The Use of Precision Medicine to Manage Obstructive Sleep Apnea Treatment in Patients with Resistant Hypertension: Current Evidence and Future Directions

  • Esther Sapiña
  • Gerard Torres
  • Ferran Barbé
  • Manuel Sánchez-de-la-TorreEmail author
Resistant Hypertension (L Drager, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Resistant Hypertension


Purpose of Review

The significant prevalence of resistant hypertension (RH) and the high cardiovascular risk of the population of patients with RH have indicated the necessity to identify its main causes. Among these, obstructive sleep apnea (OSA) is considered the most well-established cause.

Recent Findings

In recent years, several studies have shown a beneficial effect of continuous positive airway pressure (CPAP) treatment on blood pressure (BP), but this effect exhibits great variability. The diagnosis and management of OSA in patients with RH suggest a clinical option for a phenotype of patients for whom therapeutic strategies are limited to pharmaceutical therapy and renal denervation. However, the great variability in the CPAP response has increased the necessity to develop instruments to identify patients who could benefit from a treatment that reduces BP.


Application of precision medicine to these patients should be considered as a first-line intervention to avoid the prescription of ineffective treatments and excessive consumption of pharmacological drugs that do not ameliorate the cardiovascular risk.


Resistant hypertension OSA Personalized medicine CPAP Cardiovascular disease 



Supported by the following: Fondo de Investigación Sanitaria (Fondo Europeo de Desarrollo Regional (FEDER) (PI14/01266; PI16/00489; DTS15/00145)), the Spanish Respiratory Society (SEPAR), Young Researchers Award from the AstraZeneca Foundation, and ALLER.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflict of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Collins Francis SHHA. New initiative on precision medicine. N Engl J Med. 2015;372(9):793–5.CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Sánchez-de-la-torre M, Gozal D. Obstructive sleep apnea: in search of precision. Expert Rev Precis Med Drug Dev. 2017;0(0):1–12.Google Scholar
  3. 3.
    Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K, et al. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries editorial. Circulation. 2016;134:441–50.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Lawes CM, Vander Hoorn S, Rodgers A, et al. Global burden of blood-pressure-related disease. Lancet. 2008;371(9623):1513–8.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Group EPF, Europe PMC, Funders Group. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study. Lancet. 2015;386(10010):2287–323.CrossRefGoogle Scholar
  6. 6.
    Padmanabhan S. Precision medicine in Hypertension 2016; 35–8.Google Scholar
  7. 7.
    Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008;117(25):510–26.CrossRefGoogle Scholar
  8. 8.
    NICE. National Institute for Health Care Excellence. Hypertension in adults: diagnosis and management. 2017.Google Scholar
  9. 9.
    Persu A, Brien E, Verdecchia P. Use of ambulatory blood pressure measurement in the definition of resistant hypertension: a review of the evidence. Hypertens Res. 2014;37(11):967–72.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Brien EO, Parati G, Stergiou G, et al. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31(9):1731–68.CrossRefGoogle Scholar
  11. 11.
    Kumbhani DJ, Steg PG, Cannon CP, Eagle KA, Smith SC Jr, Crowley K, Goto S, Ohman EM, Bakris GL, Perlstein TS, Kinlay S, Bhatt DL, REACH Registry Investigators. Resistant hypertension: a frequent and ominous finding among hypertensive patients with atherothrombosis. Eur Heart J 2013;34(16):1204–1214.CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Pierdomenico SD, Lapenna D, Bucci A, di Tommaso R, di Mascio R, Manente BM, et al. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. AJH. 2005;18:1422–8.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Epidemiology PSD. Population studies prevalence of resistant hypertension in the United States, 2003–2008. Hypertension. 2011;57:1076–80.CrossRefGoogle Scholar
  14. 14.
    Egan BM, Zhao Y, Axon RN, Brzezinski WA. Uncontrolled and apparent treatment resistant hypertension in the U.S. 1988-2008. Circulation. 2012;124(9):1046–58.CrossRefGoogle Scholar
  15. 15.
    De La Sierra A, Segura J, Banegas JR, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension. 2011;57(5):898–902.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Gijón-Conde T, Graciani A, Banegas JR. Resistant hypertension: demography and clinical characteristics in 6292 patients in a primary health care setting. Rev Esp Cardiol. 2014;67(4):270–6.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Salles GF, Cardoso CRME. Prognostic influence of office and ambulatory blood pressures in resistant hypertension. Arch Intern Med. 2016;168(21):2340–6.CrossRefGoogle Scholar
  18. 18.
    Tsioufis C, Kasaiakogias A, Kordalis A, et al. Dynamic resistant hypertension patterns as predictors of cardiovascular morbidity: a 4-year prospective study. J Hypertens. 2014;32(2):415–22.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Daugherty SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Margolis KL, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125:1635–42.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Gonzaga C, Bertolami A, Bertolami M, Amodeo C, Calhoun D. Obstructive sleep apnea, hypertension and cardiovascular diseases. J Hum Hypertens Adv. 2015;12:1–8.Google Scholar
  21. 21.
    Sánchez-de-la-Torre M, Campos-Rodriguez F, Barbé F. Obstructive sleep apnoea and cardiovascular disease. Lancet Respir Med. 2013;1(1):61–72.CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Lévy P, Kohler M, McNicholas WT, et al. Obstructive sleep apnoea syndrome. Nat Rev Dis Prim. 2015;25(1):15015.CrossRefGoogle Scholar
  23. 23.
    Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Original contribution increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006–14.CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Torres G, Sánchez-De-La-Torre M, Barbé F. Relationship between OSA and hypertension. Chest. 2015;148(3):824–32.CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Cai A, Wang L, Zhou Y. Hypertension and obstructive sleep apnea. Hypertens Res. 2016;39(6):391–5.CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Barbe F, Marı JM, Garcia-rio F, et al. Long-term effect of continuous positive airway pressure in hypertensive patients with sleep apnea. Am J Respir Crit Care Med. 2010;181(7):718–26.CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    •• Martínez-García M-A, Capote F, Campos-Rodríguez F, et al. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension The HIPARCO Randomized Clinical Trial. JAMA. 2013;310:2407–15. In this randomized controlled trial, the authors demonstrated that CPAP treatment significantly decrease blood pressure in patients with resistant hypertension and obstructive sleep apnea CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    •• Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005;365:1046–53. In this observational study, the authors showed that severe obstructive sleep apnea-hypopnoea significantly increases the risk of fatal and non-fatal cardiovascular events. CPAP treatment reduces this risk CrossRefPubMedGoogle Scholar
  29. 29.
    •• Barbe F, Durán-Cantolla J, Sanchez-de-la-Torre M, et al. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in non sleepy patients with obstructive sleep apnea. JAMA. 2012;307(20):2161–8. The results of this randomized controlled trial highlight the importance of the compliance with CPAP to achieve the possible benefits in cardiovascular risk reduction in OSA patients for primary prevention CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Bazzano LA, Khan Z, Reynolds K, He J. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension. 2007;50(2):417–23.CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Pedrosa RP, Drager LF, Gonzaga CC, Sousa MG, de Paula LKG, Amaro ACS, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension. 2011;58:811–7.CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Gonçalves SC, Martinez D, Gus M, de Abreu-Silva EO, Bertoluci C, Dutra I, et al. Obstructive sleep apnea and resistant hypertension: a case-control study. Chest. 2007;132(6):1858–62.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Liu L, Cao Q, Guo Z, Dai Q. Continuous positive airway pressure in patients with obstructive sleep apnea and resistant hypertension : a Meta-analysis of randomized controlled trials. J Clin Hypertens (Greenwich). 2016;18(2):153–8.CrossRefGoogle Scholar
  34. 34.
    Logan AG, Perlikowski SM, Mente A, Tisler A, Tkacova R, Niroumand M, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens. 2001;19(12):2271–7.CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Silverberg DS, Oksenberg A. Are sleep-related breathing disorders important contributing factors to the production of essential hypertension? Curr Hypertens Rep. 2001;3:209–15.CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Williams B, Macdonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol , and doxazosin to determine the optimal treatment for drug-resistant hypertension ( PATHWAY-2 ): a randomised, double-blind, crossover trial. Lancet. 2015;386(10008):2059–68.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Engbaek M, Hjerrild M, Hallas J. The effect of low-dose spironolactone on resistant hypertension. J Am Soc Hypertens. 2010;4(6):290–4.CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Václavík J, Sedlak R, PlachyM, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension. 2011;57(6):1069–75.CrossRefPubMedGoogle Scholar
  39. 39.
    Parthasarathy HK, Alhashmi K, Mcmahon AD, et al. Does the ratio of serum aldosterone to plasma renin activity predict the efficacy of diuretics in hypertension? Results of RENALDO. J Hypertens. 2010;28(1):170–7.CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR, Bakris GL, SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370(15):1393–1401.CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Elmula F, Fadl M, Hoffmann P, et al. Renal denervation renal sympathetic denervation in patients with treatment-resistant hypertension after witnessed intake of medication before qualifying ambulatory blood pressure. Hypertension. 2013;62(3):526–32.CrossRefGoogle Scholar
  42. 42.
    •• Pedrosa RP, Drager LF, De Paula LKG, et al. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial. Chest. 2013;144:1487–94. In this randomized controlled trials, the authors reported that CPAP treatment significantly reduces daytime BP in patients with resistant HTN and OSA CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Lozano L, Tovar JL, Sampol G, Romero O, Jurado MJ, Segarra A, et al. Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial. J Hypertens Wolters Kluwer Heal J Hypertens. 2010;28(10):2161–8.Google Scholar
  44. 44.
    Litvin AY, Sukmarova ZN, Elfimova EM, Aksenova AV, Galitsin PV, Rogoza AN, et al. Effects of CPAP on “vascular” risk factors in patients with obstructive sleep apnea and arterial hypertension. Vasc Health Risk Manag. 2013;9:229–35.CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Muxfeldt ES, Margallo V, Costa LMS, Guimaraes G, Cavalcante AH, Azevedo JCM, et al. Effects of continuous positive airway pressure treatment on clinic and ambulatory blood pressures in patients with obstructive sleep apnea and resistant hypertension. Hypertension. 2015;65(4):736–42.CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    Iftikhar IH, Valentine CW, Bittencourt LRA, Cohen DL, Fedson AC, Gíslason T, et al. Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a meta-analysis. J Hypertens. 2014;32(12):2341–50.CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Montesi SB, Edwards BA, Malhotra A, Bakker JP. The effect of continuous positive airway pressure treatment on blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Clin Sleep Med. 2012;8(5):587–96.PubMedPubMedCentralGoogle Scholar
  48. 48.
    •• Sánchez-de-la-Torre M, Khalyfa A, Sánchez-De-La-Torre A, et al. Precision medicine in patients with resistant hypertension and obstructive sleep apnea blood pressure response to continuous positive airway pressure treatment. J Am Coll Cardiol. 2015;66(9):1023–1032. In this study, the authors described the first personalized medicine tool to predict blood pressure response to CPAP treatment in patients with resistant hypertension and OSA.Google Scholar
  49. 49.
    Sapiña-Beltrán E, Torres G, Martínez-Alonso M, et al. Rationale and methodology of the SARAH trial: long-term cardiovascular outcomes in patients with resistant hypertension and obstructive sleep apnea. Arch Bronconeumol. 2018.Google Scholar
  50. 50.
    Lloberes P, Espinel E, Segarra A, et al. A randomized controlled study of CPAP effect on plasma aldosterone concentration in patients with resistant hypertension and obstructive sleep apnea. J Hypertens. 2014;32(8):1650–7.CrossRefPubMedCentralPubMedGoogle Scholar
  51. 51.
    de Oliveira AC, Martinez D, Massierer D, et al. The antihypertensive effect of positive airway pressure on resistant hypertension of patients with obstructive sleep apnea: a randomized, double-blind, clinical trial. Am J Respir Crit Care Med. 2014;190(3):345–7.CrossRefGoogle Scholar
  52. 52.
    Lei Q, Lv Y, Li K, Ma L, Du G, Xiang Y, et al. Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a systematic review and meta-analysis of six randomized controlled trials. J Bras Pneumol. 2017;43(5):373–9.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Esther Sapiña
    • 1
    • 2
  • Gerard Torres
    • 1
  • Ferran Barbé
    • 1
    • 2
  • Manuel Sánchez-de-la-Torre
    • 1
    • 2
    Email author
  1. 1.Respiratory DepartmentHospital Universitari Arnau de Vilanova-Santa Maria, IRBLleidaLleidaSpain
  2. 2.Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES)MadridSpain

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