Continuous Positive Airway Pressure for Central Sleep Apnea and Heart Failure R1 李明峰 / Dr....

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


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


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


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


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


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


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


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


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


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


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

Thanks for your Thanks for your attention !! attention !!

Continuous Positive Airway Pressure for Central Sleep Apnea and Heart Failure R1 李明峰 / Dr....

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