Pharmacological considerations in the choice of antihypertensive monotherapy or combination therapy



by B. Lévy, France

Bernard LÉVY, MD, PhD
INSERM & Vessels and Blood
Institute, Hôpital Lariboisière
Paris, FRANCE




Over 50 years of investigation have not defined the molecular mechanisms that underlie arterial hypertension; more than 90% of cases are still called “essential hypertension,” ie, hypertension without an identified cause. Factors that increase cardiac output and/or total peripheral resistance, eg, vasoconstriction of the arterioles or reduced diuresis, will raise blood pressure, as blood pressure is directly related to these parameters. Many different pharmacological options are available to lower elevated blood pressure, and the main classes of antihypertensive drugs have been widely investigated and are well known: diuretics (thiazide-type and thiazide-like), reninangiotensin system inhibitors (angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers, and direct renin inhibitors), calcium channel blockers (CCBs), and -blockers. The variety of different pharmacological effects of these main classes reflects the diversity of mechanisms implicated in hypertension. From a pharmacological perspective, there may be good reasons for preferring antihypertensive combination therapy to monotherapy: components that act on different hypertensive mechanisms can reduce counterregulatory responses; and side effects can be attenuated via dose reduction and/or complementary pleiotropic effects of one or both components. Additional benefits of antihypertensive combinations include faster blood pressure control and greater end point reduction, and three in four hypertensive patients will ultimately require combination therapy for blood pressure control. Not all combinations are equal, and the choice of a “preferred” combination, such as ACE inhibitor/CCB, confers additional treatment benefits.

Regulation of blood pressure

Guyton’s view
Blood pressure (BP) is related to cardiac output (CO) and total peripheral resistance (TPR) by the equation BP = CO × TPR. Increases in either cardiac output or total peripheral vascular resistance produce hypertension. The control of BP by the body is an integrated response that includes regulation by neural receptors, hormones, and renal fluid balance.1 The handling of sodium within the kidney is one of the major factors that regulates BP (Figure 1, page 132). Hence, in the pathogenesis of hypertension, abnormal renal Na+ excretion increases intravascular volume, which is the primary determinant of increased cardiac output and therefore elevated BP. The importance of renal fluid balance in the control of BP is a widely accepted concept that has been extensively reviewed.2


Figure 1. Control of arterial blood pressure by dilation of arterioles
and diuresis in the kidney.
Arterial blood pressure is the product of total peripheral resistance and cardiac
output (TPR × CO). Changes in Na+ reabsorption will modify the intravascular
volume and result in an increase or decrease cardiac output and, in turn, arterial
blood pressure. Similarly, alterations in vascular tone affect the TPR, which leads
to an increase (vasoconstriction) or decrease (vasodilation) in blood pressure.
Abbreviations: Na, sodium; TPR, total peripheral resistance.




Vascular smooth muscle contraction and hypertension
A number of classes of antihypertensive agent effectively lower BP. Changes in vascular tone result in changes in total peripheral resistance and in either hyper- or hypotension, for example, vasopressor agents increase BP, whereas vasodilating drugs induce hypotension. Experimental models allow us to identify the effects of the different pathways regulating vasomotor tone. Investigators have genetically modified mice to produce abnormalities in vasomotor tone. Knock-out mice were produced and BP measured: in the β1 receptor subunit knock-out, estrogen receptor β knock-out, vascular smooth muscle cell ATP channel knock-out, and endothelial nitric oxide synthase knock-out.3 All of these mice had both vascular dysfunction and hypertension, but data from these experiments confirm that vascular dysfunction, specifically vasoconstriction, produces hypertension.

Classes of antihypertensive drugs

Diuretics
Treatment of hypertension using a diuretic-based strategy was effective in preventing stroke and cardiac disease in the earliest randomized clinical trials in the 1960s.4 Elevated BP in a large proportion of hypertensive patients, especially those of African origin, can be well controlled on simple two-drug regimens combining a diuretic with either a β-blocker or an angiotensin-converting enzyme (ACE) inhibitor. Three major diuretic classes are used to treat hypertension: (i) thiazides; (ii) loop-active agents; and (iii) potassium-sparing agents, which act as either mineralocorticoid antagonists or inhibitors of the epithelial sodium channel of the late distal renal tubule or collecting duct. Thiazide diuretics can be subdivided into thiazide- like (eg, indapamide and chlorthalidone) and thiazidetype (eg, hydrochlorothiazide) diuretics. Thiazide-like diuretics have a longer elimination half-life compared with thiazide-type diuretics and have been shown to exert additional pharmacological effects, which may be responsible for the greater reductions in cardiovascular events demonstrated by thiazidelike versus thiazide-type diuretics.5,6 Figure 2 displays the sites at which the different diuretic subclasses have their greatest effects on electrolyte and water reabsorption in the nephron after glomerular filtration has occurred.

β-Blockers
β-Blockers are competitive antagonists for endogenous catecholamines, epinephrine and norepinephrine, on adrenergic &beta-receptors. Some β-blockers bind to all types of α-adrenergic receptors, while others are more selective for β1 (in the heart and kidneys), β2 (in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle), or β3 receptors (in fat cells). β-Blockers interfere with the binding to the receptors of epinephrine and weaken its effects on the cardiovascular system. Although they are no longer the first choice for initial treatment in most patients,7 β-blockers are still widely used, particularly in hypertensive patients with concomitant coronary artery disease. However, there are several reasons why β-blockers are relatively ineffective in the prevention of cardiovascular events in hypertensive patients.8 β-Blockers have certain disadvantages compared with other antihypertensive agents:
• Brachial BP reduction is not as good
• Variability in BP between visits is large
• Central BP reduction is not equivalent
• Regression of left ventricular hypertrophy (LVH) is less marked
• Metabolic effects tend to be negative
• Vascular protection is not similar
• Adverse effects lead to diminished drug compliance

Another of the reasons for limiting the use of β-blockers in the treatment of hypertension is pharmacological: by inducing the competitive displacement of catecholamines from βto α-adrenoceptors, β-blockers unmask &lapha; receptor–mediated peripheral vasoconstriction.9,10


Calcium channels blockers
The extracellular concentration of calcium (Ca2+) is normally about 10 000-fold higher than the concentration inside cells. In vascular smooth muscle cells, an increase in intracellular calcium through membrane-embedded calcium channels induces vasoconstriction. Calcium channel blockers (CCBs) prevent or reduce the opening of these channels thereby reducing these vasomotor effects and BP elevation.

Several subclasses of CCB exist; however, almost all CCBs preferentially block the L-type voltage-gated calcium channel. These channels are responsible for excitation-contraction coupling of smooth and cardiac muscle. In the heart, they are also involved in the conduction of pacemaker signals. CCBs have three main effects:
• Reduction of vascular smooth muscle tone, vasodilation, and lowering of arterial BP
• Negative inotropic and chronotropic effects
• Reduction of aldosterone production, leading to BP lowering

Cardiac oxygen demand is reduced with the use of dihydropyridines because they lower arterial BP and afterload; at therapeutic doses, dihydropyridines do not weaken cardiac contraction nor do they modulate cardiac rhythm. The vasodilatory properties of CCBs explain common side effects, such as flushing, headache, dizziness, and hypotension. These side effects, though unwelcome, are possibly of less importance than others, like peripheral edema and ankle swelling, which often curtail the use of dihydropyridines.11

Blockers of the renin-angiotensin system
The renin-angiotensin system (RAS) is involved in the regulation of plasma sodium concentration and arterial BP. When plasma sodium concentration, and/or renal blood flow, and/or arterial pressure in the proximal glomerular artery are too low, the juxtaglomerular cells in the kidneys convert prorenin into renin, which is then secreted directly into the circulation. Plasma renin cleaves angiotensin I off the plasma protein angiotensinogen. Angiotensin I is then converted by ACE into angiotensin II, a potent vasoactive peptide that causes arterioles to constrict, resulting in increased arterial BP. Secretion of aldosterone from the adrenal cortex is regulated by angiotensin II. Aldosterone enhances ion transport in renal tubular epithelial cells in two ways: sodium ion reabsorption (from the tubular fluid back into the blood) and potassium ion excretion (into the tubular fluid) are increased (Figure 2). Increase in the concentration of sodium in blood results in an increase in intravascular volume and plays a role in increasing BP.

Three families of drugs can block the effects of the RAS: direct renin inhibitors, ACE inhibitors, and angiotensin receptor blockers (ARBs). Despite exciting promise and potential, clinical trials of direct renin inhibition have not been convincing. We will thus focus on ACE inhibitors and ARBs.

ACE inhibitors
Angiotensinogen and bradykinin are important substrates of the peptidase ACE. These substrates have a role in BP control, hematopoiesis, renal function, and immune response. Two experimental approaches have been used to discriminate between the physiological effects of angiotensin II and other ACE substrates. Firstly, mice with null mutations in ACE have been compared with mice lacking other components of the RAS, such as angiotensinogen or the angiotensin 1 (AT1) receptor. Secondly, the effects of ACE inhibitors have been compared to those of ARBs in animals and humans. Both approaches have shown that for the physiological regulation of BP, the ACE-mediated production of angiotensin II is essential.12 Both ACE inhibitors and ARBs have similar long-term effects on elevated BP in hypertension. However, because ARBs do not affect the kinin-bradykinin system, the clinical effect of ACE inhibitors and ARBs may differ substantially. Tissue and plasma bradykinin levels are elevated during the blockade of ACE. Bradykinin binds to the bradykinin receptors B1 and B2. Expression of the B1 receptor is induced by tissue injury, such as ischemia and inflammation, in contrast to B2 receptor expression, which occurs under normal conditions.14

When bradykinin binds to the B2 receptor, nitric oxide is produced and prostacyclin released, which lead to vasodilation and increased vascular permeability. At the renal level, bradykinin promotes natriuresis. Inducing bradykinin formation in experimental models of hypertension reduces BP; thus, besides reducing angiotensin II production, ACE inhibitors contribute to the control of BP by increasing the concentration of bradykinin. The effect of ACE inhibitors on bradykinin is linked to certain side effects (eg, cough), but notwithstanding this it is also linked to several beneficial effects, especially the reversal of low-grade inflammation and cardiac and vascular remodeling.

Angiotensin receptor blockers
The direct molecular targets for angiotensin II are the AT1 and AT2 receptors. The angiotensin receptor family also includes an AT4 receptor, whose ligand is not the same but rather the breakdown product of angiotensin II, angiotensin IV.15

Although ARBs and ACE inhibitors are used for the same indications (hypertension, heart failure, post–myocardial infarction), their mechanisms of action are very different. ARBs are receptor antagonists that block AT1 receptors on blood vessels and other tissues, such as the heart. AT1 receptor blockade inhibits cellular actions of angiotensin II mediated by the AT1 receptor, including mitogenic activity, cytokine production, reactive oxygen species formation, and aldosterone production. ARBs and ACE inhibitors have the following effects in common; they both:
• Diminish arterial pressure and cardiac preload and afterload by dilating arteries and veins
• Negatively modulate the sympathetic adrenergic activity by disrupting the action of angiotensin II on sympathetic nerve release and norepinephrine reuptake
• Enhance excretion of sodium and water by the kidneys by disrupting the renal action of angiotensin II and secretion of aldosterone

Several pharmacologic effects of ARBs may be attributable to actions independent of their inhibition of AT1 receptor activation with its consequent BP-lowering effect16,17; AT1 receptor blockade by ARBs also allows angiotensin II to bind to AT2 receptors, which mediates several actions. Despite the impossibility of designing a clinical trial that could unequivocally identify an AT1 receptor–independent pharmacologic effect of ARBs in patients, it has been shown that activation of the AT2 receptor in normotensive young rats results in vasodilation. Having said this, the vascular AT2 receptor phenotype switches from relaxation to contraction in spontaneously hypertensive rats18 and in ageing normotensive animals.19 The cardiovascular trophic effect of AT2 stimulation is still controversial; whereas the majority of authors have reported an antifibrotic effect with AT2 receptor stimulation,20 in experimental models the AT2 receptor has also been documented to exert a stimulatory effect in arterial and ventricular hypertrophy,21 cardiac fibrosis, and heart failure.22 Mice with AT2 receptor overexpression were found to develop severe cardiac fibrosis, heart failure, and intrinsic myocyte contractile dysfunction.23

Combinations of antihypertensive drugs

Despite the usual recommendation of initial monotherapy, the use of initial combination therapy in a broad population of hypertensive patients may facilitate key objectives of treatment, like rapid control of BP and reduction in long-term end points. In fact, several large clinical trials have shown that in patients with hypertension and one or more other cardiovascular risk factors, treatment with multiple antihypertensive medications is generally necessary to attain BP goals recommended by guidelines. Combination therapy is necessary in approximately 75% of patients with hypertension.24

Rationale for bitherapy
Acting on different mechanisms of hypertension
Drug selection in hypertension should be based both on efficacy in lowering BP and in reducing stroke, myocardial infarction, and heart failure. Although the choice of initial drug therapy may modify long-term outcomes, BP reduction per se remains the primary determinant of cardiovascular risk reduction.25 Elevated BP is multifactorial in nature; thus, acting on multiple hypertensive mechanisms leads to greater BP reduction and higher responder rates. Furthermore, halving the dose of most antihypertensive drugs has been demonstrated to substantially reduce the prevalence of adverse effects while only reducing the BP-lowering effect by approximately 20%,26 which supports proposals for the use of combinations in the first-line treatment of hypertension.27 Combinations containing lower doses of each antihypertensive component should, in theory, lower BP as much as or more than monotherapy because of the association of two or more agents that target different hypertensive mechanisms thus preventing counterregulatory responses. Counterregulatory responses are a deleterious mechanism that can negate the efficacy of antihypertensive treatment. For example, the antihypertensive effect of a dihydropyridine would be weakened by compensatory activation of the RAS.28 Concurrent RAS blockade would thus enhance the effect of CCB.

Supplemental BP lowering may also be possible with antihypertensive combinations. Although BP reduction varies little between antihypertensive classes (by just a few millimeters of mercury), when agents from different classes are combined the resultant antihypertensive effect can vary greatly.29 Associating drugs from complementary classes is about five times more effective in reducing BP than giving twice the dose of one drug.27

Pharmacokinetic compatibility
Another important requirement of a combination is smooth and continuous BP reduction over 24 hours, ie, between two doses. For this to be possible, there needs to be pharmacokinetic compatibility between the two drugs to be combined.30

Minimizing side effects
Because antihypertensive drugs are prescribed long-term for an asymptomatic condition, good tolerability is of fundamental importance. Adherence to antihypertensive treatment could be problematic, especially in patients receiving multiple medications for other indications.

Figure 3 shows a schematic view of the dose-effect relationships of a given drug for both the expected (therapeutic) effects and side effects. The latter curve is shifted right; so side effects are absent or minimal in the lower dose range. A perfect drug would have no side effects at higher therapeutic doses. In fact, side effects occur in most cases at usual therapeutic doses. Because all antihypertensive agents produce dose-dependent side effects, high-dose monotherapy inevitably leads to adverse events. When a more effective antihypertensive treatment is needed, increasing the dose of monotherapy may induce significant side effects. Combining another class of antihypertensive drug in a single pill while minimizing the doses of both components would attenuate the impact of side effects for each component, which could improve long-term compliance to treatment, especially if additional BP reduction is achieved.

Furthermore, the tolerability profile of one antihypertensive agent can be improved by the addition of another, when the adverse effects of one component are counteracted by properties of the other. For example, the incidence and magnitude of hypokalemia with diuretics is reduced by adding an ACE inhibitor to therapy because of the aldosterone-inhibiting effect of ACE inhibitor. Another example involving ACE inhibitor is the addition of this drug class to therapy in a patient who develops edema with dihydropyridine CCB at high doses. This not only allows the dose of CCB to be reduced without impacting BP control, but also for edema to be controlled,24 ostensibly via pleiotropic ACE inhibitor-induced venodilation.31

Choice of classes for a combination
Two-drug combinations can be divided into three categories: “preferred,” “acceptable,” and “less effective”.32 Categorization is based, in part, on BP-reducing efficacy and tolerability. In monotherapy, ARBs and ACE inhibitors are the best tolerated agents and diuretics the least well tolerated. Preferred combinations contain drugs from classes that have performed consistently well in long-term trials: ACE inhibitors and ARBs, long-acting CCBs, and diuretics. β-Blocker combinations are less valuable and have been excluded from the “preferred” category because they reduce end points, particularly stroke, less well than active comparators.33 Other combinations, such as ACE inhibitor and CCB, may be more valuable because of BP lowering–independent effects. ACE inhibitors appear to be the best antihypertensive agent at reducing LVH, followed by CCBs.34 The ability of ACE inhibitors to regress LVH at doses that do not affect BP shows that the cardiac RAS plays a role in heart structure and function.35 One could thus argue that an ACE inhibitor/CCB combination is potentially better at preventing cardiac hypertrophy and myocardial remodeling than other combinations. Table I summarizes the effects of both ACE inhibitors and CCBs on several target organs: kidney, arterial wall, and heart.36

From basic and clinical research, long-acting CCBs, especially dihydropyridines such as amlodipine, appear to be an evident choice as part of an antihypertensive combination. A preferred combination is that of a CCB plus a blocker of the RAS, either an ACE inhibitor or ARB. Evidence from basic research allows us to demonstrate that ACE inhibitors and ARBs affect the cardiovascular system in different ways: basically, ACE inhibitors increase the tissue bradykinin concentration and activate the nitric oxide pathway, whereas ARBs have no effect on these mechanisms, but activate the angiotensin II receptor subtype AT2 resulting not only in vasodilation, but also decreased angiogenesis and possible cardiovascular trophic effects.

Two recent meta-analyses compared the effect of both RAS blockers. Yang and colleagues37 compared the effects of ACE inhibitors and ARBs on insulin sensitivity in hypertensive patients without diabetes. Compared to ARBs, treatment with ACE inhibitors resulted in more effective improvement of insulin sensitivity in hypertensive patients without diabetes, although these two drugs did not show significant differences with regards to fasting plasma glucose, insulin plasma concentration, or BP. Thus, in hypertensive patients without diabetes and no significant difference in BP control, ACE inhibitors were more effective at improving insulin sensitivity than ARBs. Brugts and coworkers38 analyzed prospective, randomized, controlled morbidity-mortality trials (68 343 RAS inhibitor and 84 543 control subjects [on placebo or non-RAS regimen] with a mean follow-up of 4.3 years) to assess the effectiveness of RAS inhibitors in preventing all-cause death, cardiovascular death, myocardial infarction, and stroke in hypertensive patients by considering the number needed to treat. ACE inhibitors were used in 7 trials and ARBs in 11 trials. The median number of patients that needed to be treated to prevent one death was 113 in favor of RAS inhibitors, which was driven by ACE inhibitors rather than ARBs. Results for cardiovascular mortality and myocardial infarction also appeared to be driven by ACE inhibitors. There was no significant difference between ARBs and ACE inhibitors for stroke incidence. The authors concluded that in hypertensive patients, ACE inhibitors— but not ARBs—substantially reduce all-cause mortality, cardiovascular mortality, and myocardial infarction.

Conclusion

Most hypertensive patients need two or more antihypertensive drugs to reach target BP. European guidelines recommend combining drugs from different antihypertensive classes, preferably in a single pill, as simple therapy encourages good adherence.39 Improved adherence to antihypertensive therapy is a worthwhile goal because it leads to enhanced cardioprotection and attenuated morbidity and mortality.40 Dual-agent combinations as an initial treatment strategy are mentioned in the guidelines, one of the best being ACE inhibitor/ CCB. In patients with hypertension, major cardiovascular events and mortality are better prevented by ACE inhibitor/ CCB than other combinations, such as -blocker/diuretic or ACE inhibitor/thiazide diuretic. Combining ACE inhibitor and CCB may also reduce the frequency and severity of dose-dependent adverse effects related to vasodilation induced by CCB, notably leg edema. ■


References
1. Guyton AC. Blood pressure control–special role of the kidneys and body fluids. Science. 1991;252:1813-1816.
2. Johnson JA. Ethnic differences in cardiovascular drug response: potential contribution of pharmacogenetics. Circulation. 2008;118:1383-1393.
3. Brozovich FV, Nicholson CJ, Degen CV, Gao YZ, Aggarwal M, Morgan KG. Mechanisms of vascular smooth muscle contraction and the basis for pharmacologic treatment of smooth muscle disorders. Pharmacol Rev. 2016;68: 476-532.
4. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA. 1967;202: 1028-1034.
5. Olde Engberink RH, Frenkel WJ, van den Bogaard B, Brewster LM, Vogt L, van den Born BJ. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis. Hypertension. 2015;65:1033-1040.
6. Chen P, Chaugai S, Zhao F, Wang DW. Cardioprotective effect of thiazide-like diuretics: a meta-analysis. Am J Hypertens. 2015;28:1453-1463.
7. Cruickshank JM. Beta blockers in hypertension. Lancet. 2010;376(9739):415.
8. Tomiyama H, Yamashina A. Beta-blockers in the management of hypertension and/or chronic kidney disease. Int J Hypertens. 2014;2014:919256.
9. Heusch G, Baumgart D, Camici P, et al. Alpha-adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation. 2000;101:689-694.
10. Seitelberger R, Guth BD, Heusch G, Lee JD, Katayama K, Ross J Jr. Intracoronary alpha 2-adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise. Circ Res. 1988;62:436-442.
11. Parkinson Study Group. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson’s disease (STEADY-PD). Mov Disord. 2013;28:1823-1831.
12. Bernstein KE, Ong FS, Blackwell WL, et al. A modern understanding of the traditional and nontraditional biological functions of angiotensin-converting enzyme. Pharmacol Rev. 2012;65:1-46.
13. Leeb-Lundberg LM, Marceau F, Müller-Esterl W, Pettibone DJ, Zuraw BL. International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev. 2005;57:27-77.
14. Madeddu P, Emanueli C, El-Dahr S. Mechanisms of disease: the tissue kallikreinkinin system in hypertension and vascular remodeling. Nat Clin Pract Nephrol. 2007;3:208-221.
15. de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev. 2000;52: 415-472.
16. Ismail H, Mitchell R, McFarlane SI, Makaryus AN. Pleiotropic effects of inhibitors of the RAAS in the diabetic population: above and beyond blood pressure lowering. Curr Diab Rep. 2010;10:32-36.
17. Toth PP. Pleiotropic effects of angiotensin receptor blockers: addressing comorbidities by optimizing hypertension therapy. J Clin Hypertens (Greenwich). 2011;13:42-51.
18. You D, Loufrani L, Baron C, Levy BI, Widdop RE, Henrion D. High blood pressure reduction reverses angiotensin II type 2 receptor-mediated vasoconstriction into vasodilation in spontaneously hypertensive rats. Circulation. 2005;111: 1006-1011.
19. Pinaud F, Bocquet A, Dumont O, et al. Paradoxical role of angiotensin II type 2 receptors in resistance arteries of old rats. Hypertension. 2007;50:96-102.
20. Chow BSN, Allen TJ. Angiotensin II type 2 receptor (AT2R) in renal and cardiovascular disease. Clin Sci (Lond). 2016;130:1307-1326.
21. Levy BI, Benessiano J, Henrion D, et al. Chronic blockade of AT2-subtype angiotensin II receptors prevents the effect of angiotensin II on the rat vascular structure. J Clin Invest. 1996;98:418-425.
22. Lévy BI. Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system. Circulation. 2004;109:8-13.
23. Nakayama M, Yan X, Price RL, et al. Chronic ventricular myocyte-specific overexpression of angiotensin II type 2 receptor results in intrinsic myocyte contractile dysfunction. Am J Physiol Heart Circ Physiol. 2005;288:H317-H327.
24. Gradman AH, Acevedo C. Evolving strategies for the use of combination therapy in hypertension. Curr Hypertens Rep. 2002;4:343-349.
25. Gradman AH, Basile JN, Carter BL, Bakris GL; American Society of Hypertension Writing Group. Combination therapy in hypertension. J Clin Hypertens (Greenwich). 2011;13:146-154.
26. 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;326:1427-1434.
27. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290-300.
28. Jakobsen J, Glaus L, Graf P, et al. Unmasking of the hypotensive effect of nifedipine in normotensives by addition of the angiotensin converting enzymeinhibitor benazepril. J Hypertens. 1992;10:1045-1051.
29. Gradman AH. Strategies for combination therapy in hypertension. Curr Opin Nephrol Hypertens. 2012;21:486-491.
30. Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension: the cycle repeats. Drugs. 2002;62:443-462.
31. Gradman AH, Cutler NR, Davis PJ, Robbins JA, Weiss RJ, Wood BC; Enalapril- Felodipine ER Factorial Study Group. Combined enalapril and felodipine extended release (ER) for systemic hypertension. Am J Cardiol. 1997;79:431-435.
32. Gradman AH, Basile JN, Carter BL, et al. Combination therapy in hypertension. J Am Soc Hypertens. 2010;4:90-98.
33. Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005; 366:1545-1553.
34. Schmieder RE, Schlaich MP, Klingbeil AU, Martus P. Update on reversal of left ventricular hypertrophy in essential hypertension (a meta-analysis of all randomized double-blind studies until December 1996). Nephrol Dial Transplant. 1998;13:564-569.
35. Dzau VJ. Local expression and pathophysiological role of renin angiotensin in the blood vessels and heart. In: Grobecker H, Heusch G, Strauer BE, eds. Angiotensin and Heart. New York, NY: Springer Verlag; 1993:1-14.
36. Messerli FH, Michalewicz L. Cardiac effects of combination therapy. Am J Hypertens. 1997;10(7 pt 2):146S-152S.
37. Yang Y, Wei RB, Wang ZC, et al. A meta-analysis of the effects of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers on insulin sensitivity in hypertensive patients without diabetes. Diabetes Res Clin Pract. 2015;107:415-423.
38. Brugts JJ, van Vark L, Akkerhuis M, et al. Impact of renin-angiotensin system inhibitors on mortality and major cardiovascular endpoints in hypertension: A number-needed-to-treat analysis. Int J Cardiol. 2015;181:425-429.
39. Mancia G, Fagard R, Narkiewicz K, 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;34:2159-2219.
40. Mancia G, Asmar R, Amodeo C, et al. Comparison of single-pill strategies first line in hypertension: perindopril/amlodipine versus valsartan/amlodipine. J Hypertens. 2015;33:401-411.


Keywords: blood pressure regulation; vascular smooth muscle; antihypertensive drug class; hypertensive mechanism; compatibility; side effect reduction