SENIORS: Nebivolol benefits elderly heart-failure patients

August 29, 2004

Munich, Germany - The first major study of a beta blocker in an elderly heart-failure population has shown benefit with nebivolol. The Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) showed a significant reduction in the primary end point of all-cause mortality/cardiovascular hospital admissions with the beta blocker vs placebo.

Dr Andrew Coats

SENIORS is also the first major trial to test beta blockers in patients with preserved ejection fractions and showed similar benefits of nebivolol in this population as seen in patients with reduced ejection fractions. Presenting the trial at the European Society of Cardiology Congress 2004, Dr Andrew Coats (University of Sydney, Australia) said that beta blockers could now be recommended for heart-failure patients regardless of age and left ventricular function.

Nebivolol, which is currently marketed by Menarini in Europe for the treatment of hypertension, is the fourth beta blocker to be shown beneficial in heart failure, after carvedilol, metoprolol, and bisoprolol. It is a beta-1 selective blocker with vasodilating properties brought about by modulation of nitric-oxide release.

Coats noted that although several major studies have already shown benefits of beta blockers in heart failure, only around one third of heart-failure patients are actually receiving such medication in clinical practice. He suggested that this was because clinical trials have generally included younger patients (average age 61), whereas the average age of heart-failure patients in the real world was 76. Therefore, doubts have remained as to whether these agents are actually beneficial in older patients. He also pointed out that older patients are also more likely to have heart failure with preserved systolic function, which again has not been studied in previous trials of beta blockers.

The SENIORS trial involved 2135 elderly (70 years or older) heart-failure patients from 10 European countries who were randomized to nebivolol or placebo. The average age was 76 years. Nebivolol was titrated up to a target dose of 10 mg once daily over a four- to 16-week period. Patients were maintained at the maximum tolerated dose to the end of the observation period (30 months). Coats noted that the mean maintenance dose of nebivolol achieved was 7.7 mg and that two thirds of patients managed to take the target dose of 10 mg long term, showing that "elderly patients can tolerate decent doses of beta blockers."

The primary end point of the study was the combination of all-cause mortality and cardiovascular hospital admissions. This was significantly reduced by 14% in the nebivolol group, and both elements of the primary end point contributed equally to the reduction, Coats said. The secondary end point, all-cause mortality alone, was reduced by 12%, but this did not reach statistical significance.

Main results of SENIORS trial

End point

Nebivolol, n (%)

Placebo, n (%)

Hazard ratio (95% CI)

p

All-cause mortality/cardiovascular hospitalizations

332 (31.1) 375 (35.3) 0.86 (0.73-0.99) 0.039

All-cause mortality

169 (15.8) 192 (18.1) 0.88 (0.71-1.08) 0.214

Three subgroup analyses focused on left ventricular ejection fraction, sex, and age. Coats said these suggested that the benefit was present across all subgroups, but that patients with higher ejection fractions appeared to benefit a little more than those with lower ejection fractions, females showed a greater benefit than males, and patients under 75 showed a better effect than those aged over 75.

SENIORS: Death or CV hospitalization by LVEF

LVEF

Nebivolol, n (%)

Placebo, n (%)

LVEF <35%

 
219 (32.1) 249 (36.3)

LVEF >35%

110 (28.9) 125 (33.6)

  SENIORS: Death or CV hospitalization by sex

Sex

Nebivolol, n (%)

Placebo, n (%)

Male

231 (35.2) 250 (36.4)

Female

101 (24.6) 125 (33.3)

  SENIORS: Death or CV hospitalization by age

Age

Nebivolol, n (%)

Placebo, n (%)

Age <75

148 (27.5) 176 (33.5)

Age >75

184 (34.8) 199 (37.1)

Coats concluded that advanced age should no longer be a contraindication to beta-blocker treatment. "The SENIORS trial should give practitioners the courage and confidence to use beta blockers in elderly patients, and it will hopefully change clinical practice so that every elderly patient who could benefit from optimal heart-failure treatment will get it, " he added.

Packer: "Results consistent with previous trials"

Designated discussant of the SENIORS trial, Dr Milton Packer (Columbia University, New York, NY) noted that previous trials of beta blockers in heart failure have included some elderly patients (around 20%). He pointed out that the effect of beta blockade on the combined end point of all-cause mortality/hospitalizations in the elderly subgroup was examined in the COPERNICUS and MERIT HF trials and showed slightly less benefit than in younger patients but that these data were "very consistent" with the SENIORS results.

COPERNICUS, MERIT HF, and CIBIS II all examined the effect of beta blockade on all-cause mortality alone in the elderly subgroup and all showed a benefit, Packer noted, adding that the SENIORS result is consistent with this but showed somewhat less of a benefit, which was not statistically significant. He said the reason for this difference was not clear and could be due to chance, the inclusion of patients with higher ejection fractions, the inclusion of more patients over the age of 75, or different pharmacological characteristics of the drug.

Packer further commented that most of the patients in SENIORS with ejection fractions above 35% were not actually patients with diastolic dysfunction and were rather patients with milder systolic dysfunction.

Another trial needed in patients with "normal" ejection fractions

He concluded that the SENIORS data reinforced current recommendations that all patients with heart failure should receive a beta blocker. He said that the results extended the population eligible for treatment to those with ejection fractions below about 45%, but he did not believe the results were sufficient to recommend use of beta blockers for patients with normal ejection fractions (above 50%), who should have their own trial.

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