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Abstract

Clinical studies and population-based analyses show that in patients with hypertension, the majority cannot control their blood pressure (BP) by treatment with a single antihypertensive agent. Combining agents from different antihypertensive classes with complementary modes of action significantly increases efficacy and is a treatment strategy recommended by European treatment guidelines, particularly in patients at high cardiovascular risk. The combinations of antihypertensive agents recommended by the European guidelines include an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB). The single-pill combination formulation of the ARB olmesartan medoxomil plus the CCB amlodipine is an effective and well-tolerated treatment that provides greater blood pressure lowering and control than the component monotherapies and favours compliance by not increasing pill burden. Importantly, the efficacy and tolerability of olmesartan plus amlodipine is not affected by age, gender, hypertension severity, diabetes status, race or body mass index. Additional blood pressure lowering effects are observed with stepwise uptitration of olmesartan plus amlodipine with or without hydrochlorothiazide, with more patients achieving blood pressure goals. In addition, olmesartan plus amlodipine has demonstrated effects beyond BP lowering by showing beneficial effects on markers of inflammation, endothelial dysfunction and oxidative stress, as well as metabolic improvements and a reduction in new-onset diabetes incidence in hypertensive patients with metabolic syndrome.

Keywords

amlodipine besylate hypertension metabolic syndrome olmesartan medoxomil single-pill combination

Introduction

Hypertension is an important global health problem, the prevalence of which is increasing. By 2025, it is estimated that more than 1.5 billion people worldwide will have hypertension [Kearney et al. 2005]. Moreover, the prevalence of hypertension increases with age [Zeglin et al. 2009] and >50% of patients with hypertension are aged >65 years [Zannad, 2000]. Therefore, the aging population is a major contributory factor to the continuing rise in the prevalence of hypertension. The increasing prevalence of obesity, which is becoming a major health hazard in many countries, is a further significant factor [International Association for the Study of Obesity, 2011; Swinburn et al. 2011]. Obesity is an established risk factor for type 2 diabetes and a major component of metabolic syndrome, a cluster of risk factors associated with atherosclerotic cardiovascular disease and with increased risk for developing type 2 diabetes mellitus [Grundy et al. 2005]. The obesity pandemic is believed to be a major driver of the increasing prevalence of diabetes that is being seen around the world [Grundy, 2008]. Diabetes is a common endocrine disorder, currently affecting just over 6% of the world’s population, and this figure is expected to rise to approximately 8% by 2030 [Adeghate et al. 2006; Shaw et al. 2009]. Compared with healthy individuals, hypertension occurs more frequently in obese patients and in patients with diabetes, particularly those with type 2 diabetes in whom hypertension is often present as part of the metabolic syndrome [Bramlage et al. 2004; Suh et al. 2009].

Patients such as the elderly, as well as overweight and obese patients and those with diabetes, represent large subgroups of the hypertensive patient population. A cross-sectional study of 6527 hypertensive patients investigated the prevalence of cardio-metabolic risk factors and their effect on blood pressure (BP) control. Of these patients, a number of patient subgroups were evident: 25.3% were diabetic; 50.8% were aged ≥65 years; and 48.7% were obese (body mass index [BMI] ≥30 kg/m²) [Belletti et al. 2010].

Lowering BP is crucial to reducing the risk of cardiovascular (CV) events, and European hypertension treatment guidelines recommend lowering BP to <140/90 mmHg in all hypertensive patients, including those at both low and high CV risk, to maximize the reduction in the risk of CV events [Mancia et al. 2009]. However, despite clear guidelines and the well-documented relationship between hypertension and cerebrovascular and CV risk BP control rates remain suboptimal [Kannel, 1996; Bestehorn et al. 2008].

The majority (approximately 75%) of patients with hypertension require two or more antihypertensive agents from different classes to reach guideline-recommended BP targets [Mancia et al. 2009; Gradman et al. 2010]. Since a number of physiological pathways contribute to the pathophysiology of hypertension, combination antihypertensive therapy comprising agents with complementary mechanisms of action is a rational treatment strategy to lower BP, increase BP goal achievement rates and attenuate unwanted side effects [Neutel, 1999; Law et al. 2003; Wald et al. 2009].

The use of combination antihypertensive therapy is of particular relevance for patients who are more difficult to get to BP goal, including the elderly (aged ≥65 years) and those with more severe hypertension. Furthermore, the improved convenience associated with single-pill combinations may improve treatment compliance, thereby improving health outcomes. Specifically, since the risk of hypertension increases with age, the reduction in pill burden may be of benefit for elderly patients in whom comorbidities occur frequently [Yang et al. 2010].

Single-pill combination therapy with olmesartan and amlodipine: rationale, efficacy and tolerability

European hypertension treatment guidelines recommend five preferred antihypertensive combinations comprising agents from different classes [Mancia et al. 2007, 2009]:

angiotensin-converting enzyme inhibitor (ACEI) + thiazide diuretic;

angiotensin II receptor blocker (ARB) + thiazide diuretic;

ACEI + calcium channel blocker (CCB);

ARB + CCB;

CCB + thiazide diuretic.

Formerly, combinations comprising β-blockers were also recommended. To date, however, no outcome trial has investigated the combination of a CCB with a β-blocker and, furthermore, combining β-blockers with thiazide diuretics should be avoided in patients predisposed to diabetes [Mancia et al. 2009].

Outcomes data from clinical trials suggest that of the five recommended preferred combinations, some may be more useful than others, especially in specific patient populations; for example, those based on blockers of the renin–angiotensin system (RAS) (ARBs and ACEIs). This is demonstrated by findings from the Losartan Intervention For Endpoint reduction (LIFE) study which suggest that antihypertensive treatment based on an ARB may be more favourable than β-blocker-based treatment [Dahlof et al. 2002]. In 9193 patients aged 55–80 years with essential hypertension and left ventricular hypertrophy (LVH), losartan-based treatment reduced the frequency of the primary composite endpoint of CV death, stroke and myocardial infarction (MI) to a greater extent than atenolol-based treatment (24% and 28%, respectively; p = 0.021) [Dahlof et al. 2002]. Further to these findings, the use of ARB-based treatment is also supported by the results of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study [Julius et al. 2004]. This was a randomized, double-blind, parallel-group study of 15,245 patients aged ≥50 years with treated or untreated hypertension who were at high CV risk due to the presence of risk factors such as diabetes and LVH. The frequency of the main outcome, a composite of CV mortality and morbidity, did not differ significantly between the valsartan- and amlodipine-based treatment arms, however, there was a significantly lower incidence of new-onset diabetes with valsartan- versus amlodipine-based treatment (13% versus 16%, respectively; p < 0.0001) [Julius et al. 2004].

The use of another of the preferred combinations recommended by the European guidelines is supported by findings of the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) which demonstrated that antihypertensive treatment based on a CCB may be more favourable than β-blocker-based treatment [Dahlof et al. 2005]. The ASCOT-BPLA study was conducted in 19,257 patients aged 40–79 years with hypertension and at least three other CV risk factors. After a median follow up of 5.5 years, there was a lower incidence of the primary endpoint of nonfatal MI and fatal coronary heart disease (p = 0.1052) and new-onset diabetes (p < 0.0001) after treatment based on amlodipine (± perindopril) compared with atenolol-based treatment (± bendroflumethiazide) [Dahlof et al. 2005].

The use of an ACEI/CCB combination is, however, also supported by results of the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) study, one of the first major studies to investigate the effects of combination therapy [Jamerson et al. 2008]. ACCOMPLISH was a multicentre, randomized, double-blind study of 11,506 patients with hypertension who were at high risk of CV events due to the presence of risk factors such as a history of MI or stroke, impaired renal function, LVH or diabetes mellitus. It should be noted that, at baseline, 60.4% of patients were diabetic and almost half (49.6%) had a BMI of >30 kg/m². ACCOMPLISH was designed to test the hypothesis that treatment with an ACEI combined with a CCB would more effectively reduce the incidence of CV events compared with treatment with the same ACEI combined with a thiazide diuretic. Patients were randomized to receive treatment with benazepril plus amlodipine (n = 5744) or benazepril plus hydrochlorothiazide (HCTZ; n = 5762). The primary endpoint was measured as the time to the first CV event, defined as the composite of a CV event and death from CV causes. After a mean follow up of 36 months, the incidence of primary outcome events was 9.6% and 11.8% in the benazepril/amlodipine and benazepril/HCTZ treatment groups, respectively (relative risk reduction: 19.6%; hazard ratio: 0.80; 95% confidence interval [CI]: 0.72–0.90; p < 0.001) [Jamerson et al. 2008]. The findings of ACCOMPLISH demonstrate the benefits of treatment with a RAS blocker plus a CCB (amlodipine) in providing effective BP control and reducing the incidence of CV events in hypertensive patients at high CV risk and with underlying metabolic issues, compared with treatment with a RAS blocker plus a thiazide diuretic (HCTZ).

Finally, findings from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) [Progress Collaborative Group, 2001], the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) trial [Patel et al. 2007] and the Hypertension in the Very Elderly Trial (HYVET) [Beckett et al. 2008] support the use of ACEI/thiazide diuretic combinations in patients with a history of stroke or transient ischaemic attack, patients with type 2 diabetes, and the elderly (aged ≥80 years), respectively.

Single-pill combination therapy based on blockers of the RAS

Antihypertensive combination therapy based on either ACEIs or ARBs is a logical treatment approach since these agents can be used at higher doses without compromising tolerability. Such a treatment approach is also supported by findings of a recent meta-analysis of 42 trials which demonstrated that combining agents from two different classes lowered BP to a greater extent than doubling the dose of a single agent [Wald et al. 2009].

The use of combination therapy in patients who require more than one agent to achieve BP goal poses the question of ‘what to combine with an ARB?’, and hypertension treatment guidelines recommend combining an ARB with either a thiazide diuretic or a CCB [Mancia et al. 2007, 2009]. Recently, evidence has grown on the use of ARB/CCB combinations in particular, which have been shown to be ‘capable of most effectively reducing even severe hypertension’ [Mancia et al. 2009]. This is supported by the findings of the ACCOMPLISH trial which, as previously mentioned, has demonstrated that treatment with a RAS blocker plus a CCB (amlodipine) provides effective BP control and is more efficacious in reducing the incidence of CV events in patients at high CV risk and with underlying metabolic issues, than treatment with a RAS blocker plus a thiazide diuretic (HCTZ) [Jamerson et al. 2008].

Evidence suggests that ARB-based combinations may be more desirable than combinations based on ACEIs due to their superior tolerability. In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), telmisartan and ramipril were equally effective in their ability to reduce the risk of CV events, but there was a significantly lower incidence of cough (1.1% versus 4.2%; < 0.001) and angioedema (0.1% versus 0.3%; p = 0.01) in patients who received telmisartan compared with those who received ramipril [Yusuf et al. 2008].

Additional benefits of olmesartan-based treatment

ARBs exert their BP-lowering effects by blocking the action of the main effector of the RAS, angiotensin II, at the angiotensin II type I (AT₁) receptor. In addition to causing vasoconstriction, angiotensin II also acts via the AT₁ receptor to play a key role in various pathological processes that are associated with organ damage. Therefore, blockade of the AT₁ receptor by ARBs may confer additional beneficial effects.

This is illustrated by the ARB olmesartan medoxomil which provides robust AT₁ receptor blockade as demonstrated by its highly effective 24-hour BP-lowering efficacy [Fabia et al. 2007]. Further to effectively lowering BP, additional beneficial effects of olmesartan that may contribute to the reduction in the risk of cardiorenal events have been demonstrated in a number of studies.

In a 12-week, double-blind, parallel-group study, there was an increase in the number of regenerative endothelial progenitor cells in patients with type 2 diabetes after treatment with olmesartan 40 mg/day. This observation may be of clinical relevance contributing to the beneficial CV effects of ARBs [Bahlmann et al. 2005]. In the prospective, double-blind EUropean Trial on Olmesartan and Pravastatin in Inflammation and Atherosclerosis (EUTOPIA), 6 weeks of treatment with olmesartan significantly reduced markers of inflammation such as high sensitivity C-reactive protein (−15.1%; p < 0.05), high sensitivity tumour necrosis factor-α (−8.9%; p < 0.02) and interleukin-6 (−14.0%; p < 0.05) in patients with hypertension and vascular inflammation [Fliser et al. 2004]. In another study, the Vascular Improvement with Olmesartan medoxomil Study (VIOS), olmesartan significantly reduced the wall-to-lumen ratio (from 14.9% to 11.1%; p < 0.01) in the arteries of nondiabetic patients with hypertension and small artery remodelling, to a similar extent as measured in normotensive controls [Smith et al. 2008]. In contrast, no significant change was observed after treatment with the β-blocker atenolol, despite the two agents demonstrating similar effects on BP lowering. A third study, the Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study, compared the effects of olmesartan and atenolol on common carotid intima-media thickness and atherosclerotic plaque volume in patients with hypertension and carotid atherosclerosis. After 2 years of treatment, both olmesartan and atenolol significantly reduced common carotid intima-media thickness to a comparable extent, but only olmesartan reduced the volume of larger atherosclerotic plaques [Stumpe et al. 2007]. Taken together, the findings of these three studies demonstrate that effective AT₁ receptor blockade by olmesartan can reduce vascular inflammation, restore the normal morphology of small arteries and reduce the volume of large carotid atherosclerotic plaques. In each of these studies, these observed beneficial vascular-protective effects of olmesartan were in addition to its effects on BP reduction.

Therefore, the use of olmesartan in combination therapy is a logical treatment approach that offers benefits both in terms of BP reductions and additional organ-protective benefits.

The benefits of treatment with amlodipine

The CCB amlodipine has a slow onset of action and long plasma half-life, pharmacokinetic characteristics that enable it to control BP effectively with once-daily dosing [Ishimitsu et al. 1999]. One less favourable characteristic of CCBs such as amlodipine is that they are associated with peripheral oedema, but this effect can be ameliorated by treatment with agents that have a postcapillary vasodilatory effect such as ARBs [Messerli, 2002].

In animal studies, amlodipine has demonstrated cardioprotective effects, reductions in atheroma formation and regression of myocardial hypertrophy [Haria and Wagstaff, 1995]. Beneficial CV effects of amlodipine that may be beyond BP lowering have also been demonstrated in humans. In the ASCOT-BPLA study, amlodipine (± perindopril) reduced the incidence of CV events to a greater extent than atenolol (± bendroflumethiazide) despite similar reductions in brachial BP [Dahlof et al. 2005]. The favourable CV effects of amlodipine are further demonstrated by findings of the Conduit Artery Function Evaluation (CAFE) study, a substudy of ASCOT, in which amlodipine (± perindopril) reduced central aortic pressure more effectively than atenolol (± bendroflumethiazide) [Williams et al. 2006]. These observed effects of amlodipine relate to ancillary effects such as reversal of intima-media thickening [Terpstra et al. 2004], reduction of arterial stiffness [Ichihara et al. 2007], inhibition of vascular smooth muscle proliferation [Ziesche et al. 2004] and antioxidant effects such as reduction of lipid peroxidation [Turgan et al. 2003] and reversal of nitric oxide synthase inhibition [Toba et al. 2005].

Therefore, combination therapy comprising amlodipine plus olmesartan offers the potential to increase antihypertensive efficacy while preventing or reducing amlodipine-induced oedema and confer various additional organ-protective benefits.

Antihypertensive efficacy of olmesartan/amlodipine combination therapy

A single-pill combination formulation of olmesartan and amlodipine (Sevikar^®, Daiichi Sankyo; olmesartan/amlodipine 20/5, 40/5 and 40/10 mg) is approved in various European countries, and its efficacy has been evaluated in several randomized, double-blind, controlled trials. The large factorial Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) study was conducted in male and female patients aged ≥18 years with mild-to-severe hypertension. After 8 weeks of randomized, double-blind treatment, significantly greater reductions in BP were observed in patients who received combination therapy with olmesartan/amlodipine (20/5, 40/5 and 40/10 mg/day) compared with those patients who received equivalent doses of either drug administered as monotherapy (p < 0.001) [Chrysant et al. 2008]. Furthermore, a greater proportion of patients receiving olmesartan/amlodipine combination therapy achieved BP goal (42.5%, 51.0% and 49.1% for olmesartan/amlodipine 20/5, 40/5 and 40/10 mg, respectively) compared with those receiving monotherapy. Antihypertensive efficacy was maintained during the 44-week open-label extension phase of the COACH study in which patients were initiated on olmesartan/amlodipine 40/5 mg once daily [Chrysant et al. 2009]. Similarly, in the European olmesartan add-on study, 8 weeks of olmesartan/amlodipine combination therapy (20/5, 40/5 and 40/10 mg/day) provided significantly greater reductions in BP and improvements in BP control than amlodipine 5 mg/day in patients with moderate-to-severe hypertension whose BP was inadequately controlled by amlodipine 5 mg/day [Volpe et al. 2009a]. Once again, efficacy was maintained during a 28-week open-label extension phase in patients who were initiated on olmesartan/amlodipine 40/5 mg once daily [Volpe et al. 2009b, 2009b]. In both trials, uptitration of olmesartan/amlodipine to 40/10 mg/day (with the addition of HCTZ [12.5 or 25 mg] as required) resulted in further reductions in BP and enabled even more patients to achieve BP goal [Chrysant et al. 2009; Volpe et al. 2009b].

The efficacy of olmesartan/amlodipine single-pill combination therapy has also been investigated in a setting more reflective of real-life clinical practice. A large (n = 8241) observational study was conducted by primary care physicians (n = 2187) who selected and treated patients with olmesartan/amlodipine according to patient’s needs for 12–18 weeks. The overall reduction in mean systolic BP (SBP)/diastolic BP (DBP) (29.0/13.5 mmHg) and rate of BP control (69.4%) was consistent with the COACH study. Patients with severe hypertension showed the largest BP reductions (48.3/22.6 mmHg) and those with mild hypertension showed smaller reductions (18.9/12.3 mmHg) indicating that the olmesartan/amlodipine dose range provides sufficient strength and flexibility to meet the needs of a range of patients [Bramlage et al. 2010a]. This study is also of note because it is one of the relatively few investigations to have collected data on the quality of life of hypertensive patients and the effects of treatment. The effects of treatment were assessed using the Short Form 12 (SF-12) questionnaire, an internationally recognised and validated tool for assessing quality of life. After 12–18 weeks, the physical health score of olmesartan/amlodipine-treated patients was significantly higher than a control group of hypertensive patients (46.9 versus 43.5; p < 0.0001). The mental health score of olmesartan/amlodipine recipients was also higher than the hypertensive controls (52.4 versus 51.2; p = 0.0017) and was similar to a group of healthy, nonhypertensive subjects (52.4 versus 52.2). The authors note that such improvements have the potential to translate to favour patient compliance and long-term efficacy [Bramlage et al. 2010b].

In addition to providing increased antihypertensive efficacy, olmesartan/amlodipine combination therapy is well tolerated in patients with mild-to-severe hypertension. In the COACH study, the incidence of oedema was greatest among patients receiving amlodipine monotherapy 10 mg/day (36.8%) [Chrysant et al. 2008]. The addition of olmesartan 40 mg to amlodipine 10 mg significantly reduced the incidence of oedema (23.5%; p = 0.011). Furthermore, despite the substantial reductions in BP observed with olmesartan/amlodipine, the incidence of hypotension was very low (0.5%) across the treatment groups [Chrysant et al. 2008].

Olmesartan/amlodipine: efficacy and tolerability in special populations

Hypertension is prevalent in a variety of special patient populations, including the elderly, patients with diabetes and patients with metabolic syndrome. Therefore, it is important that antihypertensive agents are effective across a range of different patient subgroups.

The COACH study

To establish the efficacy of olmesartan/amlodipine combination therapy in a variety of patient populations, several prespecified subgroup analyses of the COACH study were performed after 8 weeks of randomized, double-blind treatment.

An analysis of baseline hypertension severity and prior antihypertensive medication use demonstrated that the BP-lowering and BP goal achievement effects of olmesartan/amlodipine compared with the component monotherapies were observed irrespective of baseline hypertension severity [Oparil et al. 2009]. Greater reductions in BP were observed in patients with stage 2 (severe) hypertension (mean baseline SeBP: 168.1/102.9 mmHg) than in those with stage 1 (mild) hypertension (mean baseline SeBP: 147.6/96.9 mmHg). Furthermore, a greater proportion of patients with stage 1 hypertension (65.6–80.0%) achieved BP goal (<140/90 mmHg, or <130/80 mmHg in patients with diabetes) compared with patients with stage 2 hypertension (40.5–49.2%), primarily because they had a lower baseline BP. Prior antihypertensive therapy did not affect the efficacy of olmesartan/amlodipine combination therapy [Oparil et al. 2009].

In a prespecified subgroup analysis of patients aged ≥65 years, patients with diabetes, Black patients and patients with a BMI of ≥30 kg/m², the antihypertensive effect of olmesartan/amlodipine (40/10 mg) was greater than the effect of the component monotherapies irrespective of patient age, diabetic status, race or BMI [Chrysant et al. 2010a]. High-dose olmesartan/amlodipine (40/10 mg) was equally efficacious in: patients aged <65 years and ≥65 years (change in mean SeBP from baseline: −29.1/−18.5 and −33.9/−20.9 mmHg, respectively) (Figure 1a); patients with and without diabetes (−30.3/−18.4 and −30.1/−19.1 mmHg, respectively) (Figure 1b); Black and non-Black patients (−28.7/−15.7 and −30.5/−19.9 mmHg, respectively); and patients with a BMI of <30 kg/m² and ≥30 kg/m² (−30.6/−20.6 and −29.7/−17.9 mmHg, respectively). No notable differences in the tolerability profile of olmesartan/amlodipine were observed across these patient subgroups. Furthermore, as observed in the total study patient cohort, the incidence of oedema in these patient subgroups was higher in patients receiving amlodipine 10 mg monotherapy compared with olmesartan/amlodipine 40/10 mg [Chrysant et al. 2010a].

Figure 1.

Mean reductions in seated systolic and diastolic blood pressure (SeSBP and SeDBP) from baseline to week 8 according to treatment regimen and (a) patient age and (b) patient diabetic status in the COACH study. p < 0.0001 versus baseline for each SeBP change from baseline, with the exception of ^*p < 0.01 versus baseline. ^ap < 0.0001 versus AML and OLM; ^bp < 0.0001 versus OLM; ^cp < 0.025 versus AML; ^dp < 0.01 versus AML; ^enot significant versus AML. Bars represent standard errors of the mean. AML, amlodipine; OLM, olmesartan; PL, placebo [Chrysant et al. 2010a].

A prespecified subgroup analysis of the 44-week, treat-to-target, open-label extension of the COACH trial investigated the effect of olmesartan/amlodipine ± HCTZ on BP goal achievement in specific patient populations [Oparil et al. 2010a]. By study end, BP goal was achieved by 61.0% and 68.1% of patients aged ≥65 years and <65 years, respectively, and 63.3% and 67.8% of Black and non-Black patients, respectively. As in the subgroup analysis of the double-blind phase described above, there was no evidence of modified efficacy with olmesartan/amlodipine in any of these subgroups.

The olmesartan add-on study

Prespecified subgroup analyses based on age, gender and baseline hypertension severity have also been conducted for the European olmesartan add-on study in patients with moderate-to-severe hypertension [Schmieder and Bohm, 2010]. After 8 weeks of double-blind treatment, greater BP reductions were achieved with olmesartan/amlodipine compared with amlodipine 5 mg in patients aged <65 and ≥65 years, with similar BP reductions in the two age groups [De La Sierra, 2009]. This latter observation is important because BP, and SBP in particular, increases with age and the frequency of hypertension increases in older patients [Kannel and Gordan, 1978]. Greater BP reductions were also achieved with olmesartan/amlodipine in both male and female patients. Females, however, demonstrated slightly greater mean reductions in SBP and DBP than males, and this was independent of age and dose. Finally, greater BP reductions were achieved with olmesartan/amlodipine regardless of whether patients had moderate (SBP >159 and ≤179 mmHg; DBP >99 and ≤109 mmHg) or severe (SBP >179 mmHg; DBP >109 mmHg) hypertension at baseline, with similar BP reductions in the moderate and severe hypertension subgroups (Figure 2) [Laeis and Ammentorp, 2009]. Furthermore, in patients whose BP remained uncontrolled on their initial dose of combination therapy in Period II, uptitration during Period III provided additional reductions in BP and improvements in BP goal rate achievement irrespective of patient age [De La Sierra, 2009], baseline hypertension severity (Figure 3) [Laeis and Ammentorp, 2009] or gender. Moreover, no notable differences in the incidence or types of adverse events were observed between age, gender or hypertension severity subgroups.

Figure 2.

Mean reductions in seated systolic and diastolic blood pressure (SeSBP and SeDBP) according to patients’ baseline hypertension severity after 8 weeks of treatment with olmesartan/amlodipine combination therapy or amlodipine monotherapy (Period II) in patients with moderate-to-severe hypertension whose BP was inadequately controlled by amlodipine monotherapy in the olmesartan add-on study [Schmieder and Bohm, 2010].

Figure 3.

Additional reductions in seated systolic and diastolic blood pressure (SeSBP and SeDBP) in patients whose BP was not adequately controlled (≥140/90 mmHg) during Period II and who were uptitrated during Period III of the olmesartan add-on study [Laeis and Ammentorp, 2009].

Triple combination antihypertensive therapy

Despite the improvement in antihypertensive efficacy observed after combining two different agents, approximately 15–20% of hypertensive patients are not controlled by dual therapy. Therefore, the addition of a third agent is required to enable these patients to reach BP goal. Specifically, triple combination therapy comprising an ARB, CCB and thiazide diuretic is considered to be a rational treatment strategy [Mancia et al. 2009].

The effectiveness of a triple combination treatment strategy comprising a RAS blocker, a CCB and a thiazide diuretic has been further investigated in a new randomized, double-blind study. The Triple Therapy With Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients (TRINITY) study compared the effects of triple combination therapy with olmesartan/amlodipine/HCTZ (40/10/25 mg) with single-pill dual combinations of the monotherapy components: olmesartan/amlodipine (40/10 mg), olmesartan/HCTZ (40/25 mg) and amlodipine/HCTZ (10/25 mg) on SeBP and BP goal achievement in patients aged ≥18 years with moderate-to-severe hypertension [Oparil et al. 2010b]. After 12 weeks of treatment olmesartan/amlodipine/HCTZ demonstrated significantly greater mean reductions in SeBP compared with the dual combinations. The mean change in SeDBP was −21.8 mmHg for olmesartan/amlodipine/HCTZ (40/10/25 mg) and −18.0, −16.9 and −15.1 mmHg for olmesartan/amlodipine (40/10 mg), olmesartan/HCTZ (40/25 mg) and amlodipine/HCTZ (10/25 mg), respectively (p < 0.001 for all treatment comparisons). The mean change in SeSBP was −37.1 mmHg for the triple combination treatment group and −30.0, −29.7 and −27.5 mmHg for the respective dual combination treatment groups (p < 0.001 for all treatment comparisons). Furthermore, a significantly greater proportion of patients achieved BP goal with triple versus dual combination therapy (64.3% versus 46.0%, 46.6% and 34.9%, respectively, < 0.0001).

A number of prespecified analyses of the TRINITY study were undertaken to assess the efficacy of olmesartan/amlodipine/HCTZ in different patient subgroups. A prespecified subgroup analysis based on baseline hypertension severity (moderate [SeBP <180/110 mmHg] or severe [SeBP ≥180/110 mmHg]) evaluated the mean change from baseline in SeBP and the proportion of patients achieving BP goal with triple combination therapy compared with dual combination therapy [Kereiakes et al. 2010]. After 12 weeks of randomized, double-blind treatment, triple combination therapy resulted in significantly greater mean reductions in SeBP from baseline compared with each of the dual combinations, regardless of hypertension severity (p ≤ 0.0013 for all treatment comparisons). Furthermore, a greater proportion of patients receiving triple combination therapy achieved BP goal compared with those receiving dual combination therapy (p ≤ 0.0033 for all treatment comparisons), with more patients in the moderate hypertension group reaching BP goal compared with those who had severe hypertension at baseline (69.3% versus 43.4%).

Similarly, in a prespecified subgroup analysis based on age, triple combination therapy produced significantly greater mean reductions from baseline in SeBP compared with each of the dual combinations in patients aged <65 years and patients aged ≥65 years (p ≤ 0.0001) [Chrysant et al. 2010b]. Furthermore, regardless of age, a significantly greater proportion of patients receiving triple combination therapy achieved BP goal compared with those receiving dual combination therapy (p ≤ 0.0004).

The efficacy of olmesartan/amlodipine combination therapy (with uptitration and the addition of HCTZ as required) in lowering BP and enabling patients to reach BP goal has been further demonstrated in a recent study called A Prospective, open-label, ABPM study to evaluate the safety and efficacy of an olmesartan medoXomil and amlodipine based treatment regimen in type II diabetic patients with hypertension (APEX). This multicentre US study used a titrate-to-goal approach in patients with hypertension and type 2 diabetes [Ram et al. 2011]. The stepwise treatment regimen, in which all patients received amlodipine 5 mg to which olmesartan 20 mg was added with the dose of the former and then the latter doubled if an ambitious BP target (<120/70 mmHg) was not attained, resulted in a significant reduction from baseline in mean 24-hour ambulatory BP (19.9/11.2 mmHg). Measurements of seated BP showed that each treatment step produced progressively larger decreases in BP. The largest reductions in seated BP were observed with the highest doses of olmesartan/amlodipine (40/10 mg; 22.6/10.4 mmHg). The study also contained an extension phase in which HCTZ was added and uptitrated (to 25 mg) which reduced BP even further (28.0/13.7 mmHg). The BP reductions achieved enabled 71% and 43% of patients treated with olmesartan/amlodipine 40/10 mg to achieve seated BP targets of <140/90 and <130/80 mmHg, respectively, and the addition of HCTZ increased the proportions who achieved these seated BP targets to 83% and 62%, respectively [Ram et al. 2011].

A titrate-to-goal approach was also used in another recent US study in a large group (n = 999) of harder-to-treat patients with hypertension. The Blood Pressure ContRol in all sUbgroupS with Hypertension (BP-CRUSH) study looked at BP goal achievement in patients who had previously been uncontrolled on monotherapy and included substantial representation of several major sub populations in the patient cohort including older (≥65 years), African American/Black, Hispanic, Asian, and patients with type 2 diabetes, metabolic syndrome, and obesity (BMI ≥30 kg/m²). The stepwise regimen involved all patients being treated with olmesartan/amlodipine 20/5 mg, followed by 40/5 mg and then 40/10 mg if the BP target (<120/70 mmHg) was not attained. Assessments of seated BP showed that this regimen led to stepwise increases in efficacy, with the high-dose 40/10 mg combination producing the largest drop in BP (20.3/11.3 mmHg). Similar to the APEX study, patients in BP CRUSH also entered an extension phase in which HCTZ was added and uptitrated (to 25 mg) producing an even greater drop in seated BP (25.1/13.7 mmHg). By the end of the study, the cumulative percentage of patients who had achieved the seated BP target of <140/90 mmHg was 90.3%, and the mean 24-hour ambulatory BP target of <130/80 mmHg had been achieved by 90.5% of patients in a sub group in which ABPM was measured [Weir et al. 2011].

Taken together, these findings highlight the increased efficacy of an antihypertensive treatment strategy comprising three different agents, compared with dual combination therapy and demonstrate the effectiveness of such a treatment strategy in a variety of patient subgroups, regardless of hypertension severity and age, to lower BP and enable goal achievement in hypertensive patients with diabetes.

Benefits of olmesartan/amlodipine beyond BP lowering

Hypertension is associated with cardiorenal damage and comorbid conditions such as diabetes. Antihypertensive agents that can help to reduce organ damage and lower cardiometabolic risk may be particularly beneficial in certain patient subgroups, for example, in patients with metabolic syndrome.

As mentioned previously, ARBs such as olmesartan and CCBs such as amlodipine have demonstrated cardiorenal-protective benefits beyond their BP-lowering effects. The additional benefits of olmesartan beyond BP lowering appear to be retained and observed when it is combined with amlodipine to increase antihypertensive efficacy, and this may be of particular benefit in specific patient populations. The metabolic syndrome is a collection of interrelated metabolic risk factors that increase the risk of developing both atherosclerotic CV disease and type 2 diabetes. These factors include hypertension, atherogenic dyslipidemia, obesity, proinflammatory state, prothrombotic state, insulin resistance and elevated plasma glucose [Grundy et al. 2005]. In line with the findings of EUTOPIA, in which olmesartan significantly reduced markers of inflammation such as high sensitivity C-reactive protein, high-sensitivity tumour necrosis factor-α and interleukin-6, results of the OLmesartan/Amlodipine versus olmesartan/hydrochlorothiazide in metabolic Syndrome (OLAS) study showed similar effects. In nondiabetic patients with stage 1–2 hypertension and metabolic syndrome, combination therapy with olmesartan/amlodipine demonstrated improvements in inflammatory (Figure 4a) and metabolic markers and a reduction in the incidence of new-onset diabetes (Figure 4b) compared with treatment with olmesartan/HCTZ, despite their similar effects on BP lowering and BP goal achievement [Martinez-Martin et al. 2011b]. Both olmesartan-based combinations effectively reduced BP, albuminuria and C-reactive protein levels. However, olmesartan/amlodipine reduced levels of other inflammatory markers and the incidence of new-onset diabetes to a significantly greater extent than olmesartan/HCTZ [Martinez-Martin et al. 2010]. The latest findings from OLAS show that the olmesartan/amlodipine combination also produced significant reductions in a marker of endothelial dysfunction (asymmetric dimethylarginine) and a marker of global oxidative stress (8-iso-prostaglandin F2α) [Martinez-Martin et al. 2011] (Figure 4a).

Figure 4.

Effects of olmesartan (OLM)/amlodipine (AML) and OLM/hydrochlorothiazide (HCTZ) on (a) markers of inflammation, endothelial dysfunction and oxidative stress and (b) the incidence of new-onset type 2 diabetes mellitus (T2DM) in nondiabetic patients with hypertension and metabolic syndrome in the OLAS trial. ARR, absolute risk reduction; CRP, C-reactive protein; ICAM-1, inter-cellular adhesion molecule-1; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-8, interleukin-8; OR, odds ratio; TNF-α, tumour necrosis factor-α; VCAM-1, vascular cell adhesion molecule-1; ADMA, asymmetric dimethylarginine; 8-PGF2α, 8-iso-prostaglandin F2α [Martinez-Martin et al. 2010, 2011]. Reprinted by permission from Macmillan Publishers Ltd: J Hum Hypertens; 25: 356-53, copyright 2010.

Since the patients in OLAS were overweight and all had metabolic syndrome, these findings are in line with those of ACCOMPLISH. The findings of studies such as ACCOMPLISH and OLAS indicate that combination therapy comprising a RAS blocker plus a CCB may offer advantages in patients at high CV risk and with underlying metabolic issues, compared with a RAS blocker/diuretic combination, despite the two combinations providing a similar level of BP control [Jamerson et al. 2008].

Conclusions

Owing to the complex nature of hypertension and its prevalence in a variety of patient subgroups, antihypertensive therapy should be effective across a whole range of patient subgroups. Olmesartan/amlodipine combination therapy has demonstrated excellent efficacy and tolerability in a range of patients regardless of age, gender, hypertension severity, diabetic status, race or BMI, providing greater BP lowering and BP control than the component monotherapies. Uptitration of olmesartan/amlodipine ± HCTZ provides additional BP reductions and enables even more patients to achieve BP goal. Furthermore, combination therapy with olmesartan/amlodipine has demonstrated benefits beyond BP lowering in hypertensive patients with metabolic syndrome, improving markers of inflammation, endothelial dysfunction, oxidative stress, metabolism, and reducing the incidence of new-onset diabetes.

For patients who are unable to achieve BP goal on olmesartan/amlodipine, the addition of HCTZ can increase antihypertensive efficacy and get more patients to BP goal, including special patient populations.

Footnotes

This study was funded by Daiichi Sankyo Europe GmbH. Medical writing services from Amy McCallum of inScience Communications, a Wolters Kluwer business, were supported by Daiichi Sankyo Europe GmbH.

SE has received honoraria for lectures, advisory board activities, participation in clinical trials or research funding Daiichi Sankyo Europe GmbH, Boehringer Ingelheim GmbH, Novartis AG, Sanofi-Aventis, Servier Laboratories, Pfizer and the Menarini group.

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Olmesartan/amlodipine: blood pressure lowering and beyond in special populations

Abstract

Keywords

Introduction

Single-pill combination therapy with olmesartan and amlodipine: rationale, efficacy and tolerability

Single-pill combination therapy based on blockers of the RAS

Additional benefits of olmesartan-based treatment

The benefits of treatment with amlodipine

Antihypertensive efficacy of olmesartan/amlodipine combination therapy

Olmesartan/amlodipine: efficacy and tolerability in special populations

The COACH study

The olmesartan add-on study

Triple combination antihypertensive therapy

Benefits of olmesartan/amlodipine beyond BP lowering

Conclusions

Footnotes

References