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Continuous Positive Continuous Positive Airway Pressure for Airway Pressure for
Central Sleep Apnea and Central Sleep Apnea and Heart Failure Heart Failure
R1 R1 李明峰 李明峰 / Dr. / Dr. 劉育志劉育志
BackgroundBackground
Short-term, single-center randomized triShort-term, single-center randomized trials, CPAP:als, CPAP:
Attenuated the central sleep apneaAttenuated the central sleep apnea
Increased LVEFIncreased LVEF
Reduced daytime levels of ANP and plaReduced daytime levels of ANP and plasma norepinephrine sma norepinephrine
Improved the patients' quality of life Improved the patients' quality of life
BackgroundBackground
Continuous positive airway pressure Continuous positive airway pressure (CPAP): (CPAP):
Patients who have central sleep apnea Patients who have central sleep apnea and heart failure: and heart failure:
Would improve the survival rate without Would improve the survival rate without heart transplantation? heart transplantation?
MethodsMethods
Study design:Study design:
Randomized, open-label trial Randomized, open-label trial
Men and women 18 to 79 years of age Men and women 18 to 79 years of age who had NYHA fc II - IV heart failure in who had NYHA fc II - IV heart failure in stable condition >1 monthstable condition >1 month
LVEF < 40 percent on radionuclide angiLVEF < 40 percent on radionuclide angiographyography
Central sleep apnea Central sleep apnea
MethodsMethods
Exclusion criteria:Exclusion criteria:
PregnancyPregnancy
Myocardial infarctionMyocardial infarction
Unstable anginaUnstable angina
Cardiac surgery < 3 monthsCardiac surgery < 3 months
Obstructive sleep apnea. Obstructive sleep apnea.
Baseline assessmentBaseline assessment
Overnight polysomnography :Overnight polysomnography :
Sleep stages and arousalsSleep stages and arousals
Episodes of apnea and hypopnea,Episodes of apnea and hypopnea,
Mean and lowest arterial oxygen saturatMean and lowest arterial oxygen saturation levels ion levels
Respiratory inductance plethysmographRespiratory inductance plethysmography: Respiratory effortsy: Respiratory efforts
Nasal pressure: airflowNasal pressure: airflow
Baseline Assessment Baseline Assessment
Central sleep apnea: absence of tidal vCentral sleep apnea: absence of tidal volume for >10 sec. without thoracoabdoolume for >10 sec. without thoracoabdominal motion minal motion
Central hypopnea: reduction of >50% pCentral hypopnea: reduction of >50% percent in tidal volume from baseline for ercent in tidal volume from baseline for 10 or more seconds without airflow limit10 or more seconds without airflow limitation ation
Baseline Assessment Baseline Assessment
The diagnosis of central sleep apnea: aThe diagnosis of central sleep apnea: apnea-hypopnea index of 15 or more evepnea-hypopnea index of 15 or more events per hour, with more than 50 percent nts per hour, with more than 50 percent of the events determined to be central rof the events determined to be central rather than obstructive ather than obstructive
Randomization Randomization
Eligible patients were randomly Eligible patients were randomly assigned.assigned.
Control group: optimal medical therapy Control group: optimal medical therapy for chronic heart failurefor chronic heart failure
Treatment group: CPAP + the medical Treatment group: CPAP + the medical therapy therapy
Randomization Randomization
Patients assigned to CPAP underwent fPatients assigned to CPAP underwent further randomization in a 2:1:1 ratio to ourther randomization in a 2:1:1 ratio to one of the devices (Respironics Remstar ne of the devices (Respironics Remstar Pro, ResMed Sullivan VII, or Tyco HealtPro, ResMed Sullivan VII, or Tyco Healthcare GoodKnight 420S, respectively hcare GoodKnight 420S, respectively
Initiation of CPAP Initiation of CPAP
Over 2-3 nightsOver 2-3 nights
Pressure of 5 cm of water the first night, Pressure of 5 cm of water the first night, 2 to 3 cm of water over the next 2 to 3 cm of water over the next one or two nights until reaching a one or two nights until reaching a pressure of 10 cm of water pressure of 10 cm of water
At least six hours nightly at home during At least six hours nightly at home during the trial the trial
Assessment of Outcomes Assessment of Outcomes
Clinical assessments were performed at Clinical assessments were performed at 1,3,6 months and every 6 months 1,3,6 months and every 6 months
Polysomnography: 3 and 24 months Polysomnography: 3 and 24 months
LVEF, the distance walked in six minuteLVEF, the distance walked in six minutes, and quality of life: 3, 6, and 24 months, and quality of life: 3, 6, and 24 months s
Assessment of OutcomesAssessment of Outcomes
Norepinephrine and ANP:3, 6, and 24 mNorepinephrine and ANP:3, 6, and 24 months onths
Changes in the apnea-hypopnea index, Changes in the apnea-hypopnea index, mean and minimum nocturnal oxygen smean and minimum nocturnal oxygen saturation, LVEF, and levels of plasma naturation, LVEF, and levels of plasma norepinephrine and ANP at 3 months anorepinephrine and ANP at 3 months and throughout the remainder of the trial d throughout the remainder of the trial
Assessment of OutcomesAssessment of Outcomes
The primary outcome: rate of death and heart The primary outcome: rate of death and heart transplantation transplantation
Secondary outcomes:Secondary outcomes:DeathDeath
Transplantation-free survival, with censoring of Transplantation-free survival, with censoring of data on patients who dropped out,data on patients who dropped out,
Hospital admissions confirmed on the basis of Hospital admissions confirmed on the basis of medical records,medical records,
Distance walked in 6 minutes Distance walked in 6 minutes
Quality of life. Quality of life.
Sample SizeSample Size
Use of the Use of the log-rank testlog-rank test, assuming an , assuming an annual event rate of 24 percent in the annual event rate of 24 percent in the control group, with a relative hazard control group, with a relative hazard ratio for CPAP of 0.65. ratio for CPAP of 0.65.
At a two-sided alpha level of 0.05, with At a two-sided alpha level of 0.05, with 80 percent power, we estimated that 80 percent power, we estimated that 204 patients per group would be 204 patients per group would be required. required.
Statistical Analysis Statistical Analysis
Kaplan-Meier estimatesKaplan-Meier estimates: visualize : visualize survival without heart transplantation.survival without heart transplantation.
Cox proportional-hazards analysisCox proportional-hazards analysis: : compare transplantation-free survival compare transplantation-free survival between groups.between groups.
Statistical AnalysisStatistical Analysis
Generalized linear models for binomial Generalized linear models for binomial and Poisson distributed outcomesand Poisson distributed outcomes were were used to assess changes in the overall used to assess changes in the overall event rate over time event rate over time
Statistical AnalysisStatistical Analysis
Cox proportional-hazards modelsCox proportional-hazards models: : examined the effects of examined the effects of interactions interactions between the treatment assignment and between the treatment assignment and compliance with the treatmentcompliance with the treatment, , ageage, , NYHA classNYHA class, , LVEFLVEF, , cause of heart cause of heart failurefailure, , medicationsmedications, and , and body-mass body-mass indexindex on the primary outcome on the primary outcome
Statistical AnalysisStatistical Analysis
Wilcoxon rank-sum testWilcoxon rank-sum test: compare numb: compare number of hospital admissionser of hospital admissions
Longitudinal dataLongitudinal data: for the analysis of se: for the analysis of secondary outcomes collected over timecondary outcomes collected over time
Linear mixed-effects modelsLinear mixed-effects models: interaction: interactions between time and treatment over the s between time and treatment over the duration of the trial duration of the trial
ResultResult
Reduction in the apnea-hypopnea index Reduction in the apnea-hypopnea index
Greater increases in mean and minimuGreater increases in mean and minimum Om O22 saturation saturation
Greater increase in LVEF Greater increase in LVEF
Greater reduction in levels of plasma noGreater reduction in levels of plasma norepinephrine repinephrine
ResultResult
Sleep time, distribution of sleep stages, Sleep time, distribution of sleep stages, or frequency of arousal: no changesor frequency of arousal: no changes
No significant effect on levels of atrial nNo significant effect on levels of atrial natriuretic peptideatriuretic peptide
Primary outcomePrimary outcome
No difference in transplantation-free surNo difference in transplantation-free survival (hazard ratio for heart transplantativival (hazard ratio for heart transplantation, 1.16; 95 percent confidence interval,on, 1.16; 95 percent confidence interval, 0.71 to 1.90; P=0.54) 0.71 to 1.90; P=0.54)
Hazards appeared to be nonproportionaHazards appeared to be nonproportional during the follow-up period (chi-square l during the follow-up period (chi-square = 10.9, P=0.001). = 10.9, P=0.001).
Primary OutcomePrimary Outcome
In the first 18 months favoring the In the first 18 months favoring the control group (hazard ratio for an event, control group (hazard ratio for an event, 1.5; P=0.02) 1.5; P=0.02) Reversed after 18 months to favor Reversed after 18 months to favor CPAP (hazard ratio for an event, 0.66; CPAP (hazard ratio for an event, 0.66; P=0.06). P=0.06). No significant interaction between No significant interaction between treatment assignment and the seven treatment assignment and the seven variables included in the statistical variables included in the statistical analysis analysis
Primary OutcomePrimary Outcome
A post hoc analysis did not detect any A post hoc analysis did not detect any significant difference in the primary significant difference in the primary event rate among the three CPAP event rate among the three CPAP devices (P=0.31). devices (P=0.31).
Secondary outcomeSecondary outcome
Death rates: Death rates: no significantno significant (hazard ratio (hazard ratio for death, 1.1; 95 percent confidence for death, 1.1; 95 percent confidence interval, 0.65 to 1.88; P=0.714) interval, 0.65 to 1.88; P=0.714)
Survival among the patients who drop Survival among the patients who drop out was worse (hazard ratio for death, out was worse (hazard ratio for death, 3.8; P<0.001)3.8; P<0.001)
Secondary OutcomeSecondary Outcome
Overall transplantation-free survival Overall transplantation-free survival (hazard ratio for death, 1.04; 95 percent (hazard ratio for death, 1.04; 95 percent confidence interval, 0.78 to 1.4; confidence interval, 0.78 to 1.4; P=0.778):P=0.778):not differnot differ
Survival during the first 18 months Survival during the first 18 months (hazard ratio for death, 1.4; P=0.10): (hazard ratio for death, 1.4; P=0.10): no no difference difference
Secondary OutcomeSecondary Outcome
The number of hospitalizations The number of hospitalizations did not did not differ significantlydiffer significantly (hospitalizations per (hospitalizations per patient per year, 0.56+/-0.56 vs. 0.61+/-patient per year, 0.56+/-0.56 vs. 0.61+/-0.72; P=0.45). 0.72; P=0.45).
The distance walked in six minutes The distance walked in six minutes increased more in the CPAP group at 3 increased more in the CPAP group at 3 months (20.0+/-55 vs. -0.8+/-64.8 m, months (20.0+/-55 vs. -0.8+/-64.8 m, P=0.016), P=0.016), but not over the whole study but not over the whole study period period
Secondary OutcomeSecondary Outcome
Changes in patients' scores on the Changes in patients' scores on the Chronic Heart Failure Questionnaire Chronic Heart Failure Questionnaire did did not differ significantlynot differ significantly
DiscussionDiscussion
Confirmed previous small, short-term triConfirmed previous small, short-term trials that als that CPAP attenuates central sleep CPAP attenuates central sleep apnea, improves nocturnal oxygenation apnea, improves nocturnal oxygenation and left ventricular systolic function, and and left ventricular systolic function, and lowers plasma norepinephrine levelslowers plasma norepinephrine levels
These effects are sustained with long-teThese effects are sustained with long-term therapy rm therapy
DiscussionDiscussion
Beneficial influence of CPAP on Beneficial influence of CPAP on transplantation-free survival and quality transplantation-free survival and quality of life: of life: not showednot showed
CPAP improved several physiological CPAP improved several physiological outcomes, but not transplantation-free outcomes, but not transplantation-free survival survival
DiscussionDiscussion
Because CPAP does not attenuate centBecause CPAP does not attenuate central sleep apnea in patients with heart fairal sleep apnea in patients with heart failure when the treatment is titrated over lure when the treatment is titrated over one night, we mandated a one night, we mandated a gradual upwgradual upward-titration protocolard-titration protocol
Apnea-hypopnea indexApnea-hypopnea index
Nocturnal oxygen saturation Nocturnal oxygen saturation
Persisted for at least two years Persisted for at least two years
DiscussionDiscussion
Improvement in daytime LVEF might be Improvement in daytime LVEF might be due to:due to:
Reduction in cardiac sympathetic driveReduction in cardiac sympathetic drive
LV unloading resulting from an increase LV unloading resulting from an increase in intrathoracic pressurein intrathoracic pressure
Reduced myocardial ischemia due to imReduced myocardial ischemia due to improvement in oxygen saturation provement in oxygen saturation
DiscussionDiscussion
Higher initial LVEF (24.5 percent vs. 20.Higher initial LVEF (24.5 percent vs. 20.0 percent) ? Beta-blockers ? (77 percen0 percent) ? Beta-blockers ? (77 percent vs. <20 percent) t vs. <20 percent)
Effects of beta-blockade and CPAP on Effects of beta-blockade and CPAP on ventricular: overlappedventricular: overlapped
The high rate of use of beta-blockers mThe high rate of use of beta-blockers may also have reduced the potential for a ay also have reduced the potential for a beneficial effect on clinical outcom beneficial effect on clinical outcom
DiscussionDiscussion
CPAP had an early adverse effect in CPAP had an early adverse effect in some patients ?some patients ?
The effect of the dropouts The effect of the dropouts
Improvements in background medical Improvements in background medical therapy therapy
DiscussionDiscussion
Background medical therapy is of importance Background medical therapy is of importance because the acute effect of CPAP in heart because the acute effect of CPAP in heart failure is a function of left ventricular preloadfailure is a function of left ventricular preload
Filling pressures , the cardiac outputFilling pressures , the cardiac output
Upward titration of CPAP reduced cardiac Upward titration of CPAP reduced cardiac output in some patients with low filling output in some patients with low filling pressures? pressures?
Slower CPAP titration might have avoided Slower CPAP titration might have avoided some adverse events some adverse events
SummarySummary
CPAP: CPAP:
Attenuated central sleep apnea Attenuated central sleep apnea
Improved nocturnal oxygenation, left veImproved nocturnal oxygenation, left ventricular function, sympathetic nervous antricular function, sympathetic nervous activity, and (at least initially) submaximal ctivity, and (at least initially) submaximal exercise performance. exercise performance.
Trial did not demonstrate a beneficial effTrial did not demonstrate a beneficial effect of CPAP on morbidity or mortalityect of CPAP on morbidity or mortality
SummarySummary
Declining primary event rate: possibly Declining primary event rate: possibly due to concurrent improvements in drug due to concurrent improvements in drug therapytherapy
A trial three times the size of ours is A trial three times the size of ours is requiredrequired
SummarySummary
Lack the power to conclude that CPAP Lack the power to conclude that CPAP is ineffectiveis ineffective
Data do not support its routine useData do not support its routine use
SummarySummary
Patients with heart failure who have Patients with heart failure who have obstructive sleep apnea: may have obstructive sleep apnea: may have benefitbenefit
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