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JACC: HEART FAILURE
VOL. 3, NO. 8, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
ISSN 2213-1779/$36.00
http://dx.doi.org/10.1016/j.jchf.2015.04.010
EDITORIAL COMMENT
The Ongoing Evolution of Optimal
Clinical Endpoints for Heart Failure Trials*
Henry Krum, MBBS, PHD, Ingrid Hopper, MBBS
A
dvances in heart failure (HF) drug and device
III symptoms and a weighted average left ventricular
therapies over the past 3 decades have made
ejection fraction of 27%. The trials were divided into
major inroads into the lethality of this dis-
3 groups according to the proportion of patients
ease. Angiotensin-converting enzyme (ACE) inhi-
treated with a beta-blocker. The proportion of CV
bitors and angiotensin receptor blockers (ARBs),
deaths decreased from 87% with low beta-blocker use
beta-blockers, mineralocorticoid receptor antagonists
to 80% with high beta-blocker use. Non-CV deaths
(MRAs), as well as device-based approaches including
rose from 11.4% to 19.1% with high beta-blocker
cardiac resynchronization therapy and implantable
therapy, representing a proportional increase of
cardioverter defibrillator therapy, have resulted in
two-thirds in non-CV deaths. The reduction in CV
substantial mortality, morbidity and quality of life
mortality was associated with a rise in non-CV deaths,
(QoL) benefits to such patients, particularly those
which was due mostly to malignancy.
with HF and reduced ejection fraction (HFREF).
This analysis confirms what we have known for
Beta-blockers are arguably the most potent therapy
some time, which is that mortality rates are falling
in reducing mortality in HF. Mortality reductions in
with modern HF treatment; these data allow us to go
mild to moderate as well as advanced HFREF in the
some way in quantifying the major therapeutic ad-
pivotal trials additional to background ACE inhibitors
vances that have been made in this field. This analysis
and diuretics were consistently of the order of 30%
examines background beta-blocker use within these
(1–3). This was accompanied by improvements in
trials, and as the authors acknowledge, concomitant
cardiac remodeling parameters, HF symptoms, and
with increased beta-blocker use over recent years
QoL measures.
has been increased use of ACE inhibitor/ARB, rapid
SEE PAGE 603
In this issue of JACC: Heart Failure, Rush et al. (4)
have reviewed the totality of HF randomized controlled trials in the past 3 decades, evaluating cardiovascular (CV) mortality according to beta-blocker
usage in the trials. The authors have been meticulous
in including all of the major, predominantly HFREF,
randomized control trials over this period. The analysis included 66 trials, including 136,182 participants
and 32,140 deaths, with participants mostly with New
York Heart Association (NYHA) functional class II and
uptake of MRAs following the RALES study (Randomized Aldactone Evaluation Study) (5) and the
EMPHASIS-HF study (Eplerenone in Mild Patients
Hospitalization and Survival Study in Heart Failure)
(6) as well as the advent of devices, and it is therefore
impossible to attribute improved CV mortality (and
accompanying relative increase in non-CV mortality)
entirely to beta-blocker therapy alone. However, a
sensitivity analysis adjusting for ACE inhibitor/ARB
use and adjusting for MRA use, and also using a metaanalytic approach, demonstrated that beta-blockers
contributed most to the reduction in CV deaths.
This analysis includes the individual study out-
*Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or
the American College of Cardiology.
From the Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash Uni-
comes of the placebo group and the intervention
group. Many of these interventions are of novel
agents that turned out to result in neutral or even
adverse clinical outcomes. Examples include the
versity, Melbourne, Australia. Drs. Krum and Hopper have reported that
BEST The Beta-Blocker Evaluation of Survival Trial
they have no relationships relevant to the contents of this paper to disclose.
study (7), in which bucindolol failed to improve
616
Krum and Hopper
JACC: HEART FAILURE VOL. 3, NO. 8, 2015
AUGUST 2015:615–7
Endpoints for HF Trials
survival in NYHA functional class III and IV HF, and
associated with admissions are meaningful for health
the GISSI-HF (Gruppo Italiano per lo Studio della
care payers. Again there are major issues with this as a
Sopravvivenza nell’Infarto miocardico study) (8), in
clinical outcome. HF hospitalization may reflect
which rosuvastatin failed to improve survival in
regional practices and preferences, with significant
NYHA functional class II to IV HF. By definition, none
regional variation in bed days and need for admission.
of these interventions constitute standard therapy
Some centers use short-stay units or give outpatient
and thus their inclusion in the analysis may poten-
intravenous diuretics in an effort to avoid “formal”
tially skew the results. An analysis examining just the
admissions, which further blurs the definition of a HF
placebo group would be informative.
hospitalization. It can also be difficult to determine the
The falls in CV mortality have had consequences
relative contribution of HF to an admission when
for the design of HF clinical trials. As the authors
multiple organ dysfunction exists; for example, with
note, all-cause mortality has become an increasingly
primary pneumonia resulting in HF decompensation.
insensitive endpoint in HF clinical trials. Although
All of these outcomes do not necessarily reflect
this is an easily definable and confirmable endpoint,
what is important to the patient. This has been
it has the obvious weakness that causes of death such
termed the “patient journey.” QoL measures have
as trauma and malignancy that are unrelated to HF (or
traditionally been viewed as soft science, because
its treatment) are included. More recent trials have
they are somewhat subjective and often have not
required a more refined approach to capturing out-
been particularly well-correlated with harder mor-
comes of most interest and over the past 15 years, HF
tality outcomes (10). However, for the patient, these
trials have used CV mortality rather than all-cause
measures may be far more meaningful than the blunt
mortality as at least a component of the primary
instruments described previously. Alternatives to
endpoint. All-cause mortality should not be aban-
describe the patient journey have been suggested in
doned as an outcomes measure, because no reduction
the literature (11–13); however, these have not been
in all-cause mortality in the presence of a reduction in
widely accepted nor stringently validated, and regu-
CV mortality may be a safety signal that the treatment
lators are somewhat uncertain of their clinical utility.
is shifting the cause of death. This was seen in
HF mortality is laudably falling due in large part to
The Digitalis Investigation Group trial (9), in which
the addition of beta-blockers to our clinical arma-
symptomatic HF decreased with reduced HF hospi-
mentarium. However, these major gains cannot be
talizations, but no reduction in mortality was seen
seen in isolation from the contribution of other
due to a presumed rise in arrhythmic deaths.
therapies to improvements in HF mortality. Beta-
CV mortality allows greater precision with regard to
blockers continue to be underprescribed in HF, and
evaluation of the benefits or otherwise of a HF thera-
this continues to be a major challenge going forward.
peutic agent, but practically, it is expensive because
Additionally, this analysis demonstrates that im-
independent adjudication committees are required to
provements in HF mortality forecast increasing diffi-
review the medical records and determine cause of
culty demonstrating improved outcomes in future
death. There is also residual uncertainty about the
trials, and work is needed to develop appropriate
cause of death in the absence of post-mortems and
clinical endpoints in contemporaneous HF trials. This
when the study participant is found deceased at home
endpoint evaluation work is urgently needed to
with an unwitnessed death. There is uncertainty about
optimize evaluation of new treatments to reduce the
whether these deaths should be included as CV mor-
still unacceptably high mortality and morbidity
tality or excluded from the analysis, but as the authors
associated with the condition.
found, this accounted for only 5.7% of all deaths.
The inclusion of HF hospitalizations in outcomes
REPRINT REQUESTS AND CORRESPONDENCE: Prof.
has received increasing interest. One of the advan-
Henry Krum, Centre of Cardiovascular Research and Ed-
tages of this outcome is that it reflects costs of HF
ucation in Therapeutics, School of Public Health and
treatment, which are rapidly increasing. Multiple
Preventive Medicine, Monash University, 99 Commercial
admissions for HF reflects poor prognosis, and
Road, Melbourne, Victoria 3004, Australia. E-mail: henry.
this outcome can capture that aspect, and the costs
[email protected].
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KEY WORDS beta-blockers, clinical trials,
endpoints, mortality
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