Integrated Blood Pressure Control

Published by Dove Medical Press
Online ISSN: 1178-7104
Baseline BP characteristics in the different patient subpopulations (based on full analysis set) 
Treatment difference (95% confidence interval) of single-pill combination T80/H25 versus T80 on changes in mean seated trough cuff (A) systolic blood pressure and (B) diastolic blood pressure from baseline to week 7 in the different patient populations full analysis set. Note: *P value for interaction , 0.05. Abbreviations: H25, hydrochlorothiazide 25 mg; T80, telmisartan 80 mg.  
Odds ratios (95% confidence interval) of the single-pill combination of T80/H25 versus T80 in blood pressure goal rates. (A) Systolic blood pressure (,140 mmHg), (B) diastolic blood pressure (,90 mmHg), and (C) systolic/diastolic blood pressure control (,140/90 mmHg) at week 7 in the different patient subpopulations. Abbreviations: H25, hydrochlorothiazide 25 mg; T80, telmisartan 80 mg.  
Mean change from baseline in electrolytes across patient subpopulations at week 7 (mean ± standard deviation). Abbreviations: H25, hydrochlorothiazide 25 mg; HTn, hypertension; SD, standard deviation; T80, telmisartan 80 mg.  
The purpose of this work was to describe the efficacy and safety of a telmisartan 80 mg + hydrochlorothiazide 25 mg (T80/H25) single-pill combination therapy in patients with moderate-severe hypertension (mean seated trough cuff systolic blood pressure [BP] ≥ 160 mmHg and diastolic BP ≥ 100 mmHg) in specific patient subpopulations. This was a planned analysis of a double-blind, multicenter, parallel-group trial that demonstrated the superiority of a single-pill combination of T80/H25 versus T80 monotherapy in terms of systolic BP change from baseline to week 7. Subpopulations included older (aged ≥ 65 years) versus younger, gender, race, hypertension severity, and prior antihypertensive therapy. Endpoints were change from baseline in mean seated trough cuff systolic and diastolic BP, proportion of patients achieving their BP goal (systolic/diastolic BP < 140/90 mmHg), and proportion of patients attaining systolic BP reductions of >30 mmHg and >40 mmHg. Across all subgroups, the T80/H25 single-pill combination provided consistently greater systolic and diastolic BP reductions than T80 and more patients had systolic BP reductions of >30 mmHg. In the T80 and T80/H25 groups, BP control was achieved in 34.1% and 48.8% of men, 35.5% and 62.7% of women, 34.5% and 56.6% of Asians, 22.6% and 38.6% of blacks, 36.7% and 57.8% of whites, 36.9% and 57.5% of patients < 65 years, 29.3% and 49.3% ≥65 years, 44.2% and 66.2% of those with grade 2 hypertension, 20.4% and 39.4% of those with grade 3 hypertension, 38.9% and 53.2% of previously untreated patients, 38.1% and 62.5% of patients previously treated with one antihypertensive, and 29.7% and 48.9% of patients previously treated with two or more antihypertensive agents respectively. Treatment was generally well tolerated across the patient subgroups. The T80/H25 single-pill combination provides consistent BP reductions and higher goal attainment rates versus T80 across a range of hypertensive patient subgroups, which are likely to have a positive impact on patients' cardiovascular risk.
Recent guidelines for the treatment of hypertension have focused on the need for multiple medications to get most patients to goal blood pressure (BP). Two to three different classes of antihypertensive agents are frequently required, increasing the risk of poor compliance with therapy. Hence, the guidelines have recommended starting with combination therapy in patients with BP that is over 20 mm Hg systolic or 10 mm Hg diastolic above goal. The latest advance in treatment regimen has been the development of triple-therapy combinations of an angiotensin receptor blocker, amlodipine, and hydrochlorothiazide. We review the pathophysiologic rationale for such a combination and the efficacy, safety, and tolerability of the first triple therapy that has become available: valsartan + amlodipine + hydrochlorothiazide. Finally, we suggest that use of triple therapy could improve the accuracy of diagnosing resistant hypertension, an increasingly prevalent and severe condition, by enhancing adherence to treatment and weeding out patients with pseudoresistance. This would allow for implementation of expensive and invasive workup only in those truly resistant patients in whom it is justified.
Hypertension remains a significant health burden in the United States, with almost one in three adults affected, and is an independent risk factor for cardiovascular and renal disease. The goal of antihypertensive treatment is to reduce cardiovascular and renal morbidity and mortality by reducing blood pressure (BP). Guidelines recommend a target BP of <140/90 mmHg, with a more stringent goal of <130/80 mmHg for patients with diabetes and chronic renal disease. However, BP goal attainment rates remain low and most patients require therapy with two or more antihypertensive agents. Combination antihypertensive therapy usually employs agents from different classes, thus benefitting from complementary mechanisms of action to achieve greater BP control with fewer side effects. Patient adherence to therapy is enhanced by formulating treatments as fixed-dose (single-pill) combinations. One example is the combination of amlodipine, a dihydropyridine calcium channel blocker (CCB), with olmesartan medoxomil, an angiotensin receptor blocker (ARB). Here, the rationale for the use of CCB/ARB combination therapy is discussed, as well as the pharmacology and tolerability of the amlodipine/olmesartan medoxomil combination and its efficacy in terms of achieving BP goal in patients with hypertension. Advantages of its use from the patient's perspective are also discussed.
Summary of clinical trials investigating efficacy of telmisartan
Summary of clinical trials investigating efficacy of telmisartan/HCTZ tablets
Ideal indication of telmisartan.
Abbreviation: PPARγ, peroxisome proliferator activated receptor gamma.
Rigid control of blood pressure (BP) is essential to prevent cardiovascular disease. However, only about 40% of hypertensive patients undergoing pharmacological intervention with a single agent achieve their BP goals in contemporary clinical practice. Combined therapy using currently available agents is effective in maximizing treatment outcome, although it raises medical costs and decreases the drug compliance rate. To overcome such negative consequences, a combination tablet containing an angiotensin II receptor blocker (ARB) with a small dose of hydrochlorothiazide (HCTZ) is now available on the international market, including Japan. This article briefly describes the unique properties of telmisartan, a highly selective ARB for the angiotensin II type 1 receptor, including its long-acting characteristics and recent prospective multicenter randomized clinical trials, followed by a description of a newly-introduced combination tablet in Japan, which contains telmisartan and HCTZ. This article also reviews its safety and efficacy based on currently available evidence. Finally, evidence comparing telmisartan/HCTZ with other combination therapies is presented.
Population baseline characteristics 
Classes of concomitant antihypertensive medication intake 
Patients reaching target blood pressure in each population, by risk category and hypertension grade (determined at baseline), and by therapy 
Overall physician's assessment of efficacy for each population Assessment (%) a Very good Good Sufficient Insufficient 
The Middle Eastern and North African region of developing countries is associated with poor rates of blood pressure (BP) control and antihypertensive prescribing patterns. This post hoc analysis of data from an international observational study aimed to investigate the efficacy and tolerability of long-acting nifedipine (30 mg or 60 mg; monotherapy or in combination) in the Middle Eastern and Moroccan populations defined as having high cardiovascular risk. This was a prospective, noninterventional, multicenter observational study. Observations from patients (aged ≥ 18 years) with treated or untreated hypertension from the Middle East (Jordan, Saudi Arabia, Kuwait, Lebanon, Qatar, United Arab Emirates, and Yemen) and Morocco are presented. Hypertension grade and cardiovascular risk were defined at baseline, and systolic/diastolic BP change was defined at post-baseline visits (≤3). Adverse events and ratings of therapy efficacy and patient/physician satisfaction were recorded. The study included 1466 patients from the Middle East and 524 from Morocco. Characteristics of the populations differed, with a more severe hypertension profile in Moroccan patients. Despite these differences, nifedipine reduced BP to a similar extent in each group, with efficacy dependent on cardiovascular risk factors such as hypertension grade and age. Few adverse drug reactions occurred and nifedipine was well-tolerated in both populations. Efficacy and satisfaction with therapy were rated highly. Good rates of BP control were observed with nifedipine in patients with moderate-to-severe hypertension and high added risk. Published data in these countries suggest poor antihypertensive prescribing patterns and BP control; these data confirm this trend and suggest that suboptimal dosing may be prevalent.
Effect of garlic on blood pressure via the hydrogen sulfide (H 2 S) pathway, and influence of dietary and genetic factors on homocysteine levels. Notes: Blue rectangles illustrate metabolites, blue circles represent enzymes, orange circles are dietary cofactors, green star shapes show garlic and other polysulfidecontaining nutrients, red rectangle indicates H 2 S, and purple rectangles represent direct and indirect influence of H 2 S on vasodilation and blood pressure. Red circles 1-7: Influence of dietary and genetic factors on H 2 S pathway 1= genetic polymorphism, homozygous for deleterious allele, leads to impaired folate metabolism. 2= common polymorphisms, some of which lead to increased homocysteine and decreased methylation and SAM levels; these respond well to folate supplementation. 3= genetic defects lead to increased homocysteine levels. 4= low vit B12 levels lead to increased homocysteine levels. 5= defect in CBS enzyme leads to increased homocysteine levels and reduced H 2 S production. 6= low vit B 6 * levels may increase homocysteine levels and reduce H 2 S production, and may respond to vit B 6 supplementation. 7= dietary intake of garlic polysulfides and thiosulfides can increase H 2 S nonenzymatically, and may ameliorate genetic defects in the CBS enzyme, or dietary deficiencies in Vit B 6 and/or the sulfur-containing amino acids cysteine and methionine. Abbreviations: CAT, cysteine-amino-transferase; CBS, cystathionine-β-synthase; CSe, cystathionine-γ-lyase; CysSSCys, oxidized cysteine/cystine; eNOS, endothelial nitric oxide synthase; Glu, L-glutamic acid; Gly, glycine; GSSG, oxidized glutathione; GSH, reduced glutathione; H 2 O 2 , hydrogen peroxide; K + , potassium ion; MPST, mercapto pyruvate sulfur transferase; NADPH, nicotinamide adenine dinucleotide phosphate; MTHFR, methylene-tetra-hydro-folate reductase; SAH, S-adenosyl-homocysteine; SAM, S-adenosyl-methionine; Se, selenium; vit B 6 *, activated form of vit B 6 = pyridoxal-phosphate; vit B 2 , vitamin B 2 (riboflavin); Vit B 12 , vitamin B 12 . 
Garlic supplements have shown promise in the treatment of uncontrolled hypertension, lowering blood pressure (BP) by about 10 mmHg systolic and 8 mmHg diastolic, similar to standard BP medication. Aged garlic extract, which contains S-allylcysteine as the bioactive sulfur compound, in particular is standardizable and highly tolerable, with little or no known harmful interaction when taken with other BP-reducing or blood-thinning medication. Here we describe biologically plausible mechanisms of garlic's BP-lowering effect. Garlic-derived polysulfides stimulate the production of the vascular gasotransmitter hydrogen sulfide (H2S) and enhance the regulation of endothelial nitric oxide (NO), which induce smooth muscle cell relaxation, vasodilation, and BP reduction. Several dietary and genetic factors influence the efficiency of the H2S and NO signaling pathways and may contribute to the development of hypertension. Sulfur deficiency might play a part in the etiology of hypertension, and could be alleviated with supplementation of organosulfur compounds derived from garlic.
Main results of HYvET trial 63
Changes in blood pressure control rates (%) during the study in PRETEND and PRETENDIABETES studies with the fixed combination perindopril 2 mg plus indapamide 0.625 mg. Drawn from data of.47,48
Effect of the combination perindopril/indapamide (2 mg/0.625 mg up to 8 mg/2.5 mg) and enalapril (10 mg up to 40 mg/daily) on left ventricular mass index (g/m2). Data from data of the PICXEL study.49
Effect of the combination perindopril/indapamide (2 mg/0.625 mg up to 8 mg/2.5 mg) and enalapril (10 mg up to 40 mg/daily) on urinary albumin excretion (% of change from baseline). Data from data of the PREMIER study.51
Although reducing blood pressure is the most important approach to reduce cardiovascular outcomes in the hypertensive population, the majority of patients fail to attain the targets. Most patients with hypertension need at least 2 antihypertensive agents to achieve blood pressure goals. The 2007 European hypertension guidelines state that combined therapy is needed when monotherapy does not attain blood pressure objectives and as a first-line treatment in high-risk patients. This point has been reinforced in the 2009 update of the European guidelines. 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. Moreover, the use of fixed dose combinations are specially recommended as they facilitate treatment compliance. The inhibition of the renin-angiotensin system appears to be very beneficial in the treatment of patients with hypertension along the cardiovascular continuum and the combination of a renin-angiotensin system inhibitor and a diuretic is particularly recommended. Many clinical trials have demonstrated the benefits of the fixed combination perindopril/indapamide in the treatment of hypertension. The aim of this manuscript is to update the published data on the efficacy and safety of this fixed combination.
Improvement in quality of sleep with PRM compared to placebo (3 weeks)
Efficacy of PRM vs placebo: improvement in morning alertness compared to placebo (3 weeks)
Overall patient disposition in efficacy analysis. Analysis of the short-term period included eligible patients who completed 3 weeks of double-blind treatment with prolonged-release melatonin (PRM) or placebo. Analysis of the long-term period included patients of one study27 re-randomized to PRM and placebo for 26 weeks of treatment.
Add-on prolonged-release melatonin (PRM) in antihypertensive therapy has been shown to ameliorate nocturnal hypertension. Hypertension is a major comorbidity among insomnia patients. The efficacy and safety of PRM for primary insomnia in patients aged 55 years and older who are treated with antihypertensive drugs were evaluated. Post hoc analysis of pooled antihypertensive drug-treated subpopulations from four randomized, double-blind trials of PRM and placebo for 3 weeks (N[PRM] = 195; N[placebo] = 197) or 28 weeks (N[PRM] = 157; N[placebo] = 40). Efficacy measurements included Leeds Sleep Evaluation Questionnaire scores of quality of sleep and alertness and behavioral integrity the following morning after 3 weeks, and sleep latency (daily sleep diary) and Clinical Global Impression of Improvement (CGI-I) after 6 months of treatment. Safety measures included antihypertensive drug-treated subpopulations from these four and three additional single-blind and open-label PRM studies of up to 1 year (N[PRM] = 650; N[placebo] = 632). Quality of sleep and behavior following wakening improved significantly with PRM compared with placebo (P < 0.0001 and P < 0.0008, respectively). Sleep latency (P = 0.02) and CGI-I (P = 0.0003) also improved significantly. No differences were observed between PRM and placebo groups in vital signs, including daytime blood pressure at baseline and treatment phases. The rate of adverse events normalized per 100 patient-weeks was lower for PRM (3.66) than for placebo (8.53). The findings demonstrate substantive and sustained efficacy of PRM in primary insomnia patients treated with antihypertensive drugs. PRM appears to be safe for insomnia in patients with cardiovascular comorbidity.
effects of different antihypertensive agents on arterial stiffness
effects of combination therapy of different classes of antihypertensive agents on arterial stiffness
Schematic of arterial pressure waveforms and calculation of augmentation index (AIx).3,4 A) Pulse waveforms in healthy compliant vasculature, timing of rebound wave reflection occurs during diastole (D). B) Pulse wave reflection is faster and earlier in stiffer arteries, thus amplifying the measured systolic BP peak (S), and reducing diastolic pressures (D), hence pulse pressure (PP) is increased (total height of combined pulse wave peak).
Abbreviation: AP, augmentation pressure.
Increased central arterial stiffness, involving accelerated vascular ageing of the aorta, is a powerful and independent risk factor for early mortality and provides prognostic information above and beyond traditional risk factors for cardiovascular disease (CVD). Central arterial stiffness is an important determinant of pulse pressure; therefore, any pathological increase may result in left ventricular hypertrophy and impaired coronary perfusion. Central artery stiffness can be assessed noninvasively by measurement of aortic pulse wave velocity, which is the gold standard for measurement of arterial stiffness. Earlier, it was believed that changes in arterial stiffness, which are primarily influenced by long-term pressure-dependent structural changes, may be slowed but not reversed by pharmacotherapy. Recent studies with drugs that inhibit the renin-angiotensin-aldosterone system, advanced glycation end products crosslink breakers, and endothelin antagonists suggest that blood pressure (BP)-independent reduction and reversal of arterial stiffness are feasible. We review the recent literature on the differential effect of antihypertensive agents either as monotherapy or combination therapy on arterial stiffness. Arterial stiffness is an emerging therapeutic target for CVD risk reduction; however, further clinical trials are required to confirm whether BP-independent changes in arterial stiffness directly translate to a reduction in CVD events.
Design of the CRUCIAL trial. Notes: a Hypertension, untreated: SBP $ 160 and/or DBP $ 100 mmHg; treated: SBP $ 140 and/or DBP $ 90 mmHg or diabetes: SBP. 130 and/or DBP. 80 mmHg. Abbreviations: BP, blood pressure; CHD, congestive heart failure; Cv, cardiovascular; CvD, cardiovascular disease; DBP, diastolic blood pressure; LDL-C, low-density lipoprotein cholesterol; SCORE, Systematic COronary Risk Evaluation; SBP, systolic blood pressure; TC, total cholesterol; UC, usual care. 
Retrospective assessment of differences in adherence to different combinations of antihypertensive and lipid-lowering therapies 
Concurrent antihypertensive and lipid-lowering medication use at screening and at weeks 16 and 52 in the CRUCIAL trial. Notes: a In the proactive intervention arm these are antihypertensive and lipid-lowering medications in addition to SPAA; in the UC arm these are the total number of antihypertensive and lipid-lowering medications. Abbreviations: SPAA, single-pill amlodipine/atorvastatin; UC, usual care. 
Kaplan-Meier analysis of days to Cv event in patients receiving SPAA and co-administered CCB and statin. Abbreviations: CCB, calcium channel blocker; Cv, cardiovascular; SPAA, single-pill amlodipine/atorvastatin. 
Clinical guidelines now recognize the importance of a multifactorial approach to managing cardiovascular (CV) risk. This idea was taken a step further with the concept of the Polypill™. There are, however, considerable patent, pharmacokinetic, pharmacodynamic, registration, and cost implications that will need to be overcome before the Polypill™ or other single-pill combinations of CV medications become widely available. However, a medication targeting blood pressure (BP) and lipids provides much of the proposed benefits of the Polypill™. A single-pill combination of the antihypertensive amlodipine besylate and the lipid-lowering medication atorvastatin calcium (SPAA) is currently available in many parts of the world. This review describes the rationale for this combination therapy and the clinical trials that have demonstrated that these two agents can be combined without the loss of efficacy for either agent or an increase in the incidence of adverse events. The recently completed Cluster Randomized Usual Care vs Caduet Investigation Assessing Long-term-risk (CRUCIAL trial) is discussed in detail. CRUCIAL was a 12-month, international, multicenter, prospective, open-label, parallel design, cluster-randomized trial, which demonstrated that a proactive intervention strategy based on SPAA in addition to usual care (UC) had substantial benefits on estimated CV risk, BP, and lipids over continued UC alone. Adherence with antihypertensive and lipid-lowering therapies outside of the controlled environment of clinical trials is very low (~30%-40% at 12 months). Observational studies have demonstrated that improving adherence to lipid-lowering and antihypertensive medications may reduce CV events. One means of improving adherence is the use of single-pill combinations. Real-world observational studies have demonstrated that patients are more adherent to SPAA than co-administered antihypertensive and lipid-lowering therapy, and this improved adherence translated to reduced CV events. Taken together, these findings suggest that SPAA can play an important role in helping physicians improve the management of CV risk in their patients.
The renin–angiotensin cascade and the three available approaches to pharmacologic inhibition of production or action of angiotensin II. Abbreviations: DRI, direct renin inhibitors; ACeI, angiotensin-converting enzyme inhibitor; ARB, angiotensin (AT) type 1 receptor blockers.  
Hypertension (HTN) is an important factor in progressive loss of renal function. The kidney can be both a contributor to and a target of HTN. The functional integrity of the kidney is vital for the maintenance of cardiovascular homeostasis. Chronic activation of the renin system causes HTN and, ultimately, end-organ damage. Direct renin inhibitors (DRIs) inhibit plasma renin activity (PRA), thereby preventing the conversion of angiotensinogen to angiotensin I; consequently, the levels of both Ang I and Ang II are reduced. There is no compensatory increase in PRA activity with DRIs as seen with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). There are reasons to speculate that renin inhibition might prove to be a superior strategy for blocking the renin-angiotensin-aldosterone system compared with ACEIs or ARBs. Evidence for the efficacy of aliskiren (a DRI) is considered to be relatively strong, based on published, short-term, double-blind, randomized, controlled trials showing that aliskiren is as effective as other antihypertensive agents in reducing blood pressure (BP), with no rebound effects on BP after treatment withdrawal. When combined with diuretics, fully additive BP reduction is seen. When given with an ACEI or ARB, aliskiren produces significant additional BP reduction indicative of complimentary pharmacology and more complete renin-angiotensin system blockade.
High blood pressure is the leading risk factor for death and disability worldwide, and the prevalence is increasing. Effective treatment decreases the risk of adverse events in proportion to blood pressure reduction. Combination antihypertensive therapy reduces blood pressure promptly and effectively. Single-pill combinations reduce the pill burden and improve adherence, efficacy, and tolerability of treatment compared with single drug pills. A significant portion of the hypertensive population will require three drugs for adequate control. The single-pill combination of aliskiren, amlodipine, and hydrochlorothiazide is based on complementary mechanisms of action. Clinical trials have shown it to be a safe and effective treatment for hypertension. This combination is a reasonable choice in clinical practice for patients with hypertension that requires three drugs for effective treatment.
Important studies comparing the effects of the aliskiren/hydrochlorothiazide combination with other treatment regimens
Schematic illustration of the RAAS and the sites of its blocking for existing RAAS blockers. Shown also are the alternative pathways, which are possibly activated through increase of the different components of the RAAS due to the actions of RAAS blocking agents (see also Table 1). Increased renin concentration in the blood can lead to stimulation of the (pro)renin receptor, which leads to intracellular activation of apoptosis, hypertrophy, and fibrosis pathways. Increase of angiotensin II and its metabolites leads to stimulation of alternative receptors which have different effects on vasoconstriction, endothelial function, hypertrophy, and inflammation.
Abbreviations: ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensinreceptor blocker; AT-R, angiotensin receptor.
Arterial hypertension is one of the major diseases in the Western world. It is an independent cardiovascular risk factor and is associated with increased morbidity and mortality. Several drug classes have been shown to be effective in the treatment of hypertension. Aliskiren is a direct renin inhibitor and belongs to the class of renin-angiotensin-aldosterone system inhibitors. Several large studies have shown that aliskiren is effective in lowering blood pressure, and equivalent in this respect to the angiotensin-converting enzyme (ACE) inhibitors and the angiotensin receptor-1 blockers (ARBs). Furthermore, aliskiren has a safety and tolerability profile comparable with that of the ARBs and slightly better than that of the ACE inhibitors. From a pathophysiologic perspective, it can be combined with hydrochlorothiazide successfully, because it can block the diuretic-induced increase in plasma renin activity. Its combination with hydrochlorothiazide in a single pill has been investigated and shown to be superior to monotherapy with respect to blood pressure control and improvement in patient compliance with therapy. Further studies are needed to show whether aliskiren and its combination with hydrochlorothiazide is effective in preventing cardiovascular events and mortality when end organ damage is present.
Summary of the preference for the term single pill combination (SPC) versus fixed-dose combinations (FDC) among physicians interviewed in various countries. Single pill combination expresses the practice of giving 2 or more drugs in a single pill, which means simplicity and flexibility. In contrast, fixed-dose combinations reflects the fact that 2 drugs at fixed doses are combined, implying a simplified treatment but generally less flexibility because of the term “fixed”.
Changes in mean sitting diastolic blood pressure (MSDBP) induced by increasing doses of aliskiren or hydrochlorothiazide (HCTZ) administered alone or in combination to hypertensive patients. Reproduced with permission from Villamil A, Chrysant SG, Calhoun D, et al. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens. 2007;25:217–226.29 Copyright © 2007 Wolters Kluwer Health.
A majority of hypertensive patients need more than one antihypertensive drug to control their blood pressure. For this reason, most guidelines have introduced the possibility of prescribing fixed-dose combination therapies as first-line treatment in hypertension. Today, the concept of fixed-dose combinations has evolved and the term single pill combination might become more appropriate to reflect the large choice of drug combinations available on the market. Recently, a new single pill combination has been launched which combines the first direct renin inhibitor aliskiren and low doses of hydrochlorothiazide. This paper reviews the potential advantages of single pill combinations and presents the first results obtained with the aliskiren/HCTZ single pill combination in hypertension.
The IDNT study 
Irbesartan, an angiotensin II type 1 receptor antagonist, is approved as monotherapy, or in combination with other drugs, for the treatment of hypertension in many countries worldwide. Data in the literature suggest that irbesartan is effective for reducing blood pressure over a 24-hour period with once-daily administration, and slows the progression of renal disease in patients with hypertension and type 2 diabetes. Furthermore, irbesartan shows a good safety and tolerability profile, compared with angiotensin II inhibitors and other angiotensin II type 1 receptor antagonists. Thus, irbesartan appears to be a useful treatment option for patients with hypertension, including those with type 2 diabetes and nephropathy. Irbesartan has an inhibitory effect on the pressor response to angiotensin II and improves arterial stiffness, vascular endothelial dysfunction, and inflammation in hypertensive patients. There has been considerable interest recently in the renoprotective effect of irbesartan, which appears to be independent of reductions in blood pressure. In particular, mounting data suggests that irbesartan improves endothelial function, oxidative stress, and inflammation in the kidneys. Recent studies have highlighted a possible role for irbesartan in improving coronary artery inflammation and vascular dysfunction. In this review we summarize and comment on the most important data available with regard to antihypertensive effect, endothelial function improvement, and cardiovascular risk reduction with irbesartan.
Baseline characteristics of the 56 patients
A) Shows the heart rate measured with the Holter monitor as a function of the heart rate measured with 24-hour ambulatory BP monitoring in the 56 patients (r = 0.77, P < 0.001). B) Shows the Bland-Altman plot and indicates the mean heart difference (solid line) and 95% limits of agreement (dotted lines).
A) Shows the heart rate measured with the Holter monitor as a function of the heart rate measured with 24-hour ambulatory BP monitoring in the 25 patients treated with betablockers (r = 0.58, P < 0.001). B) Shows the Bland-Altman plot and indicates the mean heart difference (= 0.50 beats/min)with dotted lines indicating 95% limits of agreement.
A) Shows the heart rate measured with the Holter monitor as a function of the heart rate measured with 24-hour ambulatory BP monitoring in the 25 patients treated with betablockers (r = 0.80, P < 0.001). B) Shows the Bland-Altman plot and the solid lines indicates the mean diffrerence (= 0.40 beats/min)with dotted lines indicating 95% limits of agreement .
Twenty four-hour ambulatory blood pressure monitoring is a clinically validated procedure in evaluation of blood pressure (BP). We hypothesised that the discomfort during cuff inflation would increase the heart rate (HR) measured with 24-h ambulatory BP monitoring compared to a following HR measurement with a 24-h Holter monitor. The study population (n = 56) were recruited from the outpatient's clinic at the Department of Nephrology, Aalborg Hospital, Aarhus University Hospital at Aalborg, Denmark. All the patients had chronic kidney disease (CKD). We compared HR measured with a 24-h Holter monitor with a following HR measured by a 24-h ambulatory BP monitoring. We found a highly significant correlation between the HR measured with the Holter monitor and HR measured with 24-h ambulatory blood pressure monitoring (r = 0.77, p < 0.001). Using the Bland-Altman plot, the mean difference in HR was only 0.5 beat/min during 24 hours with acceptable limits of agreement for both high and low HR levels. Dividing the patients into groups according to betablocker treatment, body mass index, age, sex, angiotensin-converting enzyme inhibitor treatment, statins treatment, diuretic treatment, or calcium channel blocker treatment revealed similar results as described above. The results indicate that the discomfort induced by cuff inflation during 24-h ambulatory BP monitoring does not increase HR. Thus, 24-h ambulatory BP monitoring may be a reliable measurement of the BP among people with CKD.
Guidelines for initial combination therapy
Benefits of combination therapy in hypertension
Hypertension is a major health problem worldwide and remains underdiagnosed and undertreated. Although public awareness and control of hypertension have improved over the last decade, only one-third of hypertensive patients achieve the rather conservative blood pressure (BP) goal of <140/90 mmHg. Most hypertensive patients require more than one drug for optimum BP control. Expert panels recommend use of combination therapy with two or more medications for Stage 2 and higher hypertension and in high-risk patients. However, the use of multiple drugs reduces patient compliance. Fixed-dose combination therapy helps improve patient compliance and thus achieve the target BP. Dose titration of the individual constituent drugs is recommended before switching to an equivalent fixed-dose combination. Randomized, controlled trials have shown that the fixed-dose combination of amlodipine-olmesartan medoxomil is more effective in lowering BP than monotherapy with either of these agents, with a similar side effect profile.
Effect of 8 weeks of treatment with telmisartan (T) 0 mg, 20 mg, 40 mg, and 80 mg plus amlodipine (A) 0 mg, 2.5 mg, 5 mg, and 10 mg on the change from baseline in the in-clinic seated trough (A) diastolic blood pressure (DBP) (mm Hg) or (B) systolic blood pressure (SBP) (mm Hg).
Notes: *P < 0.05 vs T monotherapy; †P < 0.05 vs A monotherapy. Data are least-squares mean (standard error) values adjusted for dosage, country/region, and baseline blood pressure.
Percentage of urinary albumin excretion rate (UAER) decrease with telmisartan–amlodipine combination at different doses.
Notes: ^p <0.05, ^^p <0.0001, ºp <0.03 ºp <0.01, ººp <0.001, Change from baseline; §p <0.05; §§p <0.01, §§§p <0.001, between treatment, +p <0.05 vs 80/2.5.
Incidence of peripheral edema (%) in the amlodipine 10 mg (A10) group compared with combinations (telmisartan 40 mg [T40] or 80 mg [T80] plus amlodipine 5 mg [A5] or 10 mg).
Notes: *P < 0.05; **P < 0.0001 vs A10.
The majority of hypertensive patients, especially those with target organ damage, are likely to require multiple-drug therapy in order to reach blood pressure (BP) targets and reduce their risk of adverse vascular outcomes. The rationale for combination therapy with agents that block the renin-angiotensin system (RAS) and a calcium channel blocker (CCB) or diuretic is well founded in growing evidence. Recent published trials have shown that the combination of an RAS suppressor and a dihydropiridinic CCB would offer additional benefits independently of BP reduction. A telmisartan-amlodipine combination has demonstrated significantly greater BP reductions compared with each monotherapy component in the overall population, and in particular in patients with moderate to severe hypertension and high-risk patients. This combination is well tolerated with a safety profile similar to placebo and is consistent with the known safety profile of its monotherapy components.
Characteristics of major amlodipine trials
Amlodipine combinations
Cumulative event rates in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial).9
ALLHAT Research Group. JAMA 2002;288(23):2991. Copyright © (2002) American Medical Association. All rights reserved.
Amlodipine is a long-acting, dihydropyridine calcium antagonist now widely used for lowering of elevated blood pressure. In recent years it has been shown to be effective in reducing both blood pressure and risk of cardiovascular (CV) events when used in combination with other antihypertensive agents of different classes. Strong evidence of cardiovascular benefit has been attained for combination of amlodipine with diuretics or angiotensin converting enzyme (ACE) inhibitors in a number of high-risk CV groups, including those with established coronary artery disease, diabetes, and at risk of renal disease. Combination therapies of amlodipine with other agents eliciting renin-angiotensin-aldosterone system blockade (angiotensin II receptor blockers or renin inhibitors) have been shown to be effective blood pressure-lowering strategies, but await the results of ongoing trials for direct evidence of benefit for renal disease progression and CV morbidity and mortality.
Carotid intima-media thickness (IMT) and plaques have been shown to have a strong continuous relationship with cardiovascular (CV) morbidity and mortality; therefore, carotid atherosclerosis, as assessed by ultrasonography, can be regarded as a reliable surrogate end-point for therapeutic interventions. In this survey, we report the results of 16 double blind, randomized, controlled studies comparing: 1) antihypertensive drugs versus placebo/no treatment (five trials including 3,215 patients); 2) different active antihypertensive drug regimens (five trials including 4,662 patients); 3) angiotensin-II receptor blockers (ARBs) versus other antihypertensive agents (six trials including 841 patients). Our main findings can be summarized as follows: I) Long-term antihypertensive treatment has a blunting effect on carotid IMT progression, regardless of types of drugs. II) Calcium-channel blockers (CCBs) are more effective than other antihypertensive drugs including diuretics, beta-blockers, and angiotensin converting-enzyme (ACE)-inhibitors in this blunting effect; III) the effect of ARBs compared to other antihypertensive regimens (mostly based on atenolol) on carotid atherosclerosis progression needs to be further elucidated, as a protective effect was demonstrated by some, but not all studies examined. Thus, further studies are needed to clarify the role of ARBs in this therapeutic area.
(A) An exponential relation between blood pressure and arterial diameter under stable physiological condition. (B) Linear relation between natural logarithm of systolic (P s ) − diastolic (P d ) pressure ratio (In P s /P d ) and arterial wall distensibility. Note: The increased slope (ie, stiffness parameter, β) in arteriosclerotic vessel compared to normal.
(A) An exponential relation between blood pressure and arterial diameter under stable physiological condition. (B) Linear relation between natural logarithm of systolic (Ps) – diastolic (Pd) pressure ratio (In Ps/Pd) and arterial wall distensibility.
Note: The increased slope (ie, stiffness parameter, β) in arteriosclerotic vessel compared to normal.
Schematic illustration of the acquisition of study parameters for computation of Cardio-Ankle Vascular Index (CAVI).
Changes in the number of Cardio-Ankle Vascular Index (CAVI)-related publications in the PubMed database since 2004.
Arterial stiffness has been identified as an independent predictor of prognostic outcomes for patients with cardiovascular disease. Although measurement of pulse wave velocity has been a widely accepted noninvasive approach to the assessment of arterial stiffness, its accuracy is hampered by changes in blood pressure. Taking the exponential relation between intravascular pressure and arterial diameter into consideration, a stiffness parameter can be obtained by plotting the natural logarithm of systolic-diastolic pressure ratio against the arterial wall extensibility. Cardio-ankle vascular index (CAVI), which is calculated based on the stiffness parameter thus obtained, is theoretically independent of changes in blood pressure. With this distinct advantage, CAVI has been widely applied clinically to assess arterial stiffness in subjects with known cardiovascular diseases including those with diagnosed atherosclerosis, coronary heart disease, and stroke as well as those at risk, including those with hypertension, diabetes, the elderly, and the obese. Because of its enhanced sensitivity, not only has the index been used to discern subtle changes in the disease process, it has also been utilized in studying normal individuals to assess their potential risks of developing cardiovascular diseases. The primary aims of assessing arterial stiffness using CAVI are not only to aid in early detection of arteriosclerosis to allow timely treatment and change in lifestyle, but also to quantitatively evaluate the progression of disease and the effectiveness of treatment. Despite its merit of being unaffected by blood pressure, discretion in data interpretation is suggested because an elevated CAVI represents not just vascular stiffness caused by pathological changes in the arterial wall, but can also be attributed to an increased vascular tone brought about by smooth muscle contraction. Moreover, certain patient populations, such as those with an ankle-brachial index < 0.9, may give falsely low CAVI and are suggested to be excluded from study.
Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor (MR) antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more MR-specific. From a marginal role as a potassium-sparing diuretic, spironolactone was shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure, as was eplerenone in subsequent heart failure trials. Neither acts as an aldosterone antagonist in the heart as the cardiac MR are occupied by cortisol, which becomes an aldosterone mimic in conditions of tissue damage. The accepted term "MR antagonist", (as opposed to "aldosterone antagonist" or, worse, "aldosterone blocker"), should be retained, despite the demonstration that they act not to deny agonist access but as inverse agonists. The prevalence of primary aldosteronism is now recognized as accounting for about 10% of hypertension, with recent evidence suggesting that this figure may be considerably higher: in over two thirds of cases of primary aldosteronism therapy including MR antagonists is standard of care. MR antagonists are safe and vasoprotective in uncomplicated essential hypertension, even in diabetics, and at low doses they also specifically lower blood pressure in patients with so-called resistant hypertension. Nowhere are more than 1% of patients with primary aldosteronism ever diagnosed and specifically treated. Given the higher risk profile in patients with primary aldosteronism than that of age, sex, and blood pressure matched essential hypertension, on public health grounds alone the guidelines for first-line treatment of all hypertension should mandate inclusion of a low-dose MR antagonist.
Diagrammatic representation of the gastrointestinal therapeutic system (GITS).  
Geometric mean plasma concentration–time curves after single-dose administration of 30 mg nifedipine gastrointestinal therapeutic system (GITS) (reference formulation) and an erosive modified-release formulation of nifedipine (test formulation) in healthy subjects under fed conditions. Copyright © 2002, Springer. Adapted with permission from Schug BS, Brendel E, Wonnemann M, et al. Dosage form-related food interaction observed in a marketed once-daily nifedipine formulation after a high-fat American breakfast. Eur J Clin Pharmacol. 2002;58(2):119–125. 20  
Responses to initiating therapy with different nifedipine formulations. (A) Plasma concentrations; (B) systolic BP; (C) heart rate; (D) plasma noradrenaline. Copyright © 2007, John Wiley and Sons. Adapted with permission from Brown MJ, Toal CB. Formulation of long acting nifedipine tablets influences the heart rate and sympathetic nervous system response in hypertensive patients. Br J Clin Pharmacol. 2007;65(5):646–652. 33 Abbreviations: BP, blood pressure; GITS, gastrointestinal therapeutic system.  
Hypertension treatment guidelines do not discriminate within drug classes and, furthermore, do not consider whether or not all of the formulations of any given drug licensed for once-daily administration can be considered to be therapeutically interchangeable. This article focuses on this issue with respect to nifedipine and the development of the gastrointestinal therapeutic system (GITS) formulation. Nifedipine GITS is regarded as the gold standard once-daily formulation of nifedipine and, as such, it is anticipated that alternative formulations will be therapeutically equivalent to nifedipine GITS. In general, this depends on demonstrating pharmacokinetic bioequivalence. This article is intended to focus attention on generic substitution and, in particular, on aspects of the scientific basis for the substitution of generic products in place of branded products. Such substitution is required for cost-saving or cost-containment reasons and is justified on the basis that the generic (substitute) drug is "therapeutically" equivalent to the branded drug. Unfortunately, there are serious shortcomings in the current methods of assessment insofar as they are typically based on statistical comparisons of average pharmacokinetic parameter values, using arbitrary comparative criteria. This article illustrates the shortcomings of the current approaches to generic substitution and concludes that, in regulatory terms, either more rigorous pharmacokinetic criteria are required or pharmacodynamic indices should be added to reinforce the regulatory criteria. Generic substitution is a balancing act but, at the moment, the cost issue is dominant. To restore the balance, equivalent efficacy must be confirmed. At present, therefore, in the absence of such regulatory rigor, the obvious course is to prefer the branded product, the therapeutic efficacy of which (including outcome benefits) has been established.
Astaxanthin is a biological antioxidant naturally found in a wide variety of aquatic living organisms, and has shown various pharmacological activities, such as anti-inflammatory and antidiabetic activities. A recent study reported that the administration of astaxanthin induced a significant reduction in blood pressure and delayed the incidence of stroke in stroke-prone spontaneously hypertensive rats, suggesting that astaxanthin also has antihypertensive effect. In a study using aortic rings of spontaneously hypertensive rats, astaxanthin induced a significant reduction of the contractile responses of the aorta to α-adrenergic receptor agonist and angiotensin II, which may contribute to the antihypertensive effect of astaxanthin. In a histopathological study, astaxanthin decreased coronary artery wall thickness compared with the control, indicating the possibility that astaxanthin ameliorates hypertension-induced vascular remodeling. Astaxanthin has anti-inflammatory, antidiabetic, antihypertensive, and antioxidative activities; therefore, we should perform further studies to elucidate an antiatherogenic effect of astaxanthin.
Recent studies with the novel ARB compound azilsartan medoxomil in hypertensive patients 
Renin-angiotensin-system (RAS) activation plays a key role in the development of hypertension and cardiovascular disease. Drugs that antagonize the RAS (angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]) have proven clinical efficacy in reducing blood pressure values and cardiovascular morbidity and mortality. ACE inhibitors partially inhibit plasma ACE, and angiotensin II generation. Thus, ARBs, which block selectively type 1 angiotensin II receptor (AT(1)R), have been developed and used in the clinical management of hypertension and cardiovascular disease. Experimental and clinical trials with ARBs indicate that this class of drug represents an effective, safe and well tolerated therapeutic option for the prevention and care of hypertension, even though there is no proven superiority as compared to ACE inhibitors except for the better tolerability. Most ARBs may not completely inhibit the AT(1)R at the approved clinical doses. Azilsartan medoxomil is a newly approved ARB for the management of hypertension. This ARB induces a potent and long-lasting antihypertensive effect and may have cardioprotective properties. This article reviews the current evidence on the clinical effectiveness of azilsartan in hypertension.
Association between serum PFOA, PFOS levels, and systolic blood pressure 
Association between serum PFOA, PFOS levels, and diastolic blood pressure 
Association between plasma PFOA, PFOS levels, and hypertension 
Hypertension is a leading cause of cardiovascular disease worldwide. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are perfluoroalkyl chemicals (PFCs) used in the manufacture of common consumer products and detected in the blood of the majority of Americans. Emerging biological data suggest that PFC exposure may have a role in the development of hypertension. However, the association between PFCs and hypertension has not yet been explored in humans. Therefore, we examined this association in a representative sample of US children. A cross-sectional study was performed on 1,655 children from the National Health and Nutrition Examination Survey, 1999-2000 and 2003-2008. The main outcome of interest was hypertension, defined as age, height, and sex specific systolic and/or diastolic blood pressure level at the 95th percentile. We found no association between serum levels of PFOA and PFOS and hypertension in either unadjusted or multivariable-adjusted analyses controlling for age, sex, race-ethnicity, body mass index, annual household income, moderate activity, total serum cholesterol, and serum cotinine. Compared with the lowest quartile, the multivariable-adjusted odds ratio (95% confidence interval) of hypertension in the highest quartile of exposure was 0.69 (0.41-1.17) for PFOA and 0.77 (0.37-1.61) for PFOS (all P-trend values >0.30). Our findings indicate that exposure to PFOA or PFOS is not significantly associated with hypertension in children at the lower PFC exposure levels typical of the general population.
The serum lipid profi le of patients in study groups
Correlation between lipid profi le and other cardiovascular risk factors in study groups
Distribution of patients in study groups into different grades of hypertension (A) and into CV risk groups according to existing risk factors before additional tests (B). Distribution into different groups showed significantly different patterns for both panels (p < 0.001, by Kruskal-Wallis test). Group comparisons were as follows: (A) p < 0.001 for Treated Referral Group vs other groups; p = 0.001 for Untreated Referral vs Untreated Primary Care Groups; (B) p < 0.001 for Treated Referral vs Untreated Primary Care groups, and p = 0.06 for Treated vs Untreated Referral Groups by Mann-Whitney U test.
The percentages of Treated, Untreated Referral and Untreated Primary Care patients in “high” plus “very high” added risk groups according to medical history and physical examination (HPE), and medical history and physical examination plus serum lipid profile (plus lipid profile). ***p < 0.001 vs HPE (McNemar test).
Hypertension, dyslipidemia, and other cardiovascular risk factors are linked epidemiologically, clinically, and metabolically. Intensive/Initial Cardiovascular Examination regarding Blood Pressure levels, Evaluation of Risk Groups (ICEBERG) study focuses on the effect of dyslipidemia on cardiovascular risk evaluation and association of lipid profile with other risk factors. The ICEBERG study consisted of two sub-protocols: ICEBERG-1, conducted at 20 university hospitals (Referral Group) and ICEBERG-2, conducted at 197 primary healthcare centers (Primary Care Group). Sub-protocol had two patient profiles: patients previously diagnosed with essential hypertension and under medical treatment (Treated Group) and patients with systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg, with no antihypertensive treatment for at least 3 months before inclusion (Untreated Group). Dyslipidemia was evaluated and cardiovascular risk stratification was performed according to ESC/ESH guidelines. More than half of the treated and untreated subjects were classified into high or very high cardiovascular risk groups. In a total of 1817 patients, the percentage of patients in "high" plus "very high" added risk groups increased to 55.2% in Treated Referral Group (p < 0.001), to 62.6% in Untreated Referral Group (p = 0.25) and to 60.7% in Untreated Primary Care Group (p < 0.001), by re-evaluation of patients' lipid values. Serum lipid levels are useful in stratifying hypertensive patients into cardiovascular risk groups more accurately, for appropriate antihypertensive treatment.
effects of new AT2R agonists on vascular tone ex vivo 
effects of new AT2R agonists on blood pressure 
effects of new AT2R agonists on vascular remodeling 
effects of new AT2R agonists on kidney function and pathology 
The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors within the renin-angiotensin system, which mediate tissue-protective actions such as anti-inflammation, antifibrosis, and antiapoptosis. In recent years, several programs have been launched in order to develop drugs that act as agonists on the AT2R or MAS to take therapeutic advantage of the protective and regenerative properties of these receptors. This review article will focus on recent data obtained in preclinical animal and in vitro models with new AT2R-agonistic molecules (Compound 21 and β-amino acid substituted angiotensin II) and with relevance for blood pressure (BP) regulation or hypertensive end-organ damage. These data will include studies on vasodilation/vasoconstriction in isolated resistance arteries ex vivo, studies on kidney function, studies on vascular remodeling, and studies that measured the net effect of AT2R stimulation on BP in vivo. Current data indicate that although AT2R stimulation causes vasodilation ex vivo and promotes natriuresis, it does not alter BP levels in vivo acutely - at least as long as there is no additional low-dose blockade of AT1R. However, AT2R stimulation alone is able to attenuate hypertension-induced vascular remodeling and reduce arterial stiffening, which in more chronic settings and together with the natriuretic effect may result in modest lowering of BP. We conclude from these preclinical data that AT2R agonists are not suitable for antihypertensive monotherapy, but that this new future drug class may be beneficial in combination with established antihypertensives for the treatment of hypertension with improved protection from end-organ damage.
Pertinent clinical studies of azilsartan/chlorthalidone in hypertension management 
Comparative cost (average wholesale price) of angiotensin receptor blocker-diuretic combination used in the United States 24 
Edarbyclor(®) is a combined angiotensin receptor blocker (ARB) and thiazide-like diuretic (azilsartan and chlorthalidone), and was approved on December 20, 2011 by the US Food and Drug Administration (FDA) for hypertension management. To review the pharmacology, pharmacokinetics, efficacy, safety, tolerability, and role of azilsartan plus chlorthalidone for hypertension management. Peer-reviewed clinical trials, review articles, and relevant treatment guidelines, were identified from the databases MEDLINE and Current Contents (both 1966 to February 15, 2013, inclusive) using search terms "azilsartan", "chlorthalidone", "pharmacology", "pharmacokinetics", "pharmacodynamics", "pharmacoeconomics", and "cost-effectiveness". The FDA website, as well as manufacturer prescribing information, was also reviewed to identify other relevant information. Azilsartan is a new ARB with high affinity for the angiotensin 1 receptor, approved by the FDA for hypertension management. Unlike other ARBs, azilsartan has no clinical data supporting improvement in cardiovascular outcomes, and is not approved for indications other than hypertension, which a select few other ARBs may be used for (eg, diabetic nephropathy and heart failure). Chlorthalidone is a longer acting thiazide-like diuretic that has been demonstrated to improve cardiovascular outcomes. Combination treatment with azilsartan/chlorthalidone is effective for reducing blood pressure. Compared to olmesartan/hydrochlorothiazide and azilsartan/hydrochlorothiazide combinations, azilsartan/chlorthalidone appears to be more efficacious for reducing blood pressure. Azilsartan/chlorthalidone can be considered an antihypertensive therapy option in patients for whom combination therapy is required (blood pressure >20 mmHg systolic or >10 mmHg diastolic above goal). Cost to patients and insurance coverage will probably determine whether azilsartan/chlorthalidone will be the most appropriate combination therapy for an individual patient.
Advantages of combining antihypertensive agents 
Currently available fixed-dose combinations 
Recent guidelines for the management of hypertension recommend target blood pressures <140/90 mmHg in hypertensive patients, or <130/80 mmHg in subjects with diabetes, chronic kidney disease, or coronary artery disease. Despite the availability and efficacy of antihypertensive drugs, most hypertensive patients do not reach the recommended treatment targets with monotherapy, making combination therapy necessary to achieve the therapeutic goal. Combination therapy with 2 or more agents is the most effective method for achieving strict blood pressure goals. Fixed-dose combination simplifies treatment, reduces costs, and improves adherence. There are many drug choices for combination therapy, but few data are available about the efficacy and safety of some specific combinations. Combination therapy of calcium antagonists and inhibitors of the renin-angiotensin-aldosterone system (RAAS) are efficacious and safe, and have been considered rational by both the JNC 7 and the 2007 European Society of Hypertension - European Society of Cardiology guidelines for the management of arterial hypertension. The aim of this review is to discuss some relevant issues about the use of combinations with calcium channel blockers and RAAS inhibitors in the treatment of hypertension.
Influence of a sodium (Na + )-restricted diet compared to a normal control diet on plasma renin activity (PRA) and plasma total renin (active plus prorenin). sodium restriction increased Pra. Note: *P,0.001. 
Immunofluorescence of rat renal cortical sections fixed in situ on the left (a) and a paired light-transmission micrograph (t) of the same field on the right. The fluorescence images show (in red) renin in the afferent arteriole (indicated by white arrows) next to the glomerulus (G), shown at 40×. This figure depicts four examples (A–D) from kidneys of rats fed a normal sodium diet. With normal sodium-diet rats, there is discrete focal localization of renin only in the juxtaglomerular apparatus abutting the glomerulus.
Immunofluorescence of rat renal cortical sections fixed in situ on the left (a) and a paired light-transmission micrograph (t) of the same field on the right. The fluorescence images show (in red) renin extending up the afferent arteriole (indicated by white arrows) from the glomerulus (G) shown at 40×. This figure depicts four examples (E–H) from kidneys of rats maintained on a sodium-restricted diet over 12 days, in which renin recruitment is clearly seen extending from the juxtaglomerular apparatus (JGA) up the afferent arteriole away from the JGA.
Demonstration of the calcium (Ca++) paradox comparing renin release (as sample renin concentration) from an isolated renal microvessel preparation from rats fed a normal sodium diet (open bars), incubated in either normal calcium (norm) or low-calcium media. This compares with similar preparations harvested from rats fed a low-sodium (Na+) diet over 12 days (hatched bars) to induce recruitment. Low-calcium incubation produced a significant 36%–39% increase in basal renin release in both groups.
Abbreviations: PRC, plasma renin concentration; Norm, normal.
Influence of a sodium (Na+)-restricted diet compared to a normal control diet on plasma renin activity (PRA) and plasma total renin (active plus prorenin). Sodium restriction increased PRA.
Note: *P<0.001.
Renin is the critical regulatory enzyme for production of angiotensin (Ang)-II, a potent vasoconstrictor involved in regulating blood pressure and in the pathogenesis of hypertension. Chronic sodium deprivation enhances renin secretion from the kidney, due to recruitment of additional cells from the afferent renal microvasculature to become renin-producing rather than just increasing release from existing juxtaglomerular (JG) cells. JG cells secrete renin inversely proportional to extra- and intracellular calcium, a unique phenomenon characteristic of the JG regulatory phenotype known as the "calcium paradox." It is not known if renin secreted from recruited renin-containing cells is regulated similarly to native JG cells, and therefore acquires this JG cell phenotype. We hypothesized that non-JG cells in renal microvessels recruited to produce renin in response to chronic dietary sodium restriction would demonstrate the calcium paradox, characteristic of the JG cell phenotype. Histology showed recruitment of upstream arteriolar renin in response to sodium restriction compared to normal-diet rats. Renin fluorescence intensity increased 53% in cortices of sodium-restricted rats (P<0.001). We measured renin release from rat afferent microvessels, isolated using iron oxide nanopowder and incubated in either normal or low-calcium media. Basal renin release from normal sodium-diet rat microvessels in normal calcium media was 298.1±44.6 ng AngI/mL/hour/mg protein, and in low-calcium media increased 39% to 415.9±71.4 ng AngI/mL/hour/mg protein (P<0.025). Renin released from sodium-restricted rat microvessels increased 50% compared to samples from normal-diet rats (P<0.04). Renin release in normal calcium media was 447.0±54.3 ng AngI/mL/hour/mg protein, and in low-calcium media increased 36% to 607.6±96.1 ng AngI/mL/hour/mg protein (P<0.05). Thus, renin-containing cells recruited in the afferent microvasculature not only express and secrete renin but demonstrate the calcium paradox, suggesting renin secretion from recruited renin-containing cells share the JG phenotype for regulating renin secretion.
Randomized controlled studies of candesartan with cardiovascular, cerebrovascular, retinal, or metabolic outcomes
controlled studies assessing the antihypertensive efficacy, safety, and tolerability of candesartan (monotherapy or in combination with other antihypertensive agents) versus placebo or versus other antihypertensive agents
Hypertension is the most prevalent cardiovascular disease of adults and is a major risk factor for cardiovascular (CV) and cerebrovascular morbidity and mortality worldwide. Treatment of hypertension leads to reduction of CV morbidity and mortality through blood pressure reduction. The role of renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of hypertension is mainly through generation of potent vasoconstrictor angiotensin II, stimulation of aldosterone secretion, and increase in sympathetic activation. Angiotensin II receptor blockers such as candesartan, a long-acting agent, alter this system by blocking the activation of angiotensin I receptors. Several important clinical trials have tested the efficacy of candesartan with placebo, antihypertensive agents, or other agents that block the RAAS for the control of hypertension and reduction of key CV risk factors such as microalbuminuria, heart failure, retinopathy, and carotid intima medial thickness. Candesartan has been shown to be a well-tolerated and effective antihypertensive agent with positive metabolic characteristics and additional benefits on CV and cerebrovascular outcomes. The aim of this review is to discuss the pharmacology, efficacy, and safety of candesartan, with an overview of key hypertension and CV studies involving candesartan.
The vascular endothelium, the largest "organ" in the body, synthesizes and releases a wide spectrum of vasoactive substances into the circulation. Endothelial dysfunction links hypertension and other cardiovascular (CV) risk factors that promote the development of atherosclerotic plaque, CV disease, and fatal and nonfatal CV events. Blood pressure (BP) reduction is the most effective way to reduce CV risk in patients with hypertension, but it is unknown whether endothelial dysfunction is a cause or consequence of hypertension. Renin-angiotensin-aldosterone system blockers improve endothelial function and have favorable vascular, metabolic, cardiac, and renoprotective effects that are independent of BP reduction. Olmesartan effectively reduces BP and also has vasoprotective properties, including reductions in endothelial dysfunction and inflammation, prevention of microalbuminuria, and reversal of vascular remodeling. Large-scale, long-term studies are needed to confirm that olmesartan has vasoprotective effects that are independent of BP control and to determine whether these pleiotropic effects translate into improved CV disease outcomes.
Studies addressing independent prognostic significance of nocturnal blood pressure on all-cause mortality and/or cardiovascular mortality/morbidity 
Studies addressing independent prognostic significance of nocturnal blood pressure on all-cause mortality and/or cardiovascular mortality/morbidity 
Nocturnal hypertension and non-dipping of blood pressure during sleep are distinct entities that often occur together and are regarded as important harbingers of poor cardiovascular prognosis. This review addresses several aspects related to these blood pressure abnormalities including definitions, diagnostic limitations, pathogenesis and associated patient profiles, prognostic significance, and therapeutic strategies. Taken together, persistent nocturnal hypertension and non-dipping blood pressure pattern, perhaps secondary to abnormal renal sodium handling and/or altered nocturnal sympathovagal balance, are strongly associated with deaths, cardiovascular events, and progressive loss of renal function, independent of daytime and 24-hour blood pressure. Several pharmacological and non-pharmacological approaches may restore nocturnal blood pressure and circadian blood pressure rhythm to normal; however, whether this translates to a clinically meaningful reduction in unfavorable cardiovascular and renal consequences remains to be seen.
Interactions between the different vasodilator systems.
Note: Inhibitory pathways = arrows interrupted by oblique lines. Adapted from Valdés G, Kaufmann P, Corthorn J, Erices R, Brosnihan KB, Joyner-Grantham J. Vasodilator factors in the systemic and local adaptations to pregnancy. Reprod Biol Endocrinol. 2009;7:799 with permission of the publisher, BioMed Central.
Abbreviations: ACE, angiotensin converting enzyme; AT-1-R, angiotensin II type 1 receptor; AT-2-R, angiotensin II type 2 receptor; B2R, bradykinin 2 receptor; eNOS, endothelial nitric oxide synthase; Flk, fetal liver kinase 1; Mas-R, Mas receptor; NO, nitric oxide; PGH2, prostaglandin H2; VEGF, vascular endothelial growth factor; VEGF-R2, VEGF receptor 2.
Diagram of the uteroplacental interface, showing its main cell types and the vasodilator repertoire of each type.9 The discontinuous yellow line depicts the path of trophoblasts that detach from the anchoring column to migrate through the uterine stroma, destroy the vascular smooth muscle, and colonize the lumen of the spiral arteries.
Note: Adapted from Valdés G, Kaufmann P, Corthorn J, Erices R, Brosnihan KB, Joyner-Grantham J. Vasodilator factors in the systemic and local adaptations to pregnancy. Reprod Biol Endocrinol. 2009;7:79 with permission of the publisher, BioMed Central.
Abbreviation: NK, natural killer.
Diagram showing the relation between the placenta and the maternal endothelium, in ischemic conditions, increased placental mass, and underlying cardiovascular risks. The microphotographs of the placental villi show syncytial knots prior to being deported into the maternal circulation (orange circles). In addition, the placenta sheds factors to the maternal circulation (green stars: sFLT-1, agonist autoantibodies to the AT-1-R, ADMA, and reactive oxygen species). Both syncytiotrophoblast microparticles and the soluble factors provoke endothelial dysfunction in pregestational healthy (smooth borders) or dysfunctional endothelial cells (spiky borders). Pregestational endothelial dysfunction also hinders uterine artery transformation (red broken arrow).
Abbreviations: ADMA, asymmetric dimethylarginine; AT-1-R, angiotensin II type 1 receptor; sFLT-1, soluble fms-like tyrosine kinase 1.
Balance of factors that determine an adequate or defective adaptation to pregnancy in the maternal hemodynamics and in the development and maintenance of the uteroplacental unit,9 based on the equilibrium initially proposed for PGI2 and TXA.45 The modulation of the maternal immune reaction and the state of the maternal vasculature have also been included, because though not analyzed in this review, they influence the adaptation to pregnancy.
Note: Adapted from Valdés G, Kaufmann P, Corthorn J, Erices R, Brosnihan KB, Joyner-Grantham J. Vasodilator factors in the systemic and local adaptations to pregnancy. Reprod Biol Endocrinol. 2009;7:79 with permission of the publisher, BioMed Central.
Abbreviations: ADMA, asymmetric dimethylarginine; AT-1-R, angiotensin II type 1 receptor; AT-1, angiotensin II type 1; AT-2, angiotensin II type 2; B2R, bradykinin 2 receptor; KDR, kinase domain receptor; FLT-1, fms-like tyrosine kinase 1; NO, nitric oxide; sFLT-1, soluble fms-like tyrosine kinase 1; VEGF, vascular endothelial growth factor.
In primates, adequate growth of the fetus depends on the development of the uteroplacental unit. On the fetal side, this is achieved by the creation of the vascular network of the placenta. On the maternal side, the transformation of the spiral arteries into saccular nonreactive vessels by the trophoblast provides high blood flow to the intervillous space. Apart from the changes in the uterine arteries, the mother expands her plasma volume - at the expense of stimulating the renin-angiotensin-aldosterone system - and her cardiac output. In the maintaining of normotension in the face of an increased cardiac output and plasma volume, the renin-angiotensin-aldosterone system requires an enhanced vasodilator synthesis. Finally, in the late stages of pregnancy, a normal endothelial function is required to provide an ample margin to the activation provoked by deportation of syncytiotrophoblast fragments/factors to the maternal circulation. These four adaptative processes require various interrelated vasodilator systems. Deficient adaptations cause isolated or proteinuric arterial hypertension, intrauterine growth restriction, preterm delivery, and stillbirths, among others. Moreover, a normal or a defective adaptation to pregnancy influences maternal cardiovascular health in later life, as evidenced by various studies, most of them epidemiological; thus, pregnancy is now considered a stress test to the maternal cardiovascular system. Because of this, women planning to become pregnant should be screened for clinical and biochemical cardiovascular risks. Inversely, women presenting with hypertension in pregnancy should be thoroughly studied to detect and correct cardiovascular risks. The incorporation of the predictive value of a hypertensive pregnancy should help reduce cardiovascular disease in women.
Possible combination drugs for hypertension 
Systemic hypertension and chronic obstructive pulmonary disease (COPD) frequently coexist in the same patient, especially in the elderly. Today, a wide variety of antihypertensive drugs with different mechanisms of action are available to the prescribing physician. In addition, combination drugs for hypertension are becoming increasingly popular. Certain antihypertensive drugs can affect pulmonary function. Therefore the management of such patients can present therapeutic challenges. We have examined the literature pertaining to the use of antihypertensive drugs in patients with systemic hypertension and coexisting COPD. Although data are often limited or of poor quality, we have attempted to review and then provide recommendations regarding the use of all the specific classes of antihypertensive drug therapies including combination drugs in patients with COPD. The antihypertensive agents reviewed include diuretics, aldosterone receptor blockers, beta blockers, combined alpha and beta blockers, angiotensin-converting enzyme inhibitors, angiotensin II antagonists, calcium channel blockers, alpha-1 blockers, centrally acting drugs, direct vasodilators, and combinations of these drugs. Of these classes, calcium channel blockers and angiotensin II antagonists appear to be the best initial choices if hypertension is the only indication for treatment. However, the limited data available on many of these drugs suggest that additional studies are needed to more precisely determine the best treatment choices in this widely prevalent patient group.
Hypertension remains one of the most prevalent diseases affecting our society, and its complications lead the list of causes of mortality all over the world. Most efforts to control the disease are unsuccessful, failing in at least two-thirds of affected patients, despite the availability of multiple drugs for its treatment. The limited number of medications available for aggressive management of hypertensive crises has intensified the search for novel drugs that can achieve a rapid decrease in blood pressure without increasing the possible complications. Clevidipine is a novel, vasculoselective, dihydropyridine calcium channel blocker characterized by a very fast onset and offset of action. Metabolism of clevidipine does not occur in the liver or kidneys, and thus there are no restrictions to using clevidipine in patients with hepatic or renal dysfunction. This agent has been widely used to reduce blood pressure when oral therapy is not appropriate, and its use in the perioperative setting has been shown to be beneficial. This manuscript reviews the key characteristics of clevidipine and its role in the management of acute hypertension.
Angiotensin receptor blocker single-pill combinations 
Changes in ambulatory systolic and diastolic blood pressure from baseline over a 24-hour period after 10 weeks of treatment in a study of 482 patients with moderate hypertension. reprinted with permission from Lacourcière Y, wright Jr JT, Samuel r, Zappe D, Purkayastha D, Black Hr. effects of force-titrated valsartan/hydrochlorothiazide versus amlodipine/hydrochlorothiazide on ambulatory blood pressure in patients with stage 2 hypertension: the evALUATe study. Blood Press Monit. 2009; 14(3):112–120. 47 Copyright © 2009 Lippincott williams & wilkins. Abbreviations: AMLO, amlodipine; BP, blood pressure; HCTZ, hydrochlorothiazide; vAL, valsartan.  
Least-squares mean changes in mean seated systolic blood pressure (MSSBP) from baseline after 4 weeks of treatment across various patient subgroups with moderate hypertension. elderly patients were 65 years of age. Notes: values in parentheses denote SeM. *P  0.05 vs amlodipine. Reprinted from Destro M, Luckow A, Samson M, Kandra A, Brunel P. Efficacy and safety of amlodipine/valsartan compared with amlodipine monotherapy in patients with stage 2 hypertension: a randomized, double-blind, multicenter study: the eX-eFFeCTS Study. J Am Soc Hypertens. 2008;2(4):294–302. 62 Copyright © 2008 with permission from elsevier. Abbreviations: AMLO, amlodipine; BMI, body mass index; ISH, isolated systolic hypertension; SeM, standard error of the mean; vAL, valsartan.  
Changes in mean seated systolic blood pressure (MSSBP) over time in black patients with moderate hypertension. reprinted by permission from Macmillan Publishers Ltd: Flack JM, Calhoun DA, Satlin L, Barbier M, Hilkert R, Brunel P. Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension: the eX-STAND study. J Hum Hypertens. 2009;23(7):479–489. 64 Copyright © 2009. Abbreviations: AMLO, amlodipine; HCTZ, hydrochlorothiazide; SeM, standard error of the mean; vAL, valsartan.  
Changes in mean seated systolic blood pressure (MSSBP) from baseline after 8 weeks of treatment in patients whose blood pressure was uncontrolled on previous antihypertensive monotherapy. results are shown by previous antihypertensive monotherapy. reprinted with permission from Allemann Y, Fraile B, Lambert M, Barbier M, Ferber P, Izzo JL Jr. Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure after Single Therapy (eX-FAST) study. J Clin Hypertens (Greenwich). 2008;10(3):185–194. 65 Copyright © 2008 John wiley and Sons, Inc. Abbreviations: ACeI, angiotensin-converting enzyme inhibitor; AMLO, amlodipine; ArB, angiotensin receptor blocker; CCB, calcium channel blocker; vAL, valsartan.  
The morbidity and mortality benefits of lowering blood pressure (BP) in hypertensive patients are well established, with most individuals requiring multiple agents to achieve BP control. Considering the important role of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of hypertension, a key component of combination therapy should include a RAAS inhibitor. Angiotensin receptor blockers (ARBs) lower BP, reduce cardiovascular risk, provide organ protection, and are among the best tolerated class of antihypertensive therapy. In this article, we discuss two ARB combinations (valsartan/hydrochlorothiazide [HCTZ] and amlodipine/valsartan), both of which are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy and as initial therapy in patients likely to need multiple drugs to achieve BP goals. Randomized, double-blind studies that have assessed the antihypertensive efficacy and safety of these combinations in the first-line treatment of hypertensive patients are reviewed. Both valsartan/HCTZ and amlodipine/valsartan effectively lower BP and are well tolerated in a broad range of patients with hypertension, including difficult-to-treat populations such as those with severe BP elevations, prediabetes and diabetes, patients with the cardiometabolic syndrome, and individuals who are obese, elderly, or black. Also discussed herein are patient-focused perspectives related to the use of valsartan/HCTZ and amlodipine/valsartan, and the rationale for use of single-pill combinations as one approach to enhance patient compliance with antihypertensive therapy.
Comparison between different HTN management strategies 13-37 
Combination therapy in HTN 10,20,40-70 
Currently approved combination therapy drugs 77 
Hypertension (HTN) is a worldwide health problem and a major preventable risk factor for cardiovascular (CV) events. Achieving an optimal blood pressure (BP) target for patients with HTN will often require more than one BP-lowering drug. Combination therapy is not only needed, but also confers many advantages such as better efficacy and a better tolerability. A better compliance and simplicity of treatment is noted with the single-pill combination (SPC). In addition, for those patients who do not achieve BP target when receiving dual combinations, triple SPCs are now available, and their efficacy and safety have been tested in large clinical trials. BP-lowering drugs used in combination therapy should have complementary mechanisms of action, leading to an additive BP-lowering effect and improvement in overall tolerability, achieved by decreasing the incidence of adverse effects. On the basis of large, outcome-driven trials, preferred dual combinations include an angiotensin receptor antagonist (ARB) or an angiotensin converting enzyme inhibitor (ACEI) combined with a calcium channel blocker (CCB), or an ARB or ACEI combined with a diuretic. Acceptable dual combinations include a direct rennin inhibitor (DRI) and a CCB, a DRI and a diuretic, a beta-blocker and a diuretic, a CCB and a diuretic, a CCB and a beta-blocker, a dihydropyridine CCB and a non-dihydropyridine CCB, and a thiazide diuretic combined with a potassium-sparing diuretic. Some combinations are not recommended and may even be harmful, such as dual renin angiotensin aldosterone system inhibition. Currently available triple SPCs combine a renin angiotensin aldosterone system inhibitor with a CCB and a diuretic. Combination therapy as an initial approach is advocated in patients with a systolic BP more than 20 mmHg and/or a diastolic BP more than 10 mmHg above target and in patients with high CV risk. In addition, using SPCs has been stressed and favored in recent international guidelines. Recently, triple SPCs have been approved and provide an attractive option for patients not achieving BP target on dual combination. The effect of such a strategy in the overall management of HTN, especially on further reducing the incidence of CV events, will have to be confirmed in future clinical and population-based studies.
Clinical trials assessing the antihypertensive efficacy of OM/HCTZ combination therapy 
Hourly mean ambulatory BP at baseline and end of study (week 12) in patients aged $65 years treated with an olmesartan medoxomil/hydrochlorothiazide-based algorithm in the BeniSILveR study. 38 Reprinted from Kereiakes, et al. J Clin Hypertens (Greenwich). 2009;11(8):411-421, with permission from John Wiley and Sons, copyright © 2010. Abbreviations: BeniSILVER, Benicar Efficacy: New Investigation Shows Olmesartan Medoxomil Treatment Increasingly Leads Various Elderly Populations to Safe BP Reductions; BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure. 
Mean hourly BP values according to treatment group during the 24-hour dosing interval, reported in an ambulatory BP monitoring substudy of the ACCOMPLISH trial. 59 Reprinted from Jamerson, et al. Efficacy and Duration of Benazepril Plus Amlodipine or Hydrochlorthiazide on 24-Hour Ambulatory Systolic Blood Pressure Control. Hypertension. 2011;57(2):174-179, with permission from Wolters Kluwer Health, copyright © 2011. Abbreviations: ACCOMPLISH, Avoiding Cardiovascular events through Combination Therapy in Patients Living with Systolic Hypertension; AMLO, amlodipine; BP, blood pressure; BZPL, benazepril; DBP, diastolic blood pressure; HCTZ, hydrochlorothiazide; SBP, systolic blood pressure. 
Hypertension affects nearly one-third of all individuals in the US, yet one-half of all treated patients achieve blood pressure (BP) controlled to recommended goals. The percentage of patients with uncontrolled BP is likely to be much higher when considering the number of patients who are not even aware of their hypertensive state. Elevated BP is associated with increased risks of cardiovascular events and end-organ damage. Antihypertensive monotherapy is not always sufficient to achieve BP goals, and thus more aggressive treatment regimens need to be considered. Antihypertensive combination therapy, which may improve tolerability, offers the benefit of targeting different mechanisms of action. Numerous outcomes studies support the use of a renin-angiotensin system inhibitor as a first-line choice in antihypertensive therapy. This review discusses the benefits of combination therapy with the angiotensin type II receptor blocker olmesartan medoxomil (OM) paired with the thiazide diuretic hydrochlorothiazide (HCTZ). The pharmacokinetic properties of OM will be reviewed in addition to efficacy studies that support OM + HCTZ combination therapy over other possible antihypertensive combinations. Finally, a rationale for choosing HCTZ over another diuretic, chlorthalidone, will also be discussed based on pharmacokinetic differences, clinical concerns, and trends in use.
Primary characteristics of β-adrenergic receptors 
Despite significant advances in pharmacologic approaches to treat hypertension during the last decades, hypertension- and hypertension-related organ damage are still a high health and economic burden because a large proportion of patients with hypertension do not achieve optimal blood pressure control. There is now general agreement that combination therapy with two or more antihypertensive drugs is required for targeted blood pressure accomplishment and reduction of global cardiovascular risk. The goals of combination therapies are to reduce long-term cardiovascular events by targeting different mechanism underlying hypertension and target organ disease, to block the counterregulatory pathways activated by monotherapies, to improve tolerability and decrease the adverse effects of up-titrated single agents, and to increase persistence and adherence with antihypertensive therapy. Multiple clinical trials provide evidence that fixed-dose combinations in a single pill offer several advantages when compared with loose-dose combinations. This review discusses the advances in hypertension control and associated cardiovascular disease as they relate to the prospect of combination therapy targeting a third-generation beta (β) 1-adrenergic receptor (nebivolol) and an angiotensin II receptor blocker (valsartan) in fixed-dose single-pill formulations.
Corticosteroids constitute an ideal treatment for various inflammatory and autoimmune disorders due to their anti-inflammatory and immunomodulatory actions. However, corticosteroids have a considerable number of side effects, including hypertension, diabetes, lipid disorders, sleep apnea, osteoporosis, myopathy, and disorders of coagulation and fibrinolysis, which are components of Cushing's syndrome (CS). Corticosteroid-induced side effects are dependent on the formulation, route, dose, and time of exposure. However, the underlying pathogenetic mechanisms have not been clearly defined. A large body of evidence supports the role of an imbalance between vasoconstriction and vasodilation with possible links to nitric oxide, prostanoids, angiotensin II, arginine vasopressin, endothelins, catecholamines, neuropeptide Y, and atrial natriuretic peptide. Increased oxidative stress, renin-angiotensin system activation, increased pressor response, metabolic syndrome, and sleep apnea appear to be pathogenetically involved as well. The ideal treatment is the withdrawal of corticosteroids, which is most often impossible due to the exacerbation of the underlying disease. Alternatively, a careful plan, including the proper selection of the formulation, time, and route, should be made, and each side effect should be treated properly. The focus of the research should be to develop synthetic corticosteroids with anti-inflammatory effects but fewer metabolic effects, which so far has been unsuccessful.
Proposed screening algorithm for patients with uncontrolled hypertension. Notes: Modified from Mahfoud F, Himmel F, Ukena C, Schunkert H, Böhm M, weil J. Treatment strategies for resistant arterial hypertension. Dtsch Arztebl Int. 2011;108(43):725–731. 23  
Causes of resistant hypertension
Arterial hypertension is the most prevalent risk factor associated with increased cardiovascular morbidity and mortality. Although pharmacological treatment is generally well tolerated, 5%-20% of patients with hypertension are resistant to medical therapy, which is defined as blood pressure above goal (>140/90 mmHg in general; >130-139/80-85 mmHg in patients with diabetes mellitus; >130/80 mmHg in patients with chronic kidney disease) despite treatment with ≥3 antihypertensive drugs of different classes, including a diuretic, at optimal doses. These patients are at significantly higher risk for cardiovascular events, in particular stroke, myocardial infarction, and heart failure, as compared with patients with nonresistant hypertension. The etiology of resistant hypertension is multifactorial and a number of risk factors have been identified. In addition, resistant hypertension might be due to secondary causes such as primary aldosteronism, chronic kidney disease, renal artery stenosis, or obstructive sleep apnea. To identify patients with resistant hypertension, the following must be excluded: pseudo-resistance, which might be due to nonadherence to medical treatment; white-coat effect; and inaccurate measurement technique. Activation of the sympathetic nervous system contributes to the development and maintenance of hypertension by increasing renal renin release, decreasing renal blood flow, and enhancing tubular sodium retention. Catheter-based renal denervation (RDN) is a novel technique specifically targeting renal sympathetic nerves. Clinical trials have demonstrated that RDN significantly reduces blood pressure in patients with resistant hypertension. Experimental studies and small clinical studies indicate that RDN might also have beneficial effects in other diseases and comorbidities, characterized by increased sympathetic activity, such as left ventricular hypertrophy, heart failure, metabolic syndrome and hyperinsulinemia, atrial fibrillation, obstructive sleep apnea, and chronic kidney disease. Further controlled studies are required to investigate the role of RDN beyond blood pressure control.
Blood pressure (BP) control is a critical part of managing patients with type 2 diabetes. Perhaps it is the single most important aspect of diabetes care, which unlike hyperglycemia and dyslipidemia can reduce both micro- and macrovascular complications. Hypertension is more prevalent in individuals with diabetes than general population, and in most cases its treatment requires two or more pharmacological agents (about 30% of individuals with diabetes need 3 or more medications to control BP). In this article we describe the key evidence that has contributed to our understanding that reduced BP translates into positive micro- and macrovascular outcomes. We review the data supporting current recommendation for BP target < 130/80 mmHg. Two studies suggest that a lower BP goal could be even more beneficial. We also present the comparative benefits of various antihypertensive drugs in reducing diabetes-related micro- and macrovascular complications. Finally we propose an evidence-based algorithm of how to initiate and titrate antihypertensive pharmacotherapy in affected individuals. Overall, achieving BP < 130/80 mmHg is more important than searching for the "best" antihypertensive agent in patients with diabetes.
Tetrahydrobioterin synthesis.
Abbreviation: BH4, tetrahydrobiopterin; sGTP-CH, GTP cyclohydrolase; PTPS, pyruvoyl tetrahydrobiopterin synthase; SR, sepiapterin reductase; DHPR, dihydrofolate reductase.
Interaction between tetrahydrobiopterin and nitric oxide synthesis.
Nitric oxide (NO) is an important regulator of vascular tone, and is also an antithrombotic, anti-inflammatory, antiproliferative, and antiatherogenic factor. Endothelial function is altered in patients with coronary artery disease, stroke, and peripheral artery disease, and endothelial dysfunction correlates with the risk factor profile for a patient. Hypertension and type 2 diabetes are risk factors for vascular disease, and are both pathologies characterized by loss of NO activity. Indeed, endothelial dysfunction is usually present in diabetic and/or hypertensive patients. Tetrahydrobiopterin is an essential cofactor for the NO synthase enzyme, and insufficiency of this cofactor leads to uncoupling of the enzyme, release of superoxide, endothelial dysfunction, progression of hypertension, and finally, proatherogenic effects. Tetrahydrobiopterin is also an important mediator of NO synthase regulation in type 2 diabetes and hypertension, and may be a rational therapeutic target to restore endothelial function and prevent vascular disease in these patients. The aim of this paper is to review the rationale for therapeutic strategies directed to biopterins as a target for vascular disease in type 2 diabetic hypertensive patients.
Figure Central (C) and brachial (B) BP of the reASON study before and after one year treatment 10. whereas the DBP reduction was similar for the 2 groups of subjects, the reduction of SBP and mostly of PP was more pronounced on central than brachial arteries, in favour of Per/Ind when compared to atenolol. reproduced with permission from Asmar et al 2001. Hypertension. 2001;38:922–926. 52 Copyright © 2001 American Heart Association.  
Figure Clinical determination of Pwv. Pwv is the ratio between: 1) the distance between the carotid and femoral transducers (L), and 2) the time delay (∆T) between the foot of the carotid and femoral BP curves simultaneously measured. From Pwv, distensibility may be deduced. 1,2
In hypertensive subjects, cardiovascular risk reduction is critically related to the decrease of systolic blood pressure (SBP). De-stiffening therapy means that, in a controlled therapeutic trial of long duration, a selective reduction of SBP has been obtained in the studied group by comparison with the control group, and that this SBP reduction is due to a decrease of either arterial stiffness, or wave reflections, or both. Central SBP reduction and cardiovascular remodeling are specifically involved. Most protocols require the presence of an angiotensin II blocker, potentially associated with a diuretic compound and/or a calcium-channel blocker. Cardiovascular outcomes are significantly reduced by comparison with the control group, particularly when this latter group involves administration of a beta-blocking agent.
Demographic, clinical, and some basic laboratory data of the study participants 
Preeclampsia (PE) is still a disease of theories as the exact cause remains uncertain. Widespread vascular endothelial cell dysfunction is thought to mediate the generalized vasospasm and hypertension characteristic of PE. Altered nitric oxide (NO) production has been associated with the endothelial dysfunction in the pathogenesis of PE but conflicting results have emerged from previous studies. To determine maternal serum levels of NO, a biomarker of endothelial function, in nonpregnant, normal pregnant, and preeclamptic women. This was a cross-sectional case-control study of 277 women comprising 75 nonpregnant, 102 normal pregnant, and 100 preeclamptic women conducted at the Korle Bu Teaching Hospital between April and June 2011. About 5 mL of venous blood was obtained from the participants for the various investigations after meeting the inclusion criteria and signing to a written consent. Serum levels of NO were determined by Griess reaction. The data obtained were analyzed with SPSS version 20. The study showed significantly elevated serum levels of NO in preeclamptic women (82.45±50.31 μM) compared with normal pregnant (33.12±17.81 μM) and nonpregnant (16.92±11.41 μM) women with P<0.001. The alteration in maternal serum NO levels was significantly more profound in early-onset (severe) PE (119.63±45.860 μM) compared to that of late-onset (mild) disease (62.44±40.44 μM) with P<0.001, indicating a more severe vascular endothelial cell dysfunction in the early-onset disease. This study has determined a profound NO upregulation in PE evidenced by significant elevation of NO metabolite levels compared to normal pregnancy. This might be due to deranged endothelial function with dysregulated production of NO to restore the persistent hypertension characteristic of PE.
Degree of BP reduction achieved with lifestyle modifications in elderly patients with hypertension
Comparison of different BP-lowering regimens in reducing cardiovascular risk in hypertensive patients .65 years old. A) Angiotensin-converting enzyme inhibitor versus diuretic or beta blocker. B) Calcium antagonist versus diuretic or beta blocker. C) Angiotensin-converting enzyme inhibitor versus calcium antagonist. Copyright © 2008. Adapted with permission from BMJ Publishing Group Ltd. Turnbull F, for the Blood Pressure Lowering Treatment Trialists' Collaboration. effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ. 2008;336:1121-1123. 23 Favors first listed 1.0 0.5 2 .0 Favors second listed
Comparison of intensive versus standard BP lowering on the composite of nonfatal stroke, nonfatal myocardial infarction, and death from cardiovascular disease (primary outcome). Copyright © 2010. Adapted with permission from Massachusetts Medical Society. All rights reserved. Cushman WC, Evans GW, Byington RP, et al., for the ACCORD Study Group. Effects of intensive blood pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–1585.30
Comparison of different BP-lowering regimens in reducing cardiovascular risk in hypertensive patients >65 years old. A) Angiotensin-converting enzyme inhibitor versus diuretic or beta blocker. B) Calcium antagonist versus diuretic or beta blocker. C) Angiotensin-converting enzyme inhibitor versus calcium antagonist. Copyright © 2008. Adapted with permission from BMJ Publishing Group Ltd. Turnbull F, for the Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ. 2008;336:1121–1123.23
Hypertension is a common and important modifiable risk factor for cardiovascular and kidney diseases. The prevalence of hypertension, particularly isolated systolic hypertension, increases with advancing age, and this is partly due to the age-related changes in the arterial tree, leading to an increase in arterial stiffness. Therapeutic lifestyle changes, such as reduced dietary sodium intake, weight loss, regular aerobic activity, and moderation of alcohol consumption, have been shown to benefit elderly patients with hypertension. Lowering blood pressure (BP) using pharmacological agents reduces the risk for cardiovascular morbidity and mortality, with no difference in risk reduction in elderly patients compared to younger hypertensives. Guidelines recommend a BP goal of <140/90 in hypertensive patients regardless of age and <130/80 in patients with concomitant diabetes or kidney disease, and lowering the BP further has not been shown to confer any additional benefit. Moreover, the choice of antihypertensive does not seem to be as important as the degree of BP lowering. Special considerations in the treatment of elderly hypertensive patients include cognitive impairment, dementia, orthostatic hypotension, and polypharmacy.
risk factors of hypertension among adults visiting the outpatient units of Jimma University hospital, southwest ethiopia, 2012 
Comparison of the current findings with previous studies conducted in the country, and in sub-Saharan Africa, India, North America, and Europe 
logistic regression analysis of the common risk factors for hypertension 
Hypertension is a common medical condition worldwide. It is an important public health challenge because of the associated morbidity, mortality, and the cost to the society. The objective of this study was to determine the prevalence of hypertension and its risk factors among attendants of adult outpatient departments at Jimma University Specialized Hospital in southwest Ethiopia. A hospital-based cross-sectional study was conducted on 734 participants aged 15 years or older from May 2012 to June 2012. A pretested structured questionnaire consisting of characteristics related to sociodemographic profiles and risk factors for hypertension was used for data collection. Three separate measurements of blood pressure and relevant anthropometric evaluation were taken according to current recommended standards. Chi-square test and other statistical analyses were done to employ appropriate interpretations of the findings. P-values of <0.05 were considered statistically significant. The mean age of the participants was 42.3 ± 13.2 years and 71.7% of them were 35 years and older; 58% of them were females. Overall prevalence of hypertension - defined by systolic blood pressure ≥140 and/or diastolic blood pressure ≥90 or reporting history of hypertension - was found to be 13.2%. Only 35.1% of them were aware of their hypertension and only 23.7% were on treatment. The overall control rate was 15.5%. Family history of hypertension, having diabetes mellitus, being overweight, and oral contraceptive use were associated with high blood pressure. Hypertension was found to be prevalent; morbidity, awareness, treatment, and control in those with hypertension were low. Hence, intervention measures should be undertaken at the community level; particular emphasis should be placed on prevention by introducing lifestyle modifications and creating awareness about the problem so that early detection and intervention is possible.
Persistence at one year by antihypertensives. 74 Copyright © 2002, Nature Publishing Group. Reproduced with permission from Hasford et al. Notes: *P = 0.001 versus all other antihypertensive classes and versus losartan; P = 0.009 versus all other angiotensin II receptor antagonists. Abbreviations: ACe, angiotensin-converting enzyme; CCBs, calcium channel blockers ; AIIRAs, angiotensin II receptor antagonists.  
Indications of the seven approved angiotensin receptor blocker (listed in order of date of appearance on the market) 89,90
In this review, we discuss the pharmacological and clinical properties of irbesartan, a noncompetitive angiotensin II receptor type 1 antagonist, successfully used for more than a decade in the treatment of essential hypertension. Irbesartan exerts its antihypertensive effect through an inhibitory effect on the pressure response to angiotensin II. Irbesartan 150-300 mg once daily confers a lasting effect over 24 hours, and its antihypertensive efficacy is further enhanced by the coadministration of hydrochlorothiazide. Additionally and partially beyond its blood pressure-lowering effect, irbesartan reduces left ventricular hypertrophy, favors right atrial remodeling in atrial fibrillation, and increases the likelihood of maintenance of sinus rhythm after cardioversion in atrial fibrillation. In addition, the renoprotective effects of irbesartan are well documented in the early and later stages of renal disease in type 2 diabetics. Furthermore, both the therapeutic effectiveness and the placebo-like side effect profile contribute to a high adherence rate to the drug. Currently, irbesartan in monotherapy or combination therapy with hydrochlorothiazide represent a rationale pharmacologic approach for arterial hypertension and early-stage and late-stage diabetic nephropathy in hypertensive type II diabetics.
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  • National Institute of Integrative Medicine
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