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The Possibilities of Single-Pill Combinations of Antihypertensive Drugs in Cerebroprotection: Focus on the Combination of Amlodipine with Ramipril

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Stroke remains one of the leading causes of death and disability both worldwide and in Russia. Acute cerebrovascular events have many risk factors, among them the most important is arterial hypertension (AH), which predisposes to the stroke development through the direct effect of increased hydrostatic blood pressure on the brain vascular system, followed by arterial remodeling and an increase in their stiffness. In addition, excessive blood pressure variability, activation of the tissue renin-angiotensin-aldosterone system, as well as target-organ damage - primarily the heart in the form of left ventricular hypertrophy, kidneys in the form of microalbuminuria and decrease in glomerular filtration rates. An additional risk factor for stroke is hyperuricemia, which is included in the current European and Russian guidelines for the management of AH as one of the new risk factors in patients with this disease. The state-of-the-art approach to antihypertensive therapy is the using of antihypertensive single-pill combinations, one of the frontline combinations in the absence of special clinical conditions is a combination of an angiotensin converting enzyme inhibitor and a calcium channel blocker. The reference drugs in both classes due to large body of evidence are ramipril and amlodipine, respectively. These drugs provide a high level of brain protection, not only due to the ultra-long and powerful antihypertensive action, but also through a unique potential in target-organ protection via left ventricular hypertrophy regression, antiatherosclerotic effects and improved endothelial function, renal protection, as well as the ability to decrease uric acid in the blood.

About the Authors

A. I. Kochetkov
Russian Medical Academy of Continuous Professional Education
Russian Federation

Alexey I. Kochetkov - MD, PhD, Associate Professor, Chair of Therapy and Polymorbid Pathology, Russian Medical Academy of Continuous Professional Education.

Barrikadnaya ul. 2/1, Moscow, 125993.

S. V. Batyukina
Russian Medical Academy of Continuous Professional Education
Russian Federation

Svetlana V. Batyukina - Resident, Chair of Therapy and Polymorbid Pathology, Russian Medical Academy of Continuous Professional Education.

Barrikadnaya ul. 2/1, Moscow, 125993.

O. D. Ostroumova
Russian Medical Academy of Continuous Professional Education; I.M. Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation

Olga D. Ostroumova - MD, PhD, Professor, Head of Chair of Therapy and Polymorbid Pathology, Russian Medical Academy of Continuous Professional Education; Professor, Chair of Clinical Pharmacology and Propaedeutics of Internal Medicine, Sechenov University.

Barrikadnaya ul. 2/1, Moscow, 125993; Trubetskaya ul. 8-2, Moscow, 119991.

M. Yu. Nazranova
I.M. Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation

Marianna Yu. Nazranova - Student, Sechenov University.

Trubetskaya ul. 8-2, Moscow, 119991.

V. N. Butorov
Russian Medical Academy of Continuous Professional Education
Russian Federation

Vasilii N. Butorov - MD, PhD, Associate Professor, Chair of Therapy and Polymorbid Pathology, Russian Medical Academy of Continuous Professional Education.

Barrikadnayaul. 2/1, Moscow, 125993.


1. Wajngarten M., Silva G.S. Hypertension and Stroke: Update on Treatment. Eur Cardiol. 2019;14(2):111-5. DOI:10.15420/ecr.2019.11.1.

2. Donkor E.S. Stroke in the 21st Century: A Snapshot of the Burden, Epidemiology, and Quality of Life. Stroke Res Treat. 2018;2018:3238165. DOI:10.1155/2018/3238165.

3. Pistoia F., Sacco S., Degan D., et al. Hypertension and Stroke: Epidemiological Aspects and Clinical Evaluation. High Blood Press Cardiovasc Prev. 2016;23(1):9-18. DOI:10.1007/s40292-015-0115-2.

4. [cited by Jan 20, 2020]. Available from: (In Russ.)

5. Guzik A., Bushnell C. Stroke Epidemiology and Risk Factor Management. Continuum (Minneap Minn). 2017;23(1, Cerebrovascular Disease):15-39. DOI:10.1212/CON.0000000000000416.

6. Bejot Y. Targeting blood pressure for stroke prevention: current evidence and unanswered questions. J Neurol. 2019 Jun 26. DOI:10.1007/s00415-019-09443-5.

7. Peixoto A.J, White W.B. Circadian blood pressure: clinical implications based on the pathophysiology of its variability. Kidney Int. 2007;71(9):855-60. DOI:10.1038/

8. Elliott WJ. Circadian variation in the timing of stroke onset. А meta-analysis. Stroke. 1998;29:992-6. DOI:10.1161/01.STR.29.5.992.

9. Kario K. Morning surge in blood pressure and cardiovascular risk: evidence and perspectives. Hypertension. 2010;56(5):765-73. DOI:10.1161/HYPERTENSIONAHA.110.157149.

10. Dahlof B., Sever P.S., Poulter N.R. et al.; ASCOT Investigators. 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 (ASCOT-BPLA): a multicentre randomized controlled trial. Lancet. 2005;366:895-906. DOI:10.1016/S0140-6736(05)67185-1.

11. O'Leary D.H., Polak J.F., Kronmal R.A., et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999;340(1):14-22. DOI:10.1056/NEJM199901073400103.

12. Hollander M., Bots M.L., Del Sol A.I., et al. Carotid plaques increase the risk of stroke and subtypes of cerebral infarction in asymptomatic elderly: the Rotterdam study. Circulation. 2002;105(24):2872-7. DOI:10.1161/01.cir.0000018650.58984.75.

13. 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.

14. Mitchell G.F. Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage. J Appl Physiol. 2008;105:1652-60. DOI:10.1152/jap-plphysiol.90549.2008.

15. O'Rourke M.F., Safar M.E. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension. 2005;46:200-4. DOI:10.1161/01.HYP.0000168052.00426.65.

16. Tzourio C., Laurent S., Debette S. Is hypertension associated with an accelerated aging of the brain? Hypertension. 2014;63:894-903. DOI:10.1161/HYPERTENSIONAHA.113.00147.

17. Verdecchia P., Porcellati C., Reboldi G., et al. Left ventricular hypertrophy as an independent predictor of acute cerebrovascular events in essential hypertension. Circulation. 2001;104(17):2039-44. DOI:10.1161/hc4201.097944.

18. Luft F.C., Agrawal B. Microalbuminuria as a predictive factor for cardiovascular events. J Cardiovasc Pharmacol. 1999;33 Suppl 1:S11-5. DOI:10.1097/00005344-199900001-00003.

19. Ettehad D., Emdin C.A., Kiran A., et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387(10022):957-67. DOI:10.1016/S0140-6736(15)01225-8.

20. Rutan G.H., Kuller L.H., Neaton J.D., et al. Mortality associated with diastolic hypertension and isolated systolic hypertension among men screened for the Multiple Risk Factor Intervention Trial. Circulation. 1988;77(3):504-14. DOI:10.1161/01.cir.77.3.504.

21. 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):3021-104. DOI:10.1093/eurheartj/ehy339.

22. Categories of clinical guidelines of Ministry of Health of the Russian Federation: clinical guidelines “Arterial hypertension in adults” [cited by Jan 20, 2020]. Available from: #!/recomend/687 (In Russ.)

23. Vasudeva K., Balyan R., Munshi A. ACE-Triggered Hypertension Incites Stroke: Genetic, Molecular, and Therapeutic Aspects. Neuromolecular Med. 2020;22(2):194-209. DOI:10.1007/s12017-019-08583-1.

24. Weir M.R. Targeting mechanisms of hypertensive vascular disease with dual calcium channel and renin-angiotensin system blockade. J Hum Hypertens. 2007;21(10):770-9. DOI:10.1038/sj.jhh.1002254.

25. Neaton J.D., Grimm R.H.Jr, Prineas R.J., et al. Treatment of Mild Hypertension Study. Final results. Treatment of Mild Hypertension Study Research Group. JAMA. 1993;270(6):713-24. DOI:10.1001/jama.1993.03510060059034.

26. Julius S., Kjeldsen S.E., Weber M., et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363(9426):2022-31. DOI:10.1016/S0140-6736(04)16451-9.

27. Iadecola C., Gorelick P.B. Hypertension, angiotensin, and stroke: beyond blood pressure. Stroke. 2004;35(2):348-50. DOI:10.1161/01.STR.0000115162.16321.AA.

28. Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Sleight P, Pogue J et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342(3):145-53. DOI:10.1056/NEJM200001203420301.

29. Bosch J., Yusuf S., Pogue J., et al. Use of ramipril in preventing stroke: double blind randomised trial. BMJ. 2002;324(7339):699-702. DOI:10.1136/bmj.324.7339.699.

30. Rothwell P.M., Howard S.C., Dolan E., et al.; ASCOT-BPLA and MRC Trial Investigators. Effects of beta blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol. 2010;9(5):469-80. DOI:10.1016/S1474-4422(10)70066-1.

31. Rothwell P.M., Howard S.C., Dolan E., et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure and episodic hypertension. Lancet. 2010;375:895-905. DOI:10.1016/S0140-6736(10)60308-X.

32. 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(13):1503-1510. DOI:10.1161/01.cir.102.13.1503.

33. Nissen S.E., Tuzcu E. M., Libby P., et al. for the CAMELOT Investigators. 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;292:2217-25. DOI:10.1001/jama.292.18.2217.

34. Lonn E., Yusuf S., Dzavik V., et al. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation. 2001;103(7):919-25. DOI:10.1161/01.cir.103.7.919.

35. Podzolkov V.I., Tarzimanova A.I. The new fixed combination of amlodipine and ramipril in the treatment of hypertension. Rational Pharmacotherapy in Cardiology. 2015;11(3):327-32 (In Russ.) DOI:10.20996/1819-6446-2015-11-3-327-332.

36. Verdecchia P., Schillaci G., Borgioni C., et al. Prognostic value of a new electrocardiographic method for diagnosis of left ventricular hypertrophy in essential hypertension. J Am Coll Cardiol. 1998;31(2):383-90. DOI:10.1016/s0735-1097(97)00493-2.

37. Okin P.M., Devereux R.B., Jern S., et al. Regression of electrocardiographic left ventricular hypertrophy by losartan versus atenolol: The Losartan Intervention for Endpoint reduction in Hypertension (LIFE) Study. Circulation. 2003;108(6):684-90. DOI:10.1161/01.CIR.0000083724.28630.C3.

38. Wachtell K., Okin P.M., Olsen M.H., et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive therapy and reduction in sudden cardiac death: the LIFE Study. Circulation. 2007;116(7):700-5. DOI:10.1161/CIRCULATIONAHA.106.666594.

39. Agabiti-Rosei E., Ambrosioni E., Dal Palu C., et al. ACE inhibitor ramipril is more effective than the beta-blocker atenolol in reducing left ventricular mass in hypertension. Results of the RACE (ramipril cardioprotective evaluation) study on behalf of the RACE study group. J Hypertens. 1995;13(11):1325-34. DOI:10.1097/00004872-199511000-00015.

40. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069):1857-63. DOI:10.1016/S0140-6736(96)11445-8

41. Dzau V.J., Bernstein K., Celermajer D., et al. The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data. Am J Cardiol. 2001;88(9A):1L-20L. DOI:10.1016/s0002-9149(01)01878-1.

42. Meisel S, Shamiss A, Rosenthal T. Clinical pharmacokinetics of ramipril. Clin Pharmacokinet. 1994;26(1):7-15. DOI:10.2165/00003088-199426010-00002.

43. Ostroumova O.D., Maksimov M.L., Bondarets O.V. Angiotensin-converting enzyme inhibitors in the physician's practice: similarities and differences. Meditsinskiy Sovet. 2011;5-6:50-7 (In Russ.)

44. Jamerson K., Weber M.A., Bakris G.L., et al. for the Accomplish trial investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417-2428. DOI:10.1056/NEJMoa0806182.

45. Bakris G.L., Sarafidis P.A., Weir M.R., et al. Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial. Lancet. 2010;375(9721):1173-81. DOI:10.1016/S0140-6736(09)62100-0.

46. Lehto S., Niskanen L., Ronnemaa T., Laakso M. Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus. Stroke. 1998;29(3):635-9. DOI:10.1161/01.str.29.3.635.

47. Storhaug H.M., Norvik J.V.., Toft I., et al. Uric acid is a risk factor for ischemic stroke and all-cause mortality in the general population: a gender specific analysis from The Troms0 Study. BMC Cardiovasc Disord. 2013;13:115. DOI:10.1186/1471-2261-13-115.

48. Jacobsen B.K., Eggen A.E., Mathiesen E.B., et al. Cohort profile: the Tromso Study. Int J Epidemiol. 2012;41(4):961-7. DOI:10.1093/ije/dyr049.

49. Tomcsany J.A. Ramipriles Amlodipin kombinacio vernyomascsokkento hatekonysaganak MOni-torozasa es beavatkozassal Nem jaro Adatgyujtese (RAMONA tanulmany). Hypertonia es Nephrologia, 2013;17:49-96.

50. Ostroumova O.D., Zykov A.A. Effectiveness of fixed combination of ramipil/amlodipine in therapy of arterial hypertension, chronic kidney disease and diabetes mellitus. Meditsinskiy Sovet. 2016;13:16-23 (In Russ.) DOI:10.21518/2079-701X-2016-13-16-23.

For citation:

Kochetkov A.I., Batyukina S.V., Ostroumova O.D., Nazranova M.Yu., Butorov V.N. The Possibilities of Single-Pill Combinations of Antihypertensive Drugs in Cerebroprotection: Focus on the Combination of Amlodipine with Ramipril. Rational Pharmacotherapy in Cardiology. 2020;16(3):487-497. (In Russ.)

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ISSN 1819-6446 (Print)
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