Abstract
Background: The target blood pressure has changed many times in the guidelines in past years. However, there is always a question; is it good to lower blood pressure below 120/80 or not? Control of blood pressure in hypertension is very important in reducing hypertension-modified organ damage. So, the guidelines recommend combining more than one antihypertensive drug to reach the target blood pressure goal.
Results: Combination therapy is recommended by guidelines to reach the blood pressure goal. The guidelines recommend many combinations, such as the combination of angiotensin receptor blockers with either calcium channel blockers (CCB) or beta-blocker (BB). Angiotensin receptor blocker (ARB) combination with CCB has gained superiority over other antihypertension drug combinations because it reduces blood pressure and decreases the incidence of CV events and organ damage. BB combinations are recommended by guidelines in patients with ischemic events but not all hypertensive patients. Unfortunately, the new generation BB, for example, nebivolol, has a vasodilator effect, making it new hope for BB.
Conclusion: Combination therapy is a must in treating the hypertensive patient. The new generation BBs may change the recommendations of guidelines because they have an effect that is similar to CCBs.
Keywords: Target blood pressure, combination therapy, hypertension, angiotensin receptor blockers, calcium channel blockers, beta-blockers.
Graphical Abstract
[1]
Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension. 1. Overview, meta-analyses, and meta-regression analyses of randomized trials. J Hypertens 2014; 32(12): 2285-95.
[http://dx.doi.org/10.1097/HJH.0000000000000378] [PMID: 25255397]
[http://dx.doi.org/10.1097/HJH.0000000000000378] [PMID: 25255397]
[2]
Volpe M, Gallo G, Tocci G. Is early and fast blood pressure control important in hypertension management? Int J Cardiol 2018; 254: 328-32.
[http://dx.doi.org/10.1016/j.ijcard.2017.12.026] [PMID: 29273242]
[http://dx.doi.org/10.1016/j.ijcard.2017.12.026] [PMID: 29273242]
[3]
Mancia G, Messerli F, Bakris G, Zhou Q, Champion A, Pepine CJ. Blood pressure control and improved cardiovascular outcomes in the International Verapamil SR-Trandolapril Study. Hypertension 2007; 50(2): 299-305.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.090290] [PMID: 17606861]
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.090290] [PMID: 17606861]
[4]
Einhorn PT, Davis BR, Massie BM, et al. The antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT) heart failure validation study: Diagnosis and prognosis. Am Heart J 2007; 153(1): 42-53.
[http://dx.doi.org/10.1016/j.ahj.2006.10.012] [PMID: 17174636]
[http://dx.doi.org/10.1016/j.ahj.2006.10.012] [PMID: 17174636]
[5]
Sawada T, Yamada H, Dahlöf B, Matsubara H. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009; 30(20): 2461-9.
[http://dx.doi.org/10.1093/eurheartj/ehp363] [PMID: 19723695]
[http://dx.doi.org/10.1093/eurheartj/ehp363] [PMID: 19723695]
[6]
Ho KKL, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: The Framingham Study. J Am Coll Cardiol 1993; 22(4) (Suppl. A): 6A-13A.
[http://dx.doi.org/10.1016/0735-1097(93)90455-A] [PMID: 8376698]
[http://dx.doi.org/10.1016/0735-1097(93)90455-A] [PMID: 8376698]
[7]
Bang CN, Devereux RB, Okin PM. Regression of electrocardiographic left ventricular hypertrophy or strain is associated with lower incidence of cardiovascular morbidity and mortality in hypertensive patients independent of blood pressure reduction - A LIFE review. J Electrocardiol 2014; 47(5): 630-5.
[http://dx.doi.org/10.1016/j.jelectrocard.2014.07.003] [PMID: 25052475]
[http://dx.doi.org/10.1016/j.jelectrocard.2014.07.003] [PMID: 25052475]
[8]
Asselbergs FW, Diercks GF, Hillege HL, et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004; 110(18): 2809-16.
[http://dx.doi.org/10.1161/01.CIR.0000146378.65439.7A] [PMID: 15492322]
[http://dx.doi.org/10.1161/01.CIR.0000146378.65439.7A] [PMID: 15492322]
[9]
Weder AB. The avoiding cardiovascular events through combination therapy in patients living with systolic hypertension (ACCOMPLISH) trial: A comparison of first-line combination therapies. Expert Opin Pharmacother 2005; 6(2): 275-81.
[http://dx.doi.org/10.1517/14656566.6.2.275] [PMID: 15757423]
[http://dx.doi.org/10.1517/14656566.6.2.275] [PMID: 15757423]
[10]
Ostergren J, Poulter NR, Sever PS, et al. The anglo-scandinavian cardiac outcomes trial: Blood pressure-lowering limb: Effects in patients with type II diabetes. J Hypertens 2008; 26(11): 2103-11.
[http://dx.doi.org/10.1097/HJH.0b013e328310e0d9] [PMID: 18854748]
[http://dx.doi.org/10.1097/HJH.0b013e328310e0d9] [PMID: 18854748]
[11]
Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): Principal results of a randomized double-blind intervention trial. J Hypertens 2003; 21(5): 875-86.
[http://dx.doi.org/10.1097/00004872-200305000-00011] [PMID: 12714861]
[http://dx.doi.org/10.1097/00004872-200305000-00011] [PMID: 12714861]
[12]
Verdecchia P, Angeli F, Reboldi G. How low should we go with blood pressure? Circ Res 2017; 120(1): 27-9.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.309971] [PMID: 28057786]
[http://dx.doi.org/10.1161/CIRCRESAHA.116.309971] [PMID: 28057786]
[13]
Ogihara T, Saruta T, Rakugi H, et al. Target blood pressure for treatment of isolated systolic hypertension in the elderly: Valsartan in elderly isolated systolic hypertension study. Hypertension 2010; 56(2): 196-202.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.146035] [PMID: 20530299]
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.146035] [PMID: 20530299]
[14]
Group JS. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertension 2008; 31(12): 2115-7.
[15]
Diao DWJ, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database Syst Rev 2012; 2012(8): CD006742.
[16]
Mancia G, Fagard R, Narkiewicz K, et al. 2013 Practice guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC): ESH/ESC Task Force for the Management of Arterial Hypertension. J Hypertens 2013; 31(10): 1925-38.
[http://dx.doi.org/10.1097/HJH.0b013e328364ca4c] [PMID: 24107724]
[http://dx.doi.org/10.1097/HJH.0b013e328364ca4c] [PMID: 24107724]
[17]
James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311(5): 507-20.
[http://dx.doi.org/10.1001/jama.2013.284427] [PMID: 24352797]
[http://dx.doi.org/10.1001/jama.2013.284427] [PMID: 24352797]
[18]
Whelton PKCR, Aronow WS, et al. 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. J Am Coll Cardiol 2017; 2017: 7.
[19]
Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018; 39(33): 3021-104.
[http://dx.doi.org/10.1093/eurheartj/ehy339] [PMID: 30165516]
[http://dx.doi.org/10.1093/eurheartj/ehy339] [PMID: 30165516]
[20]
Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373(22): 2103-16.
[http://dx.doi.org/10.1056/NEJMoa1511939] [PMID: 26551272]
[http://dx.doi.org/10.1056/NEJMoa1511939] [PMID: 26551272]
[21]
Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: A randomized clinical trial. JAMA 2016; 315(24): 2673-82.
[http://dx.doi.org/10.1001/jama.2016.7050] [PMID: 27195814]
[http://dx.doi.org/10.1001/jama.2016.7050] [PMID: 27195814]
[22]
Schiffrin EL, Calhoun DA, Flack JM. Do we need a new definition of hypertension after SPRINT? Am J Hypertens 2016; 29(10): 1127-9.
[http://dx.doi.org/10.1093/ajh/hpw068] [PMID: 27334926]
[http://dx.doi.org/10.1093/ajh/hpw068] [PMID: 27334926]
[23]
Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362(17): 1575-85.
[http://dx.doi.org/10.1056/NEJMoa1001286] [PMID: 20228401]
[http://dx.doi.org/10.1056/NEJMoa1001286] [PMID: 20228401]
[24]
Adamsson Eryd S, Gudbjörnsdottir S, Manhem K, et al. Blood pressure and complications in individuals with type 2 diabetes and no previous cardiovascular disease: National population based cohort study. BMJ 2016; 354: i4070.
[http://dx.doi.org/10.1136/bmj.i4070] [PMID: 27492939]
[http://dx.doi.org/10.1136/bmj.i4070] [PMID: 27492939]
[25]
American Diabetes Association. 9. Cardiovascular disease and risk management. Diabetes Care 2017; 40 (Suppl. 1): S75-87.
[http://dx.doi.org/10.2337/dc17-S012] [PMID: 27979896]
[http://dx.doi.org/10.2337/dc17-S012] [PMID: 27979896]
[26]
Buckley LF, Dixon DL, Wohlford GF IV, Wijesinghe DS, Baker WL, Van Tassell BW. Effect of intensive blood pressure control in patients with type 2 diabetes mellitus over 9 years of follow-up: A subgroup analysis of high-risk ACCORDION trial participants. Diabetes Obes Metab 2018; 20(6): 1499-502.
[http://dx.doi.org/10.1111/dom.13248] [PMID: 29424469]
[http://dx.doi.org/10.1111/dom.13248] [PMID: 29424469]
[27]
Beddhu S, Rocco MV, Toto R, et al. Effects of intensive systolic blood pressure control on kidney and cardiovascular outcomes in persons without kidney disease: A secondary analysis of a randomized trial. Ann Intern Med 2017; 167(6): 375-83.
[http://dx.doi.org/10.7326/M16-2966] [PMID: 28869987]
[http://dx.doi.org/10.7326/M16-2966] [PMID: 28869987]
[28]
Vidal-Petiot E, Ford I, Greenlaw N, et al. Cardiovascular event rates and mortality according to achieved systolic and diastolic blood pressure in patients with stable coronary artery disease: An international cohort study. Lancet 2016; 388(10056): 2142-52.
[http://dx.doi.org/10.1016/S0140-6736(16)31326-5] [PMID: 27590221]
[http://dx.doi.org/10.1016/S0140-6736(16)31326-5] [PMID: 27590221]
[29]
Zhang W, Zhang S, Deng Y, et al. Trial of intensive blood-pressure control in older patients with hypertension. N Engl J Med 2021; 385(14): 1268-79.
[http://dx.doi.org/10.1056/NEJMoa2111437] [PMID: 34491661]
[http://dx.doi.org/10.1056/NEJMoa2111437] [PMID: 34491661]
[30]
Gradman AH, Basile JN, Carter BL, et al. Combination therapy in hypertension. J Am Soc Hypertens 2010; 4(2): 90-8.
[http://dx.doi.org/10.1016/j.jash.2010.03.001] [PMID: 20400053]
[http://dx.doi.org/10.1016/j.jash.2010.03.001] [PMID: 20400053]
[31]
Cohuet G, Struijker-Boudier H. Mechanisms of target organ damage caused by hypertension: Therapeutic potential. Pharmacol Ther 2006; 111(1): 81-98.
[http://dx.doi.org/10.1016/j.pharmthera.2005.09.002] [PMID: 16288809]
[http://dx.doi.org/10.1016/j.pharmthera.2005.09.002] [PMID: 16288809]
[32]
Rubio-Guerra AF, Castro-Serna D, Barrera CI, Ramos-Brizuela LM. Current concepts in combination therapy for the treatment of hypertension: Combined calcium channel blockers and RAAS inhibitors. Integr Blood Press Control 2009; 2: 55-62.
[http://dx.doi.org/10.2147/IBPC.S6232] [PMID: 21949615]
[http://dx.doi.org/10.2147/IBPC.S6232] [PMID: 21949615]
[33]
Agabiti-Rosei MLME. Understanding and treating central blood pressure. Dialogues Cardiovasc Med 2015; 20.
[34]
Mallat SG, Itani HS, Tanios BY. Current perspectives on combination therapy in the management of hypertension. Integr Blood Press Control 2013; 6: 69-78.
[http://dx.doi.org/10.2147/IBPC.S33985] [PMID: 23837009]
[http://dx.doi.org/10.2147/IBPC.S33985] [PMID: 23837009]
[35]
Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: A meta-analysis. Am J Med 2007; 120(8): 713-9.
[http://dx.doi.org/10.1016/j.amjmed.2006.08.033] [PMID: 17679131]
[http://dx.doi.org/10.1016/j.amjmed.2006.08.033] [PMID: 17679131]
[36]
Liebson PR, Amsterdam EA. Ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET): Implications for reduced cardiovascular risk. Prev Cardiol 2009; 12(1): 43-50.
[http://dx.doi.org/10.1111/j.1751-7141.2008.00010.x] [PMID: 19301691]
[http://dx.doi.org/10.1111/j.1751-7141.2008.00010.x] [PMID: 19301691]
[37]
Neutel Joel M, Neutel Joel M, Smith David HG, et al. Efficacy of combination therapy for systolic blood pressure in patients with severe systolic hypertension: The systolic evaluation of lotrel efficacy and comparative therapies (SELECT) study. J Clin Hypertens (Greenwich) 2005; 7(11): 641-6.
[http://dx.doi.org/10.1111/j.1524-6175.2005.04615.x]
[http://dx.doi.org/10.1111/j.1524-6175.2005.04615.x]
[38]
de la Sierra A, Banegas JR, Vinyoles E, et al. Office and ambulatory blood pressure control in hypertensive patients treated with different two-drug and three-drug combinations. Clin Exp Hypertens 2016; 38(4): 409-14.
[http://dx.doi.org/10.3109/10641963.2016.1148160] [PMID: 27159660]
[http://dx.doi.org/10.3109/10641963.2016.1148160] [PMID: 27159660]
[39]
Littlejohn TW III, Majul CR, Olvera R, et al. Results of treatment with telmisartan-amlodipine in hypertensive patients. J Clin Hypertens (Greenwich) 2009; 11(4): 207-13.
[http://dx.doi.org/10.1111/j.1751-7176.2009.00098.x] [PMID: 19614805]
[http://dx.doi.org/10.1111/j.1751-7176.2009.00098.x] [PMID: 19614805]
[40]
Julius S, Weber MA, Kjeldsen SE, et al. The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial: Outcomes in patients receiving monotherapy. Hypertension 2006; 48(3): 385-91.
[http://dx.doi.org/10.1161/01.HYP.0000236119.96301.f2] [PMID: 16864741]
[http://dx.doi.org/10.1161/01.HYP.0000236119.96301.f2] [PMID: 16864741]
[41]
Malacco E, Santonastaso M, Varì NA, et al. Comparison of valsartan 160 mg with lisinopril 20 mg, given as monotherapy or in combination with a diuretic, for the treatment of hypertension: The Blood Pressure Reduction and Tolerability of Valsartan in Comparison with Lisinopril (PREVAIL) study. Clin Ther 2004; 26(6): 855-65.
[http://dx.doi.org/10.1016/S0149-2918(04)90129-4] [PMID: 15262456]
[http://dx.doi.org/10.1016/S0149-2918(04)90129-4] [PMID: 15262456]
[42]
Destro M, Luckow A, Samson M, Kandra A, Brunel P. Efficacy and safety of amlodipine/valsartan compared with amlodipine monotherapy in patients with stage 2 hypertension: A randomized, double-blind, multicenter study: The EX-EFFeCTS Study. J Am Soc Hypertens 2008; 2(4): 294-302.
[http://dx.doi.org/10.1016/j.jash.2008.01.004] [PMID: 20409909]
[http://dx.doi.org/10.1016/j.jash.2008.01.004] [PMID: 20409909]
[43]
Allemann Y, Fraile B, Lambert M, Barbier M, Ferber P, Izzo JL Jr. 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(3): 185-94.
[http://dx.doi.org/10.1111/j.1751-7176.2008.07516.x] [PMID: 18326958]
[http://dx.doi.org/10.1111/j.1751-7176.2008.07516.x] [PMID: 18326958]
[44]
Mazza A, Schiavon L, Zuin M, et al. Effects of the antihypertensive fixed-dose combinations on an early marker of hypertensive cardiac damage in subjects at low cardiovascular risk. Am J Hypertens 2016; 29(8): 969-75.
[http://dx.doi.org/10.1093/ajh/hpw022] [PMID: 27053407]
[http://dx.doi.org/10.1093/ajh/hpw022] [PMID: 27053407]
[45]
Zhang W, Song Y, Xu J. Effectiveness and safety of valsartan/amlodipine in hypertensive patients with stroke: China Status II subanalysis. Medicine (Baltimore) 2017; 96(26): e7172.
[http://dx.doi.org/10.1097/MD.0000000000007172] [PMID: 28658108]
[http://dx.doi.org/10.1097/MD.0000000000007172] [PMID: 28658108]
[46]
Wing LMCJ, Chalmers JP, West MJ, et al. Enalapril and atenolol in essential hypertension: Attenuation of hypotensive effects in combination. Clin Exp Hypertens A 1988; 10(1): 119-33.
[http://dx.doi.org/10.3109/10641968809046803] [PMID: 2832102]
[http://dx.doi.org/10.3109/10641968809046803] [PMID: 2832102]
[47]
Neutel JM, Giles TD, Punzi H, Weiss RJ, Li H, Finck A. Long-term safety of nebivolol and valsartan combination therapy in patients with hypertension: An open-label, single-arm, multicenter study. J Am Soc Hypertens 2014; 8(12): 915-20.
[http://dx.doi.org/10.1016/j.jash.2014.09.017] [PMID: 25492835]
[http://dx.doi.org/10.1016/j.jash.2014.09.017] [PMID: 25492835]
[48]
Giles TD, Cockcroft JR, Pitt B, Jakate A, Wright HM. Rationale for nebivolol/valsartan combination for hypertension: Review of preclinical and clinical data. J Hypertens 2017; 35(9): 1758-67.
[http://dx.doi.org/10.1097/HJH.0000000000001412] [PMID: 28509722]
[http://dx.doi.org/10.1097/HJH.0000000000001412] [PMID: 28509722]
[49]
Farag SM, Rabea HM, Mahmoud HB. Effect of amlodipine/valsartan versus nebivolol/valsartan fixed dose combinations on peripheral and central blood pressure. High Blood Press Cardiovasc Prev 2018; 25(4): 407-13.
[http://dx.doi.org/10.1007/s40292-018-0286-8] [PMID: 30390203]
[http://dx.doi.org/10.1007/s40292-018-0286-8] [PMID: 30390203]
[50]
Wang KL, Yu WC, Lu TM, Chen LC, Leu HB, Chiang CE. Amlodipine/valsartan fixed-dose combination treatment in the management of hypertension: A double-blind, randomized trial. JCMA 2020; 83(10): 900-5.
[http://dx.doi.org/10.1097/JCMA.0000000000000386] [PMID: 33009241]
[http://dx.doi.org/10.1097/JCMA.0000000000000386] [PMID: 33009241]
[51]
Ogawa H, Kim-Mitsuyama S, Jinnouchi T, et al. Rationale, design and patient baseline characteristics of OlmeSartan and calcium antagonists randomized (OSCAR) study: A study comparing the incidence of cardiovascular events between high-dose angiotensin II receptor blocker (ARB) monotherapy and combination therapy of ARB with calcium channel blocker in Japanese elderly high-risk hypertensive patients (ClinicalTrials. gov no. NCT00134160). Hypertension 2009; 32(7): 575-80.
[52]
Zhang X, Zhang H, Ma Y, Che W, Hamblin MR. Management of hypertension using olmesartan alone or in combination. Cardiol Ther 2017; 6(1): 13-32.
[http://dx.doi.org/10.1007/s40119-017-0087-5] [PMID: 28258390]
[http://dx.doi.org/10.1007/s40119-017-0087-5] [PMID: 28258390]
[53]
Koyanagi R, Hagiwara N, Yamaguchi J, et al. Efficacy of the combination of amlodipine and candesartan in hypertensive patients with coronary artery disease: A subanalysis of the HIJ-CREATE study. J Cardiol 2013; 62(4): 217-23.
[http://dx.doi.org/10.1016/j.jjcc.2013.04.004] [PMID: 23778009]
[http://dx.doi.org/10.1016/j.jjcc.2013.04.004] [PMID: 23778009]
[54]
Motozato K, Miura S, Shiga Y, et al. Efficacy and safety of two single-pill fixed-dose combinations of angiotensin II receptor blockers/calcium channel blockers in hypertensive patients (EXAMINER study). Clin Exp Hypertens 2016; 38(1): 45-50.
[http://dx.doi.org/10.3109/10641963.2015.1060982] [PMID: 26268636]
[http://dx.doi.org/10.3109/10641963.2015.1060982] [PMID: 26268636]
[55]
Arora A, Shafiq N, Jain S, Khuller GK, Sharma S, Malhotra S. Development of sustained release “NanoFDC (Fixed Dose Combination)” for hypertension - an experimental study. PLoS One 2015; 10(6): e0128208.
[http://dx.doi.org/10.1371/journal.pone.0128208] [PMID: 26047011]
[http://dx.doi.org/10.1371/journal.pone.0128208] [PMID: 26047011]
[56]
Pandey AK, Shafiq N, Bhandari RK, et al. Pharmacokinetic and pharmacodynamic evaluation of nano-fixed dose combination for hypertension. J Hypertens 2020; 38(8): 1593-602.
[http://dx.doi.org/10.1097/HJH.0000000000002429] [PMID: 32371763]
[http://dx.doi.org/10.1097/HJH.0000000000002429] [PMID: 32371763]
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