Fast track — ArticlesEffects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial
Introduction
Mortality and morbidity among patients with chronic heart failure (CHF) and reduced left-ventricular ejection fraction remain high, despite the use of full conventional treatment, including angiotensin-converting-enzyme (ACE) inhibitors, β blockers, and spironolactone. The addition of an angiotensin II type 1 receptor blocker to an ACE inhibitor is a theoretically attractive treatment strategy in CHF. Angiotensin II can be produced by non-ACE enzymatic pathways in human cardiac tissue and blood vessels, and its generation seems to continue even during chronic, high-dose, ACE-inhibitor treatment in CHF.1, 2, 3, 4, 5 Angiotensin-receptor blockers should, therefore, provide more complete inhibition of the actions of angiotensin II. Conversely, ACE inhibitors also block the breakdown of bradykinin, mediated by kininase II, which is identical to ACE. Bradykinin has direct and indirect vasodilator, antimitotic, and antithrombotic actions that could be of benefit in CHF.6, 7 Consequently, treatment with combined ACE inhibitors and angiotensin-receptor blockers might have advantages over ACE-inhibitor monotherapy.
In several studies, including the Randomized Evaluation of Strategies for Left Ventricular Dysfunction pilot study,8 favourable effects on haemodynamic indices, left-ventricular remodelling, and neurohumoral activity in CHF have been reported with combined ACE inhibitors and angiotensin-receptor blockers.8, 9 This combination of treatment also increases exercise capacity and improves New York Heart Association functional class.10
In the prospective Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added trial, part of the CHARM programme,11, 12, 13 we investigated whether combining an angiotensin-receptor blocker, candesartan, with ACE inhibitors also improves clinical outcome. We compared the effect of candesartan with that of placebo among patients with CHF and reduced left-ventricular ejection fraction.
Section snippets
Methods
The design of the CHARM programme has been described in detail elsewhere, including randomisation, monitoring, and follow-up.11, 12, 13
Results
Of 2548 patients enrolled, 1276 were assigned candesartan and 1272 placebo (figure 1). Follow-up was concluded on March 31, 2003. The median duration of follow up was 41 months.
The baseline characteristics, including details of background medical treatment, are given in table 1. Enalapril, lisinopril, captopril, and ramipril were the most commonly used ACE inhibitors, together accounting for 74% of all ACE inhibitors used. The mean daily doses of these drugs in the candesartan group were 16·8,
Discussion
Among patients with CHF and a low left-ventricular ejection fraction, the addition of candesartan to an ACE inhibitor decreased the risk of cardiovascular death, and admission to hospital for CHF. This beneficial effect of candesartan was seen in all prespecified subgroups of patients, including those treated with β blockers and other treatments, with no evidence of treatment heterogeneity.
Our findings are consistent with the evidence that angiotensin II continues to be produced despite chronic
References (22)
- 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) - 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) - et al.
Candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM)—rationale and design
J Card Fail
(1999) - et al.
Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall Programme
Lancet
(2003) - et al.
Heart failure therapy at a crossroad: are there limits to the neurohumoral model?
J Am Coll Cardiol
(2003) - et al.
Angiotensin II-forming pathways in normal and failing human hearts
Circ Res
(1990) - et al.
Functional and biochemical analysis of angiotensin II-forming pathways in the human heart
Circ Res
(1997) - et al.
Vasoconstrictor effect of the angiotensin-converting enzyme-resistant, chymase-specific substrate [Pro(11)(D)-Ala(12)] angiotensin I in human dorsal hand veins: in vivo demonstration of non-ace production of angiotensin II in humans
Circulation
(2001) - et al.
Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure
Circulation
(2000) - et al.
Bradykinin contributes to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure
Circulation
(2001)
Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study
Circulation
Cited by (1773)
Chronic heart failure with reduced EF: A decade of major pharmacological innovations
2024, Presse MedicaleAmiodarone-induced thyrotoxicosis: Should surgery be considered?
2024, Annales d'EndocrinologieClinical Implication of N-Terminal Pro-Brain Natriuretic Peptide Burden in Heart Failure With Reduced Ejection Fraction: From the GUIDE-IT
2024, American Journal of CardiologyMedical Management and Device-Based Therapies in Chronic Heart Failure
2023, Journal of the Society for Cardiovascular Angiography and InterventionsIntroduction of treatments for heart failure and reduced ejection fraction under 50 % : In-hospital optimization using an algorithmic approach
2023, Annales de Cardiologie et d'Angeiologie
For CHARM investigators and committees see page 765