Clinical and economic aspects of the use of nebivolol in the treatment of elderly patients with heart failure

Abstract

Heart failure is a common and disabling condition with morbidity and mortality that increase dramatically with advancing age. Large observational studies, retrospective subgroup analyses and meta-analyses of clinical trials in systolic heart failure, and recently published randomized studies have provided data supporting the use of beta-blockers as a baseline therapy in heart failure in the elderly. Despite the available evidence about beta-blockers, this therapy is still less frequently used in elderly compared to younger patients. Nebivolol is a third-generation cardioselective beta-blocker with L-arginine/nitric oxide-induced vasodilatory properties, approved in Europe and several other countries for the treatment of essential hypertension, and in Europe for the treatment of stable, mild, or moderate chronic heart failure, in addition to standard therapies in elderly patients aged 70 years old or older. The effects of nebivolol on left ventricular function in elderly patients with chronic heart failure (ENECA) and the study of effects of nebivolol intervention on outcomes and rehospitalization in seniors with heart failure (SENIORS) have been specifically aimed to assess the efficacy of beta-blockade in elderly heart failure patients. The results of these two trials demonstrate that nebivolol is well tolerated and effective in reducing mortality and morbidity in older patients, and that the beneficial clinical effect is present also in patients with mildly reduced ejection fraction. Moreover, nebivolol appears to be significantly cost-effective when prescribed in these patients. However, further targeted studies are needed to better define the efficacy as well as safety profile in frail and older patients with comorbid diseases.

Keywords: beta-blockers; left ventricular dysfunction; older; prognosis; therapy.

Figure 1

Der Simonian and Laird relative risks (random effects) plot of beta-blocker versus placebo in the subgroup of elderly patients with heart failure. Point estimates and 95% CIs represented next to box plot. Abbreviations: BEST, beta-blocker evaluation survival trial; CIBIS II, the cardiac insufficiency bisoprolol study II; COPERNICUS, carvedilol prospective randomized cumulative survival; MERIT-HF, metoprolol CR/XL randomized intervention trial in congestive heart failure. Copyright© 2005. Modified with permission from Elsevier. Dulin BR, Haas SJ, Abraham WT, Krum H. Do elderly systolic heart failure patients benefit from beta blockers to the same extent as the non-elderly? Meta-analysis of >12,000 patients in large-scale clinical trials. American J Cardiol. 2005;95:896–898.

Figure 2

Time to all-cause mortality or cardiovascular hospital admission (primary endpoint) in SENIORS. Abbreviations: NEB, nebivolol; PL, placebo. Copyright© 2005. Modified with permission from Oxford University Press. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215–225.

Figure 3

Prespecified sub-group analysis of SENIORS study. No interaction was found in subgroups with respect to the primary end-point. Abbreviations: MI, myocardial infarction. Copyright© 2005. Modified with permission from Oxford University Press. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215–225. *Number of events per 100 patient-years of follow-up at risk. **P-value for interaction: age and left ventricular ejection fraction considered as continuous variables.

Figure 4

Tolerability profile of nebivolol in SENIORS. Abbreviations: NEB, nebivolol; PL, placebo. Copyright© 2006. Modified with permission from Wolters Kluwer. Moen MD, Wagstaff AJ. Nebivolol: a review of its use in the management of hypertension and chronic heart failure. Drugs. 2006;66(10): 1389–1409.

Figure 5

Time to all-cause mortality in patients aged <75.2 years (median age) with left ventricular ejection fraction (LVEF) ≤35% in SENIORS. The hazard ratio was 0.62 (95% CI: 0.43, 0.89; P = 0.011). Abbreviations: NEB, nebivolol; PL, placebo. Copyright© 2006. Modified with permission from Wolters Kluwer. Moen MD, Wagstaff AJ. Nebivolol: a review of its use in the management of hypertension and chronic heart failure. Drugs. 2006;66(10): 1389–1409.

Figure 6

Hazard ratio plots (with 95% CIs) for total mortality for comparable patient subgroups from the four main beta-blockers mortality trials, ie, SENIORS [nebivolol]; COPERNICUS [carvedilol], MERIT-HF [metoprolol] and CIBIS II [bisoprolol], using data derived from the trial reports. These data are from published patient subgroups reported by the authors themselves for each trial, and the criteria, therefore, differ between trials. The reported patient age subgroups chosen here are those most similar to each other across the four trials. For nebivolol, this is left ventricular ejection fraction (LVEF) ≤35% and age less than median (70–75.2 years); for carvedilol, LVEF ≤ 25% and age ≥65 years; for metoprolol LVEF ≤ 40% and age >69 years; and for bisoprolol LVEF ≤ 35% and age ≥71 years. Copyright© 2005. Modified with permission from Coats AJS. Coats AJS, The modern tailored management of chronic heart failure: SENIORS. Proceedings of the Annual Congress of the European Society of Cardiology; 2005 Sep 3–7; Stockholm.

Figure 7

Primary and secondary outcomes (HR with 95% CI) in patients receiving placebo versus nebivolol at different maintenance doses. Abbreviation: Pts, patients. Modified from Dobre. Copyright© 2007. Modified with permission from Elsevier. Dobre D, van Veldhuisen DJ, Mordenti G, et al. Tolerability and dose-related effects of nebivolol in elderly patients with heart failure: data from the study of the effects of nebivolol intervention on outcomes and rehospitalization in seniors with heart failure (SENIORS) trial. Am Heart J. 2007;154:109–115.