cardiovascularКардиоваскулярная терапия и профилактикаCardiovascular Therapy and Prevention1728-88002619-0125«SILICEA-POLIGRAF» LLCcardiovascular-2003Research ArticleОБЗОРЫREVIEWSТерапия блокаторами рецепторов ангиотензина и кардиоваскулярная протекция. Современная доказательная база и перспективы развитияUse of angiotensin receptor blockers in cardiovascular protection. Current evidence and future directionsМунгерМ. А.MungerM. A.

Солт-Лейк Сити

Фармацевтический колледж Университета ЮтыCollege of Pharmacy of the University of Utah in Salt Lake City, Utah20110101197010793104Copyright © Мунгер М.А., 19701970Мунгер М.А.Munger M.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cardiovascular.elpub.ru/jour/article/view/2003

Цель. Дифференцировать блокаторы рецепторов ангиотензина (БРА) по степени выраженности сосудистых эффектов и влиянию на клинические исходы, регистрируемые в исследованиях кардиопротективного действия этих препаратов. Источники информации. Поиск информации происходил в период с 01.2003г по 03.2009г с помощью системы MEDLINE и с использованием следующих поисковых терминов: блокада или ингибирование ренин-ангиотензин-альдостероновой системы (РААС); БРА; кардиопротекция; вазопротекция; защита органов-мишеней; кандесартан; эпросартан; ирбесартан; лозартан; олмесартан; телмисартан; валсартан. Поиск клинических исследований в фазах продолжающегося наблюдения либо набора участников выполнялся с помощью сайта Clinicaltrials.gov (07.2008г). Отбор исследований и обобщение данных. В настоящий обзор вошли соответствующие критериям включения результаты экспериментальных и клинических исследований с сердечно-сосудистыми конечными точками, а также результаты научных обзоров, статистические данные Американской ассоциации кардиологов за 2009г и рекомендации Седьмого доклада Объединенного Национального Комитета по профилактике, диагностике и лечению повышенного артериального давления. Обобщение данных. БРА различаются по своим плейотропным вазопротективным эффектам и фармакокинетическим свойствам, которые лежат в основе фармакологической защиты в отношении сердечнососудистой заболеваемости и смертности и не зависят от антигипертензивного действия этих препаратов. Заключение. Постоянно растущая доказательная база свидетельствует об эффективности БРА при артериальной гипертензии, гипертрофии левого желудочка, сердечной недостаточности и после перенесенного инфаркта миокарда. В будущих исследованиях предстоит уточнить, в какой степени эти благоприятные клинические эффекты БРА обусловлены их плейотропным действием, не зависящим от антигипертензивной активности. Для дифференцирования БРА по их клиническим эффектам необходимо выполнение тщательно спланированных исследований сравнительной эффективности отдельных представителей этого класса препаратов. В будущем будут созданы многофункциональные БРА, фармакологическое действие которых не будет ограничиваться блокадой рецепторов ангиотензина I типа (AT1).

Aim

Aim. To differentiate angiotensin II receptor blockers (ARBs) by vascular effects and outcomes in trials on cardioprotective endpoints. Data sources. MEDLINE searches were conducted from January 2003 to March 2009 using the following search terms: renin-angiotensin-aldosterone system (RAAS) blockade or inhibition; angiotensin II receptor blocker (ARBs); cardioprotection; vascular protection; end-organ protection; candesartan; eprosartan, irbesartan; losartan; olmesartan; telmisartan; and valsartan. Ongoing and recruiting clinical trials were identified via Clinicaltrials.gov (July 2008). Study selection and data abstraction. Pertinent basic science research and clinical trials with cardiovascular endpoints and information from reviews, American Heart Association 2009 statistics, and The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines were included in this review.

Data Synthesis

Data Synthesis. ARBs differ in their vascular protective pleiotropic effects and pharmacokinetic properties, which may contribute to their pharmacological protection to reduce cardiovascular morbidity and mortality, independently of their blood pressure (BP)-lowering effects. Conclusion. Emerging data show that ARBs are effective in hypertension, left ventricular hypertrophy, postmyocardial infarction, and heart failure. To what extent their pleiotropic effects, independent of BP lowering, contribute to these outcomes will be the focus of research in the coming years. Well-designed, comparativeeffectiveness studies are needed to clinically differentiate this class of agents. The future will be marked by multifunctional ARBs that will pharmacologically do more than antagonize the angiotensin type I (AT1) receptor.

Фибрилляция предсердийкандесартансердечно-сосудистые заболеваниякардиопротекциязащита органов-мишенейэпросартансердечная недостаточностьартериальная гипертензиявысокое артериальное давлениеирбесартанлозартанолмесартанренин-ангиотензин-альдостероновая системателмисартанвалсартанвазопротекцияAtrial fibrillationcandesartancardiovascular diseasecardioprotectionend-organ protectioneprosartanheart failurehypertensionhigh blood pressureirbesartanlosartanolmesartanrenin-angiotensinaldosterone system (RAAS)telmisartanvalsartanvascular protectionReferencesLloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics—2009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009; 119: 480-6.Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics—2009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009; 119: 480-6.Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42: 1206-52.Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42: 1206-52.Heran BS, Wong MM, Heran IK. Blood pressure lowering efficacy of angiotensin receptor blockers for primary hypertension. Cochrane Database Syst Rev 2008; 4: CD003822.Heran BS, Wong MM, Heran IK. Blood pressure lowering efficacy of angiotensin receptor blockers for primary hypertension. Cochrane Database Syst Rev 2008; 4: CD003822.Smith DH. Comparison of angiotensin II type 1 receptor antagonists in the treatment of essential hypertension. Drugs 2008; 68: 1207-25.Smith DH. Comparison of angiotensin II type 1 receptor antagonists in the treatment of essential hypertension. Drugs 2008; 68: 1207-25.Dzau VJ. Theodore Cooper Lecture: Tissue angiotensin and patho-biology of vascular disease: a unifying hypothesis. Hypertension 2001; 37: 1047-52.Dzau VJ. Theodore Cooper Lecture: Tissue angiotensin and patho-biology of vascular disease: a unifying hypothesis. Hypertension 2001; 37: 1047-52.Lemarie CA, Paradis P, Schiffrin EL. New insights on signaling cascades induced by cross-talk between angiotensin II and aldosterone. J Mol Med 2008; 86: 673-8.Lemarie CA, Paradis P, Schiffrin EL. New insights on signaling cascades induced by cross-talk between angiotensin II and aldosterone. J Mol Med 2008; 86: 673-8.Furuhashi M, Ura N, Takizawa H, et al. Blockade of the reninangiotensin system decreases adipocyte size with improvement in insulin sensitivity. JHypertens 2004; 22: 1977-82.Furuhashi M, Ura N, Takizawa H, et al. Blockade of the reninangiotensin system decreases adipocyte size with improvement in insulin sensitivity. JHypertens 2004; 22: 1977-82.Jandeleit-Dahm KA, Tikellis C, Reid CM, et al. Why blockade of the renin-angiotensin system reduces the incidence of newonset diabetes. J Hypertens 2005; 23: 463-73.Jandeleit-Dahm KA, Tikellis C, Reid CM, et al. Why blockade of the renin-angiotensin system reduces the incidence of newonset diabetes. J Hypertens 2005; 23: 463-73.Kingston R. Blockade of the renin-angiotensin system decreases adipocyte size with improvement in insulin sensitivity. J Hypertens 2004; 22: 1867-8.Kingston R. Blockade of the renin-angiotensin system decreases adipocyte size with improvement in insulin sensitivity. J Hypertens 2004; 22: 1867-8.Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med 1996; 334: 1649-54.Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med 1996; 334: 1649-54.Britten MB, Zeiher AM, Schachinger V. Clinical importance of coronary endothelial vasodilator dysfunction and therapeutic options. J Intern Med 1999; 245: 315-27.Britten MB, Zeiher AM, Schachinger V. Clinical importance of coronary endothelial vasodilator dysfunction and therapeutic options. J Intern Med 1999; 245: 315-27.Zaman MA, Oparil S, Calhoun DA. Drugs targeting the reninangiotensin-aldosterone system. Nat Rev Drug Discov 2002; 1: 621-36.Zaman MA, Oparil S, Calhoun DA. Drugs targeting the reninangiotensin-aldosterone system. Nat Rev Drug Discov 2002; 1: 621-36.Barra S, Vitagliano A, Cuomo V, et al. Vascular and metabolic effects of angiotensin II receptor blockers. Exp Opin Pharmacother 2009; 10: 173-89.Barra S, Vitagliano A, Cuomo V, et al. Vascular and metabolic effects of angiotensin II receptor blockers. Exp Opin Pharmacother 2009; 10: 173-89.McConnaughey MM, McConnaughey S, Ingenito A. Practical considerations of the pharmacology of angiotensin receptor blockers. J Clin Pharmacol 1999; 39: 547-59.McConnaughey MM, McConnaughey S, Ingenito A. Practical considerations of the pharmacology of angiotensin receptor blockers. J Clin Pharmacol 1999; 39: 547-59.Kakuta H, Sudoh K, Sasamata M, et al. Telmisartan has the strongest binding affinity to angiotensin II type 1 receptor: Comparison with other angiotensin II type 1 receptor blockers. Int J Clin Pharmacol Res 2005; 25: 41-6.Kakuta H, Sudoh K, Sasamata M, et al. Telmisartan has the strongest binding affinity to angiotensin II type 1 receptor: Comparison with other angiotensin II type 1 receptor blockers. Int J Clin Pharmacol Res 2005; 25: 41-6.Maillard MP, Perregaux C, Centeno C, et al. In vitro and in vivo characterization of the activity of telmisartan: An insurmountable angiotensin II receptor antagonist. J Pharmacol Exp Ther 2002; 302: 1089-95.Maillard MP, Perregaux C, Centeno C, et al. In vitro and in vivo characterization of the activity of telmisartan: An insurmountable angiotensin II receptor antagonist. J Pharmacol Exp Ther 2002; 302: 1089-95.Miura S, Fujino M, Hanzawa H, et al. Molecular mechanism underlying inverse agonist of angiotensin II type 1 receptor. J Biol Chem 2006; 281: 19288-95.Miura S, Fujino M, Hanzawa H, et al. Molecular mechanism underlying inverse agonist of angiotensin II type 1 receptor. J Biol Chem 2006; 281: 19288-95.Miura S, Kiya Y, Kanazawa T, et al. Differential bonding interactions of inverse agonists of angiotensin II type 1 receptor in stabilizing the inactive state. Mol Endocrinol 2008; 22: 139-46.Miura S, Kiya Y, Kanazawa T, et al. Differential bonding interactions of inverse agonists of angiotensin II type 1 receptor in stabilizing the inactive state. Mol Endocrinol 2008; 22: 139-46.Zou Y, Akazawa H, Qin Y, et al. Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II. Nat Cell Biol 2004; 6: 499-506.Zou Y, Akazawa H, Qin Y, et al. Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II. Nat Cell Biol 2004; 6: 499-506.Catt KJ, Mendelsohn FA, Millan MA, et al. The role of angiotensin II receptors in vascular regulation. J Cardiovasc Pharmacol 1984; 6(Suppl 4): S575-86.Catt KJ, Mendelsohn FA, Millan MA, et al. The role of angiotensin II receptors in vascular regulation. J Cardiovasc Pharmacol 1984; 6(Suppl 4): S575-86.D’Amore A, Black MJ, Thomas WG. The angiotensin II type 2 receptor causes constitutive growth of cardiomyocytes and does not antagonize angiotensin II type 1 receptor-mediated hypertrophy. Hypertension 2005; 46: 1347-54.D’Amore A, Black MJ, Thomas WG. The angiotensin II type 2 receptor causes constitutive growth of cardiomyocytes and does not antagonize angiotensin II type 1 receptor-mediated hypertrophy. Hypertension 2005; 46: 1347-54.Bragulat E, Larousse M, Coca A, et al. Effect of long-term irbesartan treatment on endothelium-dependent vasodilation in essential hypertensive patients. Br J Biomed Sci 2003; 60: 191-6.Bragulat E, Larousse M, Coca A, et al. Effect of long-term irbesartan treatment on endothelium-dependent vasodilation in essential hypertensive patients. Br J Biomed Sci 2003; 60: 191-6.Benndorf RA, Appel D, Maas R, et al. Telmisartan improves endothelial function in patients with essential hypertension. J Cardiovasc Pharmacol 2007; 50: 367-71.Benndorf RA, Appel D, Maas R, et al. Telmisartan improves endothelial function in patients with essential hypertension. J Cardiovasc Pharmacol 2007; 50: 367-71.Ceriello A, Assaloni R, Da Ros R, et al. Effect of atorvostatin and irbesartan, alone and in combination, on post-prandial endothelial dysfunction, oxidative stress, and inflammation in type 2 diabetic patients. Circulation 2005; 111: 2518-24.Ceriello A, Assaloni R, Da Ros R, et al. Effect of atorvostatin and irbesartan, alone and in combination, on post-prandial endothelial dysfunction, oxidative stress, and inflammation in type 2 diabetic patients. Circulation 2005; 111: 2518-24.Nakayama S, Watada H, Mita T, et al. Comparison of effects of olmesartan and telmisartan on blood pressure and metabolic parameters in Japanese early-stage type-2 diabetes with hypertension. Hypertens Res 2008; 31(1): 7-13.Nakayama S, Watada H, Mita T, et al. Comparison of effects of olmesartan and telmisartan on blood pressure and metabolic parameters in Japanese early-stage type-2 diabetes with hypertension. Hypertens Res 2008; 31(1): 7-13.Navalkar S, Pathasarathy S, Santanam N, Khan BV. Irbesartan, an angiotensin type receptor inhibitor, regulates markers of inflammation in patients with premature atherosclerosis. J Am Coll Cardiol 2001; 37: 440-4.Navalkar S, Pathasarathy S, Santanam N, Khan BV. Irbesartan, an angiotensin type receptor inhibitor, regulates markers of inflammation in patients with premature atherosclerosis. J Am Coll Cardiol 2001; 37: 440-4.Bahlmann FH, De Groot K, Mueller O, et al. Stimulation of endothelial progenitor cells: A new putative therapeutic effect of angiotensin II receptor antagonists. Hypertension 2005; 45: 526-9.Bahlmann FH, De Groot K, Mueller O, et al. Stimulation of endothelial progenitor cells: A new putative therapeutic effect of angiotensin II receptor antagonists. Hypertension 2005; 45: 526-9.Tomiyama H, Yamada J, Koji Y, et al. Effect of telmisartan on forearm postischemic hyperemia and serum asymmetric dimethyl- arginine levels. Am J Hypertens 2007; 20: 1305-11.Tomiyama H, Yamada J, Koji Y, et al. Effect of telmisartan on forearm postischemic hyperemia and serum asymmetric dimethyl- arginine levels. Am J Hypertens 2007; 20: 1305-11.Bian C, Wu Y, Chen P. Telmisartan increases the permeability of endothelial cells through zonula occludens-1. Biol Pharm Bull 2009; 32: 416-20.Bian C, Wu Y, Chen P. Telmisartan increases the permeability of endothelial cells through zonula occludens-1. Biol Pharm Bull 2009; 32: 416-20.Ogawa S, Mori T, Nako K, et al. Angiotensin II type 1 receptor blockers reduce urinary oxidative stress markers in hypertensive diabetic nephropathy. Hypertension 2006; 47: 699-705.Ogawa S, Mori T, Nako K, et al. Angiotensin II type 1 receptor blockers reduce urinary oxidative stress markers in hypertensive diabetic nephropathy. Hypertension 2006; 47: 699-705.Cianchetti S, Del Fiorentino A, Colognato R, et al. Anti-inflammatory and antioxidant properties of telmisartan in cultured human umbilical vein endothelial cells. Atherosclerosis 2008; 198: 22-8.Cianchetti S, Del Fiorentino A, Colognato R, et al. Anti-inflammatory and antioxidant properties of telmisartan in cultured human umbilical vein endothelial cells. Atherosclerosis 2008; 198: 22-8.Takai S, Kirimura K, Jin D, et al. Significance of angiotensin II receptor blocker lipophillicities and their protective effect against vascular remodeling. Hypertens Res 2005; 28: 593-600.Takai S, Kirimura K, Jin D, et al. Significance of angiotensin II receptor blocker lipophillicities and their protective effect against vascular remodeling. Hypertens Res 2005; 28: 593-600.Guerra-Cuesta JI, Monton M, Rodriguez-Feo JA, et al. Effect of losartan on human platelet activation. J Hypertens 1999; 17: 447-52.Guerra-Cuesta JI, Monton M, Rodriguez-Feo JA, et al. Effect of losartan on human platelet activation. J Hypertens 1999; 17: 447-52.Sato Y, Fujii S, Imagawa S, et al. Platelet aggregability in patients with hypertension treated with angiotensin II type 1 receptor blockers. J Atheroscler Thromb 2007; 14: 31-5.Sato Y, Fujii S, Imagawa S, et al. Platelet aggregability in patients with hypertension treated with angiotensin II type 1 receptor blockers. J Atheroscler Thromb 2007; 14: 31-5.Monton M, Jimenez A, Nunez A, et al. Comparative effects of angiotensin II AT-1-type receptor antagonists in vitro on human platelet activation. J Cardiovasc Pharmacol 2000; 35: 906-13.Monton M, Jimenez A, Nunez A, et al. Comparative effects of angiotensin II AT-1-type receptor antagonists in vitro on human platelet activation. J Cardiovasc Pharmacol 2000; 35: 906-13.Jimenez A, Monton M, Garcia R, et al. Inhibition of platelet activation in stroke-prone spontaneously hypertensive rats: Comparison of losartan, candesartan, and valsartan. J Cardiovasc Pharmacol 2001; 37: 406-12.Jimenez A, Monton M, Garcia R, et al. Inhibition of platelet activation in stroke-prone spontaneously hypertensive rats: Comparison of losartan, candesartan, and valsartan. J Cardiovasc Pharmacol 2001; 37: 406-12.McDonald KM, Garr M, Carlyle PF, et al. Relative effects of a1-adrenergic blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog. Circulation 1994; 90: 3034-46.McDonald KM, Garr M, Carlyle PF, et al. Relative effects of a1-adrenergic blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog. Circulation 1994; 90: 3034-46.Pourdjabbar A, Parker TG, Nguyen QT, et al. Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: Effect of dose on survival, ventricular arrhythmias, function and remodeling. Am J Physiol Heart Circ Physiol 2005; 288: H1997-2005.Pourdjabbar A, Parker TG, Nguyen QT, et al. Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: Effect of dose on survival, ventricular arrhythmias, function and remodeling. Am J Physiol Heart Circ Physiol 2005; 288: H1997-2005.Sawicki G, Menon V, Jugdutt BI. Improved balance between TIMP-3 and MMP-9 after regional myocardial ischemia-reperfusion during AI receptor blockade. J Cardiac Fail 2004; 10: 442-9.Sawicki G, Menon V, Jugdutt BI. Improved balance between TIMP-3 and MMP-9 after regional myocardial ischemia-reperfusion during AI receptor blockade. J Cardiac Fail 2004; 10: 442-9.Konstam MA, Patten RD, Thomas I, et al. Effects of losartan and captopril on left ventricular volumes in elderly patients with heart failure. Results of the ELITE ventricular function substudy. Am Heart J 2000; 139: 1081-7.Konstam MA, Patten RD, Thomas I, et al. Effects of losartan and captopril on left ventricular volumes in elderly patients with heart failure. Results of the ELITE ventricular function substudy. Am Heart J 2000; 139: 1081-7.Solomon SD, Skali H, Anavekar NS, et al. Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction. Circulation 2005; 111: 3411-9.Solomon SD, Skali H, Anavekar NS, et al. Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction. Circulation 2005; 111: 3411-9.Iwanaga T, Sato M, Maeda T, et al. Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter. J Pharmacol Exp Ther 2007; 320: 211-7.Iwanaga T, Sato M, Maeda T, et al. Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter. J Pharmacol Exp Ther 2007; 320: 211-7.Benson SC, Pershadsingh HA, Ho CI, et al. Identification of telmi- sartan as a unique angiotensin II receptor antagonist with selective PPAR-gamma-modulating activity. Hypertension 2004; 43: 993-1002.Benson SC, Pershadsingh HA, Ho CI, et al. Identification of telmi- sartan as a unique angiotensin II receptor antagonist with selective PPAR-gamma-modulating activity. Hypertension 2004; 43: 993-1002.Schupp M, Clemenz M, Gineste R, et al. Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity. Diabetes 2005; 54: 3442-52.Schupp M, Clemenz M, Gineste R, et al. Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity. Diabetes 2005; 54: 3442-52.Schupp M, Janke J, Clasen R, et al. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptorgamma activity. Circulation 2004; 109: 2054-7.Schupp M, Janke J, Clasen R, et al. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptorgamma activity. Circulation 2004; 109: 2054-7.Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood pressure-lowering drugs: Results of prospectively designed overviews of randomized trials. Blood Pressure Lowering Treatment Trialists’ Collaboration [BPLTTC]. Lancet 2000; 356: 1955-64.Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood pressure-lowering drugs: Results of prospectively designed overviews of randomized trials. Blood Pressure Lowering Treatment Trialists’ Collaboration [BPLTTC]. Lancet 2000; 356: 1955-64.Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomized trial. Lancet 2004; 363: 2022-31.Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomized trial. Lancet 2004; 363: 2022-31.Verma S, Mamdani M, Al-Omran M, et al. Angiotensin receptor blockers vs. angiotensin converting enzyme inhibitors and acute coronary syndrome outcomes in elderly patients: A populationbased cohort study (UMPIRE study results). J Am SocHypertens 2007; 1: 286-94.Verma S, Mamdani M, Al-Omran M, et al. Angiotensin receptor blockers vs. angiotensin converting enzyme inhibitors and acute coronary syndrome outcomes in elderly patients: A populationbased cohort study (UMPIRE study results). J Am SocHypertens 2007; 1: 286-94.Turnbull F, Neal B, Pfeffer M, et al. Blood pressure-dependent and independent effects of agents that inhibit the reninangiotensin system. J Hypertens 2007; 25: 951-8.Turnbull F, Neal B, Pfeffer M, et al. Blood pressure-dependent and independent effects of agents that inhibit the reninangiotensin system. J Hypertens 2007; 25: 951-8.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: 2039-44.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: 2039-44.Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomized trial against atenolol. Lancet 2002; 359: 995-1003.Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomized trial against atenolol. Lancet 2002; 359: 995-1003.Devereux RB, Dahlof B, Gerdts E, et al. Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Trial. Circulation 2004; 110: 1456-62.Devereux RB, Dahlof B, Gerdts E, et al. Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Trial. Circulation 2004; 110: 1456-62.Hoieggen A, Alderman MH, Kjeldsen SE, et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004; 65: 1041-9.Hoieggen A, Alderman MH, Kjeldsen SE, et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004; 65: 1041-9.Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: The OPTIMAAL randomized trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002; 360: 752-60.Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: The OPTIMAAL randomized trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002; 360: 752-60.Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349: 1893-906.Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349: 1893-906.Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomized trial—the Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355: 1582-7.Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomized trial—the Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355: 1582-7.Cohn JN, Tognoni G. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345: 1667-75.Cohn JN, Tognoni G. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345: 1667-75.McMurray JJ, Ostergren J, Swedberg K, et al. Effects of cande- sartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-convertingenzyme inhibitors: The CHARM-Added trial. Lancet 2003; 362: 767-71.McMurray JJ, Ostergren J, Swedberg K, et al. Effects of cande- sartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-convertingenzyme inhibitors: The CHARM-Added trial. Lancet 2003; 362: 767-71.Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet 2003; 362: 772-6.Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet 2003; 362: 772-6.Teo K, Yusuf S, Sleight P, et al. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J 2004; 148: 52-61.Teo K, Yusuf S, Sleight P, et al. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J 2004; 148: 52-61.Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547-59.Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547-59.Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensinconverting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation [HOPE] Study Investigators. N Engl J Med 2000; 342: 145-53.Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensinconverting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation [HOPE] Study Investigators. N Engl J Med 2000; 342: 145-53.Oparil S, Yarows SA, Patel S, et al. Dual inhibition of the renin system by aliskiren and valsartan. Lancet 2007; 370: 1126-7.Oparil S, Yarows SA, Patel S, et al. Dual inhibition of the renin system by aliskiren and valsartan. Lancet 2007; 370: 1126-7.Pool JL, Schmieder RE, Azizi M, et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens 2007; 20: 11-20.Pool JL, Schmieder RE, Azizi M, et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens 2007; 20: 11-20.Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): Rationale and study design. Nephrol Dial Transplant 2009; 24: 1663-71. Epub 2009 Jan 14.Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): Rationale and study design. Nephrol Dial Transplant 2009; 24: 1663-71. Epub 2009 Jan 14.Allemann Y, Fraile B, Lambert M, et al. Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: The Exforge in Failure after Single Therapy (EX-FAST) study. J Clin Hypertens (Greenwich) 2008; 10: 185-94.Allemann Y, Fraile B, Lambert M, et al. Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: The Exforge in Failure after Single Therapy (EX-FAST) study. J Clin Hypertens (Greenwich) 2008; 10: 185-94.Volpe M, Brommer P, Haag U, et al. Efficacy and tolerability of olmesartan medoxomil combined with amlodipine in patients with moderate to severe hypertension after amlodipine monotherapy: A randomized, double-blind, parallel-group, multicentre study. Clin Drug Investig 2009; 29: 11-25.Volpe M, Brommer P, Haag U, et al. Efficacy and tolerability of olmesartan medoxomil combined with amlodipine in patients with moderate to severe hypertension after amlodipine monotherapy: A randomized, double-blind, parallel-group, multicentre study. Clin Drug Investig 2009; 29: 11-25.Littlejohn TW 3rd, Majul CR, Olvera R, et al. Results of treatment with telmisartan-amlodipine in hypertensive patients. J Clin Hypertens 2009; 11: 207-13.Littlejohn TW 3rd, Majul CR, Olvera R, et al. Results of treatment with telmisartan-amlodipine in hypertensive patients. J Clin Hypertens 2009; 11: 207-13.Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008; 359: 2417-28.Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008; 359: 2417-28.Cuspidi, C, Negri F, Zanchetti A. Angiotensin II receptor blockers and cardiovascular protection: Focus on left ventricular hypertrophy regression and atrial fibrillation prevention. Vasc Health Risk Manag 2008; 4: 67-73.Cuspidi, C, Negri F, Zanchetti A. Angiotensin II receptor blockers and cardiovascular protection: Focus on left ventricular hypertrophy regression and atrial fibrillation prevention. Vasc Health Risk Manag 2008; 4: 67-73.Kannel WB, Wolf PA, Benjamin EJ, et al. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: Population-based estimates. Am J Cardiol 1998; 82: 2N-9.Kannel WB, Wolf PA, Benjamin EJ, et al. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: Population-based estimates. Am J Cardiol 1998; 82: 2N-9.Ducharme A, Swedberg K, Pfeffer MA, et al. Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Am Heart J 2006; 151: 985-91.Ducharme A, Swedberg K, Pfeffer MA, et al. Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Am Heart J 2006; 151: 985-91.Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: Results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J 2005; 149: 548-57.Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: Results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J 2005; 149: 548-57.Schmieder RE, Kjeldsen SE, Julius S, et al. Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: The VALUE trial. J Hypertens 2008; 26: 403-11.Schmieder RE, Kjeldsen SE, Julius S, et al. Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: The VALUE trial. J Hypertens 2008; 26: 403-11.Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: The Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. JACC 2005; 45: 712-9.Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: The Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. JACC 2005; 45: 712-9.GISSI-AF Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Atrial Fibrillation). Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009; 360: 1606-17.GISSI-AF Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Atrial Fibrillation). Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009; 360: 1606-17.Comparison of effects of telmisartan and valsartan on neointima volume in diabetes. Available at: http://clinicaltrials.gov/ct2/show/NCT00599885?term=Comparison+of+effects+of+telmisartan+and+valsartan+on+neointima+volume+in+diabetes&rank=1. Accessed February 8, 2009.Comparison of effects of telmisartan and valsartan on neointima volume in diabetes. Available at: http://clinicaltrials.gov/ct2/show/NCT00599885?term=Comparison+of+effects+of+telmisartan+and+valsartan+on+neointima+volume+in+diabetes&rank=1. Accessed February 8, 2009.Kurtz TW, Klein U. Next generation multifunctional angiotensin receptor blockers. Hypertens Res 2009; 32: 826-34.Kurtz TW, Klein U. Next generation multifunctional angiotensin receptor blockers. Hypertens Res 2009; 32: 826-34.

The authors declare that there are no conflicts of interest present.