Olmesartan medoxomil plus hydrochlorothiazide for treating hypertension

Drug Evaluation

10.1517/14656566.9.1.129 © 2008 Informa UK Ltd ISSN 1465-6566 129

Olmesartan medoxomil plus hydrochlorothiazide for treating hypertension Vivencio Barrios† & Carlos Escobar † Hospital Ram ó n y Cajal, Department of Cardiology, Madrid, Spain

Although achieving blood pressure (BP) control is critical to improve cardiovascular prognosis in hypertensive patients, many of them fail to attain the targets. Most patients with hypertension need more than one antihypertensive agent to achieve the goals. Combination therapy is required when monotherapy fails to attain BP objectives (< 140/90 mmHg in general hypertensive population; < 130/80 mmHg in high-risk groups) and as a first-line treatment in certain situations, such as markedly elevated BP values, high or very high cardiovascular risk patients or when lower targets are warranted. The advantages of combination therapy are well documented with the potential for increased antihypertensive efficacy as a result of different mechanisms of action, and a lower incidence of adverse effects because of the lower doses used and the possible compensatory responses. The inhibition of the renin–angiotensin system appears to be very beneficial in the treatment of patients with hypertension. Olmesartan medoxomil 20 mg/hydrochlorothiazide 12.5 mg is the latest combination of an angiotensin receptor blocker and a diuretic approved for treatment of hypertension. The aim of this manuscript is to update the published data about the efficacy and safety of this fixed combination.

Keywords: angiotensin receptor blocker , combination therapy , hydrochlorothiazide , hypertension olmesartan

Expert Opin. Pharmacother. (2008) 9(1):129-136

1. Introduction

Hypertension is a major risk factor for cardiovascular disease. It has been estimated at a prevalence of 29.3% in the overall hypertensive population and 66.3% in the elderly ( ≥ 60 years) in the US. Although blood pressure (BP) control is critical to improve cardiovascular prognosis in these patients, many of them fail to attain the targets. As an example, the BP control rate was 29.2% in 1999 – 2000 and 36.8% in 2003 – 2004 in the US [1-3] . Moreover, this situation may be even worse as recent European guidelines for arterial hyper-tension have proposed more strict BP goals fore some high-risk patients. Thus, in contrast with the previous guidelines, present guidelines recommend that BP should be < 130/80 mmHg in high or very high-risk populations, such as those with associated clinical conditions [4,5] . This is clinically very relevant taking into account that nowadays the majority of patients daily attended in a specialist setting and even in primary care belong to high- or very high-risk subgroups [6] .

It has been reported that most of the patients with hypertension will need at least two antihypertensive drugs to achieve BP goals [7,8] . Combination therapy is required when monotherapy fails to achieve BP goals (< 140/90 mmHg in the general hypertensive population; < 130/80 mmHg in high-risk groups), but also as a first-line treatment in certain situations, such as marked BP elevations, high or very high cardiovascular risk patients or when lower BP targets are warranted [4] .

1. Introduction

2. Rationale and

pharmacology of olmesartan

medoxomil/hydrochlorothiazide

3. Effi cacy of olmesartan

medoxomil compared with

other antihypertensive drugs

4. Effi cacy of olmesartan


compared with other

antihypertensive agents

5. Safety profi le of olmesartan


6. Expert opinion

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Olmesartan medoxomil

130 Expert Opin. Pharmacother. (2008) 9(1)

Although an obvious disadvantage of initiating treatment with two drugs is that of potentially exposing some patients to an unnecessary agent, firstly, this may affect only a minority of patients with hypertension, and secondly, as European guidelines suggest, this approach has a number of important advantages [4] . The advantages of combination therapy are well documented with the potential for increased anti-hypertensive efficacy as a result of combining different mechanisms of action and a lesser incidence of adverse effects because of the lower doses used and the compen-satory responses [9,10] . Moreover, the disappointment of repetitively and unsuccessfully searching for effective monotherapies in patients with very high BP values or organ damage may be avoided. On the other hand, fixed low-dose combinations are available, allowing the two agents to be administered in a single tablet, the treatment simplification optimizing compliance. Finally, starting treatment with a two-drug combination may allow BP targets to be reached earlier than with monotherapy [4] .

In clinical practice numerous fixed-dose antihypertensive combination regimens are presently available, including β -blockers plus hydrochlorothiazide (HCTZ), ACE inhibi-tors plus HCTZ, angiotensin receptor blockers (ARB) plus HCTZ and calcium channel blockers plus ACE inhibitors or ARB [2,11] . One of the most recently launched combi-nations is olmesartan medoxomil (an ARB) plus HCTZ. This manuscript aims to update the published data about the efficacy and safety of the fixed combination olmesartan medoxomil plus HCTZ.

2. Rationale and pharmacology of olmesartan medoxomil/hydrochlorothiazide

It is well established that the renin–angiotensin–aldosterone system (RAAS) plays a key role in regulating blood volume and systemic vascular resistance. The overactivation of this system, especially through excessive production of angiotensin II, its effector peptide, has been related to the genesis and development of cardiovascular diseases [12] .

ACE inhibitors were the first available RAAS blockers acting on the production of angiotensin II. Although they have been very useful therapeutic tools for cardiovascular disease, they may not provide an optimal long-term RAAS blockade, as angiotensin II can be produced through several ACE-independent pathways. Therefore, in the last decade, the ARBs, a new generation of drugs that selectively inhibit the binding of angiotensin II to the AT1 receptor, inde-pendently of the enzymatic pathway of angiotensin II generation, have been developed. However, the beneficial effects of ARB may depend not only on the direct inhibition of AT1 receptors, but likely on the activation of AT2 receptors as well [13] .

The association of an ARB with diuretics has shown to be very effective to reduce BP values as a result of synergistic mechanisms of action. HCTZ may activate the RAAS,

which makes BP more dependent on angiotenin II, increasing consequently the antihypertensive effects of ARB. Moreover, thiazide diuretics, particularly in higher doses, promote potassium loss in the distal tubule. ARBs redress this balance by attenuating angiotensin II-mediated aldosterone release, changing electrolyte balance towards potassium retention. On the other hand, thiazide diuretics cause or worsen some metabolic disturbances such as hyperuricemia, hyperglycemia or hyperlipidemia. These side effects of thiazide diuretics are compensated by ACE inhibition [7] . Besides, as the combination of two drugs increases their antihypertensive efficacy, and tolerability, this secondarily favours a better BP control [2,14] .

Olmesartan medoxomil ( Figure 1 ) is the seventh ARB approved by the FDA for the treatment of hypertension. Olmesartan medoxomil is a prodrug that is rapidly absorbed after oral administration and completely hydrolysed in the gastrointestinal tract into its active metabolite olmesartan [2,15] . The long-terminal elimination half-life of 10 – 18 h, coupled with minimal accumulation, allows for once-daily dosing. Olmesartan is excreted via the kidneys and after secretion in bile, in the feces [16-19] . Olmesartan, as other ARBs, antagonizes the AT1 receptor. It has been shown to be a competitive antagonist with high affinity, slow dissociation and a high degree of insurmountability for the AT1 receptor [2] . This slow dissociation of olmesartan from the AT1 receptor compares favorably with other ARBs, which may in part explain its high efficacy to reduce BP values [2] .

HCTZ is a thiazide diuretic that is also rapidly absorbed after oral administration and is eliminated unchanged in the urine. It has an elimination half-life of 8 – 15 h after repeated doses and, like olmesartan, the pharmaco-dynamic response is sufficiently long to allow once-daily dosing [2,19,20] . Considering the pharmacologic characteris-tics of olmesartan medoxomil and HCTZ, the combination of both antihypertensive drugs is adequate and their properties allow a once-daily administration in a single, fixed-dose tablet. In fact, olmesartan medoxomil plus HCTZ is the most recent fixed ARB/HCTZ combination to be approved for the treatment of hypertension [2] .

3. Effi cacy of olmesartan medoxomil compared with other antihypertensive drugs

Several trials have shown that olmesartan medoxomil ≤ 40 mg/day decreases dose-dependent BP values, without a further BP lowering effect with the 80 mg/day dose [21-23] . A meta-analysis of the combined database from seven US and European clinical trials performed to assess the efficacy and safety of olmesartan medoxomil in mild-to-moderate essential hypertension has included a total of 3095 patients in the safety population and 3055 patients in the intent-to-treat (efficacy) population. The included studies were randomized, double-blind,

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Expert Opin. Pharmacother. (2008) 9(1) 131

placebo-controlled and dose-finding (2.5 – 80 mg), with treatment duration ranging from 6 to 52 weeks. This meta-analysis demonstrated that BP lowering effect tended to be dose-related up to the 40 mg dose level. All olmesartan medoxomil doses were statistically signi-ficantly more effective than placebo for responder rate, diastolic and systolic BP normalization rates. Similarly to other ARBs, the safety profile of olmesartan medoxomil was consistently equivalent to that of placebo and was not dose related [21] .

On the other hand, experimental and clinical studies have shown that olmesartan medoxomil exerts some effects beyond its BP lowering effect. It has been demonstrated that this ARB significantly reduces vascular micro-inflammation and improves endothelium-dependent coronary dilation, probably in part due to the antioxidant properties of the drug. This implies an added value of olmesartan medoxomil beyond BP reduction in the treatment of arterial hypertension [24-26] .

Olmesartan medoxomil has been demonstrated to be effective for reducing BP when compared with placebo and when compared with other antihypertensive agents [27-36] . A systematic review [36] assessed the antihypertensive activity of seven different ARBs (losartan, valsartan, irbesartan, candesartan, telmisartan, eprosartan and olmesartan). For this purpose, studies in which BP was measured using ambulatory BP monitoring for ≥ 24 h were reviewed. The final study group contained 36 publications, with a total of 47 patient cohorts receiving ARBs as monotherapy. This study showed that olmesartan achieved a more significant BP decrease when compared with other ARBs over 24 h ( Figure 2 ).

In another study [33] , the antihypertensive efficacy of olmesartan medoxomil 20 mg once daily was compared with recommended starting doses of losartan 50 mg, valsartan 80 mg and irbesartan 150 mg, through a multicenter, randomized, double-blind trial. In this trial, a total of 588 patients with a cuff diastolic BP ≥ 100 mmHg

Figure 1 . Chemical structure of olmesartan medoxomil.

N

N

NN

HN

NO

OO

OHO

O

and ≤ 115 mmHg and a mean daytime diastolic BP ≥ 90 mmHg and < 120 mmHg, as measured by ambulatory BP monitoring, were included. Cuff and ambulatory BP were monitored at baseline and after 8 weeks of treatment. Baseline BP was similar in all the groups. The reduction of sitting cuff diastolic BP attained, the primary efficacy variable of this study, was significantly greater with olmesartan than with losartan, valsartan and irbesartan (11.5 versus 8.2, 7.9 and 9.9 mmHg, respectively). The mean 24-h diastolic BP reduction was significantly greater with olmesartan than with losartan or valsartan (8.5 versus 6.2 and 5.6 mmHg, respectively) and showed a nonsignificant positive trend when compared with irbesartan (7.4 mmHg; p = 0.087). Although the sitting cuff systolic BP lowering effect was not significantly different between groups, the reduction in mean 24-h systolic BP was significantly greater with olmesartan than with losartan or valsartan (12.5 versus 9.0 and 8.1 mmHg, respectively) and equivalent to irbesartan (11.3 mmHg). Therefore, as the authors concluded, at the starting-doses olmesartan medoxomil was more effective than the other ARBs in reducing cuff diastolic BP in hypertensive patients. Similar results have been obtained in other studies [27-32,34,35] . Furthermore, a review including 2693 subjects suggested that absolute reductions in diastolic BP achieved with monotherapy of olmesartan medoxomil appeared comparable to that of the combination of other ARBs with a diuretic [37] .

Although it is crucial to achieve BP goals in hypertensive patients to reduce cardiovascular outcomes, the time to attain the goals is also extremely important, as in this initial period despite the fact that treatment has started the patients are not fully protected. Consequently, European guidelines recommend that in higher-risk hypertensives, the goal BP should be achieved more promptly, which favors drug combinations as first-line therapy and quicker adjustment of doses [4] . In this point, when compared with other ARBs, olmesartan medoxomil has demonstrated to be not only an effective antihypertensive drug, but a rapid-acting agent as well. Thus, Oparil et al. showed that at 2 weeks although treatment with losartan reduced mean diastolic BP by 7.6 mmHg, and both valsartan and irbesartan decreased it by 9.0 mmHg (p < 0.05), olmesartan lowered mean diastolic BP by 10.7 mmHg, differences that persisted along the study time [33] .

4. Effi cacy of olmesartan medoxomil/hydrochlorothiazide compared with other antihypertensive agents

4.1 Olmesartan medoxomil versus olmesartan medoxomil/hydrochlorothiazide Despite the fact that olmesartan medoxomil is an effective BP lowering drug, a significant number of hypertensive patients treated with this drug in monotherapy do not achieve the goals. Several studies have analyzed the effect of

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the addition of HCTZ to olmesartan medoxomil on BP values [38-46] . Chrysant et al. [38] performed a randomized, double-blind, factorial-design study. After a placebo run-in period, eligible patients (n = 502) with a baseline mean seated diastolic BP of 100 – 115 mmHg were randomized to 1 of 12 groups: placebo, olmesartan medoxomil monotherapy (10, 20 or 40 mg/day), HCTZ monotherapy (12.5 or 25 mg/day) or one of six groups of olmesartan medoxomil/HCTZ combination therapy. The primary end point was the change in mean trough seated diastolic BP from baseline at week 8. In this study, all olmesartan medoxomil/HCTZ combinations significantly reduced BP compared with placebo in a dose-dependent manner and induced greater reductions in both systolic and diastolic BP than monotherapy with either component. In the recently published OLMEBEST study [39] , it was examined whether or not olmesartan medoxomil dose titration ( ≤ 40 mg once daily) and olmesartan medoxomil plus HCTZ combination therapy were therapeutically equivalent in patients with mild-to-moderate essential hypertension uncontrolled with a low-dose olmesartan medoxomil monotherapy. OLMEBEST was a prospective, parallel group, partially randomized and double-blind study. A total of 2306 patients, aged 18 – 75 years, with mild-to-moderate essential hypertension (seated diastolic BP ≥ 90 and < 110 mmHg) were included. All enrolled patients received open-label olmesartan medoxomil 20 mg once daily for 8 weeks. At the end of this period, uncontrolled patients (diastolic BP ≥ 90 mmHg) were randomized to receive olmesartan medoxomil mono-therapy 40 mg (n = 302) or a combination of olmesartan medoxomil 20 mg plus HCTZ 12.5 mg (n = 325) for 4 weeks. After 8 weeks of open-label treatment with olmesartan medoxomil 20 mg, three out of four patients (76%) were responders (diastolic BP < 90 mmHg or

Figure 2 . Reduction in the blood pressure values over 24 h. p = 0.03 and p = 0.002 for systolic and diastolic blood pressure, respectively, among the drugs (adapted from Fabia et al. [36] ).

0 -4 -8mmHg

-12 -16

Olmesartan

Eprosartan

Telmisartan

Candesartan

Irbesartan

Valsartan

Losartan

Placebo Systolic blood pressure

Diastolic blood pressure

reduction of ≥ 10 mmHg) to monotherapy. During the randomized phase of the study, both treatments were associated with comparable and clinically-relevant improve-ments in seated systolic and diastolic BP (olmesartan medoxomil 40 mg showed a reduction of 5.3/5.1 mmHg and olmesartan medoxomil plus HCTZ combination therapy of 10.8/7.9 mmHg. Final mean BP values were 145.3/90.9 mmHg and 140.7/88.7 mmHg (olmesartan 40 mg and olmesartan 20 mg plus HCTZ 12.5 mg, respectively), showing that the two treatment arms were not thera-peutically equivalent. As the authors remarked, probably the high rate of BP control achieved with olmesartan 20 mg once daily, 70% observed versus 58% expected, could influence these results ( Figure 3 ). Similar results have been obtained in other trials [40-42] .

4.2 Olmesartan medoxomil/hydrochlorothiazide associated with other antihypertensive drugs Although the combination olmesartan medoxomil/HCTZ has shown to improve BP control rates, a proportion of patients treated with this combination may persist uncontrolled. Hence, Neutel et al. examined the effects of an antihypertensive treatment algorithm with olmesartan medoxomil as the initial agent in a hypertensive population in two studies [43,44] . In the most recent study [44] , stage 1 or 2 hypertensive patients were included. Initially they received olmesartan medoxomil 20 mg once-daily for 4 weeks and the regimen was modified every 4 weeks until the BP goal ( ≤ 130/85 mmHg) was attained. The therapeutic strategy was: uptitration of olmesartan medoxomil to 40 mg/day; addition of HCTZ 12.5 mg/day; increase HCTZ to 25 mg/day; addition of amlodipine besilate 5 mg/day; and finally increase amlodipine besilate to 10 mg/day. In stage 1 hypertensive patients, 80 and 56% of them achieved BP values ≤ 140/90 and ≤ 130/85 mmHg, respectively, with olmesartan medoxomil monotherapy, 94 and 89% with olmesartan/HCTZ (double therapy) and 96 and 98% with the addition of amlodipine besilate (triple therapy). In stage 2 hypertensives, the proportions of controlled patients were 42 and 19% with monotherapy, 75 and 54% with double therapy and 90 and 81% with triple therapy. As the authors remarked, this study demonstrated that an olmesartan-based treatment algorithm was effective in patients with hypertension and that olmesartan can be successfully combined with other antihypertensive agents.

4.3 Olmesartan medoxomil/hydrochlorothiazide versus other combinations Olmesartan medoxomil/HCTZ has been compared with other combinations, including other combinations of ARBs/HCTZ [45-49] . The combination olmesartan/HCTZ was compared with losartan/HCTZ in a multicenter, randomized, double-blind trial in 613 patients with moderate-to-severe essential hypertension [45] . This study

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showed that olmesartan medoxomil 20 mg/HCTZ 12.5 mg produced greater BP reductions than losartan 50 mg/HCTZ 12.5 mg. By week 12, mean seated diastolic BP reductions were similar (17.6 and 16.5 mmHg, respectively, p = 0.0708), but with higher systolic BP decreases (29.3 and 24.9 mmHg, respectively, p < 0.0003) and BP control rates (43.2 and 32.1%, respectively, p = 0.002). Ram [47] published a review of randomized, double-blind, placebo-controlled factorial studies of similar design in hypertensive patients. In this analysis, maximal approved dosages for the combinations of olmesartan medoxomil/HCTZ, irbesartan/HCTZ, telmisartan/HCTZ and valsartan/HCTZ were compared. The combination olmesartan/HCTZ resulted in greater systolic and diastolic BP reductions compared with the other combinations. Interestingly, in another study performed in 130 hyper-tensive patients, the addition of HCTZ 12.5 mg to valsartan 160 mg monotherapy produced a greater BP reduction than the addition of the same dose of HCTZ to olmesartan 20 mg monotherapy [46] . This is relevant taking into account that the equipotent dose of olmesartan 20 mg/day is valsartan 80 mg/day and not 160 mg. Therefore, it appears that direct comparative studies are warranted to confirm which ARB/HCTZ combination produces greater BP reductions and better control rates.

In another study, the BP-lowering efficacy of olmesartan medoxomil/HCTZ and amlodipine besilate/benazepril were compared in similarly-designed, randomized, placebo-controlled studies and in similar populations. As authors concluded, although a randomized clinical trial comparing the two combinations is needed, olmesartan medoxomil/HCTZ appears to be at least as effective as amlodipine besilate/benazepril [49] .

Figure 3 . Frequency of diastolic blood pressure response and normalization after 4 weeks of randomized treatment with olmesartan medoxomil 40 mg once daily or olmesartan medoxomil 20 mg with hydrochlorothiazide 12.5 mg once daily. Data adapted from OLMEBEST study [39] . HCTZ: Hydrochlorothiazide.

Olmesartan 40 mgOlmesartan 20 mg + HCTZ 12.5 mg

0

10

20

30

40

50

60

70

80

Response Normalization

5. Safety profi le of olmesartan medoxomil/hydrochlorothiazide

Olmesartan medoxomil, similarly to the other ARBs, is a safe and well-tolerated drug, with a low incidence of adverse events, comparable with placebo. The most frequently reported side effects have been headache, dizziness and flu-like symptoms. Furthermore, the metabolic profile of olmesartan medoxomil is also very good and similar to placebo [50] . On the other hand, patients treated with HCTZ may exhibit metabolic disturbances, with a higher tendency to increase plasma glucose levels and electrolyte imbalances such as hypokalemia and hyponatremia, particularly when higher doses are used [50] . The combination of olmesartan medoxomil with HCTZ may reduce the potassium loss caused by HCTZ and the development of diabetes mellitus, as ARBs have been shown to diminish the incidence of new-onset diabetes when compared with other anti-hypertensive drugs [14,51] . As a result, the combination of olmesartan with medoxomil is well tolerated and when side effects are present they are generally mild-to-moderate in severity [27,42-45] .

6. Expert opinion

The majority of patients with hypertension often require more than one drug to achieve BP goals. The most recent European guidelines clearly establish that combination therapy is recommended as first-line therapy in certain situations, such as marked BP elevations, high- or very high-risk patients or when BP targets are lower [4] . The beneficial effect of inhibiting the RAAS in patients with hypertension is well known. Olmesartan medoxomil 20 mg plus HCTZ 12.5 mg is the last ARB/HCTZ fixed combination approved for the treatment of hypertension. Clinical trials have shown that olmesartan medoxomil/HCTZ is an effective and well-tolerated, fixed-dose antihypertensive combination. As expected, it provides greater antihypertensive efficacy than either component taken as monotherapy. Some studies suggest that this combination may provide a better BP control than other antihypertensive therapies, including some ARB/HCTZ combinations. However, so far studies assessing the effects of olmesartan in reversing left ventricular hypertrophy, decreasing proteinuria, progression of renal disease or improving clinical outcomes in heart failure patients are still missing. On the other hand, the development of new drugs, such as aliskiren or combi-nations like ARB with calcium channel blockers make necessary further studies to compare the efficacy and tolerability of these therapies [11,52] .

Declaration of interest

The author has no conflict of interest to declare and no fee has been received for preparation of the manuscript.

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30. Chrysant SG, Marbury TC, Silfani TN. Use of 24-h ambulatory blood pressure monitoring to assess blood pressure control: a comparison of olmesartan medoxomil and amlodipine besylate. Blood Press Monit 2006 ; 11 : 135 -41

31. Brunner HR, Arakawa K. Antihypertensive effi cacy of olmesartan medoxomil and candesartan cilexetil in achieving 24-hour blood pressure reductions and ambulatory blood pressure goals. Clin Drug Investig 2006 ; 26 : 185 -93

32. Smith DH, Dubiel R, Jones M. Use of 24-hour ambulatory blood pressure monitoring to assess antihypertensive effi cacy: a comparison of olmesartan medoxomil, losartan potassium, valsartan, and irbesartan. Am J Cardiovasc Drugs 2005 ; 5 : 41 -50

33. Oparil S, Williams D, Chrysant SG, et al. Comparative effi cacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension. J Clin Hypertens (Greenwich) 2001 ; 3 : 283 -91

•• In this study, the antihypertensive effi cacy of olmesartan medoxomil 20 mg once daily was compared with recommended starting doses of losartan 50 mg, valsartan 80 mg and irbesartan 150 mg through a multi-center, randomized, double-blind trial, showing that the reduction of sitting cuff diastolic BP with olmesartan was signifi cantly greater than with losartan, valsartan and irbesartan.

34. Stumpe KO. Olmesartan compared with other angiotensin II receptor antagonists: head-to-head trials. Clin Ther 2004 ; 26 (Suppl A): A33 -A37

35. Giles TD, Oparil S, Silfani TN, et al. Comparison of increasing doses of olmesartan medoxomil, losartan potassium, and valsartan in patients with essential hypertension. J Clin Hypertens (Greenwich) 2007 ; 9 : 187 -95

36. Fabia MJ, Abdilla N, Oltra R, et al. Antihypertensive activity of angiotensin II AT1 receptor antagonists: a systematic review of studies with 24 h ambulatory blood pressure monitoring. J Hypertens 2007 ; 25 : 1327 -36

•• This systematic review was aimed to assess the antihypertensive activity of seven different ARBs (losartan, valsartan, irbesartan, candesartan, telmisartan, eprosartan and olmesartan), compared with amlodipine, enalapril, other ARBs or placebo.

37. Greathouse M. A review of olmesartan medoxomil monotherapy: antihypertensive effi cacy similar to that of other angiotensin II receptor blocker/hydrochlorothiazide combinations?. Congest Heart Fail 2002 ; 8 : 313 -20

38. Chrysant SG, Weber MA, Wang AC, et al. Evaluation of antihypertensive therapy with the combination of olmesartan medoxomil and hydrochlorothiazide. Am J Hypertens 2004 ; 17 : 252 -9

39. Barrios V, Boccanelli A, Ewald S, et al. Effi cacy and tolerability of olmesartan medoxomil in patients with mild to moderate essential hypertension: the OLMEBEST Study. Clin Drug Investig 2007 ; 27 : 545 -58

• In this recent study, whether or not olmesartan medoxomil dose titration and olmesartan medoxomil/HCTZ combination therapy were therapeutically equivalent in patients with mild-to-moderate essential hypertension who had shown an inadequate response to low-dose olmesartan medoxomil monotherapy in a prospective, parallel-group, partially-randomized and double-blind study was examined.

40. Sellin L, Stegbauer J, Laeis P, et al. Adding hydrochlorothiazide to olmesartan dose dependently improves 24-h blood pressure and response rates in mild-to-moderate hypertension. J Hypertens 2005 ; 23 : 2083 -92

41. Izzo JL Jr, Neutel JM, Silfani T, et al. Titration of HCTZ to 50 mg daily in individuals with stage 2 systolic hypertension pretreated with an angiotensin receptor blocker. J Clin Hypertens (Greenwich) 2007 ; 9 : 45 -8

42. Izzo JL Jr, Neutel JM, Silfani T, et al. Effi cacy and safety of treating stage 2 systolic hypertension with olmesartan and olmesartan/HCTZ: results of an open-label titration study. J Clin Hypertens (Greenwich) 2007 ; 9 : 36 -44

43. Neutel JM, Smith DH, Weber MA, et al. Use of an olmesartan medoxomil-based treatment algorithm for hypertension control. J Clin Hypertens (Greenwich) 2004 ; 6 : 168 -74

44. Neutel JM, Smith DH, Silfani TN, et al. Effects of a structured treatment algorithm on blood pressure goal rates

in both stage 1 and stage 2 hypertension. J Hum Hypertens 2006 ; 20 : 255 -62

• This study demonstrated that an olmesartan-based treatment algorithm was effective in patients with hypertension and that olmesartan can be successfully associated with other antihypertensive agents.

45. Rump LC, Ambrosioni E, Burnier M, et al. Initial combination therapy with olmesartan/hydrochlorothiazide in moderate-to-severe hypertension. J Hum Hypertens 2006 ; 20 : 299 -301

46. Fogari R, Zoppi A, Mugellini A, et al. Hydrochlorothiazide added to valsartan is more effective than when added to olmesartan in reducing blood pressure in moderately hypertensive patients inadequately controlled by monotherapy. Adv Ther 2006 ; 23 : 680 -95

47. Ram CV. Antihypertensive effi cacy of angiotensin receptor blockers in combination with hydrochlorothiazide: a review of the factorial-design studies. J Clin Hypertens (Greenwich) 2004 ; 6 : 569 -77

•• In this review of randomized, double-blind, placebo-controlled factorial studies of similar design in hypertensive patients, maximum approved dosages of olmesartan medoxomil/HCTZ, irbesartan/HCTZ, telmisartan/HCTZ and valsartan/HCTZ were compared, showing that olmesartan/HCTZ produced greater reductions in both systolic and diastolic BP values compared with the other combinations.

48. Conlin PR, Spence JD, Williams B, et al. Angiotensin II antagonists for hypertension: are there differences in effi cacy? Am J Hypertens 2000 ; 13 : 418 -26

49. Quan A, Chavanu K, Merkel J. A review of the effi cacy of fi xed-dose combinations olmesartan medoxomil/hydrochlorothiazide and amlodipine besylate/benazepril in factorial design studies. Am J Cardiovasc Drugs 2006 ; 6 : 103 -13

50. Hasford J, Mimran A, Simons WR. A population-based European cohort study of persistence in newly diagnosed hypertensive patients. J Hum Hypertens 2002 ; 16 : 569 -75

51. Verdecchia P, Angeli F, Reboldi G. New-onset diabetes, antihypertensive treatment, and outcome. Hypertension 2007 ; 50 : 459 -60

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52. van den Meiracker AH, Jan Danser AH. Aliskiren: the fi rst direct renin inhibitor for hypertension. Curr Cardiol Rep 2007 ; 9 : 470 -76

Affi liation Vivencio Barrios † & Carlos Escobar †Author for correspondence Hospital Ram ó n y Cajal, Department of Cardiology, Ctra. Colmenar km 9.100, 28034 Madrid, Spain Tel: +34 91 3368259 ; Fax: +34 91 3368665 ; E-mail: [email protected] ; [email protected]

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Documents

Olmesartan medoxomil plus hydrochlorothiazide for treating hypertension