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Circulation. 2004;110:3281-3288
doi: 10.1161/01.CIR.0000147274.83071.68
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(Circulation. 2004;110:3281-3288.)
© 2004 American Heart Association, Inc.

New Drugs and Technologies

Which Inhibitor of the Renin–Angiotensin System Should Be Used in Chronic Heart Failure and Acute Myocardial Infarction?

John J.V. McMurray, MD; Marc A. Pfeffer, MD, PhD; Karl Swedberg, MD, PhD; Victor J. Dzau, MD

From the Department of Cardiology, Western Infirmary, Glasgow, Scotland, UK (J.J.V.M.); Cardiovascular Division, Brigham & Women’s Hospital, Boston, Mass (M.A.P., V.J.D.); and Department of Medicine, Sahlgrenska University Hospital/Östra, Göteborg, Sweden (K.S.).

Correspondence to Professor John J.V. McMurray, Department of Cardiology, Western Infirmary, Glasgow, G12 8QQ, UK. E-mail j.mcmurray{at}bio.gla.ac.uk


Key Words: heart failure, congestive • myocardial infarction • pharmacology • prevention, secondary • angiotensin


*    Introduction
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 *Introduction
down arrowCHF With Reduced Left...
 down arrowSummary and Conclusions
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The value of angiotensin-converting enzyme (ACE) inhibitors in reducing mortality rates and major nonfatal cardiovascular events in patients with chronic heart failure (CHF) caused by left ventricular systolic dysfunction (LVSD) and in those with acute myocardial infarction (AMI) has been established by multiple randomized clinical trials.1–3 Angiotensin II type 1 receptor blockers (ARBs) offer an alternative means of blocking the renin-angiotensin system (RAS).4,5 The hypothetical reasons why an ARB might be more effective or better tolerated (or both) than an ACE inhibitor have been reviewed in detail.6,7 Briefly, angiotensin II is produced by enzymes other than ACE, meaning that ACE inhibitors might be less effective at blocking this peptide than an ARB (Figure 1).8,9 Angiotensin type 1 (AT1) receptor blockade also makes more angiotensin II available to stimulate the unblocked AT2 receptor (and perhaps other AT receptor subtypes)10,11 with purported beneficial actions in reducing cardiovascular disease progression.12



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  		Figure 1. Schematic of RAS and site of action of ACE inhibitors and ARBs.

Unlike ARBs, ACE (kininase II) inhibitors inhibit bradykinin breakdown. Augmentation of bradykinin may have actions including potentiation of vasodilation, fibrinolytic effects, and inhibition of cellular growth and division, which may contribute to the benefits of ACE inhibitors.6,13,14 Conversely, bradykinin accumulation may cause some of the adverse effects of ACE inhibitors, ie, cough, rash, and angioedema.6,7

The evaluation of the effects of ARBs in CHF and AMI has therefore been challenging because of the incontrovertible role of ACE inhibitors in these conditions, raising questions about trial design, dose selection, statistics, and even ethics.15,16 A particular issue has been the need for direct comparisons, including formally conducted tests for "noninferiority," with the implications this has for patient selection, choice of ACE inhibitor and dose, sample size, and end points.15–17

The 2 main approaches taken involved either a head-to-head comparison of the 2 types of treatment (1 trial in CHF and 2 in AMI) or a strategy of adding an ARB or placebo to an ACE inhibitor (2 trials in CHF and 1 in AMI). The pharmacological concepts underpinning these 2 approaches are also more complex than they appear at first sight. These alternative approaches view the actions of bradykinin in a contradictory way. The head-to-head comparison approach is based on better tolerability of an ARB because of a lack of bradykinin-mediated adverse effects, coupled with a potentially greater ability of an ARB to more completely block the RAS. Conversely, the add-on strategy assumes that the potential clinical benefits of bradykinin outweigh any adverse effects it might cause and that these might add to potentially more complete blockade of the RAS with an ARB. The add-on approach also results in a different pharmacological effect than when an ARB is used alone.7 With combination therapy, the negative feedback mediated a rise in angiotensin II, which normally occurs with an ARB (and may activate other AT receptors), that is reduced by the ACE inhibitor.

A third trial design was used in one CHF study that compared an ARB with placebo in patients who could not take an ACE inhibitor because of prior intolerance.18 The 3 major ARB trials in CHF with LVSD and the 2 trials in AMI are now completed, and it is unlikely that more will follow. Physicians will therefore have to decide how to use ACE inhibitors and ARBs, alone or in combination, in these conditions on the basis of the recently completed trials.


*    CHF With Reduced Left Ventricular Systolic Function
up arrowTop
 up arrowIntroduction
 *CHF With Reduced Left...
down arrowSummary and Conclusions
 down arrowReferences
 
ACE Inhibitor-ARB Head-to-Head Comparison
The Evaluation of Losartan in the Elderly (ELITE; n=722) study compared the tolerability of losartan 50 mg once daily and captopril 50 mg thrice daily over a period of 48 weeks (Table 1). There were 17 (4.8%) in the losartan group and 32 (8.7%) in the captopril group (relative risk reduction, 46%; 95% CI, 5 to 69; P=0.035).19 Because this finding was unexpected, the investigators properly designed ELITE 2 (n=3159), which compared the effect of these 2 treatments on all-cause mortality, prospectively.20 With a 17.7% mortality in the losartan group and 15.9% in the captopril group (hazard ratio, 1.13; 95.7% CI, 0.95 to 1.35; P=0.16), losartan was not better than captopril. ELITE-2 was not powered to test for noninferiority. However, because an ACE inhibitor has been compared with placebo in CHF and losartan has been compared with an ACE inhibitor in ELITE 2, an indirect comparison between losartan and placebo is possible (imputed placebo analysis).21 In this analysis, losartan 50 mg once daily could not be shown to be better than placebo. Concern that the dose of losartan was too low in this trial (and in another trial in AMI) led to a further large outcome trial with losartan in CHF. The Heart Failure Endpoint Evaluation With the Angiotensin II Antagonist Losartan (HEAAL) study is comparing 50 mg of losartan once daily to 150 mg once daily in patients intolerant of an ACE inhibitor.22


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  		TABLE 1. ARB Trials in Patients With Heart Failure and Reduced Left Ventricular Systolic Function

Combination ARB-ACE Inhibitor Treatment
In the Valsartan Heart Failure Trial (Val-HeFT; n=5010), placebo or valsartan 160 mg twice daily was added to standard treatment that included, in 93% of patients, an ACE inhibitor (Table 1).23 Although there was no reduction in mortality, valsartan significantly reduced the risk of the coprimary end point (death, admission to hospital with heart failure, ≥4 hours of intravenous treatment for heart failure without admission or cardiac arrest with resuscitation) by 13.2%. This was due mainly to a 27.5% reduction in the risk of hospitalization for CHF. Two subgroup analyses, however, detracted attention from this overall positive effect. One suggested that most benefit was concentrated in the minority (7%) of patients not taking an ACE inhibitor.24 The other suggested that patients taking both an ACE inhibitor and a ß-blocker at baseline (optimal treatment) did worse when valsartan was added.23 Consequently, the Food and Drug Administration (FDA) and international guidelines recommended avoidance of "triple therapy" (the combination of an ACE inhibitor, ß-blocker, and ARB) because of this apparent risk.25–27 The FDA did, however, approve valsartan for use in patients intolerant of an ACE inhibitor.27

The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program (n=7601) consisted of 3 independent but linked trials, 2 of which randomized patients with LVSD (Table 1).28 In CHARM-Added (n=2548), patients taking an ACE inhibitor (in more than half of the patients, a ß-blocker also) were randomized to either placebo or a target dose of candesartan 32 mg once daily.29 The risk of the primary outcome in this trial, death from a cardiovascular cause or hospitalization for worsening CHF, was reduced significantly by 15% with candesartan. Candesartan led to a prominent reduction in investigator-reported hospitalizations for worsening CHF. The effectiveness of candesartan was not altered by baseline use of a ß-blocker in addition to an ACE inhibitor. Indeed, those receiving triple therapy had similar incremental reductions in cardiovascular deaths and heart failure hospitalizations.

Placebo-ARB Comparison in Patients Intolerant of an ACE Inhibitor
In CHARM-Alternative (n=2028), patients with prior intolerance of an ACE inhibitor were randomized to either placebo or candesartan (Table 1).18 The risk of death from a cardiovascular cause or hospitalization for worsening CHF was reduced significantly by 23% with candesartan. Closer examination of the other outcomes of this study suggests that candesartan had clinical benefits of a magnitude similar to an ACE inhibitor from previous trials in patients with CHF and LVSD.1

Clinical Questions Arising From the Completed ARB Trials in CHF
Is an ARB an Alternative to an ACE inhibitor in CHF With LVSD?
There has only been one head-to-head comparison of an ACE inhibitor and ARB (ELITE 2), in which the 2 agents (perhaps because of an inadequate dose of the ARB) were not shown to be equivalent.20 This finding and other considerations such as cost and the length and breadth of clinical experience in using ACE inhibitors in these patients indicate that ACE inhibitors should remain the preferred initial antagonist of the RAS.

Should an ARB Be Used in a Patient Intolerant of an ACE Inhibitor?
The CHARM-Alternative trial (and, to a lesser extent, the subgroup analysis of patients not taking an ACE inhibitor in Val-HeFT) showed that these 2 ARBs and dosing regimens are beneficial in CHF and are treatment alternatives for patients intolerant of an ACE inhibitor (Figure 2).18–24 The clearest indication of intolerance is a cough or angioedema because they do not seem to be caused by an ARB. Effective doses of ARBs almost certainly cause as much hypotension and renal dysfunction as an ACE inhibitor.18 Consequently, careful monitoring of patients previously withdrawn from an ACE inhibitor for these adverse effects is merited when an ARB is used.



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  		Figure 2. Place of ACE inhibitors and ARBs in treatment of patients with CHF. CIBIS 2 indicates Cardiac Insufficiency Bisoprolol Trial; MERIT-HF, Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival Study; CONSENSUS, Co-Operative North Scandinavian Survival Study; and SOLVD-T, treatment arm of the Studies of Left Ventricular Dysfunction.

Should an ARB Be Added to an ACE Inhibitor (and ß-Blocker) in CHF?
With a greater proportion of patients on both an ACE inhibitor and ß-blocker and a longer-term follow-up, CHARM-Added had more events and therefore greater statistical power than Val-HeFT to test the hypothesis that adding an ARB to standard treatment would be of incremental benefit.23,29 The improvement in outcomes with triple therapy in CHARM-Added is consistent with other evidence of greater neurohumoral suppression,30–33 improved symptoms, and increased exercise tolerance.34 There is, however, conflicting information about "reverse remodeling" of the left ventricle. Val-HeFT showed no further favorable change when valsartan was added to background treatment with both an ACE inhibitor and a ß-blocker.35 Conversely, in the Randomized Evaluation of Strategies of Left Ventricular Dysfunction (RESOLVD; n=768) pilot study, triple therapy resulted in the greatest reverse remodeling, perhaps reflecting the different design of this study.36 In our view, there is now strong evidence that ARBs should be used in CHF patients with LVSD in addition to other standard, lifesaving treatments in patients who remain symptomatic (Figure 2) to reduce risk of cardiovascular death, heart failure hospitalization, and other indexes of disease progression.

Which Should Be Added, an ARB or Spironolactone?
The Randomized Aldactone Evaluation Study (RALES; n=1663) showed that low-dose spironolactone reduced mortality by 30% in patients with severe CHF (currently or recently in NYHA functional class IV).37 Most patients (94%) in RALES were taking an ACE inhibitor, but only 10.5% were treated with a ß-blocker. Therefore, RALES differed greatly from CHARM-Added and Val-HeFT in terms of patient severity and background ß-blocker use, making comparison difficult. Clearly, the substantial mortality benefit of spironolactone argues strongly for use of this treatment in patients with severe CHF (Figure 2). This is supported by the effectiveness of another aldosterone antagonist, eplerenone, after AMI (see below).38 Conversely, although the effects of spironolactone in less severe CHF have not been quantified, those of ARBs have. The most difficult question is whether all 3 inhibitors of the RAS (or "quadruple therapy": an ACE inhibitor, a ß-blocker, spironolactone, and an ARB) are the most effective (but also safe). Because "aldosterone escape" occurs even in patients taking both an ACE inhibitor and an ARB, there is a theoretical reason to use all 3 inhibitors of the renin-angiotensin-aldosterone-system together.31,33 CHARM-Added, with 17% of patients taking spironolactone at baseline, currently provides the firmest data with which to answer this question. The beneficial effects of candesartan in this trial did not appear to be influenced by background spironolactone treatment. There was, however, more renal dysfunction and hyperkalemia when candesartan was added in patients taking an ACE inhibitor and spironolactone at baseline compared with those taking only an ACE inhibitor. Therefore, use of all 3 RAS inhibitors mandates even more careful monitoring of blood chemistry.

Is There a Role for ARBs in Patients With CHF With Preserved Systolic Function?
The role of ARBs in this important and neglected type of CHF is uncertain, and no ARB has yet been approved to treat these patients. In CHARM-Preserved (n=3025), candesartan did not lead to a statistically significant reduction in the primary outcome of the trial, although there was a substantial and significant reduction in heart failure hospitalization39 and no evidence for heterogeneity of the candesartan benefit across the 3 trials. The Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) study is an ongoing placebo-controlled outcome study in this important group of patients testing irbesartan 300 mg once daily.

Acute Myocardial Infarction
ACE Inhibitor-ARB Head-To-Head Comparison
Two outcome studies have compared an ARB to a dose of captopril (50 mg thrice daily) proven to be effective in an earlier mortality trial (Table 2).22,40 The Optimal Therapy in Myocardial Infarction With the Angiotensin II Antagonist Losartan (OPTIMAAL; n=5477) trial used the ARB regimen tested in CHF in ELITE-2 (losartan 50 mg once daily).22 The Valsartan in Acute Myocardial Infarction (VALIANT; n=14 703) trial used the valsartan regimen studied in CHF in Val-HeFT (valsartan 160 mg twice daily).17 Both trials selected high-risk survivors of AMI because these patients had been shown to obtain the greatest benefits from ACE inhibitors. The inclusion criteria, however, differed between the 2 trials. VALIANT randomized patients with evidence of reduced LVSD, clinical or radiographic evidence of acute heart failure, or both to reflect closely the patients studied in the key prior long-term treatment ACE inhibitor trials.2 The use of a "reference" ACE inhibitor (and reference dosing regimen) and the inclusion and exclusion criteria from the reference trials were part of the strict noninferiority design of VALIANT.17 The inclusion criteria for OPTIMAAL were broader than for VALIANT (Figure 3). The primary aim of both OPTIMAAL and VALIANT was to test for superiority of the ARB over captopril (titrated to 50 mg thrice daily) in terms of all-cause mortality, although each trial was also designed to test for noninferiority if the ARB is not found to be found superior to captopril.


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  		TABLE 2. ARB Trials in Patients With AMI



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  		Figure 3. Patient selection criteria for major trials in high-risk AMI. In VALIANT, 23% of patients had only LVSD, 48% had only clinical or radiographic evidence of acute heart failure (HF), and 29% had evidence of both; ie, they were EPHESUS-like patients. LBBB indicates left bundle-branch block; SAVE, Survival and Ventricular Enlargement; AIRE, Acute Infarction Ramipril Efficacy; and TRACE, Trandolapril in Patients With Reduced Left Ventricular Function After Acute Myocardial Infarction.

In OPTIMAAL, there was a trend toward superiority of captopril over losartan for the outcome of all-cause mortality, and noninferiority could not be shown. In contrast, in VALIANT, valsartan was found to be as effective as captopril. This was confirmed by formal noninferiority analysis and an imputed-placebo analysis, which showed that valsartan preserved the mortality and other cardiovascular mortality and morbidity benefits of captopril.17 The pattern of adverse events differed between captopril (more cough, rash, and taste disturbance) and valsartan (more hypotension and renal abnormalities), although the proportion of patients who stopped treatment for any reason did not differ between the 2 treatments. On the basis of these findings, valsartan (titrated to 160 mg twice daily) is an alternative to an ACE inhibitor in these high-risk AMI patients (Figure 4).



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  		Figure 4. Place of ACE inhibitors and ARBs in treatment of patients with AMI. Abbreviations as in Figures 1 through 3UpUp.

Combination ACE Inhibitor-ARB Treatment
VALIANT is the only trial that reported survival and other outcomes after an MI in patients given an ARB and an ACE inhibitor compared with those given an ACE inhibitor alone.17 VALIANT, by design, also ensured that patients taking combination therapy received the proven dose of a proven ACE inhibitor. Patients randomized to combination treatment were titrated to valsartan (80 mg twice daily), added to captopril 50 mg thrice daily. This contrasts to the 2 CHF trials, Val-HeFT and CHARM, in which both the choice of ACE inhibitor and its dose were at the discretion of the investigator.

Mortality (and other prespecified secondary clinical outcomes) was not reduced by combination valsartan and captopril treatment compared with the proven dose of captopril (although combination treatment did increase the rate of adverse events and lower blood pressure more than captopril).

Clinical Questions Arising From the ARB Trials in AMI
Is an ARB an Alternative to an ACE Inhibitor in a Patient With LVSD, Acute Heart Failure, or Both After AMI?
VALIANT shows that valsartan 160 mg twice daily is as good as a proven dose of a proven ACE inhibitor in reducing risk of death and other major cardiovascular outcomes. This valsartan regimen is therefore an effective alternative, although the choice between these agents will be influenced by cost, tolerability, and prior clinical experience (Figure 4).

Why Did Combination ACE Inhibitor and ARB Treatment Not Improve Outcome After AMI When It Did in CHF?
There are several possible explanations for this apparent discrepancy.

It is important to state, however, that even in VALIANT there was some evidence of an additional biological effect of adding an ARB to full-dose ACE inhibitor. Arterial pressure was reduced slightly but significantly more with the combination, and there was a modest and statistically significant reduction in cumulative hospitalizations for CHF and AMI in the combination compared with captopril group.17 One further trial is testing the possible benefit of combination ACE inhibitor and ARB treatment in patients with cardiovascular disease but preserved left ventricular systolic function.47

Should an ARB or Aldosterone Blocker Be Used After AMI?
The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy SURVIVAL Study (EPHESUS; n=6642) compared placebo with eplerenone 25 to 50 mg once daily added to background ACE inhibitor (agent and dose determined by investigator) and, in most, ß-blocker treatment.38 Patients had LVSD and clinical or radiographic evidence of acute heart failure (or diabetes mellitus); ie, they were a subset of those randomized in OPTIMAAL and VALIANT (Figure 3). Eplerenone reduced mortality by 15% (P=0.008) and the coprimary outcome of death from a cardiovascular cause or hospitalization for a cardiovascular cause by 13% (P=0.002). Consequently, EPHESUS strongly supports the strategy of adding eplerenone to an ACE inhibitor or ARB. As in CHF, this makes sense from a pathophysiological standpoint because aldosterone is regulated independently of angiotensin II and escapes during long-term ACE inhibitor treatment.48 Aldosterone blockade is therefore a complementary rather than competing treatment for these survivors of AMI remaining at high risk (Figure 4). Again, the importance of monitoring for hyperkalemia must be underscored.


*    Summary and Conclusions
up arrowTop
 up arrowIntroduction
 up arrowCHF With Reduced Left...
 *Summary and Conclusions
down arrowReferences
 
With the major trials of ARBs in patients with CHF and LVSD and in patients with high-risk AMI completed, physicians now must incorporate the information they provide into rational treatment plans. We believe that the available trial data provide clear evidence that certain ARBs, when used at the clinically effective dose (titration of either valsartan to 160 mg twice daily or candesartan to 32 mg daily), can reduce cardiovascular morbidity and mortality. When an ACE inhibitor is not being used in patients with CHF or a high-risk AMI, these ARB regimens will lead to reductions in the risk of death and other cardiovascular events that are comparable to those obtained with a proven dose of a proven ACE inhibitor. In patients with CHF, additive clinical benefits have been shown with these ARBs used in combination with ACE inhibitor in both the presence and absence of ß-blocker therapy. Therefore, in CHF, ARBs provide a clear advance, offering an additional opportunity to further reduce cardiovascular morbidity and mortality when used concomitantly with both a ß-blocker and ACE inhibitor (Figure 5). In AMI complicated by LVSD, acute heart failure, or both, the combination of an ARB with a proven dose of an ACE inhibitor does not result in incremental clinical benefits, although a proven dose of a proven ARB is as effective as an ACE inhibitor. However, even in this acute setting, demonstration of the comparable effectiveness of an ARB (used in the appropriate dose) and ACE inhibitor provides clinicians with an additional tool with which to obtain the lifesaving benefits of RAS blockade in these patients. A consistent finding from all the major trials is that effective doses of these ARBs lead to hypotension and increases in creatinine and potassium. The effort and cost of the additional monitoring needed to detect and manage these generally transient adverse effects are likely offset by the improvements in prognosis that the judicious use of ARBs can produce. Through these recent international clinical trials, ARBs have now earned their position on the short list of treatments that can save lives and reduce cardiovascular morbidity in patients with CHF and high-risk AMI.



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  		Figure 5. Cumulative benefits of incremental neurohumoral inhibition in CHF. Abbreviations as in Figures 1 through 3UpUp.


*    References
up arrowTop
 up arrowIntroduction
 up arrowCHF With Reduced Left...
 up arrowSummary and Conclusions
 *References
 

  1. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA. 1995; 273: 1450–1456.[Abstract/Free Full Text]
  2. Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet. 2000; 355: 1575–1581.[CrossRef][Medline] [Order article via Infotrieve]
  3. Latini R, Tognoni G, Maggioni AP, et al. Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. Angiotensin-converting Enzyme Inhibitor Myocardial Infarction Collaborative Group. J Am Coll Cardiol. 2000; 35: 1801–1807.[Abstract/Free Full Text]
  4. Johnston CI. Angiotensin receptor antagonists: focus on losartan. Lancet. 1995; 346: 1403–1407.[CrossRef][Medline] [Order article via Infotrieve]
  5. Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med. 1996; 334: 1649–1654.[Free Full Text]
  6. Pitt B, Chang P, Timmermans PB. Angiotensin II receptor antagonists in heart failure: rationale and design of the evaluation of losartan in the elderly (ELITE) trial. Cardiovasc Drugs Ther. 1995; 9: 693–700.[CrossRef][Medline] [Order article via Infotrieve]
  7. McMurray JJ. Angiotensin II receptor antagonists for the treatment of heart failure: what is their place after ELITE-II and Val-HeFT? J Renin Angiotensin Aldosterone Syst. 2001; 2: 89–92.[Medline] [Order article via Infotrieve]
  8. Urata H, Healy B, Stewart RW, et al. Angiotensin II-forming pathways in normal and failing human hearts. Circ Res. 1990; 66: 883–890.[Abstract/Free Full Text]
  9. Petrie MC, Padmanabhan N, McDonald JE, et al. Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease. J Am Coll Cardiol. 2001; 37: 1056–1061.[Abstract/Free Full Text]
  10. Horiuchi M, Akishita M, Dzau VJ. Recent progress in angiotensin II type 2 receptor research in the cardiovascular system. Hypertension. 1999; 33: 613–621.[Abstract/Free Full Text]
  11. Akishita M, Yamada H, Dzau VJ, et al. Increased vasoconstrictor response of the mouse lacking angiotensin II type 2 receptor. Biochem Biophys Res Commun. 1999; 261: 345–349.[CrossRef][Medline] [Order article via Infotrieve]
  12. Abadir PM, Carey RM, Siragy HM. Angiotensin AT 2 receptors directly stimulate renal nitric oxide in bradykinin B2-receptor-null mice. Hypertension. 2003; 42: 600–604.[Abstract/Free Full Text]
  13. Witherow FN, Helmy A, Webb DJ, et al. Bradykinin contributes to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure. Circulation. 2001; 104: 2177–2181.[Abstract/Free Full Text]
  14. Witherow FN, Dawson P, Ludlam CA, et al. Marked bradykinin-induced tissue plasminogen activator release in patients with heart failure maintained on long-term angiotensin-converting enzyme inhibitor therapy. J Am Coll Cardiol. 2002; 40: 961–966.[Abstract/Free Full Text]
  15. Committee for Proprietary Medicinal Products. Points to consider on switching between superiority and non-inferiority. Br J Clin Pharmacol. 2001; 52: 223–228.[CrossRef][Medline] [Order article via Infotrieve]
  16. Skali H, Pfeffer MA. Prospects for ARB in the next five years. J Renin Angiotensin Aldosterone Syst. 2001; 2: 215–218.[Medline] [Order article via Infotrieve]
  17. Pfeffer MA, McMurray JJ, Velazquez EJ, et al; Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003; 349: 1893–1906.[Abstract/Free Full Text]
  18. Granger CB, McMurray JJ, Yusuf S, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003; 362: 772–776.[CrossRef][Medline] [Order article via Infotrieve]
  19. Pitt B, Segal R, Martinez FA, Meurers G, et al. Randomized trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997; 347: 747–752.
  20. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomized trial-the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000; 355: 1582–1587.[CrossRef][Medline] [Order article via Infotrieve]
  21. Berry C, Norrie J, McMurray JJ. Are angiotensin II receptor blockers more efficacious than placebo in heart failure? Implications of ELITE-2. Evaluation of Losartan In The Elderly Am J Cardiol. 2001; 87: 606–607.
  22. Dickstein K, Kjekshus J. OPTIMAAL Steering Committee of the OPTIMAAL Study Group Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomized trial Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet. 2002; 360: 752–760.[CrossRef][Medline] [Order article via Infotrieve]
  23. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001; 345: 1667–1675.[Abstract/Free Full Text]
  24. Maggioni AP, Anand I, Gottlieb SO, et al; Val-HeFT Investigators (Valsartan Heart Failure Trial). Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol. 2002; 40: 1414–1421.[Abstract/Free Full Text]
  25. Remme WJ, Swedberg K; Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J. 2001; 22: 1527–1560.[Free Full Text]
  26. Hunt SA, Baker DW, Chin MH, et al. Am College of Cardiology/Am Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of (Heart Failure); International Society for Heart and Lung Transplantation; Heart Failure Society of America. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the Am College of Cardiology/Am Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America. Circulation. 2001; 104: 2996–3007.[Free Full Text]
  27. http://www.fda.gov/cder/foi/label/2002/20665s16lbl.pdf
  28. Pfeffer MA, Swedberg K, Granger CB, et al; CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003; 362: 759–766.[CrossRef][Medline] [Order article via Infotrieve]
  29. McMurray JJ, Ostergren J, Swedberg K, et al; CHARM Investigators and Committees Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003; 362: 767–771.[CrossRef][Medline] [Order article via Infotrieve]
  30. Baruch L, Anand I, Cohen IS, et al. Augmented short- and long-term hemodynamic and hormonal effects of an angiotensin receptor blocker added to angiotensin converting enzyme inhibitor therapy in patients with heart failure. Vasodilator Heart Failure Trial (V-HeFT) Study Group. Circulation. 1999; 99: 2658–2664.[Abstract/Free Full Text]
  31. McKelvie RS, Yusuf S, Pericak D, et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation. 1999; 100: 1056–1064.[Abstract/Free Full Text]
  32. Latini R, Masson S, Anand I, et al; Valsartan Heart Failure Trial Investigators. Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2002; 106: 2454–2458.[Abstract/Free Full Text]
  33. Cohn JN, Anand IS, Latini R, et al; Valsartan Heart Failure Trial Investigators. Sustained reduction of aldosterone in response to the angiotensin receptor blocker valsartan in patients with chronic heart failure: results from the valsartan Heart Failure Trial. Circulation. 2003; 108: 1306–1309.[Abstract/Free Full Text]
  34. Hamroff G, Katz SD, Mancini D, et al. Addition of angiotensin II receptor blockade to maximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure. Circulation. 1999; 99: 990–992.[Abstract/Free Full Text]
  35. Wong M, Staszewsky L, Latini R, et al; Val-HeFT Heart Failure Trial Investigators. Valsartan benefits left ventricular structure and function in heart failure; Val-HeFT echocardiography study. J Am Coll Cardiol. 2002; 40: 970–975.[Abstract/Free Full Text]
  36. McKelvie RS, Rouleau JL, White M, et al. Comparative impact of enalapril, candesartan or metoprolol alone or in combination on ventricular remodelling in patients with congestive heart failure. Eur Heart J. 2003; 24: 1727–1734.[Abstract/Free Full Text]
  37. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341: 709–717.[Abstract/Free Full Text]
  38. Pitt B, Remme W, Zannad F, et al; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309–1321.[Abstract/Free Full Text]
  39. Yusuf S, Pfeffer MA, Swedberg K, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003; 362: 777–781.[CrossRef][Medline] [Order article via Infotrieve]
  40. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators N Engl J Med. 1992; 327: 669–677.
  41. McAlpine HM, Morton JJ, Leckie B, et al. Neuroendocrine activation after acute myocardial infarction. Br Heart J. 1988; 60: 117–124.[Abstract/Free Full Text]
  42. Rouleau JL, de Champlain J, Klein M, et al. Activation of neurohumoral systems in postinfarction left ventricular dysfunction. J Am Coll Cardiol. 1993; 22: 390–398.[Abstract]
  43. Dzau, VJ Colucci, WS Hollenberg, NK et al. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation. 1981; 63: 645–651.[Free Full Text]
  44. Borghi C, Boschi S, Ambrosioni E, et al. Evidence of a partial escape of renin-angiotensin-aldosterone blockade in patients with acute myocardial infarction treated with ACE inhibitors. J Clin Pharmacol. 1993; 33: 40–45.[Abstract]
  45. Lee AF, MacFadyen RJ, Struthers AD. Neurohormonal reactivation in heart failure patients on chronic ACE inhibitor therapy: a longitudinal study. Eur J Heart Fail. 1999; 1: 401–406.[CrossRef][Medline] [Order article via Infotrieve]
  46. Cohn JN. Interaction of beta-blockers and angiotensin receptor blockers/ACE inhibitors in heart failure. J Renin Angiotensin Aldosterone Syst. 2003; 4: 137–139.[Medline] [Order article via Infotrieve]
  47. Yusuf S. From the HOPE to the ONTARGET and the TRANSCEND studies: challenges in improving prognosis. Am J Cardiol. 2002; 89: 18A–25A.[Medline] [Order article via Infotrieve]
  48. Struthers AD. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in chronic heart failure. J Card Fail. 1996; 2: 47–54.[CrossRef][Medline] [Order article via Infotrieve]



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