treating hypertension with angiotensin ii receptor blockers

High Blood Press Cardiovasc Prev 2005; 12 (1): 9-15REVIEW ARTICLE 1120-9879/05/0001-0009/$34.95/0

© 2005 Adis Data Information BV. All rights reserved.

Treating Hypertension with Angiotensin IIReceptor BlockersA Step Ahead of Blood Pressure Reduction?

Luis M. Ruilope1 and Massimo Volpe2

1 Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain2 Cardiology, II Faculty of Medicine, University of Rome “La Sapienza”, Sant’Andrea Hospital, Rome, Italy

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91. Blood Pressure Reduction with Angiotensin II Receptor Blockers (ARBs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102. ARBs and Cardiovascular and Renal Protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

The clinical use of angiotensin II receptor blockers (ARBs) has resulted in the effective and successfulAbstracttreatment of arterial hypertension, and vast experience has been gained by physicians in this original indicationover the last years. Furthermore, promising results have been obtained with the use of ARBs in other clinicalconditions, such as type 2 diabetes mellitus with nephropathy, atrial fibrillation, acute myocardial infarctioncomplicated by left ventricular dysfunction and congestive heart failure. On the basis of the available evidence,some representative molecules of this class have been approved for other indications in addition to hypertensionin many countries, and many large clinical investigations are underway to confirm the current indications and,even more importantly, to explore whether these compounds may be effectively used in other conditions. Theevidence that ARBs can have benefits at any stage of the cardiovascular disease continuum underlies thepotential beneficial effects of these agents – independent of blood pressure reduction – in a wide variety ofpatients at risk of cardiovascular major events.

In the last 3 decades it has been shown that treatment of factors including diabetes, late initiation of antihypertensive ther-hypertension can prolong life, reduce the incidence of coronary apy, inadequate control of systolic BP and possibly other factorsevents and stroke, and also prevent or delay the development of could account for the unfavourable prognosis observed in thisheart failure and nephrosclerosis.[1,2] Even small reductions in group of hypertensive patients and in the general hypertensiveblood pressure (BP) are associated with large reductions in cardio- population. However, it is also reasonable to postulate that othervascular risk,[3] especially in hypertensive patients with additional mechanisms beyond BP elevation operate in hypertensive patientscardiovascular risk factors such as diabetes mellitus, target organ and promote the more frequent development of cardiovasculardamage or associated clinical conditions.[4-7] events.

However, a recent survey analysis of survival rates over a Such a hypothesis has been often indirectly supported by the22-year follow-up in about 700 hypertensive individuals showed analysis of therapeutic interventions. In this view, in fact, it hasthat clinical outcomes were poorer in treated hypertensive than in been suggested that the different classes of antihypertensive drugsnon-hypertensive men of similar age, even when satisfactory BP may have specific capacities for organ and cardiovascular diseasecontrol was achieved in the hypertensive patients mostly treated prevention. For instance, β-blockers and more general sympatho-with diuretics and β-blockers.[8] The concomitant presence of risk lytic agents may have an important additional property in their

10 Ruilope & Volpe

ability to block the sympatho-adrenergic drive to the heart and plus a low-dose thiazide diuretic (such as hydrochlorothiazidevessels. This property may provide benefits in addition to their 12.5–25mg),[9,11] because this combination provides reciprocalantihypertensive activities and promote cardiovascular protection. amplification of BP-lowering effects while limiting the adverseSimilarly, calcium channel antagonists are thought to be powerful effects of diuretics (particularly hypokalaemia), which is mostantihypertensive drugs in addition to having well known important for patients with metabolic disorders. In particular, theBP-lowering effects. More recently, the pharmacological agents combination of an ARB with a low-dose thiazide diuretic signifi-that counteract the effects of angiotensin II (such as ACE inhibi- cantly increases the rate of responders or normalisation in patientstors and angiotensin II receptor blockers [ARBs]) have been with mild to moderate hypertension.[9,11] On the basis of vastshown to be effective in reducing target organ damage and preclinical experience and of controlled clinical studies, a thera-preventing cardiovascular events in several conditions.[9-19] These peutic strategy based on the combination of an ARB and low-dosebeneficial properties have been linked to the favourable conse- thiazide diuretic is extensively used in clinical practice today andquences of blocking the renin-angiotensin system (RAS). has been repeatedly used in large controlled studies.[9-19]

In this view, among the strategies that can interfere with the The ARB/thiazide diuretic combination has often been requiredRAS, ARBs are provided with a more selective mechanism of to achieve the target BP (usually <140/90mm Hg) in controlledaction.[20] In addition, their excellent tolerability results in better studies and large international trials, and the interpretation of thecompliance and long-term adherence with treatment by pa- effects on outcomes is related to this combination therapy rathertients.[21] than to the effect of monotherapy. For instance, in the LIFE

(Losartan Intervention For Endpoint reduction in hypertension)This article reviews evidence suggesting additional propertiesstudy,[9] 91% of the patients were receiving combination therapy,that may confer on ARBs protective cardiovascular and renalwhile in the VALUE (Valsartan Antihypertensive Long-term Useeffects that go beyond their BP-lowering action in hypertensiveEvaluation) trial,[11] about 70% of the patients were receivingpatients.combination therapy.

1. Blood Pressure Reduction with Angiotensin II2. ARBs and Cardiovascular and Renal ProtectionReceptor Blockers (ARBs)

Since the discovery of ARBs in the early 1980s and the preclin- In addition to effective BP control, ARBs may provide signifi-ical investigation that led to the development of losartan, the cant additional benefits in hypertensive patients in terms of end-prototype molecule in this class, several other molecules, includ- organ protection, and this effect is mostly related to blockade ofing valsartan, irbesartan, candesartan cilexetil (candesartan), the RAS. The RAS, in fact, plays a key pathophysiological role,telmisartan, eprosartan and, more recently, olmesartan medoxomil and this is of relevance in patients with atherosclerosis, diabetes,(olmesartan) have been developed. Today, several millions of hypertension, ischaemic heart disease, ischaemic stroke and heartpatients around the world are treated with the -sartan compounds, failure. In these conditions, it is believed that angiotensin II canand international guidelines for the management of hypertension contribute to the development and progression of the diseasehave recognised this class as a first-choice approach to the treat- towards complications, end-stage renal disease and death.[26] Ament of hypertension together with other classes of antihyperten- high renin profile is an independent risk factor for cardiovascularsive drugs.[22,23] disease in patients with hypertension, and this cardiovascular risk

is particularly significant in patients with concomitant diabetes.[27]Substantial reductions in diastolic and systolic BP can beSeveral biological effects of angiotensin II at an organ and cellularachieved with ARB monotherapy or combinations of ARBs andlevel, including vasoconstriction and sodium retention, enhancedany other class of antihypertensive agents.[24] BP reductions withsusceptibility to thrombosis, pro-oxidant and pro-inflammatoryARBs are equivalent to those obtained with all other first-choiceactivities, vascular smooth muscle growth, myocyte hypertrophy,antihypertensive drugs, including diuretics, calcium channel an-fibrosis, remodelling of tissues and stimulation of aldosterone andtagonists, β-blockers and ACE inhibitors.[22,23] In fact, normalisa-of a number of cytokines and hormonal mediators, representtion or responder rates with ARBs alone or in combination withimportant pathophysiological mechanisms driving cardiovascularlow-dose thiazide diuretics are similar to those obtained with theand renal pathology.[28,29]other first-choice antihypertensive classes,[22,23] and there are no

significant differences between the various ARBs in terms of BP- The most effective therapeutic methods for blocking the RASlowering properties either in monotherapy or in fixed combination are based on the use of ACE inhibitors or ARBs. In particular,with diuretics.[25] The most rational combination may be an ARB ARBs selectively block the binding of and the interaction between

© 2005 Adis Data Information BV. All rights reserved. High Blood Press Cardiovasc Prev 2005; 12 (1)

Angiotensin II Receptor Blockers: Benefits Beyond BP Lowering 11

ble BP reductions to the treatment regimen based on the β-blockeratenolol (final BP of 144.1/81.3mm Hg versus 145.4/80.9mm Hg,respectively). However, the losartan-based regimens reduced therisk of the combined endpoint of cardiovascular death, stroke andmyocardial infarction by 13% (p = 0.021) and reduced the inci-dence of fatal and nonfatal stroke by 25% compared with atenolol.Analysis of most cardiovascular endpoints showed a clear advan-tage of losartan versus atenolol, and these differences were moremarked in the high-risk population of diabetic patients (figure 1).Beneficial effects of losartan on cardiovascular outcomes thatcould not be ascribed to BP reductions were, in fact, also observedin patients with isolated systolic hypertension or diabetes.[30,35]

Furthermore, in the LIFE trial in the presence of comparable

0.5 1 1.5

Hazard ratio (95% CI)

Favours losartan Favours atenolol

Composite

CV death

Stroke

MI

Total mortality

Endpoints

242

99

116

91

167

No. ofevents

Fig. 1. Primary composite endpoint and components in the diabetic popu-lation of the LIFE (Losartan Intervention For Endpoint reduction in hyper-tension) study (n = 1195).[35] CV = cardiovascular; MI = myocardial infarc-tion. reductions in BP, the strategy based on losartan positively affected

a number of intermediate endpoints, such as left ventricular hyper-angiotensin II and the angiotensin II type 1 (AT1) receptor, thus trophy,[36] albuminuria,[37-39] new onset of atrial fibrillation[40] andinhibiting the downstream pathways of postmembrane signalling new onset of diabetes,[35] to a greater extent than with the atenolol-and intracellular events. In this way, most of the biological effects based strategy. Since all these disease markers are known toof angiotensin II are antagonised. The selective mechanisms of predispose to cardiovascular events, such as ischaemic heart dis-action of ARBs may be important also because the interaction ease and ischaemic stroke, it can be reasonably speculated that abetween residual, unbound angiotensin II and the angiotensin II longer observation could demonstrate an even more remarkabletype 2 (AT2) subtype receptors may result in an amplification of difference in favour of ARBs.the beneficial effects of AT1 blockade and may favour vasorelaxa-

In the VALUE trial,[11] which compared strategies based ontion and reduced development of hypertrophy and cardiovascularamlodipine and valsartan in more than 15 000 high-risk patients,remodelling.[29]

although significantly higher BP reductions were achieved in theBlocking the RAS with ACE inhibitors or ARBs has indeed

amlodipine arm throughout the study, there was no significantbeen shown to reduce cardiovascular endpoints in a variety of

difference in the combined primary endpoint between treatments.conditions including hypertension, type 2 diabetes, stroke, renal

In addition, the analysis of the components of the combineddisease, heart failure, left ventricular dysfunction, acute myocardi-endpoints also showed that the differences in favour of amlodipineal infarction and coronary artery disease.[9-19] The clinical develop-were largely accounted for by the higher and earlier BP reductionsment of ARBs is impressive and involves both completed andobtained with the calcium channel antagonist. This emphasises theongoing studies of several hundred thousand patients with differ-need to adequately and rapidly titrate ARB dosages in patientsent diseases, including isolated systolic hypertension,[30] high-riskwith hypertension and to consider using them in combination withpatients,[14,15] ischaemic heart disease,[31-33] stroke,[9,10,34] diabe-

tes,[35] renal disease[15-19] and heart failure.[11,12] It is important topoint out that this clinical development has been characterised by avery rigorous approach from the scientific standpoint, mostlyadopting international, randomised, controlled, multicentre trials.In addition, ARBs have mostly been compared with active treat-ment or state-of-the-art therapeutic approaches, often includingACE inhibitors, calcium channel antagonists or β-blockers, ratherthan with placebo.

The initial strong evidence that ARBs have effects on cardio-vascular risk that are at least independent of BP reductions hasbeen provided by the results of the LIFE study.[9] In this large trial,which recruited more than 9000 patients with hypertension andelectrocardiographic evidence of left ventricular hypertrophy, thetreatment regimen based on the ARB losartan produced compara-

Table I. Reduction in the incidence of new onset of diabetes mellitus withangiotensin II receptor blockers (ARBs) in four major studies[50]

Study Comparator Drug % reduction innew onset ofdiabetes

LIFE[9] Atenolol Losartan –25%

SCOPE[10] CT Candesartan –20%

ALPINE[46] CT Candesartan –87%

CHARM[12] CT Candesartan –22%

ALPINE = Antihypertensive Treatment and Lipid Profile in a North ofSweden Efficacy Evaluation; CHARM = Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity; CT = conventionaltherapy; LIFE = Losartan Intervention For Endpoint reduction inhypertension; SCOPE = Study on Cognition and Prognosis in the Elderly.


12 Ruilope & Volpe

blockers or calcium channel antagonist-based regimens (table I).This has also been shown in a number of trials with ACE inhibi-tors, including the ALLHAT (Antihypertensive and Lipid-Lower-ing Treatment to Prevent Heart Attack Trial)[44] and the CAPPP(Captopril Prevention Project),[45] and more recently in a convinc-ing analysis of the VALUE trial,[11] which compared the ARBvalsartan with amlodipine. In this latter study, fewer patientsreceiving the valsartan therapy developed new-onset diabetes(about 23% fewer occurrences) than patients receivingamlodipine, as shown in figure 2.[43] This is particularly remarka-ble in the VALUE trial[11] because the new onset of diabetes wasvalidated through initiation of antidiabetic therapy and because thecomparator used, amlodipine, is believed to be neutral on themetabolic and carbohydrate profile. In addition, in the ALPINE

Favours valsartan Favours amlodipine

Hazard ratiovalsartan/amlodipine

Primary cardiac composite endpoint

cardiac mortality

cardiac morbidity

All myocardial infarction

All congestive heart failure

All stroke

All-cause death

New-onset diabetes

0.5 1 2

Fig. 2. Analysis of clinical outcomes in the VALUE (Valsartan Antihyperten-sive Long-term Use Evaluation) trial showed a significant reduction in theincidence of new-onset diabetes mellitus in patients receiving valsartan-based therapy vs amlodipine-based therapy.[11] (Antihypertensive Treatment and Lipid Profile in a North of

Sweden Efficacy Evaluation) study,[46] which was prospectivelya low-dose thiazide diuretic as a first step for therapy with high- designed to compare ARBs with a β-blocker/diuretic strategy, arisk patients, in agreement with suggestions from the most recent dramatic difference (–87%) in the new onset of diabetes in favourguidelines.[22,23,41] In this regard, detailed analysis of the VALUE of ARBs was recorded over 1 year of observation. This property oftrial results showed that the BP differences between amlodipine ARBs is particularly relevant to the subsequent development ofand valsartan in the VALUE trial were quite large during the first cardiovascular and renal disease, since new-onset diabetes duringmonths of treatment.[42] It was during these early phases of the trial long-term antihypertensive treatment is associated with increasedthat most of the excess events in the valsartan group occurred. In morbidity and mortality.[47] In addition, it is well know that devel-fact, when patients were matched for identical achieved BPs, opment of diabetes in hypertension accelerates renal impairmentcardiovascular events, if anything, tended to be slightly less fre- and evolution towards end-stage renal disease. The favourablequent in the valsartan group, particularly for heart failure and new impact of drugs that inhibit the RAS, particularly ARBs, on thediagnoses of diabetes.[43]

development of diabetes is attributable to specific mechanismsassociated with angiotensin II blockade[48,49] and cannot be ac-An additional benefit of ARBs is indeed represented by the

lower incidence of new-onset diabetes compared with diuretics, β- counted for only by the detrimental metabolic effects of the

CV death, CHF hosp 333 366

CV death 170 170

CHF hosp 241 276

CV death, CHF hosp,MI

365 399

CV death, CHF hosp,MI, stroke

388 429

CV death, CHF hosp,MI, stroke, revasc

460 497

New-onset diabetes 47 77

Candesartanbetter

Hazardratio

Placebobetter

0.8 1 .0 1.2

p-Value

0.918

0.072

0.118

0.126

0.078

0.123

Covariate-adjustedp-valueCandesartan Placebo

0.89

0.99

0.85

0.90

0.88

0.91

0.60 0.005

0.635

0.047

0.051

0.051

0.037

0.13

0.005

0.6

Fig. 3. Development of diabetes mellitus in the CHARM (Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity)-Preserved trial.Treatment with an angiotensin II receptor blocker, candesartan, reduces incidence of diabetes in hypertensive patients with heart failure and preservedsystolic ventricular function vs placebo.[55] CHF hosp = congestive heart failure hospitalisation; CV = cardiovascular; MI = myocardial infarction; revasc =revascularisation.



NoninferiorityValsartan superior

to captoril Captoril superior to valsartan

Noninferiority notdemonstrated

0.8 1 1.2

Hazard ratio(97.5% CI)

1.13

p-Value(noninferiority)

Noninferioritymargin

CV death(1657 events)

0.001

CV death or HF(2661 events) 0.0001

CV death or MI(2234 events)

0.00001

CV death,MI or HF

(3096 events)0.000001

Favours valsartan Favours captopril

Fig. 4. Cardiovascular mortality and morbidity in VALIANT (Valsartan in the Acute Myocardial Infarction Trial). Data are shown on noninferiority forreduction of cardiovascular morbidity and mortality in favour of angiotensin II receptor blocker-based treatment vs ACE inhibitor-based treatment in high-risk patients of VALIANT.[14] CV = cardiovascular; HF = heart failure; MI = myocardial infarction.

comparators (diuretics, β-blockers, calcium channel antagonists). been associated with lower cardiovascular morbidity and mortalityIn future analyses, it will be relevant to look at the influence of in a LIFE substudy.[37-39] More recently, in the DETAIL (DiabeticsARBs on metabolic syndrome as well, since this complex condi- Exposed to Telmisartan and Enalapril) study ARBs and ACEtion represents a growing health issue. inhibitors were shown to be equivalent in terms of progression of

renal disease.[52] It is noteworthy that in this latter study thePrevention of renal function deterioration is another importantincidence of major events was particularly low in both groups,target of the treatment of diabetes, hypertension and atherosclerot-again suggesting the benefits of blockade of the RAS in patientsic diseases and has a significant influence on the overall prognosiswith diabetes and hypertension.of patients.[51] Blocking the RAS represents a successful strategy

On the basis of these consistent observations, the most recentto slow the progression of renal impairment in these diseases, andmanagement guidelines[22,23] accept these new findings and recom-this has been confirmed in three large clinical trials with ACEmend the early inhibition of the RAS as a key strategy, particularlyinhibitors and more recently with ARBs in diabetic nephropa-in patients with nephropathy, ARBs being advised as the firstthy.[16-19] In this latter regard, it should be mentioned that thechoice in patients with type 2 diabetes.evidence obtained with ARBs in type 2 diabetic patients with

incipient or established nephropathy is more consistent and solid Blocking the RAS has also benefits in patients with heartthan that obtained with ACE inhibitors.[16-19] failure or left ventricular dysfunction. In the Val-HeFT (Valsartan

Heart Failure Trial),[13] the addition of valsartan to standard ther-The IRMA 2 (Irbesartan Microalbuminuria Type 2 Diabetesapy for heart failure, including ACE inhibitors and β-blockers,Mellitus in Hypertensive Patients) trial[18] showed that ARBssignificantly reduced the risk of total mortality or hospitalisationdelay the progression from microalbuminuria to macroalbumin-by 13% compared with placebo. This remarkable beneficial effecturia. In addition, ARBs delayed progression from macroalbumin-of ARBs in heart failure opens new frontiers in the therapeuticuria to end-stage renal disease in the IDNT (Irbesartan Diabeticmanagement of heart failure, a condition that still carries a disap-Nephropathy Trial)[16] and the RENAAL (Reduction of Endpointspointingly high mortality rate.in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin

II Antagonist Losartan) study.[17] The MARVAL (Microalbumin- The benefits of ARBs in patients with heart failure were recent-uria Reduction with Valsartan) study[19] extended this observation, ly confirmed in the CHARM (Candesartan in Heart failure-proving that with a strictly similar BP level valsartan was more Assessment of Reduction in Mortality and morbidity) programme.effective than amlodipine in significantly reducing In the CHARM-Alternative arm[53] (ARBs used as an alternative tomicroalbuminuria excretion. This finding again suggests that ACE inhibitors in patients who could not take ACE inhibitors),properties of ARBs beyond BP control are relevant to cardiovas- candesartan cilexetil at a target dosage of 32 mg/day significantlycular and renal protection. In fact, the reduction of reduced the risk of cardiovascular death or congestive heart failuremicroalbuminuria and of its progression to overt proteinuria has (CHF) hospitalisation by 23% compared with placebo. Further-


14 Ruilope & Volpe

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Hypertens 2004; 18: 453-9 E-mail: [email protected]


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