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Slide 1: Sleep Apnea in Heart Failure Update on Prevalence and Treatment Options S. Javaheri, M.D., FCCP Professor Emeritus of Medicine, University of Cincinnati, College of Medicine Medical Director, Sleepcare Diagnostics Cincinnati, Ohio Indianapolis, 8/2007
Slide 2: Disclosures I am a consultant and/or have received grant and/or honoraria and/or travel expenses from: BI, Cardiac Concept, Cephalon, GSK, Respironics, Res Med, Sanofi-Aventis and Takeda
Slide 3: Obstructive Apnea Normal Airway Obstructed Airway
Slide 4: Polysomnographic Breathing Disorders Event Rib cage Airflow Ribcage Abdomen Obstructive apnea
Slide 7: Interaction Between Sleep and Heart Pathology Primary Sleep Apneas & Hypopneas Secondary Cardiovascular Pathology Secondary Primary
Slide 8: Polysomnographic Breathing Disorders Event Rib cage Airflow Ribcage Abdomen Central apnea
Slide 10: Hunter- Cheyne-Stokes Breathing in SHF
Slide 11: ( N=32 ) Survival % ( N=56 ) Months Javaheri et al, JAAC,2007
Slide 12: Prevalence of Sleep Apnea in Recent Prospective Studies of SHF Country (y) (Ref) n % AHI ≥ 10/hr % AHI ≥ 15/hr % CSA % OSA % β blockers US (06) (5) anada (07) (13) N Zealand (05) (11) China (07) (12) UK (07) (18) Germany (07) (16) Germany (07) (15) Germany (07) (19) 100 287 56 126 55 700 203 102 49 47 68 71 53 52 71 54 37 21 15 46 38 33 28 37 12 26 53 25 15 19 43 17 10 80 30 80 78 85 90 80
Slide 13: Complex sleep apnea The new kid on the block or the old guy in the background
Slide 14: Prevalence of Sleep Sleep Apnea Prospective Complex Apnea in CPAP-resistant CSA and CPAP-emergent CSA Studies of SHF • CPAP-resistant Central Sleep Apnea (CSA) – – – – – – – A large number of Patients with Systolic Heart failure Patients with Atrial Fibrillation Patients on Opioids Neuromuscular Disease Over-titration Sleep Fragmentation ( Post-arousal ) S/P UPPP • CPAP-emergent CSA
Slide 15: Hunter- Cheyne-Stokes Breathing in SHF
Slide 21: SA/H: Mechanisms Contributing to Cardiovascular Disease ↓ O2 Delivery H/R ↑ PCO2 Sleep Apnea & Hypopnea Arousals Endothelial Dysfunction Syndrome Hypoxic & Hypercapnic Pulmonary Vasoconstriction Sympathetic Activation ↑ Transmural P. of L&R ventricles, and Pulmonary Microvascular Bed Organ Dysfunction Vasoconstriction Thrombosis Inflammation ↑ RV Afterload ↑ SVR/Others Changes in R&L Ventricular Preload & Afterload ↑ Lung H2O ↓ Ppl
Slide 22: CSA as a Predictor of Mortality in SHF • • • • N = 114 eligible N = 100 Enrolled N = 12 with OSA Excluded N = 88 N = 88 : 32 with AHI <5 ; 56 with AHI ≥5/hr Median F/U : 51 months Javaheri et al , J Am Coll Cardiol (May, 2007)
Slide 23: Demographic and cardiovascular parameters in 88 heart failure patients without and with central sleep apnea Variable Number Age, y BMI, kg/m2 SBP, mm Hg DSP, mm Hg Heart rate, n/min AHI<5/hr 32 62 28 127 72 78 AHI ≥5/hr 56 67 26 119 70 80 0.02 0.09 0.06 0.09 0.48 P
Slide 24: SRBD in 88 heart failure patients without and with central sleep apnea Variable AHI, n/hr CAI, n/hr OAI, n/hr CAHI, n/hr OAHI, n/hr AHI<5/hr 2 0.6 0.1 2 0.2 AHI ≥5/hr 35 23 0.5 32 1
Slide 25: Cardiovascular parameters in 88 heart failure patients without and with central sleep apnea Variable LVEF, % RVEF, % Atrial fibrillation,% NHYA Class I,% NHYA Class II, % NHYA Class III, % AHI<5/hr 27 49 6 25 53 22 AHI ≥5/hr 22 43 20 9 55 36 P 0.006 0.048 0.1 0.09 0.09 0.09
Slide 26: The Predictors of mortality in SHF Three Variables, RVEF, AHI and DBP Independently Correlated with Survival: RVEF (HR=0.97, P=0.003) AHI (HR=2.14, P=0.02) DBP (HR=0.96, P=0.02)
Slide 27: 100 100 90 90 80 80 70 70 60 60 50 50 P=0.01 90 90 Median survival Survival Median (months) P=0.01 62 62 P=0.02 59 59 44 44 36 36 P=0.003 60 60 P=0.002 60 60 P=0.002 59 59 45 45 40 40 30 30 20 20 10 10 35 35 35 35 36 36 00 AHI<5 VS >=5 AHI<5 VS ≥5 AHI<10 VS≥10 AHI<10VS >=10 AHI<15 VS ≥15 AHI<15 VS >=15 AHI<20 VS ≥20 AHI<20 VS >=20 AHI<25 VS >=25 AHI<25 VS ≥25 AHI<30 VS VS≥30 AHI<30 >=30 ■ Less than than point cutoff point to cutoff point Less cutoff the Greater or equal ■ Greater or equal than the cutoff point Javaheri et al, JAAC, 2007
Slide 28: Prevalence of Sleep apnea Stable Systolic Heart Failure Prospective Studies Variable Apnea-Hypopnea Index > 15/hr Central Sleep Apnea Obstructive Sleep Apnea 12 - 53 Range, % 47 - 49 15 - 46
Slide 29: Prevalence of SRBD in Systolic Heart Failure 100 out of 114 consecutive patients – 68% with AHI ≥ 5/h ; 49% with AHI ≥ 15/h – 56% CSA – 12% OSA – Javaheri, Ann Intern Med, 1995, Circulation 1998 – and Int J cardiol 2006
Slide 30: Prevalence of Sleep Apnea in Prospective Studies of SHF 100 80 68 68 49 AHI ≥5/hr AHI ≥10/hr AHI ≥15/hr 82 71 70 53 60 % 40 20 0 47 US Canada NZ China DCM Germany ICM Germany
Slide 31: Prevalence of Sleep Apnea in Prospective Studies of SHF OSA 60 50 40 % 30 20 10 0 US 12 37 26 37 38 35 32 53 46 37 CSA 21 15 20 17 Canada NZ China DCM ICM Germany Germany
Slide 32: Heart Failure in U.S. • • • • • • • • • • 1.5–2% of population (5 million) 6–10% of population >65 y old 400,000–700,000 new cases annually 20 million with asymptomatic cardiac impairment 11 million physician office visits annually 3.5 million hospitalizations annually Leading cause of hospitalization in people >65 y 250,000 deaths annually (direct and indirect) $27 billion (annual cost), 2003 $8–15 billion per for hospitalization
Slide 33: Mortality Trends in Heart Failure U.S. • Framingham Study (2002) 59% in men and 43% in women • Olmsted Study (2004) 43% • Worcester (2007) 79%
Slide 34: Treatment of CSA in SHF (No Guidelines) 1. Promote sleep hygiene 2. Avoiding ETOH and benzodiazepines 3. Optimization of medical thereapy of CP functions β−Βlockers vs- melatonin secretion 1. Treatment algorithm for CSA 2. Treatment of RLS/PLM
Slide 35: Optimize Therapy: ACEI; ß-Blockers; Diuretics; Digoxin; CRT SRBD Eliminated Follow-up Clinically Persistent SRBD Consider Treatment Medications Cardiac Transplantation Medical Devices Nocturnal Nasal Oxygen Theophylline Acetazolamide nCPAP APSSV Cardiac Pacing HFV Mandibular Advancement
Slide 36: Optimize Therapy: ACEI; ß-Blockers; Diuretics; Digoxin SRBD Eliminated Follow-up Clinically Persistent SRBD Consider Treatment Cardiac Transplantation Medications Medical Devices Nocturnal Nasal Oxygen Theophylline Acetazolamide nCPAP APSSV Cardiac Pacing HFV Mandibular Advancement
Slide 37: Study Design-Inclusion Criteria • • • • • Subjects transplanted between 1995-1999 At least 5 months post- transplant 59 Eligible patients 45 Participated (76%) 14 Refused (24%) Javaheri et. al., EHJ, 2004
Slide 38: AHI, no./hr 47% 21 20 15 10 5 1 0- 5 5- 10 10- 15 0 15- 20 20- 30 30- 40 40 7 5 4 53% 51% 36% 36% 24% 16% 7 Number of Subjects Javaheri et. al., EHJ, 2004
Slide 39: Demographics and Physical Examination Findings in 45 Heart Transplant Subjects Without Sleep Disorders (Group I, n=15), With PLM (Group II, n=14) or With Sleep Related Breathing Disorders (Group III, n=16) Variable Age, y Male/Female, n Ht, cm Wt, kg Wt gain since transplant, kg BMI, kg/m2 Neck size, cm Group I Group II 58 13/2 176 85 4 27 41.1 55 12/2 179• 90 9 28• 42.4 Group III 58 15/1 172 99* 16* 33* 43.9 p 0.7 — 0.03 0.045 0.03 <0.001 0.1 Values are means ± SD; * p<0.05 when compared to Group I; • p<0.05 when compared to Group III.
Slide 40: Group I Group 2 Group 3 80 70 60 50 40 30 20 10 0 P=0.02 P=0.002 P=0.03 P=0.04 P=0.01 P=0.7 * * * * Habitual Snoring % Excessive Daytime Sleepiness % Unrefreshed Sleep % Restless Legs Syndrome % Physical Component Scale Mental Component Scale Javaheri et. al., EHJ, 2004
Slide 41: Optimize Therapy: ACEI; ß-Blockers; Diuretics; Digoxin SRBD Eliminated Persistent SRBD Consider Treatment Follow-up Clinically Medications Cardiac Transplantation Medical Devices Nocturnal Nasal Oxygen Theophylline Acetazolamide nCPAP APSSV Cardiac Pacing HFV Mandibular Advancement
Slide 42: 80 70 60 50 p<0.01 Changes in AHI with low flow nasal O2 in CSA patients with heart failure and systolic dysfunction Room Air Oxygen Means±SD p<0.0001 Apnea-Hypopnea Index (n/hr) p=0.01 p<0.05 p<0.001 40 30 20 10 0 p=0.02 N=9 Hanly N=7 Walsh N=11 Staniforth N=7 Franklin N=22 Andreas N=29 Javaheri
Slide 43: • Decreases PB and central apneas • Improves hypnogram ↓ Ar; ↑ S1; ↑ S2 • Improves exercise capacity • Decreases sympathetic activity ↓ urinary norepinephrine ↓ SMNA by microneurography • Increases LVEF • Improves Quality of life Effects of Supplemental Nasal O2 on CSA in SHF • Decreases BNP
Slide 44: Optimize Therapy: ACEI; ß-Blockers; Diuretics; Digoxin ,CRT SRBD Eliminated Follow-up Clinically Persistent SRBD Consider Treatment Cardiac Transplantation Medications Medical Devices Nocturnal Nasal Oxygen Theophylline Acetazolamide nCPAP APSSV Cardiac Pacing HFV Mandibular Advancement
Slide 45: Data of HF Patients Undergoing Theophylline Trial Variable N Gender, M/F Age, y Ht, cm Wt, kg Theo, ug/ml Baseline 15 15/0 66 175 89 ND Values are means; ND=not detectable Placebo Theo 15 15 15/0 15/0 66 66 175 175 88 88 ND 11 Javaheri et al., NEJM, 1996, 335, 562-7
Slide 46: Periodic Breathing at Baseline, With Placebo and Theophylline in 15 HF Patients Variable Baseline AHI, n/h 47 CAI, n/h 26 OAI, n/h 2 MAI, n/h 2 DBArI, n/h 24 Placebo Theo 37 18* 26 6* 2 2 2 1 17 8* Values are means; * p < 0.05 Javaheri et al., NEJM, 1996, 335, 562-7
Slide 47: Optimize Therapy: ACEI; ß-Blockers; Diuretics; Digoxin;CRT SRBD Eliminated Follow-up Clinically Persistent SRBD Consider Treatment Cardiac Transplantation Medications Medical Devices Nocturnal Nasal Oxygen Theophylline Acetazolamide nCPAP APSSV Cardiac Pacing HFV Mandibular Advancement
Slide 48: Demographics and Cardiovascular Findings in 12 SHF Patients with Central Sleep Apnea Treated with Acetazolamide Variable Patients, n Age, y BMI, kg/m2 SBP, mm Hg DBP, mm Hg LVEF, % Baseline 12 66 26 110 67 19 Placebo 12 66 26 113 69 21 ACTZ 12 66 26 108 69 20 p ---0.9 1.0 0.8 0.9 0.5 Values are means. Javaheri, AJRCCM, 2006
Slide 49: Disordered Breathing Events of 12 SHF Patients with Central Sleep Apnea Treated with Acetazolamide Variable AHI, n/h CAI, n/h Baseline Placebo ACTZ 55 44 57 49 34*† 23*† p 0.002 0.004 * p < 0.05 versus baseline † = p < 0.05 versus placebo
Slide 50: Patients’ Perception of Their Sleep Quality and Daytime Symptoms Comparing Acetazolamide with Placebo Variable Acetazolamide p Sleep quality Waking up refreshed Daytime fatigue Fall asleep unintentionally Javaheri, Am J Respir Crit Care Med,2006 Improved Improved Improved Decreased 0.003 0.007 0.02 0.002
Slide 52: Continuous Positive Airway Pressure for Central Sleep Apnea and Heart Failure Background • The Canadian Continuous Positive Airway Pressure for Patients with CSA and Heart Failure trial tested the hypothesis that CPAP would improve the survival rate without heart transplantation of patients who have CSA and heart failure Bradley TD et al., N Engl J Med 2005;353:2025-33.
Slide 53: Continuous Positive Airway Pressure for Central Sleep Apnea and Heart Failure Methods • After medical therapy was optimized, 258 patients who had heart failure, were randomly assigned to receive CPAP (128) or no CPAP (130) • CAHI = 40/hr , LVEF = 25%, age = 63 yr • Patients were followed for a mean of two yr Bradley TD et al., N Engl J Med 2005
Slide 54: Effect of CPAP on the Frequency of Episodes of Apnea and Hypopnea Episodes of Apnea and Hypopnea (no. per hr of sleep) 50 40 30 20 10 0 P<0.001 0 3 24 CPAP group Control group Time from Randomization (mo) Bradley TD et al., N Engl J Med 2005
Slide 55: Heart-Transplantation-Free Survival 100 Transplantation-free Survival (%) 80 60 40 20 0 CPAP group (32 events) Control group (32 events) P=0.54 0 12 24 36 48 60 Time from Enrollment (mo) Bradley TD et al., N Engl J Med 2005
Slide 56: Potential Mechanisms of CPAP Failure 1. Hemodynamic Consequences: Effects on RV Function, LV Stroke Volume, BP and CBF. Hemodynamic Effects of Atrial Fibrillation 1. Nonresponsive Patients Importance of Hpocapnia and Failure of PAP Devices to Correct it
Slide 57: The Predictors of mortality in SHF • N = 88; 32 with AHI <5; 56 with AHI ≥5/hr • Mean AHI 2/hr vs. 32/hr (CAI = 23/hr) • Median F/U : 51 months • RVEF (HR=0.97,P=0.003), AHI (HR=2.14,P=0.01) and DBP (HR=0.96,P=0.02) independently correlated with survival
Slide 58: RV Systolic dysfunction is a predictor of mortality in SHF . . . . . . . . Palak, J Am Coll Cardiol, 1983 Disalvo, J Am Coll Cardiol, 1995 Gavazzi, J Heart Lung Transplant, 1997 Mehta, J Am Coll Cardiol, 2001 Karatasakis, J Am Cardiol. 1998 Meluzin, Int J Cardiol, 2005 De Groote, J Am Coll Cardiol, 1998 Ghio, J Am Coll Cardiol, 2001
Slide 59: CVD mortality in the elderly The lower the DBP the worse • CV effects of SBP and DBP depend on the age • In the Fram study, there was a gradual transition from DBP to SBP as the more important predictor of CV mortality • After age 60 yr, the risk of CHD correlated positively with SBP and negatively with DBP • After age 60 yr, the lower DBP was associated with a worsening CV prognosis Franklin et al, Circulation, 2001
Slide 60: The risk with aggressively lowering blood pressure in HTN patients with CAD • Low DBP and Mortality; Post hoc analysis of INVEST • N = 22576 patients with CAD, CHF (I,II) and HTN • The risk for the primary outcome, all-cause death and MI, but not stroke, progressively increased with low diastolic blood pressure. • Excessive reduction in diastolic pressure should be avoided in patients with CAD who are being treated for hypertension. • Messerli et al, AIM, 2006
Slide 61: Transplant-free survival in HF patients according to effect of CPAP on CSA 100 CPAP responders* (AHI at 3 months < 15/hr, n = 57) Transplant-free survival (%) 80 60 CPAP non-responders 40 (AHI at 3 months ≥ 15/hr, n = 43) Control 20 *versus control: HR=0.36, p=0.040 0 0 6 12 18 24 30 36 42 48 54 60 Time from enrollment (months)
Slide 62: Optimize Therapy: ACEI; ß-Blockers; Diuretics; Digoxin SRBD Eliminated Follow-up Clinically Persistent SRBD Consider Treatment Cardiac Transplantation Medications Medical Devices Nocturnal Nasal Oxygen Theophylline Acetazolamide nCPAP APSSV Cardiac Pacing HFV Mandibular Advancement
Slide 63: APSSV in CSA (mean values) Baseline O2 2l/min CPAP 8-11 Bilevel APSSV IP:11-15 ∆PI:4-10 EP: 5-6 EP: 4-6 AHI (n/hr) ArI (n/hr) PtCO2 (mm Hg) 45* 67* 32 28* 32* 37* 27* 32* 35 15* 18 35 6 17 34 *Significant vs. APSSV. Teschler et al., AJRCCM, 2001
Slide 64: APSSV in SHF/ CSA • A randomized parallel trial using Therapeutic and Subtherapeutic APSSV for one month • 15 patients with SHF in each group; mean AHI = 20/hr • AHI decreased to 5/hr in Ther. and 15 /hr in Subther. arm • In the Ther. arm: Objective (but not subjective) EDS, BNP and urinary metadrenaline excretion decreased Pepperell et al, AJRCCM, 2003
Slide 65: Studies with ASV in SHF a n Age (Y) LVEF % Duration nights Baseline AHI n/hr ASV AHI n/hr Teschler Szollosi (2001) (2006) 14 10 15 12 4 69 67 71 64 72 NR 32 30 29 38 1 1 30 180 1 47 30 25 47 63 8 14 5 <10 6 Pepperell* (2003) Phillips Kasai (2006) (2006)
Slide 66: CPAP vs. APSSV in Patients on Opioids Baseline PSG AHI OAI CAI AHI CPAP Final Setting ADAPT Final Settings OAI CAI AHI OAI CAI 1 2 3 4 74 17 44 83 45 0.5 4 1 29 3 3 60 101 27 61 34 0.0 0.0 0.0 0.0 101 22 56 33 6 12 1 5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Slide 67: Prevalence of Sleep Apnea in Recent Prospective Studies of SHF Country (y) (Ref) n % AHI ≥ 10/hr % AHI ≥ 15/hr % CSA % OSA % β blockers US (06) (5) anada (07) (13) N Zealand (05) (11) China (07) (12) UK (07) (18) Germany (07) (16) Germany (07) (15) Germany (07) (19) 100 287 56 126 55 700 203 102 49 47 68 71 53 52 71 54 37 21 15 46 38 33 28 37 12 26 53 25 15 19 43 17 10 80 30 80 78 85 90 80
Slide 68: OSA as a Cause of Mortality in SHF (Wang, JAAC, 2007) N=113 N=37
Slide 69: Treatment of OSA in CHF • • • • • • • Promote sleep hygiene Avoid ETOH , benzodiazepines and Viagra Weight loss Positive airway pressure devices CPAP, bilevel Mandibular advancement devices Upper airway procedures Nocturnal use of supplemental oxygen
Slide 70: Effects of CPAP on Systolic Heart Failure in OSA • 24 patients with systolic HF and OSA (AHI ~40/h) were randomized to CPAP (n = 12) or a control group (n = 12) • LVEF increased significantly following one month of CPAP therapy (25% to 34%) • LVEF did not change significantly in the control group CPAP = continuous positive airway pressure HF = heart failure LVEF = left ventricular ejection fraction Kaneko Y et al. N Engl J Med. 2003;348:1233.
Slide 71: A controlled study of mild to moderate OSA (AHI~25, low SaO2~78%) with CPAP (9cm H2O) for 3 months in SHF Variables N AHI, n/hr LVEF UNE ESS SF36 CHF? Control 21 21→ 18 ↑1.5% ↑2 ↑1 No change No change CPAP 19 25→ 3 ↑5% (P=0.04) ↓10 (P=0.04) ↓3 (P=0.01) Improved Improved No change in BP, Dyspnea, VO2, NYHA, BMI or Meds Mansfield et al, Am J Respir Crit Care Med, 2004
Slide 72: CPAP Improves Cardiac Efficiency Open study of 7 HF /OSA compared to 5 HF/No OSA Age yrs BMI Kg/m2 LVEF % AHI /hr SHF/OSA 61 62 37 30 31 27 38 3 SHF/No OSA Yoshinaga et al; JAAC, 2007
Slide 73: Long-term CPAP Improves Cardiac Efficiency • 2D-ECHO and “C acetate PET (K mono) baseline and 6 W • K mono = Monoexponential function fit to myocardial clearance (rate of oxidative metabolism reflecting MVO2) • Myocardial efficiency: LV WMI = SVI *SBP/K mono) Yoshinaga et al; JAAC, 2007
Slide 74: CPAP Improves Cardiac Efficiency SHF/OSA (CPAP) Base line SHF/No OSA Base line Heart rate SBP SVI LVEF Kmono WMI 59 141 37 38 38 0.047 7.1 6 wk 58 141 38 43* 43* 0.04* 8.2* 60 129 42 43 0.039 8.2 6 wk 55 121 42 44 0.036 7.0 Yoshinaga et al; JAAC, 2007
Slide 75: Effects of CPAP on LVEF in OSA/SHF Kaneko n AHI, n / h LVEF, % Change in LVEF, % Duration CPAP titration Compliance, h 12 40 25 9 4W yes 6.2 Mansfield 19 21 35 5 3M yes 5.6 Yoshinaga 7 38 38 5 6W yes NR Smith 23 36 30 N0 6W Auto 3.5
Slide 76: Treatment of OSA in CHF • • • • • • • • Promote sleep hygiene. Avoid ETOH and benzodiazepines. Weight loss. Positive airway pressure devices, CPAP, bilevel. Mandibular advancement devices. Upper airway procedures. Nocturnal use of supplemental oxygen. Pacing does not improve OSA.
Slide 77: Pacing does not improve OSA OSA without Heart Failure 1. Pepin et al, Eur Respir J, 2005 2. Luthye et al, Am J Respir Crit Med, 2005 3. Simantrikis et al, NEJM, 2005 OSA with Heart Failure 1. Garrigue et al, NEJM, 2002 2. Gabor et al, Eur Respir J, 2005 3. Pepin et al ,Eur Respir J, 2005
Slide 78: Pacing Does Not Improve OSA Baseline Pacing HR /min AHI /hr CAI /hr Minimum SaO2 % 64 43 1 83 75 50 2 84 n=15; BMI=28 kg/m2; ↓ LVEF=64 % (5<56 %) Pepin et al, ERJ;2005
Slide 79: Treatment of OSA in CHF • • • • • • • Promote sleep hygiene. Avoid ETOH and benzodiazepines. Weight loss. Positive airway pressure devices, CPAP, bilevel. Mandibular advancement devices. Upper airway procedures. Nocturnal use of supplemental oxygen.
Slide 80: Heart Failure in U.S. • • • • • • • • • • 1.5–2% of population (5 million) 6–10% of population >65 y old 400,000–700,000 new cases annually 20 million with asymptomatic cardiac impairment 11 million physician office visits annually 3.5 million hospitalizations annually Leading cause of hospitalization in people >65 y 250,000 deaths annually (direct and indirect) $27 billion (annual cost), 2003 $8–15 billion per for hospitalization