Editorial
Octogenarian Patients With Heart Failure
Commonly Encountered in Clinical Practice but
Only a Minority in Clinical Trials
Kazuhiro Yamamoto,1 MD
H
eart failure is a global burden in industrialized countries, and the number of heart failure patients will
continue to increase.1) One of the reasons for the increase is that the incidence of heart failure increases with aging, particularly after 80 years of age.1) The increase in octogenarian patients leads to elevation of the rehospitalization rate as
well as mortality in heart failure patients.2) Octogenarian patients are also characterized by worse renal function 2), which is
one of the risks of diuretic resistance.3) The ATTEND registry
has revealed that the prevalence of octogenarian patients is already more than one third of patients hospitalized for acute decompensated heart failure (ADHF) in Japan,4) and how to treat
them in the current era has become a critical issue.
Article p.137
It is well known that β-blockers improve the prognosis of
patients with heart failure and reduced ejection fraction, and
guidelines recommend the administration of β-blockers in patients without contraindication. However, their use is avoided
in elderly patients in Japan.5) Why is adherence to guidelines
low in the treatment of elderly patients? This may be partly explained by the fact that elderly, particularly octogenarian, patients were excluded from the subjects or only a small number
were included in previous clinical trials that investigated the
effects of β-blockers in heart failure patients. One may argue
that the past evidence is not generalizable and cannot necessarily be extrapolated to the treatment of octogenarian heart failure patients. To overcome such discrepancy between guidelines and clinical practice, additional data on the effects in elderly patients is needed. Although the Study of the Effects of
Nebivolol Intervention on Outcomes and Rehospitalisation in
Seniors with Heart Failure (SENIORS study) revealed the beneficial effects of the β-blocker nebivolol in heart failure patients
≥ 70 years old,6) the ratio of octogenarian patients in the study
subjects was small. Our and other previous studies have demonstrated the beneficial effects of β-blockers in elderly subject
populations that had sufficient percentages of octogenarian
heart failure patients.7,8) Although both were observational, not
randomized studies, the findings suggest the risk of underutilization of β-blockers in octogenarian heart failure patients and
raise the importance of clinical data in “real world” patients.
Diuretic therapy is frequently required in patients hospitalized for ADHF,4) because most of the symptoms and signs
of heart failure are attributed to congestion.9) The Efficacy of
Vasopressin Antagonism in Heart Failure Outcome Study With
Tolvaptan (EVEREST) showed that the vasopressin V2 receptor antagonist tolvaptan provided additive diuretic effects to
standard therapy including diuretics and improved heart failure
signs and symptoms in patients hospitalized for ADHF,10) although there was no long-term benefit in its use during the
hospitalization.11) It is very useful in clinical practice to relieve
the symptoms due to congestion in patients with resistance to
loop diuretics; however, tolvaptan acutely increased the urine
volume by more than 50%,12) raising concerns about acute hypovolemia. To avoid hypovolemia, recognition of thirst is very
helpful in clinical practice, and the administration of tolvaptan
to patients who cannot feel thirst is prohibited in Japan. It is
reasonable and justified to be worried about administration of
tolvaptan to elderly patients. In addition, Imamura, et al reported that elderly patients were significantly resistant to
tolvaptan treatment compared with younger patients, although
the number of study subjects was too small.13) Therefore, the
safety and efficiency of tolvaptan in elderly patients remain
controversial.
In a study published in this issue of International Heart
Journal, Kinugawa, et al revealed that tolvaptan is well-tolerated and effective in heart failure patients ≥ 80 years old as well
as in those < 80 years old.14) This observational study was conducted in Japan, included more than 900 octogenarian patients
hospitalized for ADHF, and showed that the administration of
tolvaptan reduced body weight and improved symptoms to a
similar degree in both groups of patients. In addition, although
the incidence of thirst was significantly lower in patients ≥ 80
years old than in those < 80 years old, the frequency of adverse
events including hypernatremia and hypovolemia was not different between the 2 groups. These results strongly suggest
that the administration of tolvaptan should be considered in
patients hospitalized for ADHF even if they are octogenarian.
In addition, this study has provided other important information. The incidence of hypernatremia in octogenarian patients
decreased after May 2013 in association with the decrease in
the initial dose of tolvaptan. Analysis showed a close relation
From the 1 Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori
University, Yonago, Japan.
Address for correspondence: Kazuhiro Yamamoto, MD, Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and
Therapeutics, Faculty of Medicine, Tottori University, 86, Nishi-cho, Yonago, 683-8503, Tottori, Japan. E-mail: [email protected]
Received for publication January 14, 2015. Accepted January 14, 2015.
Released in advance online on J-STAGE February 27, 2015.
All rights reserved by the International Heart Journal Association.
135
136
YAMAMOTO, ET AL
between the initial dose of tolvaptan and the incidence of hypernatremia in patients ≥ 80 years old. In particular, the treatment with a high initial dose of tolvaptan in octogenarian patients with serum Na ≥ 135 mEq/L at baseline was associated
with a high incidence of hypernatremia. There was no significant correlation between the incidence of hypernatremia and
the initial dose or serum Na level at baseline in patients < 80
years old. Therefore, to obtain the same efficiency and safety
in the treatment with tolvaptan in octogenarian patients with
ADHF as in patients < 80 years old, special attention should be
paid to the initial dose of tolvaptan and serum Na level at baseline. Data collection in this study was started in 2011, and the
mean value of the initial dose of tolvaptan was about 9–10 mg/
day. The Japanese Circulation Society and The Japanese Heart
Failure Society released a joint statement in October 2013 that
stated the initial dose of tolvaptan should be 7.5 mg/day (http://
www.asas.or.jp/jhfs/topics/20131107.html, in Japanese), and
the current data support the statement, in particular for octogenarian patients.
Hyponatremia is another risk of diuretic resistance 3) and
is a risk for poor prognosis in elderly patients hospitalized for
ADHF.15) Tolvaptan is likely to provide long-term benefits in
patients with extremely low serum Na (< 130 mEq/L) at baseline.16) Kinugawa, et al 14) described the safety of tolvaptan in
octogenarian patients, and thus, administration of tolvaptan
may be the treatment of choice for ADHF patients with pronounced hyponatremia, regardless of their age.
β-Blockers are most likely effective even in elderly patients with heart failure,6-8) however, β-blocker tolerance is
slightly attenuated with aging.17) The relationship between tolerability and age does not mean β-blockers are ineffective in
elderly patients, but only cautions us against careless increases
in the dose of a β-blocker. Such cautions may well improve the
utilization of β-blocker therapy for heart failure patients in
clinical practice. For example, the prescription rate of
β-blockers in elderly patients has increased in our institute,18)
and this may be at least partly explained by the accumulation
of evidence concerning points to consider as well as the beneficial effects of β-blocker therapy in elderly patients. The subjects of clinical trials are not necessarily representative of heart
failure patients that are usually encountered in clinical practice.
Observational studies with “real world” patients may help to
resolve issues left unanswered by clinical trials.
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