Obstructive Sleep Apnea and cardiovascular risk Ferran Barbé, MD

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1 Obstructive Sleep Apnea and cardiovascular risk Ferran Barbé, MD Institut de Recerca Biomedica. IRBLleida CIBERES. Instituto de Salud Carlos III. Madrid.

2 Obstructive Sleep Apnea (OSA) Obstructive Sleep Apnea (OSA)

3 Obstructive Sleep Apnea (OSA) Affects 10% of population Excessive daytime sleepiness; poor quality of life and road accidents. Increased morbi-mortality mainly due to cardiovascular causes.

4 OSA and cardiovascular consequences Sanchez de la Torre et al Lancet Respir Med 2013 Sánchez-de-la-Torre, M. The Lancet Respiratory Medicine 20

5 Obstructive Sleep Apnea (OSA) CPAP (Continuos Positive Airway Pressure) Chronic treatment More than 4 h/day to be effective (CV risk)

6 Odd Ratio for death in OSA OR (95% IC) AHI Reference 2.87 > 30 Marin. Lancet > 36 Yaggi. NEJM > 30 Young. Sleep > 30 Punjabi PLOS

7 OSA and mortality Punjabi et al Plos Med 2010 N = 6441 Follow up: 8.2 yrs 1047 participants died

8 OSA and long-term mortality MEN 1651 WOMEN 1116 ELDERLY 936 Men 49.8 (8.1) years Women 57.5 (12.1) years Elderly 71.2 (4.4) years Marin JM Lancet 2005 Rodriguez-Campos F Ann Intern Med 2011 Martinez-Garcia MA AJRCCM 2013

9 Meta-analysis of OSA and serious CVE Loke et al. Circ Cardiovasc Qual Outcomes 2012

10 Meta-analysis of OSA and serious CVE Loke et al. Circ Cardiovasc Qual Outcomes 2012 STROKE

11 Odds ratio for stroke Loke et al Circ Cardiovasc Qual Outcomes 2012 STROKE

12 Efficacy of CPAP on 5ys survival in stroke O. Parra et alt. J Sleep Res 2014 CPAP 46%

13 Meta-analysis of OSA and serious CVE Loke et al Circ Cardiovasc Qual Outcomes 2012 CHD

14 Meta-analysis of OSA and serious CVE Loke et al Circ Cardiovasc Qual Outcomes 2012 CV DEATH

15 Meta-analysis of OSA and CV mortality Loke et al Circ Cardiovasc Qual Outcomes 2012 OSA appears to be associated with stroke, but the relationship with isquemic heart disease and cardiovascular mortality needs further research.

16 Incidence of hypertension and CVE in OSA Barbé et al JAMA 2012 Effect of Continuous Positive Airway Pressure on the Incidence of Hypertension and Cardiovascular Events in Nonsleepy Patients With OSA

17 Incidence of Hypertension and CVE in OSA Barbé et al JAMA 2012 DESIGN: Randomized prospective controlled study POPULATION: Patients with AHI > 20 and Epworth scale < 10 MEASUREMENTS: Blood pressure measurement CVE EVALUATIONS: Basal, 3, 6, 12, 24, 36, 48 month 17

18 Incidence of Hypertension and CVE in OSA Barbé et al JAMA 2012 CPAP n= 357 Conservative n= 366 Age (yrs) 52 ± ± 11 Male 88% 84% AHI (h -1 ) 42 ± ± 23* BMI (K.m -2 ) 31 ± 5 31 ± 5 Epworth 6.5 ± ± 2 SBP (mmhg) 132 ± ± 17 DPB (mmhg) 80 ± ± 11 Compliance (h) 4.2 ± 2-18

19 Incidence of Hypertension and CVE in OSA Barbé et al JAMA 2012 p = 0.2 CPAP 46%

20 Incidence of Hypertension and CVE in OSA Barbé et al JAMA 2012 p = 0.2 p = 0.04 CPAP 46%

21 OSA and ongoing RCT s CV studies = 61 (n = 18,705) CV = 2 (n= 920)) CV = 1 (n= 50) CV = 18 (n= 3,166) CV = 27 (n= 8,397) CV = 6 (n= 624) CV = 1 (n= 50) CV = 1 (n= 150) CV = 2 (n= 110)) CV = 2 (n= 2500)

22 10 20 CPAP use and change in BP Martinez-Garcia et al. JAMA r = 0.3 p = CPAP use (hours/day)

23 CPAP use and change in BP Martinez-Garcia et al. JAMA 2013 r = 0.3 p = CPAP use (hours/day)

24 Precision medicine in RH and OSA Sanchez de la Torre et al. JACC 2015 Non-responders Responders (n=18) (n=20) p-value Change in mean blood pressure after CPAP treatment (pre- minus post-cpap), mmhg [-5;2.5] 11 (7.5;14.1) NA Sex, male, n(%) 18 (100) 20 (100) 1 Age, years 60 [52;66] 54 [50.8;63] 0.14 BMI, kg m [30.1;34] 32.1 [30.7;37.6] 0.39 Neck perimeter, cm 42.5 [42;43.8] 44 [42.0;46] 0.49 Apnea-hypopnea index, event/h 34.5 [22.2;47.8] 48.5 [31.5;59] 0.12 TSat 90 6 [1.5;11.2] 7 [2.00;27] 0.17 Epworth sleep scale score 9 [6.5;12] 8 [5.00;9] 0.26 CPAP mean use, h/day 5.5 [4.5;6] 5.5 [4.88;6.5] h mean blood pressure, mmhg 113 [107;114] 118 [111;122] SBP, mmhg 142 [136;150] 147 [138;152] 0.41 DBP, mmhg 82.5 [74.2;85.8] 88.5 [82.5;94] Nocturnal blood pressure pattern, n(%) 0.76 Dipper 4 (22.2) 7 (35) Non-dipper 9 (50) 9 (45) Riser 5 (27.8) 4 (20)

25 Precision medicine in RH and OSA Sanchez de la Torre et al JACC 2015 MicroARNs (mirnas): Small genetic sequences that regulate gene expression. Related with manifestation of phenotypes and diseases. Rationale: Determination of mirna expression in OSA patients with RH could lead to specific profiles and be related to response to CPAP treatment. mirna PCR array

26 Precision medicine in RH and OSA Sanchez de la Torre et al JACC 2015 Differentially expressed mirnas hsa-mir-144-3p hsa-mir-100-5p hsa-mir-486-5p hsa-mir-150-5p hsa-mir-7-5p hsa-mir-378a-3p hsa-mir-92a-3p Cardiovascular disease Differentiation/Development (Up-Regulated) Cardiomyopathy (Up-regulated) Cardiac Hypertrophy (Down-Regulated) Cardiac Hypertrophy (Down-Regulated) Cardiomyopathy (Down-regulated) Cardiomyopathy (Down-regulated) and Differentiation/Development (Up-Regulated) Cardiomyopathy (Up-regulated) 3 mirnas with the highest associations with a favorable BP response to CPAP

27 Precision medicine in RH and OSA Sanchez de la Torre et al JACC 2015 Training set (n=24). AUC=0.85 Validation set (n=14). AUC= 0.92

28 HIPARCO-Score HIPARCO- Score % favorable BP responders to CPAP (observed) % favorable BP response to CPAP (predicted) 0 0% 6% 1 50% 21% 2 50% 46% 3 67% 75% 4 67% 80% 5 100% 90% 6 100% 98%

29 Take home messages Is OSA associated with increased CV mortality? Probably YES Does CPAP reduce CV mortality? Is OSA asociated with ischemic heart disease?? Probably NO Is OSA asociated with stroke? Probably YES Does CPAP reduce the incidence of CV disease? In patients with RH and OSA, can you predict blood pressure response to CPAP treatment? Probably YES YES

30 Ferran Barbé Manuel Sánchez-de-la-Torre Alicia Sánchez Anabel Castro Asunción Seminario Cecilia Turino Estefania Galera Fernando Santamaría Joan Escobar Joan Valls Jordi de Batle Luis Fer. Casas Lydia Pascual Marina Canales Marina Flores Mireia Dalmases Manel Vilà Maricel Arbonés

31 Spanish Sleep and Breathing Network

32 CPAP and resistant hypertension Martinez-Garcia et al. JAMA 2013 Initial exclusion criteria: -Secondary RH -Aged<18 -Pregnancy -Severe hypersomnia -Previous CPAP treatment -Renal failure (creat>1.5 mg/dl) -CVE in the month prior # 82 %

33 CPAP and resistant hypertension Martinez-Garcia et al. JAMA 2013 CPAP Conservative n= 98 n= 96 Age (yrs) 58 ± ± 10 Male 72% 65% AHI (h -1 ) 41 ± ±19 BMI (K.m -2 ) 35 ± 5 34 ± 6 Epworth 9 ± 4 9 ± 4 SBP (mmhg) 145 ± ± 13 DPB (mmhg) 83 ± ± 10 Compliance (h) 5 ± 2 -

34 CPAP and resistant hypertension Martinez-Garcia et al. JAMA 2013 BP changes (mmhg) p (values) mmhg SBP DBP MeanBP SBP DBP MeanBP Intention-to-treat Per protocol (CPAP use 4h) Control group CPAP group *No changes in BMI or antaht drugs in the follow-up

35 Precision medicine in RH and OSA Sanchez de la Torre et al JACC 2015 Title: Method for predicting response to Continuous Positive Air Pressure treatment Application number: EP (European Patent Office) (December 2014) Precision Medicine in Patients with Resistant Hypertension and Obstructive Sleep Apnea: Blood Pressure Response to CPAP Treatment.

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