Hypertension 2010: what was new for the cardiologist?

1. Introduction

2. What is the best method to

estimate cardiovascular risk?

3. Evaluation of total

cardiovascular risk: practical

implications

4. When should treatment of

high BP be initiated?

5. What is the optimal goal BP in

subjects with cardiovascular

disease?

6. What is the optimal choice of

antihypertensive drug?

7. Treatment strategies in

special conditions

8. How should concomitant risk

factors be treated?

9. Conclusions

10. Expert opinion

Review

Hypertension 2010: what was newfor the cardiologist?Zbigniew Gaciong† & Bartosz Symonides†Medical University of Warsaw, Department of Internal Medicine, Hypertension and Vascular

Diseases, Poland

Importance of the field: Despite extensive clinical research, still there is some

uncertainty regarding management of hypertension, in particular initial and

goal blood pressure levels and selection of optimal pharmacotherapy, as

well as concomitant medications, to reduce other risk factors.

Areas covered in this review: An overview of recent findings from major clin-

ical trials in hypertension (until July 2010), along with a reappraisal of the

European Society of Hypertension 2009 guidelines.

What the reader will gain: Practical overview of the management of hyper-

tension, including threshold and goal blood pressure in specific situations,

choice of antihypertensive medications and indications for treatment of

concomitant risk factors.

Take home message: Primary benefits of antihypertensive therapy are medi-

ated by blood pressure reduction and the majority of patients will require

at least two drugs, with the preference of fixed-dose combinations for

effective blood pressure control.

Keywords: antihypertensive therapy, goal blood pressure, guidelines, hypertension,

renal artery stenosis

Expert Opin. Pharmacother. (2010) 11(16):2579-2597

1. Introduction

In October 2009, The European Society of Hypertension (ESH) released a docu-ment [1] that critically reviewed previous hypertension guidelines published just2 years earlier [2]. In the current paper -- appropriately named Reappraisal -- theauthors critically evaluate both contemporary and older evidence from clinical trialsto question certain statements from previous guidelines as well as endorse some rec-ommendations. This update included data from five major clinical trials publishedwithin the last 2 years addressing:

- The benefit of blood pressure (BP) lowering in patients with type 2 diabetesmellitus (ADVANCE) [3]

- The role of angiotensin receptor blocker (ARB) treatment with or without anACE inhibitor in patients at very high cardiovascular risk (ONTARGET,TRANSCEND) [4,5]

- Antihypertensive treatment in the very elderly (HYVET) [6]

- The use of combination therapy in hypertension (ACCOMPLISH) [7].

However, since the publication of Reappraisal, results of new important clinicaltrials have been presented that may influence current recommendations regarding:

- Goal blood pressure in non-diabetic (Cardio-Sis) and diabetic patients(ACCORD) [8,9]

- The role of renin-angiotensin system (RAS) inhibition in diabetes prevention(NAVIGATOR) [10]

10.1517/14656566.2010.513972 © 2010 Informa UK, Ltd. ISSN 1465-6566 2579All rights reserved: reproduction in whole or in part not permitted

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- The value of renal artery stenting for atheroscleroticstenosis (ASTRAL) [11]

- Concomitant treatment with low-dose aspirin(AAAT) [12].

Also, important new meta-analyses have determined thequantitative efficacy of different classes of antihypertensivedrugs in prevention of major clinical complications [13], riskof new-onset diabetes [14,15], incidence of episodes ofatrial fibrillation [16] or effect on BP lowering, alone or incombination [17,18].In the present survey, these new data will be presented with

an attempt to offer a practical recommendations for

cardiologists taking care of their hypertensive patients. In par-ticular, BP management in terms of treatment initiation,blood pressure goals, choice of antihypertensive drugs, andindications for pharmacotherapy of associated risk factorswill be discussed. Special emphasis will be placed on certainhigh-risk groups such as the elderly, diabetics, and patientswith a history of cardiovascular incidents.

2. What is the best method to estimatecardiovascular risk?

Assessment of total cardiovascular risk dictates the decisionabout treatment initiation, intensity and goals. The finalestimate is based on the presence of risk factors, subclinicalorgan damage, history of atherosclerotic complications andconcomitant states like diabetes or chronic kidney disease.

Current expert opinion emphasizes the role of testing forsubclinical evidence of cardiovascular disease [1,2]. Any modal-ity that can be used to detect asymptomatic target organ dam-age should be applied, from simple (EGFR, echocardiography[ECG], albumin urinary excretion) to more sophisticated,requiring special skills and equipment (echocardiography,pulse wave velocity or central arterial pressure measurements).Recent data show that certain new parameters obtained fromwidely available test have predictive power for future fatal andnonfatal events. For example, left ventricle mass (LVM) maybe more accurately estimated with a Novacode equation thatis based on both voltage and strain pattern criteria. In the pro-spective study including 7495 adults, this estimate was anindependent and significant predictor of 10-year cardiovascu-lar mortality [19]. Also, simple parameters like amplitude ofR-wave in lead aVL shows very good correlation with cardio-vascular risk and detects left ventricular hypertrophy with asensitivity similar to that of established ECG criteria like Cor-nell product [20]. Still, among relatively available methods,ECG remains the most accurate, with significant predictivevalue. In the prospective PAMELA (Pressioni Arteriose Moni-torate E Loro Associazioni) study, increase of LVM by 10%,even within normal range, was associated with an increasedrisk [21].

This is advised to examine for early vascular changes asincreased intima-media thickness (IMT) in carotid artery,and indirect indices of arteriosclerosis like carotid-femoralpulse wave velocity (PWV) or augmentation index, reflectingcentral BP. Data from recent studies show that in apopulation without significant cardiovascular disease, anyabnormalities in these parameters are harbingers of worseprognosis [22-24].

Despite the fact that different measures of arterial stiffnessand wave reflection have been considered as markers ofcardiovascular risk, there is only one analysis that comparesprognostic utility of those parameters in prospective,community-based study. In the Framingham Heart Study,2232 disease-free participants were observed for a median of7.8 years after measurement of markers of arterial stiffness

Article highlights.

. It appears reasonable to start blood pressure loweringtherapy in stage 1 hypertensive patients at low/moderate risk after a suitable period with life-stylemodification. Treatment may be initiated immediately insubjects with high risk or grade 2 or 3 hypertension.

. SBP should be lowered below 140 mm Hg and DBPbelow 90 mm Hg in all hypertensive patients. Previouslyuntreated very old patients (>80 years) should starttreatment with SBP at least 160 mm Hg with goal BPbelow 150 mm Hg. In subjects with isolated systolicblood pressure, caution should be taken not to lowerDBP below 65 mm Hg.

. There is no clinical trial evidence that diabetic subjectswould obtain additional benefit from reduction in SBPbelow 130 mm Hg. However, in subjects with diabeticnephropathy benefits of treatment were observedregardless initial BP level. In patients with advanceatherosclerotic artery disease progressive lowering ofSBP below mm Hg and DBP below 75 mm Hg may beassociated with an increased incidence of cardiovascularincidents.

. The 2007 ESC/ESH guidelines conclusion that diuretics,ACE inhibitors, ARBs, CCB, and beta-blockers can all beused for initiation of antihypertensive therapy can thusbe confirmed. Most hypertensive patients will need atleast 2 different drugs to achieve satisfactory BP control,and fixed-dose combinations seems to facilitate reachingBP target. Among different possible combinations RASinhibition and CCB seem to offer better metabolicprofile and more effective organ protection whilecombined use of ACE inhibitors with ARBs or diureticswith beta-blockers should be avoided due to increasedrisk of renal complications or new-onset diabetes,respectively.

. Treatment of associated risk factors with anti-plateletagents or statins for primary prevention should be basedon estimated risk/benefit ratio. Diabetes or subclinicalatherosclerosis without any clinical atheroscleroticcomplications cannot be considered as compellingindications for anti-platelet therapy.

This box summarizes key points contained in the article.

Hypertension 2010: what was new for the cardiologist?

2580 Expert Opin. Pharmacother. (2010) 11(16)

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(PWV), wave reflection (augmentation index, carotid brachialpressure amplification) and central pulse pressure. Using mul-tiple variable models adjusted for concomitant risk factorsonly higher aortic stiffness assessed by PWV improved predic-tion of future cardiovascular events, independently of stan-dard risk factors like age, gender, smoking, hypertension,diabetes, and lipids [25].

The 2007 ESH/ESC guidelines included urinary albuminand EGFR as measures of subclinical kidney damage associ-ated with cardiovascular risk [2]. In a recent meta-analysis,standardized data for all-cause and cardiovascular mortalitywere pooled from studies enrolling at least 1000 participantsfor whom baseline measurement were available for EGFRand urine albumin excretion. Urine albumin-to-creatinineratio (ACR) was measured in 14 studies including a total of105,872 participants (730,577 person-years), and urineprotein was measured by dipstick in seven studies enrollinga total of 1,128,310 subjects (4,732,110 person-years). Riskfor mortality was unrelated to an EGFR between 75 and105 ml/min/1.73 m2 and increased at lower EGFRs. Adjustedhazard ratios (HR) for all-cause mortality versus an EGFR of95 ml/min/1.73 m2 were 1.18 (95% CI, 1.05 -- 1.32) for anEGFR of 60 ml/min/1.73 m2, 1.57 (95% CI, 1.39 -- 1.78)for an EGFR of 45 ml/min/1.73 m2, and 3.14 (95% CI,2.39 -- 4.13) for an EGFR of 15 ml/min/1.73 m2. On thelog--log scale, ACR was linearly associated with the risk formortality without threshold effects. Adjusted HRs for all-cause mortality versus an ACR of 0.6 mg/mmol were1.20 (95% CI, 1.15 -- 1.26) for an ACR of 1.1 mg/mmol,1.63 (95% CI, 1.50 -- 1.77) for an ACR of 3.4 mg/mmol,and 2.22 (95% CI, 1.97 -- 2.51) for an ACR of 33.9 mg/mmol. ACR and EGFR were multiplicatively associatedwith the risk for mortality, and there was no evidence forinteraction. Results were similar for cardiovascular mortalityand in studies with dipstick measurements of urine protein.As stated by the authors of the study, ‘EGFR less than60 ml/min/1.73 m2 and ACR 1.1 mg/mmol (10 mg/g) ormore are independent predictors of mortality risk in thegeneral population’ [26].

For GFR calculation, authors used the Modification ofDiet in Renal Disease Study (MDRD) equation, which wasderived from primarily white subjects (mean age of 51 ±12.7 years) who had non-diabetic kidney disease, with meanGFR of 40 ml/min/1.73 m2. Like other common formulasutilized to estimate the GFR, they are less accurate in certainpopulations. These include individuals with normal GFR,children, elderly patients, specific ethnic groups, pregnantwomen, and those with unusual muscle mass, body habitus,and weight (e.g., morbid obesity, amputees).

The CKD-EPI equation (The Chronic Kidney DiseaseEpidemiology Collaboration) was developed to provide amore accurate estimate of GFR among individuals with nor-mal or only mildly reduced GFR (> 60 ml/min/1.73 m2),using data pooled from 10 studies and validated against dataderived from 16 additional studies, in which the gold

standard was direct measurement of GFR using external filtra-tion markers [27]. CKD-EPI uses the same variables (serumcreatinine level, age, gender, and race) as the MDRD equa-tion. In the validation studies, the CKD-EPI equation wasas accurate as the MDRD study equation among individualswith estimated GFR < 60 ml/min/1.73 m2 and substantiallymore accurate among those with higher GFRs. When bothequations were used to estimate GFR in > 16,000 NHANESparticipants, GFR estimates by CKD-EPI were higher thanestimates obtained using the MDRD Study equation amongindividuals with a measured GFR > 30 ml/min/1.73 m2. Asa result, the overall prevalence of CKD was lower when theCKD-EPI equation was used to define the population withchronic kidney diseases (13.0 vs 11.5%). A possible limitationof the CKD-EPI equation is that it was developed usingsample populations that included few elderly and non-whiteindividuals, as well as people selected for or against havingkidney disease.

In the recent study, EGFR calculated based on CKD-EPIand MDRD equations was correlated with cardiovascular epi-sodes in the 13,905 middle-age subjects followed by a medianof 16.9 years participating in a prospective cohort study, theAtherosclerosis Risk in Communities (ARIC) Study [28].The CKD-EPI equation better categorized individuals withrespect to long-term clinical risk compared with the MDRDstudy equation, suggesting improved clinical usefulness inthis middle-aged population.

In the algorithm for global cardiovascular risk estimationused in current guidelines, the presence of metabolic syn-drome places a hypertensive subject in the group with highor very high added risk. It is assumed that clustering ofabdominal obesity, elevated glucose, abnormal lipids, and ele-vated BP are associated with an increased risk of coronaryheart disease, greater than that conferred by its constituentcomponents. In 2005, the American Diabetes Association(ADA) and the European Association for the Study of Diabe-tes (EASD) published a joint statement raising questionsabout whether the components of the metabolic syndromecan be classified as a true ‘syndrome’ [29]. The critical weak-ness of the idea of metabolic syndrome is that treatment ofthe syndrome is no different from treatment for each of itscomponents. Other arguments raised include imprecise defi-nition due to lack of a consistent evidence base for settingthe thresholds for the various components in the definitions.Also, pathogenesis of metabolic syndrome seems to be unclearand insulin resistance may not underlie all disturbances.Within the metabolic syndrome, there are various phenotypesrequiring a different treatment approach. In some studiesthe cardiovascular risk associated with the metabolic syn-drome has not been shown to be greater than the sum of itsindividual components [30].

To investigate this issue, Mente and colleagues analyzeddata from the INTERHEART study, a case-control study ofincident acute myocardial infarction (MI) that involved12,297 cases and 14,606 controls from 52 countries. They

Gaciong & Symonides

Expert Opin. Pharmacother. (2010) 11(16) 2581

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classified the study participants using the World HealthOrganization (WHO) and International Diabetes Federation(IDF) criteria for metabolic syndrome, and their risks forMI were compared with the individual metabolic-syndromecomponent factors. Results showed that metabolic syndromewas associated with a two to three times increased risk ofMI, but the same risk was conferred by having either hyper-tension or diabetes alone [31]. Authors found the continuousrelationship between values of parameters included in the def-inition of metabolic syndrome and risk of acute MI. This cor-relation was also observed for subthreshold values -- that is,levels higher than normal but below the levels that define dia-betes, hypertension, low HDL or abdominal obesity. Aggrega-tion of risk factors with values below their threshold wasassociated with a significantly greater risk of MI, comparedwith having component factors with normal values (odds ratio1.5), but lower than the risk conferred by an aggregation ofrisk factors with values above the threshold points. In theirpaper, the investigators conclude: ‘These findings of a dose--response relationship between risk-factor severity and MIrisk suggest that a standard definition of metabolic syndromeloses information when continuous variables are converted tocategorical variables and provide support for calls to replacethe categorical definition of metabolic syndrome with a scor-ing system that may involve each risk factor being assigned aweight based on its level and a regression formula developedto estimate risk’. Therefore the advice remains to treat indi-vidual risk factors when present, and to prescribe therapeuticlifestyle changes and weight management for obese patientswith multiple risk factors.Experimental and clinical evidence have established inflam-

matory processes as important contributors to atherogenesis,as well as to the vulnerability of an atherosclerotic lesion to rup-ture or erosion. The most extensively studied biomarker ofinflammation in cardiovascular diseases is C-reactive protein(CRP), for which standardized high-sensitivity assays (hs-CRP) are widely available. In apparently healthy subjects, hs-CRP level is continuously related to the risk of cardiovascularcomplications (including sudden cardiac death, MI, ischemicstroke, atrial fibrillation, and heart failure) as well as develop-ment of hypertension and diabetes mellitus. In patients withestablished atherosclerotic vascular disease, the predictive valueof CRP for disease severity and prognosis has been studied indifferent populations including patients after acute coro-nary syndrome, revascularization procedures, cerebrovasculardisease, heart failure, atrial fibrillation and intermittentclaudication, and recipients of cardiac allograft [32].The observations that statin therapy reduces serum CRP

and that serum CRP is correlated with cardiovascular riskraises the possibility that the risk reduction with statin therapymay be attributed, at least in part, to anti-inflammatoryeffects. In a literature review of 13 controlled trials, statinsreduced CRP levels by 13 -- 50% compared with placebo;there was no advantage of one statin over another in fivestudies making direct comparisons, and more intensive statin

therapy was associated with a modestly greater reduction inCRP [33].

The 2007 European guidelines have emphasized the prog-nostic value of treatment-induced modifications of subclinicalorgan damage. Analysis of data from the LIFE (LosartanIntervention For Endpoint Reduction in Hypertension) studyshows that changes in ECG signs of left ventricular hypertro-phy (LVH), left atrial diameter and left ventricular geometryas well as albumin excretion correlated with incident cardio-vascular event rate [34,35]. These findings were confirmed byrecent data from the ADVANCE (Action in Diabetes andVascular disease; Preterax and Diamicron-MR ControlledEvaluation) trial which included 11,140 patients withtype 2 diabetes randomly treated with a fixed combinationof perindopril--indapamide or placebo, regardless of their ini-tial BP level. The level of albumin excretion correlated withrenal and cardiovascular risk, not only at entry but alsoaccording to on-treatment values. A protective effect of pro-teinuria reduction was independent of the concomitant valuesof EGFR [36].

3. Evaluation of total cardiovascular risk:practical implications

The 2007 ESH/ESC guidelines recommend that differentorgans be searched for damage, because of the evidence thatmultiple organ damage (in the kidney and the heart) carriesa worse prognosis than when limited to a single organ.However, as it discussed below, the presence of subclinicalorgan damage does not mandate earlier initiation of antihy-pertensive treatment (i.e., with high normal BP). Treat-ment-induced improvement of LVH and increased urinaryprotein excretion are associated with a reduced incidence ofcardiovascular events [37], thereby giving physician andpatients an insight on whether the applied treatment isoffering organ protection.

New technology offers better measures to assess subclinicalorgan damage. For example, MRI allows detection of silentcerebrovascular lesions, which are even more prevalent thancardiac and renal subclinical damage. And, as one studyshows, white-matter lesions may develop in the absence ofother signs of organ damage [38]. However, new methods arecostly; and, more importantly, their effect on the strategy ofantihypertensive treatment has not been established. Availabledata, like the recently published INTERSTROKE study, con-firm that ‘old’ or ‘classical’ risk factors describe at least 90% ofmodifiable cardiovascular risk [39].

4. When should treatment of high BP beinitiated?

The ESH/ESC 2007 guidelines introduced the concept of dif-ferent goal thresholds for pharmacotherapy based on globalcardiovascular risk [2]. Subjects with high risk (those withdiabetes, chronic kidney disease or atherosclerotic disease)



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should receive antihypertensive drugs when high normal bloodpressure (‡ 130/85 mmHg) is recognized. For other patientgroups, including the elderly, recommendations are to initiatetreatment where BP is persistently ‡ 140/90 mmHg. How-ever, evidence for these guidelines comes mainly from obser-vational data, post hoc analysis of outcome trials and theeffects of BP lowering on subclinical damage. Moreover, inthe majority of trials the initial BP pressure values were diffi-cult to determine because subjects were recruited while receiv-ing antihypertensive drugs at baseline. Frequently, subjectsfrom so-called ‘low-risk groups’ had symptoms of subclinicalorgan damage, which increases their risk category. Also, nor-mal BP was differently defined and, in the ‘normotensive’arm of the ABCD (Appropriate Blood Pressure Controlin Diabetes) trial, included diabetic patients with SBP< 160 mmHg [40]. In the ADVANCE trial, the significant ben-efit of antihypertensive treatment was observed in diabeticswith initial SBP values ‡ 140 mmHg, but not in those withlower values [3]. Similar objections can be raised regarding theclinical trials which included patients with coronary heart dis-ease (INVEST, HOPE) or previous cerebrovascular incident(PROGRESS) [41-43].

In the most recent Cardio-Sis trial (see below), whichincluded patients without diabetes and known signs of sub-clinical organ damage, there was a requirement that systolicBP at baseline should be ‡ 150 mmHg and subjects had tobe treated for 12 weeks and present with at least one risk fac-tor [8]. Therefore, the substantial number of patients in theCardio-Sis study might actually belong to at least a moderaterisk category. Also, there is no single trial on elderly hyperten-sive patients that recruited patients with a SBP in the grade1 hypertension range (< 160 mmHg).

The goal of BP-lowering treatment is to prevent organ dam-age, and it should be administered immediately hypertension isdiagnosed. In patients with high BP, there are no data fromclinical trials on treatment benefits; however, the therapy post-poned the development of stage 1 hypertension in prehyperten-sive subjects (TROPHY [Trial of Preventing Hypertension],PHARAO [Prevention of Hypertension with the ACE-inhibitor Ramipril in Patients with High-normal BloodPressure]) [44,45]. In the ongoing TIResiAS trial, young (aged18 -- 40 years) prehypertensive persons are temporarily treatedwith ACE inhibitors or placebo for 1 year and their BP valuesand LVMwill be estimated 2 years after cessation of therapy [46].For diabetic subjects at risk presenting with microalbuminuriaor proteinuria, early treatment based on RAS inhibition is stillrecommended [1].

5. What is the optimal goal BP in subjectswith cardiovascular disease?

The ESH/ESC 2007 guidelines recommended lowering BPto < 140/90 mmHg in the general population and to< 130/80 mmHg in subjects with high or very highcardiovascular risk [2]. As it reviewed in Reappraisal, in the

majority of analyzed trials the suggested goal pressure has notbeen reached in the prevailing group of patients [1]. Moreover,in only a few small trials (ABCD, SANDS [Stop Atherosclero-sis in Native Diabetics Study]) were SBP values < 130 mmHgactually achieved, and they were associated with questionableclinical benefit, mostly related to surrogate end points [40,47].Similar results were found in trials that included patients witha history of coronary heart disease or cerebrovascular incidentwith no further risk reduction when BP was lowered to< 130 mmHg [48-52]. According to a review based only ondata from randomized controlled trials, there is no evidencethat lowering BP to targets < 140 -- 160/90 -- 100 mmHg isbeneficial to any hypertensive patient in terms of reducing mor-bidity and mortality. The only evidence in favor of currentlyrecommended BP goals is for diastolic blood pressure(DBP) £ 90 -- 100 mmHg, but there is no additional reductionin morbidity or mortality in lowering it to £ 85 mmHg.

The ACCORD (Action to Control Cardiovascular Risk inDiabetes) BP trial addressed the possible role of more aggres-sive BP lowering [9]. A total of 4733 diabetic patients wererandomized, in a non-blinded fashion, to an intensiveBP-lowering regimen with a target systolic BP goal of< 120 mmHg -- with patients on average taking 3.5 anti-hypertensives -- or standard BP lowering, where the goalwas < 140 mmHg. The primary composite outcome was non-fatal MI, nonfatal stroke, or death from cardiovascular causes,and the mean follow-up was 4.7 years. After 1 year, the meansystolic pressure (SBP) was 119.3 mmHg in the intensiveBP-lowering group and 133.5 mmHg in the standard group.There was no significant difference in the primary end pointbetween the groups. There was also no difference betweenthe groups in terms of prespecified secondary end points,which included the primary outcome plus revascularizationor nonfatal heart failure; major coronary disease events; andfatal or nonfatal heart failure. The significant difference instroke between the intensive and standard BP-loweringarms was noted, yet stroke was relatively uncommon, and89 patients had to be treated for 5 years to prevent onestroke. Subjects assigned to the intensive-therapy groupwere more likely to experience adverse events due to anti-hypertensive therapy (3.3, vs 1.3% in the standard-therapygroup; p < 0.001).

In another recently published trial, Cardio-Sis, a total of1111 non-diabetic individuals aged ‡ 55 years withSBP ‡ 150 mmHg were randomly assigned to a targetSBP < 140 mmHg (usual control) or < 130 mmHg. All trialparticipants had been taking antihypertensive medicationfor ‡ 12 weeks and had at least one additional risk factor, asdefined by ESH/ESC hypertension management guidelines [8].The usual-control group reached a mean BP of 135.6/78.7mmHg and the tight-control group reached a mean of131.9/77.4 mmHg. Throughout the study, use of antihyper-tensive drugs increased equally in both groups, although useof diuretics and ARBs was more frequent in the tight-controlgroup. By the end of the study, 17.0% of the usual-control

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group had ECG-documented LVH, the primary end point ofthe trial, compared with only 11.4% of the tight-control group(p = 0.013). A composite cardiovascular end point occurred in9.4% of patients in the usual-control group versus 4.8% in thetight control group (p = 0.003). Among the components ofthe composite end point, rates of new-onset atrial fibrillationand coronary revascularization were significantly lower in thetight-control group than the usual-control group (1.8 vs3.8%, p = 0.044; and 0.9 vs 2.7%, p = 0.032, respectively).Adverse events were rare, generally mild, and did not differsignificantly between the two groups.The Cardio-Sis trial was not double-blind and there were

few clinical events due to the small sample size, yet its resultssuggest potential benefits for tight BP control beyondcurrently recommended levels in selected groups of patients.In many trials (VALUE, ONTARGET, PROGRESS,

INVEST, ADVANCE, TNT), post hoc analysis has been per-formed to evaluate the relationship between achieved BP andcardiovascular incidents. Data from these studies show a pro-gressive reduction in cardiovascular events with progressivelowering of SBP down to around 120 mmHg and DBPdown to about 75 mmHg. However, it should be emphasizedthat within the lower ranges of BP the observed benefit wassmaller than expected based on the difference in mmHg [53,54].These findings do not apply to nephroprotection in dia-

betic subjects. In ADVANCE trial, administration of fixedperindopril--indapamide combination resulted in reducedrisk of renal end point as the SBP achieved during treatmentdecreased to values about 110 mmHg regardless of initialBP level [36].Also, the issue of ‘the J-curve phenomenon’ reappeared

due to post hoc analyses of the results of trials on high-riskpatients. For example, a secondary analysis of the INVEST trial(The International Verapamil-Trandolapril Study) of > 22,000patients demonstrated a a strong J-shaped relationship betweenDBP and adverse outcomes (death, nonfatal MI or nonfatalstroke). In this study, however, more patients with a mean fol-low-up DBP < 70 mmHg had a history of MI and heart failurethan those with higher diastolic pressures (> 40 vs < 30%, and10 vs 5%, respectively). The J-shaped relationship wasmarkedly attenuated in multivariate analyses adjusted for MI,heart failure, and risk factors for cardiovascular disease, suggest-ing that the J-shaped relationship is partly related to underlyingcoronary artery disease [50].Previous randomized trials with placebo control have shown a

similar J-curve in both treated and placebo groups and for non-cardiovascular as well as cardiovascularmortality, suggesting thatpatients with lower DBPs are at higher risk independent ofantihypertensive therapy. The J-curve for MI and DBP hasbeen found in VALUE, TNT, ONTARGET, SYST-EUR,INSIGHT,HOT,ACTION, PROVE-IT, and other large, pro-spective, randomized trials. In most of these, the J-curve for cor-onary events and DBP was more pronounced in patients withmanifest coronary artery disease (CAD) than in patients withoutCAD. It is possible that patients with CAD do worse at these

lower pressures because much coronary filling occurs dur-ing diastole; alternatively, low DBPs may be a reflection ofunderlying severe vascular disease, or other chronic illness.This hypothesis is supported by results of the ROADMAP study(Olmesartan and Diabetes Microalbuminuria Prevention), pre-sented during the ESH meeting in Oslo in June 2010, whichshow a lower incidence of new-onset nephropathy in diabeticsubjects receiving olmesartan as compared to placebo. A slightexcess of cardiovascular deaths was noted in the ARB-treatedgroup, but only in patients with pre-existing atheroscleroticcomplications and SBP < 120 mmHg.

The current reappraisal of the ESH/ESC guidelines statesthat there is sufficient evidence to recommend that SBP belowered to < 140 mmHg and DBP < 90 mmHg in all hyper-tensive patients, regardless of their cardiovascular risk. How-ever, the benefits of lowering SBP to < 140 mmHg were nottested in clinical trials in the elderly.

Lowering SBP to < 130 mmHg may provide benefit in sub-jects with uncomplicated hypertension, but patients withadvanced atherosclerotic artery disease may be exposed tohigher risk with SBP/DBP values < 120/75 mmHg (J-curvephenomenon). However, the J-curve is probably explainedby poor health associated with lower BPs rather than anadverse effect of antihypertensive therapy. More aggressiveBP lowering slows the rate of progression of chronic renal dis-ease in patients with daily urinary proteinuria > 1 g, as well asin diabetics at risk of nephropathy [55].

6. What is the optimal choice ofantihypertensive drug?

The main benefits of antihypertensive therapy are due tolowering BP itself and are largely independent of the class ofdrugs used. The 2007 ESH/ESC hypertension guidelines listedfive classes of drugs considered appropriate as first-line therapy:

- Diuretics- ACE inhibitors- Calcium channel blockers (CCBs)- ARBs- Beta-blockers.

The choice of a particular medication is based on concom-itant diseases and risk factors that constitute indications orcontraindications for specific classes of antihypertensive drugs.The list is compelling, and relative indications has notchanged substantially. A number of major new trials and addi-tional retrospective analyses have since added important evi-dence in favor of the protective effects of ACE inhibitors,ARBs, and CCBs alone or in combination.

6.1 Beta-blockersThe use of beta-blockers in hypertension remains controver-sial [56], yet clinical trial evidence as well as meta-analysesshow that beta-blockers have relative advantages and



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inconveniences. The largest meta-analysis ever performed,which included 147 randomized trials, showed only lowerefficacy of beta-blockers (17 vs 29% reduction with otherclasses of antihypertensive drugs) in preventing stroke, nodifference in preventing coronary events and heart failure,and a higher efficacy than other drugs in patients withrecent acute coronary incidence [13]. Compared with otheragents -- particularly ACE inhibitors or ARBs -- beta-blockersare less efficient in reduction of LVH, increased intima-media thickness, arterial stiffness and central pressure.They also have well-known adverse metabolic effects, partic-ularly in combination with diuretics, and recent meta-analysis reported an increased risk of new-onset diabetesby 33% as compared to placebo or other classes of anti-hypertensive drugs [14]. However, it should be noted thatbeta-blockers do not constitute a homogenous class and‘vasodilating’ agents (carvedilol, nebivolol, celiprolol) maynot share negative properties with older agents. Carvedilolshows a better metabolic profile than metoprolol bothin terms of risk of new-onset diabetes and control ofestablished disease (COMET, GEMINI studies) -- [57,58].Nebivolol reduces central arterial pressure and improvesendothelial dysfunction as well as its use is associated withlower risk of erectile dysfunction [59]. Both drugs showbenefit in clinical outcomes in patients with heartfailure [60,61].

6.2 DiureticsAmerican guidelines (JNC-7) recognize thiazide diuretics asthe first choice in therapy of uncomplicated hypertension [62].However, the evidence base for thiazide diuretics refers to datafrom trials done in the 1980s and 1990s, when the dose ofdiuretics used was about four times greater than that nowused. Some hypertension experts draw attention to the factthat there are no data showing that 12.5 -- 25 mg of hydro-chlorothiazide (HCTZ) reduces heart attack and stroke ordeath [63]. All other trials that have shown improvements inoutcomes with diuretics have employed drugs other thanHCTZ, like chlorthalidone in SHEP and ALLHAT, andindapamide in PROGRESS, ADVANCE and HYVET.Comparisons based on 24-h ambulatory blood pressure(ABP) monitoring show that thiazide-like diuretics (chlortha-lidone and indapamide) are about 1.5 -- 2.0 times morepotent and have a much longer duration of action thanHCTZ, with a similar effect on serum potassium levels [17].In the ACCOMPLISH (Avoiding Cardiovascular Eventsin Combination Therapy in Patients Living with SystolicHypertension) trial, combination of HCTZ with an ACEinhibitor was less effective in prevention of cardiovascularcomplications than the same ACE inhibitor with a CCB [7].Also, replacement of HCTZ with a CCB in combinationwith ARB reverses glucose intolerance in subjects withmetabolic syndrome (The Study of Trandolapril/VerapamilSR and Insulin Resistance -- Long-Term Extension Trial,STAR-LET) [64].

6.3 ACE inhibitors and angiotensin receptor

antagonistsDebate is ongoing as to whether ACE inhibitors can be substi-tuted with ARBs. In the TRANSCEND (Telmisartan Ran-domized Assessment Study in ACE-I Intolerant Subjectswith Cardiovascular Disease) study, in subjects with high car-diovascular risk and intolerant of ACE inhibitors, treatmentwith telmisartan resulted in only a small and nonsignificantreduction in cardiovascular events as compared to placebo [5].Similar findings were reported in the PROFESS (PreventionRegimen for Effectively avoiding Second Strokes) trial, whichevaluated efficacy of telmisartan in secondary prevention ofcerebrovascular events [65]. Yet results of the very largeONTARGET trial have shown that telmisartan was not statis-tically inferior to ramipril in the effect on cardiovascular endpoints [4]. The results of this study question the credibilityof a different meta-analysis that suggested lower efficacy ofARBs in preventing MI, as well as claims that ACE inhibitorsare inferior to sartans in preventing strokes [66,67]. In theONTARGET trial, > 60% of patients recruited to the studyhad a history of coronary heart disease and the rates of MIand stroke were similar in both treatment groups.

Meta-analysis also suggested reduced risk of new-onsetdiabetes with treatment based on RAS blockade [15]. In partic-ular, telmisartan has repeatedly been shown to activatePPAR-g receptors, resulting in a favorable metabolic profileand anti-diabetogenic potential [68]. However, in theONTARGET trial there was no difference in diabetes riskin patients treated with telmisartan or ramipril; also ramiprilonly slightly improved glucose tolerance as compared to pla-cebo in the DREAM (Diabetes Reduction Assessment withRamipril and Rosiglitazone Medication) study [69]. Recentlypublished data from NAVIGATOR (Nateglinide and Valsar-tan in Impaired Glucose Tolerance Outcomes Research) trialshow reduced by 14% relative risk of new-onset diabetes inpatients with glucose intolerance receiving valsartan [10]. Yetimprovement in metabolic profile in valsartan-treated subjectswas not associated with reduction in cardiovascular risk.

In the CHARM (Candesartan in Heart Failure -- Assess-ment of Mortality and Morbidity) study, which includedpatients with heart failure treated with candesartan, a signifi-cant excess of fatal cancers was observed; but investigatorsconcluded that this finding was probably due to chance [70].New cancer data available for 61,950 patients from five trials,with most patients (85.7%) receiving telmisartan as the studydrug, were used for meta-analysis to assess the incidence ofnew cancer. In the meta-analysis, patients randomly assignedto receive ARBs had a significantly increased risk of new can-cer occurrence, compared with those in the control groups(7.2 vs 6.0%; risk ratio [RR] 1.08; p = 0.016). When analysiswas limited to trials where cancer was a prespecified endpoint, the RR was 1.11 (p = 0.001). Among the malignanciesexamined -- lung, breast, and prostate -- only new lung canceroccurrence was significantly higher in those randomlyassigned to ARBs than in control subjects (0.9 vs 0.7%; RR

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1.25; p = 0.01). There was no significant difference in cancerdeaths observed in the meta-analysis between those whotook ARBs and control subjects (1.8 vs 1.6%; RR 1.07;p = 0.183) [71].The mechanism of potential association between ARBs and

lung cancer risk remains speculative. In animal models, block-ade of the angiotensin receptor type 1 and direct stimulationof angiotensin receptors type 2 -- both of which are affectedby ARBs -- are capable of stimulating tumor angiogenesis.But the relevance of these observations in human malignancyis largely unknown. Also, it is difficult to explain differencesin cancer incidence over a very short period of observation,while development of lung cancer usually takes about 10 years.The observed risk is small and can be compared to that of pas-sive smoking, but the results of meta-analysis should still beconsidered hypothesis-generating and more studies in thisarea are needed. In their meta-analysis, the authors omittedmany trials that contain cancer data. Only adding cancer casesfrom the VALUE trial abolishes the association between ARBsand cancer risk [72].

6.4 Calcium antagonists (CaCB)Recent meta-analyses suggest that CaCB offer better protec-tion against stroke but are less efficient in preventing heartfailure [13]. However, when BP difference was considered,the efficacy of CaCB in preventing heart failure was onlyslightly lower than other antihypertensive agents (19 vs24%). CaCB show a neutral metabolic profile and they maybe used in combination with other drugs, in particular RASblockade (discussed below). At the moment, this group hasbeen completely cleared from the suspicion of causing anexcess of coronary complications.

6.5 Combination therapyNumerous data from clinical trials demonstrate that BPcontrol requires administration of at least two drugs in mostpatients. A meta-analysis of 42 different studies with> 11,000 patients has shown that adding another antihyper-tensive drug is five times more effective than doubling thedose of existing drug [17]. Combination therapy may offera synergism not only in lowering BP but also in organprotection. This notion is confirmed by data from various tri-als (ASCOT BPLA, STAR, ACCOMPLISH, ADVANCE)that used defined combinations of BP-lowering drugs.The 2007 guidelines strongly favored combination therapy,

which most hypertensive patients needs to achieve their BPgoal. Combinations as an initial therapy were particularlyrecommended in patients with high cardiovascular risk or/andthose who need reduction of BP by > 20/10 mmHg of SBP/DBP values, respectively. The guidelines stated that combina-tion should be based on a complementary mechanism of actionthat delivers additional BP reduction and/or minimizes individ-ual side effects. Any combination that fulfils these criteriacould be used; however, trial data suggest important clinicaldifferences between specific combinations.

The 2009 update provides practical information aboutadvantages and disadvantages of specific two-drug combina-tions. Combination of thiazide (or thiazide-like diuretic)with RAS blockade is among the most frequently used in clin-ical practice. Fixed-dose perindopril--indapamide combina-tion was used in ADVANCE -- the largest-ever study oftreatments for type 2 diabetes mellitus which included popu-lation of 11,140 patients, mean age 66 years, with at least oneadditional risk factor for cardiovascular disease who were ran-domized to combination or placebo [3]. ConcomitantBP-lowering therapy (including ARBs and ACE inhibitors),except thiazide diuretics, was allowed at the discretion ofthe treating physician. Over a mean follow-up duration of4.3 years, average BP in the active treatment group was134.7/74.8 mmHg compared with 140.3/77.0 mmHg inthe placebo group. The primary end point of the study, acomposite of major macrovascular (death from cardiovasculardisease, nonfatal stroke or nonfatal MI) and microvascular(new or worsening renal or diabetic eye disease) events, wasreduced by 9% with active treatment versus placebo (hazardratio [HR] 0.91, 95% CI 0.83 -- 1.00, p = 0.041). The relativerisk of death from cardiovascular disease was reduced by 18%(HR 0.82, p = 0.027) and all-cause mortality by 14% (HR0.86, p = 0.025) in the active treatment arm, with significantreductions also seen with active treatment in total coronaryevents (14%) and total renal events (21%). Indapamide, towhich perindopril was added if the target BP of 150/80 wasnot reached, was used in the HYVET trial, which randomizedpeople aged > 80 and with sustained systolic blood pressure> 160 mmHg. Over a follow-up of only 2 years, active treat-ment as compared to placebo resulted in a significant 21%reduction of total and cardiovascular (21%) mortality. Riskof stroke was also significantly reduced, by 30%; new heartfailure by 64%. Serious adverse events were much more fre-quent with placebo (448 vs 358 instances) than with activetreatment [6]!

However, the presence of diuretic in combination mayincrease a probability of development of diabetes in popula-tion with high metabolic risk. In the STAR trial, patientswith glucose intolerance treated with losartan/HCTZ combi-nation showed higher incidence of new-onset diabetes ascompared to those receiving trandolapril/verapamil (T/V11.0 vs L/H 26.6%; p = 0.002) [73]. In the continuation ofthe trial (STARLET), patients on losartan/HCTZ switchedto trandolapril/verapamil combination, which resulted inimprovement of serum glucose concentration and insulinvalues [64].

Combination of ACE inhibitor or ARB with CCB offersnot only better metabolic profile, but also fully additive BPreduction; more importantly, it has been shown to providethe most efficient protection against target organ damage. Inthe ASCOT-BPLA (Anglo-Scandinavian Cardiac OutcomesTrial -- Blood Pressure-lowering Arm) trial, treatment withamlodipine--perindopril combination was more effective inlowering BP and cardiovascular events than combination of



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a beta-blocker with a thiazide [74]. In the EUROPA (EuropeanTrial on Reduction of Cardiac Events with Perindopril in Sta-ble Coronary Artery Disease) trial, patients with stable coro-nary heart disease who received perindopril experienced20% relative risk reduction of a composite cardiovascularend point of cardiovascular death, nonfatal MI, and resusci-tated cardiac arrest as compared to placebo-treated controls.At baseline, 32% of the EUROPA population were receivingCCB and post hoc analysis shows a significant clinical benefit(46% reduction in total mortality) compared with patientswho were not treated with CCB along with ACE inhibitor.Altogether, these data suggest a potential synergism and clin-ically important interaction between ACE inhibitors andCCB [75].

The ACCOMPLISH study was the first clinical outcometrial to compare different fixed-dose combinations. Over11,000 hypertensive patients with elevated cardiovascularrisk were randomized to receive an ACE inhibitor (benazepril)plus a calcium channel blocker (amlodipine or HCTZ). Thetrial was prematurely stopped after 36 months because thebenazepril--amlodipine combination was superior to the bena-zepril--HCTZ combination in reducing all cardiovascular fataland nonfatal events except for heart failure [7]. Further analysishas shown that the ACE inhibitor/CCB combination slowsprogression of chronic kidney disease to a greater extentthan ACE inhibitor/HCTZ [76].

It has been suggested that double RAS blockade with anARB plus an ACE inhibitor is useful in patients with renaldisease in whom proteinuria is insufficiently reduced withan ARB or ACE inhibitor alone. Evidence that this combina-tion is protective in renal outcomes came from the COOPER-ATE (Combination Treatment of Angiotensin-II ReceptorBlocker and Angiotensin-Converting-Enzyme Inhibitor inNon-Diabetic Renal Disease) trial including subjects withchronic kidney disease, but the credibility of this study wascalled into question and it was eventually retracted by thepublisher [77]. In hypertensive subjects, as observed in theONTARGET study, ARB/ACE inhibitor combination hasbeen associated with worsening of renal outcomes [4]. Thus,the direct evidence of the advantages of dual RAS blockadefor nephro/cardiovascular protection remains limited, whereasit is often associated with an increase in side effects like hyper-kalemia or decline in GFR. ACE/ARB combinations producelittle additional BP reduction compared with monotherapywith either agent alone, and in the ONTARGET study theACE inhibitor/ARB combination was less effective in preven-tion of cardiovascular end points. Therefore, for treatment ofhypertension this combination is not recommended. Yet therole of double blockade in subjects with established glomerul-opathy with substantial proteinuria is uncertain. In the ongo-ing VA-NEPHRON-D trial, the effect of ACE inhibitor/ARBcombination versus standard treatment with ARB on the pro-gression of kidney disease in individuals with type 2 diabetesand overt nephropathy is being evaluated; the study will becompleted in 2013.

The combination of a calcium antagonist with a diuretic isaccepted in the reappraisal of current guidelines, despite lackof synergistic effect in BP lowering. This combination wasused in the FEVER (Felodipine Event Reduction), ELSA(European Lacidipine Study on Atherosclerosis) and VALUEtrials with some clinical benefits [78-80]. In a population-based case-control study, patients treated with diuretics withCCB had a higher risk of MI than subjects receiving adiuretic/beta-blocker combination [81]. These findings suggestavoiding these combinations if possible.

6.6 Fixed-dose combinationsGuidelines recommend using fixed-dose combinations of twodrugs when initial monotherapy has failed and another drug isneeded to control BP, or as the first step in subjects requiringsubstantial BP reduction due to either high initial values orcardiovascular risk. Fixed-dose combinations, by reducingthe number of medications, facilitates adherence to therapy.A study using pharmacy records found that adherence wasinversely related to the number of medications and drops dra-matically with increasing number of doses taken per day from71% with once-daily dosing to 31% with four daily doses ofantihypertensive medications [82].

Employing low-dose fixed-combination therapies, asopposed to the usual treatment guidelines, which are com-plex, allows for better BP control. This was clearly demon-strated in the Canadian STITCH (Simplified TreatmentIntervention to Control Hypertension) trial, where a simplealgorithm was used consisting of four steps: initial use ofa low dose of diuretic/ACE inhibitor or diuretic/ARBfixed-dose combination; up-titration of combination therapyto the highest dose; addition of a calcium-channel blockerand up-titration; and addition of a non--first-line antihyper-tensive agent [83]. Family physician practices were asked toenroll patients with uncontrolled hypertension and employeither the STITCH algorithm (18 practices) or the usualCanadian guidelines (27 practices), then assess the proportionof patients treated to target BP after 6 months (< 140/90mmHg for those without diabetes mellitus, < 130/80 mmHgfor those with diabetes). The proportion achieving BP targetwas significantly higher in the intervention group (64.76 vs52.7%; p = 0.026), and multivariate analysis showed thatassignment to the simple-algorithm arm increased the chanceof reaching BP target by 20% (p = 0.028).

Rational drug combinations may improve overall tolerabil-ity of the treatment when side effects associated with a partic-ular agent are neutralized by pharmacological properties ofanother drug. An example is the use of low-dose combinationof ACE inhibitor and dihydropyridine CCB in a patient whoexperienced edema at a higher CCB dose [84].

Wald and Law described the concept of the single ‘polypill’that should contain different medications (triple antihyperten-sive combination, statin, aspirin and folic acid) for primary orsecondary prevention of heart disease [85].The Indian PolycapStudy (TIPS), tested ‘Polycap�’, a new capsule version of the

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polypill containing low doses of five generic drugs: b-blocker(atenolol 50 mg), a diuretic (HCTZ 12.5 mg), an ACE inhib-itor (ramipril 5 mg), a statin (simvastatin 20 mg), and aspirin(100 mg). Each component in the formulation of Polycapshowed efficacy similar to the effects of each alone. Also, the tol-erability of the Polycap was similar to that of other treatments,with no evidence of increasing intolerability with increasingnumber of active components in a single capsule [86].The ‘red heart pill’ is another polypill combination (ACE

inhibitor, diuretic, aspirin and simvastatin) being tested inpatients at moderate risk of cardiovascular disease in the Pro-gram to Improve Life and Longevity (PILL) pilot study and inthe Improving Adherence using Combination Therapy(IMPACT) trial. Results of a three-drug polypill containingaspirin, a statin, and an ACE inhibitor for secondary preven-tion in patients who have had a MI will be available in 2010.Nevertheless, the limited efficacy of aspirin and statins inprimary prophylaxis (see Section 8) questions the originalpolypill concept, and multiple drug combinations may be rec-ommended only for secondary prevention in high-risk sub-jects. Possible combination for initiation of antihypertensivetherapy are presented in Figure 1.

7. Treatment strategies in special conditions

7.1 ElderlyPublication of the results of HYVET trial (Hypertension inthe Very Elderly Trial) provided much needed informationof the effect of BP lowering in the very elderly. In the HYVETstudy, patients aged ‡ 80 years in whom entry SBPwas ‡ 160 mmHg (average 173 mmHg) were randomizedto receive either placebo or active treatment, consisting ofindapamide (1.5 mg daily) and the eventual addition of theACE inhibitor perindopril (2 and 4 mg daily) with the targetto attain a SBP value < 150 mmHg. The trial was stoppedafter < 2 years because of evident clinical benefits, includingreduction in stroke (30%), congestive heart failure (64%),and major cardiovascular events, and all-cause death (21%)in the active treatment group as compared to placebo. Thetherapy was very well tolerated, with a similar number ofadverse effects in both treatment and placebo arms [6].It is uncertain whether the HYVET results can be trans-

lated into a population of the same age, but with the morewidespread vascular damage that clinicians often see. Resultsin sicker populations may be better because of a higher eventrate and a potentially higher absolute benefit, but may also beworse because risks may be less dependent on BP.The Reappraisal of the ESH/ESC guidelines raises an issue

of lack of evidence of benefits of antihypertensive therapy inelderly people with grade 1 hypertension (SBP 140 -- 159mmHg) as well as when on-treatment SBP values were low-ered to < 140 mmHg. Secondary analysis of available datafrom trials in subjects with isolated systolic hypertensionshows an increased risk when DBP values are loweredto < 65 mmHg [87].

Thus, the current guidelines recommend the same treatmentalgorithm in elderly and younger patients. Treatment should becontinued or initiated when subjects turn 80, with initialmonotherapy with thiazide (or thiazide-like) diuretic.

7.2 Diabetes and coronary heart diseaseThe treatment strategy regarding the threshold and goal ofBP, as well as selection of antihypertensive drugs, werediscussed earlier.

7.3 Atrial fibrillationPost hoc analyses of data from heart failure and hypertensiontrials show a lower incidence of episodes of atrial fibrillation inpatients receiving RAS blockade. Therefore, the 2009 ESH/ESC guidelines recommended ARBs or ACE inhibitors inpatients at high risk of recurrent atrial fibrillation. It washypothesized that RAS blockade inhibits atrial structural andelectrical remodeling, which was directly shown in studieson animal models of atrial fibrillation. In a recent meta-anal-ysis of 23 randomized controlled trials including87,048 patients, RAS inhibition reduced the odds for atrialfibrillation by 33% overall, with greater effect in subjectsreceiving antiarrhythmic drugs [16]. These data were not con-firmed in specific trials (Candesartan in the Prevention ofRelapsing Atrial Fibrillation -- CAPRAF, Gruppo Italianoper lo Studio della Sopravvivenza nell’Infarto Miocardico --Atrial Fibrillation -- GISSI-AF), which were designed to assessthe effect of ARBs on incidence of recurrent episodes of atrialfibrillation [88,89].

7.4 Stroke and transient ischemic attackPatients with a history of cerebrovascular incident are consid-ered a population at high risk who warrant an early andintensive antihypertensive therapy. Nevertheless, there are insuf-ficient data to recommend initiation of therapy with high nor-mal BP. Also post hoc analysis of data from the PROGRESS(Perindopril Protection against Recurrent Stroke Study) trialsuggests that lowering SBP to < 130 mmHg is not associatedwith further reduction of the risk of future incidents [54].

Another unresolved issue is optimal BP managementduring the acute phase of stroke. The relevant clinical trialshave yet to be completed. Also, the belief in neuroprotectiveactivity of RAS inhibition has not been confirmed inclinical trials. The PRoFESS trial (Prevention Regimen forEffectively Avoiding Second Strokes) randomly assigned20,332 patients with non-cardioembolic ischemic stroke toreceive either telmisartan (80 mg daily) or placebo [65]. Approx-imately three-quarters of patients had a prior history of hyper-tension, and the average BP was 144/84 mmHg in both groupsat baseline. At an average follow-up of 2.5 years, there was nodifference between the telmisartan and placebo groups in theprimary outcome of recurrent stroke, or in secondary outcomesincluding major cardiovascular events. This finding is similar tothe lack or benefit with perindopril monotherapy in thePROGRESS trial, in which benefit was seen only in patients



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treated with perindopril plus indapamide, which producedsubstantially greater BP reduction [43].

7.5 Atherosclerotic renovascular diseaseRenovascular hypertension, mostly due to atherosclerosis, isconsidered the second most common cause of secondaryhypertension, with a prevalence of approximately 2% of adulthypertensives evaluated in specialized centers [90]. With theuse of low-profile stents, atherosclerotic renal artery stenosiscan be successfully treated in about 100% of cases with reste-nosis in the range of 0 -- 23%, depending on the diameter ofthe renal artery [91]. Yet the treatment of patients with athero-sclerotic renal hypertension is a controversial issue due to thelimited number of large-scale long-term outcome trialscomparing different therapeutic approaches, as well as thedifficulty to predict BP response to renal revascularizationprocedures in individual patients [92].

Until the year 2009, data from only three randomized, rel-atively small studies comparing percutaneous angioplasty withmedical treatment alone were available [93-95]. In the year2009, two randomized trials addressing the issue of percuta-neous revascularization in patients with atheroscleroticrenovascular disease (STAR and ASTRAL) were published.

The STAR trial (Stent Placement and Blood Pressure andLipid-lowering for the Prevention of Progression of RenalDysfunction Caused by Atherosclerotic Ostial Stenosis ofthe Renal Artery) was performed in 10 centers and enrolled140 patients with ostial renal artery stenosis > 50% [96]. Otherinclusion criteria were BP controlled to < 140/90 mmHgon stable medication 1 month before the study, if

possible without ACE inhibitors, and creatinine clearance of15 -- 80 ml/min. Exclusion criteria were: renal size < 8 cm,renal artery diameter < 4 mm, estimated creatinineclearance < 15 ml/min/1.73 m2, diabetes mellitus with pro-teinuria (3 g/d), and malignant hypertension. Patients wererandomized for stent placement and medical treatment(64 patients) or medical therapy alone (76 patients), whichincluded all classes of antihypertensive drugs along withmandatory atorvastatin and low-dose aspirin.

Only 46 of the 64 patients assigned for stenting eventuallyunderwent the procedure, and they did not differ fromcontrol group in BP control, renal function and rate of cardio-vascular complications. Serious complications occurred in thestent group, including two procedure-related deaths. Theauthors concluded that stent placement with medical treat-ment has no clear effect on progression of impairedrenal function and leads to a small number of significantprocedure-related complications.

Similar conclusions come from ASTRAL (The Angiographyand Stenting for Renal Artery Lesions), another multicentertrial that randomized 806 patients with atherosclerotic renaldisease either to undergo percutaneous revascularization inaddition to receiving medical therapy or to receive medicaltherapy alone. Inclusion criteria were substantial anatomicalatherosclerotic stenosis in at least one renal artery suitable forendovascular revascularization and lack of physician’s beliefthat the patient would definitely have a worthwhile clinicalbenefit from revascularization. During the median follow-up of 34 months, the decline in renal function over time wasslightly slower in the revascularization group, but the

Thiazide/thiazide-likediuretics

ACE inhibitors

Calcium antagonists

Angiotensinreceptor blockersβ-blockers

LIFE, VALUE

ASCOTACCOMPLISH

ADVANCEPROGRESS

HYVET

ONTARGET

ASCOT

ELSAVALUEFEVER

Figure 1. Possible combinations between basic classes of BP-lowering drugs for initiation of antihypertensive therapy. The

preferred combinations are represented as solid lines, combinations that should be avoided with double lines, and the dotted

line indicates combination of questionable benefit. Acronyms of trials where these combinations were tested are noted.

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difference was not statistically significant (p = 0.06). There wasno significant difference in SBP between the studied groups.The decrease in DBP was smaller in the revascularization groupthan in the medical-therapy group, and the slope for DBPdiverged at the rate of 0.61 mmHg per year (p = 0.03).Post hoc analysis of BP control and the rate of decline of

GFR in the subgroup with severe stenosis, bilateral or narrow-ing of the one existing kidney show advantage of revasculari-zation over medical treatment alone. Serious associatedcomplications in the revascularization group were observedin 23 patients, including two deaths and three amputationsof toes or limbs [11].The results of STAR and ASTRAL, despite their obvious

limitations, suggest a conservative approach in the treatmentof atherosclerotic renovascular disease; yet they do not ruleout the possibility that, in selected patients with such classicalindications as flashing pulmonary edema or acute renalfailure, renal artery stenting may be effective. These trialsalso do not provide a clear answer as to whether percuta-neous intervention may be a valuable method of loweringBP in drug-resistant hypertension. The ongoing CORAL(Cardiovascular Outcomes in Renal Atherosclerotic Lesions)study may provide a more definite answer to that query.However, it is worth mentioning, that our meta-analysisof five randomized studies carried out to date, includingSTAR and ASTRAL, revealed significantly lower SBP in theintervention group than in the medically treated group,with a mean weighted difference of only -3.11 mmHg(95% CI -6.15, -0.07; p = 0.04) (Table 1) [96].

8. How should concomitant risk factors betreated?

Reappraisal stated that benefits observed in statin trials withhypertensive patients like ASCOT- LLA endorse their rolein primary prevention, and recommends to initiate this treat-ment in subjects with moderate cardiovascular risk (~ 15%cardiovascular events in 10 years). This statement is mostlybased on data from the JUPITER (Justification for the Useof Statins in Primary Prevention: An Intervention Trial Eval-uating Rosuvastatin) trial in which 17,802 healthy men(aged ‡ 50 years) and women (aged ‡ 60 years) with a low-density lipoprotein cholesterol (LDL-C) level < 130 mg/dl(3.4 mmol/l) and a CRP level ‡ 2.0 mg/l were randomlyassigned to treatment with 20 mg of rosuvastatin daily orplacebo. The trial was stopped early after a median follow-upof 1.9 years because the first major cardiovascular event (non-fatal MI, nonfatal stroke, hospitalization for unstable angina,arterial revascularization procedure, confirmed death fromcardiovascular causes) was lower in patients treated with rosu-vastatin (0.77 vs 1.36 events per 100 person-years; HR 0.56;95% CI, 0.46 -- 0.69), as was the risk of all-cause mortality(1.00 versus 1.25 deaths per 100 person-years; HR 0.80;95% CI, 0.67 -- 0.97) [97]. Achieved hsCRP concentrationswere predictive of event rates irrespective of the lipid end

point used, including the apolipoprotein B to apolipoproteinAI ratio. These data suggest that inclusion of inflammatorymarkers may allow better estimation of cardiovascular risk,yet current guidelines as well as their reappraisal do notrecommend measurement of hs-CRP level.

The clinical relevance of the JUPITER study has been ques-tioned by some researchers who have raised serious objectionsto the trial methodology. Premature termination excluded thepossibility of assessing treatment efficacy over longer periodsand may have exaggerated possible benefit. Furthermore,data show a major discrepancy between significant reductionof nonfatal stroke and myocardial infarction, but no effecton mortality from these two conditions. Also, cardiovascularmortality was unexpectedly lower as compared with totalmortality as well as rate of fatal MI [98]. Also, a recent meta-analysis of 11 randomized controlled trials involving 65,229high-risk participants did not find evidence for the benefiton statin therapy on total mortality in primary prevention [99].In the lipid arm of the ACCORD trial, addition of fenofi-brate to statin did not improve clinical outcome except indiabetic subjects with low high-density lipoprotein choles-terol (HDL-C) (< 34 mg/dl) and hypertriglyceridemia(> 204 mg/dl) [100]. Yet many experts advise administrationof statins in hypertensive subjects with type 2 diabetes andno coronary heart disease, regardless of initial cholesterol level,with the target values for LDL-C < 100 mg/dl (reviewedin [101]).

Current clinical practice strongly recommends low-doseacetylsalicylic acid for secondary prevention in patientswith previous cardiovascular atherosclerotic complications.Findings from secondary prevention trials invariably showoverall benefit over the risk of serious adverse events, partic-ularly intracranial bleeds. Yet the data from primary preven-tion trials are less consistent. A large meta-analysis that alsoincluded six primary prevention trials with 95,000 low-risk individuals the net benefit to be small and associatedwith significant risk of major gastrointestinal and extracra-nial bleeds [102]. Even in patients with asymptomatic athero-sclerosis (Aspirin for Asymptomatic Atherosclerosis -- AAATstudy), also associated with diabetes (Prevention and Pro-gression of Arterial Disease and Diabetes -- POPADAD),low-dose aspirin did not change the rate of cardiovascularcomplications and mortality [12,103]. Therefore, cautionshould be exercised in this group of patients whenaspirin is prescribed, in particular in patients at high risk ofbleeding [104].

9. Conclusions

Management of the hypertensive patient is guided by totalcardiovascular risk, which includes assessment of BP leveland concomitant risk factors with a special emphasis on sub-clinical organ damage and associated diseases. Despite exten-sive research, new indices like intima-media thickness andparameters of arterial stiffness do not improve estimation



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Table

1.Meta-analysisoftheeffect

ofrenalartery

interventionsonSBPco

ntrol.

Studyorsu

bgroup

Angioplasty/stenting

Medicaltreatm

ent

Meandifference

Meandifference

Mean

SD

Total

Mean

SD

Total

Weight

IV,Random,95%

CI

IV,Random,95%

CI

ASTRAL2009

146

25

332

149

25

350

65.5%

-3.00[-6.75,0.75]

Favo

urs

expe

rimen

tal

-20

-10

1020

0Fa

vour

s co

ntro

l

Bax2009

151

23

50

155

26

60

11.0%

-4.00[-13.16,5.16]

Jaarsveld

2000

169

28

55

176

30

50

7.4%

-7.00[-18.13,4.13]

Plouin

1998

140

15

23

141

15

25

12.8%

-1.00[-9.49,7.49]

Websterbilateral1998

166

38

12

177

22

15

1.6%

-11.00[-35.21,13.21]

Websterunilateral1998

170

29

11

163

27

11

1.7%

7.00[-16.42,30.42]

Total(95%

CI)

483

511

100.0%

-3.11[-6.15,-0.07]

Heterogeneity:

Tau2=0.00;Chi2=1.87;df=5(p

=0.87);I2=0%

.

Test

foroveralleffect:Z=2.01(p

=0.04).

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of cardiovascular risk and are not recommended for routineclinical practice. The Reappraisal of current ESH/ESCguidelines, as well as data from more recent research, endorsethe current recommendation to reduce SBP to < 140 mmHg(and DBP to < 90 mmHg) in patients with grade 1 or2 hypertension and low or moderate total cardiovascularrisk, although they point out that there is still no trial evi-dence for whether this should be done in elderly patients.Furthermore, there is also no solid scientific evidence to sup-port lowering BP to < 130/80 mmHg in high-risk patientswith diabetes mellitus or a history of cardiovascular disease.Effective BP control requires multiple drugs with comple-

mentary mechanisms of action, and the time needed to achievegoal BP can affect clinical outcomes. Combining RAS inhibi-tors with CCB may offer effective BP reduction with possibilityof better organ protection. In subjects without clinically evidentatherosclerotic arterial disease, anti-platelet therapy does notoffer significant cardiovascular benefit over the risk of bleedingcomplications. More interest should be directed to issues ofbetter compliance with chronic antihypertensive therapy andpractical implications of guidelines for public health.

10. Expert opinion

Despite continuously accumulating data, many decisions onhypertension management must be taken without the supportof evidence from appropriate clinical trials. We still do notknow the best strategy for dealing with patients with stage1 hypertension, and there is uncertainty about whether sub-jects with BP in the range 140 -- 1499/90 -- 99 mmHg wouldbenefit from antihypertensive treatment.Also, available data from clinical trials do not prove that

lowering BP to < 130 mmHg in high-risk groups translatesinto additional benefit. The Systolic Blood Pressure Interven-tion Trial (SPRINT), funded by the US National Institutesof Health, which will test the effects of tight control ofSBP to < 120 mmHg compared with usual controlto < 140 mmHg on prevention of cardiovascular disease inapproximately 7500 subjects. Participants in SPRINT willbe aged ‡ 55 years, with SPB ‡ 130 mmHg and at least oneadditional risk factor. People with diabetes mellitus or whohave had a stroke will be excluded from SPRINT becausethey were the target groups of other trials (ACCORD,Secondary Prevention of Small Subcortical StrokesTrial -- SPS3) that are testing a lower BP goal.Most major clinical trials have included a direct comparison

of different treatment regimens. However, overall conclusionsbased on the results and large-scale meta-analyses do not indi-cate the absolute winner. Basic drug classes (diuretics, ACEinhibitors, ARBs, calcium antagonists and beta-blockers) canall be considered suitable for both initiation and maintenance

of hypertension. Choice of antihypertensive drugs should bebased on clinical setting. Because most hypertensive patientsrequire multiple drug therapy to control their BP, treatmentwith a fixed-dose combination may offer a valuable optionfor more effective BP reduction and better patient compliance.Results of landmark clinical trials support that combinationscomprised of a RAAS blocker with either a diuretic or CCBshould be considered first-line therapy for patients unlikely toachieve BP goals on a single drug. Based on these findings, cal-cium antagonists may be preferred over diuretics as the initialchoice for dual therapy in most patients, due to lower risk ofdiabetes and possibly better organ protection.

Only one new antihypertensive drug -- aliskiren, an orallyactive renin inhibitor -- has been introduced recently toclinical practice; but many new molecules are currentlyunder investigation, including NO donors, vasopressinantagonists, neutral endopeptidase inhibitors, AT2 angioten-sin receptor agonists, antagonists of endothelin receptors,dual inhibitors of the angiotensin II receptor and neprilysin.Encouraging results from first attempts of treatment of resis-tant hypertension with catheter-mediated ablation of renalsympathetic nerves and data from the ongoing controlledSymplicity HTN-1 trial will be released by the end of 2010.

It is assumed that lowering BP by any means will reduceincidence of cardiovascular events. Given the practical diffi-culty of maintaining long-term BP reductions with lifestylemodification, it would be valuable to test whether the lifestyleapproach in grade 1 hypertensive subjects may affect at leastsubclinical target organ damage.

Finally, guidelines should reconcile scientific evidence withclinical practice and reality of health care. The results of themodeling study based on demographical data from Norwayshow that to provide medical services according to currentESH/ESC 2007 guidelines, the number of primary care physi-cians in the population studied should be at least doubled, whichcreates an unbearable burden on the healthcare system [105].

Other ways of improving BP control in society may be effec-tive, as demonstrated recently in England where rates of BPcontrol in treated patients had increased to > 50% in menand women. These latest improvements are attributed, at leastin part, to the introduction in 2004 of a pay-for-performancesystem that rewards general practitioners financially for achiev-ing certain clinical targets, including lowering BP levels toSBP < 150 mmHg and DBP to < 90 mmHg [106].

Declaration of interest

Z Gaciong has received research grants and consultancy/speaking honoraria from Servier, Sanofi-Aventis, Pfizer,ADAMED, KRKA and Novartis. B Symonides has noconflict of interest to declare.



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AffiliationZbigniew Gaciong† MD PhD &

Bartosz Symonides MD PhD†Author for correspondence

The Medical University of Warsaw,

Department of Internal Medicine,

Hypertension and Vascular Diseases,

1a Banacha Street,

02-097 Warsaw, Poland

Tel: +48 22 599 2828; Fax: +48 22 599 2828;

E-mail: [email protected]

Gaciong & Symonides


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