Evaluation of Fixed Dose Combination Perindopril/Amlodipine Influence on Target Organ Damage in Patients with Arterial Hypertension and Ischemic Heart Disease (Results of EPHES Trial)

H.D. Radchenko, L.O. Mushtenko, O.O. Torbas, S.M. Kushnir, O.A. Yarynkina, S.V. Potashev, Yu.M. Sirenko


Introduction. EPHES (Evaluation of influence of fixed dose combination Рerindopril/Amlodipine on target organ damage in patients with arterial HypErtension with or without iSchemic heart disease) trial was intended to evaluate the efficacy of a fixed dose combination of perindopril/amlodipine in terms of reducing blood pressure (BP) and dynamics of target organs damage in patients suffering from arterial hypertension (AH) with ischemic heart disease (IHD) and without it. This article is the result of an analysis of data obtained in patients with AH and clinical signs of IHD.
Materials and methods. The study included 30 patients with AH and verified IHD aged over 30 years. Systolic (SBP) and/or diastolic (DBP) blood pressure level in patients, who had not been treated before, had to be ≥ 160/100 mmHg, but < 200/120 mmHg at baseline; in those, who were on monotherapy or dual combination therapy, — ≥ 140/90 mmHg, but < 200/120 mmHg. All patients on the day of randomization were prescribed a fixed dose combination of perindopril/amlodipine at an initial dose of 5.5 mg once a day. If necessary (BP > 140/90 mmHg), the dose of components of fixed dose combination was increased gradually every 2 weeks up to 10/10 mg, and after 6 weeks of treatment, indapamide 1.5 mg was added. 96.7 % of patients received beta-blockers. All patients underwent: measurement of body weight and height, office levels of SBP, DBP and heart rate, daily BP monitoring, determination of pulse wave velocity in elastic (PWVe) and muscle arteries, central SBP, biochemical blood tests, electrocardiography, echocardiography with Doppler, measurement of ankle-brachial index, intima-media thickness (IMT). The duration of follow-up was 12 months.
Results and discussion. Treatment with a fixed dose combination of perindopril/amlodipine (in doses ranging from 5/5 to
10/10 mg/day) in patients with IHD and AH, which was not controlled in patients receiving beta-blockers and other antihypertensive drugs, provided achieving the target level of SBP and DBP in 76.7 % of cases within 6 weeks. Adding indapamide 1.5 mg daily (n = 7) provided office SBP and DBP control in 100 % of patients during 6 months of treatment. Reduction of office BP was associated with a significant decrease in average daily, day and night SBP/DBP by 20.70 ± 0.08 mmHg, 16.4 ± 0.2 mmHg, 25.1 ± 0.1 mmHg and 12.6 ± 0.1 mmHg, 14.10 ± 0.09 mmHg, 11.5 ± 0.1 mmHg, respectively. Target average daily BP (less than 130/80 mmHg) was achieved in 28 (93.3 %) patients. This reduced variability in day and night SBP/DBP, the average increase of morning SBP and the proportion of patients with morning increase in SBP over 55 mmHg.
Central SBP against the background of this treatment significantly decreased from 141.8 ± 3.5 mmHg to 121.3 ± 2.7 mmHg (P < 0.001). In parallel, there was a significant (P < 0.02) decrease in augmentation index from 29.9 ± 3.2 % to 20.1 ± 1.8 %. Therapy effective in terms of BP control during the year resulted in significant regression of target organ damage: reduced left ventricular hypertrophy, albuminuria level, IMT, improved left ventricular diastolic function and elastic properties of the aorta. Changes in albuminuria level and IMT reliably and regardless of BP changes (both office and central) correlated with changes in PWVe. Antihypertensive therapy was well tolerated by patients — among 31 patients, who received a fixed dose combination of perindopril/amlodipine, adverse events were reported in 3 (10 %), and treatment discontinuation was only in 1 (3.3 %) patient. During treatment, the number of patients with such complaints, as headaches, dizziness, pain in the heart, decreased from 60, 20 and 80 % to 3.3; 0 and 46.7 %, respectively. Among patients, who had angina at baseline, the number of angina attacks per week significantly decreased — from 2.5 ± 0.4 to 1.2 ± 0.2 (P < 0.01).


arterial hypertension; ischemic heart disease; target organs; fixed dose combination


Компендіум. Лікарські засоби / Під редакцією акад. В.М. Коваленка та проф. А.П. Вікторова. — К.: Моріон, 2010. — С. Л-219.

Методичні рекомендації Асоціації кардіологів України. Дисліпідемії: діагностика, профілактика та лікування. — К., 2011. — 49 с.

Радченко Г., Муштенко Л.О., Торбас О.О. та ін. Оцінка впливу фіксованої комбінації периндоприл + амлодипін на ураження органів-мішеней у пацієнтів з артеріальною гіпертензією (первинні результати дослідження EPHES) // Артеріальна гіпертензія. — 2015. — № 4. — С. 27-41.

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)// Journal of Hypertension. — 2013. — Vol. 31. — P. 1281-1357.

Balkestein E.J., Staessen J.A., Wang J.G. et al. Carotid and femoral artery stiffness in relation to three candidate genes in a white population // Hypertension. — 2001. — Vol. 38. — P. 1190-1197.

Barron A., Hughes A., Sharp A. et al. Long-Term Antihypertensive Treatment Fails to Improve E/e’ Despite Regression of Left Ventricular Mass An Anglo-Scandinavian Cardiac Outcomes Trial Substudy // Hypertension. — 2014. — Vol. 63. —

P. 252-258.

Bertrand M.E., Ferrari R., Remme W.J. et al. Clinical synergy of perindopril and calcium-channel blocker in the prevention of cardiac events and mortality in patients with coronary artery disease. Post hoc analysis of the EUROPA study // Am. Heart J. — 2010. — Vol. 159(5). — P. 795-802.

Bots M., Remme W., Luscher T. еt al. PERindopril — Function of the Endothelium in Coronary Artery Disease Trial: The PERFECT Study — SubStudy of EUROPA // Rationale and Design Cardiovascular Drugs and Therapy. — 2002. — Vol. 16. — P. 227-236.

Boutouyrie P., Bussy C., Tropeano A. et al. Local pulse pressure and regression of arterial wall hypertrophy during antihypertensive treatment. Celimene study. The celiprolol intima-media enalapril efficacy study // Archives des maladies du couer et des vaisseaux. — 2000. — Vol. 93. — P.911-915

Boutouyrie P., Bussy C., Lacolley P. et al. Assosiation between local pulse pressure, mean blood pressure and large-artery remodeling // Circulation. — 1999. — Vol. 100. — P. 1387-1393.

Ceconi C., Fox K.M., Remme W.J. et al. ACE inhibition with perindopril and biomarkers of atherosclerosis and thrombosis: results from the PERTINENT study // Atherosclerosis. — 2009. — Vol. 204. — P. 273-275.

Ceconi C., Fox K.M., Remme W.J. et al. ACE inhibition with perindopril and endothelial function. Results of a substudy of the EUROPA study: PERTINENT // Cardiovasc. Res. — 2007. — Vol. 73(1). — P. 237-246.

Covic A., Goldsmith D., Panaghiu L. et al. Analysis of the effect of hemodialysis on peripheral and central arterial pressure waveforms // Kidney Int. — 2000. — Vol. 57. — P. 2634-

Dahlof B., Devereux R., Kjeldsen S. еt al. for the LIFE Study Group. Cardiovascular morbidity and mortality in losartan interventional for endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol // Lancet. — 2002. — Vol. 359. — P. 995-1003.

Dahlöf 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 (ASCOT-BPLA): a multicentre randomised controlled trial // Lancet. — 2005. — Vol. 366(9489). — P. 895-906.

De Loach S.S., Townsend R.R. Vascular stiffness: its measurement and significance for epidemiologic and outcome studies // Clin. J. Am. Soc. Nephrol. — 2008. — Vol. 3(1). — P. 184-192.

de Luca N., Asmar R., London G. et al. Selective reduction of cardiac mass and central blood pressure on low-dose combination perindopril/indapamide in hypertensive subjects // J. Hypertens. — 2004. — Vol. 22. — P. 1623-1630.

Devereux R., Wachtell K., Gerdts E. et al. Prognostic significance of left ventricular mass change during treatment of hypertension // JAMA. — 2004. — Vol. 292(19). — P. 2350-2356

Dong I Shin, Ki-Bae Seung, Hye Eun Yoon, Byung-Hee Hwang et al. Microalbuminuria is Independently Associated with Arterial Stiffness and Vascular Inflammation but not with Carotid Intima-Media Thickness in Patients with Newly Diagnosed Type 2 Diabetes or Essential Hypertension // J. Korean Med. Sci. — 2013. — Vol. 28. — P. 252-260

Epstein M., Tobe S. What is the optimal strategy to intensify blood pressure control and prevent progression of renal disease? // Current Hypertension Reports. — 2001. — Vol. 3. — P. 422-428.

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. — 2015; DOI:10.1016/S0140-6736(15)01225-8.

Foppa M., Duncan B., Rohde L. Echocardiography-based left ventricular mass estimation. How should we define hypertrophy? // Cardiovasc. Ultrasound. — 2005. — Vol. 3. — P.17.

Gosse Ph., Sheridan D., Zannad F. et al. on behalf of the LIVE investigators. Regression of left ventricular hypertrophy in hypertensive patients treated with indapamide SR 1.5 mg versus enalapril 20 mg: the LIVE study // Journal of Hypertension. — 2000. — Vol. 18. — P. 1465-1475.

Ibsen H., Olsen M.H., Wachtell K. et al. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study // Hypertension. — 2005. — Vol. 45(2). — P. 198-202

Kamberi L.S., Bakalli A.B., Budima N.M. et al. Pleiotropic and Lipid-lowering Effects of Statins in Hypertension // Mater. Sociomed. — 2012. — Vol. 24 (2). — Р. 84-86.

Kario K., Pickering T., Umeda Y. et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study // Circulation. — 2003. — Vol. 18. — Vol. 107(10). — P. 1401-1416.

Klag M.J., Whelton P.K., Randall B.L. et al. Blood pressure and end-stage renal disease in men // N. Engl. J. Med. — 1996. — Vol. 334. — P. 13-18.

Kim B.J., Lee H.A., Kim N.H. et al. The association of albuminuria, arterial stiffness, and blood pressure status in nondiabetic, nonhypertensive individuals // J. Hypertens. — 2011. — Vol. 29(11). — P. 2091-2098.

La Rosa J.C., Grundy S.M., Waters D.D. et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease // N. Engl. J. Med. — 2005. — Vol. 352(14). — P. 1425-1435.

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. — Vol. 37. — P. 1236-1241.

Levey A., Stevens L., Schmid C. et al. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate // Ann. Intern. Med. — 2009. — Vol. 150 (9). — P. 604-612.

London G.M., Pannier B., Guerin A.P. et al. Cardiac hypertrophy, aortic compliance, peripheral resistance, and wave reflection in end-stage renal disease: comparative effects of ACE inhibition and calcium channel blockade // Circulation. — 1994. — Vol. 90. — P. 2786-2796.

Mahmud A., Feely J. Reduction in arterial stiffness with angiotensin II antagonist is comparable with and additive to ACE inhibition // Am. J. Hypertens. — 2002. — Vol. 15. — P. 321-325.

Mancia G., Carugo S., Grassi G. et al. Prevalence of Left Ventricular Hypertrophy in Hypertensive Patients Without and With Blood Pressure Control Data From the PAMELA Population // Hypertension. — 2002. — Vol. 39. — P. 744-749.

McEniery C., Yasmin, McDonnell B. et al. on behalf of the ACCT Investigators. Central pressure: variability and impact of cardiovascular risk factors. The anglo-cardiff collaborative trial II // Hypertension. — 2008. — Vol. 51. — P. 1476-1482.

Mogensen C.E., Viberti G., Halimi S. et al. Effect of low-dose perindopril/indapamide on albuminuria in diabetes: preterax in albuminuria regression: PREMIER // Hypertension. — 2003. — Vol. 41(5). — P. 1063-1071.

Мorgan T., Lauri J., Bertram D., Anderson A. Effect of different antihypertensive drug classes on central aortic pressure // Am. J. Hypertens. — 2004. — Vol. 17. — 118.

Moser M., Herbert P. Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials // J. Am. Coll. Cardiol. — 1996. — Vol. 27. — P. 1214-1218.

Nair S., Malik R., Khattar R. Carotid intima-media thickness: ultrasound measurement, prognostic value and role in clinical practice // Postgrad. Med. J. — 2012. — Vol. 88 (1046). — P. 694-699.

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. — Vol. 292. — P. 2217-2225.

Nissen S.E., Tuzcu E.M., Schoenhagen P. et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial // JAMA. — 2004. — Vol. 291(9). — P. 1071-1080.

Palmieri V. Reliability of echocardiographic assessment of left ventricular structure and function: the PRESERVE study. Prospective Randomised Study Evaluating Regression of Ventricular enlargement // J. Am. Coll. Cardiol. — 1999. — Vol. 34. — P. 1625-1632.

Pannier B.M., Guerin A.P., Marchais S.J., London G.M. Different aortic reflection wave responses following long-term angiotensin-converting enzyme inhibition and beta-blocker in essential hypertension // Clin. Exp. Pharmacol. Physiol. — 2001. — Vol. 28. — P. 1074-1077

Patel A.; ADVANCE Collaborative Group et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial // Lancet. — 2007. — Vol. 370. — P. 829-840.

Pitt B., Byington R., Furberg C. et al. Effect of Amlodipine on the Progression of Atherosclerosis and the Occurrence of Clinical Events // Circulation. — 2000. — Vol. 102. — P. 1503-1510.

Poulter N.R. A new dimension in hypertension management with the amlodipine/perindopril combination // J. Hypertens. — 2011. — Vol. 29, Suppl. 1. — S. 15-21.

Prospective Study Collaboration. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies // Lancet. — 2009. — Vol. 373. — P. 1083-1096.

Protogerou A., Blacher J., Stergiou G. et al. Blood Pressure Response Under Chronic Antihypertensive Drug Therapy The Role of Aortic Stiffness in the REASON (Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind) Study // Journal of the American College of Cardiology. — 2009. — Vol. 53. — P. 445-451.

Ritz E., Menne J., Haller H. Prevalence of microalbuminuria in type 2 diabetes: lessons learned from the ROADMAP study // Nephrol. Dial. Transplant. — 2012. — Vol. 27, Suppl. 4. — P. 28-30.

Roman M., Devereux R., Kizer J. et al. High Central Pulse Pressure Is Independently Associated With Adverse Cardiovascular Outcome The Strong Heart Study // J. Am. Coll. Cardiol. — 2009. — Vol. 54. — P. 1730-173.

Roman M., Okin P., Kizer J. et al. Relation of central and brachial blood pressure to left ventricular hypertrophy and geometry: the strong heart study // J. Hypertens. — 2010. — Vol. 28. — P. 384-388.

Rothwell P., Howard S.C., Dolan E. Et al. ASCOT-BPLA and MRC Trial Investigators Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension // Lancet. — 2010. — Vol. 375. — P. 895-905.

Ryotaro Bouchi, Tetsuya Babazono, Michino Mugishima et al. Arterial Stiffness Is Associated With Incident Albuminuria and Decreased Glomerular Filtration Rate in Type 2 Diabetic Patients // Diabetes Care. — 2011. — Vol. 34. — P. 2570-2575.

Safar M. Macro- and Microcirculation in Hypertension. — London: Lippincott Williams & Wilkins, 2005. — 151 p.

Sever P., Dahlöf B., Poulter N. et al. Potential synergy between lipid-lowering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac Outcomes Trial // Eur. Heart J. — 2006. — Vol. 27. — P. 2982-2988.

Smulyan H., Lieber A., Safar M.E. Hypertension, Diabetes Type II, and Their Association: Role of Arterial Stiffness // Am. J. Hypertens. — 2015. — Jul 8. pii: hpv107. [Epub ahead of print]

Stein J., Korcarz C., Hurst R. et al. American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography carotid intima-media thickness task force endorsed by the society of vascular medicine // J. Am. Society Echoc. — 2008. — Vol. 21 (2). — P. 93-111.

The CAFE Investigators, for the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Investigators CAFE Steering Committee and Writing Committee. 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. — Vol. 113. — P. 1213-1225

Tomiyama H., Kimura Y., Sakuma Y. et al. Effects of an ACE inhibitor and a calcium channel blocker on cardiovascular autonomic nervous system and carotid distensibility in patients with mild to moderate hypertension // Am. J. Hypertens. — 1998. — Vol. 11. — P. 682-689.

van den Meiracker Anton H., Mattace-Raso Francesco U.S. Large artery stiffness and microalbuminuria: a causal relationship? // Journal of Hypertension. — 2009 — Vol. 27 — P. 1355-1357.

Viberti G., Wheeldon N.M. MicroAlbuminuria Reduction with VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect // Circulation. — 2002. — Vol. 106(6). — P. 672-678.

Wang K., Cheng H., Chuang S. еt al. Central or peripheral systоlic or pulse pressure: which best related to target organs and future mortality? // J. Hypertens. — 2009. — Vol. 27. — P. 461-467.

White W. Blood pressure monitoring in Cardiovascular Medicine and Therapeutics. — N. Jersy: Humana Press, 2001. — P. 308.

Wohlfahrt P., Wichterle D., Seidlerova J. et al. Relation of central and brachial blood pressure to left ventricular hypertrophy: the czech post-monica study // J. Human Hypertens. — 2012. — Vol. 26. — P. 14-19.

Yusuf S., Hawken S., Ounpuu S., Dans T., Avezum A., Lanas F. et al., INTERHEART Study Investigators. Effect of potentiallymodifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study // Lancet. — 2004. — Vol. 364. — P. 937-952

Copyright (c) 2016 HYPERTENSION

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.


© Publishing House Zaslavsky, 1997-2018


   Seo анализ сайта