Consilium MedicumConsilium MedicumConsilium MedicumConsilium Medicum2075-17532542-2170Consilium Medicum9509910.26442/2075-1753_2018.10.72-78ArticlesСтатьиResearch ArticleTriple drug combinations in cardiologyТройные комбинации препаратов в кардиологииArutiunovA. GАрутюновАлександр Григорьевич

д-р мед. наук, проф. каф. пропедевтики внутренних болезней, общей физиотерапии и лучевой диагностики педиатрического фак-та

agarutyunov@mail.ruDragunovD. OДрагуновДмитрий Олегович

канд. мед. наук, доц. каф. пропедевтики внутренних болезней, общей физиотерапии и лучевой диагностики педиатрического фак-та, зав. организационно-методическим отд. по терапии

SokolovaA. VСоколоваАнна Викторовна

канд. мед. наук, ассистент каф. пропедевтики внутренних болезней, общей физиотерапии и лучевой диагностики педиатрического фак-та, вед. специалист организационно-методического отд. по терапии

N.I.Pirogov Russian National Research Medical University of the Ministry of Health of the Russian FederationФГБОУ ВО «РНИМУ им. Н.И.Пирогова»N.I.Pirogov Russian National Research Medical University of the Ministry of Health of the Russian FederationФГБОУ ВО «РНИМУ им. Н.И.Пирогова», ГБУ НИИОЗММResearch Institute of Health Organization and Medical Management of the Department of Health of MoscowФГБОУ ВО «РНИМУ им. Н.И.Пирогова», ГБУ НИИОЗММN.I.Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation151020182010VOL 20, NO10 (2018)ТОМ 20, №10 (2018)727828122021Copyright ©; 2018, Consilium MedicumCopyright ©; 2018, ООО "Консилиум Медикум"2018Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://consilium.orscience.ru/2075-1753/article/view/95099

At present cardiac medications occupy an important place among polypills. According to European Society of Hypertension and European Society of Cardiology 2013 guidelines on hypertension treatment either free or fixed (preferable) combinations of two, three or more antihypertensive drugs are applicable at present. It should be noted that fixed combination has some advantages compared to a free one, especially in patients' compliance, that in its turn will contribute to cardiovascular risk reduction. It allows to reach target blood pressure (BP) level, has simple administration, dose titration and dosage regimen, and eliminates the risk of irrational combinations use. Also counter-regulatory mechanisms blockade is quite important: when fixed combination of drugs of different groups is used these medications can compensate adverse effects of each other, for example reduce edema that develops secondary when calcium channel blocking agents are used. Dosage regimen and titration are key stages in clinical practice. Fixed combination amlodipine + indapamide + perindopril has the greatest "flexibility" among triple fixed combinations. Advances of triple combination amlodipine + indapamide + perindopril use were studied in many randomized controlled trials. ADVANCE trial demonstrated effectiveness of triple fixed combinations use in all-cause mortality decrease of 14%, as well as cardiovascular mortality decrease of 28% compared with 5% in patients who received double therapy (р=0.02). PIANIST study showed high treatment compliance and effective BP reduction: target BP was reached in 72% of patients. Therefore, a lot of various polypills exist at present that allows clinicians to increase therapy effectiveness with the use of rational drug combinations and patients' compliance increase.

На сегодняшний день значительное место среди полипилов занимают кардиологические препараты. Согласно действующим рекомендациям по лечению артериальной гипертонии Европейского общества по артериальной гипертонии/Европейского общества кардиологов 2013 г. на сегодняшний день возможны двух-, трех- и более компонентные комбинации гипотензивных препаратов, как в свободной, так и фиксированной (предпочтительнее) комбинации. Стоит отметить преимущества фиксированной комбинации над свободной, особенно в разделе комплаентности пациента, что, в свою очередь, позволит снизить сердечно-сосудистый риск: достижение целевых цифр артериального давления (АД), простота назначения, простота титрации дозы и соблюдения режима приема препарата, исключение нерациональных комбинаций. Также немаловажным является блокада контррегуляторных механизмов: так, при назначении фиксированной комбинации препаратов разных классов они могут компенсировать побочные реакции друг друга, например вызвать уменьшение отеков, возникающих вторично при назначении блокаторов медленных кальциевых каналов. Одним из ключевых этапов в клинической практике является режим дозирования и титрации препарата. Наибольшая «гибкость» фиксированных тройных комбинаций - у комбинации амлодипин + индапамид + периндоприл. Преимущества тройной комбинации амлодипин + индапамид + периндоприл были изучены во многих рандомизированных контролируемых исследованиях. Исследование ADVANCE демонстрирует эффективность применения фиксированной тройной комбинации в отношении снижения смертности от всех причин на 14%, а также снижения сердечно-сосудистой смертности на 28% по сравнению с 5% у пациентов, находившихся на двойной терапии (р=0,02). Исследование PIANIST демонстрирует приверженность лечению и эффективное снижение АД: целевого уровня АД достигли 72% пациентов. Таким образом, на сегодняшний день существует множество разнообразных полипилов, позволяющих клиницисту увеличить эффективность терапии за счет абсолютно рациональных комбинаций препаратов и повышения приверженности пациента лечению.

combination therapyarterial hypertensioncardiovascular riskpolypillкомбинированная терапияартериальная гипертониясердечно-сосудистый рискполипилыCook N.R et al. Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Ann Intern Med 2013; 159 (2): 77-85.Burn J et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet Lond Engl 2011; 378 (9809): 2081-7.Bibbins-Domingo K, U.S. Preventive Services Task Force. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2016; 164 (12): 836-45.Selak V, Webster R. Polypills for the secondary prevention of cardiovascular disease: effective in improving adherence but are they safe? Ther Adv Drug Saf 2018; 9 (2): 157-62.Thom S et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA 2013; 310 (9): 918-29.Patel A et al. A pragmatic randomized trial of a polypill-based strategy to improve use of indicated preventive treatments in people at high cardiovascular disease risk. Eur J Prev Cardiol 2015; 22 (7): 920-30.Selak V et al. Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: randomised controlled trial in primary care. BMJ 2014; 348: g3318.Castellano J.M et al. A polypill strategy to improve adherence: results from the FOCUS project. J Am Coll Cardiol 2014; 64 (20): 2071-82.Webster R et al. Effectiveness of fixed dose combination medication ('polypills’) compared with usual care in patients with cardiovascular disease or at high risk: A prospective, individual patient data meta-analysis of 3140 patients in six countries. Int J Cardiol 2016; 205: 147-56.Cushman W.C, Goff D.C. More HOPE for Prevention with Statins. N Engl J Med 2016; 374 (21): 2085-7.Webster R, Castellano J.M, Onuma O.K. Putting polypills into practice: challenges and lessons learned. Lancet 2017; 389 (10073): 1066-74.Wald N.J, Law M.R. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326 (7404): 1419.Athyros V.G et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010; 376 (9756): 1916-22.Karlson B.W et al. Comparison of the effects of different statins and doses on lipid levels in patients with diabetes: results from VOYAGER. Nutr Metab Cardiovasc Dis 2012; 22 (9): 697-703.Writing Group Members et al. Heart Disease and Stroke Statistics - 2012 Update: A Report From the American Heart Association. Circulation 2012; 125 (1): e2-e220.Филиппов Е.В., Якушин С.С. Распространенность и особенности ведения больных артериальной гипертонией с различным риском сердечно-сосудистых осложнений (по данным исследования МЕРИДИАН-РО). Мед. совет. 2013; 9.Итоги реализации Федеральной целевой программы по профилактике и лечению артериальной гипертензии в России в 2002-2012 гг.Результаты реализации программы по борьбе с артериальной гипертонией в России в 2002-2012 годах (реферат). Терапевт. арх. 2013; 1.Bramlage P et al. A global perspective on blood pressure treatment and control in a referred cohort of hypertensive patients. J Clin Hypertens Greenwich Conn 2010; 12 (9): 666-77.Böhm M et al. Association of cardiovascular risk factors with microalbuminuria in hypertensive individuals: the i-SEARCH global study. J Hypertens 2007; 25 (11): 2317.Шальнова С.А. и др. Артериальная гипертония: распространенность, осведомленность, прием антигипертензивных препаратов и эффективность лечения среди населения Российской Федерации. Рос. кардиол. журн. 2017; 4: 45-50.Pruijm M.T, Maillard M.P, Burnier M. Patient adherence and the choice of antihypertensive drugs: focus on lercanidipine. Vasc Health Risk Manag 2008; 4 (6): 1159-66.Ambrosioni E et al. Patterns of hypertension management in Italy: results of a pharmacoepidemiological survey on antihypertensive therapy. Scientific Committee of the Italian Pharmacoepidemiological Survey on Antihypertensive Therapy. J Hypertens 2000; 18 (11): 1691-9.Vrijens B et al. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ 2008; 336 (7653): 1114-7.Frank J. Managing hypertension using combination therapy. Am Fam Physician 2008; 77 (9): 1279-86.Mancia G et al. Рекомендации по лечению артериальной гипертонии. ESH/ESC 2013. Рос. кардиол. журн. 2015; 1: 7-94.Egan B.M et al. Initial monotherapy and combination therapy and hypertension control the first year. Hypertens 2012; 59 (6): 1124-31.Kjeldsen S.E et al. Are fixed-dose combination antihypertensives suitable as first-line therapy? Curr Med Res Opin 2012; 28 (10): 1685-97.Ram CVS Fixed-dose triple-combination treatments in the management of hypertension. Manag Care Langhorne Pa 2013; 22 (12): 45-55.Hypertension Management: Rationale for Triple Therapy Based on Mechanisms of Action - Neutel - 2013 - Cardiovascular Therapeutics - Wiley Online Library. http://onlinelibrary.wiley.com/doi/10.1111/1755-5922.12015/abstractWhelton P.K et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA 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. Hypertension 2017; HYP.0000000000000065.Gradman A.H. Rationale for Triple-Combination Therapy for Management of High Blood Pressure. J Clin Hypertens 2010; 12 (11): 869-78.Van Vark L.C et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients. Eur Heart J 2012; 33 (16): 2088-97.Ruschitzka F, Taddei S. Angiotensin-converting enzyme inhibitors: first-line agents in cardiovascular protection? Eur Heart J 2012; 33 (16): 1996-8.Ruggenenti P, Aros C, Remuzzi G. Renin-angiotensin system, proteinuria, and tubulointerstitial damage. Contrib Nephrol 2001; 135: 187-99.Manotham K et al. Evidence of tubular hypoxia in the early phase in the remnant kidney model. J Am Soc Nephrol 2004; 15 (5): 1277-88.Investigators T.H.O.P.E.S. Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients. N Engl J Med 2000; 342 (3): 145-53.Shudo C et al. Effects of efonidipine, nicardipine and captopril on proteinuria in aged spontaneously hypertensive rats. Arzneimittelforschung 1996; 46 (9): 852-4.Patel A 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 Lond Engl 2007; 370 (9590): 829-40.Slíva J. The current position of hydrochlorothiazide among thiazide and thiazide-like diuretics. Vnitr Lek 2018; 64 (1): 83-5.Преображенский Д.В., Сидоренко Б.А., Маренич А.В., Шатунова И.М. Диуретики в лечении артериальной гипертензии: место гидрохлортиазида. Артериальные гипертензии. 2005Kaplan N.M et al. Potassium supplementation in hypertensive patients with diuretic-induced hypokalemia. N Engl J Med 1985; 312 (12): 746-9.Ganado P et al. Growth inhibitory activity of indapamide on vascular smooth muscle cells. Eur J Pharmacol 2001; 428 (1): 19-27.Sassard J, Bataillard A, McIntyre H. An overview of the pharmacology and clinical efficacy of indapamide sustained release. Fundam Clin Pharmacol 2005; 19 (6): 637-45.Глезер М.Г. Результаты программы «Базовое лечение и антигипертензивный эффект: препарат Равел СР у пациентов с артериальной гипертонией» (БОЛЕРО). Гендерные аспекты. Проблемы женского здоровья. 2007; 2 (3): 5-13.Roush G.C et al. Hydrochlorothiazide and alternative diuretics versus renin-angiotensin system inhibitors for the regression of left ventricular hypertrophy: a head-to-head meta-analysis. J Hypertens 2018.Wang S et al. Comparison between the effects of hydrochlorothiazide and indapamide on the kidney in hypertensive patients inadequately controlled with losartan. J Hum Hypertens 2017; 31 (12): 848-54.Lévy B.I, Taddei S. Vascular legacy beyond blood pressure control: benefits of perindopril/indapamide combination in hypertensive patients with diabetes. Curr Med Res Opin 2018; p. 1-14.Glezer On Behalf Of The Forsage Program Participants M.G. Adherence of Patients to Antihypertensive Therapy With Combination of Perindopril and Indapamide According to Data of the FORSAGE Program. Kardiologiia 2017; 57 (4): 33-7.Hanon O et al. Treatment of Hypertensive Patients With Diabetes and Microalbuminuria With Combination Indapamide SR/Amlodipine: Retrospective Analysis of NESTOR. Am J Hypertens 2015; 28 (8): 1064-71.Tkachyeva O.N, Kotovskaya Y.V, Dudinskaya E.N. Indapamide SR/Amlodipine Fixed Dose Combination: Novel Approach to Effective Control of Systolic Arterial Pressure. Kardiologiia 2017; 57 (11): 76-83.Okamura K et al. Prospective direct comparison of antihypertensive effect and safety between high-dose amlodipine or indapamide in hypertensive patients uncontrolled by standard doses of angiotensin receptor blockers and amlodipine. Clin Exp Hypertens 2018; 40 (2): 99-106.Kobalava D.Z, Shavarova K.E. Clinical Features of Arterial Hypertension in the Elderly and Senile Age and the Rationale for Using the Combination of Amlodipine/Indapamide-retard. Kardiologiia 2017; 57 (8): 60-70.Akram J et al. Antihypertensive efficacy of indapamide SR in hypertensive patients uncontrolled with a background therapy: the NATIVE study. Curr Med Res Opin 2007; 23 (12): 2929-36.Waeber B, Rotaru C, Feihl F. Position of indapamide, a diuretic with vasorelaxant activities, in antihypertensive therapy. Expert Opin Pharmacother 2012; 13 (10): 1515-26.Baguet J.P et al. Updated meta-analytical approach to the efficacy of antihypertensive drugs in reducing blood pressure. Clin Drug Investig 2007; 27 (11): 735-53.Ambrosioni E et al. Low-dose antihypertensive therapy with 1.5 mg sustained-release indapamide: results of randomised double-blind controlled studies. European study group. J Hypertens 1998; 16 (11): 1677-84.Tóth K, PIANIST Investigators. Antihypertensive efficacy of triple combination perindopril/indapamide plus amlodipine in high-risk hypertensives: results of the PIANIST study (Perindopril-Indapamide plus AmlodipiNe in high rISk hyperTensive patients). Am J Cardiovasc Drugs Drugs Devices Interv 2014; 14 (2): 137-45.Páll D, Szántó I, Szabó Z. Triple combination therapy in hypertension: the antihypertensive efficacy of treatment with perindopril, amlodipine, and indapamide SR. Clin Drug Investig 2014; 34 (10): 701-8.Skibitsky V.V, Fendrikova A.V, Skibitsky A.V. Efficiency of triple antihypertensive therapy in patients with uncontrolled hypertension and depressive disorders. Ter Arkh 2017; 89 (8): 22-8.