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Giuseppe MANCIA, MD, PhD

Guido GRASSI, MD
Clinica Medica
Ospedale S Gerardo
Via Pergolesi 33
20052 Monza (Milano)
ITALY

The 2007 guidelines document on the diagnosis and management of hypertension, jointly issued by the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC),¹ and the recently published update paper² make a number of statements and recommendations on how to handle essential hypertension in current clinical practice. Along with these recommendations, the two documents also provide an overview of the priorities for hypertension research as well as on the perspectives of hypertension treatment in the next few years, based on the evidence available from clinical trials and metaanalyses. There are four areas of major clinical impact: (i) the assessment of global cardiovascular risk; (ii) blood pressure thresholds and targets for treatment; (iii) the need for combination drug treatment; and (iv) the so-called polypill issue. These four major areas contain novel elements, but also elements of controversy. Both will be addressed in a concise way by this editorial.

Novel elements

The 2007 guidelines paper and the 2009 update document, even more so, recognize the crucial importance of the assessment of total cardiovascular risk in the management of hypertension and, more specifically, in the decision-making process for treatment initiation.^1,2 This differentiates European guidelines from American ones,³ which still mainly appear focused on blood pressure values rather than on global risk. In particular, the guidelines update document published a few months ago makes a number of recommendations that can be summarized as follows.

First, quantification of total cardiovascular risk must include a search for subclinical organ damage, which is common in the clinical course of the hypertensive state and retains independent prognostic significance. Second, in hypertension the detection of organ damage brings cardiovascular risk into the high range independently of the severity of blood pressure elevation. Third, several measures of renal, cardiac, and vascular damage can be taken into account for total cardiovascular risk quantification. Measures based on urinary protein excretion (including microalbuminuria) and electrocardiograms can be regarded, nevertheless, as more simple and widely available approaches. In addition, these measures are characterized by limited cost and satisfactory sensitivity.

Several other novel elements provided by the 2007 ESH/ESC guidelines and by the 2009 update on the assessment of organ damage and, more generally, on the evaluation of total cardiovascular risk deserve to be mentioned.^1,2 Both the documents recommend organ damage to be searched for in different organs because of the evidence that multiple organ damage (eg, in the kidney and the heart) carries a worse prognosis than damage limited to a single organ. They also recommend organ damage be assessed before and during treatment because data are now available that show that treatment-induced improvement of left ventricular hypertrophy (regression) and decreased urinary protein excretion (antiproteinuric effect) is associated with a reduced incidence of cardiovascular events.

Finally, they critically review the issue of markers of organ damage, which, although not yet recommended in clinical practice, may become of practical use in the not-too-far-distant future, such as pulse wave velocity, central blood pressure, endothelial dysfunction, cardiac and vascular tissue composition, and collagen markers. For some of these markers, it will also be possible to predict in the near future their use as indices of effectiveness of antihypertensive treatment. This is particularly the case for central blood pressure, given the evidence provided by the Conduit Artery Function Evaluation (CAFE) study that the combination amlodipine/perindoprilmay trigger more favorable effects on central aortic pressure than a β-blocker/diuretic association.⁴ This finding may thus represent the pathophysiological background for the evidence provided by the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) that an amlodipine/perindopril combination has a better impact on cardiovascular outcomes than a β-blocker/ diuretic association.⁵

Other areas of considerable interest are represented by blood pressure thresholds and treatment goals. Guidelines recommend starting drug treatment in grade 1 hypertensive patients at low or moderate risk when blood pressure is equal to or above 140/90 mm Hg after lifestyle modifications. These thresholds are similar in elderly hypertensives, based on the results of the HYpertension in the Very Elderly Trial (HYVET).⁶ Prompter treatment is recommended in grade 2 and 3 hypertension. In patients with high-normal blood pressure (a condition also known by the term “prehypertension”), drug treatment should be delayed when the overall cardiovascular risk is low.

As far as goals of treatment are concerned, the 2009 update document recommends that systolic blood pressure should be lowered below 140 mm Hg (and diastolic to 90 mm Hg) in all hypertensive patients, irrespective of their grade of risk.² On the basis of the results of recent clinical studies,^7-12 it appears prudent to lower blood pressure to values within the 130-139 mm Hg range for systolic and 80-85 mm Hg range for diastolic blood pressure. It thus appears that the concept of pursuing lower blood pressure goals in diabetics or veryhigh- risk patients is not recommended any more. This is because there is no evidence from trials of a greater benefit being derived from tight blood pressure control, nor can this procedure be regarded as easily achievable in current clinical practice. Lastly, the update document underlines the so-called “J-curve phenomenon” (ie, an increase rather than a reduction in the incidence of coronary events when blood pressure values are below 120-125 mm Hg for systolic and 70-75 mm Hg for diastolic blood pressure),^13,14 suggesting that blood pressure should not be lowered too much, particularly in patients with a history of a previous coronary event.

Two further questions addressed by the ESH/ESC 2007guidelines and by the 2009 update document^1,2 are: (i) whether treatment of individuals at high or very high risk differs from that of lower risk ones only as regards the blood pressure threshold and target values for treatment; and (ii) whether similar treatment recommendations pertain to individuals in whom elevated cardiovascular risk is due to conditions other than diabetes or a history of cardiovascular or renal disease.

The former question has a clear answer because evidence exists that additional treatment peculiarities distinguish highor very-high-risk individuals from lower-risk ones. For example, in high- and very-high-risk individuals, treatment with a combination of two or more antihypertensive drugs is almost always necessary, given that the size of blood pressure reduction to achieve is greater and that the chance of obtaining it with monotherapy is small. Also, starting treatment with a two-drug antihypertensive combination is advisable because delaying blood pressure control, even by a few months, may lead to an event. Finally, evidence exists that high- or veryhigh- risk hypertensive patients may obtain additional benefit by the addition of an antiplatelet treatment and a statin to an effective antihypertensive drug regimen, the latter independently of whether serum cholesterol values are elevated or not.^1,2

The last consideration brings us to the third area of innovation in the guidelines update document,² namely the crucial role of combination drug treatment in achieving effective blood pressure control. Indeed, as already mentioned in the 2007 ESH/ESC guidelines,¹ combination drug treatment is the only approach that allows effective blood pressure control to be achieved in current clinical practice. The 2009 guidelines update document² recommends this treatment strategy, which may also offer advantages over monotherapy for treatment initiation, particularly, asmentioned above, in high-risk patients in whom early blood pressure control is indicated. Fixed-drug combinations are indicated, with the possibility of making a choice based on a wide range of two-drug combinations that include an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker with a diuretic, a β-blocker, or a calcium channel blocker. An ACE inhibitor/calcium channel blocker combination, as shown by the results of the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial,¹⁵ may be particularly effective and well tolerated, although further data on the effects of this combination need to be collected. Further data is also needed for the combination between angiotensin II receptor blockers and calcium antagonists, for which at present no outcome data have been provided.

Given the potential dysmetabolic effects of a diuretic/β-blocker combination, this therapeutic strategy should be avoided, but single components of the association can be safely combined to the other drug classes (particularly those acting on the renin-angiotensin system). The same conclusion applies to the combination of an ACE inhibitor and an angiotensin II receptor blocker, in the light of the negative data collected in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), particularly its unfavorable effects on renal function.¹²

In conclusion, the guidelines update document discusses the potential advantages of the polypill (ie, a pill containing three antihypertensive agents—an ACE inhibitor, a β-blocker, and a diuretic—together with a statin and aspirin at low dose).16 Although promising, the polypill approach requires further evaluation, particularly in the primary prevention of cardiovascular disease.

Elements of controversy

Although providing conclusive answers to a number of questions raised following the publication of recent clinical trials and meta-analyses, the 2009 guidelines update document also focuses on a number of issues that still remain unresolved.2 This is the case, for example, for the implementation of the clinical use of alternative blood pressure measurements, such as 24-hour ambulatory blood pressure or home blood pressure. This is also the case for the future clinical use of “new” markers of organ damage and for the therapeutic approach to specific clinical states, such as high-normal blood pressure ormild hypertension, ie, conditions in which no clearcut data based on the results of clinical trials have been provided so far. Due to the lack of ad hoc clinical studies, it is also difficult to know whether antihypertensive treatment needs to be started in patients with grade 1 hypertension, even if they are at low risk. These unresolved issues may explain why the agenda for future clinical investigations in the field of hypertension still remains crowded. _

References
1. Mancia G, De Backer G, Dominiczak A, et al. Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105-1187.
2. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121-2158.
3. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003; 42:1206-1252.
4. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressurelowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006; 113:1213-1225.
5. Poulter NR,Wedel H, Dahlöf B, et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet. 2005;366:907-913.
6. Beckett NS, Peters R, Fletcher AE, et al; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358: 1887-1898.
7. Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet. 2004;363:2049-2051.
8. Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med. 2006;144:884-893.
9. Pohl MA, Blumenthal S, Cordonnier DJ, et al. Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the Irbesartan Diabetic Nephropathy Trial: clinical implications and limitations. J Am Soc Nephrol. 2005;16:3027-3037.
10. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:1755-1762.
11. de Galan BE, Perkovic V, Ninomiya T, et al.; ADVANCE Collaborative Group. Lowering blood pressure reduces renal events in type 2 diabetes. J Am Soc Nephrol. 2009;20:883-892.
12. Yusuf S, Teo KK, Pogue J, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358: 1547-1559.
13. Bangalore S, Messerli FH,Wun C, et al. Treating to New Targets Steering Committee and Investigators. J-Curve revisited: an analysis of the Treating to New Targets (TNT) Trial. J Am Coll Cardiol. 2009;53:A217.
14. Boutitie F, Gueyffier F, Pocock S, Fagard R, Boissel JP. J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data. Ann Intern Med. 2002;136:438-448.
15. Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in highrisk patients. N Engl J Med. 2008;359:2417-2428.
16. Yusuf S, Pais P, Afzal R, et al; Indian Polycap Study (TIPS). Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet. 2009;373: 1341.

Le document des directives 2007 sur le diagnostic et la prise en charge de l’hypertension, publié conjointement par la Société européenne de l’hypertension (European Society of Hypertension, ESH) et la Société européenne de cardiologie (European Society of Cardiology, ESC)¹, ainsi que la mise à jour récemment publiée² formulent un certain nombre de déclarations et de recommandations sur la manière de prendre en charge l’hypertension essentielle dans la pratique clinique actuelle. Parallèlement à ces recommandations, les deux documents fournissent également un aperçu des priorités de recherche dans l’hypertension, ainsi que des perspectives pour le traitement de l’hypertension au cours des prochaines années, sur la base des preuves recueillies au cours des études cliniques et des méta-analyses. Quatre domaines sont susceptibles d’avoir un impact clinique majeur : (1) l’évaluation du risque cardio-vasculaire global ; (2) les valeurs seuils de pression artérielle et les valeurs cibles pour le traitement ; (3) la nécessité d’un traitement médicamenteux d’association ; et (4) le problème de la soi-disante polypilule. Ces quatre domaines principaux contiennent des données nouvelles, mais également des éléments de controverse. Ces deux aspects seront abordés de façon concise dans cet éditorial.

Enfin, ces documents examinent de façon critique le problème des marqueurs des lésions organiques, qui, bien qu’ils ne soient pas encore recommandés en pratique clinique pourraient faire leur apparition en pratique dans un futur relativement proche, par exemple, la vitesse de l’onde de pouls, la pression artérielle centrale, le dysfonctionnement endothélial, la composition des tissus cardiaques et vasculaires et les marqueurs du collagène. Pour certains de ces marqueurs, il sera également possible de prédire dans un proche avenir leur utilisation comme indice de l’efficacité du traitement antihypertenseur. Cela est particulièrement le cas pour la pression artérielle centrale, compte tenu des preuves apportées par l’étude CAFE (Conduit Artery Function Evaluation), qui a démontré que l’association de l’amlodipine et du périndopril pouvait entraîner des effets plus favorables sur la pression aortique centrale que l’association d’un bêtabloquant et d’un diurétique⁴. Ce résultat peut par conséquent constituer le pendant physiopathologique des preuves fournies par l’étude ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), qui a conclu que l’association de l’amlodipine et du périndopril exerçait un meilleur impact sur les critères d’évaluation cardio-vasculaires que l’association d’un bêtabloquant et d’un diurétique⁵.

Les autres domaines suscitant un intérêt considérable sont constitués par les valeurs seuils de pression artérielle et les objectifs thérapeutiques. Les directives recommandent de mettre en oeuvre un traitement initial chez les patients atteints d’hypertension de grade 1 présentant un risque faible à modéré lorsque la pression artérielle est supérieure ou égale à 140/90 mm Hg après des modifications du style de vie. Ces valeurs seuils sont similaires chez les patients âgés hypertendus, sur la base des résultats de l’étude HYVET (HYpertension in the Very Elderly Trial)⁶. Un traitement plus rapide est recommandé en cas d’hypertension de grades 2 et 3. Chez les patients dont la pression artérielle est à la limite supérieure des valeurs normales (une situation également désignée par le terme de « préhypertension »), le traitementmédicamenteux doit être retardé lorsque le risque cardio-vasculaire global est faible.

Le dernier point nous amène à aborder le troisième domaine d’innovation traité dans le document de mise à jour des directives², c’est-à-dire le rôle crucial du traitement d’association dans le contrôle efficace de la pression artérielle. En fait, comme cela a déjà été mentionné dans les directives 2007 de l’ESH/ESC¹, le traitement d’association est la seule approche qui permet un contrôle efficace de la pression artérielle en pratique clinique. Le document de mise à jour des directives 2009² recommande cette stratégie thérapeutique, qui peut également offrir des avantages par rapport à unemonothérapie, en particulier, comme cela a été mentionné ci-dessus, pour les patients à haut risque chez lesquels un contrôle rapide de la pression artérielle est conseillé. Les associations fixes sont indiquées, avec la possibilité de choisir dans une vaste offre d’associations de deux médicaments comprenant un inhibiteur de l’enzyme de conversion de l’angiotensine (ECA) ou un antagoniste des récepteurs de l’angiotensine II avec un diurétique, un bêtabloquant ou un inhibiteur calcique. L’association d’un inhibiteur de l’ECA et d’un inhibiteur calcique, comme le montrent les résultats de l’étude ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension)¹⁵, s’avère particulièrement efficace et bien tolérée, bien que des données complémentaires sur les effets de cette association doivent encore être collectées. Des résultats additionnels sont également nécessaires sur l’association des antagonistes des récepteurs de l’angiotensine II et des inhibiteurs calciques, pour laquelle aucune évaluation n’a été fournie jusqu’à présent.

Compte tenu des effets dysmétaboliques éventuels de l’association d’un diurétique et d’un bêtabloquant, cette stratégie thérapeutique doit être évitée, mais les composants individuels de l’association peuvent être ajoutés sans risque à d’autres classes pharmacothérapeutiques (en particulier celles agissant sur le système rénine-angiotensine). La même conclusion peut être formulée pour l’association d’un inhibiteur de l’ECA et d’un antagoniste des récepteurs de l’angiotensine II, à la lumière des données négatives collectées au cours de l’étude ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), concernant en particulier ses effets défavorables sur la fonction rénale¹².

Bien qu’il apporte des réponses concluantes à un certain nombre de questions soulevées à la suite de la publication de récentes études cliniques et méta-analyses, le document de mise à jour des directives de 2009 souligne également différents problèmes restés sans réponse². C’est le cas, par exemple, de l’utilisation clinique de mesures alternatives de la pression artérielle, notamment la pression artérielle ambulatoire sur 24 heures ou l’automesure de la pression artérielle à domicile. C’est également le cas de la future utilisation clinique des « nouveaux » marqueurs des lésions organiques, et de l’approche thérapeutique appliquée à des situations cliniques spécifiques, par exemple une pression artérielle à la limite supérieure de la normale ou une légère hypertension, c’est-à-dire des situations dans lesquelles aucune donnée seuil déterminée sur la base de résultats d’études cliniques n’a été fournie jusqu’à présent. Compte tenu de l’absence d’études cliniques ad hoc, il est également difficile de savoir si un traitement antihypertenseur doit être mis en oeuvre chez des patients présentant une hypertension de grade 1, même s’ils sont exposés à des risques faibles. Ces problèmes non résolus peuvent expliquer pourquoi le programme des futures investigations cliniques dans le domaine de l’hypertension reste particulièrement chargé. _

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Neil POULTER
MB, MSc, FRCP, FMedSci
International Centre for
Circulatory Health
Imperial College London
London, UK

by N. Poulter, United Kingdom

National and international surveys are consistent in showing that the management of hypertension is suboptimal, with a minority of hypertension patients getting their blood pressures (BPs) controlled to currently recommended targets. Raised BP is currently the biggest single contributor to global death, and the prevalence of hypertension is expected to increase over the next 2 decades. It is therefore critical to improve the management of raised BP, so that the dreadful toll on global health caused by raised BP is reduced. The reasons for the poor BP control observed around the world are multiple and various, but include inadequate use of antihypertensive agents as a result of physician inertia, drug side effects and drug costs, which adversely affect adherence to therapy, and drug resistance. Every year in England, a nationally representative survey of various aspects of health of the noninstitutionalized population takes place. Intermittently—approximately every 4 years—the focus of investigation is cardiovascular (CV) disease, which includes a systematical evaluation of BP. This database provides an invaluable source of data about mean BP levels, the prevalence of hypertension, and how BP is managed in the English adult population. In the most recent CV focus year, 2006, results showed that raised BP was being managed more effectively than in previous years (1994, 1998, and 2003), with higher rates of awareness, treatment, and control. Taking these 4 surveys into account, the key explanation for improving BP management appears to be raised levels of education among doctors and patients, which leads to raised levels of awareness, treatment, and the use of dietary measures. In addition, among those treated with drugs, more antihypertensive agents are being used to greater effect.

Raised blood pressure (BP) is currently the biggest single contributing risk factor to global death.¹ Furthermore, it is estimated that the prevalence of hypertension will increase over the next two decades.² These anticipated changes reflect two critical facts. Firstly, the world’s population is getting older, and hypertension is usually an age-related condition. Secondly, the majority of the world is in a stage of ecological transition, whereby there is increased exposure to the adverse environmental conditions that are associated with adverse cardiovascular (CV) risk, ie, “development.” These apparently “inevitable” features of “development” include increased intake of fat, calories, salt, and alcohol, increased smoking, reduced intake of fresh fruit and vegetables, and reduced physical activity. Almost all of these changes are associated with raised BP. Despite our increasing knowledge of the pathophysiology of CV diseases and the major risk factors for these disorders, such as hypertension, we face a major increase in the prevalence of hypertension, which currently generates more deaths than any other risk factor, due to the adverse effects of the process of development.

It is therefore critical that major efforts are devised for trying to prevent the currently anticipated increases in the prevalence of hypertension and that improvements in the treatment for those with hypertension are made.

It is apparent from national and international survey data from all over the world that the management of hypertension is suboptimal.³ Although there are clear variations by age, sex, and geography in the proportion of patients with hypertension who get their BPs controlled to current targets, overall a minority of patients are controlled to what is currently considered optimal. The reasons for this are multiple and vary from patient to patient, but explanations include inadequate drugs, drug side effects, poor adherence to therapy, drug costs, confusing guidelines, resistant hypertension, and physician inertia. Physicians favor all except the last of these reasons as plausible, but in reality the failure of physicians to act on currently available knowledge with currently available drugs is undoubtedly a major contributor to the suboptimal hypertension management that prevails worldwide.

This article reviews how BP treatment may be improved in terms of achieving better BP control based on evidence from the latest in the series of annual national surveys carried out in England (the Health Survey for England).

Health Survey for England: methods

The Health Survey for England (HSE) is an annual, nationally representative sample of the noninstitutionalized population of all ages randomly selected from residential addresses in England. The primary focus of the survey varies from year to year, but in 1994, 1998, 2003, and 2006, the focus was on CV disease. The detailed sampling and data collection methods have been described elsewhere.⁴

Data collection took place throughout the year and was essentially the same in all the CV focus years. It involved an interview, which was followed by a visit by a nurse, who measured BP, took a blood sample, and recorded the use of medicines. Sitting BP readings were taken on the right arm after 5 minutes of rest using an Omron HEM 907 and an appropriately sized cuff. BP data presented here are based on the means of the last 2 of 3 measurement. Participants were excluded if they had exercised, eaten, drunk alcohol, or smoked in the 30 minutes before BP measurement. The interviewers collected sociodemographic information, including self-assigned ethnicity, and participants were asked if they had been told by a doctor or a nurse that they had high BP. Information about diabetes mellitus and history of CV disease (angina, heart attack, or stroke) was also collected. Research ethics approval was obtained from the appropriate committees before each survey. Hypertension was defined as systolic blood pressure (SBP) ≥140 mm Hg, diastolic blood pressure (DBP) ≥90 mm Hg, or being on treatment for blood pressure. Isolated systolic hypertension was defined as follows: stage 1 was defined as an SBP of 140 to 159 mm Hg and DBP <90 mm Hg; and stage 2 was defined as SBP ≥160 mm Hg and DBP <90 mm Hg. Details of antihypertensive agents being taken, if any, were recorded by the nurse. Respondents who were not sure whether an antihypertensive drug had been prescribed to treat hypertension were considered a treated hypertensive individual if they also reported a history of hypertension. We examined the use of antihypertensive drugs by class and compared this with the current British guidelines by age and ethnicity. Analyses were restricted to participants aged ≥16 years with no missing data. Samples were weighted to allow for nonresponse differences both to the interview and then to the nurse visit. We computed awareness, treatment, and control rates among hypertensive men and women from HSE 2006 and compared these with data from previous years. Awareness was defined as a self-report of having been diagnosed as hypertensive by a doctor or nurse (excluding women during pregnancy). For control rates, we considered blood pressure target levels: <140/90 mm Hg (the target recommended in most hypertension guidelines).

Results

In 2006, 10 489 adults aged ≥16 years were interviewed and had a nurse visit. Of these, 7478 had valid blood pressure readings (3314 men and 4164 women) with a mean age of 47 years in both sexes. The full results relating to BP and hypertension of the 2006 survey have been published previously.⁵ Mean SBP rose across the whole age range in both men and women, but was higher in men than women until the age of 70 years (Figure 1). DBPs also rose with age in both sexes, but only until the age of 60 years, above which blood pressures fell systematically. DBPs were generally, but not always, higher in men than women. Overall mean BP levels were 130.8/ 74.2 mm Hg in men and 124.0/72.4 mm Hg in women. Hypertension rates increased with age in both sexes and were more prevalent in men than women, except in the age range 70 to 79 years.

Figure 1. Mean systolic (A) and diastolic (B) blood pressures by age in 2003 and 2006 for men and women.

Table I. Awareness, treatment, and control among those with
hypertension (≥140/90 mm Hg or on medication) in HSE 2003
and HSE 2006.

Overall, hypertension was observed in 30% of informants (32% of men and 29% of women), and in those aged ≥30 years, almost half of this hypertension (16% of men and 12% of women) was stage 1 isolated systolic hypertension. Mean BP levels and prevalences of hypertension in 2006 compared favorably with those reported in 2003 when mean blood pressures were 131.4/74.5mmHg inmen and 125.7/73.3mmHg in women, and overall hypertension rates were 33%and 30%, respectively.

In 2006, two thirds of those classified as hypertensive were aware of their diagnosis, awareness being more common among women than men in all age groups (Table I; and Figure 2, page 230). Among the hypertensive population, more than 60% of women, but fewer than half of the men were on treatment for hypertension. Similarly, control rates to <140/90 mm Hg were higher overall among women than men, with approximately one third and one quarter, respectively, having controlled BP levels.

In 2006, of those on treatment for hypertension, 52% of informants (52%of men and 53%of women) had controlled BP (Table II, page 230). This compared with 46% (48% and 44%, respectively) for the equivalent populations in 2003. Similarly, the rates of awareness, treatment, and control observed in 2006 were all consistently greater than the equivalent figure reported in 2003, particularly among women.

Figure 2. Prevalence of awareness, treatment, and control of hypertension (≥140 mm Hg or on medication) in 2003 and 2006 for men (A) and women (B).

Table II. Management of hypertension among those with past history
of angina, heart attack, or stroke; diabetes mellitus; and CVD
risk ≥20%.

About three quarters of patients with a self-reported history of CV or diabetes mellitus or an estimated 10-year risk of CV disease of ≥20% were hypertensive (Table II). Of those hypertensive patients who had CV disease or diabetes mellitus, about 85% were treated and about 44% had their BPs controlled to <140/90 mm Hg. However, for those hypertensives who did not have coronary heart disease or stroke, but whose estimated CV risk was ≥20%, only 55% were treated and 17% controlled. These rates are all greater than the equivalent figures in 2003. More than 60% of patients on treatment for hypertension were receiving ≥2 antihypertensive drugs (Table III), which compares with 56% in 2003. For those receiving monotherapy, the most common agents used were blockers of the renin-angiotensin system (RAS), either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers. Overall, diuretics, β-blockers, and calciumchannel blockers (CCBs) were the second, third, and fourth most commonly used agents, with similar levels of usage. However, this order changed when stratified by age and ethnicity (data not shown): β-blockers were clearly the second most commonly used agents for those <55 years of age, but diuretics and CCBs were more frequently used than β-blockers among older patients or those of African origin (data not shown). The most common combination of drugs among those taking 2 agents was a RAS blocker plus a diuretic, with a diuretic plus a CCB, a RAS blocker plus a β-blocker, and a RAS blocker plus a CCB having similar but lower levels of usage than a RAS blocker plus a diuretic (Table III). Again, when stratified by age and ethnicity, the order of preference changed for those aged <55 years, with greater use of RAS blockade plus β-blockers, whereas diuretics plus CCBs were used together relatively less often in this age group (data not shown). When 3 agents were used, the most common combination of agents was a RAS blocker, diuretic, and CCB, with a RAS blocker, diuretic, and β-blocker a close second.

Table III. Type of drugs used in the Health Survey for England
2006.

Discussion

The HSE 2006 data show that for the first time in England, the majority of those treated for hypertension were controlled to the target of <140/90 mm Hg. These results represent improvements compared with HSE data from 1994, 1998, and 2003 in terms of awareness and treatment and control rates, formen and women.^6-8 In the UK, the local hypertension guidelines recommend treating all BPs greater than 160/90mmHg, but for BPs >140/90 mm Hg treatment should only be initiated if the estimated 10-year CV risk is ≥20% and/or if the patient has diabetes or established CV disease.^9,10 However, using 140/90 mm Hg as the recommended treatment threshold— in keeping with the latest European¹¹ and American guidelines¹²—only 54% of those above this threshold were treated and, therefore overall, only 28% are controlled. Nevertheless, this compares favorably with overall control rates (using the 140/90 mm Hg definition for treatment threshold and target) in several other countries13 and with English data in earlier years.^6-8 Taking the British recommendation to treat those at ≥20% 10-year risk, only 55% were treated and of those less than one third were controlled. Clearly using the more aggressive target of <130/80 mm Hg for patients with diabetes, significant renal dysfunction, or established CV disease, control rates are worse than those shown in Table II.

One of the major reasons for improved hypertension management in the UK between 1994 and 2006 is the increased use of two or more agents. In 1994, only 40% of treated patients were on ≥2 drugs for hypertension, whereas in 2006, 61% were on ≥2 drugs. The improvements reported between 1994 and 1998 were thought, in part at least, to be attributable to improved uptake of nonpharmacological advice.⁷ It may also be that better BP control is partly attributable to better selection of antihypertensive agents and combinations of agents, which in turnmay reflect successes of the guidelines produced by the British Hypertension Society (BHS)^9,10,14 and latterly by the BHS in collaboration with the National Institute for Health and Clinical Excellence (NICE).¹⁰

These guidelines currently recommend the use of either an “A+C” (where “A” stands for ACE inhibitors or angiotensin receptor blockers and “C” for CCBs) or “A+D” (where “D” stands for diuretics) combination.

In contrast with the results in 1994⁶ and in contradiction to the latest British Guidance, the most common first-line agent was a RAS blocker—“A” drug, using the terminology used in the British Guidelines.^9,10 The most common second-line drug was a diuretic (or “D” drug), being used by 55% of patients using two agents, and the most common combination of drugs used by those using two agents was “A+D.” However, the results of the recent Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial¹⁵ show that benazepril plus amlodipine (“A+C”) was significantly superior to benazepril plus hydrochlorothiazide (“A+D”) in terms of preventing major CV events.

Furthermore, the Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm (ASCOT-BPLA) trial provided evidence of the superiority of an antihypertensive regimen using the CCB amlodipine and adding the ACE inhibitor perindopril over a regimen using a β-blocker and adding a low-dose thiazide diuretic, in terms of preventing both all-cause and CV mortality and major CV events. It may be therefore that practice changes in England to reflect the evidence base, and the combination of “A+C” may increase from its current position as the fourth most common combination used.

It is hard to tell how far the improvements in BP management that occurred between 2003 and 2006 reflect the new contract to which general practitioners have been working since April 2004,¹⁶ because improvements had been apparent between 1994 and 1998⁷ and between 1998 and 2003.⁸ However, the pattern of treatment and control rates for those targets that attracted financial rewards suggests that the contract is likely to have contributed to improvements.

Meanwhile, whatever the reasons for the improvements that did occur during this 3-year period, we estimate that between 4000 and 8000 fatal or major nonfatal CV events were prevented as a result of the improved BP control apparent in Table I.

Summary and conclusions

Progressive improvement in several aspects of hypertension management—rates of awareness, treatment, and control— has been apparent in England between 1994 and 2006, as witnessed by data from four of the annual HSEs that focused on CV disease and associated risk factors. These four surveys in 1994,⁶ 1998,⁷ 2003,⁸ and 2006⁵ provide high-quality and standardized nationally representative data on BP levels and the management of hypertension.

The determinants of the improvements observed cannot be definitely identified, but appear to include:
_ The increased use of nonpharmacological advice.
_ The increased use of more antihypertensive agents and different classes of agents.

The stimuli for these changes are again not certain, but are likely to include at least two major factors. Firstly, the publication of a series of guidelines by the BHS,^9,10,14 and the attempts of this society to disseminate and implement the recommendations included in the guidelines. Secondly the new GP contract, the new General Medical Services (nGMS) contract, which included a pay-for-performance component for aspects of hypertension management, including BP control.¹⁶

During the last 15 years, the critical role that raised BP plays in terms of contributions to global death has become increasingly clear and increasing trial evidence^17-19 has become available. Both types of data have helped guide and encourage improved hypertension management.

Looking to the future, “more of the same” is required—that is, continued improvements are required particularly with regard to those who are at high estimated CV risk, but who have not yet experienced CV symptoms and are not diabetic (Table II).

Meanwhile, more data are required to confirm that treating raised BP in the systolic range 140-159 mm Hg and diastolic range 90-99 mm Hg is cost-effective for subjects at low estimated CV risk. Furthermore, more data are needed to confirm which combinations of therapy are best when two, three, and four drugs are combined. Current best evidence based on two major trials ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) and ACCOMPLISH suggests “A+C” drugs are likely to be the most effective at preventing CV events,^15,20 but only observational data are available to advise drug sequencing thereafter.

Whether any new drug classes—currently available (direct renin inhibitor) or in the pipeline—will impact importantly on optimal drug sequencing remains to be seen, but trials are in progress evaluating the management of resistant hypertension.

References
1. Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJL. Selected major risk factors and global and regional burden of disease. Lancet. 2002;360: 1347-1360.
2. Kearney PM,Whelton M, Reynolds K, Muntner P,Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217-223.
3. Whelton PK. Hypertension curriculum review: epidemiology and the prevention of hypertension. J Clin Hypertens (Greenwich). 2004:6:636-642.
4. Craig R, Mindell J, eds. Health Survey for England 2006. London, United Kingdom: The Information Centre; 2008.
5. Falaschetti E, Chaudhury M, Mindell J, Poulter NR. Continued Improvement in Hypertension Management in England: Results from the Health Survey for England 2006. Hypertension. 2009;53:480-486.
6. Colhoun HM, Dong W, Poulter NR. Blood pressure screening, management and control in England; results from the Health Survey for England 1994. J Hypertens. 1998;16:747-753.
7. Primatesta P, Brookes M, Poulter NR. Improved hypertension management and control. Results from the Health Survey for England 1998. Hypertension. 2001;38:827-832.
8. Primatesta P, Poulter NR. Improvement in hypertension management in England: results from the Health Survey for England 2003. J Hypertens. 2006;24: 1187-1192.
9. Williams B, Poulter NR, Brown MJ, et al. British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ. 2004;328: 634-640.
10. National Collaborating Centre for Chronic Conditions. Hypertension: Management of Hypertension in Adults in Primary Care: Partial Update. NICE Clinical Guideline. London, United Kingdom: Royal College of Physicians; 2006.
11. Mancia G, De Backer G, Dominiczak A, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121-2158.
12. Chobanian AV, Bakris GL, Black HR, et al; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.
13. Wolf-Maier K, Cooper RS, Kramer H, et al. Hypertension treatment and control in five European countries, Canada, and the United States. Hypertension. 2004;43:10-17.
14. Ramsay LE, Williams B, Johnston GD, et al. British Hypertension Society National Guidelines for Hypertension Management 1999: A Summary. BMJ. 1999; 319:630-635.
15. Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417-2428.
16. Department of Health. Delivering Investment in General Practice: Implementing the New GMS Contract. London, United Kingdom: Department of Health; 2003.
17. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362: 1527-1535.
18. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. 2005;165:1410-1419.
19. Turnbull F, Woodward M, Neal B, et al; Blood Pressure Lowering Treatment Trialists’ Collaboration. Do men and women respond differently to blood pressurelowering treatment? Results of prospectively designed overviews of randomized trials. Eur Heart J. 2008;29:2669-2680.
20. Dahlöf B, Sever PS, Poulter NR, et al; for the ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac outcomes Trial – Blood Pressure Lowering Arm(ASCOT-BPLA): amulticentre randomised controlled trial. Lancet. 2005;366: 895-906.

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Michel E. SAFAR,MD
Université Paris Descartes
Assistance Publique-Hôpitaux de Paris, Hôtel-Dieu
Centre de Diagnostic et de Thérapeutique
Paris, FRANCE

by M. E. Safar,France

“Destiffening therapy” means that, in controlled therapeutic trials, a significant and selective reduction of systolic blood pressure (BP) has been obtained in long-termtreatment by comparison with a control group. The demonstration requires a reduction of central BP in association with a significant decrease of arterial stiffness and/or attenuation of wave reflections. For this purpose, all clinical trials in recent years have used angiotensin II blockade, mainly through angiotensin-converting enzyme inhibition, and frequently in combination with a diuretic and/or a calcium antagonist. Cardiovascular outcomes are significantly better than in controls, particularly when such controls involve a β-blocking agent.

Prospective studies from Framingham have focused attention on brachial systolic blood pressure (SBP) as a better guide than brachial diastolic blood pressure (DBP) for evaluation of cardiovascular (CV) risk.1-3 In large populations, antihypertensive drug therapy frequently achieves adequate DBP control (90 mm Hg), but SBP control (SBP 140 mm Hg) is much more difficult to attain.4 The findings have focused attention on the factors that modulate central (aortic) SBP and pulse pressure (PP) levels in hypertensive individuals, and therefore on the role of increased arterial stiffness and/or wave reflections in the mechanism of hypertension, and hence CV risk.

A major function of central (aortic) arteries is to change the PP arriving from the heart into a steady pressure at the peripheral level, thus obtaining optimal oxygenation of tissues. This major modification is a consequence of the so-called Windkessel effect.1-3 During systole, part of the stroke volume flows directly toward the periphery, causing systolic perfusion. The other part of stroke volume is stored within the elastic thoracic aorta wall and restored during diastole, causing diastolic perfusion. The combination of systolic and diastolic perfusion is responsible for a continuous and steady flow, which contrasts with the alternating cyclic movement initiated by the heart. This Windkesse effect has a major impact on central SBP and PP regulation, through alterations produced by aortic stiffness and wave reflections.

This review consists of 2 parts: (i) the hemodynamic and epidemiological basis of propagation of the pressure wave along the vascular tree; and (ii) the principal strategies to lower large artery stiffness and wave reflections in the treatment of hypertension.

Hemodynamic and epidemiological basis of pressure wave propagation
_ Components of the BP curve
There are 2 different components of the blood pressure (BP) curve in the arterial tree: a steady component and a pulsatile component. The former is expressed by mean arterial pressure (MAP), the product of blood flow by vascular resistance, which represents the main index reflecting the status of small arteries, mainly their diameter. The latter is PP, the difference between SBP and DBP. This parameter is determined by stroke volume, aortic stiffness, and wave reflections. The two latter factors, but not stroke volume, contribute, through the aorta’s elastic properties, to the Windkessel effect. Although MAP and PP are associated within the same BP curve, each of these parameters is a significant and independent predictor of CV risk.5 Whereas MAP is a predictor of overall CV risk (stroke, heart failure, renal insufficiency), PP is mainly related to the unique presence of coronary risk. Central PP, not brachial PP, is the more powerful predictor in this context.5-8

_ BP propagation and aortic stiffness
Following ventricular contraction, the pressure pulse generated by the heart travels along the aorta as a wave.6 The velocity of propagation of this wave (ie, pulse wave velocity [PWV]) along the aorta is calculated from the interval between two BP curves located at two different sites in the aortic tree (Figure 1).6 Because a fundamental principle is that pulse waves travel faster in stiffer arteries, PWV measurement is considered the best surrogate to evaluate aortic stiffness in man. Its value is 3-5 m/s in young persons at rest, but increases considerably with age (Figure 1).6 Carotid-femoral (aortic) PWV is nowadays considered as a significant and powerful predictor of CV risk independent of age and MAP.5 PWV of the upper and lower limbs has no predictive value.

When BP measurements are recorded simultaneously at different points along the aorta, the pressure wave changes shape as it travels down the aorta. Whereas SBP and PP actually rise with distance from the heart, DBP and MAP fall slightly (about 4 mm Hg) during the same course along the aortic pathway (Figure 2).2 Thus, pressure oscillation amplitude between systole and diastole, ie, PP, nearly doubles. This SBP and PP amplification (Figure 2)2 is a physiological finding and approximately 14 mm Hg between the thoracic root of the aorta and the brachial artery.

Figure 1. Principle of arterial stiffness measurement by pulse wave velocity with the foot-to-foot method.
Abbreviations: L, distance; t, time.
Modified after reference 6: Laurent et al. Eur Heart J. 2006;27:2588-2605. © 2006, The European Society of Cardiology.

Figure 2. Wave amplification of systolic blood pressure and pulse pressure along
the aorta of a 24-year-old.
After reference 2: Nichols WW, O’Rourke MF. McDonald’s Blood Flow in Arteries. Theoretical, Experimental and Clinical Principles. 4th ed. London, UK: Edward Arnold; 2006. © 2006, Edward Arnold.

_ Central wave reflections and age If an individual’s body length is about 2 m at most and aortic PWV is approximately 5 m/s, something must happen to the BP-curve shape within each beat if heart rate is 60 beats/min. What happens is the generation of wave reflections7 and their summation with the incident wave, as summarized in (Figure 3, upper part on the left, page 236). The incident wave is driven away from the heart through highly conductive arteries. However, it encounters impedance mismatch at the junction of the highly conductive artery and high resistance arterioles, blocking its entry into the arterioles, and it is reflected backwards towards the heart. Thus, the shape of every pulse wave results from the summation of the incident (forward-traveling) and reflected (backward-traveling) pressure waves (Figure 3, upper part on the right).

Reflected waves initiate from any discontinuity of the arterial or arteriolar wall, but mainly issue from high resistance vessels and their arteriolar bifurcations.2,3 Nevertheless, pulse-wave propagation and reflection vary considerably according to age (Figure 3, lower part). In young adults with maximum elasticity of their central arteries (low PWV), the summation of the incident arterial pressure wave and the reflected wave results in progressive PP amplification, so that SBP is higher in the brachial artery than the ascending aorta. Because PWV is relatively low in the thoracic aorta, the reflected wave comes back during diastole, thereby maintaining DBP and boosting coronary perfusion (Figure 3). Hence, optimal arterial function is obtained along with adequate coronary perfusion.

Figure 3. BP curve with description of its principal components.
In the upper part on the left, a schematic representation of the BP curve and its two components, forward and reflected waves. While on the right, the totality of the BP curve is represented. In the lower part, the BP curve is represented using 2 different shapes, dependent on age (see text). The augmentation index (AIx) is the ratio between: (i) the difference between peak SBP and the shoulder of the ascending part of the BP curve; and (ii) pulse pressure. AIx measured in % (or AI in mm Hg) represents the supplementary increase in SBP due to wave reflections. This hemodynamic profile is observed in the elderly, not in young people. MAP corresponds to the pressure needed if the cardiac work was constant.
Abbreviations: AIx, augmentation index; BP, blood pressure; MAP, mean arterial pressure; PP, pulse pressure; SBP, systolic blood pressure.
After reference 6: Laurent et al. Eur Heart J. 2006;27:2588-2605. © 2006, The European Society of Cardiology.

The development of increasing arterial stiffness (high PWV) and altered wave reflections with aging completely abolishes the differences between central and peripheral PP by the age of 50-60 years, with major consequences on ventricular load and coronary perfusion. The increased PWV means that the reflected waves return to the aortic root earlier, during late systole. In this case, the reflected waves summate with the forward-traveling wave to create an increased “augmentation” in central SBP and ventricular load (Figure 3, lower part). Central SBP and PP, and also the disappearance of PP amplification, are thus the more significant predictors of CV risk.8 In elderly persons with isolated systolic hypertension, aortic SBP can be elevated by 30-40 mm Hg as a result of the early return of wave reflections.2,3 Furthermore, because the backward pressure returns in systole, and not in diastole, as a consequence of enhanced PWV, DBP and coronary blood flow tend to be reduced, a situation promoting coronary ischemia. It can be noted that, in clinical practice, several factors can modulate the transit of wave reflections and thus central SBP and PP. First, reduced heart rate shifts wave reflections from diastole to systole, thus increasing “augmentation pressure” and central SBP.7 Second, angiotensin II inhibition and calcium blockade as well as insulin administration reduce wave reflections and central SBP.9 Insulin resistance has a reverse effect on central wave reflections.

_Modulation of aortic stiffness and wave reflections
In the long term, mechanical forces (shear or tensile stress) participate in the modulation of arterial stiffness, wall thickness, and wave reflections. In the absence of drug treatment, hypertensive remodeling is characterized, according to the Laplace law, by an increased wall/lumen ratio of arteries and arterioles, which represent the main site of vascular resistance and microcirculation, but also the origin of wave reflections.10-13 Druginduced regression of arteriolar hypertrophy is associated with a reduction in vascular resistance and reflection coefficients, thereby attenuating wave reflections, and, in the end, decreasing central SBP and PP.11-13 This process becomes significant approximately 1 year after the beginning of drug treatment of hypertensive subjects. Reduction of arteriolar hypertrophy is consistently obtained with angiotensin or calcium blockade, but never with â-blocking agents or hydrochlorothiazide.12 Endothelial dysfunction may affect this process, mainly through attenuation of NO dysfunction and/or oxidative stress under drug treatment.2,3,10-14

Pulsatile arterial hemodynamics and the basis of risk-reduction strategies in hypertension Risk reduction strategies should reduce together and independently increased MAP and PP. While the latter is principally sensitive to angiotensin II blockade alone, the former requires the addition of diuretics and/or calcium channel blockers, but not of traditional â-blocking agents (with the exception of coronary ischemic disease). This entire process is explained.

_ Importance of angiotensin blockade Renin-angiotensin system blockade either by angiotensin-converting enzyme (ACE) inhibition or, to a lesser extent, AT1 receptor blockade is classically associated with reductions of vascular resistance and MAP. However, the effects on aortic PWV and central and peripheral PP have been incompletely investigated until recently, but are important to develop.

Studies on animal models and hypertensive subjects have shown that angiotensin II blockade, mainly with the ACE inhibitor perindopril, is associated with reverse remodeling of both small and large arteries via specific mechanisms, including anti-inflammatory and antifibrotic effects as well as changes in arterial attachments linking á5â1-integrin to its specific ligand fibronectin.15-17 These mechanisms are very important to consider in order to obtain a significant and selective reduction in central PP and arterial stiffness with angiotensin II blockade. Their effect on mechanotransduction is primarily subject to the mitogen-activated protein kinase system.

In hypertensive rats fed a low-salt diet, angiotensin II blockade by the angiotensin receptor blocker (ARB) valsartan normalizes central PP (<50 mm Hg), whereas MAP is not normalized (>100 mm Hg) with the same drug dosage.15,16 Furthermore, in hypertensive subjects under angiotensin II blockade with a normal sodium diet, not only is PWV decreased, but central BP and wave reflections are also attenuated and carotid-brachial SBP and PP amplifications are increased. Angiotensin II blockade improves or even normalizes the wall thickness of small resistance arteries and, at the same time, reduces carotid wave reflections, suggesting a cause-and-effect relationship between the two factors. This is the basis of all the new strategies using destiffening drug therapy.1-3

However, to further reduce MAP, angiotensin blockade may be given in combination either with diuretics or calcium channel blockers (CCBs), but not usually with conventional â-blockers, as described below.

Figure 4. Change in MBP and aortic PWV with drug treatment in endstage renal disease patients. On the left, surviving patients have a parallel and significant decrease in MBP and PWV. On the right, deceased patients are characterized by decreased MBP, but increased PWV.
Abbreviations: BP, blood pressure; MBP, mean blood pressure; PWV, pulse wave
velocity.
Modified from reference 18: Guerin et al. Circulation. 2001;103: 987-992. © 2001,
American Heart Association, Inc.

_ Angiotensin II blockade and diuretics
The main therapeutic trial demonstrating the predictive role of aortic stiffness in hypertensive subjects was conducted in end-stage renal disease patients on hemodialysis.18 The objective was to lower CV morbidity and mortality through a therapeutic regimen involving successively: salt and water depletion by dialysis; then, after randomization, an ACE inhibitor or CCB; and, finally, the combination of the two agents and/or their association with a â-blocker. Using this protocol, it was possible to evaluate with long-term follow-up (51 months) whether or not the drug-induced mean blood pressure (MBP) reduction was associated with a concomitant decrease in arterial stiffness impacting on CV risk.

During follow-up, it was clearly shown that in survivors, MBP, brachial PP, and aortic PWV were concomitantly lower (Figure 4). In contrast, for patients who died from CV events, MBP had been reduced to the same extent as in survivors, but neither PWV nor brachial PP had been significantly modified by drug treatment (Figure 4). Thus, survival in end-stage renal disease patients was significantly better when aortic PWV declined in response to BP lowering. The adjusted relative risks for all-cause and CV mortality rates in those with unchanged PWV in response to BP changes were: 2.59 (95% confidence interval [CI], 1.51 to 4.43) and 2.35, respectively (95% CI, 1.23 to 4.51); P<0.01. The prognostic value of PWV sensitivity to BP reduction on survival was independent of age, BP changes, and blood-chemistry abnormalities. The results indicated that arterial stiffness was not only a risk factor contributing to the development of CV disease, but also a marker of established, more advanced, and less reversible arterial lesions. Finally, in this trial, survival seemed to be more closely associated with the use of an ACE inhibitor than other drugs. The use of â-blockers and/or CCB had no direct impact on the outcomes.18

The Complior study was the first study to show the feasibility of a large-scale interventional trial using PWV as the end point in 1703 hypertensive patients (mean age 50±12 years old; mean baseline SBP, 158±15 mm Hg; mean baseline DBP, 98±7 mm Hg; mean baseline carotid-femoral PWV, 11.6±2.4 m/s). Patients were treated for 6 months with the ACE inhibitor perindopril, adding indapamide if BP still was above 140/90 mm Hg. Significant decreases (P<0.001) in BP (SBP, –23.7±16.8 mm Hg; DBP, –14.6±10 mm Hg) and carotid-femoral PWV (–1.1±1.4 m/s) were obtained at 2 and 6 months.19

The REASON (pREterax in regression of Arterial Stiffness in a contrOlled double- bliNd study) study11,20 was the first trial to investigate the long-term interactions between central PP, arterial stiffness, and wave reflections, on the one hand, and drug treatment or end-organ damage (cardiac mass) of hypertensive subjects inmiddle age, on the other hand. The ACE inhibitor perindopril, combined with low-dose indapamide, was compared for 1 year of treatment with the â-blocker atenolol. For the same DBP and MBP decreases, perindopril/indapamide lowered SBP and PP more than atenolol. This finding was observed using not only routine BP measurement, but also 24-hour BP measurements.21 The reduction was more pronounced centrally (carotid artery) than peripherally (brachial artery). While the two drug regimens lowered PWV equally, only perindopril/indapamide (and not atenolol) reduced central PP and AIx (Figure 3).11,20 In addition, perindopril/indapamide decreased cardiac hypertrophy more than atenolol, and that decrease was attributed to the augmentation index (AIx) decrease, indicating that reduction of cardiac end-organ damage was mainly associated with a reduction of central SBP, PP, and wave reflections.11,20 In contrast, atenolol increased wave reflections and AIx through reduction of heart rate and a shift of the backward pressure wave from diastole to systole, thus excluding this drug from the destiffening strategy. Similar findings were observed when atenolol was compared to the ARB irbesartan.22

Figure 5. Effect of amlodipine±perindopril versus atenolol±bendroflumethiazide on central aortic blood pressure. Results of the ASCOT-CAFE study.
Abbreviations: ASCOT-CAFE, Anglo-Scandinavian Cardiac Outcomes Trial–Conduit Artery Function Evaluation; PP, pulse pressure.
Modified from reference 23: Williams et al. Circulation. 2006;113:1213-1225. © 2006, American Heart Association, Inc.

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Eoin O’BRIEN,DSc, MD, FRCP
Blood Pressure Unit
St Michael’s Hospital, Dublin
The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield
Dublin, IRELAND

by E. O’Brien,Ireland

In this review, I discuss the important information that ambulatory blood pressure monitoring can provide in clinical practice and make the case once again for making this technique available to all doctors engaged in managing patients with hypertension. I review the evidence on how nocturnal variation in blood pressure (BP) can influence outcome, consider interesting preliminary evidence that some drug classes may be superior to others in modifying nocturnal BP, and suggest that the time of administration of medication may also have an influence on the correction of abnormal nocturnal patterns. There is a need to direct research to determine if correcting abnormal nocturnal patterns either with drugs specifically targeted at nocturnal BP or by manipulating the time of drug administration will improve outcome.

The technique for measuring blood pressure (BP) was introduced into clinical medicine in 1896 and has survived largely unchanged for over a century, despite being inherently inaccurate.¹ Why, we might ask, have we connived for so long in perpetuating an inaccurate measurement in both clinical practice and hypertension research? The identification of white-coat and masked hypertension and the realization that many patients are being treated needlessly with BP-lowering drugs, whereas others are being denied drugs that could prevent cardiovascular (CV) sequelae, are the latest factors in the growing case against the traditional technique of BP measurement.

ABPM is indispensable to good clinical practice

These concerns have resulted in considerable research into techniques for assessing BP away from the medical environment, foremost among which has been ambulatory blood pressure monitoring (ABPM). Indeed, this technique is now accepted as being indispensable to good clinical practice.^1,2 There are guidelines and recommendations laying down the criteria for validation of devices for ABPM and the website www.dableducational.org provides up-to-date information on recommended devices.^3-5 The advantages of ABPM are many. First and foremost, the technique simply gives more measurements than conventional BP measurement, and real BP is reflected more accurately by repeated measurements. ABPM provides a profile of BP away from the medical environment, thereby allowing identification of individuals with a white-coat response or masked hypertension, who are in need of careful management. ABPM shows BP behavior over a 24-h period rather than giving a snapshot of BP measured with an inaccurate technique under artifi- cial circumstances. Rather than relying on one or a few conventional measurements confined to a short period of the diurnal cycle, the efficacy of antihypertensive medication over a 24-h period becomes apparent.

Figure 1. Schema of ambulatory blood pressure.

Figure 2. ABPM suggests optimal 24-hour blood pressure (128
mm Hg/78 mm Hg daytime, 110 mm Hg/62 mm Hg nighttime).
Normal dipping pattern.

ABPM can identify patients with abnormal patterns of nocturnal BP; the technique can demonstrate a number of patterns of BP behavior that may be relevant to clinical practice. Finally and importantly, evidence is now available from longitudinal studies that ABPM is a much stronger predictor of CV morbidity and mortality than conventional measurement. Moreover, evidence is growing that nocturnal BP measured by ABPM may be the most sensitive predictor of CV outcome, from which it follows that the measurement of nighttime BP should be an important part of clinical practice.³

Windows of the 24-hour circadian profile

In contemporary clinical practice, mean daytime and nighttime BPs are generally taken as being the most valuable parameters of ABPM,^6-9 but ongoing research indicates that there is much more information to be gleaned from the 24-h BP cycle. First, the 24-h period can be divided into a number of windows (Figures 1 and 2).

_ White-coat window
The white-coat window is the period that extends from the beginning of ABPM recording and lasts for 1 hour.^7,9 During the white-coat window, BP may be influenced by the medical environment. The most popular definition of white-coat hypertension is that BP measured by conventional techniques in the office, clinic, or surgery exceeds 140 mm Hg systolic or 90 mm Hg diastolic, but when ABPM is performed the average BP is <135 mm Hg systolic and 85 mm Hg diastolic during the daytime period.¹⁰ It has been shown that the whitecoat window on ABPM recordings cannot only diagnose the white-coat phenomenon, but also allows identification of a white-coat hypertensive subgroup with significantly higher pressures who may be at greater risk and in need of antihypertensive medication.¹¹ ABPM remains the method of choice for diagnosing white-coat hypertension.^2,11,12

_ Daytime window
The daytime window follows the white-coat window and is the period when the subject is away from the medical environment and engaged in usual activities.¹¹ For almost all subjects with hypertension, BPs during this window are lower than conventionally recorded pressures in the office, clinic, or surgery setting.^12,13 However, BPs during this period are subject to stress, activity, arm movement, and the effect of exercise and other activities, such as driving, all of which may have an influence on the mean level of BP recorded.¹⁴ These effects are largely absent from BP measured during the nocturnal period.^6,15

_ Vesperal window
In the normal individual, there is a decline in BP in the vesperal window from daytime levels of BP that reaches a plateau during the nighttime period. This period (9.01 PM to 0.59 AM on the basis of ABPM commencing at 9 AM) is not included in the estimation of day and night mean pressures because this period represents a time during which bed rest is inconsistent and, therefore, cannot be categorized reliably.¹⁶ In hypertensive patients (or some normotensive patients with CV disease), the decline in BP during the vesperal window may be absent (nondipping) so that BPs do not reach basal levels. ^15,17-19 BP may even rise in the vesperal window to reach levels that are higher than daytime levels (reverse dipping).²⁰ Alternatively, there may be a marked fall in BP during the vesperal window to give the phenomenon of extreme dipping.²¹ Therefore, what happens to BP in the vesperal window predicates the BP level in the basal window.

_ Basal window
The nighttime window follows the vesperal window and is the period between 1.00 AM and 6.00 AM.¹¹ BPs in this window are most likely to coincide with sleep (or if not with actual sleep, with the greatest cessation of activity) and are likely, therefore, to represent a steady state. There is compelling evidence that basal BP is superior to casual pressure in predicting outcome.^6,15,19,22 Nighttime BP is superior to all other BP measurements in predicting CV outcome and mortality, which suggests that nighttime BP obtained by ABPM is similar to basal BP. Moreover, it has also been shown that the use of a mild sedative during ABPM may help in identifying patients with a very high CV risk, namely those patients who continue to manifest a blunted nocturnal dip despite sedation.²³

Valuable though the information derived from the basal window may be, there are a number of methodological limitations to recording BP at night.^6,17,24 Ironically, despite doubts about reproducibility of the night-to-day ratio, it may be that nighttime BP is more standardized and consequently more reproducible than daytime BP (sleep being a more stable state than activity) and that it is this feature that gives nocturnal BP its predictive value. In clinical practice when the sleep and awakening periods are clearly defined, nocturnal changes in BP are surprisingly reproducible.^25,26

_ Matinal window
The matinal window extends from the end of the basal window to the commencement of daytime activities following rising. This period (6.01 AM to 8.59 AM) is not included in the estimation of day and night mean pressures because this period represents a time during which bed rest is inconsistent and, therefore, cannot be categorized reliably.16 However, the magnitude of the rise in BP in the matinal window may yield the most valuable prognostic information. In normal subjects, a modest rise in BP occurs in the matinal window preceding awakening from sleep to merely restore the previous daytime level of BP.²⁷ However, this preawakening rise in BP in hypertensive patients may exceed the daytime average—the preawakening or morning surge—and this phenomenon is associated with a poor CV outcome.²¹

Patterns of ABPM

Within the windows of the 24-h BP profile, several variations of BP behavior may be discerned, allowing differentiation of patients into subforms and patterns.^2,3,5,28 ABPM may also be used to gauge the severity of BP—the higher the initial 24-h ABPM, the more frequent the occurrence of cardiovascular events.²⁹

_ White-coat hypertension
The risk associated with white-coat hypertension remains controversial, but there is general agreement that the condition should not be regarded as benign, with the risk of developing sustained hypertension at some time being almost inevitable (Figure 3).^30-32

Figure 3. ABPM suggests white-coat hypertension (175 mm Hg/
95 mm Hg) with otherwise normal 24-hour systolic blood pressure
(133 mm Hg daytime, 119 mm Hg nighttime) and optimal 24-hour
diastolic blood pressure (71 mm Hg daytime, 59 mm Hg nighttime).
Normal dipping pattern.

_ White-coat effect
White-coat hypertension must be distinguished from the “white-coat effect,” which is the term used to describe the increase in pressure that occurs in the medical environment regardless of daytime ABPM. In other words, the term indicates the phenomenon found in most hypertensive patients whereby clinic BP is usually greater than the average daytime ABPM, which is nonetheless increased above normal (Figure 4, page 244).⁵

_ Masked hypertension
This phenomenon denotes subjects classified as normotensive by conventional office or clinic measurement that are hypertensive with ABPM or self-measurement. The prevalence of masked hypertension in adults seems to be at least 10% and may indeed be higher, with a tendency to decrease with age. Adult subjects with masked hypertension have increased target organ involvement and increased CV morbidity. The logical extension of this line of reasoning is that future studies will also show CV mortality to be increased. The problem for clinical practice is how to identify and manage these patients who, it is estimated, may number as many as ten million people in the USA.^5,32

Figure 4. ABPM suggests mild daytime systolic hypertension
(150 mm Hg), borderline daytime diastolic hypertension (87 mm Hg),
borderline nighttime systolic hypertension (123 mm Hg), and normal
nighttime diastolic blood pressure (68 mm Hg) with a whitecoat
effect (187 mm Hg/104 mm Hg). Normal dipping pattern.

Figure 5. ABPM suggests low daytime systolic and diastolic
blood pressure (100 mm Hg/59 mm Hg) and moderate nighttime
systolic and diastolic hypertension (146 mm Hg/89 mm Hg) with
a white-coat effect (181 mm Hg/102 mm Hg). Reverse dipping
pattern.

_ Ambulatory hypotension
Hypotension is particularly common in the elderly, who may have autonomic or baroreceptor failure and who may also experience postprandial and postural hypotension. ABPM may also be useful in identifying hypotensive episodes in young patients in whom hypotension is suspected of causing symptoms.^2,32 In treated hypertensive patients, ABPM may also demonstrate drug-induced decreases in BP that may have untoward effects in patients with compromised arterial circulation, such as individuals with coronary and cerebrovascular disease (Figure 5).³³

_ Daytime systo-diastolic hypertension
Many patterns of BP behavior can be discerned from ABPM. By far the most common pattern is systo-diastolic hypertension.²⁸ Generally,mean daytime levels of BP are superior to clinic BPs in predicting outcome, but inferior to nocturnal BP.^15,34

_ Isolated systolic hypertension
Isolated systolic hypertension can be apparent on clinic BP measurement, but it can be overestimated. ABPM allows for confirmation of the diagnosis as well as predicting outcome more accurately. The results of the ABPMsubstudy of the Systolic Hypertension in Europe Trial showed that systolic blood pressure (SBP)measured conventionally in the elderlymay average 20 mm Hg more than daytime ABPM, thereby leading to the inevitable overestimation of isolated systolic hypertension in the elderly and probable excessive treatment of the condition.³⁵ In women with CV disease, SBP is most strongly related to the risk of secondary CV events (Figure 6).³⁶

_ Isolated diastolic hypertension
Isolated diastolic hypertension, which can be present on clinic measurement, can be more readily studied with ABPM. The prevalence of the condition in one study was 3.6%.²⁸ It is generally accepted that if SBP is normal, high diastolic blood pressure (DBP) is not associated with an adverse prognosis.³⁷

_ Dipping and nondipping
The “dipper/nondipper” classification was first introduced in 1988 when a retrospective analysis suggested that nondipping hypertensive patients had a higher risk of stroke than the majority of patients with a dipping pattern.¹⁸ It is generally accepted that a diminished nocturnal BP fall is associated with a poor prognosis.^2,16 For example, blunted nighttime dipping of BP is independently associated with angiographic coronary artery stenosis in men.³⁸ In elderly people with long-standing hypertension, a blunted nocturnal dip in BP is independently associated with lower cognitive performance.³⁹ Among elderly patients with recently diagnosed isolated systolic hypertension, those with a nondipping nocturnal pattern have been shown to have significantly higher left ventricular masses on echocardiography than dippers.⁴⁰ A nondipping nocturnal pattern is also associated with renal and cardiac target organ involvement.⁴¹ Moreover, nocturnal BP is now known to be an independent risk factor for CV outcome over and above all other measures of BP.^15,42 For example, in the Dublin Outcome Study for each 10-mm Hg increase in mean nighttime SBP, the mortality risk increased by 21% (Figures 6 and 7).¹⁵

Figure 6. ABPM suggests severe daytime isolated systolic hypertension
(176 mm Hg/68 mm Hg), severe nighttime systolic hypertension
(169 mm Hg), and borderline nighttime masked diastolic
hypertension (70 mm Hg). Nondipping pattern.

_ Reverse dipping
In some patients, BP rises above daytime pressures rather than falling during the night. These patients (also referred to as risers, or extreme nondippers) have the worst CV prognosis, both for stroke and cardiac events (Figure 5).²⁰

_ Extreme dipping
Patients with a marked nocturnal fall in BP, known as extreme dippers, are at risk for nonfatal ischemic stroke and silent myocardial ischemia. This is particularly likely in extreme dippers who already have atherosclerotic disease and in whom excessive BP reduction is induced by injudicious antihypertensive medication.²⁰ This possibility was originally enunciated by Floras as long ago as 1988.⁴³ Extreme dipping is closely associated with an excessive morning surge in BP, which is associated with cerebral infarction and a high risk of future stroke (Figure 8).²⁰

_ Siesta dipping
A siesta dip in BP on ABPM is common in societies in which an afternoon siesta is an established practice, but in many elderly patients regardless of cultural practice a siesta is often part of the daily routine. There is evidence that ignoring the dipping pattern associated with a siesta distorts the day/night ratio of ABPM,^44,45 and the magnitude of the siesta dip may have prognostic implications (Figure 8).⁴⁶

_ Nocturnal hypertension
Although daytime ambulatory hypertension is a good predictor of outcome, a number of studies have shown that ambulatory nocturnal hypertension is associated with a worse CV outcome.^15,42,47 Further confirmation of the importance of nocturnal hypertension comes from a recent study showing that a nondipping pattern and increased nighttime DBP predicted the occurrence of congestive heart failure independently of antihypertensive treatment and established risk factors for cardiac failure (Figures 4 to 8).⁴⁸

_ The morning surge
CV events, such asmyocardial infarction, ischemia, and stroke, are more frequent in the morning hours soon after waking than at other times of day.⁴⁹ Circadian variations in biochemical and physiological parameters help to explain the link between acute CV events and the early morning BP surge.^49,50 The occurrence of stroke and heart attack is more common during this period than at any other time of the day.⁵⁰ In older hypertensive subjects, a morning surge in BP—defined as a rise in BP >55 mm Hg from the lowest nighttime reading—carries a risk of stroke almost three times greater than that seen in patients without amorning surge.⁵¹ Greater carotid intima-media thickness and circulating inflammatory markers coexist in hypertensive patients with a morning BP surge and might contribute to the increased CV risk in these patients (Figure 8).⁵²

_ Indices of risk in the circadian profile
ABPM can also provide interesting and informative indices that are associated with outcome. The subject has been reviewed recently.⁹ These include pulse andmean BP, heart rate, indices of BP variability, chronobiological calculations, Cusum derived statistics, and most recently the ambulatory arterial stiffness index (AASI), which has been shown to predict CV mortality in a large cohort of hypertensive individuals (particularly from stroke). This association was evident even in normotensive subjects. As a result, AASI may prove to be a readily applicable index that can be derived from routine ABPM to predict outcome. The practical importance of such an index is that it may permit early categorization of hypertensive patients at risk from CV events thus indicating those in need of aggressive BP lowering.⁵³

Figure 7. ABPM suggests severe 24-hour systolic and diastolic
hypertension (209 mm Hg/135 mm Hg daytime, 205 mm Hg/130
mm Hg nighttime). Nondipping pattern.

Figure 8. ABPM suggests mild daytime systolic and diastolic hypertension
(152 mm Hg/94 mm Hg), optimal nighttime systolic blood
pressure (111 mm Hg), and normal nighttime diastolic blood pressure
(66 mm Hg) with a white-coat effect (158 mm Hg/90 mm Hg).
Measurements taken during the siesta are not included in these averages. Extreme
dipping pattern.

Treatment of hypertension using ABPM

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) showed significantly lower rates of all-cause mortality (11% lower), CV mortality (24% lower), and stroke (23% lower) with an amlodipine/perindopril combination compared with an atenolol- thiazide combination, even in hypertensive patients without coronary heart disease.⁵⁴ The intertreatment difference in event rates was only partly explained by better lowering of clinic BP with amlodipine/perindopril.^55-57 In fact, it now seems possible that the explanation for this discrepancy may be because the amlodipine/perindopril combination reduced both mean BP and BP variability.

An ambulatory substudy of ASCOT was performed in 1900 patients from four ASCOT centers who had repeated ABPMs over 5.5 years in order to examine the impact of the two BPlowering treatment regimens on ambulatory BP. Clinical BP was examined every 6 months. ABPM was performed once a year from recruitment. ABPM was measured every half an hour throughout a 24-h period—mean daytime BP [9.00 AM to 9.00 PM], nighttime BP [1.00 AM to 6.00 AM], 24-h SBP, 24-h DBP, pulse pressures, and heart rates were calculated from each ABPM. Three post hoc–defined composite end points were analyzed: total CV events + revascularization procedures; total coronary events (fatal coronary heart disease and nonfatal myocardial infarction) + coronary revascularization procedures; and fatal + nonfatal stroke.

Like all the total ASCOT blood pressure–lowering arm population, patients from the ABPM substudy were treated with amlodipine/perindopril. Clinical BP values were 1.4/1.1mmHg lower. No difference in SBP was found between treatment groups during the 24-h period, but nighttime systolic BP was significantly lower (2.2 mm Hg) with amlodipine/perindopril treatment. This difference might be explained by the synergistic effect of amlodipine and perindopril (with trough-to-peak ratios of 85%-87% and 75%-100%, respectively) on 24 hour BP control.^58,59

The ABPM substudy showed that the amlodipine/perindopril and atenolol/thiazide regimens had different effects on daytime and nighttime BP, which may have contributed to the lower rate of events in patients treated with amlodipine/perindopril (Figure 9).⁶⁰ Nocturnal ABPM values complemented clinical BP values for the prediction of CV risk in hypertensive patients receiving treatment. These data reinforce the concept that BP-lowering treatment should be directed towards the reduction of nocturnal BP.

Figure 9. Nighttime systolic blood pressure difference between
patients randomized to receive atenolol/thiazide (blue line) or amlodipine/
perindopril therapy (red line).
Mean BPs, mean intertreatment BP difference (95% confidence interval), and
P value are shown. Time indicated is from randomization onward.

Can drugs be targeted to reduce BP in circadian periods of greatest risk?

Traditionally, BP-lowering drugs with a once-daily regimen of administration are taken in the morning. The hypertension guidelines require that antihypertensive medication with oncedaily administration should possess at least a 50% troughto- peak (T/P) ratio to ensure a 24-hour duration of action. It is surprising how little attention has been paid to the possibility of achieving amore beneficial effect on CV outcome by reducing nocturnal BP either by nighttime dosing or by designing drugs aimed specifically to reduce nocturnal BP.8 The importance of 24-hour BP coverage, even if achieved by manipulating the timing of drug administration, has been well illustrated in the Heart Outcomes Prevention Evaluation study.⁶¹

In the main study, the group receiving ramipril had approximately 35% fewer CV events, despite an insignificant reduction in BP of 3/2 mm Hg; the outcome benefit was attributed to angiotensin-converting enzyme (ACE) inhibition, which was recommended in all high-risk patients regardless of baseline BP. However, it became evident from a later analysis of the ABPM substudy that ramipril (T/P ratio 50%-63%)^58,59 was actually taken in the evening with outpatient BP measured some 10 to 14 hours later the following day.⁶² The reported insignificant change in BP in the main study gave no indication of a “whopping” 17/8 mm Hg reduction in BP during the nighttime period, which translated into a 10/4 mm Hg average reduction in BP over the entire 24-hour period.⁶³

Interestingly from a historical perspective, the first paper to describe the effects of antihypertensive medication on 24-hour BP was in 1982, when Floras and his colleagues demonstrated using direct intra-arterial BP measurement that atenolol and slow-release propranolol lowered nighttime BP, whereas metoprolol and pindolol did not.⁶⁴ A few years later, we presented data showing a discrepancy between antihypertensive drug efficacy when measured by clinic and noninvasive ambulatory daytime measurement methods. We concluded that “noninvasive ambulatory blood pressure measurement should be considered an essential part of the evaluation of antihypertensive drugs.”⁶⁵ Why, we might ask, have we had to wait nearly a quarter of a century to explore the therapeutic potential of nocturnal BP lowering and the differing effects of drugs on ambulatory BP?

Efficacies of the various classes of antihypertensive drugs for restoring normal dipping are not well studied. However, diuretics, ACE inhibitors, angiotensin II receptor blockers, and calcium channel blockers appear to be superior to α- and β-blockers.^49,66,67 Individualized antihypertensive medication targeting abnormal diurnal patterns may offer particularly good protection in high-risk groups, such as patients with a rise in nocturnal BP and in extreme dippers.^68,69

As much of the morning surge may be mediated by involvement of the renin-angiotensin system, it would seem logical to assess agents targeting angiotensin II.^49,70,71 Another mechanism worthy of manipulation to enhance nocturnal pharmacological therapy is dietary potassium supplementation and sodium restriction to restore normal dipping.⁶⁶ The consistent lowering of nocturnal BPs by the renin inhibitor aliskiren in combination with a thiazide diuretic, an ACE inhibitor, or an angiotensin receptor blocker is a potential therapeutic strategy for reducing nocturnal hypertension.⁷²

The evidence to date clearly suggests that pharmacological research should be directed towards designing drugs with the primary purpose of modifying nocturnal manifestations of hypertension. However, it should also be possible to modify nocturnal BP using the drugs or drug combinations presently available with 24-hour BP coverage. Hermida and colleagues examined the hypothesis that nondipping in hypertensive patients might be due, at least in part, to the absence of 24-hour therapeutic coverage in patients treated with single morning doses. They showed that in patients taking bedtime medication, ABPM control was double that of patients taking morning medication. Moreover, in patients with true resistant hypertension, bedtime medication resulted in a significant reduction in the 24-hour mean of SBP and DBP, and this reduction was much more prominent at nighttime.⁷³ Bedtime dosing with an ACE inhibitor in patients with a nondipping pattern of hypertension improves efficacy during the nocturnal period.⁷⁴

Antihypertensive medication directed at nighttime BP may not necessarily alter nocturnal hypertension patterns for the better. For example, a nondipping or dipping pattern could be transformed into an extreme dipping pattern with injudicious therapy. The objective should be to reduce BP at the same time as preserving the physiological circadian dipper pattern. This is particularly important in stroke survivors, in whom ABPM is mandatory because it determines the appropriate dose of antihypertensive drug and the optimum time of administration to avoid inducing nondipper, riser, and extreme dipper circadian profiles with treatment.⁷⁵

Given the extensive evidence for the increased prevalence of CV events in the early morning hours, antihypertensive drugs that provide BP control during the early morning surge should provide greater protection against target-organ damage and enhance patient prognosis. This period has been dubbed the “blind spot” in current clinical practice.⁷⁶ Pharmacological research into ways of altering the morning surge is limited.⁷⁷ However, reduction of the morning surge in BP may be beneficial in preventing target-organ involvement in hypertension.⁷⁸

From the evidence available there is a need in clinical practice to use antihypertensive therapies with proven 24-hour duration of action and with superior nighttime BP coverage, as demonstrated in the ASCOT trial with an amlodipine/perindopril regimen. There is a need for pharmaceutical research to develop drugs that correct nocturnal BP abnormalities and for clinical research to determine if correcting nocturnal BP abnormalities will result in improved outcome. _

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66. Sachdeva A, Weder AB. Nocturnal sodium excretion, blood pressure dipping, and sodium sensitivity. Hypertension. 2006;48:527-533.
67. Ben-Dov IZ, Ben-Arie L, Mekler J, Bursztyn M. How should patients treated with alpha-blockers be followed? Insights from an ambulatory blood pressure monitoring database. J Hypertens. 2006,24:861-865.
68. Kario K, Shimada K. Risers and extreme-dippers of nocturnal blood pressure in hypertension: antihypertensive strategy for nocturnal blood pressure. Clin Exp Hypertens. 2004;26:177-89.
69. Hoshide Y, Kario K, Schwartz JE, Hoshide S, Pickering TG, Shimada K. Incomplete benefit of antihypertensive therapy on stroke reduction in older hypertensives with abnormal nocturnal blood pressure dipping (extreme-dippers and reverse-dippers). Am J Hypertens. 2002;15:844-850.
70. White WB, Larocca GM. Improving the utility of the nocturnal hypertension definition by using absolute sleep blood pressure rather than the “dipping” proportion. Am J Cardiol. 2003;92:1439-1441.
71. White WB, Lacourciere Y, Davidai G. Effects of the angiotensin II receptor blockers telmisartan versus valsartan on the circadian variation of blood pressure: impact on the early morning period. Am J Hypertens. 2004;17:347-353.
72. O’Brien E, Barton J, Nussberger J, et al. Aliskiren provides antihypertensive efficacy and suppression of plasma renin activity in combination with a thiazide diuretic, an angiotensin converting enzyme inhibitor, or an angiotensin receptor blocker. Hypertension. 2007;49:276-284.
73. Hermida RC, Ayala DE, Calvo C, et al. Effects of time of day of treatment on ambulatory blood pressure pattern of patients with resistant hypertension. Hypertension. 2005;46(part 2):1-7.
74. Hermida RC, Calvo C, Ayala DE, et al. Treatment of non-dipper hypertension with bedtime administration of valsartan. J Hypertens. 2005;23:1913-1922.
75. Sierra C, Coca A. Nocturnal fall of blood pressure with antihypertensive therapy and recurrence of ischaemic stroke: ‘the lower the better’ revisited. J Hypertens. 2005,23:1131-1132.
76. Kario K. Time for focus on morning hypertension: pitfall of current antihypertensive medication. Am J Hypertens. 2005;18:149-151.
77. Eguchi K, Kario K, Shimada K. Comparison of candesartan with lisinopril on ambulatory blood pressure and morning surge in patients with systemic hypertension. Am J Cardiol. 2003;92:621-624.
78. Marfella R, Siniscalchi M, Nappo F, et al. Regression of carotid atherosclerosis by control of morning blood pressure peak in newly diagnosed hypertensive patients. Am J Hypertens. 2005;18:308-318.

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Victoria VANDZHURA,
MD, PhD
Servier International
Suresnes, FRANCE

by V. Vandzhura, France

The ultimate goal of antihypertensive therapy is to minimize the risk of hypertension- related death and morbidity. Reappraisal of European guidelines on hypertension has underlined the importance of blood pressure (BP) reduction per se, and highlighted the fact that systolic pressure, 24-hour BP profile, and central BP are strong predictors of cardiovascular events. Guidelines now recommend tailored management of hypertension adapted to each individual patient’s needs, and to initiate treatment with combination antihypertensive therapy. Based on recent evidence from the Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm(ASCOT-BPLA), the combination of an angiotensin-converting enzyme inhibitor with a calciumchannel blocker (CCB) is one of the preferred therapeutic options. ASCOTBPLA was a breakthrough as it showed that antihypertensive strategies could differ in cardiovascular outcomes despite producing comparable brachial BP decreases. The amlodipine/perindopril regimen was more effective than atenolol/bendroflumethiazide in preventing death and major cardiovascular events. More efficient control of central BP, BP variability, and nocturnal hypertension with amlodipine/perindopril contributed to the difference in outcomes. Following the ASCOT trial results, Coveram was developed as a fixed combination of perindopril and amlodipine, and has already received consistent evidence-based support. Coveram provides rapid and effective brachial BP reduction in a broad range of hypertensive patients and acts synergistically on each and every component of antihypertensive efficacy: central BP, 24-hour BP, BP variability, and nocturnal hypertension. Coveram, indicated for both hypertension and coronary artery disease, stands out among currently available combinations of renin-angiotensin system inhibitors and CCBs, as it has been shown to decrease the risk of death and cardiovascular events.

Hypertension is the leading risk factor for premature death, responsible for 12.8% (7.5 million) of deaths worldwide, as well as causing up to 54% of cardiovascular deaths, according to a report from the World Health Organization published in 2010.¹ At the same time, a so-called hypertension paradox was described, consisting of an increase in the number of uncontrolled hypertensive patients, despite therapeutic advances.² More than two thirds of hypertensive adults in the United States fail to reach the blood pressure (BP) goal of <140/90 mm Hg, and over 80% of patients in Canada and Europe show suboptimal BP control.^3,4

However, hypertension, as a disease whose defining feature is elevated blood pressure, has as many faces as the patients it impacts. In practice, physicians have to treat patients with systolic and/or diastolic hypertension, those whose BP increases in the evening or at night, and BP that “jumps” several times a day. Thus, a patient’s specific BP profile as well as concomitant risk factors and diseases determine each patient’s risk.

To improve the management of hypertension, the Reappraisal of European Guidelines on Hypertension Management: A European Society of Hypertension Task Force Document⁵ emphasizes the need for overall cardiovascular risk evaluation and the importance of BP reduction per se. Furthermore, guidelines recognize that central blood pressure and 24-hour BP profile are more informative than clinic (brachial) BP in determining cardiovascular risk as well as the treatment decision.

Based on evidence from clinical trials, use of antihypertensive drug combinations for treatment initiation, “particularly in patients at high cardiovascular risk in which early blood pressure control may be desirable” is recommended.⁵ The combination of an angiotensin-converting enzyme (ACE) inhibitor and a calcium channel blocker (CCB) is one of the regimens preferentially recommended, as the guidelines point out. Data on morbidity-mortality for angiotensin receptor blocker (ARB)/ CCB combinations are lacking.⁵

The Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure– Lowering Arm (ASCOT-BPLA) was the first, and is still the only, clinical trial to demonstrate effective reduction in mortality among hypertensive patients treated with a CCB in combination with a renin-angiotensin system (RAS) inhibitor. A significant decrease of 11% in deaths from all causes and of 24% in cardiovascular mortality was achieved with an amlodipine/ perindopril regimen, despite almost comparable lowering of brachial BP with a β-blocker/diuretic combination. In addition, ASCOT substudies have demonstrated that a better prognosis is directly associated with more effective reduction in central aortic and central carotid BP as well as BP variability and true 24-h efficacy with nighttime hypertension reduction by the amlodipine/perindopril regimen.

Furthermore, the recent subanalysis of the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) provided evidence that patients receiving perindopril (Coversyl) together with a CCB benefited from a markedly greater decrease in the risk of cardiovascular mortality and morbidity.⁶

Following the results of the ASCOT and EUROPA trials, Coveram, a fixed-dose combination of Coversyl (perindopril) and amlodipine, was developed. Coveram is the focus of this review. Representing a type of exception among antihypertensive treatments, Coveram:
_ Was introduced into clinical practice as a consequence of evidence-based support in clinical trials (ASCOT, EUROPA).
_ Decreases elevated BP rapidly and markedly (SafeTy and efficacy analysis of coveRsyl amlodipine in uncOntrolled and Newly diaGnosed hypertension [STRONG], StudY of opti- Mized Blood pressure lowerIng therapy with fixed cOmbination perindopril/amlodipine [SYMBIO]); and
_ On top of its superior BP reduction, Coveram improves central and nocturnal BP control and BP variability, thus providing lifesaving benefits for a broad range of patients with hypertension.

Evidence for Coveram in mortality and cardiovascular morbidity prevention: a primary objective of antihypertensive treatment

_ ASCOT-BPLA

ASCOT-BPLA was a landmark multicenter prospective randomized controlled trial in 19 257 patients with hypertension (mean BP at baseline was roughly 164/94 mm Hg), 40 to 79 years of age, and who had at least three other cardiovascular risk factors, but were still free from coronary artery disease (CAD). Patients were assigned either to amlodipine plus perindopril as required to achieve target BP or atenolol plus bendroflumethiazide as required.

The rationale for the ASCOT study was the lack of morbidity or mortality evidence on optimum combinations of antihypertensive agents. In addition, for a given reduction in blood pressure, some authors suggested that newer agents such as amlodipine with perindopril (Coversyl) would confer advantages over the traditional approach of diuretics and β-blockers. The study was discontinued prematurely because of a significant reduction in cardiovascular mortality (RRR,–24%; P=0.001), all-cause mortality (RRR,–11%; P=0.02), and in stroke (RRR, –23%; P=0.0003) in favor of the amlodipine/ perindopril group, even though the necessary number of primary end point events was not reached due to early termination. The amlodipine/perindopril group also had a significantly lower incidence of new-onset diabetes (RRR-31%; P<0.0001) as well as fatal and nonfatal stroke, total cardiovascular events, and renal impairment (Figure 1).⁷

Figure 1. The ASCOT-BPLA study results.

Mean brachial BP reduction vs baseline was 27.5/17.7 mm Hg with the amlodipine/perindopril regimen and 25.7/15.6 mm Hg with β-blocker/diuretic with a mean difference of 2.7 mm Hg in systolic blood pressure (SBP). Based on long-term observational data,⁸ this systolic difference should translate into a difference in the rate of coronary events of about 8% and in the rate of stroke of about 11%, while the actual differences in coronary and stroke events reported in ASCOT-BPLA were 14% and 23%, respectively.⁷ Yet, in 2005, the ASCOT investigators demonstrated that the adjustment for BP difference only explained about half of the differences in coronary and stroke events. They suggested, that some of the benefits of the amlodipine/Coversyl regimen might relate to differences in other variables on blood pressure, such as blood pressure variability or central blood pressure, or to other treatment benefits not related to blood pressure.⁹ This hypothesis has been recently confirmed by additional results of ASCOT-BPLA substudies, detailed here below.

_ The EUROPA study

The clinical synergy of Coversyl and a CCB in the prevention of cardiac events and mortality in CAD patients was investigated to determine the effects of addition of Coversyl to longterm continuous treatment with a CCB on cardiac outcomes in the stable CAD population of the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA),¹⁰ and explore the presence of synergy between Coversyl and CCB in secondary prevention. Patients receiving a CCB at every visit during the 4.2-year followup were identified and the effect of adding perindopril was analyzed (n=1022 perindopril/ CCB versus n=1100 placebo/CCB). Addition of Coversyl to CCB significantly reduced total mortality by 46% (P<0.01 versus placebo+CCB) and the primary end point (a composite of cardiovascular mortality, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 35% (P<0.05 versus placebo+CCB). There were 41%, 54%, and 28% reductions in cardiovascular mortality, hospitalization for heart failure, and myocardial infarction, respectively (Figure 2, page 284).⁶ The magnitude of benefits suggests the existence of a clinical synergy between perindopril and CCB. The synergy of Coversyl with CCB was observed independently of baseline BP. It must therefore be related to other “beyond BP” mechanisms, similar to those observed with perindopril in the overall EUROPA population.⁶

It was concluded that the addition of Coversyl to a CCB in patients with stable CAD had a significant additional impact on decreasing the risk of cardiovascular mortality and other cardiovascular complications, suggesting the potential for lifesaving benefits as well for the use of the perindopril/amlodipine fixed-dose combination (Coveram) in hypertensive coronary patients.

Synergy is one of the most widely mentioned properties of combinations of two different drug classes, particularly in the field of hypertension. The additive efficacy of an ACE inhibitor and a CCB in terms of vasorelaxation and BP lowering is well known.^11-13 One possible mechanism is the potentiation of each drug’s efficacy on reduction of central aortic BP. A preferential reduction in central aortic BP was postulated as a source of benefit on cardiac outcomes with amlodipine/perindopril vs the β-blocker/thiazide diuretic in ASCOT.⁷ Other mechanisms exist underlying the pharmacodynamic synergy between Coversyl and CCB, where one component counteracts effects of the other. For example, CCBs stimulate the sympathetic nervous system and, indirectly, the RAS, whereas ACE inhibition with perindopril has the opposite effect. We could also summarize the synergy of perindopril and CCB on atherosclerosis. In this context, the positive impact of perindopril on endothelial function was demonstrated in the EUROPA population,^14,15 together with a reduction in the size of early noncalcified plaque.¹⁶ A trend has been detected toward reduced progression of atherosclerosis with amlodipine versus placebo in the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) trial.¹⁷

Figure 2. Results of a post hoc subanalysis of the EUropean trial on Reduction Of
cardiac events with Perindopril in stable coronary Artery disease (EUROPA) study.

Synergistic effects also have a positive impact on side effects. ACE inhibitors reduce lower-limb edema associated with use of CCBs. Clinical synergy may also be expected given the combination of the cardioprotective properties of Coversyl with the anti-ischemic and antianginal activity of amlodipine.¹³

Evidence for Coveram in blood pressure lowering: an early clinical criterion of antihypertensive therapy

_ Blood pressure–lowering efficacy of Coveram simply assessed by brachial tonometry
The pronounced antihypertensive efficacy of Coveram was demonstrated in the STRONG study. STRONG, a multicenter observational study, evaluated the efficacy and safety of Coveram at a dose equivalent to that of perindopril arginine/ amlodipine 5 mg/5 mg in 1250 patients with stage 2 hypertension (newly diagnosed or untreated at baseline, patients uncontrolled on monotherapy, those inadequately managed on another free- or fixed-combination therapy) in a real-world clinical practice setting.¹⁸

No additional antihypertensive drugs were permitted throughout the 2-month study period. Coveram decreased BP rapidly and progressively during the study with a significant reduction of mean SBP/DBP from 167.4±15.2/101.4±9.1 mm Hg to 125.4± 33.1/78.2±20.3 mm Hg (both P<0.0001 vs baseline), representing a decrease of 25.0% and 22.9% in SBP and diastolic blood pressure (DBP), respectively.¹⁸ Overall, 66.1% of patients reached the BP target of ≤140/ 90 mm Hg (≤130/80 mm Hg in diabetics).¹⁸ The combination was well tolerated. During the study, treatment was discontinued by 0.4% of patients because of cough, and by 0.2% because of ankle edema. Treatment- related adverse events not resulting in withdrawal were mild cough (1.1%), ankle edema (0.5%), headache with dizziness (0.3%), and nausea (0.2%).¹⁸ A longitudinal StudY of optiMzed Blood pressure lowerIng therapy with fixed cOmbination perindopril/amlodipine (the SYMBIO study) evaluated efficacy of Coveram in 2132 patients (age 60.8±11.9 years, 49% female, BMI 29.7±5.1) with treated but uncontrolled hypertension (ie, SBP/DBP ≥140/90 mm Hg or ≥130/ 80 mm Hg in the presence of high cardiovascular risk) from 223 healthcare centers. At study inclusion, patients receiving an angiotensin-converting enzyme inhibitor (77% of patients) and/or CCBs (59%), either as individual drugs or in combination, were switched to treatment with Coveram (5/5 mg, 5/ 10 mg, 10/5 mg, or 10/10 mg). Dosages were determined at the discretion of the treating physician and were titrated to optimize management of hypertension. Other antihypertensive treatments remained unchanged.¹⁹

At baseline, SBP and DBP values were 158.5±17.5 mm Hg and 93.6±9.8 mm Hg, respectively. Cardiovascular risk factors included dyslipidemia (70% of patients), smoking (24%), and diabetes (23%). Notable medical histories included coronary heart disease (34%), myocardial infarction (8% of patients), left ventricular hypertrophy (34%), and stroke (8%).

At month 3, BP had decreased to 132.9±10.6 /80.6±6.3 mm Hg (ΔBP = –25.9/-13 mm Hg vs baseline; P<0.00001). Furthermore, 74% of patients achieved recommended target BP levels. According to the grade of hypertension, 84% of patients with previously uncontrolled grade 1 hypertension achieved target BP, and 72% and 52% of those with grade 2 and grade 3 hypertension, respectively. Lower-limb edema was reported in 5.4% of patients.

_ Effective BP normalization: the Coveram solution to the contemporary emphasis on SBP
The rise in SBP is linear throughout life, starting from the age of 30 years, while DBP falls progressively from the age of 50 years. As more than 75% of people with hypertension are over the age of 50, the burden of disease is mainly due to elevated SBP. Moreover, systolic hypertension is a better predictor of stroke, coronary heart disease, heart failure, as well as allcause mortality than DBP.^20-22

The clinical advantages of achieving high rates of BP treatment goals with Coveram in a broad range of patients, such as those with newly diagnosed, untreated, or uncontrolled hypertension (the STRONG study), are obvious, as well as additional BP reduction and BP control in patients previously unsuccessfully treated with multiple antihypertensive therapies (the SYMBIO study). Of note, the rates of guideline-recommended BP goals (<140/90 mm Hg and <130/80 mm Hg in patients with diabetes) reported with Coveram (66% to 74%) seem to be the most effective, since results published for other combinations often include add-on therapy with a diuretic as a 3rd antihypertensive agent (Table I).^18,19,23-27

Table I.