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Resistant Hypertension: Questions and Contemporary Answers

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The review presents the important problem of resistant hypertension. Its real prevalence is unknown. According to population studies and metaanalyzes of clinical studies, the prevalence of this most severe form of hypertension reaches 12-15% in the general population and 15-18% in clinical cohorts. Over the past decades, an increase in its frequency among patients with hypertension has been noted. Based on the results of large-scale studies, risk factors are detected that allow to assess the risk for the resistance to antihypertensive drugs. Adherence to ongoing antihypertensive therapy is crucial to addressing the issue of hypertension resistance; there are acceptable ways to evaluate it in clinical practice. The review discusses the most common mistakes in the choice of therapy, which can cause resistance to antihypertensive treatment, namely irrational drug combinations, insufficient dosage of the drug, and the use of non-prolonged forms of drugs. The latest recommendations for the diagnosis and treatment of hypertension, including its resistant form, are analyzed. The review contains a rationale based on the results of randomized clinical trials, the choice antihypertensive strategy in this variant of arterial hypertension. The importance of fixed combination antihypertensive drugs, as well as thiazine-like diuretics and amlodipine is stressed. The results of studies demonstrate the rational for the use of antimineralcorticoid drugs, namely spironolactone, for this category of patients. The authors offer an updated algorithm for the diagnosis and treatment of resistant hypertension, based on the sections of the latest clinical recommendations on this problem.

About the Authors

V. I. Podzolkov
I.M. Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation

Valery I. Podzolkov – MD, PhD, Professor, Head of Chair of Faculty Therapy №2, Sechenov University

Trubetskaya ul. 8-2, Moscow, 119991 Russia

A. E. Bragina
I.M. Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation

Anna E. Bragina – MD, PhD, Professor, Chair of Faculty Therapy №2, Sechenov University

Trubetskaya ul. 8-2, Moscow, 119991 Russia

K. K. Osadchiy
I.M. Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation

Konstantin K. Osadchiy – MD, PhD, Associate Professor, Chair of Faculty Therapy №2, Sechenov University

Trubetskaya ul. 8-2, Moscow, 119991 Russia


1. Lewington S., Clarke R., Qizilbash N., et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903-13. DOI:10.1016/S0140-6736(02)11911-8.

2. Williams B., Mancia G., Spiering W., et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). Eur Heart J. 2018;39:3021-104. DOI:10.1093/eurheartj/ehy339.

3. Whelton P.K., Carey R.M., Aronow W.S., et al. 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines JACC. 2018;71(19):e127-248. DOI:10.1161/HYP.0000000000000066.

4. Carey R.M., Calhoun D.A., Bakris G.L., et al. Resistant Hypertension: Detection, Evaluation, and Management A Scientific Statement From the American Heart Association Hypertension. 2018;72:e53e90. DOI:10.1161/HYP.0000000000000084.

5. Calhoun D.A., Booth J.N. 3rd, Oparil S., et al. Refractory hypertension: determination of prevalence, risk factors, and comorbidities in a large, population-based cohort. Hypertension. 2014;63(3):4518. DOI:10.1161/HYPERTENSIONAHA.113.02026.

6. Daugherty S.L., Powers J.D., Magid D.J., et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125:1635-42. DOI:10.1161/CIRCULATIONAHA.111.068064.

7. Boytsov S.A., Balanova Y.A., Shalnova S.A., et al. Arterial hypertension among individuals of 25-64 years old: prevalence, awareness, treatment and control. By the data from ESSE-RF. Cardiovascular Therapy and Prevention. 2014;13(4):4-14 (In Russ.). DOI:10.15829/1728-8800-2014-4-4-14.

8. Sim J.J., Bhandari S.K., Shi J., et al. Characteristics of resistant hypertension in a large, ethnically diverse hypertension population of an integrated health system. Mayo Clin Proc. 2013;88:1099-107. DOI:10.1016/j.mayocp.2013.06.017.

9. Egan B.M., Zhao Y., Axon R.N., et al. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988-2008. Circulation. 2011:124;1046-58. DOI:10.1161/CIRCULATIONAHA.111.030189.

10. Persell S.D. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension. 2011:57;1076-80. DOI:10.1161/HYPERTENSIONAHA.111.170308.

11. Diaz K.M., Booth J.N. 3rd, Calhoun D.A., et al. Healthy lifestyle factors and risk of cardiovascular events and mortality in treatment-resistant hypertension: the Reasons for Geographic and Racial Differences in Stroke study. Hypertension. 2014;64:465-71. DOI:10.1161/HYPERTENSIONAHA.114.03565.

12. Tanner R.M., Calhoun D.A., Bell E.K., et al. Prevalence of apparent treatment-resistant hypertension among individuals with CKD. Clin J Am Soc Nephrol. 2013;8:1583-90. DOI:10.2215/CJN.00550113.

13. Borghi C., Tubach F., De Backer G., et al. Lack of control of hypertension in primary cardiovascular disease prevention in Europe: results from the EURIKA study. Int J Cardiol. 2016;218:83-8. DOI:10.1016/j.ijcard.2016.05.044.

14. de la Sierra A., Segura J., Banegas J.R., et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension. 2011:57;898-902. DOI:10.1161/HYPERTENSIONAHA.110.168948.

15. Thomas G., Xie D., Chen H.Y., et al. Prevalence and prognostic significance of apparent treatment resistant hypertension in chronic kidney disease: report from the Chronic Renal Insufficiency Cohort Study. Hypertension. 2016;67:387-96. DOI:10.1161/HYPERTENSIONAHA.115.06487.

16. Egan B.M., Zhao Y., Li J., et al. Prevalence of optimal treatment regimens in patients with apparent treatment-resistant hypertension based on office blood pressure in a community-based practice network. Hypertension. 2013;62:691-7. DOI:10.1161/HYPERTENSIONAHA.113.01448.

17. Muntner P., Davis B.R., Cushman W.C., et al. Treatment-resistant hypertension and the incidence of cardiovascular disease and end-stage renal disease: results from the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension. 2014;64:1012-21. DOI:10.1161/HYPERTENSIONAHA.114.03850.

18. Gupta A.K., Nasothimiou E.G., Chang C.L., et al. Baseline predictors of resistant hypertension in the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT): a risk score to identify those at high-risk. J Hypertens. 2011;29:2004-13. DOI:10.1097/HJH.0b013e32834a8a42.

19. Daugherty S.L., Powers J.D., Magid D.J., et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125(13):1635-42. DOI:10.1161/CIRCULATIONAHA.111.068064.

20. Jamerson K., Weber M.A., Bakris G.L., et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417-28. DOI:10.1056/NEJMoa0806182.

21. Jamerson K., Bakris G.L., Dahlöf B., et al. Exceptional early blood pressure control rates: the ACCOMPLISH trial. Blood Press. 2007;16:80-6. DOI:10.1080/08037050701395571.

22. Smith S.M., Gong Y., Handberg E., et al. Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension. J Hypertens. 2014;32:635-43. DOI:10.1097/HJH.0000000000000051

23. Pimenta E., Calhoun D.A. Resistant hypertension: incidence, prevalence, and prognosis. Circulation. 2012;125:1594-96. DOI:10.1161/CIRCULATIONAHA.112.097345.

24. Otero F.R., Grigorian L.S., Lado ML, et al. Association between refractory hypertension and cardiometabolic risk. The HIPERFRE study. Nefrologia. 2008;28(4):425-32.

25. Podzolkov V.I., Osadchiy K.K. Refractory arterial hypertension. In: Podzolkov V.I. Arterial hypertension. Moscow: MIA; 2016. p.170-202 (In Russ.).

26. Chazova I.E., Fomin V.V., Razuvayeva M.A., Vigdorchik A.V. Resistant and uncontrolled essential hypertension in the Russian Federation: epidemiological characteristics and treatment approaches (Russian register of uncontrolled and resistant arterial hypertension REGATA «Resistant essential hypertension»). Kardiologicheskiy Vestnik. 2011;6(18):40-8 (In Russ.).

27. Gupta P., Patel P., Strauch B., et al. Biochemical screening for nonadherence is associated with blood pressure reduction and improvement in adherence. Hypertension. 2017;70:1042-8. DOI:10.1161/HYPERTENSIONAHA.117.09631.

28. Burnier M., Egan B.M. Adherence in hypertension. A review of prevalence, risk factors, impact, and management. Circ Res. 2019;124:1124-40. DOI:10.1161/CIRCRESAHA.118.313220.

29. Morisky D.E., Green L.W., Levine D.M. Concurrent and predictive validity of a self-reported measure of medication adherence. Med Care. 1986;24(1):67-74

30. Kim M.T., Hill M.N., Bone L.R., Levine D.M. Development and testing of the Hill-Bone Compliance to High Blood Pressure Therapy Scale. Prog Cardiovasc Nurs. 2000;15:90-6.

31. Bhatt H., Siddiqui M., Judd E., et al. Prevalence of pseudoresistant hypertension due to inaccurate blood pressure measurement. J Am Soc Hypertens. 2016;10:493-9. DOI:10.1016/j.jash.2016.03.186.

32. Sim J.J., Handler J., Jacobsen S.J., Kanter M.H. Systemic implementation strategies to improve hypertension: the Kaiser Permanente Southern California experience. Can J Cardiol. 2014;30:544-52. DOI:10.1016/j.cjca.2014.01.003.

33. Gu Q., Burt V.L., Dillon C.F., Yoon S. Trends in antihypertensive medication use and blood pressure control among United States adults with hypertension: The National Health and Nutrition Examination Survey, 2001 to 2010. Circulation. 2012;126:2105-14. DOI:10.1161/CIRCULATIONAHA.112.096156.

34. Chazova I.E., Zhernakova Yu.V. on behalf of the experts. Clinical guidelines. Diagnosis and treatment of arterial hypertension. Systemic Hypertension. 2019;16(1):6-31 (In Russ.). DOI:10.26442/2075082X.2019.1.190179.

35. Pitt B., Byington R.P., Furberg C.D., et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators. Circulation. 2000;102:1503-10.

36. Nissen S.E., Tuzcu E.M., Libby P., et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA. 2004;292:2217-26. DOI:10.1001/jama.292.18.2217.

37. Dahlof B., Sever P.S., Poulter N.R., et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOTBPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895-906. DOI:10.1016/S0140-6736(05)67185-1.

38. Williams B., Lacy P.S., Thom S.M., et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113:1213-25. DOI:10.1161/CIRCULATIONAHA.105.595496.

39. Leenen F.H., Nwachuku C.E., Black H.R., et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension 2006;48:374-84

40. Musini V.M. Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. Cochrane Database Syst Rev. 2014;29;(5):CD003824. DOI:10.1002/14651858. CD003824.pub2.

41. Marre M., Puig J. G., Kokot F., еt al. Equivalence of indapamide SR and enalapril on microalbuminuria reduction in hypertensive patients with type 2 diabetes: the NESTOR study. J Hypertens. 2004;22:1613-22. DOI:10.1097/01.hjh.0000133733.32125.09.

42. Gosse P., Sheridan D.J., Zannad F., et al. Regression of left ventricular hypertrophy in hypertensive patients treated with indapamide SR 1,5 mg versus enalapril 20 mg: the LIVE study. J Hypertens. 2000;18:1465-75.

43. Beckett N.S., Peters R., Fletcher A.E., et al for the HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887-98. DOI:10.1056/NEJMoa0801369.

44. Leonova M.V., Steinberg L.L., Belousov Y.B., et al. Results of pharmacoepidemiologic study of arterial hypertension PIFAGOR IV: physicians compliance. Russian Journal of Cardiology. 2015;(1):59-66 (In Russ.). DOI:10.15829/1560-4071-20151-59-66.

45. James P.A., Oparil S., Carter B.L., et al. 2014 Evidence-Based Guidelines for the Management of High Blood Pressure in Adults. Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-20. DOI:10.1001/jama.2013.284427.

46. Chaturvedi N., Sjolie A.K., Stephenson J.M., et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet. 1998;351:28-31.

47. Podzolkov V.I., Bragina A.E., Osadchiy K.K. A fixed-dose lisinopril+amlodipine+rosuvastatin combination: prospects for its use in patients with hypertension and concomitant dyslipidemia. Ter Arkh. 2017;89(12):133-140 (In Russ.). DOI:10.17116/terarkh20178912133-140.

48. Gupta A.K., Arshad S., Poulter N.R. Compliance, Safety, and Effectiveness of Fixed-Dose Combinations of Antihypertensive Agents, A Meta-Analysis. Hypertension. 2010;55:399-407. DOI:10.1161/HYPERTENSIONAHA.109.139816.

49. Sassarda J., Bataillard A., McIntyre H. An overview of the pharmacology and clinical efficacy of indapamide sustained release. Fundamental & Clinical Pharmacology. 2005;19:637-45. DOI:10.1111/j.1472-8206.2005.00377.x.

50. de Faria A.P., Demacq C., Figueiredo V.N., et al. Hypoadiponectinemia and aldosterone excess are associated with lack of blood pressure control in subjects with resistant hypertension. Hypertens Res. 2013;36:1067-72.

51. Gaddam K.K., Nishizaka M.K., Pratt-Ubunama M.N., et al. Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med. 2008;168:1159-64. DOI:10.1001/archinte.168.11.1159.

52. Ni X., Zhang J., Zhang P., et al. Effects of Spironolactone on Dialysis Patients With Refractory Hypertension: A Randomized Controlled Study. The Journal of Clinical Hypertension 2014;16:658-63. DOI:10.1111/jch.12374.

53. Abolghasmi R., Taziki O. Efficacy of low dose spironolactone in chronic kidney disease with resistant hypertension. Saudi J Kidney Dis Transpl. 2011;22:75.

54. Bobrie G., Frank M., Azizi M., et al. Sequential nephron blockade versus sequential renin-angiotensin system blockade in resistant hypertension: a prospective, randomized, open blinded endpoint study. J Hypertens. 2012;30:1656-64. DOI:10.1097/HJH.0b013e3283551e98.

55. Oxlund C.S., Henriksen J.E., Tarnow L., et al. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J Hypertens. 2013;31:2094-102. DOI:10.1097/HJH.0b013e3283638b1a.

56. Va´clavı´k J., Sedla´k R., Jarkovsky´ J., et al. Effect of Spironolactone in Resistant Arterial Hypertension: A Randomized, DoubleBlind, Placebo-Controlled Trial (ASPIRANT-EXT). Medicine. 2014;93:e162. DOI:10.1097/MD.0000000000000162.

57. Wang C., Xiong B., Huang J. Efficacy and safety of spironolactone in patients with resistant hypertension: a meta-analysis of randomized controlled trials. Heart, Lung and Circulation. 2016;25(10):1021-30. DOI:10.1016/j.hlc.2016.02.016.

58. Rosa J., Widimsky P, Waldaii P. et aL, Rote of Adding Spironolactone and Renal Denervation in True Resistant Hypertension, One-Year Outcomes of Randomized PRAGUE-15 Study, Hypertension. 2016;67:397-403. DOI:10.1161/HYPERTENSIONAHA.115.06526

59. Oliveras A., Armario P., Clarà A., et al. Spironolactone versus sympathetic renal denervation to treat true resistant hypertension: results from the DENERVHTA study a randomized controlled trial. J Hypertens. 2016;34(9):1863-71. DOI:10.1097/HJH.0000000000001025.

60. Williams B., MacDonald T.M., Morant S., at al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. For The British Hypertension Society’s PATHWAY Studies Group. Lancet. 2015;386:2059-68. DOI:10.1016/S0140-6736(15)00257-3.


For citations:

Podzolkov V.I., Bragina A.E., Osadchiy K.K. Resistant Hypertension: Questions and Contemporary Answers. Rational Pharmacotherapy in Cardiology. 2019;15(4):568-577. (In Russ.)

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