Heart failure epidemiology
The incidence of heart failure (HF) increases with age and its prevalence is increasing due to an ageing population.1 Although some HF patients can live for many years, absolute survival rates are poor in both sexes, with 50% of men dead at 2.3 years (range: 1.3–2.3 years) and 50% of women dead at 1.7 years (range: 1.32–1.79 years).2 Recent reports, however, suggest that the prognosis has substantially improved in the UK, thought to be related to better treatment and monitoring.3,4
The National Institute for Health and Clinical Excellence (NICE) published guidelines on the diagnosis and management of chronic heart failure in 2003,5 with more recent guidelines being published by the European Society of Cardiology (ESC)6 in 2008. The treatment algorithm recommended for patients with heart failure due to left ventricular systolic dysfunction in the ESC guideline is shown in figure 1.
Based on these guidelines, current first-line pharmacological therapy comprises a combination of oral loop diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors) and beta-blockers. If an ACE inhibitor is not tolerated then an angiotensin receptor blocker (ARB) can be used instead. If patients fail to respond symptomatically then specialist advice needs to be obtained, but options at this point include spironolactone at 25 mg per day (based on the RALES study7) or candesartan up to a dose of 32 mg per day (based on the CHARM-Added study8).
Clinical trial evidence for ARB treatment of heart failure
The evidence for the use of ARBs in HF is based on a large number of randomised studies, starting with the first-in-class ARB, losartan.
The ELITE study9 compared losartan with captopril in 722 elderly ACE inhibitor-naïve patients with HF. Patients treated with losartan were found to have fewer hospital admissions for HF compared to those in the captopril group (risk reduction 32% [95% confidence interval [CI] -4% to + 55%], p=0.075). The unexpected finding was an impressive reduction in all-cause mortality (4.8% vs. 8.7%; risk reduction 46% [95% CI 5%, 69%], p=0.035), although this was not the primary study end point. These surprise findings led to the design of the much larger ELITE II trial.
ELITE II study
The ELITE II study10 was performed to confirm whether losartan 50 mg once daily was superior to captopril 50 mg three times daily in improving patient survival and if it was better tolerated. A total of 3,152 patients aged ≥60 years with New York Heart Association (NYHA) class II-IV HF and ejection fraction of ≤40% were enrolled. During the two-year trial, 7.3% of the captopril group and 9% of the losartan group experienced sudden cardiac death and/or resuscitated cardiac arrest. Although the difference in outcome was not statistically significant between losartan and captopril in terms of reducing all-cause mortality (11.7 vs. 10.4% average annual mortality rate) or sudden death or resuscitated arrests (9.0 vs. 7.3%), (hazard ratios 1.13 [95% CI 0.95, 1.35], p=0.16; and 1.25 [95% CI 0.98, 1.60], p=0.08, respectively), there was a trend to worse outcome in the losartan group. The outcomes were also worse in the subgroup of patients on beta-blockers plus losartan, so this combination is not recommended with losartan. Losartan was better tolerated, with significantly fewer patients discontinuing losartan treatment compared to captopril due to adverse effects (9.7 vs. 14.7%, p<0.001), including cough (0.3 vs. 2.7%). The study concluded that although ACE inhibitors remained the treatment of choice for patients with HF, the ARB could be used in those who could not tolerate an ACE inhibitor.
The Val-HeFT study11 recruited 5,010 patients and demonstrated a combined end point of death or hospitalisation due to HF that was 13.2% lower when valsartan rather than placebo was added to ‘standard treatment’ (relative risk 0.87; [97.5% CI 0.77, 0.97], p=0.009). This was predominantly due to a lower number of patients hospitalised for HF (18.2% in the placebo group and 13.8% in the valsartan group, p<0.001). However, in a post-hoc analysis of subgroups according to baseline treatment with ACE inhibitors or beta-blockers, valsartan showed an adverse effect in patients receiving both ACE inhibitors and beta-blockers in combination, raising concerns about the potential safety of this triple combination.
The CHARM programme was designed to assess candesartan therapy in relatively low-risk HF patients, with eligibility defined simply as patients aged ≥18 years with a NYHA class II-IV of at least four weeks’ duration. The entire CHARM programme included 7,601 patients from 26 countries worldwide. It comprised three randomised, double-blind, placebo-controlled clinical trials, each in a distinct patient population with symptomatic HF:12 CHARM-Alternative in patients with left ventricular ejection fraction (LVEF) ≤40% and intolerant of ACE inhibitors; CHARM-Added in patients with LVEF ≤40% who tolerated and were treated with whichever ACE inhibitor the patient’s physician chose; and CHARM-Preserved in patients with LVEF >40%, who may or may not have received an ACE inhibitor.
In the CHARM-Alternative13 study 2,028 patients were randomised and evaluated for a median of 33.7 months. All patients included in this study were ACE inhibitor-intolerant. During follow-up, 33% of patients receiving candesartan had a primary outcome of cardiovascular (CV) death or hospitalisation for HF, compared with 40% of those on placebo. This represented a 23% relative risk reduction (RRR) for CV death or hospitalisation (p=0.0004) (figure 2).
The CHARM-Added study randomised 2,548 patients and showed that candesartan was associated with a statistically significant 15% reduction in the relative risk of CV death or hospital admission.8 Importantly, the adverse effect on clinical outcomes of combining an ACE inhibitor with a beta-blocker and an ARB that was found with valsartan in Val-HeFT was not found in the CHARM-Added study.8
CHARM-Preserved14 did not show conclusive evidence of benefit for candesartan, with no significant difference between candesartan and placebo for the composite end point of CV death or HF hospital admission, although fewer patients in the candesartan group were admitted to hospital for HF (230 vs. 279, p=0.017). As a result, candesartan is not licensed for this patient population.
The HEAAL study15 was a double-blind study investigating losartan use (‘low’ dose 50 mg versus ‘high’ dose 150 mg) in ACE inhibitor-intolerant patients. Recently reported results from 3,846 patients showed that, with 4.7-year median follow-up in each group, 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were hospitalised for HF (hazard ratio [HR] 0.90, [95% CI 0.82, 0.99], p=0.027). Therefore it was concluded that losartan 150 mg daily reduced the rate of death or admission for HF compared with losartan 50 mg daily and suggested that the appropriate dose of an ARB for patients with heart failure may be higher than the doses most commonly used to treat hypertension (although it should be noted that the 150 mg dose is currently unlicensed).
However, there is some conflicting evidence from clinical trials regarding the benefits conferred by ARBs in the treatment of HF occurring in the context of acute myocardial infarction, including the effect of combining ARBs with standard therapies, as shown from the two studies below.
The OPTIMAAL study16 was conducted in 5,477 patients to test the hypothesis that losartan 50 mg once daily would be superior or non-inferior to captopril 50 mg three times daily. Results showed a non-significant difference in total mortality in favour of captopril, with 499 deaths in the losartan group (18%) compared to 447 (16%) in the captopril group (relative risk 1.13 [95% CI 0.99, 1.28], p=0.07). However, losartan was significantly better tolerated than captopril, with fewer patients discontinuing study medication. On the basis of these results, it was concluded that ACE inhibitors should remain first-choice treatment in patients after complicated acute myocardial infarction but that ARBs were a suitable alternative in patients unable to tolerate an ACE inhibitor. The dose of 50 mg losartan used may have been the reason for the result, but the results of a higher dose (such as 150 mg used in one arm of the HEAAL study) are unknown.
The VALIANT study17 enrolled a total of 14,703 patients with HF, left ventricular systolic dysfunction, or both, after acute MI, who were treated with captopril, valsartan or a combination of both drugs. The primary end point was death from any cause. During a median follow-up of 24.7 months, 979 patients in the valsartan group, 941 patients in the valsartan/captopril group and 958 patients in the captopril group died (hazard ratio in the valsartan group compared with the captopril group, 1.00; [97.5% CI 0.90, 1.11]; p=0.98; hazard ratio in the valsartan/captopril group compared with the captopril group, 0.98; [97.5% CI 0.89, 1.09]; p=0.73). The study concluded that valsartan was as effective as captopril in patients who were at high risk for CV events after myocardial infarction. However, the combined valsartan and captopril group had the most drug-related adverse events without improving survival. Most guidelines continue to suggest that in post-MI heart failure an ACE inhibitor remains first-line, but an ARB should be considered if the ACE inhibitor is not tolerated.
There is good evidence supporting the use of ARBs in HF. According to the ESC guidelines, ARBs are recommended first-line in combination with a diuretic in patients who are ACE inhibitor-intolerant, or second-line in patients who fail to respond to the combination of diuretic plus ACE inhibitor. If patients fail to respond symptomatically to therapy with a diuretic, ACE inhibitor and beta-blocker, then candesartan or spironolactone can be added. Usually this would be decided by a specialist. The results of randomised trials though are not uniform, and it would be unwise to disregard the differences in outcome related to agent, dose and clinical context. The strongest evidence base for ARBs in chronic heart failure remains with the CHARM programme. Indeed, in patients with symptomatic CHF and LVEF ≤40%, candesartan is the only ARB found to reduce all-cause mortality, CV death and HF hospitalisations significantly when added to standard therapies, including ACE inhibitors, beta-blockers and an aldosterone antagonist •
Conflict of interest
TMcD has received honoraria from unrestricted educational grants, provided by Takeda, for speaking at several heart failure-related meetings.
- Despite advances in care of patients with chronic heart failure (CHF), absolute survival remains poor in both men and women
- Patients need to be monitored closely and the dose of neurohormonal antagonists titrated to achieve maximum benefit
- Guidelines from the National Institute for Health and Clinical Excellence (NICE) and the European Society of Cardiology (ESC) exist to guide pharmacological options
- Candesartan is the angiotensin receptor blocker (ARB) with the strongest evidence for use in CHF, based on the results of the CHARM study
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- Jhund PS, Macintyre K, Simpson CR et al. Long-term trends in first hospitalization for heart failure and subsequent survival between 1986 and 2003: a population study of 5.1 million people.). Circulation 2009;119(4):515–23.
- Mehta PA, Dubrey SW, McIntyre HF et al. Mode of death in patients with newly diagnosed heart failure in the general population. Eur J Heart Fail 2008;10(11):1108–16.
- Javed U, Deedwania PC. Beta-adrenergic blockers for chronic heart failure. Cardiol Rev 2009;17(6):287–92.
- NICE clinical guidelines No. 5. Chronic heart failure: National clinical guideline for diagnosis and management in primary and secondary care. October 2003.
- Dickstein K, Cohen-Solal A, Filippatos G et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008;29(19):2388–442.
- Pitt B, Zannad F, Remme WJ et al. (for the Randomized Aldactone Evaluation Study Investigators). The effect of spironolactone on morbidity and mortality in patients with severe heart failure. NEJM 1999;341(10):709–17.
- McMurray JJ, Ostergren J, Swedberg K et al. for the 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(9386):767–71.
- Pitt B, Segal R, Martinez FA et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997;349(9054):747–52.
- 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;6:355(9215):1582–7.
- 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(23):1667-75.
- Swedberg K, Pfeffer M, Granger C, for the Charm-Programme Investigators. Candesartan in heart failure–assessment of reduction in mortality and morbidity (CHARM): rationale and design. J Card Fail 1999;5:276–82.
- Granger CB, McMurray JJ, Yusuf S et al. for the 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(9386):772–6.
- Yusuf S, Pfeffer MA, Swedberg K et al. for the 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; 362:777–81.
- Konstam MA, Neaton JD, Dickstein K et al. (for the HEAAL Investigators). Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 2009;374(9704):1840–8.
- 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 randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002;360(9335):752–60.
- Pfeffer MA, McMurray JJ, Velazquez EJ et al. (for the 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(20):1893–906.