Efficacy and Tolerability of Olmesartan Medoxomil in Patients

Abstract and Introduction

Abstract

Background and objective: Achieving target BP is important to control the increased cardiovascular risk associated with uncontrolled hypertension. However, failure to respond to therapy is common with all classes of antihypertensive agents. Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) possess many of the positive features of angiotensin-converting enzyme inhibitors, with fewer adverse effects. However, many patients fail to respond adequately to low-dose monotherapy. This study examined whether olmesartan medoxomil dose titration and olmesartan medoxomil/hydrochlorothiazide 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.
Methods: This was a prospective, parallel group, partially randomised, double-blind study set in 463 centres in nine European countries. 2306 male and female adult patients aged 1875 years with mild to moderate essential hypertension (sitting diastolic BP [DBP] =90mm Hg and <110mm Hg) were enrolled. All enrolled patients received open-label olmesartan medoxomil 20mg once daily for 8 weeks. At the end of this period, patients whose BP had not normalised (sitting DBP =90mm Hg) were randomised to receive olmesartan medoxomil monotherapy (40mg once daily, n = 302) or olmesartan medoxomil (20mg once daily)/hydrochlorothiazide (12.5mg once daily) combination therapy (n = 325) for 4 weeks. The main outcome measure was change in mean sitting DBP during randomised treatment.
Results: After 8 weeks of open-label treatment with olmesartan medoxomil 20 mg/day, 76% of patients showed a DBP response (sitting DBP <90mm Hg or reduction of =10mm Hg). During the randomised phase of the study, both treatments were associated with further improvements in sitting SBP/DBP: a reduction of 5.3/5.1mm Hg with olmesartan medoxomil 40 mg/day, and a reduction of 10.8/7.9mm Hg with olmesartan medoxomil/hydrochlorothiazide combination therapy. Final mean BPs of 145.3/90.9mm Hg (olmesartan medoxomil 40 mg/day) and 140.7/88.7mm Hg (olmesartan medoxomil 20mg + hydrochlorothiazide) were achieved, compared with a mean BP of 160.8/100.5mm Hg at baseline. The two treatments were not therapeutically equivalent. Sitting DBP showed a response and was normalised (<90mm Hg) in 62% and 47% of olmesartan medoxomil monotherapy patients, respectively. In the combination therapy group, these endpoints were achieved by 71% (response) and 59% (normalisation) of patients. Treatment with olmesartan medoxomil 40 mg/day was associated with a lower frequency of adverse events than olmesartan medoxomil/hydrochlorothiazide combination therapy (21.5% vs 28.3%, respectively).
Conclusion: For patients who did not achieve adequate BP control after initial treatment with olmesartan medoxomil 20 mg/day, olmesartan medoxomil dose titration (to 40 mg/day) or addition of hydrochlorothiazide (12.5 mg/day) elicited a sitting DBP response in the majority of patients who had failed to respond to low-dose monotherapy, and normalisation of sitting DBP in approximately 50% of patients. Both these strategies represent effective and well tolerated treatment options in patients who show an inadequate response to low-dose monotherapy with olmesartan medoxomil.

Introduction

Hypertension, which is generally defined as a systolic BP (SBP) =140mm Hg and a diastolic BP (DBP) =90mm Hg,^[1,2,3] is a major cause of cardiovascular disease worldwide.^[4,5] Reducing the burden of hypertension should be a primary aim. However, achieving control of elevated BP is a complex, multifactorial process that involves primary prevention, early detection and adequate treatment to prevent complications.

Current treatment guidelines recommend that BP should be reduced to <130/80mm Hg in patients with diabetes mellitus or chronic renal disease and to <140/90mm Hg in all others.^[1,2] However, many patients with essential hypertension fail to achieve these targets with currently recommended treatments. For example, data collected by the National Health and Nutrition Examination Survey show that, during the period 20012, only 34% of hypertensive American adults achieved a BP <140/90mm Hg.^[6] Elsewhere, documented BP control rates (i.e. BP <140/90mm Hg) range from 3% (in China) to 28% (Hungary).^[7,8]

Of the drug classes that are used most widely in the treatment of elevated BP, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) are among the most recently introduced. These agents possess many of the positive features of angiotensin-converting enzyme (ACE) inhibitors, including effective lowering of BP, prevention of target organ damage, reduced risk of new-onset diabetes and cardiovascular protection.^[9,10,11] However, evidence suggests that ARBs also have a better tolerability profile and are associated with greater patient compliance with therapy than with ACE inhibitors.^[11,12,13]

Olmesartan medoxomil is the most recently introduced ARB. Its active metabolite (olmesartan) has high selectivity and potency for the angiotensin AT₁ receptor,^[14] and it has been shown to be more effective in the treatment of hypertension than other ARBs with which it has been directly compared.^{[15,16,17,18,19,20]} In addition, olmesartan medoxomil is well tolerated, with an adverse effect profile similar to that of placebo.^[21]

In order to achieve their BP goal, many hypertensive patients require titration of their initial anti-hypertensive medication and/or inclusion of a second pharmacological agent in the therapeutic regimen.^[1,2,22] The BP-lowering efficacy of olmesartan medoxomil 20 mg/day can be increased by dose titration to 40 mg/day^[23,24,25] or addition of hydro-chlorothiazide.^[26] Since the olmesartan medoxomil/hydrochlorothiazide combination therapy is well tolerated,^[27] either of these approaches could be adopted in patients who show an inadequate response to olmesartan medoxomil 20 mg/day.

This paper describes the results of OLMEBEST, a prospective, multinational, partially randomised, double-blind study designed to compare the efficacy of olmesartan medoxomil monotherapy (40mg once daily) and olmesartan medoxomil/hydrochlorothiazide combination therapy (20mg and 12.5mg once daily, respectively) in patients with mild to moderate essential hypertension who had shown an inadequate response to 8 weeks of open-label treatment with olmesartan medoxomil administered at its starting dose (20mg once daily).

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