This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by McMurray, J. J. Search for Related Content PubMed PubMed Citation Articles by McMurray, J. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Failure Social Bookmarking                         What's this?

Angiotensin inhibition in heart failure

Department of Cardiology, Western Infirmary, Glasgow, G11 6NT, UK, j.mcmurray@ bio.gla.ac.uk

Survival in patients with heart failure remains very poor, and is worse than that for most common cancers, including bowel cancer in men and breast cancer in women. The renin-angiotensin-aldosterone system (RAAS) is not completely blocked by angiotensin-converting enzyme (ACE) inhibition. Blockade of the RAAS at the AT₁-receptor has the theoretical benefit of more effective blockade of the actions of angiotensin II. ACE inhibitors (ACE-Is) prevent the breakdown of bradykinin: this has been blamed for some of the unwanted effects of ACE-Is although bradykinin may have advantageous effects in heart failure. Consequently, ACE-Is and ARBs might be complementary or even additive treatments; recent trials have tested these hypotheses.

The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme compared the angiotensin receptor blocker (ARB) candesartan (target dose 32 mg once daily) to placebo in three distinct but complementary populations of patients with symptomatic heart failure. These were: patients with reduced left ventricular ejection fraction (LVEF) who were ACE-I-intolerant (CHARM-Alternative); patients with reduced LVEF who were being treated with ACE-Is (CHARM-Added); and patients with preserved left ventricular systolic function (CHARM-Preserved).

There were substantial and statistically significant reductions in the primary composite end point (risk of cardiovascular death or hospital admission for heart failure) in CHARM-Alternative. This was also the case in CHARM-Added, supporting and extending the findings of Val-HeFT. In CHARM-Preserved, the effect of candesartan on the primary end point did not reach conventional statistical significance though hospital admission for heart failure was reduced significantly with candesartan. In the CHARM-Overall programme there was a statistically borderline reduction in all-cause mortality with a clear reduction in cardiovascular mortality. All-cause mortality was reduced by 12% in the two CHARM trials in patients with low LVEF.

CHARM succeeded in answering a number of questions about the safety and efficacy of ARB use in heart failure. It showed evidence for a clinical benefit of candesartan both additive to and independent of ACE-I use. The benefits in terms of clinical outcomes were seen irrespective of β-blocker usage. Benefits in patients with preserved LVEF were shown in the proportion of patients hospitalised with worsening heart failure and in overall number of admissions for heart failure. Candesartan had expected effects on blood pressure and renal function, emphasising the need for careful patient monitoring.

Key Words: heart failure • angiotensin-converting enzyme inhibitors • angiotensin receptor blockers • candesartan • CHARM programme • β-blockers

References

• Cowie MR, Mosterd A., Wood DA et al. The epidemiology of heart failure. Eur Heart J 1997;18:208-25.[Free Full Text]
• McMurray JJ, Stewart S. Epidemiology, aetiology, and prognosis of heart failure. Heart 2000;83:596-602.[Free Full Text]
• Petrie M.,McMurray J. Changes in notions about heart failure. Lancet 2001;358:432-4.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• [No authors listed]. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429-35.[Abstract]
• [No authors listed]. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991; 25: 293-302.
• Garg R., Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on the mortality and morbidity in patients with heart failure. JAMA 1995;18:1450-5.
• The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial [editorial]. Lancet 1999;353:9-13.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) [editorial]. Lancet 1999;353:2001-07.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Packer M., Coats AJ, Fowler MB et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344: 1651-8.[Abstract/Free Full Text]
• Pitt B., Zannad F., Remme WJ et al. The effect of spironolactone on morbidity and mortality in patient with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-17.[Abstract/Free Full Text]
• [No authors listed]. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997;336:525-33.[Abstract/Free Full Text]
• Stewart S., MacIntyre K., MacLeod et al. Trends in hospitalization for heart failure in Scotland, 1990-1996. An epidemic that has reached its peak? Eur Heart J 2001;22:209-17.[Abstract/Free Full Text]
• 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;99:990-2.[Abstract/Free Full Text]
• 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;100:1056-64.[Abstract/Free Full Text]
• 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;24:1727-34.[Abstract/Free Full Text]
• Latini R., Masson S.,Anand I. et al. Valsartan Heart Failure 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;106:2454-8.[Abstract/Free Full Text]
• 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;108:1306-09.[Abstract/Free Full Text]
• Granger CB, Ertl G., Kuch J. et al. Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors. Am Heart J 2000;139:609-17.[Web of Science][Medline] [Order article via Infotrieve]
• Pitt B., Poole-Wilson PA, Segal R. et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial - the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582-7.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 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;345:1667-75.[Abstract/Free Full Text]
• Swedberg K., Pfeffer M., Granger C. et al. Candesartan in heart failure - assessment of reduction in mortality and morbidity (CHARM): rationale and design. Charm-Programme Investigators. J Card Fail 1999;5:276-82.[CrossRef][Medline] [Order article via Infotrieve]
• McMurray J., Ostergren J., Pfeffer M. et al. Clinical features and contemporary management of patients with low and preserved ejection fraction heart failure: baseline characteristics of patients in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur J Heart Fail 2003;5:261-70.[Abstract/Free Full Text]
• Granger CB, McMurray JJ, Yusuf S. et al. Effects of candesartan in patients with chronic heart failure and reduced leftventricular systolic function intolerant to angiotensin-converting-enzyme I inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772-6.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• McMurray JJ, Ostergren J., Swedberg K. et al. Effects of candesartan in patients with chronic heart failure and reduced leftventricular systolic function taking angiotensin-convertingenzyme inhibitors: the CHARM-Added trial. Lancet 2003;362: 767-71.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Yusuf S., Pfeffer MA, Swedberg K. et al. Effects of candesartan in patients with chronic heart failure and preserved leftventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362:777-81.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• N.Pfeffer MA, Swedberg K., Granger CB et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362:759-66.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Brenner BM, Cooper ME, de Zeeuw D. et al. RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-9.[Abstract/Free Full Text]
• Lewis EJ, Hunsicker LG, Clarke WR et al. Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-60.[Abstract/Free Full Text]
• Berl T., Hunsicker LG, Lewis JB et al. Irbesartan Diabetic Nephropathy Trial. Collaborative Study Group. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med 2003;138:542-9.[Abstract/Free Full Text]
• Dahlof B., Devereux RB, Kjeldsen SE et al. LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359: 995-1003.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Lithell H., Hansson L., Skoog I. et al. SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003;21:875-86.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Journal of Renin-Angiotensin-Aldosterone System, Vol. 5, No. 1 suppl, S17-S22 (2004)
DOI: 10.3317/jraas.2004.019


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by McMurray, J. J. Search for Related Content PubMed PubMed Citation Articles by McMurray, J. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Failure Social Bookmarking                         What's this?