According to an analysis of data from the National Health and Nutrition Examination Survey, optimal control of blood pressure (BP) to <120/80 mm Hg could prevent 37% of coronary heart disease (CHD) events in men and 56% of events in women.1 Despite an encouraging improvement in the rates of BP control in the United States, the prevalence of hypertension continues to increase (possibly because people are living longer and not dying from diseases at an earlier age). In addition, BP control rates remain inadequate, with only about one-third of all persons with hypertension and less than two-thirds of all treated hypertensive persons achieving their BP goals.2,3 A recent online survey of 1245 hypertensive individuals found, however, that more than 90% of them were receiving antihypertensive drug therapy, and more than 60% were controlled to goal levels (<140/90 mm Hg).4 Suboptimal BP control rates have been reported in Canada and Europe.5 Different approaches may be needed to optimize treatment regimens and help patients achieve BP goals.
Fixed-dosed combination regimens consisting of a calcium channel blocker and an angiotensin II type 1 receptor blocker represent a new addition to the available antihypertensive treatment options. Clinical trials demonstrate that both the dihydropyridine calcium channel blocker amlodipine and angiotensin II receptor blockers are effective agents for the management of hypertension in individuals with or without cardiovascular disease. When combined, these 2 classes of agents have complementary effects on blood pressure, as each targets separate signaling pathways in the vasculature pivotal to the regulation of vascular function. In clinical trials this combination has demonstrated better efficacy, defined by time to reach blood pressure targets as well as levels of blood pressure achieved, compared with the individual agents. In a comparative trial, a combination of amlodipine plus valsartan (an angiotensin II receptor blocker) also produced greater reductions in blood pressure compared with a combination of lisinopril (an angiotensin-converting enzyme inhibitor) and hydrochlorothiazide. The combination of amlodipine and an angiotensin II receptor blocker is well tolerated, including in patients with stage 2 hypertension and the elderly.
NEW APPROACHES TO ANTIHYPERTENSIVE THERAPY
The argument has been made that treatment of the patient at high risk for cardiovascular disease should be based on an evaluation of global risk and not on the pretreatment severity of individual risk factors.6,7 Studies of antihypertensive therapy have shown that the magnitude of reduction in risk is related to the magnitude of reduction in BP.8,9 However, some data in patients with clinically defined CHD or at very high risk also indicate that antihypertensive therapy reduces the risk of stroke and CHD regardless of pretreatment BP levels.10–12 Such findings, coupled with data demonstrating that increased risk for cardiovascular and renal complications of hypertension may begin below the threshold of 140/90 mm Hg,13 suggest that certain high-risk populations may benefit from lower levels of BP than those currently recommended. To date, however, no data exist from prospective clinical trials to support this hypothesis. For patients with diabetes mellitus, the data will be provided by the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,14 which has randomized patients to 2 levels of systolic BP control: 140 and 120 mm Hg.
Evidence also suggests that early intervention and prompt attainment of BP goals may be critical to reducing the risk associated with elevated BP. In patients with stage 2 hypertension, early BP control has achieved significant reductions in the risk of stroke and cardiovascular events.9,15 A post hoc analysis of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE), in which BP response after 1 month predicted events and survival, underscores the importance of prompt BP control.9 More importantly, cardiovascular risk reductions in VALUE were similar in patients whose BP was controlled at 6 months, regardless of treatment group assignment, compared with those whose BP was not controlled.
These findings lend further support to recommendations from guideline writing groups such as the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension and of the European Society of Cardiology to consider using 2 or 3 drugs or combination therapy for persons in whom the probability of achieving BP control with monotherapy is low, eg, those with stage 2 hypertension.7,16 These recommendations were based in part on evidence from clinical trials indicating that most patients, especially those with stage 2 hypertension and/or target organ involvement, require 2 or more drugs to achieve their BP goals.16
Compared with monotherapy, multiple drug or combination therapy may result in more effective and more prompt BP lowering, at lower doses, with potentially fewer adverse events.16 Compared with free combinations, fixed-dose regimens have the advantages of greater convenience and potentially reduced costs, both of which may translate into improved adherence and superior BP reductions.10,17 Data from the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial,18 which is the first trial to randomize patients to fixed-dose combinations as initial agents, show impressive BP reductions at 6 months.
The majority of currently available fixed-dose combinations are diuretic-based. These include angiotensin-converting enzyme (ACE) inhibitors plus diuretics, angiotensin II type 1 receptor blockers (ARBs) plus diuretics, and β-blockers plus diuretics. It is well known that the combination of an ACE inhibitor or an ARB plus a diuretic has enhanced efficacy compared with either component administered as monotherapy.16,19 Combinations of a renin-angiotensin-aldosterone system (RAAS) blocker and a calcium channel blocker (CCB) also have an additive BP-lowering effect. The combination of an ACE inhibitor plus a CCB is well established20–22 and will not be discussed here. The first ARB plus CCB combination to become commercially available was amlodipine plus valsartan; a combination of amlodipine plus olmesartan was subsequently approved by the US Food and Drug Administration. The combination of amlodipine plus telmisartan is also under investigation.
RATIONALE FOR COMBINATION OF A CCB AND AN ARB
Both CCBs and ARBs are effective in lowering BP as monotherapy. The use of these agents in combination has the potential to achieve additive BP reductions by targeting multiple mechanisms involved in BP regulation.23 ARBs interfere with the RAAS by blocking the angiotensin II type 1 receptor and hence the deleterious effects of angiotensin II, thereby promoting vasodilation and sodium and water excretion.24 The angiotensin II type 2 receptor is not affected, and it remains exposed to its agonist angiotensin II, with potentially beneficial vasodilative, anti-inflammatory, and antiproliferative effects.23,24 CCBs block calcium channels in vascular smooth muscle cells, thereby reducing peripheral vascular resistance. Targeting multiple systems has benefit in terms of overcoming potential counter-regulatory mechanisms, eg, the compensatory activation of the RAAS induced by the use of a CCB.23
Laboratory and animal studies suggest that ARBs and CCBs act on separate albeit pivotal underlying mechanisms of vascular disease, including endothelial dysfunction.25 One mechanism by which angiotensin II induces endothelial dysfunction is through proinflammatory effects, such as increased production of reactive oxygen species, inflammatory cytokines such as interleukin-6, and adhesion molecules.26 Angiotensin II also increases production of superoxide anion through activation of the reduced forms of nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide phosphate oxidase, thereby reducing the availability of nitric oxide.27 By promoting oxidative stress, angiotensin II induces endothelial dysfunction, leading to vasoconstriction, thrombosis, and vascular remodeling.27 In laboratory and animal studies, ARBs and CCBs have demonstrated anti-inflammatory, antioxidant, antiproliferative, and prorelaxant effects that could potentially attenuate the endothelial dysfunction characteristic of patients with established cardiovascular disease.24,27,28
Evidence that attenuation of these effects translates into cardiovascular risk reduction is still lacking, and further studies are required to clarify the value of targeting these underlying mechanisms of cardiovascular disease. However, the use of ARBs and CCBs has independently demonstrated each agent's benefits on morbidity and mortality in patients with hypertension and comorbid conditions. Some studies suggest that these benefits may go beyond BP lowering. In the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study,29 a losartan-based (ARB) regimen significantly reduced the relative risk of cardiovascular-related morbidity and death in hypertensive patients with left ventricular hypertrophy by 13% (P=.02). The reduction came, however, mostly as a result of a 25% reduction in the relative risk of stroke (P=.001), compared with atenolol-based therapy, yet the between-group difference in systolic BP was only 1 mm Hg. In another study, the Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) trial,30 hypertensive patients (N=1405) with a history of stroke within the previous 24 months were treated with (an ARB) eprosartan 600 mg or (a CCB) nitrendipine 10 mg for a mean of 2.57 years. Eprosartan was associated with a 25% lower incidence of stroke compared with nitrendipine (P=.03) for the same decrease in BP. Proposed BP-independent mechanisms of stroke protection with ARBs include effects on cerebrovascular regulation and activation of the angiotensin II type 2 receptors, which could potentially provide vascular protection.31
EFFICACY AND TOLERABILITY OF CCB/ARB COMBINATIONS
A recently published study32 reported results of 2 randomized, double-blind, placebo-controlled, 8-week trials assessing the efficacy and tolerability of amlodipine and valsartan, alone and in combination, in patients with mild to moderate hypertension. The study examined changes from baseline in mean sitting systolic and diastolic BP, time to achieve BP control (<140/90 mm Hg), and the occurrence of adverse events. As anticipated, greater BP reductions overall were observed with combination therapy compared with the monotherapy components.32 In addition, significantly more (approximately 50%) patients treated with the combination of amlodipine 10 mg and valsartan 320 mg achieved the BP goal at 2 weeks compared with the individual agents and placebo (P<.05).33
Prespecified and post hoc subgroup analyses of these 2 studies have also been published,34 reporting results in specific subgroups of patients considered difficult to control: those with stage 2 hypertension (post hoc), and the elderly (≥65 years of age) and blacks (both prespecified). Amlodipine plus valsartan combination therapy was associated with greater BP-lowering effects in all 3 subgroups compared with each respective monotherapy and placebo.34 In keeping with the primary efficacy results from the overall populations of the 2 studies,32 greater BP reductions generally were observed in each of the subgroups as the dose of the combination was increased.
Another recent, randomized, double-blind, parallel-group study examined the safety (primary end point) and efficacy of 6-week therapy with the combination of amlodipine/valsartan (5–10 mg/160 mg) compared with the combination of lisinopril/hydrochlorothiazide (HCTZ) (10–20 mg/12.5 mg) in patients with stage 2 hypertension (mean sitting diastolic BP ≥110 mm Hg and <120 mm Hg).35
Both treatment regimens were well tolerated, with only mild to moderate adverse events. Most adverse events were not considered to be related to the study drugs. The most common adverse events in the amlodipine/valsartan group were headache (10.9%) and peripheral edema (7.8%). In the lisinopril/HCTZ group, the most common events were diarrhea and pharyngitis (6.1% for both). Peripheral edema was more common in the amlodipine/valsartan group (7.8%) than in the lisinopril/HCTZ group (1.5%). Cough was less frequent in the amlodipine/valsartan group (1.6%) than in the lisinopril/HCTZ group (3.0%).35
BP was significantly reduced from baseline by both regimens: −35.8/28.6 mm Hg in the amlodipine/valsartan group and −31.8/27.6 mm Hg in the lisinopril/HCTZ group (P<.001 vs baseline for both). Subgroup analyses showed that both combination regimens reduced BP from baseline in 2 important patient groups, patients aged ≥65 years at baseline (Figure 1) and patients with severe hypertension (mean sitting systolic BP ≥180 mm Hg at baseline) (Figure 2).35
Results were recently reported of a trial in 1940 patients with mild to severe hypertension (seated diastolic BP ≥95 and ≤120 mm Hg).36 Combinations of amlodipine 5 to 10 mg/d plus olmesartan 10 to 40 mg/d for 8 weeks were associated with significantly greater reductions in mean seated systolic and diastolic BP compared with the respective monotherapy components (P<.0001 for all comparisons). The greatest reductions in mean seated systolic BP/diastolic BP occurred with amlodipine 10 mg plus olmesartan 40 mg (−30.1/−19.0 mm Hg vs −4.8/−3.1 mm Hg with placebo and −19.7/−12.7 mm Hg with amlodipine 10 mg as monotherapy). The adverse-event profile of combination therapy was similar to that with monotherapy, and most events were mild in intensity.36
An ongoing trial37 is evaluating telmisartan 20, 40, and 80 mg in combination with amlodipine 2.5, 5, and 10 mg. More than 1400 patients with stage 1 or 2 hypertension will be treated for 8 weeks in a randomized, double-blind, placebo-controlled trial. The primary efficacy measure is change from baseline in seated trough cuff diastolic BP; secondary outcome measures include change after 8 weeks in seated cuff systolic BP, percent of patients with BP response to treatment, and safety and tolerability.37
Hypertension remains a major public health challenge because of low, although increasingly improving, BP treatment and control rates. Antihypertensive therapy has demonstrated efficacy for decreasing morbidity and mortality related to stroke, CHD, and renal disease; the greater the reduction in BP, the greater the reduction in risk of events. Specific agents (eg, an ACE inhibitor or ARB) that block the RAAS may offer enhanced cardioprotection and renoprotection, as well as a greater reduction in the risk of stroke compared with β-blockers, which are less potent in decreasing the activities of this system. The availability of combinations of an RAAS-blocking agent, such as an ARB or an ACE inhibitor, with a CCB such as amlodipine is promising. In laboratory and experimental studies, ARBs and CCBs have demonstrated anti-inflammatory, antioxidant, antiproliferative, and prorelaxant effects, but the clinical implications of these effects remain unclear. Recently published clinical trials have demonstrated the BP-lowering efficacy and tolerability of combinations of valsartan or olmesartan plus amlodipine, including among patients whose BP is often considered difficult to control, such as the elderly and patients with greater elevations in systolic BP. These combination products represent a new addition to available antihypertensive regimens.
Dr Bakris has received investigator-initiated grants from the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases/National Heart, Lung, and Blood Institute), Abbott, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Myogen. He has served as a consultant and on the Speakers' Bureau of AstraZeneca, Abbott, Boehringer Ingelheim, BMS/SanofiAventis, GlaxoSmithKline, Merck, Novartis, Lilly, Walgreens (formulary committee), and Myogen. The author acknowledges the assistance of Landmark Programs, Inc. in preparing this review article and styling the paper for journal submission. Editorial support was funded by Novartis Pharmaceuticals Corporation and the author received an honorarium for time and effort spent preparing this article.