Tailored-treatment approaches for the management of hypertension

Servier International
Suresnes, FRANCE

Tailored-treatment approaches for the management of hypertension

by N. Clavreul, France

When initiating antihypertensive treatment, most hypertension guidelines have the goal of preventing cardiovascular disease. However, treated hypertensive patients, even when controlled, have significant levels of residual cardiovascular risk; in other words, lowering blood pressure per se is not sufficient. As pharmacological classes, and molecules within them, differ significantly from each other, it seems logical to adopt a tailored approach for each patient based on the progression of disease. Perindopril has compelling evidence supporting its initiation early in the diagnosis of hypertension, as its ability to reduce angiotensin II while preserving bradykinin protects patients from the progressive stiffening of large arteries and further alteration of the microcirculation. Bradykinin is involved in the fundamental mechanism of the additive, dose-dependent benefit of angiotensinconverting enzyme inhibitors for both blood pressure reduction and vascular protection. Bradykinin preservation may help explain the difference between renin-angiotensin-aldosterone system blockers in blood pressure reduction and coronary protection. However, many hypertensive patients already have stiffened arteries and substantial rarefaction of the microcirculation when diagnosed. Treatment with a combination of vasodilatory agents, such as thiazide- like diuretic and a calcium channel blocker (CCB), eg, indapamide and amlodipine, decreases wave reflection in the peripheral circulation and lowers systolic blood pressure. As such, CCB/diuretic is effective at decreasing the risk of stroke, a predominant risk in the elderly. A greater understanding of disease progression is essential for proposing the best treatment solutions to hypertensive patients.

Medicographia. 2015;37:440-448 (see French abstract on page 448)

With the exception of a few parts of the world in Africa and eastern Europe, the death rate among adults has declined worldwide over the past few decades.1 High blood pressure remains, however, the major risk factor contributing to death.2 Indeed, a recent survey in England highlighted that despite an improvement since 1994, the rate of blood pressure control according to the current European guidelines threshold (<140/90 mm Hg) barely attains 37% of the putative hypertensive population.3 A first explanation is inertia to treatment initiation, as only 58% of patients receive antihypertensive treatment. But treatment strategy is not always optimal, and two major principles are not considered sufficiently: hypertensive patients’ residual risk and time to blood pressure control. A subanalysis of PRIME (Prospective Epidemiological Study of Myocardial Infarction) revealed that patients receiving antihypertensive medication at baseline, despite having their blood pressure controlled, were still at significantly increased risk of total cardiovascular events (+50%, P<0.001) and cardiovascular death (+62%, P<0.05).4 This study illustrates that treating hypertension is not only about lowering blood pressure figures, but also about doing so in the right way, in a timely manner, and with an appropriate strategy for each patient.

Parameters other than traditional clinic blood pressure may be useful and could be introduced in the decision-making process, in particular arterial stiffness assessment. Assessment of arterial stiffness has been recommended in the European guidelines for the management of hypertension since their 2007 revision, and it is now considered a true surrogate marker.5 Numerous studies have indeed shown that it is independently correlated to cardiovascular events and mortality, mostly through the measurement of pulse wave velocity. As it more precisely characterizes the development of hypertension, it represents an interesting and relevant parameter for a better selection of treatment approach. The availability of a growing number of combination therapies with perindopril, amlodipine, and indapamide, with strong evidence of cardiovascular benefits, will be an opportunity to develop a more scientifically sophisticated, tailored-treatment approach for each patient.

The fundamentals of individualized treatment of hypertension

Hypertension is the result of a process of aging of the cardiovascular system. As such, it should be considered as a progressive disease with multiple steps corresponding to different stages of alteration of blood vessels and organs.

Modifications to the structure of blood vessels are an integral part of the development of high blood pressure. In a simplified model, these modifications can be viewed as essentially occurring at two levels: in large elastic arteries; and in resistance microvascular blood vessels constituting what is often called the microcirculation.6

Large arteries absorb the pulsatility of the blood ejected by the heart, by deforming themselves during systole and restoring the energy during diastole, in order to convert this pulsatility into a steady flow allowing peripheral organ perfusion. These properties rely on elastic fibers, which allow large arteries to distend, and collagen fibers, which act as the structural “backbone” of the artery.7 The pool of elastin is often considered to be established by birth; the process of aging, due to repeated pulsatile constraints, leads to a continuous fragmentation of these proteins, which have a very low rate of replacement. Metalloproteases, which are progressively upregulated, have been identified as important contributors to this phenomenon by degrading matrix proteins.8 Metalloproteases also favor the deposition and accumulation of collagen in the media, which is reorganized as a matrix, and lower its capacity to distort. As a consequence, intima-media thickness increases, with a progressive enlargement of proximal arteries, but not of distal arteries, which are more muscular.

In summary, with age large arteries lose their elastic properties and become stiffer. Risk factors such as obesity, dyslipidemia, or high glucose levels favor systemic inflammation that promotes endothelial dysfunction, through the generation of oxidative stress, and that decreases the bioavailability of the natural vasodilator nitric oxide. In addition to structural modifications, arteries also lose their mechanical capacity to vasodilate. A large number of mechanisms have been proposed to promote arterial wall stiffness, but the renin-angiotensin aldosterone system (RAAS) seems to be particularly involved in this phenomenon.

The first consequence of large artery remodeling and endothelial dysfunction is an increase in the pressure necessary to stretch arteries during systole when blood is ejected into the ascending aorta.6 In addition, this dilatation of the aortic wall generates a pressure wave that moves along the arterial tree.9 The velocity of this pressure wave gives a measurement of arterial compliance, which is now widely recognized as an important independent marker of cardiovascular events and mortality.5 However, with progressive arterial stiffening, pressure waves move down the arteries faster, and this increased pulse wave velocity causes the reflected wave moving back toward the heart to overlap with incident wave during systole. This overlapping contributes to an increase in central systolic blood pressure due to a higher afterload on the ventricle.10

At the other end of the system, capillaries—especially those in the heart, brain, and kidneys—are the main source of blood pressure regulation, as they are responsible for most of the peripheral vascular resistance: about 50% for small arteries and arterioles (>350 μm in lumen diameter) and about 30% for capillaries (>7 μm in lumen diameter). They act as a filter to protect organs from damage by preventing large fluctuations in blood pressure from penetrating the microcirculation too deeply. However, when central blood pressure increases as a result of large artery stiffening, small arteries will undergo remodeling to comply with this increase in order to preserve their function as a protective filter. This remodeling is mostly qualified as eutrophic, with development of a thicker media in an inward direction, meaning blood flow is reduced.11 With time, this leads to wall rupture and microinfarcts due to the weaker structure of the microcirculation, fatigue, and uneven fragmentation of elastin. The consequent thrombosis can block blood flow and cause small vessels to collapse. This is the phenomenon of capillary rarefaction. Based on preclinical models, this phenomenon is considered to start with functional rarefaction—ie, blood vessels do not allow correct blood flow anymore— and lead to structural rarefaction, when actual blood vessels disappear. Both have been observed in hypertensive patients: primarily in the skin, but also in the myocardium.11

The immediate consequence is an increase in peripheral resistance as there are less small vessels to absorb central blood flow, and therefore blood pressure rises. In addition, due to this higher peripheral resistance, reflected waves that return to the heart are greater in amplitude and, as pulse wave velocity is already higher, add to the first systolic peak enhancing pulse pressure.12 Tissue perfusion is eventually reduced causing ischemic events. At the level of the heart, the diastolic blood pressure responsible for myocardial tissue perfusion becomes suboptimal. In addition, large artery stiffness is reinforced by capillary rarefaction of the nutritive blood vessels of the aorta.12

Interestingly, a recent analysis of the Framingham population has proven that development of arterial stiffness could precede the development of true hypertension by years.13 This means that upon diagnosis, vascular modifications have already been occurring and should be considered when initiating treatment. Furthermore, pharmacological strategies, though still effective, seem to have difficulty in lowering residual risk in patients with complicated hypertension. This could be a reflection of the advanced state of arterial modifications and the increased difficulty in reversing them.

These two phenomena illustrate that, beyond blood pressure reduction, therapeutic strategies must address either the stiffness of large arteries to lower pulse wave velocity or enable vasodilation of the capillaries to prevent wave reflection in order to offer full, efficient protection from cardiovascular disease.

Figure 1
Figure 1. Estimated cardiovascular benefits offered with ACE inhibitors and ARBs
in hypertensive patients for a similar systolic/diastolic blood pressure reduction of
10/5 mm Hg.

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CHD, coronary
heart disease; NS, nonsignificant.
Modified from reference 16: Thromopoulos et al. J Hypertens. 2015;33:195-211. © 2015, Wolters
Kluwer Health, Inc.

Pharmacological strategies

Pharmacological classes have been shown in numerous meta-analyses to be different to each other, with differences in specific beyond–blood pressure–lowering effects. Indication may also differ between molecules within a class.14 For instance, angiotensin-converting enzyme (ACE) inhibitors were shown, using meta-regression, to provide protection against coronary events even when not lowering blood pressure.15 Calcium channel blockers, on the other hand, are particularly good at preventing stroke. Another illustration comes from a recent meta-analysis by Thomopoulos et al that reported that for a similar blood pressure reduction of 10/5 mm Hg, ACE inhibitors would reduce coronary events by 35%, stroke by 48%, and heart failure by 53%, while ARBs would only reduce stroke and heart failure by 20% and 25%, respectively (Figure 1).16 This apparent absence of coronary event reduction with ARBs has been the subject of long-lasting debates since 2006,17 when the so-called “MI paradox” was first proposed. Debate about the paradox was recently resuscitated with the presentation of a meta-regression of randomized trials studying RAAS blockers.18 In this analysis, in the absence of any blood pressure reduction, the net effect of ARBs was to increase the rate of coronary events by 13%, while ACE in- hibitors reduced these events by 9% (with the ACE inhibitor perindopril reducing events by 13%). In another meta-analysis in more than 100 000 patients, Savarese et al reported that perindopril did indeed prevent myocardial infarction better than other ACE inhibitors, with a 43% better reduction in the risk compared with ramipril, for instance.19

In a previous meta-analysis of mortality in hypertensive patients, perindopril was shown to significantly reduce all-cause mortality by 13% and cardiovascular mortality by 22%, while the benefit of other ACE inhibitors and ARBs versus comparator was not obvious.20 In fact, in a large registry of more than 15 000 patients, it was demonstrated that newly treated hypertensive patients initiated on perindopril had a 8% lower risk of all-cause mortality and 15% lower risk of cardiovascular mortality compared with lisinopril.21 The rate of hospitalization for diabetes was also lower with perindopril.22 This illustrates that not only do pharmacological classes act differently, yielding different rates of outcomes, but also that within each class, molecules can differ significantly.

Based on the previous description of the development and progression of arterial disease, treatment strategy can be adapted with the objectives of stopping, or even reversing, the progression of large artery stiffness and of lowering wave reflection at the microcirculation level.

Blockade of the RAAS
As previously stated, the RAAS is intrinsically involved in the process of the stiffening of large arteries, as well as in the remodeling and progressive disappearance of small arteries and capillaries (Figure 2). Renin itself has been shown to promote the generation of reactive oxygen species via NADPH oxidase, by binding to the recently identified renin receptor. Nevertheless, angiotensin II is by far the most important mediator of impaired vascular function.23 Binding of angiotensin II to the AT1 receptor is also responsible for increased oxidative stress, promotion of vascular inflammation, and infiltration of monocytes and macrophages through expression of adhesion molecules, a preliminary step in atherosclerosis.24

Inhibition of the RAAS has been shown to improve symptoms of blood vessel stiffness by restoring their distensibility and compliance. In REASON (pREterax in regression of Arterial Stiffness in a contrOlled double-bliNd study), treatment with perindopril/indapamide was better at reducing central pulse pressure than atenolol in 471 patients over a period of 12 months, despite a similar reduction in diastolic blood pressure.25 Arterial stiffness improved significantly, as demonstrated by a reduction in pulse wave velocity and carotid wave reflection. In the Conduit Artery Function Evaluation (CAFE) subanalysis of ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), perindopril/amlodipine was better at reducing central blood pressure over the long term (follow-up of 5.5 years) than atenolol/thiazide, despite a similar reduction in brachial blood pressure with both regimens.26 The prognostic value of reducing pulse wave velocity with perindopril has been demonstrated in patients with end-stage renal disease over a 10-year follow-up. In two groups of patients with similar brachial blood pressure reduction, those whose pulse wave velocity remained persistently high despite treatment were at significantly greater risk of mortality.27

Figure 2
Figure 2. Dual mode of action of the ACE inhibitor perindopril. Bradykinin is preserved
and can exert its vasodilatory and endothelial protective effects. In addition,
conversion of angiotensin I to angiotensin II is inhibited, preventing the deleterious
effects of the binding of angiotensin II to the AT1 and AT2 receptors.

Abbreviations: ACE, angiotensin-converting enzyme; AT, angiotensin [receptor].

In addition, treatment with RAAS blockade has also been shown to improve myocardial capillary density in different models of hypertensive rats. Perindopril promoted new formation of blood vessels, which led to an increase in microcirculatory density and improved muscle perfusion.11 In hypertensive patients, coronary flow reserve has also been shown to improve consistently.

For ARBs, it was recently proposed that their positive effect on arterial stiffness and remodeling due to the reduction in angiotensin II binding to the AT1 receptor was counterbalanced by unopposed stimulation of AT2 receptors. Stimulation of AT2 receptors is associated with cellular growth, hypertrophy, and fibrosis, as well as a proatherogenic and prionflammatory state.17 For instance, in cardiac myocytes, stimulation of the AT2 receptors has been shown to promote cardiac hypertrophy. This pharmacological specificity may help explain the absence of reduction in coronary events associated with the use of ARBs, which was reported in the large meta-analysis that revealed the MI paradox in 2006. Interestingly, in vitro studies have revealed that the benefit of RAAS blockade on vascular stiffness or remodeling requires the presence of endothelial cells.28 This strongly suggests that the principal mode of action of RAAS blockade is the preservation of the bioavailability of nitric oxide, a vasodilating and anti-inflammatory agent. Nitric oxide is massively scavenged by reactive oxygen species, whose production is stimulated by angiotensin II in hypertensive patients. Preservation of nitric oxide allows vascular smooth muscle to relax and prevents the expression of adhesion molecules and penetration of inflammatory cells. At the perivascular level, inhibition of the RAAS translates into lower metalloprotease activity and reduction in collagen deposition. Preclinical models in hypertensive rats have shown that prolonged treatment with perindopril can improve vascular function, by decreasing pulse wave velocity, reducing markers of oxidative stress, and protecting against arterial remodeling.29

Bradykinin, the essential partner in cardiovascular protection
Hypertension is characterized by an imbalance in the homeostasis between angiotensin II and bradykinin, the active mediator of the kallikrein-kinin pathway. Under normal conditions, bradykinin can oppose most of the deleterious vascular effects of angiotensin II: it is a potent vasodilator, but it also has anti-inflammatory and antiatherosclerotic properties that help maintain arterial compliance (Figure 2). In addition, bradykinin promotes the elimination of electrolytes and fluid by the kidney, which lowers cardiac output and enhances blood pressure reduction.24

Bradykinin is synthesized by endothelial cells and is stored as a precursor at their surface, being released upon stimulation. It binds locally to the bradykinin receptor andpromotes the synthesis of the vasodilatory agents nitric oxide and prostacyclin.30 In hypertensive patients, the level of bradykinin has been reported to be abnormally low, and it has been clearly demonstrated that these patients have impaired vascular function, meaning a lack of nitric oxide response, which predisposes them to cardiovascular disease.31

It therefore seems logical to set up strategies that enable the restoration of normal endogenous levels of bradykin and nitric oxide signaling to slow, or even reverse, the process of arterial stiffening. At the moment, there is no specific stimulator of the bradykinin receptor, and the most efficient way to do so is by using ACE inhibitors.30 ACE inhibitors have been shown to enhance bradykinin secretion at lower doses and before any therapeutic effect related to the reduction of angiotensin II occurs. Differences exist between the agents in this class, and Ceconi et al have shown that perindopril has the highest level of affinity for the bradykinin site of ACE compared with other ACE inhibitors.32 In practical terms, for the same reduction in angiotensin II, perindopril will have a greater effect on bradykinin preservation. The highly lipophilic profile of perindopril confers it with the ability to penetrate deeper into tissue, helping it exert this bradykinin-protecting effect.

Figure 3
Figure 3. Schematic representation of the impact of the difference in mode of action
of ACE inhibitors and ARBs on their dose-related efficacy. Inhibition of the angiotensin
II pathway is rapidly saturated at low doses in both cases, limiting the clinical
impact of this mechanism. In addition, ACE inhibitors dose-dependently increase
bioavailable bradykinin, the predominant mechanism of blood pressure reduction
and cardiovascular protection of this class at high dosage.

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; RAS, reninangiotensin

The EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease) trial is considered a good illustration of the pleiotropic effects of perindopril on blood vessels, especially endothelial function.33 Because blood pressure decreased only marginally in this population with coronary artery disease, the significant 20% reduction in cardiovascular morbidity and mortality must be explained by other factors, bradykinin being one of the first. In PERTINENT (PERindopril-Thrombosis InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial), one year of treatment with perindopril 10 mg in patients with coronary artery disease significantly increased the level of bradykinin compared with placebo (+17%; P<0.05), with a direct enhancement of the nitric oxide pathway since the activity of endothelial nitric oxide synthase was upregulated versus placebo (+27%; P<0.05).34 In contrast, other ACE inhibitors failed to demonstrate the same vasculoprotective effect in large randomized trials: quinapril in QUIET (QUinapril Ischemic Event Trial) and trandolapril in PEACE (Prevention of Events with Angiotensin Converting Enzyme inhibition) both failed to reach their primary end point in a similar population.35,36 Preclinical studies confirmed that perindopril had the ability to protect endothelial cells of normotensive rats from apoptosis, while quinapril and trandolapril had no significant effect. As previously mentioned, a recent study in a large population of more than 15 000 patients also reported that newly diagnosed hypertensive patients initiated on perindopril rather than lisinopril had a significantly lower rate of all-cause mortality (–8%) and cardiovascular mortality (-15%) over a mean follow-up of 15 years.21

Another important aspect of bradykinin signaling is its pharmacologic response to ACE inhibitors, especially perindopril. Preclinical studies examining the effect of dose escalation with perindopril on both angiotensin II and bradykinin bioavailability in plasma revealed that upon administration of the ACE inhibitor, angiotensin II would rapidly decrease and become almost undetectable even with low dosages. Meanwhile, the concentration of bradykinin would gradually increase with higher dosages of perindopril, with no apparent plateau being reached at pharmacological dosages.37 This dose-dependent effect of perindopril on plasma bradykinin was further confirmed in healthy volunteers, where a single-dose administration of perindopril rapidly increased concentrations of this peptide in a linear, dose-dependent manner up to 20 mg. Plasma generation of angiotensin II was inhibited by 80% with the lowest dose of 2.5 mg of perindopril.38

From a mechanistic perspective, this sounds a rational explanation for the potentially greater effect on blood pressure reduction and blood vessel protection with ACE inhibitors compared with ARBs. Although both ACE inhibitors and ARBs down regulate angiotensin II signaling, only ACE inhibitors dosedependently preserve bradykinin, a mechanism that becomes predominant at higher dosages and seems to be responsible for most of the cardioprotective effect of this class (Figure 3). Therefore, early administration of an ACE inhibitor with high selectivity for the bradykinin degradation site of angiotensin- converting enzyme is a prerequisite for obtaining the full benefits. Perindopril is an example of a RAAS blocker that at high dosage lowers blood pressure better than other RAAS blockers and of an effective cardioprotective agent, thanks to its antiremodeling properties (Figure 4).

Vasodilation of small arteries: when stroke matters…
As previously described, hypertension is essentially the result of the aging process, and its diagnosis can happen at any stage of development of the disease. In developing countries, high blood pressure remains critically underdiagnosed, and early treatment with a vasculoprotective ACE inhibitor is not always possible.

Figure 4
Figure 4. Schematic representation of perindopril-based strategies according to the stage of hypertension. In young hypertensives, perindopril (combined with amlodipine or indapamide when needed) will prevent early arterial remodeling and further consequences of arterial stiffness and raised central blood pressure at the capillary level. In aging hypertensive patients, for whom the risk of stroke is key, combination indapamide and
amlodipine actively reduces wave reflection via peripheral vasodilation and is the most efficient strategy at reducing systolic blood pressure.

Abbreviations: BP, blood pressure; PWV, pulse wave velocity.

When large arteries have stiffened to a high degree and a substantial proportion of the microcirculation has started to collapse, systolic blood pressure becomes critically high due to the joint effect of earlier wave return and increased wave reflection at the capillary level.10 Patients are therefore exposed to a particularly high risk of stroke, whose rate is linearly dependent on systolic blood pressure and which dramatically increases with age.39 For these patients, the most urgent step is to rapidly lower systolic blood pressure and because large arteries lack compliance, the best way to do this might be to promote vasodilation at the capillary level. This immediate- ly lowers the amount of wave reflection (Figure 4). Diuretics and calcium channel blockers are both powerful peripheral vasodilators. In these two classes of antihypertensive agents, indapamide and amlodipine have been shown to be among the most effective agents at lowering systolic blood pressure,40 and the recent EFFICIENT (EFfects of a FIxed Combination of Indapamide sustained-release with amlodipine on blood prEssure iN hyperTension) study confirmed the potency of the combination of indapamide and amlodipine for lowering systolic blood pressure and pulse pressure.41 A recent meta-analysis by the group of Messerli recently reported that combining these two classes proved to be systematically more efficient at reducing stroke in large randomized trials than other strategies (-23%).42

Combining indapamide and/or amlodipine with perindopril has also been demonstrated in large trials to reduce stroke and mortality. In HYVET (HYpertension in the Very Elderly Trial), elderly patients receiving the combination of perindopril/ indapamide experienced a significant 39% reduction in death from stroke (P=0.046), as well as a 21% reduction in all-cause death (P=0.02).43 In high-risk patients, the recent subanalysis of ADVANCE (Action in Diabetes and Vascular disease: Preter- Ax and DiamicroN MR Controlled Evaluation) revealed that the relative risk of all-cause mortality fell by 28% in patients on calcium channel blocker at baseline who received combination perindopril/indapamide in addition, a new piece of evidence in the era of multiple combinations, as underlined in an editorial by Prof Barkris.44,45

The earlier, the better
The recent publication of ADVANCE-ON (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation–ObservatioNal study), the follow-up study over ten years of the ADVANCE trial that compared the perindopril/ indapamide combination to standard treatment in diabetic patients, reported long-term preservation of the benefits provided by ACE inhibitor–based treatment.46 Indeed, while patients in both arms became rapidly equally treated, reaching the same blood pressure level, after the end of the randomized phase of the trial (4.5 years), a significant 9% reduction in all-cause mortality remained after 10 years in patients who received perindopril/indapamide at baseline versus standard therapy. These new results in particular highlight the long-term benefits of the well-known properties of perindopril on blood vessels, ie, protection of endothelial cells from apoptosis, preservation of the microcirculation at the organ level, and reversal of wall stiffness in large arteries. This example is a perfect illustration that starting with the right treatment early gives patients greater benefits in the future because the ability to reverse vascular remodeling is greater at a younger age.

Figure 5
Figure 5. Benefit of faster blood pressure control. Epidemiological data have demonstrated that 23% faster blood pressure control after
6 months (A) yielded a 34% lower risk of cardiovascular events (B). In a large population, the new combination of perindopril/amlodipine for first-line administration (3.5/2.5 mg and then 7/5 mg) was 27% faster at controlling blood pressure within 2 months compared to a
valsartan/amlodipine stepped-care strategy, and therefore had the protective benefits expected (C).
Abbreviation: CV, cardiovascular.

Modified from reference 49: Gradman et al. Hypertension. 2013;61:309-318. © 2013, American Heart Association, Inc.

Time to blood pressure control is an important aspect of treatment success as well. A recent retrospective analysis of 1762 patients who received initial antihypertensive treatment confirmed that those who had received a combination from the beginning had a better rate of blood pressure control over the one-year follow-up period (median time to achieve blood pressure control of 9.7 versus 11.9 months; P=0.004) and had a 34% lower risk of cardiovascular events (Figure 5).49 ACE inhibitors, even though a gold standard treatment for initiation of antihypertensive therapy for the reasons developed above, may need to be combined from the beginning to achieve this goal. A recent study comparing a new strategy for newly diagnosed hypertensive patients based on a combination of perindopril 3.5 mg and amlodipine 2.5 mg, which was then uptitrated by systematically doubling doses, was superior to a stepped-care strategy based on valsartan and amlodipine. In fact, the rate of blood pressure control was 23% and 27% higher in the perindopril/amlodipine group after 1 and 2 months of treatment, respectively.50

Together with the ADVANCE-ON study, this suggests that optimized combination treatment with perindopril will shift the odds in favor of patients, both by achieving blood pressure control earlier and by preserving the vascular structure of patients from further remodeling. An important feature of ACE inhibitors that allows their easy first-line administration is their excellent tolerability and the absence of dose-related adverse effects. With ARBs, individual trials as well as meta-analyses have reported a significant increase in the risk of kidney injury (+48%; P<0.001), hyperkalemia (+57%; P=0.008), and hypotension (+56%; P<0.001); the last of these is probably related to their mode of action, which is completely dependent on the abrupt blockade of the angiotensin pathway.51


Compelling evidence now supports the need to address the residual risk of hypertensive patients as much as their elevated blood pressure. An approach based on a thorough understanding of the pathophysiological development of the disease seems justified to maximize the potential of each pharmacological treatment. The cardiovascular protective properties of perindopril have been well demonstrated. Its early initiation in hypertensive patients allows a more efficient counteraction of the progressive remodeling of large arteries and, therefore, prevention of further alterations to the microcirculation, especially at the coronary level. Combining perindopril with amlodipine right from initiation in newly diagnosed hypertensive patients allows even faster blood pressure control. In patients with advanced vascular stiffness and capillary rarefaction, like the elderly for instance, the combination of indapamide and amlodipine allows the risk of stroke to be reduced by decreasing wave reflection, which lowers systolic blood pressure.

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Keywords: bradykinin; RAAS blockade; vasodilation; early treatment; perindopril; indapamide; amlodipine