Review of the SENIORS trial
Randomized trial to determine the effect of Nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS)
J Am Coll Cardiol 2009;53:2150-8
Eur J Heart Fail 2012;14:1171-8
Background: Both selective and non-selective beta blocker drugs including metoprolol, bisoprolol and carvedilol were found to reduce morbidity and mortality in well selected patients with chronic systolic heart failure. However, the average age of patients in these trials was 64, 61 and 63 years, respectively. Age is an important factor in determining drug response. Older patients have higher rates of multimorbidity and polypharmacy. Thus, testing drugs in older patients is necessary for demonstrating safety and efficacy, especially as it pertains to clinical translation in real world settings.
Nebivolol is a highly selective beta blocker that binds primarily to beta 1 receptors in the heart and has minimal side effects associated with blocking beta 2 receptors in the lungs and other tissues, such as bronchospasm and cold extremities. For this reason, some suspected Nebivolol would have better tolerability in elderly patients. Nebivolol also has mild vasodilating properties related to nitric oxide modulation and this could have advantages in patients with diastolic dysfunction - a condition that increases with aging.
The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization (SENIORS) trial sought to test the hypothesis that Nebivolol would reduce morbidity and mortality in elderly patients with heart failure, regardless of ejection fraction.
Patients: Eligible patients had to be >/=70 years of age with chronic heart failure and at least one of the following features: hospital admission for heart failure within the previous 12 months or LVEF </=35% within the previous 6 months. Patients were excluded if they had any of the following: new drug therapy for heart failure in the 6 weeks prior to randomization, any change in cardiovascular drug within 2 weeks prior to randomization, heart failure due to uncorrected valvular heart disease, contraindication or previous intolerance to beta blockers (e.g., heart rate <60 bpm or SBP <90 mmHg), current use of beta-blockers, significant hepatic or renal dysfunction, cerebrovascular accident within the previous 3 months, being on waiting list for coronary revascularization, or any other major medical conditions that have may have reduced survival during the study period.
Baseline characteristics: The average age of patients was 76 years, 64% were men, and 57%, 39%, and 2% were NYHA class II, III, and IV, respectively. The mean LVEF was 36% and 64% of patients had an LVEF </= 35%. The cause of heart failure was not specified but the majority of patients had a history of CAD (68%) as well as hypertension (61%), while 34% had AFib and 26% diabetes. The mean SBP was 139 mmHg and mean HR was 79 bpm.
Among the 1,359 patients with LVEF </=35%, the mean age was 76, 70% were men, and 52%, 43%, and 2% were NYHA class II, III, and IV, respectively. The mean LVEF was 29%. The mean SBP was 136 mmHg and mean HR was 79 bpm.
For the 752 patients with LVEF >35%, the mean age was 75, 50% were men, and 63%, 32%, and 2% were NYHA class II, III, and IV, respectively. The mean LVEF was 49%. The mean SBP was 145 mmHg and mean HR was 78 bpm.
Patients with an LVEF </=35% were more likely to have smoked, had a heart attack, PCI or bypass surgery whereas patients with an LVEF >35% were more likely to have a history of CAD or hypertension. Other risk factors like AFib and diabetes were similar between EF-based subgroups.
Trial procedures: Patients were randomized 1:1 to receive Nebivolol or matching placebo. The initial dose was 1.25 mg daily, and, if tolerated, was increased to 2.5 mg then 5 mg then to the target dose of 10 mg, every 1-2 weeks, over a maximum of 16 weeks. Dose titration was performed during a visit to the hospital or clinic, and patients were observed for up to 2 hours after taking the new dose to assess tolerability.
Following the dose titration phase, clinic visits were scheduled for 4 and 6 months after randomization and every 3 months thereafter until the end of the study.
Endpoints: The primary endpoint was a composite of all cause mortality or cardiovascular hospitalization. The investigators specify that this outcome was chosen to reflect the potential effect of Nebivolol on quality of life of older patients as well as the risk of death. Cardiovascular admissions included those for cardiac causes or cerebrovascular causes. All other causes of hospital admission were classified as non-cardiovascular or unknown. Other secondary endpoints included functional capacity by NYHA assessment and 6-minute walk test at 6 months.
It was estimated that 1,700 patients followed for 1.5 years would provide 90% power to detect a 25% relative risk reduction with a two-sided alpha level of 0.05. This was based on a mean annual rate for the primary endpoint of 25% in the placebo group and a 20% non-compliance rate in the Nebivolol group. To allow for the possibility of lower than expected event rates and higher levels of non-adherence, and losses to follow-up, a total sample of 2,000 patients was specified.
Results: A total of 2,128 patients were included in the intention-to-treat analysis with 1,067 in the Nebivolol group and 1,061 in the placebo group. A total of 37 patients (1.7%) were lost to follow-up. The average follow up time was 21 months or 1.8 years. Compared to placebo, Nebivolol significantly reduced the primary composite endpoint (31% vs 35%; HR 0.86; 95% CI 0.74-0.99). Numerical reductions in both all-cause mortality (16% vs 18%; HR 0.88; 95% CI 0.71-1.08) and CV hospitalization (24% vs 26%; HR 0.90; 95% CI 0.76-1.06) were noted but neither achieved statistical significance alone. The fragility index for the primary composite endpoint was 2 and as noted above, 37 patients were lost to follow-up, including 16 in the Nebivolol group. No significant differences were noted in CV mortality (12% vs 14%; HR 0.84; 95% CI 0.66-1.07) or all-cause hospitalization, which was nearly identical in both groups (34% vs 34%; HR 0.96).
The mean daily dose in the Nebivolol group was 7.7 mg and 8.5 mg in the placebo group. The proportion of patients reaching the target dose was 68% in the Nebivolol group and 80% in the placebo group. The mean SBP and HR at 4 months was 132 mmHg and 135 mmHg, and 69 bpm and 77 bpm in the Nebivolol and placebo groups, respectively. Changes from baseline in the Nebivolol and placebo groups for SBP and HR were -6 mmHg vs -4 mmHg and -10 bpm vs -2 bpm.
No significant subgroup interactions were noted, which included a subgroup based on EF (</35% vs >35%); however, event rates were slightly higher in the lower EF subgroup. For every subgroup presented, the group with the higher event rate had a smaller effect size favoring the study drug. For example, the event rates for the primary outcome for Nebivolol versus placebo were 29% vs 28% for patients with diabetes compared to 17% vs 23% for patients without diabetes and they were 25% vs 27% for patients >/= 75 years compared to 17% vs 21% for patients <75 years.
Conclusions: In well-selected, elderly patients with chronic heart failure, Nebivolol significantly reduced the primary composite endpoint of all-cause death or CV hospitalization compared to placebo. The number of patients who need to be treated with Nebivolol compared to placebo to prevent 1 patient from experiencing this composite outcome over 1.8 years is approximately 25 patients. While the NNT itself stacks up well compared to many contemporary medical interventions, our confidence in the results are limited by the fragility of the results. If 2 more patients in the Nebivolol group had a primary endpoint event, the result would not be statistically significant and 16 patients in this group were ultimately lost to follow up.
It should also be noted that this is the first major beta blocker trial we have reviewed where the primary endpoint was not all-cause mortality. While all-cause mortality was not the primary endpoint, the trial contained sufficient power (>80%) to assess for a 25% relative reduction in all-cause mortality - that difference was not achieved. The same is true for the individual endpoints of CV hospitalization and all-cause hospitalization, neither of which were significantly reduced on an individual basis.
Ultimately, SENIORS was a positive trial on the basis of the prespecified hypothesis that was tested; however, its results did not have a major impact on clinical practice. At this time, the drug is not strongly recommended or commonly used for patients with chronic systolic or diastolic heart failure in the United States. However, in our opinion, it would be unfortunate if the main takeaway from SENIORS is that Nebivolol is a less effective beta blocking drug compared to Carvedilol, Metoprolol or Bisoprolol, we do not feel the data is strong enough to comment on that. Rather, we would emphasize the importance of selecting patients for beta blocker therapy who are most likely to benefit and least likely to be harmed; similar to what we noted for Bucindolol in the BEST trial.
Patients in SENIORS were older and this matters due to the relationship of aging with multimorbidity and polypharmacy, which are accompanied by higher rates of competing causes of death and hospitalization. Selecting the proper patient for any intervention generally requires navigating a fairly tight space where risk is high enough to derive a measurable benefit but not so high that the relatively narrow benefits of the intervention are lost by other more meaningful factors, like age. To this end, the investigators performed a post-hoc subgroup analysis of patients most similar to those included in other major beta blocker trials, defined by age < 75 (the median age of the trial) and an LVEF </= 35%. In these patients, Nebivolol significantly reduced the primary endpoint (HR 0.73; 95% CI 0.56-0.96) as well as the endpoint of all-cause mortality alone (HR 0.62; 95% CI 0.43-0.89). However, a separate subgroup analysis shows the benefits of Nebivolol were lost with advancing age. In patients between the age of 75-85, the HR for the primary endpoint was 0.91 with a 95% CI of 0.74-1.13 and for patients > 85, the HR was 1.32 (95% CI 0.73-2.37).
For another example of how increasing risk of a patient population may nullify the positive effects of an intervention, Mulder et al. reported that in a post-hoc subgroup analysis of patients from SENIORS with and without AFib, Nebivolol significantly reduced the primary endpoint in patients in sinus rhythm (28% vs 33%; HR 0.82; 95% CI 0.67-0.99) but not in those in AFib, who were at a significantly higher risk of having a primary endpoint event (37% vs 40%; HR 0.92; 95% CI 0.73-1.17).
In conclusion, while age is just a number, and we do not advocate withholding effective therapies based on age alone, its importance must be respected and common sense needs to be applied. Based on findings from SENIORS, we would add age to the list of factors, along with low-normal SBP (</= 120 mmHg) and advanced heart failure (NYHA IV) based on the BEST trial, for which we advise caution in starting and up-titrating beta blocker therapy in patients with chronic systolic heart failure.