Sleep Disordered Breathing and Cardiovascular Disease Obstructive Sleep
Sleep Disordered Breathing and Cardiovascular Disease Obstructive Sleep Apnea and Cardiovascular Risk David P. White, MD, Chief Medical Officer, Philips Respironics Professor of Medicine Harvard Medical School September 10, 2009
Sleep and Cardiovascular Disease Confidential Dr. David White, International Group HHS, 09. 10. 2009 2
Confidential Dr. David White, International Group HHS, 09. 10. 2009
OSA and Cardiovascular Disease • Intermediate Outcomes – Hypertension – Diabetes • Hard Outcomes – Myocardial infarction – Stroke – Congestive Heart Failure – Death Confidential Dr. David White, International Group HHS, 09. 10. 2009
OSA and Cardiovascular Disease • Intermediate Outcomes – Hypertension – Diabetes • Hard Outcomes – Myocardial infarction – Stroke – Congestive Heart Failure – Death Confidential Dr. David White, International Group HHS, 09. 10. 2009
Systemic Hypertension and Obstructive Sleep Apnea • Human/animal physiologic data • Human epidemiologic data • OSA treatment trials Confidential Dr. David White, International Group HHS, 09. 10. 2009
Hedner et al J Hypertension, 1988 Muscle nerve sympathetic activity Blood pressure (mm. Hg) Heart rate (mine-1) Respiratory movements Nose Air flow Mouth Oxygen saturation Sa. O 2 (%) Confidential Dr. David White, International Group HHS, 09. 10. 2009
Somers et al J Clin Invest, 1995 AWAKE NORMAL OSA 10 sec Confidential Dr. David White, International Group HHS, 09. 10. 2009
J Clin Invest - 1997 Obstructive Sleep Apnea as a Cause of Systemic Hypertension Evidence from a Canine Model Dina Brooks, Richard L. Horner, Louise F. Kozar, Caroline L. Render-Teixeira, and Eliot A. Phillipson Department of Medicine, University of Toronto, Ontario, Canada, M 5 S 1 A 8 Confidential Dr. David White, International Group HHS, 09. 10. 2009
JCI 1997 Brooks et al Protocol • 4 dogs studied. • Sleep apnea induced mechanically for 1 -3 months. • Arousal induced to sound recurrently for 1 -3 months. • Mean BP assessed frequently awake and asleep. Confidential Dr. David White, International Group HHS, 09. 10. 2009
Mean Nighttime BP (% Control) Brooks et al. JCI 1997 110 100 90 control Confidential 1 -2 wk Dr. David White, International Group HHS, 09. 10. 2009 >4 wk First Night
Mean Nighttime BP (% Control) Brooks et al. JCI 1997 130 120 110 100 90 control Confidential 1 -2 wk 2 -5 wk >5 wk Dr. David White, International Group HHS, 09. 10. 2009 1 -3 wk >5 wk
Confidential Dr. David White, International Group HHS, 09. 10. 2009
New England Journal of Medicine, 2000 Peppard et al The Apnea-Hypopnea Index at Base Line Confidential Dr. David White, International Group HHS, 09. 10. 2009
24 Hour BP Before and After 1 Month of CPAP, Therapeutic Versus Sub-therapeutic (Pepperell et al, Lancet 359: 204, 2002) After. Treatment Mean blood pressure (mm. Hg) Before Treatment Time from wake and sleep onset (hours) Confidential Time from wake and sleep onset (hours) Dr. David White, International Group HHS, 09. 10. 2009
Results: Pooled Analysis Systolic Blood Pressure Usui 2005 Barnes 2004 Kaneko 2003 Becker 2002 Pepperell 2002 Barnes 2002 Barbe 2001 Monasterio 2001 Overall -50 -40 -30 -20 -10 0 Point estimates and 95% confidence intervals of each study are shown. A negative value indicates that CPAP reduced blood pressure compared to control. Confidential Dr. David White, International Group HHS, 09. 10. 2009 10 Lung 2007
Results: Pooled Analysis Diastolic Blood Pressure Usui 2005 Barnes 2004 Kaneko 2003 Becker 2002 Pepperell 2002 Barnes 2002 Barbe 2001 Monasterio 2001 Overall -30 -20 -10 0 Point estimates and 95% confidence intervals of each study are shown. A negative value indicates that CPAP reduced blood pressure compared to control. Confidential Dr. David White, International Group HHS, 09. 10. 2009 10 Lung 2007
Effect of CPAP on Blood Pressure MAP systolic diastolic 15 10 * * * 5 mm. Hg 0 -5 -10 -15 -20 -25 Figure 2. Changes in blood pressure with effective (closed bars) and subtherapeutic (open bars) n. CPAP. “Significant difference. MAP indicates mean arterial blood pressure; systolic, systolic blood pressure; and diastolic, diastolic blood pressure. MAP, P=0. 01: systolic blood pressure, P=0. 04; diastolic blood pressure, P<0. 005. Becker et al, 2003 Confidential Dr. David White, International Group HHS, 09. 10. 2009
OSA and Cardiovascular Disease • Intermediate Outcomes – Hypertension – Diabetes • Hard Outcomes – Myocardial infarction – Stroke – Congestive Heart Failure – Death Confidential Dr. David White, International Group HHS, 09. 10. 2009
Alterations in Glucose Disposal in Sleep-disordered Breathing Naresh M. Punjabi 1 and Brock A. Beamer 1 1 Department Confidential of Medicine, John Hopkins University School of Medicine, Baltimore, Maryland Dr. David White, International Group HHS, 09. 10. 2009
Punjabi et al, AJRCCM 2009 Confidential Dr. David White, International Group HHS, 09. 10. 2009
Punjabi et al, AJRCCM 2009 Confidential Dr. David White, International Group HHS, 09. 10. 2009
Punjabi et al, AJRCCM 2009 Confidential Dr. David White, International Group HHS, 09. 10. 2009
Arch of Intern Med 2005 Type 2 Diabetes, Glycemic Control, and Continuous Positive Airway Pressure in Obstructive Sleep Apnea Ambika R. Babu, MD; James Herdegen, MD; Leon Fogelfeld, MD; Susan Shott, Ph. D; Theodore Mazzone, MD Confidential Dr. David White, International Group HHS, 09. 10. 2009
Babu et al Arch of Intern Med 2005 Confidential Dr. David White, International Group HHS, 09. 10. 2009
Thorax 2007 Effect of CPAP on insulin resistance and Hb. A 1 c in men with obstructive sleep apnoea and type 2 diabetes Sophie D West, Debby J Nicoll, Tara M Wallace, David R Matthews, John R Stradling Confidential Dr. David White, International Group HHS, 09. 10. 2009
West SD. et al Thorax 2007 Confidential Dr. David White, International Group HHS, 09. 10. 2009
West SD. et al Thorax 2007 Confidential Dr. David White, International Group HHS, 09. 10. 2009
OSA and Cardiovascular Disease • Intermediate Outcomes – Hypertension – Diabetes • Hard Outcomes – Myocardial infarction – Stroke – Congestive Heart Failure – Death Confidential Dr. David White, International Group HHS, 09. 10. 2009
Sleep-disordered Breathing and Cardiovascular Disease Cross-sectional Results of the Sleep Heart Health Study EYAL SHAHAR, CORALYN W. WHITNEY, SUSAN REDLINE, ELISA T. LEE, ANNE B. NEWMAN, F. JAVIER NIETO, GEORGE T. O’CONNOR, LORI L. BOLAND, JOSEPH E. SCHWARTZ, and JONATHAN M. SAMET for the Sleep Heart Health Study Research Group Confidential Dr. David White, International Group HHS, 09. 10. 2009
Am J Respir Crit Care Med - 2000 Adjusted* Relative Odds (95% Confidence Interval) of Prevalent Coronary Heart Disease, Heart Failure, or Stroke, According to Quartile of the Apnea-Hypopnea Index Quartile I Confidential II IV P Value* Coronary heart disease Full Model 1. 01 (0. 77– 1. 32) 1. 20 (0. 92– 1. 57) 1. 22 (0. 93– 1. 59) 0. 08 Coronary hear t disease Parsimonious Model 1. 0 0. 92 (0. 71– 1. 20) 1. 20 (0. 93– 1. 54) 1. 27 (0. 99– 1. 62) 0. 004 Heart Failure Full Model 1. 0 1. 19 (0. 56– 2. 53) 1. 96 (0. 99– 3. 90) 2. 20 (1. 11– 4. 37) 0. 008 Heart Failure Parsimonious Model 1. 0 1. 13 (0. 54– 2. 39) 1. 95 (0. 99– 3. 83) 2. 38 (1. 22– 4. 62) 0. 002 Stroke Full Model 1. 0 1. 24 (0. 76– 2. 01) 1. 38 (0. 86– 2. 83) 1. 55 (0. 96– 2. 50) 0. 06 Stroke Parsimonious Model 1. 0 1. 15 (0. 72– 1. 83) 1. 42 (0. 91– 2. 21) 1. 58 (1. 02– 2. 46) 0. 03 Dr. David White, International Group HHS, 09. 10. 2009
Lancet - 2005 Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study Jose M Marin, Santiago J Carrizo, Eugenio Vicente, Alvar G N Agusti Confidential Dr. David White, International Group HHS, 09. 10. 2009
Marin et al Lancet 2005 Confidential Dr. David White, International Group HHS, 09. 10. 2009
Marin et al – Lancet, 2005 Confidential Dr. David White, International Group HHS, 09. 10. 2009
OSA and Cardiovascular Disease • Intermediate Outcomes – Hypertension – Diabetes • Hard Outcomes – Myocardial infarction – Stroke – Congestive Heart Failure – Death Confidential Dr. David White, International Group HHS, 09. 10. 2009
Articles Investigating the Relationship Between Stroke and Obstructive Sleep Apnea Mark E. Dyken, MD; Virend K. Somers, MD, DPhil; Thoru Yamada, MD; Zong-Ying Ren, MD M. Bridget Zimmerman, Ph. D Confidential Dr. David White, International Group HHS, 09. 10. 2009
Dyken et al Stroke 1996 Non- Stroke 77% 71% % with OSA 64% Stroke 19% All Subjects 23% 14% Men Copyright © 1996 American Heart Association Confidential Dr. David White, International Group HHS, 09. 10. 2009 Women
Am J Respir Crit Care Med - 2000 Adjusted* Relative Odds (95% Confidence Interval) of Prevalent Coronary Heart Disease, Heart Failure, or Stroke, According to Quartile of the Apnea-Hypopnea Index Quartile I Confidential II IV P Value* Coronary heart disease Full Model 1. 01 (0. 77– 1. 32) 1. 20 (0. 92– 1. 57) 1. 22 (0. 93– 1. 59) 0. 08 Coronary hear t disease Parsimonious Model 1. 0 0. 92 (0. 71– 1. 20) 1. 20 (0. 93– 1. 54) 1. 27 (0. 99– 1. 62) 0. 004 Heart Failure Full Model 1. 0 1. 19 (0. 56– 2. 53) 1. 96 (0. 99– 3. 90) 2. 20 (1. 11– 4. 37) 0. 008 Heart Failure Parsimonious Model 1. 0 1. 13 (0. 54– 2. 39) 1. 95 (0. 99– 3. 83) 2. 38 (1. 22– 4. 62) 0. 002 Stroke Full Model 1. 0 1. 24 (0. 76– 2. 01) 1. 38 (0. 86– 2. 83) 1. 55 (0. 96– 2. 50) 0. 06 Stroke Parsimonious Model 1. 0 1. 15 (0. 72– 1. 83) 1. 42 (0. 91– 2. 21) 1. 58 (1. 02– 2. 46) 0. 03 Dr. David White, International Group HHS, 09. 10. 2009
Obstructive Sleep Apnea as a Risk Factor for Stroke and Death H. Klar Yaggi, M. C. , M. P. H. , John Concato, M. D. , M. P. H. , Walter N. Kernan, M. D. , Judith H. Lichtman, Ph. D. , M. P. H. , Lawrence M. Brass, M. D. , and Vahid Mohsenin, M. D. Confidential Dr. David White, International Group HHS, 09. 10. 2009
Yaggi et al – N Engl J Med, 2005 Confidential Dr. David White, International Group HHS, 09. 10. 2009
Yaggi et al – N Engl J Med, 2005 Confidential Dr. David White, International Group HHS, 09. 10. 2009
Yaggi et al – N Engl J Med, 2005 Confidential Dr. David White, International Group HHS, 09. 10. 2009
OSA and Cardiovascular Disease • Intermediate Outcomes – Hypertension – Diabetes • Hard Outcomes – Myocardial infarction – Stroke – Congestive Heart Failure – Death Confidential Dr. David White, International Group HHS, 09. 10. 2009
Am J Respir Crit Care Med - 2000 Adjusted* Relative Odds (95% Confidence Interval) of Prevalent Coronary Heart Disease, Heart Failure, or Stroke, Accorindg to Quartile of the Apnea-Hypopnea Index Quartile Confidential I II IV P Value* Coronary heart disease Full Model 1. 01 (0. 77– 1. 32) 1. 20 (0. 92– 1. 57) 1. 22 (0. 93– 1. 59) 0. 08 Coronary hear t disease Parsimonious Model 1. 0 0. 92 (0. 71– 1. 20) 1. 20 (0. 93– 1. 54) 1. 27 (0. 99– 1. 62) 0. 004 Heart Failure Full Model 1. 0 1. 19 (0. 56– 2. 53) 1. 96 (0. 99– 3. 90) 2. 20 (1. 11– 4. 37) 0. 008 Heart Failure Parsimonious Model 1. 0 1. 13 (0. 54– 2. 39) 1. 95 (0. 99– 3. 83) 2. 38 (1. 22– 4. 62) 0. 002 Stroke Full Model 1. 0 1. 24 (0. 76– 2. 01) 1. 38 (0. 86– 2. 83) 1. 55 (0. 96– 2. 50) 0. 06 Stroke Parsimonious Model 1. 0 1. 15 (0. 72– 1. 83) 1. 42 (0. 91– 2. 21) 1. 58 (1. 02– 2. 46) 0. 03 Dr. David White, International Group HHS, 09. 10. 2009
OSA and Cardiovascular Disease • Intermediate Outcomes – Hypertension – Diabetes • Hard Outcomes – Myocardial infarction – Stroke – Congestive Heart Failure – Death Confidential Dr. David White, International Group HHS, 09. 10. 2009
Marin et al – Lancet, 2005 Confidential Dr. David White, International Group HHS, 09. 10. 2009
Yaggi et al – N Engl J Med, 2005 Confidential Dr. David White, International Group HHS, 09. 10. 2009
Sleep 2008 Sleep Disordered Breathing and Mortality: Eighteen-Year Follow-up of the Wisconsin Sleep Cohort Terry Young, Ph. D 1; Laurel Finn, MS 1; Paul E. Peppard, Ph. D 1; Mariana Szklo-Coxe, Ph. D 1; Diane Austin, MS 1; F. Javier Nieto, Ph. D 1; Robin Stubbs 1, BS; K. Mae Hla, MD 2 Confidential Dr. David White, International Group HHS, 09. 10. 2009
Young T et al Sleep 2008 Table 3—Mortality Risk with Sleep-Disordered Breathing (n = 1522): Adjusted Hazard Ratios* Baseline AHI Category All-cause mortality Hazard Ratio (95% CI) Cardiovascular mortality Hazard Ratio (95% CI) None: 0 - < 5 Reference Mild: 5 - < 15 1. 6 (0. 9, 2. 8) 1. 8 (0. 7, 4. 9) Moderate: 15 - < 30 1. 4 (0. 6, 3. 3) 1. 2 (0. 3, 5. 8) Severe: > 30 3. 0 (1. 4, 6. 3) 2. 9 (0. 8, 10. 0) P trend = 0. 008 P trend = 0. 12 *adjusted for age, age 2, sex, body mass index, and body mass index 2 Confidential Dr. David White, International Group HHS, 09. 10. 2009
PLo. S Medicine 2009 Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study Naresh M. Punjabi 1*, Brian S. Caffo 1, James L. Goodwin 2, Daniel J. Gottlieb 3, Anne B. Newman 4, George T. O’Connor 5, David M. Rapoport 6, Susan Redline 7, Helaine E. Resnick 8, John A. Robbins 9, Eyal Shahar 2, Mark L. Unruh 4, Jonathan M. Samet 10 Confidential Dr. David White, International Group HHS, 09. 10. 2009
Punjabi et al PLo. S Medicine 2009 Confidential Dr. David White, International Group HHS, 09. 10. 2009
OSA and Cardiovascular Disease • Intermediate Outcomes – Hypertension – Diabetes • Hard Outcomes – Myocardial infarction – Stroke – Congestive Heart Failure – Death Confidential Dr. David White, International Group HHS, 09. 10. 2009
Sleep Apnea Cardio. Vascular End Points • 5, 000 patients with OSA plus documented: - coronary artery disease - cerebrovascular disease • 100 sites (China, India, and Australia) • Patients randomized to either: - Standard medical care + CPAP Confidential Dr. David White, International Group HHS, 09. 10. 2009
Sleep Apnea Cardio. Vascular End Points • Outcomes: - Subsequent MI’s and strokes - Survival Confidential Dr. David White, International Group HHS, 09. 10. 2009
Sleep and Cardiovascular Disease Confidential Dr. David White, International Group HHS, 09. 10. 2009 55
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