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Authors and Disclosures

Stefano Taddei, Rosa Maria Bruno and Lorenzo Ghiadoni Department of Internal Medicine, University of Pisa, Pisa, Italy Correspondence Prof. Stefano Taddei, Department of Internal Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy. E-mail: s.taddei@unipi.it

From American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions

The Correct Administration of Antihypertensive Drugs According to the Principles of Clinical Pharmacology
Stefano Taddei; Rosa Maria Bruno; Lorenzo Ghiadoni Posted: 02/09/2011; Am J Cardiovasc Drugs. 2011;11(1):13-20. 2011 Adis Data Information BV

Abstract and Introduction

Abstract

Control of cardiovascular (CV) risk factors, particularly hypertension, is still unsatisfactory, resulting in excess CV morbidity and mortality worldwide. CV risk is linearly associated with an increase in blood pressure (BP) values, and clinical studies have clearly demonstrated that BP lowering represents the most effective means of preventing CV events. However, while BP reduction is a fairly easy target, BP normalization is much more difficult to achieve, and adequate BP control (<140/90 mmHg) is attained only in a small percentage of the hypertensive population. One of the main reasons for the lack of efficacy of antihypertensive pharmacological treatment is that very often drugs are not administered at the correct dosage. In this review, we discuss the importance of using clinical pharmacology to guide treatment of hypertension. Controlled clinical trials, including HOPE, EUROPA, and CONSENSUS, are used to guide prescribing decisions. Unfortunately, the results obtained in pivotal studies such as these have been obtained using drug dosages much higher than those usually used in clinical practice. The prescription of a drug for the treatment of hypertension should take into consideration the potency of the drug, i.e. the degree of BP reduction required, and the duration of action of the drug, i.e. the need to cover the dosing interval (possibly 24 hours) in a homogeneous way. This is especially the case for angiotensin-converting enzyme (ACE) inhibitors, compounds characterized by a flat dose-response curve. The significance of this flat dose-response curve is that a low dose of an ACE inhibitor has the same potency as a high dose but a shorter duration of action. If a low dosage is administered to a hypertensive patient it causes BP fluctuations, which have been associated with negative CV outcomes. In contrast, other drug classes, including calcium channel antagonists, diuretics, and -adrenoceptor antagonists, can be used at different dosages in order to modulate their hemodynamic effects. Thus, it is important to be aware of the clinical pharmacology of antihypertensive drugs in order to choose not only the class or the molecule best suited to the clinical characteristics of the patient, but also the correct dosages to ensure effective and homogeneous 24-hour BP reduction.

1. Introduction

Despite the great value that we attribute to scientific literature and guidelines, very often the clinical reality is far from what would be expected on the basis of shared knowledge. Atypical example is the effectiveness of hypertension treatment in the general population. It is well established that cardiovascular (CV) diseases represent the leading causes of morbidity and mortality worldwide, and that this is related to the high prevalence of CV risk factors and the failure to control them adequately.[1,2] Essential hypertension is considered the most important CV risk factor on the basis of its very high incidence (around 50% in the adult population) and its direct, linear relationship with CV events.[3,4] Treatment of hypertensive patients is based on blood pressure (BP) normalization, which represents the main mechanism by which antihypertensive treatment reduces morbidity and mortality.[5] In line with this, the 2007 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines on the management of hypertension recommend a target BP within the range of 130139/8089mmHg in all hypertensive patients.[6,7] In this review, we discuss how clinical pharmacology can be used to achieve BP goals in patients with hypertension. PubMed searches were performed for English-language articles on the treatment of hypertension, antihypertensive therapy, combination therapy in hypertension, and clinical pharmacology of antihypertensive drugs, published from 2000 to the present. In particular, reviews, consensus statements/guidelines, and meta-analyses relevant to the above-mentioned issues were included. Earlier works, particularly those concerning the clinical pharmacology of antihypertensive drugs, were also evaluated. As a limitation, it has to be noted that this is not a systematic and exhaustive review of the published literature. This was beyond the purpose of this review, which was to merge the evidence from clinical trials, pharmacology studies, and the recommendations of international guidelines, in order to implement them in daily practice.

2. BP Normalization in the Community

One would expect that the availability of a relatively large number of classes of antihypertensive drugs would make the reduction of BP an easily achievable target. However, reducing BP is not equivalent to normalizing it, particularly in clinical practice. BP normalization (<140/90 mmHg) is not an easy target, as demonstrated by the relatively low percentage of hypertensive patients achieving this BP goal (less than 40% of patients worldwide).[8] The situation is similar in Italy, where only 30% of the population has BP values controlled by therapy.[9] Obviously, poor BP control is related to poor CV outcome.[10] Why is it so difficult to normalize BP values in clinical practice? Is it only a problem of medical inertia, as is usually (though wrongly) believed, or should other causes be considered? First of all, BP normalization generally requires a large BP reduction. This target is very difficult to achieve, particularly for systolic BP. Controlled clinical trials showed that only 50% of patients achieved the systolic BP goal of 140 mmHg, while diastolic BP was easily lowered below 90 mmHg.[11] The situation is even worse if we consider patients who require more aggressive BP control, such as diabetic patients; the systolic BP target of 130 mmHg was not reached in any of the trials on antihypertensive treatment enrolling diabetic patients, while as many as 50% of patients reached a diastolic BP target of 80 mmHg.[11] Since the above-mentioned data refer to controlled clinical trials, a setting in which patient compliance and medical attention are usually higher than in everyday clinical practice, other reasons should be considered for the failure to achieve the systolic BP target. The relative difficulty in reducing systolic BP might be related to increased arterial stiffness, a process that characterizes vascular aging. [12] Older age, obesity, diabetes mellitus, and chronic renal failure are the strongest risk factors for uncontrolled hypertension, and the prevalence of all these risk factors is expected to increase in the future. [13] Successful treatment of the

emerging epidemic of resistant hypertension requires the correction of lifestyle factors (e.g. high sodium intake), the diagnosis and appropriate treatment of secondary causes of hypertension, and the use of effective multidrug regimens.[13] It is therefore necessary for physicians to start considering BP normalization as a difficult goal that cannot be achieved by a simplistic approach. Knowledge of some basic principles of clinical pharmacology can be a useful tool to reach this aim.

3. The Dosing of Antihypertensive Drugs According to Guidelines

The 2007 ESH/ESC guidelines recommend starting antihypertensive treatment with drugs at low dosages (figure 1).[6] Although this principle might be applicable to some agents, it should be noted that it cannot be applied to all antihypertensive drug classes. Thus, one major problem that should be reconsidered in the treatment of hypertensive patients is the utilization of drugs at the correct and most effective dosages. More consideration should be given to the application of the basic principles of clinical pharmacology to achieve good antihypertensive treatment efficacy.

Figure 1. Therapeutic strategies in hypertensive patients according to European Society of Hypertension/European Society of Cardiology guidelines. It is evident that guidelines always suggest starting treatment in hypertensive patients with drugs at low doses. For certain drug classes, namely ACE inhibitors, this is not correct, because of their pharmacological characteristics. Adapted from Mancia et al [6]. CV= cardiovascular. When we prescribe a drug for the treatment of hypertensive patients we should have in mind the following issues: (i) potency of the drug, i.e. the degree of BP reduction; (ii) the duration of action of the drug, i.e. the need for homogeneous BP reduction over the dosing interval (possibly 24 hours); and (iii) the specific effect on target organ damage or related clinical conditions. A relevant problem arises from the fact that very often we choose drugs on the basis of the efficacy demonstrated in clinical trials, but we administer dosages without a clear knowledge of the clinical pharmacology of the specific products. Pivotal studies such as CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study), [14] HOPE (Heart Outcomes Prevention Evaluation)[15] and EUROPA (EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease)[16] have changed our clinical practice, indicating that blockade of the renin-angiotensin-aldosterone system (RAAS) with an angiotensin-converting enzyme

(ACE) inhibitor can improve the prognosis of patients with high CV risk, such as those with coronary heart disease or heart failure. However, the clinical application of these scientific results has been very disappointing, since the dosage regimen used in clinical practice is usually lower than that employed in clinical studies or indicated by the pharmacological characteristics of the molecules. As an example, in clinical trials enalapril is used at dosages of 2040 mg/day,[14] but in clinical practice it is common to see hypertensive patients treated with dosages of 510 mg/day. In the HOPE and EUROPA studies, ramipril and perindopril were used at dosages of 8 and 10 mg/day,[15,16] which are not the most commonly used dosages in clinical practice. It is also necessary to observe that several commercial formulations are not rational in terms of clinical pharmacology, and are commercialized for marketing purposes only. This is particularly true for fixed combinations, as explained in section 5. This kind of practice can generate a great deal of confusion, especially among general practitioners who do not have specific experience in CV pharmacology. In other words, what is the right dosage for each drug? Is it correct to adjust the dosage according to BP values? Should the choice of dosage bemade in the same way for different drug classes, for instance, for ACE inhibitors or calcium channel antagonists? As mentioned above, effective BP lowering must take into account two main principles: (i) the extent of BP reduction (which is expressed by the potency of the drug); and (ii) the need to cover the 24-hour dosing interval (which requires using either compounds with a prolonged half-life or extended-release formulations for once-daily administration). While the physician is aware of the extent of BP reduction, usually there is no assessment of the 24-hour effect, which is a big mistake. A prolonged duration of action and a balanced effectiveness throughout the 24-hour period reduces large fluctuations between the 'peak' and the 'trough' effects,[17] which is an important aspect to consider because 24-hour mean values and BP variability are closely related to CV events.[18,19]

4. The Dose-response Curve of Antihypertensive Drugs

Antihypertensive drug classes can be divided into two groups according to the characteristics of their doseresponse curve. As discussed above, current guidelines suggest the initiation of a low-dose antihypertensive treatment.[6] However, this strategy can be applied only to drugs that present a linear doseresponse curve, i.e. their BP-lowering effect is proportional to the dose used (figure 2a). The prescription of these molecules, which include diuretics, -adrenoceptor antagonists (-blockers), 1-adrenoceptor antagonists, and calcium channel antagonists,[2023] allows the dosage to be tailored to the clinical characteristics of each patient.

Figure 2. Dose-response curves of antihypertensive drugs. (a) Drugs characterized by a linear doseresponse curve in terms of BP-lowering effect and with a duration of action sufficient to cover 24 hours. Drugs with these pharmacological characteristics can be used at different doses according to the potency needed. (b) Drugs characterized by a non-linear dose-response curve. Drugs with these pharmacological characteristics are not properly used at different doses, because the degree of BP reduction induced by the low dose is the same as that determined by the high dose. The difference between the doses is only in the duration of action. (c) Drug classes characterized by an incorrect titration. If BP is only measured at the dosing interval (usually 24 hours) and not also at the peak time, it is not possible to ascertain whether the different BP-lowering effects observed over 24 hours are related to a different potency or a different duration of action. In contrast, for drug classes characterized by a non-linear dose-response curve, dosages differ mainly in terms of duration of action, rather than in BP-lowering effect (figure 2b). Typical examples of such drugs are ACE inhibitors[24] and possibly some angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]).[25] To better explain this concept, the extent of BP reduction produced by an ACE inhibitor at a low dosage (e.g. enalapril at 5mg/day) at peak is the same as that produced by a high dosage (e.g. 20 mg/day).[24] The difference between the two dosages concerns the duration of action, which is several hours with the 5mg/day dosage, but covers an entire day with the 20 mg/day dosage.[24] In some cases, physicians may believe that a low dosage of ACE inhibitor is effective in a patient with mild hypertension (for example, during summer). This is a big mistake, from a pharmacological and clinical point of view, and it generally originates from the fact that usually the patient takes the drug in the morning and BP is measured during the daytime, when the compound has maximal efficacy, while during the night BP values increase again. This pharmacological approach to hypertension is not adequate, because BP control, as previously discussed, should be homogeneous throughout the 24-hour period. If a full dosage of an ACE inhibitor is not well tolerated because of an excessive BP reduction, patients should be investigated to confirm they really are hypertensive and, if this is the case, the presence of a renal artery stenosis should be ruled out. Thus, it is necessary to stress the concept that antihypertensive treatment should be titrated not only considering the extent of BP reduction but also to achieve a constant 24-hour duration of action. This is particularly true for drugs with a non-linear dose-response curve and in the case of combination therapy. These parameters can be obtained by 24-hour ambulatory BP monitoring, or, though less precisely, by repeated (at peak and trough) home BP recordings.[17,19] Why are ACE inhibitors on the market at low dosages? Low dosages were marketed for patients with heart failure, usually having low BP values and receiving concomitant diuretic therapy. Thus, in these patients it is crucial to check whether the administration of the ACE inhibitor is well tolerated, especially in terms of BP reduction. The fact that these drugs do not have a linear dose-response curve makes the use of a low dosage ideal for establishing the tolerability of the treatment.[17] In fact, the BP reduction induced by a low dosage is similar to that induced by a high dosage, but with a shorter duration, which can be useful in the case of excessive hypotension. If the low dosage is well tolerated, it can be progressively increased to reach the full dosage. However, in clinical practice, even in patients with heart failure, ACE inhibitors are underused and underdosed.[26] A contributing factor might be that the summary of product characteristics and the prescribing information documents may sometimes be misleading in terms of dosage adjustments. For instance, according to these documents, the initial dosage recommended in hypertensive patients not on diuretics is 5mg/day for enalapril and 2.5 mg/day for ramipril and the maintenance dosages range between 10 and 40 mg/day for enalapril and 510 mg/day for ramipril, which suggests the drug dosage should be adjusted according to the BP response.[27,28]

Utilization of an ACE inhibitor at a low dosage is a big clinical mistake, not only in terms of evidence-based medicine, but also in terms of the pharmacological properties of these drugs. Moreover, the physician must be very careful to avoid compounds or formulations of ACE inhibitors that do not ensure full coverage of the 24-hour effect.[29] The different ACE inhibitors can be classified according to their duration of action (table I). Of course, compounds characterized by a short duration of action should be administered at least twice daily, while compounds characterized by a long duration of action should always be administered at the standard dosage (e.g. enalapril 20 mg/day).
Table I. Duration of action of ACE inhibitors

Short duration of action Captopril, delapril, quinapril, spirapril Dosing: two or three times daily Long duration of action Enalapril, benazepril, cilazapril, fosinopril, lisinopril, perindopril, ramipril, trandolapril, zofenopril Dosing: once daily A different approach can be used with drugs characterized by a linear dose-response curve. These drugs have a duration of action sufficient to cover 24 hours (because of a prolonged half-life or the availability of slow-release formulations) and dosage increases are associated with a greater BP-lowering effect.[20,21,23] Thus, a low dosage might be appropriate as a starting dosage for calcium channel antagonists (e.g. amlodipine 5mg/day or lercanidipine 10mg/day) or diuretics (e.g. hydrochlorothiazide 12.5mg/day or indapamide 0.625mg/day). The dosage can be increased progressively according to the extent of BP control and, in principle, one might expect that the recommended dosages of these drugs can be exceeded if BP reduction is still insufficient. Unfortunately, this approach is often not possible in clinical practice due to an increase in the incidence of side effects (figure 3).[21,23] Typical examples include ankle edema caused by calcium channel antagonists, electrolyte alterations caused by diuretics, and orthostatic hypotension caused by 1-adrenoceptor antagonists. For example, the dose-response relationship for hydrochlorothiazide is linear between 3 and 25mg/day; higher dosages achieve only minor further BP reductions, while the incidence of hypokalemia continues to increase.[21] In contrast, it is important to observe that the most frequent side effect induced by ACE inhibitors, i.e. cough, is not dose dependent and, therefore, even considering this issue, it is not rational to reduce the dosage to improve tolerability.

Figure 3. Usually the shapes of drug dose-response curves are different for the BP-lowering effect and incidence of side effects. At low doses, side effects are minimal while at high doses the incidence of side effects dramatically increases (typical examples are the ankle edema caused by calcium channel antagonists or the electrolyte alterations caused by diuretics). Whether ARBs present a linear or non-linear dose-response curve has been debated for a long time. This derives largely from a wrong interpretation and design of studies performed during drug development. Indeed, regulatory agencies (e.g. the US FDA and the European Medicines Agency) usually request that dose-finding studies with parallel design be conducted, i.e. using different doses in different patient groups, for regulatory purposes. Results from dose-finding studies suggested that the dose-response curve for some ARBs may be flat; however, it must be taken into account that BP values were measured at the dosing interval (24 hours). Without a further measurement of BP at the peak time, it is not possible to ascertain whether the different BP-lowering effects observed during the 24-hour period are related to a different potency or to a different duration of action (figure 2c). Conversely, dose-titration studies within the same patient groups and studies using 24-hour BP monitoring[30] indicate that the dose-response relationship of ARBs is linear. Therefore, significant improvements in BP control can be achieved by increasing the dosage of the ARB.[25] This finding was confirmed by the fact that the wide majority of ARBs have been further assessed for clinical activity and marketed at increased dosages.

5. Combination Therapy
The basic principles of clinical pharmacology should also be applied to combination therapy.

Combination therapy is needed in the majority of hypertensive patients. Combination therapy may be effective in patients who do not respond to monotherapy, and it is necessary to achieve BP control in 7580%of those with mild to moderate hypertension.[6] Furthermore, physiological and pharmacological synergies justify the greater effectiveness of drug combinations (table II).
Table II. Rational combinations of antihypertensive drugs Drug class First choice Second choice

ACE inhibitors

Diuretics (thiazide or loop) Calcium channel antagonists

1-Adrenoceptor antagonists

AT1 receptor antagonists (angiotensin receptor blockers) Calcium channel antagonists (DHP)

Diuretics (thiazide or loop) ACE inhibitors AT1 receptor antagonists -Adrenoceptor antagonists

1-Adrenoceptor antagonists 1-Adrenoceptor antagonists Central SNS modulators

Calcium channel antagonists (non-DHP)

ACE inhibitors AT1 receptor antagonists

1-Adrenoceptor antagonists

-Adrenoceptor antagonists

Diuretics (thiazide or loop) Calcium channel antagonists (DHP)

1-Adrenoceptor antagonists

Thiazide diuretics

ACE inhibitors AT1 receptor antagonists -Adrenoceptor antagonists

a

1-Adrenoceptor antagonists Central SNS modulators

a Documented negative metabolic effect. AT1 = angiotensin II type 1; DHP= dihydropyridine; SNS= sympathetic nervous system. The 2007 ESH/ESC guidelines[5] recommend the use of two drug combinations as initial treatment in hypertensive patients with a high initial BP or at high/very high CV risk due to the presence of organ damage, diabetes, renal disease, or a history of CV disease. As previously discussed for monotherapy, current guidelines recommend initiating treatment with two-drug combinations at low dosages (figure 1). In many cases this is not pharmacologically correct, particularly considering that most combinations used in clinical practice include drugs blocking the RAAS. These drugs can be used rationally in combination with diuretics or calcium channel antagonists. The combination of a RAAS blocker with a diuretic has been largely prescribed in hypertensive patients because of effectiveness and tolerability, since ACE inhibitors or ARBs prevent the negative effects of diuretics on electrolytes or metabolic profile.[31,32] In addition, there are many fixed combinations that are very convenient to use, and can therefore improve patient compliance. The RAAS blocker should be given at full dosages while the diuretic should be administered at low dosages (e.g. hydrochlorothiazide 12.5 mg/day or indapamide 0.625 mg/day). Problems can arise when using fixed combinations that are not rational according to the drugs' clinical pharmacology. Typical examples are the fixed combinations of ramipril 2.5 mg with hydrochlorothiazide 12.5 mg, or perindopril 2mg with indapamide 0.625 mg. In these cases, the antihypertensive effect is almost totally sustained by the diuretic, while the beneficial effects of the ACE

inhibitors are very modest. It is far more convenient to use fixed combinations combining an ACE inhibitor at full dose (e.g. enalapril 20 mg, lisinopril 20 mg, benazepril 20 mg) with a low dose of diuretic (e.g. hydrochlorothiazide 12.5 mg). It is worth noting that no fixed combination is available with ramipril 10 mg, the dose that should be prescribed more often. In recent years, there has been a great deal of interest around the combination of an ACE inhibitor and a calcium channel antagonist, as a consequence of the important results of the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm)[33] and ACCOMPLISH (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension)[34] trials. These studies have demonstrated that this combination is superior to the combination of a -blocker with a thiazide diuretic and an ACE inhibitor with a thiazide diuretic, respectively. Based on the results of the ACCOMPLISH trial (figure 4), the combination of an ACE inhibitor with a calcium channel antagonist should be considered a first-line treatment in hypertensive patients. It is also important to underline that administration of an ACE inhibitor reduces the principal side effect of calcium channel antagonists, i.e. ankle edema.[35]

Figure 4. Main results from the ACCOMPLISH study. The combination of an ACE inhibitor (benazepril) with a calcium channel antagonist (amlodipine) was more effective (relative risk reduction of 20%) for reducing primary events (composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization) than the combination of an ACE inhibitor (benazepril) with a diuretic (hydrochlorothiazide). Adapted from Jamerson et al [34]. On this basis, in the near future several fixed combinations of RAAS antagonists and calcium channel antagonists will become available.[36] The availability of fixed combinations of ACE inhibitors with calcium channel antagonists rather than with diuretics is crucial, as significant improvements in compliance, and therefore in BP control, can be achieved with the fixed-combination approach.[37] It is important that the expert physician chooses the right formulation. This should be a RAAS blocker at full dose and a calcium channel antagonist at low dose when starting treatment, while a formulation with both drugs at full dose is crucial to reach target BP values.

6. Conclusions

BP normalization is crucial to reduce the CV risk of hypertensive patients. However, while BP reduction is a fairly easy target, BP normalization is much more difficult to achieve. One of the main reasons for the lack of efficacy of pharmacological treatment is that drugs are very often not administered at the correct dosage. This is particularly the case for ACE inhibitors, compounds characterized by a non-linear dose-response curve. A low dose of an ACE inhibitor has the same potency as a high dose but a shorter duration of action. If a low dosage is administered to a hypertensive patient, it causes BP fluctuations, which have been associated with negative CV outcomes. It is therefore important to be aware of the clinical pharmacology of antihypertensive drugs in order to choose not only the class or the molecule best suited to the clinical characteristics of the patient, but also the correct dosages to ensure effective and homogeneous 24-hour BP reduction. A correct pharmacological approach is fundamental to obtain the maximal beneficial effect, i.e. BP normalization and the consequent reduction in CV risk, from antihypertensive treatment.
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Acknowledgments The authors thank Claire Byrne, from inScience Communications (a Wolters Kluwer business), who provided native English language assistance. This assistance was funded by Recordati. Prof. Taddei has received honoraria for serving on the speakers bureau for: Servier International, Boehringer Ingelheim, Menarini, Recordati International, Sanofi-Aventis, and Pfizer. Dr Ghiadoni has received honoraria for serving on the speakers bureau for Recordati and Servier. Dr Bruno has no conflicts of interest that are directly relevant to the content of this review. Am J Cardiovasc Drugs. 2011;11(1):13-20. 2011 Adis Data Information BV