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APPROACHES TO THERAPY OF CENTRAL SLEEP APNEA IN HEART FAILURE T. Douglas Bradley, MD

APPROACHES TO THERAPY OF CENTRAL SLEEP APNEA IN HEART FAILURE T. Douglas Bradley, MD Director, Centre for Sleep Medicine and Circadian Biology, Toronto General Hospital and Toronto Rehabilitation Institute, University of Toronto. 100. 80. 60. Transplant-free survival (%). 40. 20. 0. 0.

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APPROACHES TO THERAPY OF CENTRAL SLEEP APNEA IN HEART FAILURE T. Douglas Bradley, MD

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  1. APPROACHES TO THERAPY OF CENTRAL SLEEP APNEA IN HEART FAILURE T. Douglas Bradley, MD Director, Centre for Sleep Medicine and Circadian Biology, Toronto General Hospital and Toronto Rehabilitation Institute, University of Toronto

  2. 100 80 60 Transplant-free survival (%) 40 20 0 0 6 12 18 24 30 36 42 48 54 60 Time from randomization (months) Transplant Free Survival: CSR-CSA vs non-CSR-CSA Non-CSR-CSA CSR-CSA N = 66 P=0.032 Sin D et al. Circulation 2000

  3. Types of Mechanical Ventilation Tested in Cheyne-Stokes Respiration • Adaptive Pressure Support Servo-Ventilation (ASV) • Bilevel Pressure Support Ventilation (BPSV) • Continuous Positive Airway Pressure (CPAP)

  4. Teschler H et al. Am J Respir Crit Care Med 2001

  5. RESULTS • ASV: • Reduced BNP and urinary metnorepinephrine • Improved alertness on the Osler Test • ASV had no effect on: • LVEF • Quality of life • Performance on a driving simulator test Pepperell J et al. AJRCCM 2003

  6. CONCLUSIONS In HF Patients with CSA: • Effect of ASV for 1 month on CSA was not assessed, so we cannot say whether it improved CSA compared to sham ASV • ASV increased alertness (Osler), and reduced BNP and 24 hr urinary metnorepinephrine • ASV had no effect on LVEF • Clinical cardiovascular endpoints were not assessed • Accordingly, there is insufficient evidence to support the use of ASV to treat CSA in patients with HF

  7. CANPAP Eligible Patients HF, LVEF <40%, CSA (AHI 15/hr) RANDOMIZATION (to detect HR of 0.65) n = 408 Optimal Medical Therapy Alone n = 204 Optimal Medical Therapy & CPAP n = 204 Predicted Mean Follow Up Period = 2.5 yrs Predicted Max Follow Up Period = 5 yrs Primary Outcome Cumulative combined all cause mortality-heart transplant rate during study period Secondary Outcomes  AHI and mean nocturnal SaO2 Resting LVEF  6-minute walk distance  Plasma Norepinephrine (PNE)  Atrial Natriuretic Peptide (ANP)  Hospital admissions  Chronic Heart Failure Questionnaire Scores

  8. PRIMARY EVENT RATE OVER TIME CANPAP Constant Anticipated Event Rate (Control Group) 25 20 15 Event Rate/100 person-years 10 Observed Event Rate 5 0 1998/1999 2000 2001 2002 2003 2004 Bradley et al. NEJM 2005 Calendar Year

  9. CANPAP TERMINATION OF THE TRIAL • Interim analysis on the 1st 200 patients: a) a post hoc subgroup analysis of NYHA class 3 & 4 patients revealed an early divergence of event rates favouring the control group, b) enrollment only 50% of predicted, and c) >50% decline in the event rate over the course of the trial. • The DSMC recommended stopping the trial even though the event rate crossed over to favour the CPAP group after 18 months. • The trial was stopped in May, 2004 Bradley et al. NEJM 2005

  10. CANPAP Enrollment, Drop-outs and Compliance • Enrollment began in December, 1998 • 258 patients were enrolled at the time the trial was stopped in May, 2004 • Mean 24 month follow-up (range 0-64 months) • Only 15% of subjects dropped-out (20 in each group) • Average daily CPAP use was ≈ 4 hr at 8-9 cm H2O throughout the trial Bradley et al. NEJM 2005

  11. 40 30 20 10 0 CANPAP Effects of CPAP on CSA Controlgroup CPAP group AHI (no. /hr) P<0.001 96 CPAP group 95 94 93 SaO2 (%) Control group 92 91 P<0.001 0 0 3 24 Time From Randomization (mo) Bradley et al. NEJM 2005

  12. CANPAP Effects of CPAP on LVEF 35 CPAP group 30 LVEF (%) 25 Control group 20 P=0.007 0 0 3 6 24 Time From Randomization (mo) Bradley et al., NEJM 2005

  13. CANPAP Effect of CPAP on Transplant-free Survival 100 CPAP group 80 (32 events) 60 Transplantation-free Survival (%) Control group 40 (32 events) 20 P=0.54 0 0 12 24 36 48 60 Time from Enrollment (mo) No. at Risk 128 104 79 59 49 42 33 24 20 12 6 CPAP 130 Control 117 96 79 59 46 37 27 19 12 4 Bradley et al., NEJM 2005

  14. CANPAP Cumulative Number of Hospitalizations Bradley et al. NEJM 2005 150 Compare Total Hospitalizations P = 0.83 100 Cumulative Total Number of Hospitalizations 50 Group CPAP Control 0 0 12 24 36 48 60 Time From Randomization (months)

  15. CANPAP OTHER SECONDARY OUTCOMES • 6-Minute Walking Distance: increased more in CPAP than in control group at 12 weeks (20.0 ± 55.0 vs –0.8 ± 64.8 m, P = 0.016) • PNE: Decreased more in the CPAP than the control group over course of the trial (-1.03 ± 1.84 vs 0.02 ± 0.99 nmol/L, P = 0.009) • ANP and Quality of Life:No significant change in either group Bradley et al. NEJM 2005

  16. Hypothesis CPAP will improve LVEF and transplant-free survival of HF patients with CSA, if it causes attenuation of CSA

  17. 100 80 60 Transplant-free survival (%) CPAP unsuppressed (AHI at 3 months  15/hr) Control 40 20 *versus control: HR=0.36, p=0.040 0 0 6 12 18 24 30 36 42 48 54 60 Time from enrollment (mo) CANPAP Transplant-free survival in HF patients according to effect of CPAP on CSA CPAP suppressed* (AHI at 3 months < 15/hr) Arzt M et al. Circulation 2007

  18. Summary • CPAP improved LVEF and transplant-free survival in those HF patients in whom CPAP attenuated CSA • In contrast, HF patients, whose CSA was not attenuated in response to CPAP, did not improve their LVEF and had reduced transplant-free survival rates

  19. CANPAP CONCLUSIONS I • CPAP was well tolerated, alleviated CSA and improved cardiovascular function • However, the primary analysis showed no difference in transplant-free survival or hospitalizations between the two groups Bradley et al. NEJM 2005

  20. CONCLUSIONS II • Our data demonstrate that early reduction in the AHI (within 3 months) in response to CPAP occurs in conjunction with improvement in LVEF, and is a predictor of improved transplant-free survival in HF patients with CSA • Alleviation of CSA by CPAP may be an important therapeutic target to improve transplant-free survival in such patients

  21. CONCLUSIONS III • Our data demonstrate that the failure to attenuate CSA by CPAP within 3 months is not associated with an improvement in LVEF, and is a predictor of reduced transplant-free survival in HF patients with CSA • CPAP may have adverse effects in HF patients whose CSA does not improve with CPAP

  22. Perspective • Based on our observation that in HF patients with CSA, an early reduction in AHI is accompanied by improvement in LVEF and higher transplant-free survival, we believe that it may be reasonable to provide a trial of CPAP to such patients, and to reassess CSA 1 to 3 months later by PSG • If the AHI does not decrease, then CPAP should be stopped • If the AHI decreases substantially, then one could recommend continuation of CPAP with close follow-up

  23. Fellows Ruzena Tkacova Don Sin Matt Naughton Michael Arzt Colleagues John Floras Sandy Logan Research Assistants Fabia Fitzgerald Nicole Catherine Gisella Hopkins Fiona Rankin Ruth Rutherford ACKNOWLEDGMENTS

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