Editorial
Angiotensin-Converting Enzyme Inhibitors or -Blockers in
Heart Failure
Does It Matter Who Goes First?
James C. Fang, MD
A
ngiotensin-converting enzyme (ACE) inhibitors and
-blockers are potent therapies in heart failure. They
lower total mortality and heart failure hospitalizations
by 25% to 40% across all ages, functional capacities, degrees of
left ventricular dysfunction, and causes.1,2 But does it matter
which intervention is given first? There are 2 primary reasons
why clinicians initiate heart failure therapy with ACE inhibitors
for patients with systolic dysfunction: (1) ACE inhibitors were
the first agents to demonstrate a mortality benefit in heart failure
and therefore have since served as background therapy for all
heart failure trials, and (2) heart failure is a hemodynamic as well
as a neurohormonal condition that acutely improves with vaso-
dilation.3 In acutely decompensated patients, initial hemodynam-
ic stabilization through vasodilation improves the neurohor-
monal profile, including a reduction in norepinephrine levels.4
This stabilization may allow the subsequent introduction of
-blockers, which are acutely associated with a decline in
ventricular function.5,6
Article p 2426
However, when a patient has compensated heart failure,
would a -blocker first be tolerated, safe, and even better? There
are putative reasons why -blockers first may lead to greater
survival and improved quality of life. The adrenergic system is
activated earlier than the renin-angiotensin system (RAS)7 and is
an important stimulus for RAS activation. Norepinephrine is a
potent predictor of mortality.8 Enhanced sympathetic renal
activity may contribute to sodium and water avidity.9 Evidence
suggests that there is less escape and greater suppression of
angiotensin II by ACE inhibitors when the adrenergic system is
also blocked.10 Cardiorenal complications of heart failure may
be avoided because rises in serum creatinine with ACE inhibi-
tors may be decreased by pretreatment with a -blocker.11
-Blockers may have a greater impact on ventricular remodeling
than ACE inhibitors.12 In contrast to ACE inhibitors,2 -blockers
also appear to have a greater impact on the lowering of sudden
death risk, which accounts for one half to two thirds of total
mortality in moderate heart failure.13 Finally, in clinical practice
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Cardiovascular Division, Brigham and Womens Hospital,
Boston, Mass.
Correspondence to James C. Fang, MD, Cardiovascular Division,
Brigham and Womens Hospital, 75 Francis St, Boston, MA 02115.
E-mail jfang@partners.org
(Circulation. 2005;112:2380-2382.)
2005 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.105.586545
2380
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the first drug rather than the second drug started is more likely to
be titrated to target doses used in the clinical trials. Therefore, the
benefits of effective -blockade, which are dose related,14 may
be attenuated. Being first no longer appears to be sufficient
rationale to justify the optimal sequence to initiate these agents.
After all, digoxin, once favored as a first-line agent (and
certainly our oldest agent in heart failure), is now considered
second-line therapy with a Class II recommendation in the 2005
American College of Cardiology/American Heart Association
heart failure guidelines.
Two previous trials have suggested that a -blockerfirst
strategy is safe and potentially beneficial. In the multicenter
Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure
Evaluation (CARMEN) trial,12 572 patients with mild heart
failure and clinically stable for 2 weeks were randomly assigned
in a blinded fashion to carvedilol 25 mg twice daily, enalapril 10
mg twice daily, or the combination (with titration first of
carvedilol) for 18 months. Combination therapy led to a greater
improvement in end systolic volume followed by carvedilol and
enalapril monotherapy. Most importantly, safety, mortality, hos-
pitalizations, and withdrawal rates were comparable in all 3 trial
arms. In a smaller single-center nonblinded study,15 78 NYHA
class II/III patients with newly diagnosed idiopathic dilated
cardiomyopathy were randomized to 6 months of either carve-
dilol or perindopril first followed by titration of the second agent
with functional class and ejection fraction as primary end points.
The carvedilol-first group reached a greater total carvedilol dose
(4317 mg versus 3318 mg, P0.03), had greater improve-
ment in symptoms, had a greater ejection fraction (1516%
versus 613%, P0.05), and experienced greater lowering of
plasma N-terminal pro-brain natriuretic protein (166142
pg/mL versus 51384 pg/mL, P0.02).
It is against this background that the CIBIS III investigators16
are to be congratulated for undertaking a trial with a large sample
size that addresses both the safety and efficacy of a -blocker
first strategy in heart failure. The investigators randomized 1010
patients with mild to moderate heart failure, and an ejection
fraction 35%, to open-label monotherapy with either bisopro-
lol (target dose 10 mg/day) or enalapril (target dose 10 mg twice
daily) for 6 months followed by uptitration of the second drug
for 6 to 24 months. The study randomization was not blinded,
but the end point and safety committees were blinded. The
investigators chose a conservative strategy of a noninferiority
trial using a primary end point that combined all-cause mortality
and all-cause hospitalization. In the intention-to-treat sample,
there were 178 patients (35.2%) with a primary end point in the
bisoprolol-first group compared with 186 (36.8%) in the
enalapril-first group. Although the prespecified criteria for non-
 Fang
inferiority was met with the intention-to-treat analysis (absolute
difference 1.6%, 95% CI 7.6 to 4.4%, HR 0.94; 95% CI 0.77
to 1.16), it did not quite meet the requirements of the per-protocol
analysis (the most rigorous analysis to use in noninferiority trials),
although it was close (absolute difference 0.7%, 95%CI 6.6 to
5.1%, HR 0.97; 95% CI 0.78 to 1.21). There were 65 all-cause
deaths and 151 all-cause hospitalizations in the bisoprolol-first
group versus 73 deaths and 157 hospitalizations in the enalapril-first
group; neither end point reached statistical significance.
Several issues are worthy of note. By design, the patients
studied were 1 decade older than those studied in most heart
failure trials (ie, 72 versus 62 years old). In part, this older age
led the investigators to use a 6-month period of monotherapy
because rapid additions of multiple therapies are often not
tolerated in elderly patients. Although some practitioners may
find withholding ACE inhibitors in symptomatic but ambulatory
patients troublesome, participating institutional review boards
did not find fault with this practice. More important, patients
were excluded if they received RAS antagonists and/or
-blockers for 7 days in the 3 months before randomization, so
the findings are not confounded by pretreatment effects. Clinical
stability for 7 days was also required before enrollment, which
would exclude many patients either hospitalized or recently
hospitalized for heart failure. Titration of bisoprolol was also
cautious and slower than the protocol used in CIBIS II (respect-
ing the older age of the study population and the lack of
concomitant vasodilator therapy). This strategy was appropriate
in that bisoprolol is a -1 selective agent without ancillary
vasodilator properties that could limit its tolerability in the
absence of a vasodilator during monotherapy titration.
Despite the use of this titration protocol, there was some cause
for concern. The bisoprolol-first strategy was associated with a
nonsignificant trend toward worsening of heart failure requiring
hospitalization or occurring in the hospital (63 versus 51, HR
1.25, 95% CI 0.87 to 1.81, P0.23) and may be a consequence
of using a -1 selective agent without concomitant vasodilator
properties. This issue may have also resulted in a greater number
of serious adverse events reported during the monotherapy
phases of the bisoprolol-first arm as compared with the
enalapril-first arm (192 versus 163). Particular patients may be
especially prone to this issue because the percentage of patients
reporting these events were similar between the 2 groups (22.4%
versus 22.1%), suggesting that more than one event occurred in
the same patient. Despite this issue, there was little need in either
group to introduce the second agent early during monotherapy
for clinical reasons (bisoprolol-first 7.7% versus enalapril-first
7.3%, P0.81). Furthermore, few patients in either arm discon-
tinued either drug during the monotherapy or combined-drug
phases. During the entire trial, 60 bisoprolol-first patients and 59
enalapril-first patients withdrew formally from the trial.
Patients with significant renal impairment (Cr 220
mol/L or 2.5 mg/dL) were also excluded, which is a
common problem in older adults with heart failure. Further-
more, follow-up renal function was not reported but would be
of great interest considering the cardiorenal limitations in the
treatment of elderly patients with heart failure. There did not
appear to be a difference in outcome when renal function was
stratified between a baseline creatinine clearance of 60 and
80 mL/min, but these ranges may not be the most appro-
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ACE Inhibitors or -Blockers in Heart Failure 2381
priate because most patients 70 years old and with heart
failure will have a creatinine clearance 50 mL/min.
As anticipated, the first drug titrated resulted in a greater
proportion of patients taking the target dose of that drug
during the combined therapy phase. For example, 64.8% of
the bisoprolol-first group was taking 10 mg/day at the end of
the study compared with 53.8% of the enalapril-first group,
which may explain the survival difference seen; however, the
lack of blinding and open label design may have had a
significant impact on these final doses. In contrast, only
42.5% of patients in CIBIS II reached this goal dose when
both active and placebo arms were blinded.17
The study has other limitations and these were acknowledged
by the authors. It did not meet the strictest criteria for noninfe-
riority because the per-protocol analysis boundaries were not
met. (In a per-protocol analysis, only patients who strictly
followed the protocol to the end of the study are included in the
analysis.) As outlined by the investigators, however, the statis-
tical power of such an analysis was reduced because the number
of patients diminished rapidly with time and brings to light that
there were a significant number of protocol violations and
withdrawals (thus, the need for an intention-to-treat analysis in
most prospective randomized clinical trials).
The study was not blinded, although the analyses of the end
points were. The open study design was specifically chosen by
the investigators to allow separate titration of the drugs during
the follow-up combined-drug period because of a concern that
side effects could not be adequately addressed if blinding were
present. The lack of blinding could have lowered the threshold to
hospitalize for heart failure but not for other reasons in the
bisoprolol-first group (as was seen) and could have had an
impact on the small difference in the numbers of deaths between
groups. Although the authors address this problem, noting that
blinding of the end points committee limits bias,18 such blinding
does not eliminate bias.
Although there were trends toward fewer hospitalizations and
fewer deaths in the bisoprolol-first group, the absolute differ-
ences were small and not conclusive (8 deaths, 6 hospitaliza-
tions). Small absolute differences have been seen before in
clinical trials but not confirmed in subsequent adequately pow-
ered studies (ie, remember the supposed mortality benefit of
losartan over captopril in ELITE I but not confirmed in ELITE
II). Although the target doses used in the trial were the targets
used in the clinical trials of these drugs, many practice environ-
ments do not have the capacity to get patients to such doses over
the course of weeks. It is not clear what the results would have
shown if the monotherapy duration were shorter than 6 months
because many clinicians would be uncomfortable withholding
ACE inhibitors for such a long period of time, despite the
apparent safety of the practice in the trial. Most important, the
patients studied were ambulatory, compensated, and only mild
to moderately symptomatic and therefore least prone to serious
hemodynamic collapse from the negative inotropic effects of
-blockers in the absence of background vasodilator therapy
with an ACE inhibitor.
What, then, should we take away from the CIBIS III trial?
We can feel safe that in mild to moderately symptomatic
elderly patients with heart failure who are ambulatory,
clinically compensated, and appropriately supervised, the use
2382 Circulation October 18, 2005
of -blockerfirst therapy is tolerated and appears to be as
effective as an ACE inhibitorfirst strategy. It would be an
overstatement to conclude that starting with a -blocker is
better; strictly speaking, CIBIS III did not meet criteria for
noninferiority, much less superiority. Furthermore, vigilance
for decompensated heart failure during -blocker mono-
therapy is essential if safety is to be maintained.
The key concepts, however, are compensated and supervised.
-Blockers do not provide a hemodynamic rescue for the acutely
decompensated patient with volume overload and/or low output;
in fact, in such settings, -blockers should either be cut back or
withheld. I would still prefer beginning with an ACE inhibitor in
patients with moderately severe to advanced symptoms and/or a
decompensated state (ie, hospitalized). It is premature to let go
entirely of current practice standards because the data do not
suggest that reversing the traditional order of things is especially
advantageous to our patients, even if higher doses can be
achieved. Although it is reasonable to extrapolate the CIBIS III
findings to younger patients and to other proven -blockers
(especially ones with vasodilator properties), it remains to be
shown that routinely starting with -blockade is the preferred
strategy in all patients. Rather, we should feel reassured that we
can tailor our approach to our patients without harm. What are
the principles of such a tailored approach? In patients in whom
blood pressure is limiting, ACE inhibitors should be cut back to
maximize -blocker doses, as has been done in all -blocker
trials to date. In tachycardic patients who are clinically well
perfused, euvolemic, and not hypotensive (ie, tachycardic car-
diomyopathies, adriamycin cardiomyopathy19), -blockers can
be initiated first and titrated to goal doses before the addition of
an ACE inhibitor. It is imperative that such a practice be
undertaken only if close and frequent follow-up can be ensured,
as in the context of a disease management program. Despite the
potential benefits of certain therapies in closely supervised
clinical trials, indiscriminant and loosely supervised use of these
therapies may result in significant harm, which was underesti-
mated in the clinical trial. Such has been the case with spirono-
lactone since the publication of the Randomized ALdactone
Evaluation Study (RALES) study, in which an increase in
clinically important hyperkalemia has been seen despite the
modest rates of this life-threatening problem in the trial itself.20
These findings must also be put into the context of other proven
agents in heart failure for which we do not yet know their
optimal use (ie, angiotensin receptor blockers, aldosterone an-
tagonists, diuretics).
It is important to understand that the greatest benefit for
our patients is realized when both agents are used. The
sobering facts are that 50% of patients with a diagnosis of
heart failure are on ACE inhibitors in real life21; even in the
highly supervised environment of a contemporary heart
failure clinical trial, -blocker use ranges from 35% to 55%.
It is therefore important not to lose sight of our primary
challenge: to encourage physicians to use -blockers and
RAS antagonists in patients with heart failure.
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KEY WORDS: Editorials heart failure drugs adrenergic
beta-antagonists angiotensin-converting enzyme inhibitors
Angiotensin-Converting Enzyme Inhibitors or -Blockers in Heart Failure: Does It Matter
Who Goes First?
James C. Fang

Circulation. 2005;112:2380-2382
doi: 10.1161/CIRCULATIONAHA.105.586545
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2005 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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