and diastolic function |
CPAP: continuous positive airway pressure; ASV: adaptive servoventilation; EPAP: expiratory positive airway pressure; IPAP: inspiratory positive airway pressure; NP: not provided; CHF: chronic heart failure; OSA: obstructive sleep apnea; CSR: Cheyne-Stokes respiration; CSA: central sleep apnea; SA: sleep apnea; SDB: sleep-disordered breathing; SMT: standard medical treatment; LVEF: left ventricular ejection fraction; MSNA: muscle sympathetic nerve activity; BNP: B-type natriuretic peptide; AHI: apnea/hypopnea index; eGFR: estimated glomerular filtration rate; hs-CRP: high-sensitivity C- reactive protein; ANP: atrial natriuretic peptide; UNE: urinary norepinephrine; BP: blood pressure; HR: heart rate; MIP: maximal inspiratory pressure; MEP: maximal inspiratory pressure; LVESD: left ventricular end-systolic diameter; LVEDD: left ventricular end-diastolic dimension; LVEDV: left ventricular end-diastolic volume; LVESV: left ventricular end-systolic volume; LVDd: left ventricular end-diastolic dimension; LVDs: left ventricular end-systolic dimension.
Literature screening flow.
Risk of bias of the included studies. (a) Risk of bias graph; (b) risk of bias summary.
The weighted mean difference of the total is 5.34 favoring NPPV (95% CI,
The weighted mean difference of the cPAP subgroup was 3.85 favoring cPAP (95% CI,
The weighted mean difference of the ASV subgroup was 6.83 favoring ASV (95% CI,
Forest plot of the effect of noninvasive positive airway pressure (cPAP and ASV) therapy for chronic heart failure on left ventricular ejection fraction (LVEF). CI: confidence interval; IV: inverse variance; SD: standard deviation; MD: mean difference.
The weighted mean difference of LVEF < 30% was 4.94 favoring NPPV (95% CI,
The weighted mean difference of LVEF > 30% was 5.73 favoring NPPV (95% CI,
The weighted mean difference of the European subgroup was 5.05 favoring ASV (95% CI,
The weighted mean difference of the Asian subgroup was 7.92 favoring ASV (95% CI,
Five studies reported data on change in LVEDD between before and after intervention. The weighted mean difference of the total was −1.91 favoring NPPV (95% CI,
The weighted mean difference of the cPAP subgroup was 0.45 favoring control (95% CI,
The weighted mean difference of the ASV subgroup was −3.60 favoring ASV (95% CI,
Six studies reported data on plasma BNP level before and after intervention; 5 from the ASV subgroup and one from the cPAP subgroup. The weighted mean difference of the total was −117.37 favoring NPPV (95% CI,
The mean difference of the cPAP subgroup was 4.50, not significantly favoring the control (95% CI,
In 19 trials involving 913 patients, we did not find difference in overall mortality between patients treated with NPPV plus standard medical treatment (SMT) and with SMT alone (RR 1.00, 95% CI,
Forest plot of the effect of noninvasive positive airway pressure (cPAP and ASV) therapy for chronic heart failure on total mortality. CI: confidence interval; M-H: inverse variance; RR: risk ratio.
Refractory heart failure and worsening heart failure: of the 19 studies included, 6 reported the events as defined. We found no difference in the incidence of refractory heart failure and worsening heart failure between patients treated with NPPV plus SMT and SMT alone (RR 1.07, 95% CI,
Cardiac arrest: 3 studies reported the incidence of cardiac arrest and we found no difference in the incidence of cardiac arrest between the two groups (RR 1.02, 95% CI,
Angina and acute myocardial infarction (AMI): 3 studies reported the incidence of angina and AMI. We found no difference in the incidence of angina and AMI between the two groups (RR 1.01, 95% CI,
Sensitivity analyses by sequentially dropping individual trials and then evaluating the overall outcomes failed to identify any of the individual trials as having influenced the primary outcomes of the present meta-analysis to a significant extent (Table
Sensitivity analysis showing the effect sizes for the primary outcomes after removing individual trials included in the meta-analysis.
LVEF | Overall mortality | |||
---|---|---|---|---|
MD [95% CI] | | RR [95% CI] | | |
All trials | RE: 5.34 [3.85, 6.82] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.89 [3.08, 4.69] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Naughton et al. 1995 omitted | RE: 5.24 [3.72, 6.75] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.83 [3.02, 4.64] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Granton et al. 1996 omitted | RE: 5.23 [3.73, 6.73] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.84 [3.03, 4.65] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Tkacova et al. 1997 omitted | RE: 5.23 [3.72, 6.74] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.83 [3.02, 4.64] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Kaneko et al. 2003 | RE: 5.19 [3.67, 6.72] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.75 [2.93, 4.57] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Mansfield et al. 2004 | RE: 5.45 [3.90, 7.00] | <0.00001 | RE: 1.01 [0.97, 1.04] | 0.74 |
FE: 3.89 [3.08, 4.70] | <0.00001 | FE: 1.01 [0.97, 1.05] | 0.77 | |
Bradley et al. 2005 | RE: 5.63 [4.25, 7.00] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 5.15 [4.14, 6.17] | <0.00001 | FE: 1.00 [0.96, 1.03] | 0.86 | |
Usui et al. 2005 | RE: 5.37 [3.85, 6.89] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.89 [3.08, 4.69] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Arzt et al. 2005 | RE: 5.55 [3.99, 7.12] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.94 [3.12, 4.76] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Egea et al. 2008 | RE: 5.64 [4.04, 7.24] | <0.00001 | RE: 1.00 [0.96, 1.03] | 0.79 |
FE: 4.01 [3.17, 4.85] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.96 | |
Johnson et al. 2008 | RE: 5.43 [3.86, 7.00] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.87 [3.06, 4.69] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Ferrier et al. 2008 | RE: 5.45 [3.88, 7.01] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.88 [3.07, 4.70] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Pepperell et al. 2003 | RE: 5.50 [3.97, 7.03] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.92 [3.12, 4.73] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Koyama et al. 2010 | RE: 5.04 [3.58, 6.49] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.74 [2.92, 4.55] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Hastings et al. 2010 | RE: 5.09 [3.65, 6.54] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.80 [3.00, 4.61] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Oldenburg et al. 2011 | RE: 5.60 [3.91, 7.29] | <0.00001 | RE: 1.00 [0.97, 1.04] | 0.79 |
FE: 3.90 [3.02, 4.79] | <0.00001 | FE: 1.01 [0.96, 1.05] | 0.78 | |
Koyama et al. 2011 | RE: 5.21 [3.67, 6.75] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.70 [2.87, 4.53] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Haruki et al. 2011 | RE: 5.23 [3.71, 6.74] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.82 [3.01, 4.63] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 | |
Yoshihisa et al. 2011 | RE: 5.33 [3.79, 6.88] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.86 |
FE: 3.84 [3.03, 4.65] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.87 | |
Joho et al. 2012 | RE: 4.95 [3.52, 6.38] | <0.00001 | RE: 1.00 [0.97, 1.03] | 0.98 |
FE: 3.69 [2.87, 4.50] | <0.00001 | FE: 1.00 [0.96, 1.04] | 0.95 |
LVEF: left ventricular ejection fraction; MD: mean difference; RR: risk ratio; RE: random effect model; FE: fixed effect model.
Two main conclusions can be drawn for the present meta-analysis. Firstly, NPPV plus standard medical treatment (SMT) improved LVEF but did not improve overall mortality. Secondly, relative to SMT plus sham-NPPV/SMT alone, NPPV improved plasma BNP level but did not improve LVEDD and decrease threats of cardiac arrest events, angina, and AMI events.
The present meta-analysis revealed that NPPV improves cardiac function by increasing LVEF. Among included studies, the majority of patients already had reduced LVEF or were in the course of developing heart failure with reduced LVEF and therefore were considered more likely to benefit from the use of NPPV. The results are consistent with those of many previous studies [
In our analyses, the weighted mean difference of the cPAP subgroup was 3.85 favoring cPAP, while that of the ASV subgroup was 6.83 favoring ASV. This might indicate that ASV is better than cPAP in the improvement of LVEF. However, the conclusion did not come from the direct comparison of cPAP and ASV since none of the included studies presented such a direct comparison. Interestingly, two randomized controlled trials showed that CHF patients with SDB might gain greater benefit from treatment with ASV than with CPAP [
The total heterogeneity of the aforementioned part of the analysis is significant (Figure
Funnel plot of NPPV on LVEF.
Secondly, we analyzed the difference in LVEF-change among study regions for the ASV subgroup. According to the reported geographical location where the study was conducted, we divided the 8 studies into the European subgroup (3 studies, 2 in UK, and 1 in Spain) and Asian subgroup (5 studies, all in Japan). We found that the Asian subgroup’s heterogeneity was small (
According to the result of the analysis, the use of NPPV plus SMT did not improve overall mortality among patients with chronic heart failure. The analysis showed good homogeneity among all 19 studies enrolled (
Funnel plot of NPPV on total mortality.
Despite the aforementioned results, the impact of NPPV on overall mortality and cardiac adverse events remains to be further investigated. The longest follow-up period among the 19 studies was only 12 months and the shortest was 4 weeks. In a single center cohort study in Canada, patients with OSA were followed up for a decade; however, the study unfortunately did not provide information on cPAP use [
Five studies reported changes in LVEDD. The present analysis showed that NPPV did not reduce LVEDD; however, heterogeneity was significant. Subgroup analysis, however, yielded a different result. The weighted mean difference was 0.45 favoring (not significantly) control (
Among included studies, 6 reported the plasma BNP level at baseline and after intervention. One study focuses on cPAP, while the other five studies focus on ASV. The present analysis showed that the use of NPPV reduced plasma BNP level in CHF patients. Because BNP level can be used to indicate prognosis and predict mortality and clinical outcome of patients with chronic heart failure [
ASV was designed to meet the patients’ ventilation support by providing inspiratory positive airway pressure (IPAP) and adjust the rate of change of airflow through sensing the patient airflow. cPAP, however, provided a continuous pressure which could not be adjusted according to the patients breath [
Our study has several potential limitations. First, the sample sizes of component trials included in our analysis are generally not large, which may bring “small-study effects.” “Small-study effects” refer to the fact that trials with limited sample sizes are more likely to report larger beneficial effects than large trials [
In the present meta-analysis, relative to SMT plus sham-NPPV/SMT alone, NPPV plus SMT improved LVEF and reduced plasma BNP level but did not improve overall mortality and adverse event rates.
Noninvasive positive pressure ventilation
Continuous positive airway pressure
Adaptive servoventilation
Bilevel positive airway pressure
Sleep-disordered breathing
Obstructive sleep apnea
Central sleep apnea
Cheyne-Stokes respiration
Left ventricular ejection fraction
Left ventricular end-diastolic dimension
Left ventricular end-systolic dimension
Brain natriuretic peptide
Peak oxygen consumption.
The authors have no financial disclosures or competing interests to declare.
Hao Jiang and Yi Han contributed equally to this work.
This work was supported by the National Science Fund for Distinguished Young Scholars (81625002 to Jun Pu), Program for New Century Excellent Talents of Ministry of Education of China (NCET-12-0352), Shanghai Shuguang Program (12SG22), Program of Shanghai Committee of Science and Technology (15411963600 and 14JC1404500), Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20152209), Shanghai Jiaotong University (YG2013MS420), and Shanghai Jiao Tong University School of Medicine (15ZH1003 and 14XJ10019).