The role of angiotensin II receptor blockers in the management of heart failure

European Heart Journal Supplements (2005) 7 (Supplement J), J10 J14 doi:10.1093/eurheartj/sui057 The role of angiotensin II receptor blockers in the management of heart failure John J.V. McMurray* Department of Cardiology, Western Infirmary, Glasgow G11 6NT, UK KEYWORDS Heart failure; Treatment; Angiotensin II receptor blockers Angiotensin-converting enzyme inhibitors (ACE-inhibitors) are first-line treatment for chronic heart failure (CHF) with a low left ventricular ejection fraction because they improve symptoms and reduce mortality and admission to hospital. Many CHF patients do not receive these agents because of intolerance. Like ACE-inhibitors, angiotensin II type 1 receptor blockers (ARBs) reduce the action of angiotensin II but achieve this effect by an alternative mechanism, thus they may be effective in patients who are intolerant to ACE-inhibitors. Recommendations concerning the efficacy of ARBs in CHF, in the 2001 European Society of Cardiology (ESC) guidelines, were appropriately cautious and their use has remained limited, reflecting uncertainties concerning their role in CHF. However, a number of large-scale clinical trials (including OPtimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan, VALsartan In Acute Myocardial infarction, and Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity) have been completed since the publication of the 2001 guidelines that support the efficacy and safety of ARBs in CHF. Findings from these trials suggest that ARBs may improve outcomes across the CHF patient spectrum, including those with preserved or low ejection fractions, ACE-intolerant patients, in all cases as part of a polytherapeutic strategy. On the basis of these trial data, the revised 2005 ESC guidelines provide stronger recommendations for the use of ARBs in the management of CHF. Introduction Angiotensin-converting enzyme inhibitors (ACE-inhibitors) are first-line treatment for chronic heart failure (CHF) patients with a low left ventricular ejection fraction (LVEF) and were given a level A, class I recommendation in the 2001 European Society of Cardiology (ESC) guidelines for the management of CHF, 1 and the 2005 update of these. 29 This is because ACE-inhibitors improve symptoms and reduce mortality and admission to hospital in patients with CHF, regardless of age, gender, or New York Heart Association (NYHA) class. 2 ACE-inhibitors are believed to exert these effects by competitively inhibiting the conversion of angiotensin (AT) I into AT II, thus * Corresponding author. Tel: þ44 141 211 1838; fax: þ44 141 211 2252. E-mail address: j.mcmurray@bio.gla.ac.uk reducing circulating, and probably tissue, levels of AT II. 2 AT II has a myriad of actions thought to be detrimental in CHF, including vasoconstriction, promotion of abnormal cellular growth, and sodium and water retention. AT II augments the production of aldosterone also, which itself has potentially detrimental actions in CHF. ACEinhibitors do not prevent the production of AT II through non-ace enzymatic pathways in cardiac tissue and blood vessels. 2,3 Thus, complete blockade of AT II production is not achieved, even with high-dose ACE-inhibitor treatment. 3 Conversely, ACE-inhibitors also block the action of kininase II, resulting in inhibition of bradykinin breakdown. The resultant increase in bradykinin with ACEinhibitor treatment may increase levels of nitric oxide, prostaglandins, and other molecules. These may have additional beneficial actions in CHF, but may also cause some of the characteristic adverse effects of ACE-inhibitors, especially cough. & The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Angiotensin receptor blockers in HF management J11 More than 20% of patients with HF do not receive ACEinhibitors, in part, because of intolerance to these agents. 4 The EuroHeart Failure survey revealed that ACE-inhibitors were being prescribed to 61.8% of patients at the time of the survey, 5 whereas only 60% of patients in the international IMPROVEMENT of Heart Failure Programme was receiving these agents. 6 The most common adverse event leading to discontinuation of an ACEinhibitor in the SPICE (Study of Patients Intolerant of Converting Enzyme Inhibitors) registry was cough, which occurs in 3 5% of all patients. 2,4 Angiotensin II type 1 receptor blockers (ARBs) block the renin angiotensin aldosterone system (RAAS) in a different way from ACE-inhibitors. 7 By inhibiting the binding of AT II to the AT 1 receptor, ARBs block the action of AT II at the AT 1 receptor, regardless of its synthesis by ACE-dependent or -independent pathways. By preventing the binding of AT II to the AT 1 receptor, ARBs increase circulating AT II concentrations which, in turn, bind to the AT 2 receptor. With an ARB, there is, therefore, unopposed over-stimulation of the AT 2 receptor, which, theoretically, may have beneficial cardiovascular actions. ARBs do not block kininase II also and, thus, are not believed to enhance bradykinin levels. Therefore, ARBs provide a mechanism for inhibiting the RAAS, which is distinct from that of ACEinhibitors. 8,9 Thus, they may be effective in CHF patients who are intolerant to ACE-inhibitors or may offer potential benefits in addition to optimal medical therapy that includes ACE-inhibitors. 9 This latter possibility is based on the hypothesis that ARBs may offer more complete blockade of AT II (by blocking non-ace-generated AT II) but that the bradykinin-related actions of ACE-inhibitors may also be therapeutically important; consequently, the combination of both an ACE-inhibitor and an ARB may be better than either treatment alone. A number of randomized placebo-controlled clinical outcome trials have been conducted in recent years to investigate the efficacy of ARBs in the treatment of patients with CHF or left ventricular systolic dysfunction (LVSD), HF, or both after myocardial infarction (MI). These trials included the ELITE II (Evaluation of Losartan In The Elderly), 8 ValHeFT (Valsartan Heart Failure Trial), 10,11 OPTIMAAL (OPtimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan), 12 VALIANT (VALsartan In Acute Myocardial infarction), 13 and the CHARM Programme of three trials (Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity). 3,9,14 17 On the basis of these trials, substantial data are now available concerning the efficacy of ARBs in the management of CHF. Until recently, recommendations concerning the use of ARBs in HF remained appropriately cautious. The most recent trials with ARBs (VALIANT and CHARM) had not been published when the 2001 ESC CHF guidelines were developed and, consequently, limited data were available on which the guidelines could be based. Physicians prescribed ARBs to their patients with CHF with caution and their use remained limited in most European countries, reflecting continuing uncertainties regarding their efficacy in CHF and their benefits when administered in conjunction with standard therapies. 5 This article will review the use of ARBs prior to the new data that have become available since the publication of the 2001 guidelines, evaluate those new data and review the revised recommendations from the updated 2005 ESC guidelines. Current use of ARBs for CHF management in Europe Surveys and registries investigating current prescribing patterns indicate that the use of ARBs for the management of CHF in Europe remains low. 5,18,19 The EuroHeart Failure Survey was the first pan-european survey to investigate the diagnosis and treatment of hospitalized CHF patients. 5,20 The survey revealed that ARBs were prescribed infrequently to European CHF patients, which the authors attributed to uncertainties over the role of these agents as an alternative or addition to ACE-inhibitor therapy. 5 The ongoing IN-CHF (Italian Network on Congestive Heart Failure) registry showed similar findings for Italian CHF patients. 18 Established to collate data on the clinical features, treatments and outcomes of more than 21 000 CHF outpatients managed in 150 cardiology centres, the registry showed that the rate of ARB use in Italy had increased considerably from 0% in 1995 to 17.5% in 2004 but still remains low, particularly in elderly patients. 18,21 Data from a study in The Netherlands comparing the management of CHF patients treated by either primary care physicians (n ¼ 103) or cardiologists (n ¼ 99) support these findings. 19 The use of ARBs was low in both patient cohorts, but was particularly low among patients managed in primary care (6 vs. 13% among those treated by cardiologists). 19 Similar data from a national survey investigating the prevalence, incidence, primary care burden, and treatment of CHF patients in Scotland (1999 2000) showed that only 4.8% of 1008 patients received an ARB. 22 Data from these surveys suggest that a large proportion of European CHF patients do not receive ARB therapy where it may now be appropriate, following the results of the new trials mentioned earlier. Recommended use of ARBs in the 2001 guidelines Despite their infrequent use in Europe, ARBs have been recommended by the ESC for some years as a treatment that leads to symptom improvement in CHF. 1 The 2001 guidelines advised that ARBs should be considered: 1. For symptomatic treatment in CHF patients who are intolerant to ACE-inhibitors (level of evidence C; recently revised in May 2005, see below).. In combination with ACE inhibition, to improve HF symptoms and reduce hospitalization for worsening HF (level of evidence B; recently revised in May 2005, see below).

J12 J.J.V. McMurray The guidelines also noted that, although ARBs are not superior to ACE-inhibitors in terms of efficacy, side effects (notably cough) may be less with ARBs. 1 However, the guidelines were cautious regarding the efficacy of ARBs in reducing HF-related mortality compared with ACE-inhibitors. They also advised that the safety of adding an ARB to existing treatment with both an ACE-inhibitor and a beta-blocker required further investigation. 1 The 2001 guidelines on the use of ARBs in CHF management were based on data from the ELITE II 8 and ValHeFT 10 studies. The more recent publication of findings from the OPTIMAAL, 12 VALIANT, 13 and CHARM 3,9,14 17 studies provides greater support for the efficacy of ARBs in CHF. Data from these trials have been considered for the re-evaluation of ARBs in the 2005 revision of the guidelines. New data on the efficacy, safety, and tolerability of ARBs in CHF A number of trials have assessed the efficacy and safety of ARBs and their effects on mortality and rates of hospitalization in patients with CHF. In this section, data from large-scale randomized clinical trials investigating the efficacy and safety of ARBs in CHF, including the recent VALIANT and CHARM studies and the ongoing I-PRESERVE (Irbesartan in Heart Failure with Preserved Systolic Function) trial, will be reviewed to evaluate the potential benefits of this drug class in key patient subgroups. Efficacy of ARBs in patients intolerant to standard therapies Many CHF patients do not receive ACE-inhibitors because of actual or perceived intolerance, 11 and physicians are unable to prescribe recommended gold standard treatments in these individuals. A number of trials have assessed the efficacy of ARBs with or as alternatives to ACE-inhibitors in the management of CHF. 8,11 14 The ELITE II and OPTIMAAL trials compared survival and tolerability with losartan (50 mg once daily) against captopril (50 mg thrice daily) in addition to standard medical therapy in patients with CHF and after MI, respectively. 8,12 The results from both trials revealed no significant differences in total mortality between treatment groups but a definite trend for patients to do better when treated with captopril. In both trials, the low dose of losartan tested was significantly better tolerated and with fewer discontinuations than captopril. 8,12 In contrast, the VALIANT trial showed that valsartan (160 mg twice daily) was as effective as captopril (50 mg thrice daily) in reducing mortality (and morbidity) in patients with HF, LVSD, or both after MI. 13 However, there was a similar frequency of adverse effects with valsartan as with captopril, with the exception of cough. The efficacy of an ARB was evaluated in ACE-intolerant patients with CHF (NYHA II IV; EF, 40%) in the CHARM- Alternative trial. 14 Candesartan reduced the risk of cardiovascular death by 15% and hospitalization for HF by 32%; the number needed to treat in order to avoid one cardiovascular death or HF-related hospital admission was 14. 14 Candesartan was well tolerated, although patients with prior renal dysfunction or hyperkalaemia remained at relatively high risk of these complications. 14 In a retrospective subgroup analysis of a small number of patients not taking an ACE-inhibitor (because of presumed intolerance) in ValHeFT, similar benefits were seen with valsartan. 11 These new data have led to an updating of the 2001 ESC guideline recommendations. The 2005 revision states as follows:. ARBs are a good alternative to ACE-inhibition in symptomatic patients intolerant to ACE-inhibitors to improve morbidity and mortality (Class of recommendation I, level of evidence B).. ARBs and ACE-inhibitors have similar efficacy in CHF (Class of recommendation IIa, level of evidence B).. After acute MI with signs of HF or LV dysfunction, ARBs have similar efficacy to ACE-inhibitors (Class of recommendation I, level of evidence B). Use of ARBs in addition to ACE-inhibitors and beta-blockers in CHF Clinical trials have convincingly demonstrated the favourable effects of adding a beta-blocker to an ACEinhibitor, and this combination should be the bedrock of treatment in CHF. 23 25 Whether an ARB should be added to this combination became a controversial question following the publication of data from ValHeFT, a subgroup analysis of which appeared to show harm rather than benefit with this triple therapy. 10 The overall results from ValHeFT showed that valsartan reduced mortality and morbidity when added to conventional treatment, including an ACE-inhibitor in most patients. The triple therapy subgroup finding was always likely to represent a spurious or fluke finding but safety concerns mandated appropriate caution until more data on the use of ARBs with an ACE-inhibitor and a beta-blocker were available. Subsequent investigation of triple therapy in the VALIANT trial removed this concern about valsartan, showing no increase in mortality or other cardiovascular outcomes when all three drugs were used together. 13,26 No concern about triple therapy has ever existed with candesartan. In the RESOLVD study, combination therapy was associated with favourable effects on blood pressure, LV dimensions, and neurohormonal factors. 27 The greatest improvements in LV volumes and LVEF were seen with triple therapy (i.e. all of metoprolol, candesartan, and enalapril) compared with single or dual therapy. 27,28 Similarly, in the CHARM-Added trial, patients receiving an ACE-inhibitor (with or without a beta-blocker) gained additional benefit from candesartan, whereas triple therapy (i.e. all of candesartan, an ACE-inhibitor, and a beta-blocker) was associated with the lowest mortality. 3 The treatment benefit associated

Angiotensin receptor blockers in HF management J13 with candesartan was considerable, conferring a 15% RRR in cardiovascular death or hospitalization, and the number needed to treat to prevent one first event of cardiovascular death or hospitalization was 23. 3 The data from the RESOLVD and CHARM-Added trials indicate that the addition of an ARB to an ACE-inhibitor-based treatment regimen is effective in the treatment of CHF patients with LVSD, both in terms of the important disease mechanisms in HF and clinical outcomes. As a result, the 2005 revision of the ESC CHF guidelines now recommends adding an ARB in patients with CHF and a low LVEF who remain symptomatic despite treatment with an ACE-inhibitor and a betablocker to reduce mortality (Class of recommendation IIa, level of evidence B) and hospital admission for worsening HF (Class of recommendation I, level of evidence A). 29 Efficacy of ARBs in patients with preserved ejection fraction Approximately 15 20 million CHF patients worldwide (30 50% of CHF patients) are currently estimated to have preserved ejection fraction (PEF). Although they have a better life expectancy than those with a low LVEF, they do have a high risk of hospitalization with worsening CHF and other cardiovascular problems. 30 However, characterization of this patient group is poor, few outcome studies have been conducted and optimum treatment strategies remain unclear. 31 The CHARM-Preserved trial assessed the efficacy of candesartan against placebo in more than 3000 patients with CHF and PSF (EF. 40%) and represents the first large-scale study to publish data on the efficacy of ARBs in patients with preserved EF. 15 Patients in the trial tended to be older, female, have milder symptoms and be more likely to have a history of hypertension. 15 There was no significant difference in cardiovascular deaths between the two treatment groups; however, candesartan treatment led to fewer investigator-reported hospital admissions for HF than placebo treatment. 15 One further large outcome trial is currently investigating the potential efficacy of the ARB irbesartan in patients with CHF and a preserved LVEF. I-PRESERVE is a randomized, placebo-controlled trial assessing the efficacy of irbesartan in reducing death or cardiovascular hospitalization in approximately 4130 symptomatic patients with CHF and PEF (EF. 45%) receiving optimal medical therapy and enrolled in.300 clinical centres worldwide. Data from this trial are awaited with interest. Recommended use of ARBs in the 2005 ESC guidelines The 2005 ESC guidelines for the management of CHF have been revised on the basis of trial data that were not available for the development of the 2001 guidelines. The updated guidance concerning the use of ARBs incorporates data from the VALIANT, OPTIMAAL, and CHARM trials and provides stronger recommendations for the use of ARBs in the management of CHF. 29 The guidelines state that ARBs represent a good alternative to ACEinhibitors to improve mortality and morbidity in symptomatic ACE-intolerant patients with LVSD. They also show similar efficacy to ACE-inhibitors in the treatment of CHF with LVSD and in patients with acute MI with LVSD, HF, or both. The use of ARBs should be considered:. In patients with acute MI complicated by HF, LVSD, or both, if intolerant to an ACE-inhibitor, to reduce cardiovascular mortality and morbidity (Class of recommendation I, level of evidence A);. In patients with CHF, if intolerant to an ACE-inhibitor, to reduce mortality and morbidity (Class of recommendation I, level of evidence B);. In patients with CHF who remain symptomatic, added to an ACE-inhibitor (and a beta-blocker, unless contraindicated or not tolerated), to reduce mortality (Class of recommendation IIa, level of evidence B) and hospital admissions for HF (Class of recommendation I, level of evidence A). Summary Large-scale randomized placebo-controlled clinical trials conducted within the last few years show the value of ARBs in low LVEF HF, both in patients intolerant to standard therapies and as part of a combination treatment strategy. On the basis of data from these trials, the revised 2005 ESC CHF guidelines now provide stronger recommendations for the use of ARBs in CHF management, indicating that these agents represent effective alternative or additional therapies to ACE-inhibitors to optimize patient outcomes. Acknowledgements This work was supported by an unrestricted educational grant from Takeda Pharmaceuticals Limited. Content from the 2001 and 2005 ESC CHF guidelines 1,29 is cited with permission granted by the ESC. Conflict of interest: none declared. References 1. Remme WJ, Swedberg K. The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure. 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