Single Pill Indapamide and Perindopril Arginine Combination: Optimal Coupling of Vascular Protection and Hemodynamic Risk Factors Reduction in Patients with Essential Arterial Hypertension

Objective: to investigate the impact of indapamide / perindopril single-pill combination (I / P SPC) on arterial stiffness parameters, blood pressure (BP) level and BP variability (BPV) in middle-aged patients with stage II grade 1–2 essential arterial hypertension (EAH). Materials and methods. We retrospectively formed a group of patients with stage II grade 1–2 EAH who had not previously received regular antihypertensive therapy (AHT) (n=52, mean age 52.9±6.0 years). All patients were treated with I / P SPC and all of them achieved target office BP level (less than 140 / 90 mm Hg). After 12 weeks of follow-up (from the time of reaching the target BP) assessment of AHT effectiveness (general clinical data, ambulatory blood pressure monitoring [ABPM], volume sphygmography, echocardiography), and vascular stiffness evaluation were performed. Results. At the end of follow-up office systolic BP (SBP), diastolic BP (DBP), pulse BP, day-time, night-time and 24‑hour SBP and DBP significantly (p<0.001 for all) decreased. According to the ABPM data day-time, nighttime, and 24‑hour systolic BPV significantly decreased (p=0.029, p=0.006 and p<0.001, respectively); day-time and 24‑hour diastolic BPV also significantly decreased (p=0.001 and p<0.001, respectively). Day-night standard deviation (SDdn) significantly decreased too (p=0.002 and p<0.001, respectively). Volumetric sphygmography showed significant decrease of right cardio-ankle vascular index (CAVI) (from 8.20±1.29 to 7.58±1.44, p=0.001) and of left CAVI (from 8.13±1.40 to 7.46±1.43, p<0.001), as well as reduction of the number o f patients with a right- and / or left-CAVI >9.0 (from 32.7 to 11.5 %, p=0.018). According to assessment of arterial stiffness using the Vasotens24 software package, the arterial stiffness index (ASI) significantly (p<0.001) decreased from 153.5±29.9 to 138.3±20.0 (by –9.2±13.1 %). Transthoracic echocardiography data demonstrated significant decrease (p<0.001) in effective arterial elastance (from 1.82±0.43 to 1.58±0.36 mm Hg; by –11.85±16.29 %) and significant (p<0.001) increase in the arterial compliance – from 1.27±0.34 to 1.54±0.38 mm Hg / ml (+26.95±38.06 %). Conclusion. In AHT naive patients 40–65 years old with stage II grade 1–2 EAH therapy with I / P SPC provided effective 24‑hour BP control, reduced BPV and improved arterial stiffness parameters. 

1. Chazova I.E., Oschepkova E.V., Zhernakova Yu.V. et al. Diagnostics and treatment of arterial hypertension. Clinical recommendations. Moscow: 2013, p.63. Russiаn.

2. Williams B., Mancia G., Spiering W. et al.; ESC Scientific Document Group. 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(33):3021–3104. DOI: 10.1093/eurheartj/ehy339.

3. Ostroumova O.D., Borisova E.V., Ostroumova T.M., Kochetkov A.I. 24-Hour Arterial Pressure Variability: Prognostic Significance, Methods of Evaluation, Effect of Antihypertensive Therapy. Kardiologiia 2017;57(12):62–72. DOI: 10.18087/cardio.2017.12.10068. Russiаn.

4. Mancia G., Fagard R., Narkiewicz K. et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension. The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013;31:1281–1357. DOI: 10.1097/01.hjh.0000431740.32696.cc.

5. Zhang Q.Q., Zhang X.J., Chang B.B. et al. [Blood pressure variability correlates with target-organ damage in elderly patients with hypertension]. [Article in Chinese]. Sichuan Da Xue Xue Bao Yi Xue Ban 2011;42(2):252–255.

6. Chazova I.E., Oschepkova E.V., Zhernakova Yu.V. et al. Diagnostics and treatment of arterial hypertension. Clinical recommendations. Moscow: 2013, p.63. Russiаn.

7. Tatasciore А., Renda G., Zimarino M. et al. Awake Systolic Blood Pressure Variability Correlates With Target-Organ Damage in Hypertensive Subjects. Hypertension 2007;50:325–332.

8. Ostroumova O.D., Borisova E.V., Ostroumova T.M., Kochetkov A.I. 24-Hour Arterial Pressure Variability: Prognostic Significance, Methods of Evaluation, Effect of Antihypertensive Therapy. Kardiologiia 2017;57(12):62–72. DOI: 10.18087/cardio.2017.12.10068. Russiаn.

9. Ozawa M., Tamura K., Okano Y. et al. Blood pressure variability as well as blood pressure level is important for left ventricular hypertrophy and brachial-ankle pulse wave velocity in hypertensives. Clin Exp Hypertens 2009;31(8):669–679. DOI: 10.3109/10641960903407033.

10. Zhang Q.Q., Zhang X.J., Chang B.B. et al. [Blood pressure variability correlates with target-organ damage in elderly patients with hypertension]. [Article in Chinese]. Sichuan Da Xue Xue Bao Yi Xue Ban 2011;42(2):252–255.

11. Kastanayan A.A., Zheleznyak E.I., Hagush A.K. et al. Interrelation of blood pressure variability and cardiovascular remodeling with development of arterial hypertension in old age. Arterial’naya gipertenziya 2016;22 (4):389–400. Russian DOI: 10.18705/1607-419X-2016224389400.

12. Tatasciore А., Renda G., Zimarino M. et al. Awake Systolic Blood Pressure Variability Correlates With Target-Organ Damage in Hypertensive Subjects. Hypertension 2007;50:325–332.

13. Juhanoja E.P., Niiranen T.J., Johansson J.K. et al. Agreement between ambulatory, home, and office blood pressure variability. J Hypertens 2016;34(1):61–67. DOI: 10.1097/HJH.0000000000000772.

14. Ozawa M., Tamura K., Okano Y. et al. Blood pressure variability as well as blood pressure level is important for left ventricular hypertrophy and brachial-ankle pulse wave velocity in hypertensives. Clin Exp Hypertens 2009;31(8):669–679. DOI: 10.3109/10641960903407033.

15. Madden J.M., O’Flynn A.M., Fitzgerald A.P., Kearney P.M. Correlation between short-term blood pressure variability and left-ventricular mass index: a meta-analysis. Hypertens Res 2015. DOI:10.1038/hr.2015.126.

16. Kastanayan A.A., Zheleznyak E.I., Hagush A.K. et al. Interrelation of blood pressure variability and cardiovascular remodeling with development of arterial hypertension in old age. Arterial’naya gipertenziya 2016;22 (4):389–400. Russian DOI: 10.18705/1607-419X-2016224389400.

17. Mancia G., Parati G., Hennig M. et al. Relation between blood pressure variability and carotid artery damage in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis (ELSA). J Hypertens 2001;19(11):1981–1989.

18. Juhanoja E.P., Niiranen T.J., Johansson J.K. et al. Agreement between ambulatory, home, and office blood pressure variability. J Hypertens 2016;34(1):61–67. DOI: 10.1097/HJH.0000000000000772.

19. Kawai T., Ohishi M., Kamide K. et al. Differences between daytime and nighttime blood pressure variability regarding systemic atherosclerotic change and renal function. Hypertens Res 2013;36(3):232–239. DOI: 10.1038/hr.2012.162. Epub 2012 Oct 18.

20. Madden J.M., O’Flynn A.M., Fitzgerald A.P., Kearney P.M. Correlation between short-term blood pressure variability and left-ventricular mass index: a meta-analysis. Hypertens Res 2015. DOI:10.1038/hr.2015.126.

21. Ichihara A., Kaneshiro Y., Takemitsu T. et al. Ambulatory blood pressure variability and brachial-ankle pulse wave velocity in untreated hypertensive patients. J Hum Hypertens 2006;20:529–536. DOI: 10.1038/sj.jhh.1002023

22. Mancia G., Parati G., Hennig M. et al. Relation between blood pressure variability and carotid artery damage in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis (ELSA). J Hypertens 2001;19(11):1981–1989.

23. Schillaci G., Bilo G., Pucci G. et al. Relationship Between Short-Term Blood Pressure Variability and Large-Artery Stiffness in Human Hypertension: Findings From 2 Large Databases. Hypertension 2012;60:369–377. DOI: 10.1161/HYPERTENSIONAHA.112.197491

24. Kawai T., Ohishi M., Kamide K. et al. Differences between daytime and nighttime blood pressure variability regarding systemic atherosclerotic change and renal function. Hypertens Res 2013;36(3):232–239. DOI: 10.1038/hr.2012.162. Epub 2012 Oct 18.

25. Eguchi К., Hoshide S., Schwartz J. E. et al. Visit-to-visit and Ambulatory Blood Pressure Variability as Predictors of Incident Cardiovascular Events in Patients with Hypertension. Am J Hypertens 2012;25(9):962–968. DOI: 10.1038/ajh.2012.75

26. Ichihara A., Kaneshiro Y., Takemitsu T. et al. Ambulatory blood pressure variability and brachial-ankle pulse wave velocity in untreated hypertensive patients. J Hum Hypertens 2006;20:529–536. DOI: 10.1038/sj.jhh.1002023

27. Pringle E., Phillips C., Thijs L. et al., Syst-Eur investigators. Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly hypertensive population. J Hypertens 2003;21:2251–2257.

28. Schillaci G., Bilo G., Pucci G. et al. Relationship Between Short-Term Blood Pressure Variability and Large-Artery Stiffness in Human Hypertension: Findings From 2 Large Databases. Hypertension 2012;60:369–377. DOI: 10.1161/HYPERTENSIONAHA.112.197491

29. Verdecchia P., Angeli.F, Gattobigio R. et al. Impact of blood pressure variability on cardiac and cerebrovascular complications in hypertension. Am J Hypertens 2007;20:154–161.

30. Eguchi К., Hoshide S., Schwartz J. E. et al. Visit-to-visit and Ambulatory Blood Pressure Variability as Predictors of Incident Cardiovascular Events in Patients with Hypertension. Am J Hypertens 2012;25(9):962–968. DOI: 10.1038/ajh.2012.75

31. Mena L.J., Maestre G.E., Hansen T.W. et al. on behalf of the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes (IDACO) Investigators How Many Measurements Are Needed to Estimate Blood Pressure Variability Without Loss of Prognostic Information? Am J Hypertens 2014;27(1):46–55.

32. Pringle E., Phillips C., Thijs L. et al., Syst-Eur investigators. Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly hypertensive population. J Hypertens 2003;21:2251–2257.

33. Stevens S. L., Wood S., Koshiaris C. et al. Blood pressure variability and cardiovascular disease: systematic review and meta-analysis. BMJ 2016;354:9;354: i4098. DOI: 10.1136/bmj.i4098.

34. Verdecchia P., Angeli.F, Gattobigio R. et al. Impact of blood pressure variability on cardiac and cerebrovascular complications in hypertension. Am J Hypertens 2007;20:154–161.

35. Laurent S., Cockcroft J., Van Bortel L. et al.; European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur heart J 2006;27:2588–2605. DOI:10.1093/eurheartj/ehl254.

36. Mena L.J., Maestre G.E., Hansen T.W. et al. on behalf of the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes (IDACO) Investigators How Many Measurements Are Needed to Estimate Blood Pressure Variability Without Loss of Prognostic Information? Am J Hypertens 2014;27(1):46–55.

37. Consensus of Russian experts on the evaluation of arterial stiffness in clinical practice. Cardiovascular Therapy and Prevention 2016:15(2):4–19. Russian.

38. Stevens S. L., Wood S., Koshiaris C. et al. Blood pressure variability and cardiovascular disease: systematic review and meta-analysis. BMJ 2016;354:9;354: i4098. DOI: 10.1136/bmj.i4098.

39. O’Brien E., Parati G., Stergiou G. et al., on behalf of the European Society of Hypertension Working Group on Blood Pressure Monitoring. Guidelines European Society of Hypertension Position Paper on Ambulatory Blood Pressure Monitoring. J Hypertens 2013;31:1731–1768. DOI:10.1097/HJH.0b013e328363e964

40. Laurent S., Cockcroft J., Van Bortel L. et al.; European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur heart J 2006;27:2588–2605. DOI:10.1093/eurheartj/ehl254.

41. Laurent S., Boutouyrie P., Asmar R. et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001;37:1236–1241.

42. Consensus of Russian experts on the evaluation of arterial stiffness in clinical practice. Cardiovascular Therapy and Prevention 2016:15(2):4–19. Russian.

43. van Sloten T.T., Stehouwer C.D. Carotid Stiffness: A Novel Cerebrovascular Disease Risk Factor. Pulse (Basel) 2016;4(1):24–27. DOI: 10.1159/000445354.

44. O’Brien E., Parati G., Stergiou G. et al., on behalf of the European Society of Hypertension Working Group on Blood Pressure Monitoring. Guidelines European Society of Hypertension Position Paper on Ambulatory Blood Pressure Monitoring. J Hypertens 2013;31:1731–1768. DOI:10.1097/HJH.0b013e328363e964

45. Laurent S., Katsahian S., Fassot C. et al. Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke 2003;34(5):1203–1206. DOI: 10.1161/01.STR.0000065428.03209.64.

46. Laurent S., Boutouyrie P., Asmar R. et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001;37:1236–1241.

47. Kullo I.J., Bielak L.F., Turner S.T. et al. Aortic pulse wave velocity is associated with the presence and quantity of coronary artery calcium: a community-based study. Hypertension 2006;47(2):174–179. DOI: 10.1161/01.HYP.0000199605.35173.14.

48. van Sloten T.T., Stehouwer C.D. Carotid Stiffness: A Novel Cerebrovascular Disease Risk Factor. Pulse (Basel) 2016;4(1):24–27. DOI: 10.1159/000445354.

49. Pavlova Е.А., Kobalava Zh.D., Kotovskaya Yu.V. Effects of perindopril/indapamide fixed high dose combination on ambulatory blood pressure in subjects with previously uncontrolled arterial hypertension. Arterial’naya gipertenziya 2012;18(6):505–513. Russian.

50. Laurent S., Katsahian S., Fassot C. et al. Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke 2003;34(5):1203–1206. DOI: 10.1161/01.STR.0000065428.03209.64.

51. Aksenova A. V., Elfimova E. M., Litvin A. Yu., Chazova I. E. Chronotherapy’s opportunities of a fixed combination of perindopril 10 mg/indapamide 2.5 mg in patients with a lack of night reduction in blood pressure. Systemic Hypertension 2016;13(2):37–45. DOI: 10.26442/2075-082X_13.2.37-45. Russian.

52. Kullo I.J., Bielak L.F., Turner S.T. et al. Aortic pulse wave velocity is associated with the presence and quantity of coronary artery calcium: a community-based study. Hypertension 2006;47(2):174–179. DOI: 10.1161/01.HYP.0000199605.35173.14.

53. Nedogoda S.V., Chumachek E.V., Ledyaeva A.A. et al. Optimization of Control of Blood Pressure, Metabolic Disorders and Target Organs Protection With Fixed Perindopril and Indapamide Combination in Treated Patients With Arterial Hypertension. Kardiologiya 2017;57(2):5–11. DOI: 10.18565/cardio.2017.2.5-11. Russian.

54. Pavlova Е.А., Kobalava Zh.D., Kotovskaya Yu.V. Effects of perindopril/indapamide fixed high dose combination on ambulatory blood pressure in subjects with previously uncontrolled arterial hypertension. Arterial’naya gipertenziya 2012;18(6):505–513. Russian.

55. Protasov K.V., Sinkevich D.A., Reshina I.V. et al. Vascular effects of perindopril arginine and indapamide fixed combination in patients with arterial hypertension. Kardiologiia 2012;52(9):8–14. Russian.

56. Aksenova A. V., Elfimova E. M., Litvin A. Yu., Chazova I. E. Chronotherapy’s opportunities of a fixed combination of perindopril 10 mg/indapamide 2.5 mg in patients with a lack of night reduction in blood pressure. Systemic Hypertension 2016;13(2):37–45. DOI: 10.26442/2075-082X_13.2.37-45. Russian.

57. Koz C., Baysan O., Yokusoglu M. et al. The effects of perindopril on aortic elasticity and inflammatory markers in hypertensive patients. Med Sci Monit 2009;15(7):PI41–5.

58. Nedogoda S.V., Chumachek E.V., Ledyaeva A.A. et al. Optimization of Control of Blood Pressure, Metabolic Disorders and Target Organs Protection With Fixed Perindopril and Indapamide Combination in Treated Patients With Arterial Hypertension. Kardiologiya 2017;57(2):5–11. DOI: 10.18565/cardio.2017.2.5-11. Russian.

59. Sesso H.D., Buring J.E., Rifai N. et al. C-reactive protein and the risk of developing hypertension. JAMA 2003;290(22):2945–2951. DOI: 10.1001/jama.290.22.2945.

60. Protasov K.V., Sinkevich D.A., Reshina I.V. et al. Vascular effects of perindopril arginine and indapamide fixed combination in patients with arterial hypertension. Kardiologiia 2012;52(9):8–14. Russian.

61. Blake G.J., Rifai N., Buring J.E., Ridker P.M. Blood pressure, C-reactive protein, and risk of future cardiovascular events. Circulation 2003;108(24):2993–2999. DOI: 10.1161/01.CIR.0000104566.10178.AF

62. Koz C., Baysan O., Yokusoglu M. et al. The effects of perindopril on aortic elasticity and inflammatory markers in hypertensive patients. Med Sci Monit 2009;15(7):PI41–5.

63. Rocha R., Rudolph A.E., Frierdich G.E. et al. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 2002;283(5):H1802–10. DOI: 10.1152/ajpheart.01096.2001.

64. Sesso H.D., Buring J.E., Rifai N. et al. C-reactive protein and the risk of developing hypertension. JAMA 2003;290(22):2945–2951. DOI: 10.1001/jama.290.22.2945.

65. Rocha R., Martin-Berger C.L., Yang P. et al. Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinology 2002;143(12):4828–36. DOI: 10.1210/en.2002-220120.

66. Blake G.J., Rifai N., Buring J.E., Ridker P.M. Blood pressure, C-reactive protein, and risk of future cardiovascular events. Circulation 2003;108(24):2993–2999. DOI: 10.1161/01.CIR.0000104566.10178.AF

67. Fernandez-Real J.M., Vayreda M., Richart C. et al. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab 2001;86(3):1154–1159. DOI: 10.1210/jcem.86.3.7305.

68. Rocha R., Rudolph A.E., Frierdich G.E. et al. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 2002;283(5):H1802–10. DOI: 10.1152/ajpheart.01096.2001.

69. Park S., Lakatta E.G. Role of inflammation in the pathogenesis of arterial stiffness. Yonsei Med J 2012;53(2):258–261. DOI: 10.3349/ymj.2012.53.2.258.

70. Rocha R., Martin-Berger C.L., Yang P. et al. Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinology 2002;143(12):4828–36. DOI: 10.1210/en.2002-220120.

71. Wang M., Zhang J., Jiang L.Q. et al. Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension 2007;50(1):219–227. DOI: 10.1161/HYPERTENSIONAHA.107.089409.

72. Fernandez-Real J.M., Vayreda M., Richart C. et al. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab 2001;86(3):1154–1159. DOI: 10.1210/jcem.86.3.7305.

73. Nedogoda S.V., Chalyabi T.A., Salasyuk A.S. et al. Algorithm for selection of antihypertensive treatment in patients with metabolic syndrome and hypertension. Medical Council 2013;9:56–64. DOI: 10.21518/2079-701X-2013-9-56-64. Russian.

74. Park S., Lakatta E.G. Role of inflammation in the pathogenesis of arterial stiffness. Yonsei Med J 2012;53(2):258–261. DOI: 10.3349/ymj.2012.53.2.258.

75. Ouchi N., Parker J.L., Lugus J.J., Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011;11(2):85–97. DOI: 10.1038/nri2921.

76. Wang M., Zhang J., Jiang L.Q. et al. Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension 2007;50(1):219–227. DOI: 10.1161/HYPERTENSIONAHA.107.089409.

77. Sassard J., Bataillard A., McIntyre H. An overview of the pharmacology and clinical efficacy of indapamide sustained release. Fundam Clin Pharmacol 2005;19(6):637–645. DOI: 10.1111/j.1472-8206.2005.00377.x

78. Nedogoda S.V., Chalyabi T.A., Salasyuk A.S. et al. Algorithm for selection of antihypertensive treatment in patients with metabolic syndrome and hypertension. Medical Council 2013;9:56–64. DOI: 10.21518/2079-701X-2013-9-56-64. Russian.

79. Ouchi N., Parker J.L., Lugus J.J., Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011;11(2):85–97. DOI: 10.1038/nri2921.

80. Sassard J., Bataillard A., McIntyre H. An overview of the pharmacology and clinical efficacy of indapamide sustained release. Fundam Clin Pharmacol 2005;19(6):637–645. DOI: 10.1111/j.1472-8206.2005.00377.x