Hypertension / therapy; Antihypertensive Agents / pharmacology; Antihypertensive Agents / therapeutic use
Arterial hypertension (AH) is a highly prevalent disease, and is a major cardiovascular (CV) risk factor11. Sociedade Brasileira de Cardiologia. Departamento de Hipertensão Arterial. VI Diretrizes brasileiras de hipertensão. Rev Bras Hipertens. 2010;17(1):4-62.; therefore, achieving blood pressure (BP) control goals as soon as possible is paramount to reduce that risk22. Mancia G, Laurent S, Agabiti-Rosei E, Burnier M, Caulfield MJ, Cifkova R, et al. Reappraisal of Europeanguidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press.2009;18(6):308-47.. That means that approximately 70% of hypertensive individuals will need antihypertensive drug combination33. Gradman AH, Basile JN, Carter BL, Bakris GL;American Society of HypertensionWritingGroup. Combination therapy in hypertension. J Am SocHypertens. 2010;4(1):42-50.Erratum in: J AmSocHypertens. 2010;4(2):99., and up to 30% of hypertensive individuals are estimated to use four or more drugs to achieve BP control44. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The AntihypertensiveandLipid-LoweringTreatmenttoPrevent Heart AttackTrial.Major outcomes in high risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-97.Erratum in JAMA. 2004;291(18):2196, JAMA. 2003;289(2):178.. Thus, drug combination is currently described as an important strategy to manage AH, providing effective and safe BP reduction.
Drug choice is based on effective BP reduction and CV outcomes. Despite the existence of a significant number of drugs to treat AH, their control rates are still very low, contributing to the high CV morbidity and mortality rates observed in Brazil and worldwide11. Sociedade Brasileira de Cardiologia. Departamento de Hipertensão Arterial. VI Diretrizes brasileiras de hipertensão. Rev Bras Hipertens. 2010;17(1):4-62. , 22. Mancia G, Laurent S, Agabiti-Rosei E, Burnier M, Caulfield MJ, Cifkova R, et al. Reappraisal of Europeanguidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press.2009;18(6):308-47..
According to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the Hypertension Optimal Treatment (HOT) Study, only 26% and 33% of the patients, respectively, could control their BP with monotherapy, while in the Losartan Intervention for Endpoints Reduction (LIFE) Study, 90% of the patients needed combined therapy for that purpose33. Gradman AH, Basile JN, Carter BL, Bakris GL;American Society of HypertensionWritingGroup. Combination therapy in hypertension. J Am SocHypertens. 2010;4(1):42-50.Erratum in: J AmSocHypertens. 2010;4(2):99. .
Drug combination is mainly aimed at increasing antihypertensive efficacy, with fewer
adverse events. It is worth noting the importance of considering therapy adherence. The
pathophysiology of AH involves multiple factors and mechanisms, making its control
difficult when only one drug is used, because counterregulatory mechanisms that
attenuate the antihypertensive effect of the drug can occur. The association of drugs
with different mechanisms of action has a greater impact on BP reduction as long as
there is pharmacokinetic compatibility and no disparity of effects and properties33. Gradman AH, Basile JN, Carter BL, Bakris GL;American Society of
HypertensionWritingGroup. Combination therapy in hypertension. J Am SocHypertens.
2010;4(1):42-50.Erratum in: J AmSocHypertens. 2010;4(2):99.
4. ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. The AntihypertensiveandLipid-LoweringTreatmenttoPrevent Heart
AttackTrial.Major outcomes in high risk hypertensive patients randomized to
angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the
Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
JAMA. 2002;288(23):2981-97.Erratum in JAMA. 2004;291(18):2196, JAMA.
2003;289(2):178.
-
55. Sever PS,Messerli MH. Hypertension management 2011: optimal
combination therapy. Eur Heart J . 2011;32(20):2499-506..
Thus, the choice of the drugs to be combined should contemplate two aspects: synergism
of the mechanisms of action and opposition to counterregulatory mechanisms triggered
after the beginning of therapy with a certain drug. The desired antihypertensive
efficacy is more likely to be achieved by using lower doses of the drugs involved. Thus,
fewer adverse events are observed, with no loss of antihypertensive drug potency33. Gradman AH, Basile JN, Carter BL, Bakris GL;American Society of
HypertensionWritingGroup. Combination therapy in hypertension. J Am SocHypertens.
2010;4(1):42-50.Erratum in: J AmSocHypertens. 2010;4(2):99.
4. ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. The AntihypertensiveandLipid-LoweringTreatmenttoPrevent Heart
AttackTrial.Major outcomes in high risk hypertensive patients randomized to
angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the
Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
JAMA. 2002;288(23):2981-97.Erratum in JAMA. 2004;291(18):2196, JAMA.
2003;289(2):178.
-
55. Sever PS,Messerli MH. Hypertension management 2011: optimal
combination therapy. Eur Heart J . 2011;32(20):2499-506..
Another important aspect is that drugs should be preferably combined in a single galenic presentation, facilitating their administration, and assuring lower cost, with a consequent improvement in treatment adherence22. Mancia G, Laurent S, Agabiti-Rosei E, Burnier M, Caulfield MJ, Cifkova R, et al. Reappraisal of Europeanguidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press.2009;18(6):308-47. , 66. Gupta AK, Arshad S, Poulter NR. Compliance, safety and effectiveness of fixed-dose combinations of anti-hypertensive agents:ameta-analysis. Hypertension. 2010;55(2):399-407..
Evidence of clinical trials
Data available have suggested that most of the hypertensive population requires combined therapy to achieve BP control goals11. Sociedade Brasileira de Cardiologia. Departamento de Hipertensão Arterial. VI Diretrizes brasileiras de hipertensão. Rev Bras Hipertens. 2010;17(1):4-62.. A meta-analysis of 354 double-blind randomized clinical trials has found mean BP reductions with monotherapy of only 9.1 mm Hg and 5.5 mm Hg for systolic BP (SBP) and diastolic BP (DBP), respectively. There were only few differences in the responses to the following drugs assessed: diuretics; beta-blockers (BBs); angiotensin-converting-enzyme inhibitors (ACEIs); type 1 angiotensin-receptor blockers (ARBs); and calcium channel antagonists (CCAs)77. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326(7404):1427-35.. In the ALLHAT, only 26% of the patients achieved the BP control goal with monotherapy, even considering the goal for diabetic patients (36% of the patients) of < 140/90 mm Hg, rather than 130/80 mm Hg as recommended by several guidelines at the time44. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The AntihypertensiveandLipid-LoweringTreatmenttoPrevent Heart AttackTrial.Major outcomes in high risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-97.Erratum in JAMA. 2004;291(18):2196, JAMA. 2003;289(2):178.. In the HOT Study, only 33% of the patients met the DBP goal with monotherapy; 45% required two drugs and 22% needed three drugs to meet that goal88. Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. HOT StudyGroup. Lancet. 1998;351(9118):1755-62.. The mean SBP at the end of the HOT Study was 141 mm Hg, indicating that an even higher percentage of patients would have needed combined therapy to meet the goal of < 140 mmHg55. Sever PS,Messerli MH. Hypertension management 2011: optimal combination therapy. Eur Heart J . 2011;32(20):2499-506.. In the LIFE Study, treatment to meet the recommended goal (<140/90 mmHg) was aggressively pursued in elderly patients with left ventricular hypertrophy (LVH). Considering an initial mean BP of 175/98 mm Hg, more than 90% need to use at least two antihypertensive drugs99. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet. 2002;359(9311):995-1003.. The Strategies in Treatment of Hypertension (STRATHE) Study, in which treatment was initiated with a combination of low doses and compared to monotherapy, has found a greater percentage of individuals in the low-dose combination group who met the BP control goal (BP < 140/90 mm Hg) as compared to those receiving sequential monotherapy (62% vs. 49%, p = 0.02)1010. MouradJJ, Waeber B, ZannadF, Laville M, Duru G, Andréjak M; investigators of the STRATHE trial. Comparison of different therapeutic strategies in hypertension: a low-dose combination of perindopril / indapamide versus a sequential monotherapy or a stepped-care approach. J Hypertens. 2004;22(12):2379-86. Erratum in J Hypertens.2007;25(1):258..
Based on the criteria of efficacy, tolerability, likelihood of higher adherence, evidence of CV and kidney protections, and safety, the associations of antihypertensive drugs can be divided as follows: preferential; acceptable; less usual; and unusual (Chart 1)1111. Gradman AH, Basile JN, Carter BL, Bakris GL;American Society of Hypertension Writing Group. Combination therapy in hypertension. J ClinHypertens (Greenwich). 2011;13(3):146-54.. Chart 2 summarizes the current recommendations for drug association in AH treatment1212. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55(2):399-407.. It is worth noting that non-pharmacological measures of lifestyle change should be always emphasized to improve AH control and prevention of its complications.
Benefits of adherence to drug combination
Current guidelines recommend and encourage the use of fixed drug combinations (FDC) to make adherence to treatment easier22. Mancia G, Laurent S, Agabiti-Rosei E, Burnier M, Caulfield MJ, Cifkova R, et al. Reappraisal of Europeanguidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press.2009;18(6):308-47.. In addition, previous studies have shown that complex drug treatment and polypharmacy have a deleterious effect on treatment adherence and persistence1212. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55(2):399-407..
As compared to non-FDC, FDC improves treatment adherence and persistence because of the following advantages:
- Daily single dose and fewer tablets to be ingested, resulting in higher convenience to the patient, and lower risk of dose confusion1313. Oparil S, Weber MA. Hypertension: companion to Brenner & Rector´s: the kidney. 2nd ed. Philadelphia: Saunders; 2005. p. 522-9.;
- Potential lower cost, due to the reduced number of tablets1313. Oparil S, Weber MA. Hypertension: companion to Brenner & Rector´s: the kidney. 2nd ed. Philadelphia: Saunders; 2005. p. 522-9.;
- Better BP control, possibly due to simultaneous and/or synergic action in multiple pathophysiological AH factors and attenuation of therapeutic inertia1414. Dusing R. Otimizing blood pressure control through the use of fixed combinations. Vasc Health Risk Manag. 2010;6:321-5.. Greater 24 hour BP stability in synergic FDC, with adequate trough-peak ratio and doses, promoting higher CV protection44. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The AntihypertensiveandLipid-LoweringTreatmenttoPrevent Heart AttackTrial.Major outcomes in high risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-97.Erratum in JAMA. 2004;291(18):2196, JAMA. 2003;289(2):178.;
- The goal is met earlier, leading to a faster reduction in CV risk44. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The AntihypertensiveandLipid-LoweringTreatmenttoPrevent Heart AttackTrial.Major outcomes in high risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-97.Erratum in JAMA. 2004;291(18):2196, JAMA. 2003;289(2):178. and greater patients' trust in physicians and drugs1313. Oparil S, Weber MA. Hypertension: companion to Brenner & Rector´s: the kidney. 2nd ed. Philadelphia: Saunders; 2005. p. 522-9.;
- Lower rate of adverse events1313. Oparil S, Weber MA. Hypertension: companion to Brenner & Rector´s: the kidney. 2nd ed. Philadelphia: Saunders; 2005. p. 522-9., because FDC often associates two drugs at non-maximum doses capable of reducing BP without leading to the adverse events that result from their use at higher doses; or the undesired effects of the drugs are balanced or even suppressed because of their combined action.
Blood pressure should be reduced over days or weeks, rather than abruptly within a few hours, which can lead to either mild adverse events, such as vertigo and visual blurring, or even severe events, especially in the elderly1313. Oparil S, Weber MA. Hypertension: companion to Brenner & Rector´s: the kidney. 2nd ed. Philadelphia: Saunders; 2005. p. 522-9.. To avoid adverse events in patients with co-morbidities or orthostatic hypotension, previous dose adjustment with the non-FDC is necessary, and should be initiated with low doses.
Evidence in cardiovascular outcomes
The benefits of combined therapy have been demonstrated in a meta-analysis showing reductions of 63% and 46% in stroke and coronary artery disease (CAD), respectively, as compared to monotherapy77. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326(7404):1427-35.. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) and (International Verapamil SR and Trandolapril (INVEST) Study have evidenced that BP reduction in a shorter period of time reduces the risk of events and death1515. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al; VALUE trial group.Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363(9426):2022-31. , 1616. Jamerson K, Weber MA, BakrisGL, Dahlöf B, Pitt B, Shi V, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-28..
The Avoiding Cardiovascular Events through combination Therapy (ACCOMPLISH) Study, which tested a new treatment strategy for AH, has compared two FDC (Benazepril + Amlodipine vs. Benazepril + hydrochlorothiazide). In the benazepril + amlodipine group, a 15% reduction in CV morbidity and mortality was observed in high CV-risk hypertensive patients as compared to the other group, leading to early interruption of the study by the data monitoring committee1717. Jamerson KA, Bakris GL, Wun CC, Dahlöf B, Lefkowitz M, Manfreda S, et al. Rationale and design of the avoiding cardiovascular events through combination therapy in patients living with systolic hypertension (ACCOMPLISH) trial: the first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension. Am J Hypertens. 2004;17(9):793-801..
Some combinations, however, need to be reassessed, and should be avoided until new evidence appears, because they might not be beneficial to patients. In the Ongoing Telmisartan Alone and in Combination with Ramipril Trial (ONTARGET) and in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) with double renin-angiotensin system blockade, there was no reduction in morbidity and mortality, but significant worsening of kidney function and hypotension1818. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547-59. , 1919. Parving HH, Brenner BM, McMurray JJ,de Zeeuw D, Haffner SM, Solomon SD, et al; ALTITUDE Investigators. Cardiorenalend points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204-13..
Double combinations of antihypertensive drugs
There are several classes of antihypertensive drugs, making a large amount of combinations possible (fig. 1).
Possible combination of antihypertensive drugs: continuous green line (preferential combinations); dotted green line (acceptable combinations); dotted black line (less usual combinations); red line (unusual combinations). Modified from Mancia et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension. ARB: angiotensin receptor blocker; CCA: calcium channel antagon ist; ACEI: angiotensin-converting-enzyme inhibitor.
• Renin-angiotensin system inhibitors + diuretics
The combination of an ACEI, an ARB or a DRI with a thiazide diuretic (hydrochlorothiazide, chlorthalidone or indapamide) at low doses results in a significant additional effect on BP reduction. In addition, that association attenuates the reflex activation of the renin-angiotensin-aldosterone system (RAAS) by diuretics and hypokalemia in susceptible patients2020. MacKayJH, Arcuri KE, Goldberg AI, Snapinn SM, Sweet CS. Losartan and low-dose hydrochlorothiazide in patients with essential hypertension: a double-blind, placebo-controlled trial of concomitant administration compared with individual components. Arch Intern Med. 1996;156(3):278-85..
Based on the efficacy, safety and favorable performance of those agents, fixed combinations of ACEI or ARB with diuretics are preferential. Most fixed combinations use hydrochlorothiazide as a diuretic, although chlorthalidone has shown to be more effective in reducing BP and CV outcomes2121. Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006;47(3):352-8..
The best evidence of the reduction of overall and CV mortality in hypertensive individuals by use of the association of ACEI or ARB with thiazide diuretics was observed with indapamide, which also needs to be considered preferential relative to hydrochlorothiazide2222. Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, et al; ADVANCE Collaborative Group. 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;370(9590):829-40..
• Renin-angiotensin system inhibitors + calcium channel antagonists
That combination results in a significant BP reduction2323. Chrysant SG, Melino M, Karki S, Lee J, Heyrman R. The combination of olmesartanmedoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind, controlled, 8-week factorial efficacy and safety study. ClinTher. 2008;30(4):587-604. and improves, via sympatholytic and venodilating actions of ACEI or ARB, tolerance to CCA, attenuating reflex tachycardia and peripheral edema caused by the predominant arteriole dilation of CCA2424. Gradman AH, Cutler NR, Davis PJ, Robbins JA, Weiss RJ, Wood BC, et al. Combined enalapril and felodipine extended release (ER) for systemic hypertension. Enalapril-Felodipine ER Factorial Study Group. Am J Cardiol. 1997;79(4):431-5.. The ACCOMPLISH study has compared clinical outcomes in high-risk hypertensive patients receiving the combinations of ACEI + CCA or ACEI + diuretics. The ACEI + CCA group showed a higher and significant BP reduction and a 20% decrease in the incidence of combined outcomes (CV mortality, myocardial infarction and stroke) as compared to the ACEI + diuretics group. It is worth noting that 60% of the patients had diabetes and a high percentage showed evidence of CAD1717. Jamerson KA, Bakris GL, Wun CC, Dahlöf B, Lefkowitz M, Manfreda S, et al. Rationale and design of the avoiding cardiovascular events through combination therapy in patients living with systolic hypertension (ACCOMPLISH) trial: the first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension. Am J Hypertens. 2004;17(9):793-801..
• Calcium channel antagonists + thiazide diuretics
That combination results in an additive effect with small repercussion on BP, probably due to the overlap of their pharmacological effects2525. Salvetti A, Magagna A, Innocenti P, Ponzanelli F, Cagianelli A, Cipriani M, et al. The combination of chlorthalidone with nifedipine does not exert an additive antihypertensive effect in essential hypertensives: a crossover multicenter study. J CardiovascPharmacol.1991;17(2):332-5.. Calcium channel antagonists increase the renal excretion of sodium, although not with the same potency of diuretics, and, in the long run, both showed vasodilation with no volume depletion. The VALUE study1515. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al; VALUE trial group.Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363(9426):2022-31. has shown no unfavorable effects of the addition of hydrochlorothiazide to patients randomized to use amlodipine. Therefore, that is considered a possible combination.
• Beta-blockers + thiazide diuretics
Although BBs have shown the ability to reduce clinical outcomes in placebo-controlled studies, meta-analyses (mainly with atenolol) have suggested that BBs are less effective than diuretics, ACEIs, ARBs and CCAs2626. Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005;366(9496):1545-53.. Similarly to ACEIs and ARBs, BBs attenuate the RAAS activation induced by diuretics resulting in additional BP reduction. The addition of diuretics also improves BB effectiveness in Afrodescendant individuals and others with AH and low renin levels. It is worth noting that such association might increase the risk for developing glucose intolerance, fatigue and sexual dysfunction2727. Frishman WH, Bryzinski BS, Coulson LR, De Quattro VL, Vlachakis ND, Mroczek WJ, et al. A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide. Arch Intern Med. 1994;154(13):1461-8. Erratum in Arch Intern Med. 1995;155(7):709..
• Thiazide diuretics + potassium-saving diuretics
The fixed combination of either hydrochlorothiazide or chlorthalidone with amiloride can potentiate even more BP reduction, preserving potassium plasma levels (important in the AH treatment, considering the potassium vasodilating actions), and reducing the incidence of hypokalemia2828. Guerrero P, Fuchs FD, Moreria LM, Martins VM, Bertoluci C, Fuchs SC. Blood pressure-lowering efficacy of amiloride versus enalapril as add-on drugs in patients with uncontrolled blood pressure receiving hydrochlorothiazide. Clin Exp Hypertens. 2008;30(7):553-64.. In addition, there is evidence of the superiority of chlorthalidone relative to hydrochlorothiazide, because of its longer half-life, greater potency and higher number of studies showing a reduction in CV outcomes44. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The AntihypertensiveandLipid-LoweringTreatmenttoPrevent Heart AttackTrial.Major outcomes in high risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-97.Erratum in JAMA. 2004;291(18):2196, JAMA. 2003;289(2):178.. The association with amiloride is considered acceptable in individuals with preserved kidney function (glomerular filtration > 50 mL/min/1.73 m2). Glomerular filtration rates below that value increase the risk of hyperkalemia2929. Khosla N, Kalaitzidis R, Bakris GL. Predictors of hyperkalemia risk following hypertension control with aldosterone blockade. Am J Nephrol. 2009;30(5):418-24..
• Calcium channel antagonists + beta-blockers
The pharmacological effects of those two classes of drugs are complementary in reducing BP. The Metoprolol Succinate-Felodipine Antihypertension Combination Trial (M-FACT), a combination of low doses of felodipine and metoprolol, both of prolonged release, has reported a BP reduction comparable to that of maximum doses of each drug separately, and edema incidence similar to that of placebo3030. Frishman WH, Hainer JW, Sugg J; M-FACT Study Group. A factorial study of combination hypertension treatment with metoprolol succinate extended release and felodipine extended release results of the Metoprolol Succinate-Felodipine Antihypertension Combination Trial (M-FACT). J Clin Hypertens. 2006;19(4):388-95.. The combination of BB with dihydropyridine CCA is considered acceptable, but that with non-dihydropyridine CCA, such as verapamil and diltiazem, should be avoided because of its additional effect on heart rate and atrioventricular conduction, which can result in severe bradycardia and/or atrioventricular blocks.
Unusual combinations
• Angiotensin-converting-enzyme inhibitors + type 1 angiotensin-receptor blocker
The combination of ACEI with ARB is not recommended. That combination has a small
additional effect on BP reduction, comparable to the reduction determined by each
agent isolated. The ONTARGET trial has reported that patients on the
telmisartan/ramipril combination, as compared to others using those drugs in
isolation, showed no improvement in CV outcomes despite the additional BP reduction,
on average, 2.4/1.4 mm Hg; in addition, more side effects were observed with that
combination than with those drugs in isolation1818. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al;
ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for
vascular events. N Engl J Med. 2008;358(15):1547-59.
19. Parving HH, Brenner BM, McMurray JJ,de Zeeuw D, Haffner SM, Solomon
SD, et al; ALTITUDE Investigators. Cardiorenalend points in a trial of aliskiren for
type 2 diabetes. N Engl J Med. 2012;367(23):2204-13.
20. MacKayJH, Arcuri KE, Goldberg AI, Snapinn SM, Sweet CS. Losartan and
low-dose hydrochlorothiazide in patients with essential hypertension: a double-blind,
placebo-controlled trial of concomitant administration compared with individual
components. Arch Intern Med. 1996;156(3):278-85.
21. Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB,
Zimmerman MB, et al. Comparative antihypertensive effects of hydrochlorothiazide and
chlorthalidone on ambulatory and office blood pressure. Hypertension.
2006;47(3):352-8.
22. Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, et
al; ADVANCE Collaborative Group. 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;370(9590):829-40.
23. Chrysant SG, Melino M, Karki S, Lee J, Heyrman R. The combination of
olmesartanmedoxomil and amlodipine besylate in controlling high blood pressure:
COACH, a randomized, double-blind, controlled, 8-week factorial efficacy and safety
study. ClinTher. 2008;30(4):587-604.
24. Gradman AH, Cutler NR, Davis PJ, Robbins JA, Weiss RJ, Wood BC, et
al. Combined enalapril and felodipine extended release (ER) for systemic
hypertension. Enalapril-Felodipine ER Factorial Study Group. Am J Cardiol.
1997;79(4):431-5.
25. Salvetti A, Magagna A, Innocenti P, Ponzanelli F, Cagianelli A,
Cipriani M, et al. The combination of chlorthalidone with nifedipine does not exert
an additive antihypertensive effect in essential hypertensives: a crossover
multicenter study. J CardiovascPharmacol.1991;17(2):332-5.
26. Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain
first choice in the treatment of primary hypertension? A meta-analysis. Lancet.
2005;366(9496):1545-53.
27. Frishman WH, Bryzinski BS, Coulson LR, De Quattro VL, Vlachakis ND,
Mroczek WJ, et al. A multifactorial trial design to assess combination therapy in
hypertension. Treatment with bisoprolol and hydrochlorothiazide. Arch Intern Med.
1994;154(13):1461-8. Erratum in Arch Intern Med. 1995;155(7):709.
28. Guerrero P, Fuchs FD, Moreria LM, Martins VM, Bertoluci C, Fuchs SC.
Blood pressure-lowering efficacy of amiloride versus enalapril as add-on drugs in
patients with uncontrolled blood pressure receiving hydrochlorothiazide. Clin Exp
Hypertens. 2008;30(7):553-64.
29. Khosla N, Kalaitzidis R, Bakris GL. Predictors of hyperkalemia risk
following hypertension control with aldosterone blockade. Am J Nephrol.
2009;30(5):418-24.
30. Frishman WH, Hainer JW, Sugg J; M-FACT Study Group. A factorial
study of combination hypertension treatment with metoprolol succinate extended
release and felodipine extended release results of the Metoprolol
Succinate-Felodipine Antihypertension Combination Trial (M-FACT). J Clin Hypertens.
2006;19(4):388-95.
-
3131. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al;
ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for
vascular events. N Engl J Med. 2008;358(15):1547-59..
• Direct renin inhibitor + renin-angiotensin system inhibitors
That combination has an additive effect on BP reduction; however, studies on morbidity and mortality reduction with that association have found no benefits, therefore, it is not recommended1919. Parving HH, Brenner BM, McMurray JJ,de Zeeuw D, Haffner SM, Solomon SD, et al; ALTITUDE Investigators. Cardiorenalend points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204-13..
• Renin-angiotensin system inhibitors + beta-blockers
Those drugs are cardioprotective and frequently administered to individuals with CAD and/or heart failure. When combined, however, a small additional BP reduction, comparable to that of their isolated use, is observed3232. Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised double-blind trial. Lancet. 2007;370(9583):221-9. Erratum in: Lancet. 2007;370(9598):1542.. Therefore, that is a less effective association when the goal is BP reduction.
• Beta-blockers + central action drugs
Beta-blockers and central action drugs (clonidine and alpha-methyldopa) interfere with the sympathetic nervous system. The extent of BP reduction with that combination has not been assessed. That combination can cause important bradycardia or atrioventricular block. In addition, individuals on that combination, who suddenly discontinued their treatment, had rebound hypertension. Therefore, that is considered a less effective combination3333. Mehta JL, Lopez LM. Rebound hypertension following abrupt cessation of clonidine and metoprolol. Treatment with labetalol. Arch Intern Med. 1987;147(2):389-90..
Triple and quadruple combinations
Triple combination
In 15% to 20% of hypertensive patients, the double combination is estimated not to be effective to achieve BP goal, requiring the triple combination22. Mancia G, Laurent S, Agabiti-Rosei E, Burnier M, Caulfield MJ, Cifkova R, et al. Reappraisal of Europeanguidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press.2009;18(6):308-47..
The triple combination in one single tablet has proven to be more effective than the separate use of the three drugs, relative to both treatment adherence and abandonment risk, with improvements of 29% and 24%, respectively66. Gupta AK, Arshad S, Poulter NR. Compliance, safety and effectiveness of fixed-dose combinations of anti-hypertensive agents:ameta-analysis. Hypertension. 2010;55(2):399-407..
The use of the triple combination in one single tablet has been associated with faster BP control and consequent greater reduction in CV risk as compared with monotherapy followed by the double combination, contributing, thus, to improve therapeutic inercia3434. Gradman AH, Parise H, Lafeuille MH, et al. Impact of initial antihypertensive treatment with a single-pill combination on blood pressure (BP) goal attainment: a matched cohort study [abstract]. J Clin Hypertens. 2011;13(Suppl 1):A128, p. 26..
When triple therapy is indicated, combining an ACEI or ARB with a CCA and a diuretic is recommended as the most rational and effective association22. Mancia G, Laurent S, Agabiti-Rosei E, Burnier M, Caulfield MJ, Cifkova R, et al. Reappraisal of Europeanguidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press.2009;18(6):308-47..
Calhoun et al3535. Calhoun DA, Lacourciere Y, Chiang YT, Glazer RD. Triple
antihypertensive therapy with amlodipine, valsartan, and hydrochlorothiazide: a
randomized clinical trial. Hypertension. 2009;54(1):32-9., assessing the association
of valsartan, amlodipine and hydrochlorothiazide, have found more marked BP
reductions and a higher proportion of goals achieved as compared with the double
combinations of those drugs. In the Triple Therapy with Olmesartan Medoxomil,
Amlodipine and Hydrochlorothiazide in Hypertensive Patients (TRINITY) Study, the
triple combination of olmesartan, amlodipine and hydrochlorothiazide has resulted
in a significant reduction in SBP and DBP as compared with each double
association3636. Oparil S, Melino M, Lee J, Fernandez V, Heyrman R. Triple therapy
with olmesartanmedoxomil, amlodipine besylate, and hydrochlorothiazide in adult
patients with hypertension: the TRINITY multicenter, randomized, double-blind,
12-week, parallel-group study. Clin Ther. 2010;32(7):1252-69.. The triple association of
aliskiren, amlodipine and hydrochlorothiazide has yielded reductions of 16.3 ± 8.2
mm Hg and 11.4 ± 4.9 mm Hg in SBP and DBP, respectively, in patients with severe
AH, and such reductions were greater than those obtained with double
combinations3737. Novartis gains FDA approval for Amturnide(tm), a triple-combination
pill to treat high blood pressure in patients uncontrolled on two medications.
Novartis Pharmaceuticals Corporation. [Acessed in 2013 Feb 10]. Available from:
http://www.pharma.us.novartis.com/assets/pdf/pressreleases/FINAL_US_Amturnide_FDA_Approval_Press_Release.pdf.
http://www.pharma.us.novartis.com/assets...
.
Quadruple therapy
The combination of four drugs in AH relates to resistant hypertension3838. Alessi A, Brandão AA, Coca A, Cordeiro AC, Nogueira AR, Diógenes de Magalhães F, et al. I Posicionamento Brasileiro sobre hipertensão arterial resistente. Arq Bras Cardiol. 2012;99(1):576-85. Erratum in Arq Bras Cardiol. 2013;100(3):304.. The choice of the fourth drug involves a lot of discussion, because of the lack of studies with appropriate design to answer that question, regarding both antihypertensive efficacy and CV protection. The mineralocorticoid receptor blocker is the most indicated fourth drug to be associated, because it promotes significant additional BP reductions, as shown in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), regardless of the aldosterone/renin plasma activity ratio3939. Chapman N, Dobson J, Wilson S, Dahlöf B, Sever PS, Wedel H, et al; Anglo-Scandinavian Cardiac Outcomes Trial Investigators. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension. 2007;49(4):839-45.. In case of either intolerance to spironolactone or not achieving BP goal, the fourth drug can be clonidine, BB or direct vasodilators.
Strategy in left ventricular hypertrophy
The major manifestation of hypertensive disease is LVH, present in 36% to 41% of the
patients and an independent predictor of CV complications. Patients with LVH have a
2-4 times increased risk for cardiac and cerebrovascular events4040. Cuspidi C, Sala C, Negri F, Mancia G, Morganti A; Italian Society of
Hypertension. Prevalence of left-ventricular hypertrophy in hypertension: an updated
review of echocardiographic studies. J Hum Hypertens.
2012;26(6):343-9.. The presence of target-organ lesions, regardless of the
hypertensive stage, already indicates high to very high CV risk, and the combination
of antihypertensive drugs should be the initial strategy11. Sociedade Brasileira de Cardiologia. Departamento de Hipertensão
Arterial. VI Diretrizes brasileiras de hipertensão. Rev Bras Hipertens.
2010;17(1):4-62.. In monotherapy, the most effective drugs to reduce LVH are
ARBs and ACEIs, followed by CCAs, BBs and diuretics. Some clinical trials comparing
those classes of drugs have eventually used double or even triple combined therapy to
reduce BP and achieve the goals proposed. Several studies have reported that double
or triple combinations were more effective to reduce left ventricular mass and CV
mortality4141. Devereux RB, Dahlöf B, Gerdts E, Boman K, Nieminen MS, Papademetriou
V, 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(11):1456-62.
42. Dahlöf B, Gosse P, Guéret P, Dubourg O, de Simone G, Schmieder R, et
al; PICXEL Investigators. Perindopril/indapamide combination more effective than
enalapril in reducing blood pressure and left ventricular mass: the PICXEL study. J
Hypertens. 2005;23(11):2063-70.
-
4343. Barrios V, Escobar C, Calderón A, Tomás JP, Ruiz S, Moya JL, et al.
Regression of left ventricular hypertrophy by a candesartan-based regimen in clinical
practice. The VIPE study. J Renin Angiotensin Aldosterone Syst. 2006;7(4):236-42.
Erratum in: J Renin Angiotensin Aldosterone Syst. 2007;8(1):33..
Patient with chronic kidney disease
Chronic kidney disease (CKD) in hypertensive individuals is usually associated with volume overload and RAAS activation. Those patients require combined therapy, in which RAAS blockers should be preferred in association with other antihypertensive drugs4444. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 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). Eur Heart J. 2013;34(28):2159-219..
The use of ACEIs or ARBs is more effective in preventing the progressive deterioration of kidney function than that of other antihypertensive drugs, in patients with and without diabetes, with and without proteinuria4545. Sharma P, Blackburn RC, Parke CL, McCullough K, Marks A, Black C. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD007751..
For patients with AH and CKD without proteinuria, the first-line drug class has not been well established, and, thus, other drug classes can be used. In those patients, hydrosaline retention often occurs, thus requiring the use of diuretics (thiazide and loop diuretics)4646. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-72. Erratum in: JAMA. 2003;290(2):197..
Other drugs that can be associated in the presence of CKD are CCAs, which are considered the second or third option to treat AH with CKD4646. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-72. Erratum in: JAMA. 2003;290(2):197. , 4747. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-266.. Although no significant differences in BP reduction were observed with the use of dihydropyridines (amlodipine and nifedipine) and non-dihydropyridines (verapamil, diltiazem), the latter have been able to reduce proteinuria, either in monotherapy or in association with ACEIs or ARBs4848. Bakris GL, Weir MR, Secic M, Campbell B, Weis-McNulty A. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int. 2004;65(6):1991-2002..
Aldosterone antagonists have reduced proteinuria when used in association with ACEIs or ARBs, and can be the third or fourth option in drug combination in selected cases and in gross proteinuria4949. Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease. Clin J Am Soc Nephrol. 2009;4(3):542-51. , 5050. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol. 2009;20(12):2641-50.. However, the possibility of hyperkalemia should be considered.
Although aliskiren improves albuminuria, its association with ACEIs or ARBs has the risk of kidney function worsening, hyperkalemia and hypotension in hypertensive individuals with diabetes and CKD5151. US Department of Health and Human Services. Aliskiren-containing medications: drug safety communication - new warning and contraindication. US Food and Drug Administration [on line]; 2012..
The use of BB in the presence of CKD is indicated when there is CAD and/or heart failure associated4646. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-72. Erratum in: JAMA. 2003;290(2):197..
Combinations in diabetes and metabolic syndrome
The presence of diabetes or metabolic syndrome characterizes the patient as of high CV risk, and combined therapy is indicated. The preferential combinations are either ACEIs or ARBs in association with CCAs, because of metabolic neutrality. When a third drug is needed, a thiazide diuretic at low doses is preferred5252. Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-28. , 5353. Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al; ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo- Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366(9489):895-906..
The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, using perindopril and indapamide combined for patients with diabetes, has shown a reduction in overall mortality and in micro- and macrovascular outcomes; therefore, that is a treatment alternative5454. Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, et al; ADVANCE Collaborative Group. 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;370(9590):829-40..
Combinations in coronary artery and cerebrovascular diseases
For hypertensive individuals with CAD or after acute myocardial infarction, the therapeutic classes of BBs, ACEIs, ARBs and dihydropyridine CCAs have priority of use. The association of an ACEI and a BB is preferential, mainly after myocardial infarction. If intolerance to an ACEI occurs, it should be replaced by an ARB. Thiazide diuretics and aldosterone antagonists have a more restrict indication.
In patients with cerebrovascular disease, the association of thiazide diuretics and ACEIs is preferential, and an ARB can replace the ACEI, if not tolerated. The CCA is more restrict to acute cerebral events, its use being reserved to six hours after the event or in patients whose BP is greater than 180/115 mmHg5555. Rosendorff C, Black HR, Cannon CP, Gersh BJ, Gore J, Izzo JL Jr, et al; American Heart Association Council for High Blood Pressure Research; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Epidemiology and Prevention. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation. 2007;115(21):2761-88. , 5656. Sever PS, Messerli FH. Hypertension management 2011: optimal combination therapy. Eur Heart J. 2011;32(20):2499-506.. Evidence has suggested that the benefit of reducing cerebrovascular disease in hypertensive individuals is mainly due to BP reduction. Thus, all drugs available and their rational combinations can be used5555. Rosendorff C, Black HR, Cannon CP, Gersh BJ, Gore J, Izzo JL Jr, et al; American Heart Association Council for High Blood Pressure Research; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Epidemiology and Prevention. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation. 2007;115(21):2761-88..
Certain drug combinations are more favorable in the presence of CAD and AH. Associating a BB with an ACEI can suggest a less usual combination, but that is the most effective in that situation.
Drug combination in the elderly
The antihypertensive drug treatment in the elderly reduces CV outcomes and helps to prevent CKD and dementia syndromes5757. Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, et al; PROGRESS Collaborative Group. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003;163(9):1069-75.. The use of combined therapy in the elderly, preferably of FDC, provides the opportunity to solve some frequent situations of that age group, such as isolated systolic hypertension, and improves arterial stiffness and adherence to treatment.
Combined therapy should be initiated with low doses, which should be increased slowly and gradually, and periodic review of its effect performed. That is important, because the hypotension symptoms in the elderly often present atypically as sleepiness, vertigo and mental confusion.
Creatinine clearance should be estimated in all elderly patients, because CKD is common in that age group and plasma creatinine does not reflect kidney function. The Cockcroft and Gault equation is the most used for that purpose5858. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41..
The greatest evidence of a reduction in CV outcomes in the elderly is the Hypertension in the Very Elderly Trial (HYVET), which used ACEIs in association with indapamide5959. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887-98.. Current evidence suggests that the association of a RAAS blocker with a dihydropyridine CCA can be better to reduce CV outcomes6060. Jamerson K, Weber M, Bakris GL, Dahlöf B, Pitt B, Shi V, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-28.. The benefits of that combination, at least in part, are speculated to be associated with a greater reduction in central BP6161. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al; CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial 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;113(9):1213-25..
Thiazide diuretics can have beneficial effects on osteoporosis, which is frequent in female elderly. Patients older than 80 years are at higher risk for arterial hypotension and co-morbidities. The SBP reduction to 150-140 mm Hg in that age group had a great impact on decreasing CV mortality and morbidity5959. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887-98. , 6262. Aronow WS, Fleg JL, Pepine CJ, Artinian NT, Bakris G, Brown AS, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. J Am Soc Hypertens. 2011;5(4):259-352..
Referências
-
1Sociedade Brasileira de Cardiologia. Departamento de Hipertensão Arterial. VI Diretrizes brasileiras de hipertensão. Rev Bras Hipertens. 2010;17(1):4-62.
-
2Mancia G, Laurent S, Agabiti-Rosei E, Burnier M, Caulfield MJ, Cifkova R, et al. Reappraisal of Europeanguidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press.2009;18(6):308-47.
-
3Gradman AH, Basile JN, Carter BL, Bakris GL;American Society of HypertensionWritingGroup. Combination therapy in hypertension. J Am SocHypertens. 2010;4(1):42-50.Erratum in: J AmSocHypertens. 2010;4(2):99.
-
4ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The AntihypertensiveandLipid-LoweringTreatmenttoPrevent Heart AttackTrial.Major outcomes in high risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-97.Erratum in JAMA. 2004;291(18):2196, JAMA. 2003;289(2):178.
-
5Sever PS,Messerli MH. Hypertension management 2011: optimal combination therapy. Eur Heart J . 2011;32(20):2499-506.
-
6Gupta AK, Arshad S, Poulter NR. Compliance, safety and effectiveness of fixed-dose combinations of anti-hypertensive agents:ameta-analysis. Hypertension. 2010;55(2):399-407.
-
7Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326(7404):1427-35.
-
8Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. HOT StudyGroup. Lancet. 1998;351(9118):1755-62.
-
9Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet. 2002;359(9311):995-1003.
-
10MouradJJ, Waeber B, ZannadF, Laville M, Duru G, Andréjak M; investigators of the STRATHE trial. Comparison of different therapeutic strategies in hypertension: a low-dose combination of perindopril / indapamide versus a sequential monotherapy or a stepped-care approach. J Hypertens. 2004;22(12):2379-86. Erratum in J Hypertens.2007;25(1):258.
-
11Gradman AH, Basile JN, Carter BL, Bakris GL;American Society of Hypertension Writing Group. Combination therapy in hypertension. J ClinHypertens (Greenwich). 2011;13(3):146-54.
-
12Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55(2):399-407.
-
13Oparil S, Weber MA. Hypertension: companion to Brenner & Rector´s: the kidney. 2nd ed. Philadelphia: Saunders; 2005. p. 522-9.
-
14Dusing R. Otimizing blood pressure control through the use of fixed combinations. Vasc Health Risk Manag. 2010;6:321-5.
-
15Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al; VALUE trial group.Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363(9426):2022-31.
-
16Jamerson K, Weber MA, BakrisGL, Dahlöf B, Pitt B, Shi V, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-28.
-
17Jamerson KA, Bakris GL, Wun CC, Dahlöf B, Lefkowitz M, Manfreda S, et al. Rationale and design of the avoiding cardiovascular events through combination therapy in patients living with systolic hypertension (ACCOMPLISH) trial: the first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension. Am J Hypertens. 2004;17(9):793-801.
-
18Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547-59.
-
19Parving HH, Brenner BM, McMurray JJ,de Zeeuw D, Haffner SM, Solomon SD, et al; ALTITUDE Investigators. Cardiorenalend points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204-13.
-
20MacKayJH, Arcuri KE, Goldberg AI, Snapinn SM, Sweet CS. Losartan and low-dose hydrochlorothiazide in patients with essential hypertension: a double-blind, placebo-controlled trial of concomitant administration compared with individual components. Arch Intern Med. 1996;156(3):278-85.
-
21Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006;47(3):352-8.
-
22Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, et al; ADVANCE Collaborative Group. 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;370(9590):829-40.
-
23Chrysant SG, Melino M, Karki S, Lee J, Heyrman R. The combination of olmesartanmedoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind, controlled, 8-week factorial efficacy and safety study. ClinTher. 2008;30(4):587-604.
-
24Gradman AH, Cutler NR, Davis PJ, Robbins JA, Weiss RJ, Wood BC, et al. Combined enalapril and felodipine extended release (ER) for systemic hypertension. Enalapril-Felodipine ER Factorial Study Group. Am J Cardiol. 1997;79(4):431-5.
-
25Salvetti A, Magagna A, Innocenti P, Ponzanelli F, Cagianelli A, Cipriani M, et al. The combination of chlorthalidone with nifedipine does not exert an additive antihypertensive effect in essential hypertensives: a crossover multicenter study. J CardiovascPharmacol.1991;17(2):332-5.
-
26Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005;366(9496):1545-53.
-
27Frishman WH, Bryzinski BS, Coulson LR, De Quattro VL, Vlachakis ND, Mroczek WJ, et al. A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide. Arch Intern Med. 1994;154(13):1461-8. Erratum in Arch Intern Med. 1995;155(7):709.
-
28Guerrero P, Fuchs FD, Moreria LM, Martins VM, Bertoluci C, Fuchs SC. Blood pressure-lowering efficacy of amiloride versus enalapril as add-on drugs in patients with uncontrolled blood pressure receiving hydrochlorothiazide. Clin Exp Hypertens. 2008;30(7):553-64.
-
29Khosla N, Kalaitzidis R, Bakris GL. Predictors of hyperkalemia risk following hypertension control with aldosterone blockade. Am J Nephrol. 2009;30(5):418-24.
-
30Frishman WH, Hainer JW, Sugg J; M-FACT Study Group. A factorial study of combination hypertension treatment with metoprolol succinate extended release and felodipine extended release results of the Metoprolol Succinate-Felodipine Antihypertension Combination Trial (M-FACT). J Clin Hypertens. 2006;19(4):388-95.
-
31Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547-59.
-
32Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised double-blind trial. Lancet. 2007;370(9583):221-9. Erratum in: Lancet. 2007;370(9598):1542.
-
33Mehta JL, Lopez LM. Rebound hypertension following abrupt cessation of clonidine and metoprolol. Treatment with labetalol. Arch Intern Med. 1987;147(2):389-90.
-
34Gradman AH, Parise H, Lafeuille MH, et al. Impact of initial antihypertensive treatment with a single-pill combination on blood pressure (BP) goal attainment: a matched cohort study [abstract]. J Clin Hypertens. 2011;13(Suppl 1):A128, p. 26.
-
35Calhoun DA, Lacourciere Y, Chiang YT, Glazer RD. Triple antihypertensive therapy with amlodipine, valsartan, and hydrochlorothiazide: a randomized clinical trial. Hypertension. 2009;54(1):32-9.
-
36Oparil S, Melino M, Lee J, Fernandez V, Heyrman R. Triple therapy with olmesartanmedoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension: the TRINITY multicenter, randomized, double-blind, 12-week, parallel-group study. Clin Ther. 2010;32(7):1252-69.
-
37Novartis gains FDA approval for Amturnide(tm), a triple-combination pill to treat high blood pressure in patients uncontrolled on two medications. Novartis Pharmaceuticals Corporation. [Acessed in 2013 Feb 10]. Available from: http://www.pharma.us.novartis.com/assets/pdf/pressreleases/FINAL_US_Amturnide_FDA_Approval_Press_Release.pdf.
» http://www.pharma.us.novartis.com/assets/pdf/pressreleases/FINAL_US_Amturnide_FDA_Approval_Press_Release.pdf -
38Alessi A, Brandão AA, Coca A, Cordeiro AC, Nogueira AR, Diógenes de Magalhães F, et al. I Posicionamento Brasileiro sobre hipertensão arterial resistente. Arq Bras Cardiol. 2012;99(1):576-85. Erratum in Arq Bras Cardiol. 2013;100(3):304.
-
39Chapman N, Dobson J, Wilson S, Dahlöf B, Sever PS, Wedel H, et al; Anglo-Scandinavian Cardiac Outcomes Trial Investigators. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension. 2007;49(4):839-45.
-
40Cuspidi C, Sala C, Negri F, Mancia G, Morganti A; Italian Society of Hypertension. Prevalence of left-ventricular hypertrophy in hypertension: an updated review of echocardiographic studies. J Hum Hypertens. 2012;26(6):343-9.
-
41Devereux RB, Dahlöf B, Gerdts E, Boman K, Nieminen MS, Papademetriou V, 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(11):1456-62.
-
42Dahlöf B, Gosse P, Guéret P, Dubourg O, de Simone G, Schmieder R, et al; PICXEL Investigators. Perindopril/indapamide combination more effective than enalapril in reducing blood pressure and left ventricular mass: the PICXEL study. J Hypertens. 2005;23(11):2063-70.
-
43Barrios V, Escobar C, Calderón A, Tomás JP, Ruiz S, Moya JL, et al. Regression of left ventricular hypertrophy by a candesartan-based regimen in clinical practice. The VIPE study. J Renin Angiotensin Aldosterone Syst. 2006;7(4):236-42. Erratum in: J Renin Angiotensin Aldosterone Syst. 2007;8(1):33.
-
44Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 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). Eur Heart J. 2013;34(28):2159-219.
-
45Sharma P, Blackburn RC, Parke CL, McCullough K, Marks A, Black C. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD007751.
-
46Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-72. Erratum in: JAMA. 2003;290(2):197.
-
47National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-266.
-
48Bakris GL, Weir MR, Secic M, Campbell B, Weis-McNulty A. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int. 2004;65(6):1991-2002.
-
49Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease. Clin J Am Soc Nephrol. 2009;4(3):542-51.
-
50Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol. 2009;20(12):2641-50.
-
51US Department of Health and Human Services. Aliskiren-containing medications: drug safety communication - new warning and contraindication. US Food and Drug Administration [on line]; 2012.
-
52Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-28.
-
53Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al; ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo- Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366(9489):895-906.
-
54Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, et al; ADVANCE Collaborative Group. 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;370(9590):829-40.
-
55Rosendorff C, Black HR, Cannon CP, Gersh BJ, Gore J, Izzo JL Jr, et al; American Heart Association Council for High Blood Pressure Research; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Epidemiology and Prevention. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation. 2007;115(21):2761-88.
-
56Sever PS, Messerli FH. Hypertension management 2011: optimal combination therapy. Eur Heart J. 2011;32(20):2499-506.
-
57Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, et al; PROGRESS Collaborative Group. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003;163(9):1069-75.
-
58Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41.
-
59Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887-98.
-
60Jamerson K, Weber M, Bakris GL, Dahlöf B, Pitt B, Shi V, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-28.
-
61Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al; CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial 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;113(9):1213-25.
-
62Aronow WS, Fleg JL, Pepine CJ, Artinian NT, Bakris G, Brown AS, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. J Am Soc Hypertens. 2011;5(4):259-352.
Publication Dates
-
Publication in this collection
Mar 2014
History
-
Received
13 Nov 2013 -
Reviewed
03 Dec 2013 -
Accepted
03 Dec 2013