Effective treatment for high blood pressure represents a key strategy in reducing total cardiovascular risk and, as a consequence, the burden of cardiovascular and renal diseases [1-3]. Consistent findings have repeatedly demonstrated significant reductions in cardiovascular and renal morbidity and mortality through the systematic and intensive use of blood-pressure-lowering therapies [4-7]. In spite of these well-established concepts, hypertension remains poorly controlled worldwide, mostly in Western countries [8,9]. In this regard, recent international surveys reveal a rising prevalence of uncontrolled hypertension in developing countries as well [10-12]. Studies have also demonstrated that hypertension is frequently associated with other cardiovascular risk factors , such as smoking, dyslipidemia, obesity, metabolic syndrome, and diabetes mellitus, thus conferring to hypertensive patients a generally “high” cardiovascular risk profile, which raises the susceptibility for developing major cardiovascular and renal events, including acute myocardial infarction, stroke, and heart and renal failure [14,15]. These features make hypertension the leading factor to drive morbidity and mortality worldwide. In addition, treated patients with hypertension remain at higher risk as compared to the general normotensive population, even when a satisfactory blood pressure reduction is achieved . This latter point has prompted the search for agents or strategies that exert an effective control of blood pressure and that, at the same time, are able to provide benefits beyond blood-pressure-lowering effects, with low incidence of side effects and good tolerability profile [17,18].
The renin-angiotensin system (RAS) is intimately involved in different pathophysiological mechanisms contributing to the development of major cardiovascular and renal events . A large and growing body of evidence accumulated over the last two decades, either from experimental models or clinical data, has consistently demonstrated that RAS-blocking agents, mostly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), may confer significant improvement in cardiovascular and renal outcomes in a number of different clinical settings, including hypertension, diabetes, coronary artery disease, stroke, and heart and renal failure . Therefore, these pharmacological agents are viewed today as suitable and useful therapeutic tools to antagonize the deleterious consequences of abnormal RAS activation in disease conditions and to improve prognosis in patients with cardiovascular or renal disease or diabetes. In particular, ARBs represent an attractive alternative among the therapeutic options for hypertension management, in view of the selective mechanism of action, related to the specific antagonism of the binding between the principal biological effector of this system, angiotensin II, and the AT1 subtype receptors. This antagonism is responsible for most of the potentially unfavorable effects of RAS activation in different clinical conditions, including hypertension .
Large, international, randomized clinical trials and meta-analyses have demonstrated not only that the blood pressure control achieved with ARB-based therapy is substantially equivalent to that obtained with the other major classes of antihypertensive therapies (including diuretics, beta-blockers, and calcium channel blockers) , but, most of all, that their ability to reduce development or progression of the hypertension-related organ damage may confer additional clinical benefits across the entire spectrum of the cardiovascular continuum [22-25]. These favorable effects in terms of organ damage protection have been related to the significant reduction in the incidence of major cardiovascular and renal outcomes, observed in large, randomized, controlled clinical trials, performed with ARBs. What appears of particular interest is that data from these studies suggest that the cardiovascular protective effects of ARBs are at least, in part, independent from the blood-pressure-lowering properties . Furthermore, flexible dosing and optimal tolerability profile of the ARB compounds translate into the possibility to effectively and safely combine ARBs with all other classes of antihypertensive agents [26,27]—with the exception of ACE inhibitors—in high-risk patients with vascular disease . This property is particularly important to achieve adequate blood pressure control in a high proportion of patients with hypertension and, thus, to reduce the long-term risk of hypertension-related morbidity and mortality, as recommended by current guidelines .
Among the potential combination therapies that can be based on ARBs, the combination strategy with thiazide diuretics or calcium channel blockers, especially in fixed-combination regimens, has been tested in recent clinical trials and is widely used in clinical practice . This approach represents a very convenient option to get, simultaneously, effective control of blood pressure levels in a high percentage of patients with hypertension, high rate of responders to antihypertensive therapy, less discontinuation due to high-dose-related side effects, and more complete blockade of the RAS and its pathophysiological sequelae.
The present article provides an overview of the evidence derived from recent clinical trials performed with ARBs, highlighting the role for pharmacological strategies based on fixed combinations with this class of antihypertensive drugs in both primary and secondary prevention of cardiovascular and renal disease. In addition, the article provides a more specific updated appraisal of the combination therapy based on olmesartan medoxomil and amlodipine besylate.
CLINICAL EXPERIENCE WITH RAS-BLOCKING AGENTS
The notion of the central physiological role of the RAS in maintaining fluid and electrolyte homeostasis, together with the established evidence of its involvement in the pathophysiology and natural history of several cardiovascular and renal conditions, have led in the last three decades to an unrelenting hunt for pharmacological compounds able to antagonize the effects of RAS activation and, particularly, its biological effector, angiotensin II.
In this view, the development of the ACE inhibitors has been associated with a revolutionary impact on the treatment of different clinical conditions, including high-risk hypertension [30-32], diabetes mellitus , stroke , coronary artery disease [35,36], left ventricular dysfunction and congestive heart failure [37-40], and renal disease . However, it soon became clear that the degree of RAS blockade achievable with ACE inhibitors is far from complete, even when these agents are given at doses high enough to inhibit plasma ACE [42,43]. In fact, both angiotensin II and aldosterone tend to escape the ACE-dependent blockade over time, while angiotensin I accumulates . At the same time, the conversion of angiotensin I to angiotensin II via ACE is not an exclusive pathway for angiotensin II generation, especially in cardiovascular tissues . Indeed, angiotensin II can be formed via a number of alternative pathways, involving cathepsin G, elastase, tissue plasminogen activator, and, particularly in cardiovascular tissues, chymases . According to this hypothesis, chymases seem to be responsible for 80% of ACE-independent angiotensin II formation in human heart tissue, with the ACE-dependent pathway playing only a minor contributory role . These considerations have been proposed to explain, at least in part, the relative failure of ACE inhibition to maintain over time the clinical benefits in some clinical conditions [44,45]. As a consequence of this relatively poor specificity of the mechanism of action of ACE inhibition, the observation of some relevant side effects of these compounds—mostly cough, but also first-dose hypotension and angioedema—is not surprising.
Because of these limitations of ACE inhibitors, research was focused on the AT1 subtype receptor, which mediates the vast majority of the biological responses to angiotensin II. In fact, AT1 subtype receptors are expressed in several adult tissues and virtually mediate all known actions of angiotensin II in cardiovascular, renal, neuronal, endocrine, and other target cells, as schematically shown in Figure 1 . Altogether, in physiological conditions these actions largely contribute to the homeostasis of arterial blood pressure, electrolyte and water balance, thirst, hormone secretion, renal function, and cellular growth . In comparison, in pathological conditions, angiotensin II actions substantially contribute to the development and maintenance of cardiac, vascular, and renal abnormalities, leading to an increased cardiovascular risk and precipitating cardiovascular and renal events .
||Figure 1. Schematic representation of the renin-angiotensin system.
(Data taken from Volpe M, Tocci G, Pagannone E. [Activation of the renin-angiotensin-aldosterone system in heart failure]. Ital Heart J 2005;6(Suppl 1):16S-23S)
UNDERACHIEVEMENT IN BLOOD PRESSURE CONTROL IN HYPERTENSION: DATA FROM RECENT EPIDEMIOLOGICAL STUDIES AND META-SURVEYS
Results of recent clinical studies have demonstrated that the reduced incidence of major cardiovascular events, mostly stroke, are strictly related to the degree of blood pressure decrease, so that better blood pressure control is associated with a remarkable clinical benefit in terms of outcome reduction [5-7]. The strong relationship between blood pressure reduction, mostly systolic blood pressure levels, and reduced incidence of cardiovascular events has also been confirmed by recent meta-regression analyses [46,47]. In spite of the established benefits achieved by effective blood pressure reduction in recent, large, randomized, controlled clinical trials, results of the most recent surveys on blood pressure control confirm that the rate of success of antihypertensive therapy is still very low [8,13], and that part of the failure in reaching blood pressure goals is linked to a persistently high use of monotherapy, while combination therapy is still largely viewed as a second-choice option [48-50].
Unfortunately, monotherapy can provide blood pressure control in less than 40%. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which employed a general uncomplicated hypertensive population, the prevalence of monotherapy at the beginning of the trial was associated with only 25% of patients controlled . In the same trial, a much higher proportion of patients were controlled when they were shifted to a combination regimen . An analysis of hypertensive trials, in fact, showed that even in the controlled conditions of a clinical trial, adequate control of systolic blood pressure is practically not achieved on average in any of the studies . These observations substantially confirm that blood pressure control is difficult to achieve. Especially in high-risk patients [52,53] combination therapy should be used much more frequently than monotherapy. As shown in Figure 2, different combination thgerapies granted blood pressure control below 140/90 mmHg in proportion of patients ranging between 45-82% [52,53]. In particular, about two thirds of participants in clinical trials on hypertension receive combination therapy to approach the blood pressure goals (usually <140/90 mmHg; see Figure 2) [52,53]. In the recent Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) study , an antihypertensive strategy based on the use of combination therapy from the beginning of the study resulted in a high percentage (80%) of blood pressure control.
||Figure 2. Percent of patients reaching the Joint National Committee 7 (JNC-7) blood pressure (BP) goals in the Avoiding Cardiovascular events through Combination therapy
in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, International Verapamil SR-Trandolapril Study (INVEST), Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), and Losartan Intervention For Endpoint reduction in hypertension study (LIFE) trials.
(Reprinted with permission from Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. J Am Coll Cardiol 2008;52(22):1749-1757)
In order to improve blood pressure control in the general hypertensive population, and mostly in high-risk patients, the latest sets of European Society of Hypertension–European Society of Cardiology (ESH–ESC) guidelines  recommend starting antihypertensive treatment according to blood pressure levels and total risk profile of the patients.
Although different rational combinations of antihypertensive drug classes are possible (including diuretics and calcium channel blockers, calcium channel blockers and ACE inhibitors, beta-blockers and diuretics, ARBs and calcium channel blockers), as indicated by current European guidelines  (Figure 3), they are not really interchangeable, particularly since they do not share the same efficacy and safety profile, and mostly because they appear not equally effective in terms of organ protection or impact on metabolic abnormalities.
||Figure 3. Possible combinations between some classes of antihypertensive drugs. The preferred combinations in the general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to be beneficial in controlled intervention trials. Red lines highlight possible combination therapies based on renin-angiotensin system (RAS)-blocking agents.
(Reproduced with permission from Mancia G, De Backer G, Dominiczak A, et al. 2007 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). J Hypertens 2007;25(6):1105-1187)
RATIONALE FOR THE FIXED-DOSE COMBINATION STRATEGY TO IMPROVE THERAPEUTIC GOALS IN HYPERTENSION
Combination therapy in the clinical management of hypertension is an emerging strategy, the usefulness of which is now recommended in international practice guidelines [1-3]. Some key aspects related to the use of combination therapy, however, are still a matter of current debate within the scientific community. First, the appropriate start time for combination therapy, rather than monotherapy, is not well defined. Second, which combination therapy should be used as a first-line regimen and which should be postponed to more advanced stages in the natural history of the hypertensive disease is not clear. Finally, whether all available fixed-combination therapies are really interchangeable and whether physicians should indifferently choose among the various antihypertensive strategies have not been elucidated.
International, randomized, controlled studies have proven the benefits of blocking the RAS in different clinical conditions, from asymptomatic patients with cardiac disease to severe refractory heart failure, end-stage renal disease, and cardiovascular death . In several clinical settings, such as in patients with hypertension and left ventricular hypertrophy, stroke, coronary artery disease, type 2 diabetes and renal failure, and congestive heart failure, the favorable effects of ARBs in terms of reduced cardiovascular morbidity and mortality as compared to conventional treatment have been extensively proven and validated . On the basis of the results of these clinical trials, in which ARBs were systematically associated with other classes—mostly thiazide diuretics or calcium channel blockers—there are potential advantages in implementing the use of combination therapies based on ARBs in daily clinical practice .
The first convincing evidence in terms of how important even small reductions in blood pressure are can be derived from the results of the Hypertension Optimal Treatment (HOT) study . In this study, three target diastolic blood pressure levels, defined as <90, 85, or 80 mmHg, had to be reached according to a predefined strategy based on starting with felodipine monotherapy, followed by dosage increments and additional agents (mostly enalapril) . Between 62 and 74% of patients achieved the target blood pressure with combination therapy, and less than one third of patients reached the target values with monotherapy based on a calcium channel blocker . In contrast, there was a difference in the incidence of cardiovascular events and cardiovascular mortality per 1000 patient-years (blood pressure reductions, 51 and 67%, respectively) between diastolic blood pressure targets of <90 and 80 mmHg . These results emphasize the impact of small reductions of blood pressure on outcomes. In the HOT study , however, combination therapy was used in an extremely high proportion of patients, in order to achieve the target blood pressure levels. Following this experience, in the Losartan Intervention For Endpoint (LIFE) trial , a combination therapy (mostly based on thiazide diuretics added to an ARB or a beta-blocker) was required in approximately 90% of the patients to approach the target blood pressure levels of <140/90 mmHg.
Another example of the potential advantage of the combination therapy based on ARBs in terms of blood pressure reduction can be derived from the results of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study , which compared strategies based on amlodipine and valsartan in more than 15,000 high-risk patients. In this study, despite a significantly higher blood pressure reduction in the amlodipine arm, especially in the early phases of treatment, both groups reached blood pressure levels below 140/90 mmHg, on average, while there was no significant difference in the combined primary end point . Analysis of the secondary end points, however, showed that there were “separate” advantages with the calcium channel blocker in terms of reduced incidence of stroke and coronary artery disease, and with ARBs in terms of reduced incidence of heart failure, renal failure, and new-onset diabetes mellitus . Post-hoc analysis of the VALUE population showed, in fact, that, when patients were matched for identical achieved blood pressures, there tended to be less incidence of cardiovascular events and, especially, heart failure and new-onset diabetes in the valsartan group . In any case, prompt reduction of blood pressure may improve compliance and adherence to antihypertensive treatment and significantly reduce morbidity and mortality in high-risk patients.
More recently, the results of the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT–BPLA) study , employing patients with hypertension with three additional risk factors, clearly showed that a number of relevant cardiovascular end points and also new-onset diabetes mellitus were significantly reduced in the patients treated with amlodipine/perindopril as compared with patients treated with the atenolol/thiazide diuretic. It must be pointed out, however, that this study was largely based on combination therapies aimed at achieving blood pressure control and, indeed, that the vast majority of patients received a combination of amlodipine plus perindopril versus a combination of atenolol plus a thiazide diuretic . The study was prematurely interrupted due to an excess of mortality in the conventional antihypertensive strategy group based on the association between beta-blockers and diuretics, as compared to ARBs and calcium channel blockers.
A second aspect that needs to be addressed is the landmark evidence that ARBs have effects on cardiovascular risk that are independent of blood pressure reductions. This evidence has been provided for the first time by the LIFE study, which involved more than 9000 patients with hypertension and left ventricular hypertrophy . In this large study, the treatment regimen based on the ARB losartan produced comparable blood pressure reductions to the treatment regimen based on the beta–blocker atenolol . However, the losartan-based regimen reduced the risk of the combined primary end point of cardiovascular death, stroke, and myocardial infarction by 13% compared with the atenolol-based regimen and reduced the incidence of fatal and nonfatal stroke by 25% compared with atenolol . Beneficial effects of ARB-based therapy on cardiovascular outcomes, that could not be ascribed to blood pressure reductions, were also observed in patients with isolated systolic hypertension , echocardiographic evidence of left ventricular hypertrophy , atrial fibrillation , microalbuminuria , and diabetes mellitus . In this latter group, significant benefits that were largely independent from blood pressure control were observed on a number of cardiovascular end points, so that the advantage in terms of relative risk reduction on the primary end point was 25% over the comparator strategy . It should be noted again that in the LIFE study, combination therapy was systematically used in the attempt to achieve blood pressure control , so that in the end about 90% of patients in both arms were on a combination strategy.
FIXED-DOSE COMBINATION THERAPY: CURRENT RECOMMENDATIONS, RESULTS, AND PERSPECTIVES
To summarize the lessons learned from recent large trials in hypertension, the following can be concluded:
- The lower the blood pressure levels, the better the outcome, and even a difference of a few millimeters of mercury can impact clinical events.
- The earlier blood pressure goals are achieved, the better the outcome, since the timing of antihypertensive treatment can impact clinical events.
- In almost three quarters of patients with hypertension, combination therapies are needed to achieve blood pressure goals.
- Antihypertensive therapy can impact the metabolic status of patients.
On the basis of these considerations, the choice of combination therapy appears critical.
The rationale of combination therapy is, in fact, based on an increase in efficacy related to the synergistic and additive effects of the different compounds on blood pressure, the effects on several pathophysiological mechanisms of hypertension, and the inhibition of the contraregulating mechanisms, as well as a decrease of side effects [64-66]. In comparison, it is important to consider the relevance of the most favorable combination in terms of reduction of metabolic effects, protection of organ damage, and prevention of cardiovascular and renal morbidity and mortality [64-66]. From this point of view, currently there is a preference for the combination of RAS-blocking agents and calcium channel blockers in a number of clinical situations, such as patients with grade 2 or 3 hypertension, obesity, metabolic syndrome or diabetes mellitus, history of previous myocardial infarction, and stroke or renal diseases [67,68].
In particular, the combination based on RAS-blocking agents and calcium channel blockers appears to be rational for a number of pharmacological, therapeutic, and clinical reasons. First, this combination is based on the concomitant use of two of the most documented antihypertensive principles of evidence-based medicine. Clinical studies have, in fact, largely supported the beneficial effects of this combination strategy. Second, this combination therapy is substantially neutral from the metabolic point of view and has been demonstrated to provide consistent advantages in terms of new-onset diabetes mellitus, when compared with other types of classical combination therapies, such as beta-blockers and thiazide diuretics. Third, this combination has important clinical advantage in terms of tolerability. In fact, it favors a significant reduction of the side effects of one component (eg, ankle edema related to calcium-channel-blocker-based therapy) through the antagonistic peripheral vascular actions of RAS-blocking agents (ACE inhibitors or ARBs; Figure 4). In addition, evidence is available demonstrating the favorable effects provided by combination therapy based on RAS-blocking agents, mostly ARBs and calcium channel blockers in terms of reduced incidence of renal complications in patients with hypertension with or without diabetic nephropathies.
||Figure 4. Schematic representation of beneficial effects provided by combination therapy based on angiotensin receptor blockers (ARBs) and calcium channel blockers at the
(Data taken from Tocci G, Palano F, Pagannone E, Chin D, Ferrucci A, Volpe M. Fixed-combination therapies in hypertension management: focus on enalapril/lercanidipine.
Expert Rev Cardiovasc Ther 2009;7(2):115-123)
Another potential advantage associated with the use of a combination therapy based on ACE inhibitors or ARBs and calcium channel blockers as compared to that of “traditional” antihypertensive agents is the demonstration of a significant improvement in a series of intermediate end points or disease markers, in the presence of comparable blood pressure reductions . As an example, ARBs have significantly reduced the risk of the incidence of new-onset diabetes, mostly compared with diuretics, beta-blockers, and even calcium channel blockers . This property of ARBs may be particularly relevant to the subsequent development of cardiovascular and renal disease in patients with hypertension. In fact, new-onset diabetes during long-term antihypertensive treatment is associated with poor prognosis , and development of diabetes in hypertension accelerates renal impairment and evolution toward end-stage renal disease . The favorable impact of RAS-inhibiting drugs and, particularly ARBs, on development of diabetes, is attributable to specific mechanisms associated with angiotensin II blockade, and cannot be accounted for only by the detrimental metabolic effects of the comparators, since it is observed with drugs acting through different mechanisms (diuretics, beta-blockers, and calcium channel blockers) [6,21].
Another example is that antihypertensive therapy based on ARBs represents a successful strategy to slow or prevent the progression of cardiac, vascular, and renal impairment . In this regard, antihypertensive strategy based on ARBs has effectively delayed the progression or favored the regression of left ventricular hypertrophy , reduced atrial enlargement and new onset of atrial fibrillation , and improved left ventricular diastolic and systolic function . ARBs have consistently provided a favorable impact on vascular structure and function in patients with hypertension as compared to a traditional antihypertensive regimen. For the same blood pressure reduction, ARBs have a more favorable influence on vascular remodelling and structural abnormalities than atenolol [73-75]. Moreover, ARBs significantly delay the progression from microalbuminuria to macroalbuminuria, and the progression from macroalbuminuria to overt end-stage renal disease [24,25]. In view of the large prevalence of microalbuminura in patients with hypertension and its considerable predictive value [76,77], this feature of ARBs is quite relevant to cardiovascular protection. Also, these findings suggest that properties of ARBs, beyond their blood-pressure-lowering efficacy, are relevant for achieving better cardiovascular and renal protection. In fact, the reduction of microalbuminuria and its progression to overt proteinuria has been associated with a lower cardiovascular morbidity and mortality in a LIFE substudy . More recently, the Angiotensin-Receptor Blockade versus Converting-Enzyme Inhibition in type 2 Diabetes and Nephropathy (DETAIL) study  demonstrated that antihypertensive treatment based on an ARB—telmisartan—is not inferior to therapy based on an ACE inhibitor—enalapril—in providing renal protection in patients with type 2 diabetes and early nephropathy. As a consequence, the most recent guidelines on hypertension accept these new findings and recommend the early inhibition of the RAS, particularly in patients with nephropathy .
Finally, it should also be noted that the fixed-dose combination (or single-pill combination) with ACE inhibitors or ARBs and calcium channel blockers may provide additional, substantial advantages in terms of patients’ compliance when compared with the separate administration of the two drugs, by preserving at the same time the efficacy on blood pressure control and cardiovascular and renal protection.
In evaluating the potential differences between the combination of an ACE inhibitor or an ARB with dihydropyridinic calcium channel blockers, there are many considerations that clearly tend to favor the ARB-based fixed combination with a calcium channel blocker:
- The pharmacological mechanism of action of ARBs in inhibiting RAS is more selective.
- The potential advantages of AT2 subtype receptor by residual unbound angiotensin II are attainable only with ARBs, and not by ACE inhibitors.
- The adverse side effects typical of ACE inhibitors (cough, first-dose-related hypotension) are definitely less common with ARBs and may, indeed, jeopardize the clinical benefits of combination with amlodipine.
- Clinical studies with ARBs in hypertension are more modern, rigorous, and solid than most of those performed with ACE inhibitors.
- The reduction of amlodipine-induced ankle edema from ARBs is reported to be up to 50% in recent studies.
PHARMACOLOGICAL PROFILE OF OLMESARTAN AND AMLODIPINE
The pharmacological profiles of olmesartan medoxomil and amlodipine besylate are well established. Olmesartan medoxomil is an orally administered prodrug of olmesartan (Figure 5), a nonpeptide ARB that has high selectivity for the AT1 receptor, to which it is highly bound . Olmesartan does not bind to the type 2 receptor . Activation of the AT1 receptor by angiotensin II, the primary vasoactive RAS peptide, produces arteriolar vasoconstriction, increased sympathetic nervous system activity, increased salt and water retention, and aldosterone secretion, as previously described . Olmesartan is presumed to reduce blood pressure mostly by blocking the vasoconstrictor and aldosterone-secreting effects of angiotensin II [80,81].
|Figure 5. Chemical structure of olmesartan medoxomil and amlodipine besylate.
Consistent with this mechanism of action, animal and human studies demonstrated that the effects of olmesartan medoxomil on blood pressure parallel the effects on the RAS. In animals, olmesartan medoxomil is a potent and selective, dose-dependent antagonist of pressor and vasoconstrictor responses to angiotensin II, while in patients with hypertension treatment olmesartan medoxomil reduces blood pressure levels and increases plasma renin and angiotensin II levels [80,81]. In patients with hypertension, olmesartan medoxomil produces gradual and sustained dose-dependent reductions in both systolic and diastolic blood pressure levels (Figure 6), without first-dose hypotension, tachyphylaxis during extended treatment, or rebound hypertension when treatment is discontinued [80,81]. Comparative clinical studies consistently have shown that olmesartan produces the highest reductions of systolic and diastolic blood pressure levels within the class of ARBs, either in monotherapy (Figure 7) or in combination therapy with thiazide diuretics (Figure 8) [80,81]. In animal models and clinical studies in patients with diabetes mellitus, chronic renal disease, or hypertension with or without metabolic syndrome, olmesartan medoxomil had protective effects on organ damage . It appears that these effects are to some extent independent of the blood-pressure-lowering effect of olmesartan medoxomil. Treatment based on olmesartan medoxomil significantly reduced from baseline wall-to-lumen ratio and arterial stiffness in small resistance arteries , proteinuria and renal vascular resistance [84-86], sympathetic activity and inflammatory markers , and insulin sensitivity .
||Figure 6. Dose-dependent systolic (SBP) and diastolic blood pressure (DBP) reductions in hypertensive patients treated with olmesartan medoxomil.
(Data taken from Scott LJ, McCormack PL. Olmesartan medoxomil: a review of its
use in the management of hypertension. Drugs 2008;68(9):1239-1272)
||Figure 7. Mean reduction in systolic (SBP) and diastolic blood pressure (DBP) levels
with the maximal tested dose of different angiotensin receptor blockers (ARBs).
(Data taken from Ram CV. Antihypertensive efficacy of angiotensin receptor blockers in combination with hydrochlorothiazide: a review of the factorial-design studies. J Clin Hypertens 2004;6(10):569-577)
||Figure 8. Differences in blood pressure levels among different combination therapies based on olmesartan medoxomil and other angiotensin receptor blockers (ARBs): efficacy in terms of systolic and diastolic blood pressure levels (mmHg).
(Data taken from Greathouse M. Olmesartan medoxomil combined with hydrochlorothiazide for the treatment of hypertension. Vasc Health Risk Manag 2006;2(4):401-409)
A thorough clinical program to assess the organ protective properties of olmesartan medoxomil was undertaken a few years ago, and included, among others, studies based on relevant cardiovascular and renal end points; for example, the Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study , the Vascular Improvement with Olmesartan medoxomil (VIOS) study , and the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study .
Amlodipine besylate is a dihydropyridinic calcium channel blocker (Figure 5) able to reduce the extracellular calcium influx at cardiac and vascular smooth muscle cell levels by inhibiting L-type calcium channels [92,93]. Amlodipine has a greater effect on calcium influx in vascular smooth muscle cells in arteries and arterioles than it has on cardiac muscle cells, and has no effect on serum calcium levels [92,93]. As a result of the relaxation of arterial smooth muscle, vessel dilation is observed in arteries and arterioles following amlodipine administration, thus reducing peripheral vascular resistance and lowering blood pressure levels . Long-term oral administration of amlodipine has little or no effect on heart cardiac conduction, plasma lipids, insulin sensitivity, blood glucose, blood insulin or plasma catecholamine levels, and plasma renin activity or aldosterone levels . Reduced peripheral resistance (and thus reduced myocardial oxygen consumption) and dilation of coronary arteries and arterioles, with increased myocardial oxygen delivery, are thought to be responsible for the antianginal effect of amlodipine . Amlodipine is characterized by a gradual and sustained antihypertensive effect over hours in patients with mild to moderate hypertension, with no postural hypotension and a preserved circadian blood pressure pattern . Amlodipine does not cause first-dose hypotension, tachyphylaxis with long-term treatment, or rebound hypertension when treatment is discontinued abruptly . As with other calcium channel blockers, amlodipine produces a small increase in cardiac index, during exercise and rest, in patients with normal left ventricular function. There is no significant influence on left ventricular end-diastolic pressure or volume and no negative inotropic effect detected in animals or humans at therapeutic dosages. Amlodipine increases renal blood flow, lowers renovascular resistance and increases the glomerular renal blood flow, without changing proteinuria or filtration fraction [99,100]. Amlodipine repeatedly has been reported effective in reducing cardiovascular outcomes in major, recent clinical trials in high-risk patients [32,54,56,101]. In particular, studies such as Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) , ASCOT–BPLA , VALUE , and ACCOMPLISH  have characterized the cardiovascular protective role of amlodipine in hypertension, either in monotherapy or in combination therapy with ACE inhibitors or ARBs.
EFFICACY AND SAFETY OF OLMESARTAN/AMLODIPINE IN CLINICAL TRIALS
The efficacy and safety of combination therapies based on olmesartan medoxomil have been tested in numerous clinical studies , the results of which have provided evidence that they significantly reduce blood pressure levels and substantially improve the rates of blood pressure control, with a good tolerability profile and low incidence of adverse events [103,104].
A randomized, double-blind study, performed by Chrysant and associates , compared the antihypertensive efficacy of the starting dose of olmesartan medoxomil with that amlodipine in patients with mild-to-moderate hypertension. Following a 4-week, single-blind placebo run-in period, 440 patients >18 years of age were randomized to the starting dose of olmesartan medoxomil (20 mg/day), amlodipine (5 mg/day), or placebo for 8 weeks. Patients were evaluated by 24-h ambulatory blood pressure monitoring and by seated clinic blood pressure measurements. The primary end point was the change from baseline in mean 24-h diastolic blood pressure by ambulatory blood pressure monitoring at week 8 . Secondary end points included change from baseline in mean 24-h ambulatory systolic blood pressure at 8 weeks, change from baseline in mean seated systolic and diastolic blood pressure measurements, and response and control rates for systolic and diastolic blood pressure . Olmesartan medoxomil and amlodipine produced significantly greater reductions in ambulatory and seated systolic and diastolic blood pressure levels compared with placebo (Figure 9) . Mean reductions in ambulatory and seated blood pressure levels were similar between the two active agents; however, in the olmesartan medoxomil group, significantly more patients achieved the systolic blood pressure goal of <130 mmHg and the diastolic blood pressure goal of <85 mmHg (Figure 10) . Both drugs were well tolerated at the recommended starting dose, although amlodipine was associated with a not statistically significant higher incidence of edema .
||Figure 9. A 24-h antihypertensive efficacy of olmesartan medoxomil compared with amlodipine in patients with mild-to-moderate hypertension: efficacy in terms of systolic (SBP) and diastolic blood pressure (DBP) levels (mmHg).
(Reprinted by permission from Macmillan Publishers Ltd: Journal of Human Hypertension. Chrysant SG, Marbury TC, Robinson TD. Antihypertensive efficacy and safety of olmesartan medoxomil compared with amlodipine for mild-to-moderate hypertension. 17:425-432, Copyright © 2003)
||Figure 10. A 24-h antihypertensive efficacy of olmesartan medoxomil compared with amlodipine in patients with mild-to-moderate hypertension: efficacy in terms of blood pressure control rate (%).
(Reprinted by permission from Macmillan Publishers Ltd: Journal of Human Hypertension. Chrysant SG, Marbury TC, Robinson TD. Antihypertensive efficacy and safety of olmesartan medoxomil compared with amlodipine for mild-to-moderate hypertension. 17:425-432, Copyright © 2003)
Previous studies have invesitgate clinical efficacy of combination therapy based on olmesartan/hydroclorothiazide (HCTZ) in hypertension. A randomized, double-blind, multicenter 12-week study performed by Kereiakades et al  was aimed at comparing the efficacy, safety, and tolerability of a combination therapy of olmesartan medoxomil/HCTZ with that of benazepril/amlodipine in patients with mild-to-moderate hypertension. Patients were eligible for randomization following a 3- to 4-week placebo run-in period if they had either mean seated diastolic blood pressure >90 mmHg but <115 mmHg and mean seated systolic blood pressure >160 mmHg but <200 mmHg, or mean seated diastolic blood pressure >100 mmHg but <115 mmHg .
In addition, a mean 8-h daytime ambulatory diastolic blood pressure >95 mmHg and <115 mmHg or systolic blood pressure >145 mmHg and <190 mmHg were required . Eligible patients were randomized to treatment with olmesartan medoxomil (20 mg/day for 2 weeks; then 40 mg/day for 2 weeks; then olmesartan medoxomil/HCTZ 40/12.5 mg/day for 4 weeks; then olmesartan medoxomil/HCTZ 40/25 mg/day for 4 weeks) or benazepril (10 mg/day for 2 weeks; then 20 mg/day for 2 weeks; then benazepril 20 mg/day plus amlodipine 5 mg/day for 4 weeks; then benazepril 20 mg/day plus amlodipine besylate 10 mg/day for 4 weeks) . The primary end point was the change from baseline in mean systolic blood pressure levels at the end of week 12 . Secondary end points included diastolic blood pressure after completion of monotherapy and combination therapy at the end of weeks 4 and 12, systolic blood pressure at the end of week 4, and percentage of patients attaining blood pressure goals of <140/90 mmHg, <130/85 mmHg, and <130/80 mmHg at the end of weeks 4 and 12 . After the run-in phase, 190 patients were randomized to receive at least one dose of study medication.  The primary efficacy end point of change in mean seated systolic blood pressure at week 12 was significantly greater with olmesartan medoxomil/HCTZ than it was with benazepril/amlodipine (mean change: -32.5 vs -26.5 mmHg, p = .024; mean treatment difference -6.0 mmHg; 95% confidence interval [CI] -11.1, -0.8 mmHg) . The mean change for reduction in diastolic blood pressure approached statistical significance with olmesartan medoxomil/HCTZ compared with the benazepril-based regimen (p = .056) at week 12 . Blood pressure reductions showed statistically significant differences between treatment groups favoring olmesartan medoxomil/HCTZ in both systolic and diastolic blood pressure levels at week 8 . The percentage of patients achieving goal rates at the end of the study for olmesartan medoxomil/HCTZ and benazepril/amlodipine, respectively, were 66.3 versus 44.7% (p = .006) for <140/90 mmHg, 44.9 versus 21.2% (p = .001) for <130/85 mmHg, and 32.6 versus 14.1% (p = .006) for <130/80 mmHg . Both treatments were generally well tolerated . In a study by Chrysant SG et al, comparing olmesartan/HCTZ 20/12,5 mg per day or olmesartan 20/25 mg per day, after 8 weeks of treatment the responder rate rose progressively to 68,3%, 78,6% and 89,1% with these three regimens, respectively (Table 1) .
||TABLE 1. Responder and control rate for 12 groups at week 8
(Data taken from Chrysant SG, Marbury TC, Robinson TD. Antihypertensive efficacy and safety of olmesartan medoxomil compared with amlodipine for mild-to-moderate hypertension. J Hum Hypertens 2003;17:425-432)
The combination of olmesartan medoxomil and amlodipine in controlling high blood pressure was tested in a multicenter, randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study—the Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) trial, performed by Chrysant et al . The aim of this study was to compare the efficacy and tolerability of the combination therapy of olmesartan medoxomil and amlodipine with those of the component monotherapies in patients with mild to severe hypertension . Patients who were naive to antihypertensive therapy or who underwent a washout of previous antihypertensive therapy for up to 2 weeks and had a seated diastolic blood pressure of 95 to 120 mmHg were randomized to receive 1 of the following antihypertensive regimens for 8 weeks: olmesartan medoxomil 10, 20, or 40 mg, amlodipine 5 or 10 mg, each possible combination of olmesartan medoxomil and amlodipine, or placebo . The primary end point was the change from baseline in seated diastolic blood pressure at week 8. Secondary end points included change in seated systolic blood pressure, proportions of patients reaching the blood pressure goal, and proportions of the intention-to-treat population reaching blood pressure thresholds of <120/80, <130/80, <130/85, and <140/90 mmHg . Safety and tolerability were also evaluated, with a particular focus on the incidence and severity of edema. Of the 1940 randomized patients at the end of the study, 54.3% were male. The mean age of the study population was 54.0 years old. The mean baseline blood pressure was 164/102 mmHg, and 79.3% of patients had stage 2 hypertension. Combination therapy with olmesartan medoxomil and amlodipine was associated with dose-dependent reductions in seated diastolic blood pressure levels (from -13.8 mmHg with olmesartan/amlodipine 10/5 mg to -19.0 mmHg with olmesartan/amlodipine 40/10 mg) and seated systolic blood pressure levels (from -23.6 mmHg with olmesartan/amlodipine 20/5 mg to -30.1 mmHg with olmesartan/amlodipine 40/10 mg) that were significantly greater than the reductions obtained with the corresponding component monotherapies (p <.001) . At week 8, the number of patients achieving the blood pressure goals ranged from 57 of 163 (35.0%) to 84 of 158 (53.2%) in the combination therapy groups, from 32 of 160 (20.0%) to 58 of 160 (36.3%) in the olmesartan medoxomil monotherapy groups, and from 34 of 161 (21.1%) to 53 of 163 (32.5%) in the amlodipine monotherapy groups (p <.005, combination therapies as compared to each monotherapy), compared with 14 of 160 (8.8%) in the placebo group . Achievement of the blood pressure thresholds was highest in the combination therapy groups, with 56.3% of patients achieving a blood pressure <140/90 mmHg with olmesartan/amlodipine 20/10 and 54.0% achieving it with 40/10 mg . Combination therapy was generally well tolerated, with the most common adverse events being edema (ranging from 9.9% for olmesartan medoxomil 20 mg, to 36.8% for amlodipine 10 mg, compared with 12.3% with placebo) and headache (ranging from 2.5% for olmesartan/amlodipine 10/5 mg to 8.7% for olmesartan medoxomil 20 mg, compared with 14.2% with placebo) .
In this latter regard, it should also be noted that in these trials the incidence of edema was actively watched rather than passively, as it has been reported, for example, in the VALUE trial , in which the incidence of this amlodipine-induced side effect was less frequent (about 32.9%). The advantage of this kind of approach is that it definitely could be demonstrated that combining amlodipine with ARBs, particularly olmesartan, may significantly reduce the incidence of peripheral edema by more than 50%.
Finally, the efficacy and tolerability of olmesartan medoxomil combined with amlodipine in patients with moderate to severe hypertension after amlodipine monotherapy was evaluated in a randomized, double-blind, parallel-group, multicenter study, performed by Volpe . In this study, a total of 1017 patients entered the open-label amlodipine monotherapy stage; mean blood pressure at baseline was 164/102 mmHg . After 8 weeks of amlodipine monotherapy (5 mg/day), nonresponding patients (n = 755) were randomized to receive placebo plus amlodipine 5 mg or a combination of olmesartan medoxomil (10 to 40 mg) with amlodipine 5 mg for 8 weeks . At week 16, patients who had achieved systolic and diastolic blood pressure goals continued on randomized treatment for an additional 8 weeks . Patients in whom both systolic and diastolic blood pressure were higher than 140/90 mmHg at week 16 had their medication up-titrated to olmesartan medoxomil/ amlodipine 20/5 mg, olmesartan medoxomil/amlodipine 40/5 mg, or olmesartan medoxomil/amlodipine 40/10 mg . At the end of the follow-up period, the combination of olmesartan medoxomil (10-40 mg) with amlodipine 5 mg for 8 weeks (double-blind) reduced mean systolic blood pressure levels by up to 16.8 mmHg and mean diastolic levels to 9.6 mmHg (Figure 11 and Figure 12) . The additional adjusted mean change in seated diastolic blood pressure levels (primary end point) with the last observation carried forward compared with placebo/ amlodipine 5 mg was -2.0 mmHg (p = .0207), -3.7 mmHg (p <.0001), and -3.8 mmHg (p <.0001) for olmesartan medoxomil/amlodipine 10/5 mg, 20/5 mg, and 40/5 mg, respectively . The corresponding additional adjusted mean change in seated systolic blood pressure compared with placebo/amlodipine 5 mg was -3.5 mmHg (p = .0103), -5.8 mmHg (p <.0001), and -7.1 mmHg (p <.0001) for the olmesartan medoxomil/amlodipine 10/5 mg, 20/5 mg, and 40/5 mg groups, respectively . Up-titration was associated with further mean reductions of up to 12.6 mmHg (seated systolic blood pressure levels) and 8.2 mmHg (seated diastolic blood pressure levels), and allowed additional patients to achieve the blood pressure goal (Figure 13) . Target blood pressure was defined using both systolic and diastolic blood pressure criteria (patients without diabetes <140/90 mmHg; patients with diabetes <130/80 mmHg). More than 70% of patients on active combination therapy achieved their blood pressure goal by week 24 . All combination regimens were well tolerated .
||Figure 11. Mean change in seated systolic blood pressure levels (SeSBP) at the end of 12 and 16 weeks.
(Reproduced from Volpe M, Brommer P, Haag U, Miele C. Efficacy and tolerability of olmesartan medoxomil combined with amlodipine in patients with moderate to severe hypertension after amlodipine monotherapy: a randomized, double-blind, parallel-group, multicentre study. Clin Drug Investig 2009;29(1):11-25, with permission from Wolters Kluwer Health | Adis [© Adis Data Information BV 2009. All rights reserved])
Figure 12. Mean change in seated diastolic blood pressure levels (SeDBP) at the end of 12 and 16 weeks.
(Reproduced from Volpe M, Brommer P, Haag U, Miele C. Efficacy and tolerability of olmesartan medoxomil combined with amlodipine in patients with moderate to severe hypertension after amlodipine monotherapy: a randomized, double-blind, parallel-group, multicentre study. Clin Drug Investig 2009;29(1):11-25, with permission from Wolters Kluwer Health | Adis [© Adis Data Information BV 2009. All rights reserved])
Figure 13. Effects of open-label amlodipine (AML) monotherapy, double-blind olmesartan medoxomil (OLM)/amlodipine combination therapy, and double-blind continuation or up-titration on blood pressure levels over a period of 24 weeks.
(Reproduced from Volpe M, Brommer P, Haag U, Miele C. Efficacy and tolerability of olmesartan medoxomil combined with amlodipine in patients with moderate to severe hypertension after amlodipine monotherapy: a randomized, double-blind,
parallel-group, multicentre study. Clin Drug Investig 2009;29(1):11-25, with permission from Wolters Kluwer Health | Adis [© Adis Data Information BV 2009. All rights reserved])
Overall, these results suggest that fixed combination therapy based on the association between olmesartan medoxomil and amlodipine besylate represents a modern, rational, effective, safe, and well-tolerated antihypertensive strategy, which is able to reduce blood pressure levels in patients with moderate to severe hypertension. Further studies will better clarify the potential advantages provided by such a combination therapy in terms of organ protection and long-term reduction in cardiovascular morbidity and mortality.
Today, fixed combination therapies represent one of the best available strategies to fight current poor control of hypertension worldwide and, thus, to reduce the deleterious consequences of uncontrolled hypertension. In particular, combination therapies based on ARBs represent a new, effective, well-tolerated therapeutic tool for the treatment of patients with hypertension within a wide range of cardiovascular risk profiles, from patients with concomitant risk factors, such as hypercholesterolemia, obesity, metabolic syndrome, and diabetes mellitus; patients with organ damage, including carotid atherosclerosis, left ventricular hypertrophy, or systolic/diastolic dysfunction and microalbuminuria; or patients with atrial fibrillation, previous stroke, or heart or renal failure. That is, most patients with “challenging hypertension” may take advantage of this therapeutic approach. In particular, combination therapy with ARBs and calcium channel blockers is based on rational grounds ensuring a synergistic effect in lowering blood pressure levels, reduction of organ damage, and excellent tolerability and safety profile. Based on the favorable outcome results of studies using the combination strategy, which included amlodipine and blockers of the RAS (eg, the ACCOMPLISH study ), it is predictable that this combination will most likely hold a preferential position among those recommended in upcoming updates of guidelines for hypertension management. Among the different compounds of the ARB and dihydropiridinic classes, the combination of olmesartan/amlodipine, also based on the data available in the literature, is certainly characterized by a powerful and sustained blood-pressure-lowering effect that allows for very high rates of blood pressure control in patients with moderate to severe hypertension in the presence of a good tolerability profile.
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