Shahrokh Javaheri, MD

Transcription

1 Central Sleep Apnea Shahrokh Javaheri, MD Sleep Physician Bethesda North Hospital Professor Emeritus of Medici University of Cincinnati, Cincinnati, Ohio Adjunct Professor of Medicine, Division of Cardiology, Ohio State Medical School, Columbus Ohio Annual Sleep Meeting 2016 Associated Professional Sleep Societies, LLC 1

2 Disclosures Relevant Companies 1. Res Med 2. Philips/Respironics 3. Respicardia 4. Sorin Group Associated Professional Sleep Societies, LLC 2

3 CSA in HF 1. CSA A Good or Bad Bed Fellow? 2. SERVE-HF 3.The hpoxia burden 4.What is in the Pipe? Associated Professional Sleep Societies, LLC 3

4 CSA in HF 1. CSA was always a bad bed fellow Until SERVE-HF Failed and an opinion surfaced! Associated Professional Sleep Societies, LLC 4

5 Cheyne-Stokes respiration: friend or foe? Naughton CSA associated with the beneficial effects of 1. Hyperventilation-related increases in end-expiratory lung volume, intrinsic positive airway pressure assistance to stroke volume 2. Avoidance of hypercapnic acidosis 3. The provision of periodic rest to fatigue-prone respiratory pump muscles 4. Attenuation of excessive sympathetic nervous activity Associated Professional Sleep Societies, LLC 5

6 CSA is a good friend of HF: Do not treat! You can t be serious! ( JM 1. In my opinion this hypothesis has little scientific basis and lacks experimental support 2. In fact, statements 2,3 and 4 are inconsistent with human data Associated Professional Sleep Societies, LLC 6

7 Cheyne-Stokes respiration: friend or foe? Naughton CSA associated with the beneficial effects 1. Hyperventilation-related increases in end-expiratory lung volume, intrinsic positive airway pressure assistance to stroke volume But, hyperventilation is also associated with negative swings in intrathoracic pressure PAP devices do the same with elimination of the negative swings Associated Professional Sleep Societies, LLC 7

8 Esophageal Pr: Negative swings in Pr Modified from Javaheri Blue J, 1990, Associated Professional Sleep Societies, LLC 8

9 Cheyne-Stokes respiration: friend or foe? Naughton CSA associated with the beneficial effects of 2. Avoidance of hypercapnic acidosis 3. The provision of periodic rest to fatigue-prone respiratory pump muscles 4. Attenuation of excessive sympathetic nervous activity Associated Professional Sleep Societies, LLC 9

10 Mean AHI and PCO 2 (Teschler, 2001) Baseline Old ASV AHI Mean overnight PtCO PaCO 2 Evening: 32 Morning: 35 Associated Professional Sleep Societies, LLC 10

11 Fluctuation in PCO 2 Associated Professional Sleep Societies, LLC 11

12 PB begets PB Periodic chemoreceptor stimulation and inhibition CA/hypopnea PCO 2 and PO 2 Chemoreceptor stimulation Hyperventilation PCO 2 and PO 2 chemoreceptor inhibition CA and hypopnea Associated Professional Sleep Societies, LLC 12

13 Association of Smoking, Sleep Apnea, and Plasma Alkalosis With Nocturnal Ventricular Arrhythmias in Men With Systolic Heart Failure (Javaheri et al, Chest 2012) Variable OR 95%CI p value ArI [H + ] Age Smoking Associated Professional Sleep Societies, LLC 13

14 Cheyne-Stokes respiration: friend or foe? Naughton CSA associated with the beneficial effects of 3. The provision of periodic rest to fatigue-prone respiratory pump muscles 4. Attenuation of excessive sympathetic nervous activity Associated Professional Sleep Societies, LLC 14

15 OSA: Increased work of breathing Decreased work of breathing Associated Professional Sleep Societies, LLC 15

16 Work of breathing with periodic breathing Decreased work of breathing with CA Hyperventilation: Increased work of breathing Associated Professional Sleep Societies, LLC 16

17 WOB in 25 patients with HFrEF Stable OSA CSA breathing ) 12.0± ± ± 0.9 WOB in Joules/min Kee et al, AJRCCM 189;2014:A3892 Associated Professional Sleep Societies, LLC 17

18 In chronic heart failure, WOB is increased during central sleep apnea as much as in obstructive sleep apnea. However, PTP is reduced in CSA suggesting greater efficiency and reduced fatigability. My conclusion: If true, this means that treatment of CSA should promotes fatigability. Associated Professional Sleep Societies, LLC 18

19 Inspiratory Muscle Strength in Patients with HFrEF and CSA; RCT in 2 groups of HFrEF- small no; 3m In CPAP group, AHI decreased from 49 to 17 (p < 0.001) MIP increased from 79 to 91 Cm H 2 O ( p < 0.02) Symptoms of fatigue and dyspnea were alleviated LVEF increased from 24 to 33 (p < 0.02) No significant changes in the control group Associated Professional Sleep Societies, LLC 19

20 CPAP Improves Inspiratory Muscle Strength in Patients with Heart Failure and Central Sleep Apnea RCT in HFrEF with CSA Our data indicate that nightly application of NCPAP in patients with CHF and CSR-CSA (and not CHF without CSR) improves inspiratory muscle strength and LVEF, and relieves dyspnea and fatigue GRANTON, NAUGHTON AJRCCM 1996 Associated Professional Sleep Societies, LLC 20

21 What happens to MV when CSA improves? Associated Professional Sleep Societies, LLC 21

22 Minute ventilation in HCSB Associated Professional Sleep Societies, LLC 22

23 Minute ventilation in HCSB MV= 8.9 MV=4.8 Associated Professional Sleep Societies, LLC 23

24 We examined the effect of NCPAP on AHI, Ptco 2, VI in a 12 consecutive patients with CHF and CSA-CSA during stage 2 sleep: RCT: 12 patients with HFrEF and CSA From baseline to 1 month, with CPAP (10 cm H 2 O) AHI decreased (59 to 23, p < 0.001) Mean VI decreased (8 to 5, p < 0.01) Mean Ptco 2 increased (35 to 41, p <0.001) No significant change in the control group (n=6) Associated Professional Sleep Societies, LLC 24

25 My conclusion: The reduction in minute ventilation suggest that treatment of CSA decreases the work of breathing, and this may account, in part, for improved diaphragmatic strength Associated Professional Sleep Societies, LLC 25

26 Cheyne-Stokes respiration: friend or foe? Naughton CSA associated with the beneficial effects of 4. Attenuation of excessive sympathetic nervous activity Associated Professional Sleep Societies, LLC 26

27 Simulated CSA increases Peroneal N activity Andreas et al. Chest 2003 Associated Professional Sleep Societies, LLC 27

28 Somers et al Associated Professional Sleep Societies, LLC 28

29 Mixed (central and obstructive) sleep apneas produce marked sympathoexcitation and transient blood pressure elevations in a patient with sleep apnea syndrome. Jerome A. Dempsey et al. Physiol Rev 2010;90: Associated Professional Sleep Societies, LLC 29

30 Overnight Sympathetic Activity in HF Patients With and Without Central Sleep Apnea Variable Urine NE (nmol/mmol Cr) Without CSA 16 With CSA Baseline 30* Plasma NE (nmol/l) 2 3* *Significant vs control group. Modified from Naughton et. al., AJRCCM, 1995 Associated Professional Sleep Societies, LLC 30

31 We hypothesized that attenuation of CSR/CSA by CPAP would reduce UNE and PNE concentration: RCT Variable AHI, n/h Baseline CSA 48 CPAP 1 month 19* Urine NE (nmol/mmol Cr) 31 19* Plasma NE (nmol/l) * HR decreased by 5 bpm with CPAP All changes were minimal in the control arm Associated Professional Sleep Societies, LLC 31

32 We hypothesized that attenuation of CSR/CSA by CPAP would reduce UNE and PNE concentration: RCT Variable AHI, n/h Baseline CSA 48 CPAP 1 month 19* Urine NE (nmol/mmol Cr) 31 19* Plasma NE (nmol/l) * M. Naughton, AJRCCM, 1995 Associated Professional Sleep Societies, LLC 32

33 A RCT with ASV( n=15) and sham ASV( n=15) 1 month; Class II IV; AHI = 24; LVEF= 37% Plasm BNP(363 to 278, p=.0001) and urinary metadrenaline excretion (61 to 45, p=.02) and metnoradrenaline(190 to 153, NS) decreased This study suggests improvements in neurohormonal activation with this treatment Pepperell et al, Blue J, 2003 Associated Professional Sleep Societies, LLC 33

34 Attenuation of CSA with nocturnal O 2 decreases sympathetic activity Baseline Oxygen Air P TST(min) AHI, n/h CAI, n/h Min SaO 2 % Urinary noradrenaline excretion nmol. mmol urinary creatin -1 Staniforth, Eur Heart J, 1998 Associated Professional Sleep Societies, LLC 34

35 Design of SERVE-HF Chronic HF with LVEF 45% NYHA class III or IV, or NYHA class II with 1 hospitalization for HF in the previous 24 months Predominant central SDB was defined as an AHI 15 events/h with 50% central events and a central AHI 10 events/h, derived from PG or PSG and based on total recording time, documented within 4 weeks of randomization, with flow measurement performed using a nasal cannula Associated Professional Sleep Societies, LLC 35

36 Patients in the ASV group undergo polygraphy or PSG and a data download from the ASV device ASV started in hospital with full face mask. Standard ASV settings. Pressure levels adjusted based on the results of respiratory monitoring. It is recommended that major mask leaks should be avoided if possible. The target is to reduce AHI to 10/h within 14 days of starting ASV. If this is shown not to be the case at clinic visits (based on the data downloaded) then proper mask fitting is again undertaken and device settings adjusted for each patient Patients contacted by telephone at 6 and then every 12m. Associated Professional Sleep Societies, LLC 36

37 SERVE-HF trial did not meet its primary endpoint The study did not show a statistically significant difference between patients randomized to ASV therapy and those in the control group in the primary endpoint of time to all-cause mortality or unplanned hospitalization for worsening heart failure HR = % CI = 0.974, p-value = Associated Professional Sleep Societies, LLC 37

38 SERVE-HF Trial Announcement (5/13/2015) There was a statistically significant 2.5 % absolute increased risk of annual CV mortality Control Group 7.5 % per year ASV Group 10% per year Relative Risk= /7.5=33.5% HR= % CI = 1.07 to 1.67, p=.01 Associated Professional Sleep Societies, LLC 38

39 in SERVE-HF ASV average pressures : PEEP of 5 cm H 2 O Min IPS=3 cm H 2 O Average IPS was 5.8 cm H 2 O Backup rate auto Patients used the device 4-5 hours per night on average Associated Professional Sleep Societies, LLC 39

40 What is wrong? Increased CV mortality with ASV, even though ASV improved AHI? 1. CSA is a good friend of HF: Do not treat! You can t be serious! ( JM) 2. The patient /device interaction is the problem Associated Professional Sleep Societies, LLC 40

41 Increased CV mortality with CPAP 100 Control arm N=130 Transplantation-free Survival (%) CPAP arm, N=128 Significant : More patients died on CPAP early on (Pr = 9 cm H 2 O) Time from Enrollment (mo) Bradley TD et al., N Engl J Med 2005 Associated Professional Sleep Societies, LLC 41

42 History Repeats itself Increased CV mortality with CPAP CANPAP Trial NEJM, 2005 Respondres and nonresponders Increased CV mortality with ASV Even though ASV improved AHI? Associated Professional Sleep Societies, LLC 42

43 More Questions Than Answers Shahrokh Javaheri, MD, FCCP; Lee K. Brown, MD, FCCP; Winfried Randerath, MD; Rami Khayat, MD, FCCP Chest 2016 Associated Professional Sleep Societies, LLC 43

44 Design of SERVE-HF NEJM online 666 patients were assigned to ASV, of whom 21 did not receive the device: = 645. Of these 82 withdrew, 2 discontinued ASV and 1 lost to follow up: = 560. Of these 168 patients discontinued ASV: = 392 who should have completed. Meanwhile 87 patients from the control arm began using PAP device, mostly ASV. In intention to treat analysis you consider all patients in the arm they were allocated to and also include those who did not use ASV, etc. Associated Professional Sleep Societies, LLC 44

45 SERVE-HF Statistical analysis-2 Once the primary endpoint proved non-significant, all other analyses are only hypothesis generating and subj to type 1 error. However, if there is a safety issue, the results cannot be ignored. That is why both ResMed and Philips Respironics declared ASV contraindication for HFrEF/CSA Associated Professional Sleep Societies, LLC 45

46 SERVE-HF Protocol violation: LVEF issues-1 Inclusion criteria: 45% Mean LVEF= 32% Range: ASV arm: 10% to 54% Control arm 9% to 71% Associated Professional Sleep Societies, LLC 46

47 Design of SERVE-HF Protocol violation: LVEF issues-2 Missing LVEF ASV arm: 130 (N= 666, 20%) Control arm: 126(N=659, 19%) Associated Professional Sleep Societies, LLC 47

48 SERVE-HF : Protocol violations Not clear to me how these issues were handled? Subgroup analysis HFrEF only How many HFpEF and its implications In my opinion, these protocol violations speak to the poor quality of the trial Associated Professional Sleep Societies, LLC 48

49 SERVE-HF : Long-term follow up Clinic visits First 2w 3m 12 m 24m 36m 48m 60m Associated Professional Sleep Societies, LLC 49

50 SERVE-HF : ASV data; NEJM How effective is ASV in treating SA? In SERVE-HF ASV effectively treated sleep apnea Associated Professional Sleep Societies, LLC 50

51 SERVE-HF : ASV data; NEJM ASV effectively treated sleep apnea Baseline 3m 12 m 24m 36m 48m AHI, mean AHI, range SaO 2 < 90% min range Associated Professional Sleep Societies, LLC 51

52 Algorithms APNEA Reduction in MV 75 % Hypopnea Reduction in MV 50 % Associated Professional Sleep Societies, LLC 52

53 SERVE-HF : ASV data; NEJM ASV effectively treated sleep apnea Baseline AHI, mean (SD) 31.2±12.7 Central AHI/total AHI % 80.8± % of events considered obstructive Of 98 patients with follow-up sleep studies and LVEFs, 18 converted spontaneously to predominantly OSA Associated Professional Sleep Societies, LLC 53

54 SERVE-HF : ASV data; NEJM ASV effectively treated sleep apnea Changing phenotype: Shift in sleep apnoea type in heart failure patients in the CANPAP trial 98 patients with follow-up sleep studies 18 converted spontaneously to predominantly OSA Ryan et al, ERJ, 2010 Associated Professional Sleep Societies, LLC 54

55 CAHI/AHI % Baseline 3m 12m 24m 36m 48m Associated Professional Sleep Societies, LLC 55

56 SERVE-HF ASV Fixed EPAP Associated Professional Sleep Societies, LLC 56

57 OSA not suppressed by the fixed EEPP ASV device used was equipped with only one strategy for suppressing these events: progressively increasing IPS in an attempt to open the closed airway Once the airway opened, the prevailing high pressures is reflected within the thorax excessive rise in intrathoracic pressure, and excess ventilation with consequent adverse effects Associated Professional Sleep Societies, LLC 57

58 Associated Professional Sleep Societies, LLC 58

59 Effect of lung volume on PVR Capillary network Coursing through alveolar walls With increased ER of the alveolar walls, extra-alveolar vessels expand Associated Professional Sleep Societies, LLC 59

60 Hypoxic Burden in SERVE-HF Baseline 3m 12 m 24m 36m 48m SaO 2 < 90% min range Associated Professional Sleep Societies, LLC 60

61 Prevalence of sleep apnea 962 HFrEF patients Age, years 65 BMI, kg/m 2 27 Male, % 81 Ischaemic, % 51 DM, % 32 II, III, IV, % 34, 57, 8 LVEF, % 30 AF, % 25 Paced, % 9 PM, ICD, CRT-P, CRT-D% 8, 14,2, 13 ACE-I/ARB 94%, β-blockers 89 %,Diuretics 91 %, Spironolactone/eplerenone 61%, Digitalis glycosides 49 % Associated Professional Sleep Societies, LLC 61

62 Prevalence of sleep apnea 962 HFrEF patients AHI, /h 22 ± 17 No SDB (AHI <5/h), n (%) 192 (20%) Mild SDB (AHI 5 14/h), n (%) 211 (22%) Moderate SDB (AHI 15 29/h), n (%) 263 (27%) Severe SDB (AHI 30/h), n (%) 297 (31%) Type of SDB, n (%) OSA (AHI 5/h), n (%) 295 (31%) CSA (AHI 5/h), n (%) 464 (48%) OSA, AHI 15/h, n (%) 156 (16%) CSA,AHI 15/h, n (%) 403 (42%) T90 (h) 0.8 ± 1.3 Oldenburg et al, EHJ 2016 Associated Professional Sleep Societies, LLC 62

63 Kaplan Meier curve of overall survival by the presence and severity of sleep-disordered breathing. Olaf Oldenburg et al. Eur Heart J 2015;eurheartj.ehv624 age, gender, NYHA class,icm, diabetes, BMI, heart rhythm, ICD, or CRT devices, and the use of diuretics, b-blockers and digitalis glycosides. Associated Professional Sleep Societies, LLC 63

64 Kaplan Meier survival analysis for patients with no or mild sleep-disordered breathing (apnoea hypopnoea index <15/h) vs. patients with moderate-to-severe obstructive or central sleep apnoea (apnoea hypopnoea index 15/h). N=962 CSA Olaf Oldenburg et al. Eur Heart J 2015;eurheartj.ehv624 Associated Professional Sleep Societies, LLC 64

65 Kaplan Meier survival curves by quartile of time with nocturnal oxygen saturation below 90% (T90). Olaf Oldenburg et al. Eur Heart J 2015;eurheartj.ehv624 Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oup.com. Associated Professional Sleep Societies, LLC 65

66 Hypoxia, Not the Frequency of Sleep Apnea, Induces Acute Hemodynamic Stress in Patients With Chronic Heart Failure (Gottlieb et al, JACC 2009) Associated Professional Sleep Societies, LLC 66

67 Hypoxia, Not the Frequency of Sleep Apnea, Induces Acute Hemodynamic Stress in Patients With Chronic Heart Failure(Gottlieb et al, JACC 2009) BNP prior to sleep, pg/ml 243 each 10% increase in duration of hypoxemia increased BNP by 9.6% (95% confidence interval: 1.5% to 17.7%, p 0.02). Associated Professional Sleep Societies, LLC 67

68 Hypoxemic burden A predictor of hemodyamic burden A predictor of all-cause mortality The risk of death increased by 16.1% (95% CI 1.086, 1.242) for every 1-h increase in Time below 90% Oxygen trial is coming to surface! Associated Professional Sleep Societies, LLC 68

69 80 70 Room Air Oxygen Changes in AHI with low flow nasal O 2 in CSA patients with heart failure and systolic dysfunction Javaheri, PPSM, In Press p< Apnea-Hypopnea Index (n/hr) Means SD p<0.01 p<0.05 p=0.01 p=0.02 p< N=9 N=7 N=11 N=7 N=22 N=29 Hanly Walsh Staniforth Franklin Andreas Javaheri Associated Professional Sleep Societies, LLC 69

70 Effect of Nocturnal Oxygen Therapy in Sleep Disorder Oxygen Desaturation Index Apnea Hypopnea index Oxygen Desaturation Index (event/h) P<0.001 NS P<0.001 P<0.001 Oxygen Control P<0.001 Apnea/Hypopnea Index (event/h) NS P<0.001 NS P=0.028 Oxygen Control Weeks Weeks 12 Associated Professional Sleep Societies, LLC 70

71 Effect of Nocturnal Oxygen Therapy in Sleep Disorder [%] Oxygen NS Control 60 P = Weeks Associated Professional Sleep Societies, LLC 71

72 RCT:Nocturnal O 2 improves QOL and LVEF (12 W) Control Group 3L/min O 2 n ODI/h * NYHC No change 28% Improved LVEF % * QOL [SAS(Mets)] * Sasayama et al; Circ J (Jap), 2006 Associated Professional Sleep Societies, LLC 72

73 Treatment of CSA in HF: What Now? Maximize medical therapy (Meds and CRT) ASV CPAP Cardiac transplantation Nocturnal O 2 PNS Acetazolamide Theophylline Associated Professional Sleep Societies, LLC 73

74 Stimulation Location Right Phrenic Nerve Left Phrenic Nerve Stimulation Site Right Brachiocephalic Vein Stimulation Site Left Pericardiophrenic or Left Brachiocephalic Vein Diaphragm Associated Professional Sleep Societies, LLC 74

75 Left Pericardiophrenic Vein Cardima Catheter in Left Pericardiophrenic Vein Augostini et al. Heart Rhythm Society 2011 Associated Professional Sleep Societies, LLC 75

76 Therapy Terminates CSA Ponikowski et al Eur Heart J doi: /eurheartj/ehr298 Associated Professional Sleep Societies, LLC 76

77 Changes in SRBD with neurostimulation Central Apnea Index Apnea Hypopnea Index p < 0.001* p = 0.002* Index (per hour) Mean + SD Index (per hour) Mean + SD *Wilcoxon matched pairs signed rank test Associated Professional Sleep Societies, LLC 77

78 Changes in consequences of SRBD with neurostimulation Oxygen Desaturation Index 4% p = 0.002* Arousal Index p = 0.001* Index (per hour) Mean + SD Index (per hour) Mean + SD *Wilcoxon matched pairs signed rank test Associated Professional Sleep Societies, LLC 78

79 The remedē System Pilot Study Effects on Sleep Parameters at 3 and 6 M n=44 Parameter Baseline* 3 Months* 6 Months* P Value AHI, no./hr of sleep CAI, no./hr of sleep < OAI, no./hr of sleep MAI, no./hr of sleep < HI, no./hr of sleep ODI4, no./hr of sleep < ArI, no./hr of sleep < Repeated measures ANOVA. Associated Professional Sleep Societies, LLC 79

80 The remedē System Pilot Study Effects on Sleep Efficiency and REM Sleep All changes are statistically significant at 3 and 6 months (all P < , except for REM Sleep P = ) Associated Professional Sleep Societies, LLC 80

81 The remedē System Pilot Study Effect on Patient Global Assessment at 6 Months Associated Professional Sleep Societies, LLC 81

82 Don t ever go to sleep. Too many people die there. Mark Twain Associated Professional Sleep Societies, LLC 82