In retrospect, there is a relative paucity of high quality studies to guide heart failure therapy in the elderly. The conclusions drawn from this study must be taken with caution because of the reliance on data from smaller observational studies and many retrospective studies. Perhaps the most important conclusion is that there is more work that needs to be done to characterize ADEs in the elderly, understand the magnitude of the effect size of these medications on morbidity and mortality, and understand whether the potential side effects outweigh the benefits in a quality-adjusted life years analysis.
Despite the limitations, the data in this review seems to suggest that there is an increased adverse drug event rate in relation to beta blocker and spironolactone therapy. The increased adverse drug event rate was noted in observational studies, population-based studies, and randomized control trials. In the case of beta blockers, specifically increased amounts of bradycardia, hypotension, and syncope were noted.(12,13,14,15,16,17,18)
Studies on spironolactone revealed increased rates of hyperkalemia, acute renal failure, and medication discontinuation, although study populations were small.(23,24,25)
Given the mere suggestion that the older persons with heart failure experience adverse events to a greater degree, we feel that further characterization in prospective studies is warranted.
It is possible that the less rigorous follow-up that patients receive outside of randomized controlled trials could contribute to the increased rates of ADEs. It remains unclear, however, how age and frailty could be independent predictors. The increased events rates in both the RCT and observational data when compared to younger patients do beg that question.
With regards to efficacy, it appears that the benefits of beta blockers and ACE inhibitors extend to the very elderly heart failure population. This trend was noted in both large-scale retrospective analyses, as well as a prospective blinded randomized control trial in the case of beta blockers.(5,18,19)
The effect appears to apply to both hospitalizations and mortality; however; the magnitude of the effect size was not equal across all studies.
In the SENIORS trial, the magnitude of the effect size was smaller than it was in the younger patient populations, and statistical significance was not gained when measuring mortality as an endpoint. It is possible that the class effect shared between metroprolol, carvedilol, and bisoprolol for systolic heart failure does not translate directly to the use of nebivolol. Another possibility, which the study seemed to suggest, is that the population greater than 75 did not benefit as much from the intervention and skewed the results in a negative fashion. The patients under 75 did benefit in a similar magnitude to other heart failure studies with similar relative risk reductions.(18)
Despite the fact that the elderly do have multiple medical comorbidities and that they were measured in many studies, there are no clear predictors of adverse events based on a validated prediction model. For beta blockers, advanced NYHA class and decreased left ventricular ejection fraction predicted poor tolerability in two studies. Possible predictors include advanced age, obstructive airways disease, and baseline blood pressure, although the data were conflicting. Further evaluation is necessary. Functional status was measured but not utilized in predicting outcomes with any HF therapy.(13,17,23)
Additional information that would be valuable in this patient population is the measurement of quality-adjusted life years. Patients may survive longer and avoid hospitalization, but if the side effects that they experience severely diminish the quality of the life that they experience, perhaps the therapy is not as valuable in this patient population as it clearly is in patients with a mean age of approximately 65.
In the study by Sin and McCalister,(5)
the mortality benefits were seen despite controlling for adverse events such as bradycardia. Despite that fact, perhaps living longer while experiencing significant side effects or functional impairment imposed by these medications is not what these patients desire.
There were several limitations in our study. The first is the strong dependence upon observational data due to paucity of data from randomized studies. In spite of this, the observational studies, specifically related to the efficacy of beta blocker and ACE inhibitor therapies, were very large and of higher quality.(5,18)
Perhaps this allows for stronger external validity for the conclusions made with regard to these topics. We did attempt to control for heterogeneity where possible, but even this methodology has its limitations in terms of minimizing bias.
The spironolactone studies were small in number, and utilized smaller populations. Also, we attempted to extrapolate answers from studies that the original design of the study was not constructed to answer. Specifically, the focus of the Juurlink study was not to relate increased rates of adverse events to age, but to the application of RCT data to “real-life” circumstances. However, the fact that the findings of increased ADEs in an older population did parallel the findings of the observational data strengthens the overall conclusions made.(23,24,25)
The second limitation is the nonuniform group of patients involved. ACE inhibitor, beta blocker therapy, spironolactone, and digoxin are indicated for the reduction of morbidity and mortality for systolic heart failure only. Some of the observational studies utilized did not distinguish between the two.
Patients with diastolic heart failure are sometimes mistakenly treated with systolic HF medications. Diastolic HF is extremely common in the elderly. We felt that it was important to include the diastolic heart failure patients in order to detect if there were significant number of diastolic heart failure patients that were being inappropriately treated and being exposed to side effects without any hope of benefiting from the medications. We did not find this explicitly in this study. However, including these patients increased the heterogeneity of our study. Where possible, the distinction between the two has been made in the manuscript.
Our study points to the need for randomized control trials for systolic heart failure in the elderly, specifically with the medications that are already known to be efficacious in younger populations. The adverse event rates need to be measured in a comprehensive manner. The standardized measurement of medical comorbidities, functional status, and quality of life are essential. Finally, the above information should be analyzed to see whether or not prediction rules exist for adverse events and tolerability.